Guidelines for the Management of Haematological Malignancies

Yorkshire Cancer Network
and
Humber and Yorkshire Coast Cancer Network
Guidelines for the Management of
Haematological Malignancies
Produced by: Humber & Yorkshire Coast and Yorkshire Cancer Network
Haematology Group
Address: Arthington House, Cookridge Hospital, Hospital Lane,
Leeds, LS16 6QB
Telephone: 0113 3924033
Fax: 0113 3924131
Website: www.ycn.nhs.uk
Document Version Version 3.1
Publication Date Revised and published January 2008
Review Date January 2009

CONTENTS
CONTENTS............................................................................................................................................................2
1 INTRODUCTION..........................................................................................................................................4
2 IMAGING FOR HAEMATOLOGICAL MALIGNANCIES ......................................................................5
3 CLASSICAL HODGKIN LYMPHOMA .....................................................................................................7
4 LYMPHOCYTE PREDOMINANT NODULAR HODGKIN LYMPHOMA (LPNHL)..........................10
5 DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL) .............................................................................11
5.1 PRIMARY AND SECONDARY CEREBRAL LYMPHOMA............................................................................13
5.2 CNS PROPHYLAXIS FOR PRESENTING PATIENTS WITH DIFFUSE LARGE B-CELL LYMPHOMA...........13
6 BURKITT LYMPHOMA ............................................................................................................................14
7 FOLLICULAR LYMPHOMA ....................................................................................................................15
8 CHRONIC LYMPHOCYTIC LEUKAEMIA.............................................................................................17
9 MANTLE CELL LYMPHOMA..................................................................................................................21
10 SYSTEMIC MARGINAL ZONE LYMPHOMA.......................................................................................22
11 EXTRANODAL MARGINAL ZONE LYMPHOMA (MALT–TYPE LYMPHOMA) ............................24
11.1 GASTRIC MARGINAL ZONE LYMPHOMA..............................................................................................24
11.2 NON-GASTRIC EXTRANODAL MZL ......................................................................................................25
12 HAIRY-CELL LEUKAEMIA .....................................................................................................................26
13 PERIPHERAL T-CELL LYMPHOMA.....................................................................................................27
13.1 ANGIOIMMUNOBLASTIC T-CELL LYMPHOMA .......................................................................................27
13.2 ANAPLASTIC T-CELL LYMPHOMA ........................................................................................................27
13.3 PERIPHERAL T-CELL LYMPHOMA, COMMON (UNSPECIFIED).............................................................27
13.4 ENTEROPATHY TYPE T-CELL LYMPHOMA ..........................................................................................28
13.5 ANAPLASTIC LARGE CELL LYMPHOMAS - T(2,5) AND / OR ALK+VE .................................................28
13.6 OTHER NODAL AND EXTRANODAL PERIPHERAL T-CELL LYMPHOMAS ................................................28
13.7 PATIENTS WITH PRIMARY INTRAMUCOSAL ENTEROPATHIC DISEASE..................................................29
13.8 T-PROLYMPHOCYTIC LEUKAEMIA.......................................................................................................29
14 CUTANEOUS LYMPHOMA.....................................................................................................................30
14.1 PRIMARY CUTANEOUS T CELL LYMPHOMA........................................................................................31
15 MULTIPLE MYELOMA AND RELATED DISORDERS.......................................................................36
15.1 MULTIPLE MYELOMA...........................................................................................................................36
15.2 MONOCLONAL GAMMOPATHY OF UNCERTAIN SIGNFICANCE (MGUS) .............................................36
15.3 PLASMACYTOMA OF BONE..................................................................................................................37
15.4 MONOCLONAL DEPOSITION DISEASE (INCLUDING AMYLOIDOSIS) .....................................................37
15.5 SOLITARY PLASMACYTOMA.................................................................................................................38
15.6 AMYLOIDOSIS......................................................................................................................................39
16 ACUTE MYELOID LEUKAEMIA ............................................................................................................40
17 PRECURSOR CELL LYMPHOBLASTIC LEUKAEMIA IN ADULTS...............................................42
17.1 PRECURSOR B-CELL LYMPHOBLASTIC LEUKAEMIA ...........................................................................42
17.2 PRECURSOR T-LYMPHOBLASTIC LEUKAEMIA.....................................................................................42
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18 MYELODYSPLASTIC SYNDROMES ....................................................................................................45
18.1 CHRONIC MYELOMONOCYTIC LEUKAEMIA (CMML) ..........................................................................45
19 CHRONIC MYELOID LEUKAEMIA........................................................................................................48
20 CHRONIC MYELOPROLIFERATIVE DISORDERS............................................................................52
21 REPORTING PATHOLOGICAL SPECIMENS FROM HAEMATO-ONCOLOGY PATIENTS......54
21.1 INTRODUCTION....................................................................................................................................54
21.2 NETWORK POLICY...............................................................................................................................54
21.3 DESIGNATED PATHOLOGISTS .............................................................................................................54
21.4 REPORTING STANDARDS....................................................................................................................55
21.5 EXPECTED REPORTING TIMES ...........................................................................................................55
21.6 INVESTIGATION PROTOCOLS ..............................................................................................................55
21.7 PROCEDURE FOR REFERRAL OF SPECIMEN .....................................................................................55
21.8 SPECIMEN TYPES HANDLED BY HMDS.............................................................................................56
21.9 COLLECTION AND TRANSPORT OF TISSUE SPECIMENS....................................................................56
21.10 URGENT AND OUT OF HOURS SPECIMENS ..................................................................................56
21.11 TRANSMISSION OF REPORTS ........................................................................................................56
21.12 REFERENCES .................................................................................................................................57
22 FACILITIES NECESSARY FOR PROVISION OF INTENSIVE CHEMOTHERAPY (NICE 2003)58
22.1 FACILITIES...........................................................................................................................................58
22.2 STAFFING ............................................................................................................................................58
22.3 CLINICAL SUPPORT.............................................................................................................................59
23 CARE PATHWAYS FOR TEENAGERS AND YOUNG ADULTS WITH A HAEMATOLOGICAL
MALIGNANCY IN YORKSHIRE AND THE HUMBER AND EAST COAST CANCER NETWORKS...60
23.1 LEEDS TEENAGE AND YOUNG ADULT SERVICE.................................................................................63
24 GUIDELINES FOR CONVENTIONAL CYTOGENETIC ANALYSIS IN ADULT PATIENTS WITH
HAEMATOLOGICAL MALIGNANCIES..........................................................................................................64
24.1 B-CELL LYMPHOPROLIFERATIVE DISORDERS INCLUDING MYELOMA ..................................................64
24.2 CHRONIC MYELOPROLIFERATIVE DISORDERS ....................................................................................64
24.3 ACUTE LYMPHOBLASTIC LEUKAEMIA...................................................................................................64
24.4 ACUTE MYELOID LEUKAEMIA ..............................................................................................................65
24.5 MYELODYSPLASTIC SYNDROMES........................................................................................................65
24.6 CHRONIC MYELOID LEUKAEMIA...........................................................................................................65
25 AUDIT & DATA COLLECTION PROTOCOL .......................................................................................66
26 CHEMOTHERAPY REGIMENS ..............................................................................................................68
26.1 THE INTERNATIONAL PROGNOSTIC INDEX (IPI) .................................................................................68
27 FLIP INDEX FOR FOLLICULAR LYMPHOMA (FLIPI).......................................................................69
28 ANN ARBOR STAGING CLASSIFICATION FOR NHL .....................................................................70
29 BINET DISEASE STAGE FOR CLL.......................................................................................................71
30 INTERNATIONAL HODGKIN LYMPHOMA PROGNOSTIC SCORE: .............................................72
31 ECOG PERFORMANCE STATUS .........................................................................................................73
32 KARNOFSKY PERFORMANCE STATUS SCALE .............................................................................74
33 WEBSITES .................................................................................................................................................75
34 REFERENCES...........................................................................................................................................76
35 APPENDICES.............................................................................................................................................81
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1 INTRODUCTION
These guidelines are designed for use in all centres treating haematological malignancies in the
combined Yorkshire and Humberside and Yorkshire Coast Cancer Networks.
The organisation of services within the combined network will follow the recommendations set out in
the National Institute of Clinical Excellence Improving Outcomes Guidance for Haematological
Oncology and the Cancer Standards Manual.
The key points include:
• All patients with haematological malignancy will be managed within a multi-disciplinary team.
• Diagnostic work will be carried out within a specialist haematopathology laboratory.
• Patients requiring in-patient chemotherapy will be treated in centres that meet the specified
standard.
The purpose of this document is to present consensus guidance for the diagnosis and management of
individual patients. These have been prepared as follows:
Diagnostic guidelines
These are based on the WHO classification of haematological malignancies. A number of areas have
been modified to improve both clarity and increase the stringency of diagnostic tests. These
modifications were developed by staff involved in reporting at HMDS. These criteria are published
separately as a booklet and at www.hmds.org.uk. Also available is the new standard operating
procedure for diagnosis and definitions of risk for each condition.
Treatment Guidelines
Treatment guidelines are based on:
• Guidance from NICE
• NCRI phase 2 and 3 clinical trials
• Guidance from recognised authorities (e.g. BSH, BCSH, UKMF, etc)
• Consensus at the Network guidelines meeting and editorial groups meetings
The implementation of these guidelines will be audited according to the protocol below. A network
audit group representing all multi-disciplinary teams, HMDS and clinical oncology is established for
this purpose.
Treatment should involve entry into current trials. However, exceptions should be considered
individually through the multi-disciplinary team (MDT) process
Guidelines for the Management of Haematological Malignancies
1. INTRODUCTION
4

2 IMAGING FOR HAEMATOLOGICAL
MALIGNANCIES
Lymphoma Staging – CT
• All patients should have a CT chest, abdomen and pelvis
• CT neck if neck involved, especially if future RT required
• For Cutaneous T Cell Lymphoma CT is indicated, if:
Sezary
CD30 negative large cell lymphoma
Presence of lymphadenopathy
Prior to RT or chemo
• Should use IV and oral contrast
MRI is indicated if looking for:
• CNS disease
• Musculoskeletal disease
• Upper aero-digestive tract disease, although CT is usually adequate for routine staging.
PET scanning
Order of priority for access for patients having treatment with curative intent:
• Women

Other Disease
ALL & AML
CXR
CML
US abdomen to document spleen size
CMD
US abdomen to assess spleen & liver
Follow up imaging
Routine follow up imaging is generally not indicated in haematological malignancies outside of trials.
Interval CT may be considered in patients with Hodgkin’s and High grade NHL who have residual
masses post therapy to ensure stability. PET CT should be considered prior to radiotherapy to residual
masses.
For further details on imaging refer to the draft HYCCN haematology imaging guidelines (Chapter 35)
Guidelines for the Management of Haematological Malignancies
2. IMAGING FOR HAEMATOLOGICAL MALIGNANCIES
6

3 CLASSICAL HODGKIN LYMPHOMA
Key Issues
• The role of radiotherapy in early stage disease
• The role and timing of PET scanning in the assessment of disease
• The interface with diffuse large B-cell lymphoma in a small number of cases
• Uncertainty about behaviour of Hodgkin lymphoma in the elderly
• Late effects (fertility, second malignancy e.g. breast and lung cancer)
• Management of patients with poor prognosis disease
Diagnostic Criteria
Classical Hodgkin Lymphoma (CHL) is a B-cell malignancy with a distinctive activated B-cell
phenotype and absence of immunoglobulin production.
Typical Cases
1. Morphologically typical Reed-Sternberg cells in a reactive background including normal T-cells
and eosinophils
2. Immunophenotype: CD30 + , CD15 +/- , Bob1 - and/or Oct2 - , CD20 - , CD3 -
A range of morphological and immunophenotypic variants are found. The clinical significance
of these is not fully understood.
Essential Investigations
Calculate the International Hodgkin’s Disease Prognostic score (Franklin, Paulus et al. 2000;
Josting, Rueffer et al. 2000)
1. Age >45 years
2. Male
3. Stage IV
4. Hb

Primary Treatment
Non-bulky Stage IA and IIA (< or =3 sites of disease and 60 years old should be considered for the SHIELD study for, either with registration
only +/- treatment according to trial protocol .
Stage IA and IIA non-bulky disease
If not fit for ABVD they can be considered for Shield regimen + IFRT or ChlVPP x3 +IFRT
All other disease should be considered for SHIELD study and treatment can be either ChlVPP
or chemo as per SHIELD
• For patients not entering the trial, ABVD x 6-8cycles. (Klimm, Engert et al. 2005)If fertility is an
issue then ABVD is the treatment of choice. (Level 1)
• Patients considered unfit for these treatments may be treated with ChlVPP.(Level 1)
If there is bulky disease (i.e. mass >10cm maximum diameter on CT scan at presentation) the
possibility of adjuvant radiotherapy should be discussed with a clinical oncologist, accepting that any
such cut-off is somewhat arbitrary. There is no indication for adjuvant radiotherapy in patients who
achieve a complete response to chemotherapy(Laskar, Gupta et al. 2004) .There may be a role for
radiotherapy in patients who receive suboptimal chemotherapy. Patients should be referred to the
Cookridge or Hull MDT for review, to consider the potential benefits and risks (e.g. cardiovascular and
second malignancy risk, especially risk of breast cancer in women aged 16-35 years with mediastinal
disease).
Preservation of fertility must be discussed, documented and the patient referred to a specialist centre
as appropriate.
8

Assessments
• Assessments should be carried out after 3 or 4 cycles of chemotherapy or according to trial
protocol.
• If patient is in complete remission, proceed to 6 cycles and stop.
• If patient is in partial remission, reassess after 6 cycles and if there is further response,
continue to 8 cycles of chemotherapy.
• Patients with involved bone marrow should have a bone marrow aspirate and trephine at the
end of treatment
• If there is a residual mass (CRu), a scan should be repeated 3 months after the end of
treatment and at 3-6 monthly intervals until the mass remains stable. The presence of a
residual mass alone is not an indication for radiotherapy. The role of PET in selected cases
may be considered by the MDT post treatment.
Relapsed Classical Hodgkin Lymphoma
Relapse following radiotherapy or radiotherapy and VAPECB
• Patients should be treated with first line chemotherapy i.e. ABVD x 6
Primary refractory disease or relapse
• Patients should be treated with a relapse chemotherapy, e.g. ifosfamide plus mitoxantrone,
IVE, FluDAP or ESHAP 2-4 cycles with stem cell harvest followed by BEAM autograft.(Level
1/3)
• Patients resistant to conventional dose chemotherapy may still benefit from a BEAM autograft.
(Kewalramani, Zelenetz et al. 2000; Tarella, Cuttica et al. 2003)
• If not suitable for an autograft with an isolated relapse wide field or involved field radiotherapy
should be considered. This will salvage 25-51% (5yr survival) in selected chemo-refractory
patients (Josting, Rueffer et al. 2000)
• For patients who relapse after all of the above, and who are still candidates for treatment, a
non-myeloablative allogeneic transplant should be considered. (Level 4)
Follow up
Follow-up should be aimed at detecting and managing long-term side effects not solely relapse.
This should involve counselling regarding lifestyle risks, e.g. smoking, obesity, hypercholesterolemia
and hypertension.
Protocols for long term follow-up need to be developed.
Guidelines for the Management of Haematological Malignancies
3. CLASSICAL HODGKIN LYMPHOMA
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4 LYMPHOCYTE PREDOMINANT NODULAR
HODGKIN LYMPHOMA (LPNHL)
Key Issues
• Recognised as separate disease entity from classical HL.(Fan, Natkunam et al. 2003)
• Uncertainty over clinical behaviour of early stage disease - is treatment required in some
patients? (Murphy, Morgan et al. 2003)
• Data on treatment and outcomes confused by inclusion of most cases in trials with classical
Hodgkin lymphoma.
• Possible role of Rituximab as single agent therapy. (Ekstrand, Lucas et al. 2003)
Diagnostic Criteria
LPNHL is clinically, pathologically and prognostically distinct from classical Hodgkin Lymphoma.
• Abnormal expanded B-cell follicles with mixture of mantle and germinal centre B-cells and
reactive T-cells including a CD4+, CD57+ population
• Polylobated and large mononuclear B-cells, usually associated with T-cell rosettes
• Immunophenotype: CD20+, CD30-, BCL-6+, CD79+, CD15-, Bob1+/ Oct2+++
There is risk of transformation to Diffuse Large B-cell Lymphoma.
Essential investigations
• Bone marrow biopsy in all cases
• CT scanning of thorax, abdomen and pelvis (and neck if clinically involved)
Primary Treatment
Stage IA
• Following complete resection no treatment is necessary.
• Other patients – involved field radiotherapy
Stage IIA disease
• Involved field radiotherapy
• Patients should not be entered in NCRI Hodgkin trials
All other patients
Advanced stage LPNHL is very rare at presentation.
• In this situation, the distinction between disseminated LPNHL and the T-cell rich variant of
DLBCL may be difficult and is to some extent arbitrary.
• For this reason these patients should be treated as for Diffuse Large B-cell lymphoma,
currently CHOP-R (Level 1) (Boudova, Torlakovic et al. 2003)
Localised relapse treatment
• Re-biopsy is essential, as reactive lymph nodes are common.
• If the disease is outside the initial radiotherapy field, further involved field radiotherapy may be
given.
• If the relapse is within the initial radiotherapy field treat with CHOP-R x6.
Generalised relapse treatment
• These patients should be treated as for Diffuse Large B-cell lymphoma.
Guidelines for the Management of Haematological Malignancies
4. LYMPHOCYTE PREDOMINANT NODULAR HODKIN LYMPHOMA
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5 DIFFUSE LARGE B-CELL LYMPHOMA
(DLBCL)
Key Issues
• Incorporation of new prognostic factors into treatment stratification
• Therapy for limited stage disease
• Effective treatment of relapsed disease
• Primary mediastinal large B-cell lymphoma
• CNS prophylaxis
Diagnostic Criteria
This is a tumour that shows diffuse replacement of normal nodal architecture by a population of large
B-lymphoid cells.
Typical Cases
1. Diffuse infiltrate of large lymphoid cells
2. Proliferation fraction of at least 30%
3. Immunophenotype may be:
• Germinal centre type; as for follicular lymphoma (CD10 + , BCL-6 + )
• Post germinal centre phenotype, some cases are BCL-6 positive
• CD5 + , BCL-1/ t(11;14) -ve (rare)
Variants
1. Anaplastic morphology should be regarded as DLBCL.
2. T-cell rich variant. Greater than 50% T-cells and a B-cell population with morphology and
phenotype as above. No definitive evidence of prognostic significance.
3. Mediastinal large B-cell lymphoma. This is a distinct entity. Diagnosis requires mediastinal
mass, clear cell morphology, pericellular fibrosis, CD10-, IgM and IgG negativity, CD21 - ,
CD30 + or - . Cases not meeting these criteria are DLBCL.
4. Extranodal. Cases should be classified as above unless clear evidence of underlying marginal
zone lymphoma.
5. Intravascular. Cellular features as above but tumour cells mainly within vessels and adherent
to the endothelium.
6. Plasmablastic type. This diagnosis should only be made for soft tissue tumours with no
evidence of myeloma. Diagnosis requires plasmablastic morphology, CD138 + , cCD79 + , CD20 -
, cIg + , and high proliferation. In these cases an HIV test should be suggested.
7. Secondary DLBCL arising from an underlying indolent lymphoma.
Molecular and Cellular Prognostic factors
Good prognosis
Germinal centre phenotype with no evidence of 3q27 rearrangement or BCL-2 expression/ t(14;18)
Poor Prognosis
Germinal centre phenotype with t(14;18) or 3q27 rearrangement and p53 mutation/ deletion
Non-Germinal centre phenotype with BCL-2 expression or 3q27 rearrangement and p53 mutation/
deletion and FOX P-1.
Guidelines for the Management of Haematological Malignancies
5. DIFFUSE LARGE B-CELL LYMPHOMA
11

Essential Investigations
• Bone marrow biopsy
• CT scan of thorax, abdomen and pelvis (and neck if clinically involved)
• LDH
• ECOG performance status
• Calculation of International Prognostic Index (IPI) and age adjusted IPI.
• For assessing cardiac function the criteria used in CHOP 14 v 21 can be used. (age over 70,
known diabetic over 65, past history of cardiac disease or hypertension or abnormal resting
ECG)
Primary Treatment
Non-bulky Stage IA
CHOP x 3 plus involved field radiotherapy.The use of Rituximab is not approved by NICE. Treatment
can be done at level 1 centre with referral for RT
All other patients
All eligible patients should in entered in the NCRI CHOP14-R v CHOP21-R
For non-trial patients with both nodal and extranodal presentations should be treated with CHOP &
Rituximab in accordance with NICE guidance. The standard treatment based on published trials is 8
courses. However, if a patient is in remission after 4 courses total courses can be shortened to 6.
For non-trial patients CHOP should be given in full doses and at 21-day intervals according to the
standard protocol, with G-CSF support as necessary. Age by itself is not an indication for attenuation
of chemotherapy dose assuming adequate organ function.
High-risk patients
All patients age less than 60 with high and high intermediate age adjusted IPI should be encouraged
to enter into R-CODOX-M/R-IVAC phase 2 trial. This therapy could also be used for low or
intermediate disease with poor risk biology. (Level 2)
Patients with poor cardiac function
R-GCVP phase 2 trial is about to be open.(Gemcitabine is added to day 1 and day 8 of RCVP) (Level
1)
Primary extranodal DLBCL
Treat as for systemic DLBCL. Radiotherapy has specific indications (Reyes, Lepage et al. 2005)
• Testicular Lymphoma: contra lateral testis 30 Gy
• Primary lymphoma of bone
Relapsed DLBCL
Biopsy to be done in a relapsing patient who relapse after CR and Prior to repeat treatment with
rituximab
Data on outcomes in this group are very sparse. It is essential that treatment be standardised whether
included in a clinical trial or not. The strategy should be to induce remission and consolidate using a
BEAM autograft.
• All eligible patients should be considered for entry to the NCRI CORAL trial comparing ICE-
Rituximab and DHAP- Rituximab with a peripheral blood stem cell transplant in responding
patients. Local MDT to decide whether the patient should be treated at level 1 or level 2
• Non-trial patients of all ages considered fit for autologous stem cell transplantation should
receive one of the trial schedules, followed by a BEAM autograft in responding patients.
• Patients who are fit but in whom stem cells cannot be harvested should receive the same
initial chemotherapy as above and be considered for a marrow harvest or possibly an
allogeneic option – these procedures should be discussed at the MDT and with the transplant
team.
Guidelines for the Management of Haematological Malignancies
5. DIFFUSE LARGE B-CELL LYMPHOMA
12

• Patients not considered candidates for autologous transplantation should be treated
palliatively. The outcome of chemotherapy without a high dose procedure is very poor.
• Allograft should only be considered as part of a clinical study following autograft. Discuss
individual patients with the local transplant consultant.
• Radiotherapy has a role in limited stage relapse where autograft is not an option or as
palliative therapy.
5.1 Primary and secondary cerebral lymphoma
In the non-immunosuppressed, DLBCL may involve the central nervous system either as a primary
tumour localised to the brain or as a secondary deposit in a patient known to have systemic
involvement by DLBCL or Burkitt Lymphoma. There is no evidence at present that these groups of
patients should be managed differently.
Primary Treatment
• Many patients with secondary cerebral lymphoma will be eligible for R-CODOX-M/IVAC trial
when it is open (Level 2)
• Phase I trial of escalating high dose methotrexate supported by glucarpidase is about to begin
(Level 2)
• All patients who are not in trial should be treated with High Dose Methotrexate (3g/m2 in 24
hours) (level 1 or 2 decided by MDT)
• If High dose Methotrexate is not working then IDARAM should be considered.(Level 2)
• There is no evidence for the use of allograft transplant in CR1 currently.
5.2 CNS prophylaxis for presenting patients with Diffuse Large B-cell
Lymphoma
• The assessment of risk of CNS involvement is controversial and data is lacking. About 5% of
patients with DLBCL develop CNS lesions.
• The optimum approach to CNS prophylaxis is uncertain.
On the basis of current data CNS prophylaxis should be considered in the following circumstances:
1. Primary testicular lymphoma and breast DLBCL
2. High risk of direct invasion of the CNS (orbit, sinus, etc)
3. DLBCL with more than 1 extranodal site plus raised LDH
4. Burkitt lymphoma
Suggested Prophylaxis
The following treatments are used in the UK as CNS prophylaxis:
• Within the CHOP 14 vs. 21 trial Intrathecal (IT) methotrexate 12.5mg is given with the first 3
courses.
• IT methotrexate 12mg and/ or cytosine arabinoside 70mg between each pulse of systemic
chemotherapy to a total of 6 courses.
• Systemic high dose methotrexate - following CHOP, for example three courses of 3g/m 2 .
The Consensus in the guideline meeting is that all high risk patients should receive minimum of 3
courses of IT Methotrexate 12.5mg as in CHOP 14 v 21 trial protocol. However in particular high risk
cases the MDT should consider giving high dose systemic methotrexate. (Level 1 or 2 decided by
MDT)
Guidelines for the Management of Haematological Malignancies
5. DIFFUSE LARGE B-CELL LYMPHOMA
13

6 BURKITT LYMPHOMA
Currently, the treatment strategy for this entity is also applied to high grade B cell NHL with a high
proliferation rate (100% Ki67 +ve) as well as the more typical Burkitt Lymphoma – see diagnostic
criteria below.
Key issues
• Effectiveness of short duration high intensity therapy remains unclear. (Mead, Sydes et al.
2002; Wang, Straus et al. 2003)
• Continuing problems with diagnostic criteria.
Diagnostic Criteria
Burkitt lymphoma is defined as a germinal centre cell lymphoma with c-myc deregulation and absence
of other balanced translocations.
Typical Cases
1. Large B-cell lymphoma with round nuclei, central nucleoli and vacuolated cytoplasm.
2. Germinal centre phenotype: CD10 + , BCL-6 + by immunocytochemistry with BCL-2 - .
3. A hyperproliferative state demonstrated by Ki67 approaching 100%, p53 + , p21 - and evidence
of apoptosis.
4. t(8;14) or variants demonstrated by FISH.
Atypical Cases
1. Morphological variants - not clinically significant.
2. All above features except c-myc rearrangement - clinical significance not known.
3. All above features and t(14;18). Many of these patients have underlying follicular lymphoma.
This is a poor prognostic feature. (Macpherson, Lesack et al. 1999)
Essential Investigations
• As for Diffuse Large B-cell lymphoma plus examination of the CNS in all cases.
Primary Treatment
• R-CODOX-M/R-IVAC study when available.
• Treatment outside trial should be with R-CODOX-M/R-IVAC.
• There are considerable issues regarding initial treatment toxicity and tumour lysis –
Rasburicase pre-treatment should be considered especially in patients with high bulk and/ or
abnormal renal function.
• Patient should be treated in a level 2 centre or above.
Relapsed disease
There is no consensus or trial. Outcome would be expected to be very poor. There is little evidencebase
for intensification of therapy and cases should be carefully reviewed in the relevant MDT.
Guidelines for the Management of Haematological Malignancies
6. BURKITT LYMPHOMA
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7 FOLLICULAR LYMPHOMA
Key Issues
• Role of high dose therapy in relapsed disease (Armitage 2001; van Besien, Loberiza et al.
2003)and poor risk patients.
• Role of rituximab in primary and relapsed disease
• Role of radiolabeled monoclonal antibodies
• Role of reduced intensity allograft
• Emergence of biological risk models
• Concept of large cell transformation
Diagnostic Criteria
Follicular lymphoma is a tumour of the germinal centre cell that in lymph nodes shows a follicular
growth pattern.
Typical Cases
In lymph node biopsy specimens the following features must be present:
1. The tumour must contain a mixture of cells with the morphology of centrocytes and
centroblasts.
2. The tumour must have a germinal centre phenotype:
• Immunocytochemistry: CD20 + , CD79 + , CD10 + , BCL-6 + , CD23 variable
• Flow Cytometry: clonal sIgM or sIgG, CD19 + , CD10 + , CD38 + , CD5 - , and BCL-6 demonstrated
by immunocytochemistry
3. BCL-2 expression by the neoplastic cells and/ or t(14;18) by FISH or PCR.
4. Partially or wholly follicular growth pattern.
Variants
1. As above but BCL-2 and t(14;18) negative; clonality should be demonstrated by PCR or flow
cytometry, or unequivocal evidence of bone marrow infiltration should be present.
2. Large cell variant where the neoplastic follicles consist mainly of centroblasts (WHO grade
3B).
3. Diffuse follicle centre lymphoma variant composed of a mixture of centrocytes and
centroblasts with a germinal centre immunophenotype but lacking a follicular architecture.
Transformation
The diagnosis of transformation is made when diffuse areas are present that consist mainly of large
lymphoid cells with a high rate of cell proliferation. The relationship between morphological
transformation and progressive or refractory disease is complex.
Essential Investigations
• The International Prognostic Index modified for follicular lymphoma (FLIPI) should be
calculated for all patients (Kondo, Ogura et al. 2001; Montoto, Lopez-Guillermo et al. 2002)
• CT scan of thorax, abdomen, pelvis (and neck if clinically involved)
• Bone marrow biopsy
Primary Treatment
Stage IA
Although there is relatively little data there is some evidence that patients with stage 1A may be
curable. All patients should be referred for consideration of radiotherapy.
Guidelines for the Management of Haematological Malignancies
7. FOLLICULAR LYMPHOMA
15

All other patients
• active monitoring / watch and wait trial in asymptomatic patients.
• Rituximab containing regimen eg. R-CVP for the majority of patients. (NICE guideline
September 2006.) (Colombat, Salles et al. 2001; Hiddemann, Kneba et al. 2005; Marcus,
Imrie et al. 2005)(Level 1)
• Chlorambucil should be considered if other therapies are not tolerated.(Chlorambucil +
Rituximab trial is expected to be coming in the near future) (Level 1)
Large cell variant +/- t(14;18)
• Investigate and treat as for DLBCL (WHO 3B)
Transformed Follicular Lymphoma
This group includes patients presenting in transformation and those relapsing with transformed
disease.
• Investigate and treat as for DLBCL
• CHOP-Rituximab should be given as primary therapy (Level 1)
• Those who have previously received CHOP should be treated as for a relapsed DLBCL with
DHAP, ESHAP etc (Level 2 or 3 decided by MDT)
• Autograft
• If autograft is not an option, zevalin may be an alternative or maintenance therapy with
Rituximab could be considered.
Relapsed Follicular NHL
Rebiopsy should be done if the disease relapse after response, prior to repeat treatment with
rituximab, and if there is change in the rate of disease progression of FL.
Trial evidence shows improved outcome for patients on Rituximab maintenance with or without
Rituximab in the reinduction treatment. All patients, Rituximab naïve or greater than 6 months post
Rituximab should be treated with Rituximab containing chemotherapy followed by R maintenance.
(Level 1)(Forstpointner, Unterhalt et al. 2006; van Oers, Klasa et al. 2006)
Patients who relapse within 6 months or after Rituximab maintenance should be considered for
Zevalin (IbritumomabTiuxetan) or Autograft.(Level 3)
Patients not considered suitable for the above treatment should be treated with Rituximab(NICE
Guidance), Chlorambucil or Fludarabine (Level 1)
Palliative radiotherapy and consideration for FORT trial ( Comparing standard palliative radiotherapy
with a low dose radiotherapy for symptom control) are other options
Guidelines for the Management of Haematological Malignancies
7. FOLLICULAR LYMPHOMA
16

8 CHRONIC LYMPHOCYTIC LEUKAEMIA
These guidelines are to be used in conjunction with the BCSH guidelines.(Oscier, Fegan et al. 2004)
Diagnostic Criteria
This is a chronic leukaemia of CD5 + B-cells. The term includes cases presenting as lymphadenopathy,
formerly known as small lymphocytic leukaemia.
Typical cases
Consists mainly of small lymphocytes with clumped heterochromatin, although considerable
morphological variation can occur.
Lymph nodes show a diffuse infiltrate usually with pseudofollicle formation.
Immunophenotype: CD5 + , CD19 + , CD20 wk , CD79b wk , FMC7 -, weak sIg (sIgM + /sIgD + or sIgM - /sIgD + )
Patients with circulating peripheral blood B-CLL counts of

Lymph node biopsy is indicated if:
The diagnosis is uncertain from the peripheral blood and bone marrow examinations.
To assess localized bulky lymphadenopathy to exclude transformation
CT-scans/US
If the presence of splenomegaly is uncertain on physical examination
To assess lymphadenopathy prior to therapy
Management of CLL
All newly diagnosed patients with CLL should have their management defined by a formal Multi-
Disciplinary Team Meeting.
Monoclonal B-lymphocytosis (CLL phenotype) – MBL-CLL
MBL-CLL is defined as the presence of a B-cell clone that has a CLL immunophenotype but at a level
too low to meet the current criteria for the diagnosis of CLL (50% increase over 2 months
lymphocyte doubling time 10% in previous 6 months
Fever >38 o C for >2 weeks
Extreme fatigue
Severe night sweats
Autoimmune cytopenias which are poorly controlled by corticosteroids.
Guidelines for the Management of Haematological Malignancies
8. CHRONIC LYMPHOCYTIC LEUKAEMIA
18

Initial therapy for advanced CLL
There are several trials to be opened in the near future for untreated advanced CLL:
CLL 6: For patients without comorbidities to address the role of rituximab and mitoxantrone, to be
started by the end of 2007. (Level 1)
CLL208/CLL7: For patients with co-morbidity to address role of rituximab added to chlorambucil.
(CLL208-Single arm Phase II trial of chlorambucil+rituximab by summer 2007 and CLL7-Randomised
Phase III trial comparing chlorambucil +/- rituximab by 2008) (Level 1)
CLL205 (CamPred) study- Trial open for patients with 17p deletion.
Chlorambucil and fludarabine are both licensed for the front-line therapy of CLL. Fludarabine
monotherapy as front-line therapy results in higher response rates and prolonged progression-free
survival compared to chlorambucil but does not result in an improved overall survival. The combination
of fludarabine with cyclophosphamide results in higher response rates and prolonged progression-free
survival compared to fludarabine monotherapy. (Eichhorst, Busch et al. 2003; Flinn, Kumm et al. 2004;
Catovsky, Richards et al. 2005)The follow-up of the key trials comparing fludarabine to FC is not
mature enough to address the question of overall survival. FC has several advantages over
fludarabine alone which include:
lower incidence of autoimmune haemolytic anaemia
lower cost (due to lower dose of fludarabine used in FC)
higher response rates and prolonged progression-free survival
Recommendations for initial therapy in CLL:
In patients without significant co-morbid conditions (regardless of age) the combination of fludarabine
plus cyclophosphamide (FC) should be considered standard first line therapy for the above reasons.
NICE has not reported on the FC combination but has recommended against single agent
Fludarabine. (more cytopenias were observed with FC in patients over 70 years of age in the LRF
CLL4 trial but FC therapy was still significantly superior in terms of response rate and progression-free
survival). (Level 1)
Patients considered fit enough for more intensive therapy and achieving a very good partial response
or a complete remission should be considered for entry into MRD eradication trial CLL207 (Single arm
Phase II trial of alemtuzumab consolidation) or its successor CLL8 (Randomised Phase III trial
comparing alemtuzumab consolidation versus watch and wait.) when they are open. (Level 1 or 2
decided by MDT)
Chlorambucil is indicated for elderly patients and those with significant co-morbid conditions. (Level 1)
Relapsed but not refractory CLL (fludarabine-sensitive relapse)
Patients who have no significant co-morbid conditions should be considered for entry into the NCRI
FCM/FCM-R trial (a randomised Phase II trial of FCM [fludarabine + cyclophosphamide +
mitoxantrone] versus FCM-rituximab). (Level 1)
Patients with relapsed but not refractory CLL who are not eligible or decline entry into the NCRI
FCM/FCM-R trial should be considered for re-treatment with the same therapy as long as their initial
remission was at least a year from the end of therapy. If the initial therapy was fludarabine alone then
it is reasonable to re-treat with FC (see above). Patients relapsing between 6 and 12 months after
completing initial therapy should be considered for alternative therapies such as FC or FCM. (Level 1)
Patients who are considered eligible for either conventional myeloablative or reduced intensity
conditioning allogeneic stem cell transplantation should be referred for an opinion to the CLL MDT in
Leeds either after initial therapy (if they have adverse prognostic features) or following second-line
therapy. (Level 4)
Fludarabine-refractory CLL
The prognosis for patients with fludarabine-refractory CLL treated with conventional therapy is very
poor with a median survival of less than 12 months and a 5-year survival of approximately 10%. The
incidence of p53 pathway abnormalities in these patients is extremely high and probably largely
Guidelines for the Management of Haematological Malignancies
8. CHRONIC LYMPHOCYTIC LEUKAEMIA
19

explains the resistance to conventional chemotherapeutic agents. The only licensed therapy for
fludarabine-refractory CLL is alemtuzumab. The response rates to alemtuzumab are most influenced
by the size of lymphadenopathy. The duration of remission and survival following alemtuzumab are
related to the depth of remission including whether minimal residual disease is eradicated. It is
recommended that these patients are referred for consideration by the specialist CLL MDT. The
following approaches are indicated for patients with refractory CLL who are considered suitable for
intensive treatment:
CLL206(CamPred) trial: Phase II trial for Fludarabine refractory patients with p53 deletion analysing
the efficacy of high dose steroids and alemtuzumab. (Level 1 or 2)
Patients with predominantly blood and marrow disease with relatively small lymph nodes should be
treated with alemtuzumab. (Moreton, Kennedy et al. 2005)The aim of therapy should be to eradicate
detectable minimal residual disease from the marrow.
Patients with bulky lymphadenopathy should receive initial therapy to reduce the bulk of lymph nodes
prior to treatment with alemtuzumab in order to eradicate detectable minimal residual disease. Highdose
methyl prednisolone (1g/m 2 /day for 5 days every 4 weeks) is effective in patients for whom high
dose steroids are not contra-indicated. (Level 1)
Allogeneic stem cell transplantation
CLL is an incurable disease by conventional treatment approaches. The transplant related morbidity
and mortality for allogeneic stem cell transplantation is very high. However there is a significant graftversus-CLL
effect and long-term disease free survival is achievable following allogeneic stem cell
transplantation. Patients who are possible candidates for allogeneic stem cell transplantation should
be considered by the MDT in Leeds on a case-by-case basis. Patients are generally only considered
for allogeneic transplantation if they have poor-risk disease either according to biological
characteristics of their CLL or because they have fludarabine-refractory disease. (Level 4)
Guidelines for the Management of Haematological Malignancies
8. CHRONIC LYMPHOCYTIC LEUKAEMIA
20

9 MANTLE CELL LYMPHOMA
Key Issues
Uncertainty as to the efficacy of current therapy (Densmore and Williams 2003; Hiddemann and
Dreyling 2003)
Diagnostic Criteria
Typical Cases
1. Monomorphic population of small to intermediate sized B-cells
2. Phenotype: sIg ++/+++ (IgM & IgD), CD5 + , CD23 - , CD20 +
3. BCL-1 expression/ t(11;14)
Variants
Blastic or large cell variant associated with an aggressive clinical course
Essential Investigations
• Bone marrow aspirate and trephine
• CT scan of thorax, abdomen and pelvis (and neck if clinically involved)
• Calculation of International Prognostic Index
• Gastrointestinal investigations e.g. Upper GI endoscopy/ sigmoidoscopy and biopsy, if
symptomatic
• Consideration of possible allogeneic transplant at time of presentation
Primary Treatment
• A Phase 3 randomised controlled trial of Fludarabine/ cyclophosphamide combination with or
without Rituximab in patients with untreated MZL is available and all eligible patients should
be treated under trial if possible. (Level 1)
• Patients who are not in trial:
Young and fit patients -should receive FC (Fludarabine and cyclophosphamide), FC
Rituximab, HyperCVAD-R, or CHOP-R and considered for Autotransplant (Level 1,2 or 3
decided by MDT)
Older patients- if asymptomatic and nonprogressive disease should be observed.
Patients who are unfit for more aggressive treatments -should be considered for chlorambucil.
Relapse Treatment
• Patients who didn’t have an Autograft in the primary treatment should be considered
for Autograft.(Level 3)
• Alternate front line regimen should be used for those who can’t have a transplant.
• Young fit patients who achieve a response should be considered for an allogeneic stem cell
transplant (conventional conditioning or reduced intensity conditioning). (Level 4)
• Thalidomide, especially combined with rituximab has a potential action but there is poor data
regarding this. (Level 1)
Guidelines for the Management of Haematological Malignancies
9. MANTLE CELL LYMPHOMA
21

10 SYSTEMIC MARGINAL ZONE LYMPHOMA
This is the preferred term within the network to denote a spectrum of disease with very similar biology
and natural history - and therefore therapy. It embraces the following terms/ entities (which will not be
used):
• Waldenstrom’s Macroglobulinaemia
• Lymphoplasmacytic lymphoma
• SLVL/ Splenic MZL
• Primary nodal MZL (monocytoid B cell lymphoma)
It excludes the extranodal (MALT) lymphomas, which are dealt with in the next section.
Key Issues
• Continuing uncertainty over classification; lack of positive markers (Owen, Barrans et al. 2001;
Owen 2003)
Diagnostic Criteria
Typical Cases
1. Cellular composition includes small lymphocytes, centrocyte-like cells, 'monocytoid' B-cells,
plasmacytoid cells.
2. Pattern of infiltration (a trephine biopsy or other tissue biopsy is always required for this
diagnosis):
• Bone Marrow: nodular, interstitial, diffuse
• Spleen: marginal zone infiltration
• Nodes: interfollicular expansion with replacement of germinal centres
3. Immunophenotype: CD5 - , CD10 - , CD19 + , CD20 + , CD23 - , sIgM + , sIgD + or - , BCL-6 -
Transformation
The criteria are the same as for follicular lymphoma. The significance of increased numbers of large
lymphoid cells is uncertain in otherwise typical cases.
Essential Investigations
• Bone aspirate and trephine
• CT scan of thorax, abdomen and pelvis (and neck if clinically involved)
• Serum immunoglobulins and determination of paraproteins
• Direct Antiglobulin Test (DAT)
• LDH
• Β-2-microglobulin
Primary Treatment
• Patient with stage 1 disease should be referred for consideration of local radiotherapy.
• All other patients, if asymptomatic – watch and wait.
• If therapy required, all eligible patients should be entered into the WM1 trial
(www.waldenstroms.org), which randomises between chlorambucil and fludarabine.(Level 1)
• Patients not entering the trial should receive either chlorambucil or fludarabine.
• Single agent Rituximab is active in this condition particularly in patients with heavy marrow
infiltration and low blood counts (should be aware of “IgM Flare” phenomenon seen with this
treatment). (Level 1)
• Rituximab could be used in cold haemagglutinin disease. (Level 1)
• Plasma exchange should only be used in the emergency treatment of hyperviscosity
syndrome.
Guidelines for the Management of Haematological Malignancies
10. SYSTEMIC MARGINAL ZONE LYMPHOMA
22

• Splenectomy should only be considered in patients with bulky symptomatic splenomegaly who
are refractory to chemotherapy.
Relapse Treatment
• If more than 1 year from treatment, retreat with the same agent again.
• If within a year, patients who received chlorambucil first-line should receive fludarabine. (Level
1)
• purine analogue combinations, single agent rituximab, thalidomide and Bortezomib all have
activity in the relapse setting. (Level 1)
• Patients who fail a purine analogue can be considered for the local Phase II trial of
alemtuzumab (CAMPATH). (Level 1 or 2)
• Patients may be referred to Leeds or Hull MDT for lymphoma, for consideration of entry into
‘Combined PS341 with cyclophosphamide and prednisolone’ study.
• High dose therapy should be considered in younger patients with relapsed disease.
Guidelines for the Management of Haematological Malignancies
10. SYSTEMIC MARGINAL ZONE LYMPHOMA
23

11 EXTRANODAL MARGINAL ZONE
LYMPHOMA (MALT–type lymphoma)
Key Issues
• Identification of patients who require active treatment with chemotherapy
• Great uncertainty about the impact of treatments on overall survival
Diagnostic Criteria
Typical Cases
1. Cellular composition includes small lymphocytes, centrocyte-like cells, 'monocytoid' B-cells,
plasmacytoid cells.
2. Invasion of epithelial structures and existing germinal centres.
3. CD5 - , CD10 - , CD19 + , CD20 + , CD23 - , sIgM + , sIgD + or - .
4. Disease localized to or centred on an extranodal site.
Assessment of residual disease
The definitive diagnosis of residual disease requires the same criteria as at presentation. Solitary or
multiple B-cell aggregates without germinal centres and cellular morphology suggestive of marginal
zone lymphoma should be reported as suspicious and further follow up advised. The significance of
molecular remission remains uncertain.(Bertoni, Conconi et al. 2002)
Transformation
The criteria are the same as for follicular lymphoma. The significance of increased numbers of large
lymphoid cells is uncertain in otherwise typical cases.
Prognostic Factors
Extranodal marginal zone lymphoma with t(11;18)(Streubel, Simonitsch-Klupp et al. 2004) in the
stomach may be resistant to helicobacter eradication. (Nomura, Yoshino et al. 2003)
Essential Investigations
• Bone aspirate and trephine
• CT scan of thorax, abdomen and pelvis
• Serum immunoglobulins
• Direct Antiglobulin Test (DAT)
• LDH
11.1 Gastric Marginal Zone Lymphoma
Primary Treatment
• Patients with Stage IE disease should receive Helicobacter pylori eradication as sole therapy.
(Wotherspoon, Doglioni et al. 1993; Wotherspoon 1998)
• Follow-up with upper GI endoscopy and biopsy every 6 months for the first 2 years.
• Patients with recurrent disease after 1 year, stage greater than 1E or persistent and
symptomatic disease with visible bulky disease after helicobacter eradication should be
treated with chlorambucil (NCRI trial of chlorambucil vs. chlorambucil/ Rituximab
IELSG19/MALT trial is closed now and is on follow up). (Level 1)
• Patients with persistent / recurrent symptomatic disease despite chlormabucil may be treated
with a purine analogue or single agent rituximab.
Guidelines for the Management of Haematological Malignancies
11. EXTRANODAL MARGINAL ZONE LYMPHOMA
24

• Surgery is generally to be avoided except in emergency situations to control bleeding or repair
a perforation; these are very rare in gastric marginal zone lymphoma
• Radiotherapy is effective but usually not indicated given the excellent prognosis of this group
of patients.
• Patients with recurrent / persistent histological disease and macroscopically normal stomach
do not require therapy
Recurrence or resistance to above therapies
• Patients with persistent/ recurrent asymptomatic disease after chlorambucil or trial therapy can
be followed up by repeat endoscopy without further treatment.
• For patients with large cell transformation, CHOP & Rituximab chemotherapy. (Level 1)
Long-term follow-up(Zucca, Bertoni et al. 2000)
• There is no need for upper GI endoscopy after resolution of lesions and eradication of H.
pylori if patients are asymptomatic.
• Endoscopy is only indicated if symptomatic.
11.2 Non-gastric extranodal MZL
Primary Treatment(Zucca, Conconi et al. 2003)
• Stage 1A disease may be treated with radiotherapy, if not in the trial, depending on the site of
disease.
• All other patients if asymptomatic – a watch and wait policy or enrolment in the NCRI
extranodal lymphoma trial as mentioned above are reasonable options.
• If treatment is required (e.g. > stage 1 disease) then patients should be considered for the
NCRI extranodal lymphoma trial.
• Chlorambucil is the usual 1st line therapy in non-trial patients.
Relapse Treatment
• If disease is disseminated, treat in a similar way to follicular NHL – single agent or
combination chemotherapy as appropriate, eg. with chlorambucil or consider purine analogue
or single agent rituximab
• For patients with large cell transformation, CHOP & Rituximab chemotherapy.
Guidelines for the Management of Haematological Malignancies
11. EXTRANODAL MARGINAL ZONE LYMPHOMA
25

12 HAIRY-CELL LEUKAEMIA
Daignosis (Allsup and Cawley 2002; Allsup and Cawley 2004)
Typical hairy-cells seen in blood and/or bone marrow in patients with splenomegaly or cytopenias.
Tartate-resistant phosphate activity in abnormal cells.
Infiltration of bone marrow of cells with halo appearance.
Immunophenotype:- CD19+, CD22++, CD11c, CD25+, CD103+.
Immunocytochemistry:- CD20+, DBA44+
Indications for treatment
1. Systemic symptoms, Recurrent Infection
2. Significant cytopenias (Hb

13 PERIPHERAL T-CELL LYMPHOMA
Key Issues
• Very little data on effective treatment.
• Most patients appear to have a poor prognosis/ present with advanced stage disease.
(Armitage, Greer et al. 1989; Arrowsmith, Macon et al. 2003)
• Increasing awareness of intra-mucosal T-cell lymphoma in the small intestine
Diagnostic Criteria
13.1 Angioimmunoblastic T-cell Lymphoma
This is a peripheral T-cell lymphoma associated with a distinctive syndrome of systemic effects.
1. Loss of nodal architecture with proliferation of high endothelial cells, follicular dendritic cells,
reactive T and B-cells and plasma cells.
2. Neoplastic population consists of intermediate sized T-cells with clear cytoplasm. CD4 + T-cells
which may express CD10.
3. Clonal TCR rearrangement demonstrated by PCR (only performed if fresh biopsy available).
4. Systemic features including rashes, pleural effusions, fever, hypergammaglobulinaemia and
DAT positive haemolytic anaemia.
13.2 Anaplastic T-cell Lymphoma
This group of peripheral T-cell lymphomas is defined by anaplastic morphology and expression of
CD30.
Typical Cases
1. Anaplastic large lymphoid cells some of which have horseshoe-shaped nuclei and eosinophilic
paranuclear cytoplasm.
2. Immunophenotype: CD30 + , CD45 + , CD15 - with variable expression of T-cell markers.
3. Sometimes sinusoidal or perivascular pattern of infiltration is present.
4. Clonal TCR rearrangement.
Prognostic factors
ALK rearrangement implies a favourable prognosis and is more common in younger patients. Typical
translocations show nuclear and cytoplasmic ALK expression. Variant translocations show only
cytoplasmic ALK.
13.3 Peripheral T-cell Lymphoma, Common (Unspecified)
This term is used for all other types of peripheral T-cell lymphoma.
Tissue Specimens
1. Tumour deposit or nodal replacement by cytologically abnormal T-cells.
2. Peripheral T-cell phenotype. This will almost always be abnormal.
3. Does not meet specific criteria for angioimmunoblastic or anaplastic large cell types.
Guidelines for the Management of Haematological Malignancies
13. PERIPHERAL T-CELL LYMPHOMA
27

13.4 Enteropathy Type T-cell Lymphoma
This is a specific type of peripheral T-cell lymphoma associated with enteropathy/ coeliac disease.
Typical Cases
1. History of coeliac disease or morphological evidence of enteropathy.
2. Ulcer, perforation or mass in small intestine.
3. Infiltrate of large lymphoid cells.
4. Immunophenotype: CD3 + , CD4 - , CD5 - , CD7 +/- , CD8 - , CD56 +/- , CD30 +/- .
5. Clonal T-cell rearrangement by PCR.
Variant
• Intramucosal Type (Cellier, Delabesse et al. 2000; Daum, Weiss et al. 2001)
1. History of refractory coeliac disease/ jejunal ulceration.
2. Intra-epithelial lymphocytes show cytological atypia.
3. Intra-epithelial lymphocytes CD8 - , CD4 - , CD56 +/- .
4. Clonal TCR rearrangement.
All these diagnostic criteria must be present.
Essential Investigations
• Bone marrow aspirate and trephine
• CT scan of thorax, abdomen and pelvis (and neck if clinically involved)
• Serum immunoglobulins
• Direct Antiglobulin Test (DAT)
• LDH
• International Prognostic Index
13.5 Anaplastic large cell lymphomas - t(2,5) and / or ALK+ve
(Gascoyne, Aoun et al. 1999; Stein, Foss et al. 2000; Suzuki, Kagami et al. 2000)
Primary Treatment
• CHOP chemotherapy x 6-8
Relapse Treatment
• As for Diffuse large B-cell lymphoma
13.6 Other nodal and extranodal peripheral T-cell lymphomas
(Including Angioimmunoblastic T cell lymphoma, Anaplastic large cell lymphomas lacking t(2;5)/ ALK,
enteropathy associated with a definable mass and peripheral T-cell lymphoma-common type but
excluding primary cutaneous disease)
Primary Treatment
• NCRI phase II trials for peripheral T-cell lymphoma (CHOP & alemtuzumab (CAMPATH) is
opening soon and patients should be encouraged for the trial.(Level 1)
• All non trial - patients should be treated with CHOP
• Enteropathy associated T-cell Lymphoma (ICE) trial and Phase II Trial of FluCy followed by
Thalidomide for Angioimmunoblastic Lymphoma are planned to be launched in the near
future). (Level 2)
Guidelines for the Management of Haematological Malignancies
13. PERIPHERAL T-CELL LYMPHOMA
28

Relapse Treatment
• Patients with relapsed or refractory disease who are considered fit for autologous stem cell
transplantation should receive a non-crossreacting treatment e.g. ifosfamide/ mitoxantrone or
a platinum containing regime, followed by a high dose procedure.
• Younger patients could be considered for a reduced intensity conditioning allogeneic
transplant.
• Other patients may be suitable for combinations of alemtuzumab (CAMPATH) & second line
chemotherapy or alemtuzumab alone and this could be discussed at the Cookridge, LGI or
Hull MDTs. (Dearden, Matutes et al. 2001; Dearden, Matutes et al. 2002)
13.7 Patients with primary intramucosal enteropathic disease
This is rare entity and the relationship to refractory coeliac disease is not understood. There is no
consensus on appropriate treatment.
• All patients should be referred to Leeds MDT (Lymphoproliferative clinic – Wednesday) or Hull
MDT
13.8 T-Prolymphocytic Leukaemia
Diagnostic Criteria
Typical cases
1. Immunophenotype CD2 + , CD3 + , CD4 + , CD5 + , CD7 + , TCRαβ + , HLA-DR - .
2. Expression of CD52 antigen should be demonstrated in all cases for therapeutic purposes.
3. All cases must have TCR gene rearrangement studies.
4. High proportion of cases show inv(14) by cytogenetics.
Variants
1. CD4 + CD8 + a late thymic phenotype that may show weak mCD3 + .
2. CD4 - CD8 + rare subtype.
3. Cases associated with ataxia telangiectasia (mutations of the ATM gene).
Primary Treatment
This is a complicated area. All patients may be referred to Leeds MDT for discussion.
• Alemtuzumab (CAMPATH) to maximum response for patients without CNS disease or
possibly significant effusions.
• Consider for conventional or reduced intensity allogeneic transplant (discuss with Transplant
Director).
Refractory Disease
• Consider higher doses of alemtuzumab or combination therapy of alemtuzumab or
combination therapy of alemtuzumab with cytotoxic chemotherapy.
Relapse Treatment
• Repeat treatment with alemtuzumab may be appropriate (confirm with HMDS that leukaemia
cells express CD52)
• Low response rates to purine analogues reported but may be considered in refractory
patients.
Guidelines for the Management of Haematological Malignancies
13. PERIPHERAL T-CELL LYMPHOMA
29

14 CUTANEOUS LYMPHOMA
The WHO classification of cutaneous T cell lymphomas
There are three main groups in decreasing order of prevalence:-
1. Mycosis fungoides and Sezary syndrome
Rare variants: Pagetoid reticulosis ( a verrucous acral variant)
MF-associated follicular mucinosis
Granulomatous slack skin disease
2. Primary cutaneous CD-30 positive T-cell lympho-proliferative disorders
Variants: Lymphomatoid papulosis (types A and B)
Primary cutaneous Anaplastic Large Cell Lymphoma
Borderline types
3. Other rare T cell lymphomas presenting in the skin
a. Subcutaneous panniculitis-like T-cell lymphoma
b. Peripheral T-cell lymphoma unspecified - an aggressive lymphoma which always
requires systemic therapy
Peripheral T-cell Lymphoma involving the skin at presentation
• The skin and sub-cutaneous tissue is commonly involved by systemic T-cell lymphomas.
• All of these lymphomas have an aggressive course and poor prognosis, even if they appear
localised to the skin at presentation.
• All of these tumours are treated using combination chemotherapy
• These patients must be referred urgently to a haemato-oncology MDT (Leeds, Hull, Mid-
Yorks, Bradford and Airedale, York & Harrogate).
• Peripheral T cell lymphoma should not be confused with CD30+ T-cell lymphoproliferative
disorders (see below).
Cutaneous CD30 positive lymphoproliferative disorders
Diagnostic Criteria
Typical Type A lymphomatoid papulosis
1. A wedge shaped lesion with a peripheral zone which contains a mixed inflammatory infiltrate
and a central zone containing atypical large lymphoid cells. In the central zone there may be
necrosis or ulceration.
2. The characteristic cells are large with highly anaplastic or multilobated nuclei. They have a Tcell
phenotype with strong CD30 expression. ALK1 is negative.
3. The definitive diagnosis requires a history of self-healing lesions.
Variants
1. CD30 + primary cutaneous anaplastic large cell lymphoma. The cells are the same as in
lymphomatoid papulosis but in the context of a progressive non-healing lesion. The presence
of ALK1 almost certainly implies that the tumour is a systemic anaplastic lymphoma, which
may be otherwise identical, and these markers must be shown to be negative for a diagnosis
of primary cutaneous T-cell lymphoma to be made. A final diagnosis can only be made after
staging investigations.
Patients with anaplastic lymphoma must be referred to a Haemato-oncology Unit URGENTLY
2. Type B lymphomatoid papulosis. This consists of small cells, similar to mycosis fungoides and
CD30 negative. Diagnosis only possible if typical history available.
Guidelines for the Management of Haematological Malignancies
14. CUTANEOUS LYMPHOMA
30

Essential Investigations
• CT scan of thorax, abdomen, pelvis
• Bone marrow biopsy
Treatment (Bekkenk, Geelen et al. 2000)
• All new patients should be referred to Cookridge MDT (Thursday clinic) to be seen in
conjunction with dermatologist for initial review. Patients from Grimsby, Hull, Scunthorpe and
Scarborough should be referred to the Hull MDT for review.
• Newly presenting patients should be observed for 4-8 weeks after histological confirmation of
disease to determine whether spontaneous regression occurs.
• Solitary non-regressing lesions should be treated with radiotherapy.
• Multiple non-regressing lesions confined to the skin can be treated with:
PUVA
Interferon
Radiotherapy
Or as a last resort with chemotherapy.
• Patients who have multiple episodes of regressing skin lesions may be managed as above to
diminish the frequency of attacks.
• Total skin electron therapy or alemtuzumab (CAMPATH) therapy may be considered for
patients with disease refractory to other treatments.
• Further biopsies should be considered if there is any change in the pattern of disease, any
doubt about the diagnosis or lesions persist or progress.
Patients with stage greater than 1E, i.e. have disease beyond the skin, are treated as for
systemic peripheral T-cell lymphoma and require urgent treatment with combination
chemotherapy.
14.1 Primary Cutaneous T Cell Lymphoma
All biopsies should be reviewed by the Haematological Malignancy Diagnostic Service (HMDS)
at Leeds General Infirmary.
Primary Diagnosis
A definitive diagnosis of mycosis fungoides will be made when the following histological criteria are
met in a skin biopsy:
1. A dense band-like infiltrate replacing the upper dermis with epidermal infiltration of the basal
and mid-epidermis by atypical T-cell (larger than normal PBL with significant nuclear
convolution. Pautrier abscesses consist of clusters of these cells in association with
Langerhans cells.
2. The epidermal component should have the phenotype CD2 + , CD3 + , CD5 + , CD7 - , CD45RO + ,
CD4 + , CD8 -
The phenotype tends to be the same in granulomatous slack skin disease and follicular
mucinosis.
3. Mono-clonality is demonstrated using BIOMED 2 PCR methods for the determination of T-cell
clonality (ideally fresh tissue is required for this although sometimes a result can be obtained
from formalin fixed tissue).
4. Dematological assessment that the pattern of skin involvement is consistent with MF.
OR
In patients with sparse dermal infiltration and/or equivocal clinical findings the diagnosis will require:
1. Cells with atypical morphology and the phenotype listed above within the epidermis.
2. The same clone demonstrated in biopsies from two anatomically separate sites, one of which
could be blood.
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14. CUTANEOUS LYMPHOMA
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Notes:
1. The immunophenotypic investigation of T-cell lymphoma is being reviewed and a new protocol
is likely.
2. Clonality studies in the absence of the morphological immunophentypic and clinical features
are of no value in making a diagnosis of T-cell lymphoma and are potentially misleading
because of false positives.
3. In granulomatous slack skin disease, diffuse granulomata and lymphocytic infiltrate are seen
in the dermis. Macrophage mediated destruction of elastic tissue occurs which leads to the
development of pendulous folds of slack skin.
Mycosis Fungoides
Diagnosis requires:
1. The development of tumour nodules in the clinical background of established mycosis
fungoides
2. A cohesive population of large lymphoid cells within the tumour; in some cases CD30+
3. Cell cycle fraction in this population greater than 30%
4. Abnormal P53 expression.
Lymph Node Involvement
Involved lymph nodes in MF/Sezary show a range of changes histologically. Some units use a grading
system (category I to III after Clendenning and Rappaport) and in others molecular methods are being
evaluated. We recommend however that this system be adopted.
1. Dermatopathic reaction only: which may include scattered atypical lymphocytes or even small
clusters.
2. Focal or diffuse nodal replacement by tumour cells.
Sezary Syndrome
Sezary syndrome is characterized by erythroderma, lymphadenopathy, splenomegaly and leukaemia
(Greenberg, Cox et al. 1997; Wood and Greenberg 2003)
The diagnosis requires:
1 Generalised erythroderma
2 A skin biopsy showing infiltration by atypical T-cell as described for MF although the
histological appearances may be difficult to interpret and obscured by secondary infection
(Wood and Greenberg 2003)
3 Population of circulating T-cell with the phenotype CD4+,CD7- by flow cytometry. This
population must exceed 1x10 9 /l.
4 T-cell clonality as above
Notes:
1. Patients will be classified as primary or secondary according to the presence of preceding
mycosis fungoides
2. Although morphologically derived “counts” of Sezary cells are widely used in definitions of
Sezary this test is inaccurate and poorly reproducible (Wood and Greenberg 2003)and
therefore will not be performed.
3. The detection of circulating cells with the above phenotype is not a test for common type
mycosis fungoides and will not be performed in the absence of a diagnosis of erythroderma
and histological evidence of MF or lymphocytosis.
4. All patients with a diagnosis of Sezary syndrome should be referred to an appropriate
Haematology MDT.
Staging investigations
When the diagnosis of MF/Sezary is histologically verified, the following staging investigations are
recommended:
• FBC, ESR, differential WCC
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14. CUTANEOUS LYMPHOMA
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• Peripheral blood for flow cytometry if there is a lymphocytosis
• Biochemical screen including LDH (Diamandidou, Colome et al. 1999)
• Chest radiograph
• If lymph nodes significantly enlarged – biopsy
• CT scan should only be carried out
• In Sezary syndrome
• In CD 30 negative large cell CTCL
• With clinically or pathologically involved glands
• Prior to chemotherapy or radiotherapy
• A bone marrow may be carried out if
• lymph glands are pathologically involved
• Sezary syndrome is diagnosed
Note:
Although the BAD guidelines recommend that the CD4/8 ratio and HTLV-1 serology should be
performed there is no indication for this in the absence of suggestive clinical features.
Staging
The TNMB classification agreed at the NCI in 1978 is recommended as below:
STAGE DEFINITION
T0 Clinically and/or histologically suspicious – premycotic syndrome
T1 Limited plaques or patches less than 10% skin surface
T2 Generalised plaques or patches greater than 10% skin surface
T3 One or more skin tumours
T4 Generalised erythroderma
N0 No nodal enlargement
N1 Clinically enlarged nodes – histologically negative
N2 Nodes not enlarged but sampled and found histologically positive
N3 Clinically enlarged nodes – histologically positive
B0 Atypical circulating cells not present or less than 5%
B1 Atypical circulating cells present and greater than 5%
M0 No visceral involvement
M1 Visceral involvement – biopsy proven
The BAD/UKCLG guidelines use the Bunn Lamberg staging system(Wood and Greenberg 2003):
Stage 1A T1 N0
Stage 1B T2 N0
Stage IIA T1/2 N1 but nodes dermatopathic
Stage IIB T3 N0/1 but nodes if enlarged dermatopathic
Stage III T4 N0/1
Stage IVA Any T N2/3
Stage IVB Any T Any N, M1
The Cancer Network should organise services to ensure that patients have appropriate access to the
full range of disciplines and expertise. The rarity of this condition necessitates centralization of
multidisciplinary team review and co-ordination of care for affected patients.
For this to be achieved effectively:
• Patients need to be reviewed at a specialist skin lymphoma MDT at presentation.
• The membership of this MDT should include a haemato-pathologist, a dermatologist, a clinical
oncologist, a haemato-oncologist and nurse specialist as a minimum..
• The resource implications of this MDT approach will need to be addressed.
• For the Yorkshire Cancer Network (YCN), the MDT meeting will be in the new Oncology
Centre at St James Hospital from 2008 and at Cookridge Hospital until then, so that all the
necessary personnel can meet.
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14. CUTANEOUS LYMPHOMA
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• in the interim for YCN, a single skin MDT should take responsibility for reviewing patients with
CTCL and the Cookridge MDT will provide the lymphoma MDT review. (Referrals to be sent to
Dr Di Gilson).
• For Humber & Yorkshire Coast Cancer Network, the MDT meeting will be in the new
Oncology/Haematology building at Castle Hill Hospital but until then patients will be reviewed
at the Hull Haematology MDT meeting.
The following patients require referral for central MDT review:
• Stage IA with a solitary lesion, as this may be amenable to cure with radiotherapy
• Stage I B and higher at presentation
• When disease is failing to respond to current treatment, for example:
• disease not controlled with phototherapy
• disease is progressing through systemic therapy
• Toxicity of treatment is unacceptable, for example:
• Where unacceptable doses of phototherapy have proved necessary (>1000 J/cm 2 .)
• PUVA or systemic therapy is not being tolerated
• End stage disease where no further active therapy is being offered
Treatment
• The aim is to control the disease with the minimum of inconvenience and toxicity for the
patient, for all except transformed disease
• There are many treatment options.
• Selection of appropriate treatment is based mainly on clinical stage.
• Other factors may be relevant, e.g. the patient’s age, co-morbid conditions and accessibility of
different treatment approaches.
• Optimal treatment for each patient requires multi-disciplinary co-operation.
• Referral for multi-disciplinary review should be considered.
• Multi-disciplinary clinics take place Cookridge Hospital in Leeds (Dr Di Gilson) or Hull Royal
Infirmary (Dr Russell Patmore).
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14. CUTANEOUS LYMPHOMA
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Guide to treatment options by stage
STAGE IA Pre-mycotic and limited patch
disease
Solitary patch or plaque disease
Stage IB Patch and plaque disease
extending over 10% of body
surface
Stage IIA Extensive plaque stage MF with
dermatopathic nodes
Guidelines for the Management of Haematological Malignancies
14. CUTANEOUS LYMPHOMA
1st line
2nd line
Radical
1st line
2nd line
3rd line
4th line
5th line
Stage IIB Tumour stage MF For tumours
In addition
Emollients, topical steroids,
Intermittent PUVA or narrow band
UVB
Radical local radiotherapy
Steroids and emollients
Narrow band UVB or PUVA as for
psoriasis to a max of 30 exposures
per year
If requiring >30 phototherapy
sessions a year add acitretin +/-
maintenance acitretin
Refer to MDT for interferon and
total skin electron therapy
Bexarotene
Refer to MDT for interferon +/-
phototherapy
+/- total skin electron therapy
Local radiotherapy
Interferon
+/- total skin electron therapy +/maintenance
PUVA
2nd line Bexarotene
Stage III Erythrodermic MF 1st line Interferon +/-PUVA
2nd line Single agent chemotherapy
3rd line CamPath
Sezary syndrome 1st line Interferon and PUVA
2nd line Plasmapheresis
3rd line Chemotherapy
Stage IVA Nodal MF Localised Control skin as above.
nodes
Local radiotherapy and interferon
Chemotherapy
Widespread
nodes
Alemtuzumab
Stage IVB Visceral disease Chemotherapy
Alemtuzumab
35

15 MULTIPLE MYELOMA AND RELATED
DISORDERS
15.1 Multiple Myeloma
Diagnostic Criteria
Typical Cases
1. At least 10% plasma cells by morphology or flow cytometry.
2. Immunophenotype: CD19 - , CD56 + or - , with no normal plasma cells.
3. Interstitial, diffuse or nodular patterns of marrow infiltration.
Almost all patients meeting these criteria either have or will shortly develop symptomatic disease.
Variants
1. Normal phenotype (CD19 + , CD56 - ); in these cases clonality must be proven by light chain
restriction.
2. IgM producing myeloma: this is very rare and clinical features are required to exclude marginal
zone lymphoma.
Prognostic Factors
Peripheral blood involvement greater than 1 x 10 6 /l plasma cells is a poor prognostic factor. The term
plasma cell leukaemia will not be used. (Rawstron, Owen et al. 1997)
Adverse cellular features
t(4;14) – IgH/FGFR3 switch region translocation present in about 15-20% of Myeloma
t(14;16) – IgH/c-MAF
Assessment of Response by HMDS(Durie, Harousseau et al. 2006)
This is only made when aspirate and trephine specimens are available at the same time and
processed by HMDS. The aspirate must be assessed as adequate.
1. Unchanged stable disease.
2. Improved - >90% reduction in degree of infiltration by morphology, very good partial response.
3. Low-level residual disease - flow cytometry positive, morphology negative, partial response.
4. Complete remission (CR) - no evidence of disease by morphology and flow cytometry.
5. CR with increased normal plasma cells, complete bone marrow clearance.
15.2 Monoclonal Gammopathy of Uncertain Signficance (MGUS)
Diagnostic Criteria
1. Less than 10% plasma cells by morphology and flow cytometry.
2. Plasma cell population may be exclusively neoplastic (high-risk) or a mixture of normal and
neoplastic cells (low-risk).
Prognostic Factors
The presence of normal plasma cells is associated with a low risk of progression.
Guidelines for the Management of Haematological Malignancies
15. MULTIPLE MYELOMA AND RELATED DISORDERS
36

15.3 Plasmacytoma of Bone
Diagnostic Criteria
1. Plasma cell features as for myeloma with clonal cIg.
2. One or more localised lytic bone lesions.
3. Bone marrow shows low level of neoplastic plasma cells or MGUS pattern in almost every
case. The criteria for risk assessment used in MGUS will also apply.
15.4 Monoclonal Deposition Disease (including amyloidosis)
This includes primary amyloidosis and light chain deposition disease. Almost all cases will have
neoplastic plasma cells in the bone marrow.
Diagnostic Criteria
1. Diagnosis of amyloid by Congo red stain.
2. Low level of marrow infiltration by neoplastic plasma cells. The diagnostic criteria used for
MGUS and myeloma will apply.
Essential Investigations for all patients with suspected plasma cell disorders
• Bone aspirate and trephine – essential to allow entry into MRD plan
• Skeletal survey
• Serum immunoglobulins
• Urinary Bence Jones protein
• Urea and electrolytes
• ß2 microglobulin and albumin – used to calculate the International Staging System (ISS)
(Greipp, San Miguel et al. 2005)
• Stage I: ß2M 35
• Stage II: ß2M

Relapse Treatment
• Patients should again be divided into 2 groups according to suitability for transplant:
1. Suitable for transplant:
• Myeloma X is about to be started. This is to compare High versus Low dose alkylating agent
consolidation regimens for relapsed Multiple Myeloma (Level 1)
If not entering the trial
• If poor response to induction (i.e. no response after 4 courses) consider intermediate-dose
melphalan (70-100mg/m 2 ) prior to HDT (Level 1 and 3)
• If HDT not part of first line therapy consider CVAD & HDT
• If thalidomide not part of first line therapy consider thalidomide alone or in combination.
Thromboprophylaxis while on thalidomide should be individualised based on other risk factors
also. (Level 1)
• If HDT part of first line therapy and adequate stem cells collected, consider 2 nd HDT (Level 3)
• Melphalan/ melphalan & prednisolone/ C-weekly/ combination therapy are alternatives
• Consider tertiary referral for novel therapies eg. Revlamid
• Reduced intensity conditioning transplants should only be considered in the context of a trial
(Level 4)
• Myeloablative allogeneic transplants should be discussed with the Regional Transplant
Director (Level 4)
• Patients with primary refractory disease should receive either VAD or bortezomib followed by
stem cell mobilisation. (Level 1)
2. Unsuitable for transplant:
• If thalidomide not part of first line therapy consider thalidomide alone or in combination (Level
1)
• Retreat with melphalan/ melphalan & prednisolone/ C-weekly/ dexamethasone alone (Level 1)
• Consider tertiary referral for novel therapies
• EPO should be considered for continuing anaemia following chemotherapy
• Palliative RT for symptoms, nerve and bone disease as indicated.
3. Bortezomib
NICE has approved Bortezomib as a treatment option in first relapse and this should therefore be one
of the treatment options discussed with patients. If used reimbursement for non-response should be
sought as per NICE. As Dexamethasone is known to improve response to Bortezomib its use should
be considered as this was not assessed by NICE.
NICE did not approve the use of Bortezomib in second or subsequent relapse although this was
approved by SMC and the drug is known to be active in this setting. In suitable patients, especially
those who did not have access to Bortezomib at first relapse its use should be considered by the MDT
and if felt appropriate approval should be sought from the patients PCT.
The use of Bortezomib in primary resistant disease is experimental and little evidence is currently
available. However it does appear to have activity and may be useful in younger patients to obtain a
response prior to autologous transplantation. Approval should be sought on an individual basis from
the patients PCT.
15.5 Solitary plasmacytoma
Primary Treatment
• Radiotherapy
Relapse Treatment
• Radiotherapy
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15. MULTIPLE MYELOMA AND RELATED DISORDERS
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15.6 Amyloidosis
Primary and Relapse Treatment
• Consider referral to Leeds Myeloma MDT or Hull MDT
• Consider referral to Royal Free Hospital
• Treatment options include:
1. Stem cell transplantation (discuss with Transplant Director). The Comenzo
risk/staging guidelines should be followed including gastric biopsy. (Comenzo,
Vosburgh et al. 1998; Bird, Cavenagh et al. 2004)
2. VAD chemotherapy
3. Intermediate-dose melphalan
4. CTD chemotherapy
5. Melphalan and prednisolone
For detailed guidance refer to BCSH Amyloid guideline from the following link
http://www.bcshguidelines.com/pdf/ALamyloidosis_210604.pdf
Guidelines for the Management of Haematological Malignancies
15. MULTIPLE MYELOMA AND RELATED DISORDERS
39

16 ACUTE MYELOID LEUKAEMIA
Diagnostic Criteria
Core Criteria
• More than 20% blast cells by flow cytometry, or morphology when the quality of the EDTA
sample is sub-optimal (use higher figure), or more than 5% blasts in the presence of a
balanced translocation
Peripheral blood (PB) with high white count in older patients is acceptable. However,
cytogenetics not valid on PB samples.
• Myeloid lineage demonstrated by immunophenotype
• The immunophenotype can be one of two patterns:
Type A: CD34+, CD117+, CD13+, CD33+, HLA-DR+, cCD3-, cCD79-
Type B: CD34-, CD117+, CD13+, CD33+, CD15var+, cCD3-, cCD79-, MPO+ (by flow)
Intermediate phenotypes occur and are acceptable to define myeloid lineage.
• Cytogenetics allows risk stratification. Conventional karyotyping is restricted to the
initial/diagnostic evaluation of paients aged 70 or less, and should be supplemented by PCR
for the balanced translocations and the Flt3 ITD
• Molecular analysis
FLT3 ITD / ?TKD (not yet defined as adverse risk) 40% CN (cytogenetically normal) AML
MLL PTD 8% CN AML
NPM mutn. ~50% CN AML
CEBPa mutn. 15-20% CN AML
All cases of acute promyelocytic leukaemia (APML) must have:
• CD34+/-, CD13-hetero+, CD33-homo+++, CD117+, CD15-, HLA-DR-, MPO+++ (by flow)
• Microparticulate pattern with anti-PML
• Confirmation of t(15;17) by PCR or cytogenetics
Essential Investigations
• Coagulation screen
• renal and liver function tests
• CXR
• ECG +/- echocardiogram
Definitions
Induction chemotherapy is given to induce a complete remission – in NCRI (MRC) trials this is defined
as a normocellular marrow with less than 5% blasts.
Consolidation or post-remission chemotherapy is necessary to prevent early relapse and increase the
chance of cure, and may include stem cell transplantation.
Risk stratification is used to determine consolidation therapy. From the results of AML 10 and 11 the
MRC have defined the following risk groups:
Good risk: Any patient with favourable genetic abnormalities – t(8;21), inv(16), t(16;16),
irrespective of other genetic abnormalities or marrow status after Course 1.
Standard: Any patient not in either good or poor risk groups.
Poor risk: Any patient with more than 15% blasts in the bone marrow after Course 1, or with
adverse genetic abnormalities: -5, -7, del(5q), abnormal (3q) or complex (5 or more
abnormalities) – and without favourable genetic abnormalities or with Flt3 ITD
(Wheatley, Burnett et al. 1999; Grimwade, Walker et al. 2001; Kottaridis, Gale et al.
2001)
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16. ACUTE MYELOID LEUKAEMIA
40

Primary Treatment
BCSH guidelines should be followed for all AML and APL patients. (Milligan, Grimwade et al. 2005)
All cases of acute myeloid leukaemia, except acute promyelocytic leukaemia
• All eligible patients up to age 60, or above this and suitable for intensive therapy, with de novo
or secondary AML should be considered for entry to NCRI AML 15 study or the successor
AML17 trial . (www.aml15.bham.ac.uk/trial/index.htm)
• Non-trial patients fit for intensive chemotherapy should receive standard DA induction
chemotherapy. Options for consolidation chemotherapy include MACE & MidAC, HD AraC
and/or stem cell transplantation. (High dose Ara-C is preferred for non-trial patients with corebinding
factor leukaemia and stem cell transplantation in CR1 as course 4 or 5 for non trial
patients with adverse risk)
• All patients over the age of 60 with one of the forms of acute myeloid leukaemia (except Acute
Promyelocytic Leukaemia), this can be any type of de novo or secondary AML – or high risk
Myelodysplastic Syndrome, defined as greater than 10% marrow blasts (RAEB-2) who are fit
for intensive treatment should be entered into AML 16 intensive arm.They should normally be
over the age of 60, but patients under this age are eligible if they are not considered fit for the
MRC AML15 trial.If a clinician is not willing to randomise between the chemotherapy options,
then DA must be given.
• Patients >60 unable to tolerate induction should be entered into the non-intensive arm of AML
16(Lancet, Gojo et al. 2007).Non-trial patients lacking an adverse risk karyotype are
candidates for low-dose Ara-C.
• All induction remission chemotherapy should be delivered in level II/III trusts. Non-intensive
arm can be delivered in level 1 after discussion in MDT
• Patients not able to tolerate induction chemotherapy should be treated palliatively or offered
experimental therapy where available.
Acute promyelocytic leukaemia (APL)
• All eligible patients up to age 60 with APL should be asked to participate in the NCRI AML 15
study or the successor AML17 trial.
• APL patients in complete remission (CR) should have molecular monitoring every 3 months
for 2-3 years to look for signs of early relapse.
• Non-trial patients should be treated per AML15 Spanish arm protocol with molecular
monitoring
Poor risk, refractory or relapsed patients (Kantarjian, Gandhi et al. 2003; Craddock, Tauro et al.
2005)
• For patients aged 1 year, offer reinduction if
not fit for re-induction or short CR, experimental therapy or supportive care. (Level 1 or 2)
Guidelines for the Management of Haematological Malignancies
16. ACUTE MYELOID LEUKAEMIA
41

17 PRECURSOR CELL LYMPHOBLASTIC
LEUKAEMIA IN ADULTS
Diagnostic Criteria
17.1 Precursor B-cell Lymphoblastic Leukaemia
Typical Cases
• Bone marrow or solid tissue infiltration with blast cells
• Immunophenotype: CD19+, CD22+, Tdt+, CD117-, CD34var, CD45 wk
Variants
• CD10 and cytoplasmic µ heavy chain define common and pre-B subtypes according to
traditional criteria. These distinctions are of no clinical value.
• BCR-ABL associated phenotype: CD34-homo+++, CD10-homo+, CD13+ and/or CD33+,
CD38wk/-.
• t(12;21) associated: common ALL phenotype with CD10-hetero+, CD13+ and/or CD33+.
17.2 Precursor T-lymphoblastic Leukaemia
Typical Cases
• Bone marrow or solid tissue infiltration with blast cells
• Immunophenotype: CD19-, Tdt+, cCD3+, CD2+, CD7+, CD22-, MPO- (by flow)
Definition of Remission Status
When a blast cell population with a leukaemia-associated phenotype is detected unequivocally by flow
cytometry on the basis of patterns of CD34, CD19, CD20 and CD10 expression or PCR this will be
reported as not in remission, with the extent of infiltration stated. Where these techniques are not
available remission will be defined as a morphological blast cell count of

Patients aged 15-24 (up to 25th birthday) with Ph neg ALL:
Already ceased to be eligible for UKALLXII at the most recent amendment and should be entered into
UKALL2003. They should be offered treatment and or support from adolescent unit in Leeds if
possible. (Level 2)
Patients aged 15-24 (up to 25th birthday) with Ph pos ALL:
UKALLXII Ph positive arm is still open. Having entered UKALL2003 and found to be Ph positive, such
patients should transfer back to UKALLXII Ph pos arm (Level 2)
Adults (Ph+ve) eligible but not in trial
Should be treated with the current NCRI UKALL XII trial protocol. Early notification to the transplant
team is essential for these patients. (Level 2)
Adults too old for trial entry
Fit patients who are only a few years older than the cut-off could be discussed with the trial coordinators.
It should be remembered that the prognosis for patients 50-60 years and older is poor,
particularly if there are other poor prognostic features (e.g. Ph+ve/ t(4;11)). A ‘step-down’ approach in
intensity is suggested as follows:
1. Fit, informed and willing: consider a UKALL XII–like schedule in this circumstance but note the
above cautions. (Level 2)
2. Less fit, older or uncertain: a less intensive schedule is appropriate. Induction with 2 doses of
daunorubicin, weekly vincristine x 4, asparaginase and prednisolone (similar to the previous
UKALL Xa schedule) is effective and may be followed with a consolidation block or simply
standard maintenance at the clinician’s discretion. CNS prophylaxis is with serial LPs only.
(Level 2)
3. Elderly or frail: Vincristine x4 (1mg) and prednisolone followed by standard maintenance is
simple. CNS prophylaxis may be considered on a case-by-case basis, and would be with
serial lumbar punctures following the completion of the vincristine phase. (Level 1)
Treatment of primary refractory disease
This will be defined post 2nd phase induction in UKALL XII regime or equivalent time point in other
treatments.
• See below for a discussion of the use of Imatinib in Ph+ve cases.
Refractory disease has a dismal outlook with no schedule being clearly optimal.
• We suggest HyperCVAD(Kantarjian, O'Brien et al. 2000) for B cell ALL and hyper-
CVAD/CLAEG for T cell ALL as a preference in this network, with other alternatives including
FLAG or High dose Ara-C schedules e.g. HAM**. (Level 2)
* The fludarabine and Ara-C doses and schedule are as in the MRC AML-HR protocol.
http://leuktrials.uwcm.ac.uk/trials/aml/current/aml-hr/protocol/protocol.htm The G-CSF is given for 7 days, starting the day before
the chemotherapy. No G-CSF dose is standard – we suggest 1 vial of Lenograstim 263mcg or Filgrastim 300mcg daily s/c.
(HAM schedule: footnote next page)
** HAM schedule is: Ara-C 1g/m2 bd i.v. days 1-4 (by 3 hour infusion), Mitoxantrone 10mg/m 2 daily i.v. days 3-5, and ‘triple
intrathecal therapy’ all on day 1 only, consisting of methotrexate 15mg, Ara-C 40mg and Methylprednisolone 40mg all given
once IT.
It may be worth discussing these patients with the trial co-ordinators and they should all be reviewed
at the MDT.
Treatment of ALL relapsing after CR(Fielding, Richards et al. 2007)
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17. PRECURSOR CELL LYMPHOBLASTIC LEUKAEMIA IN ADULTS
43

• There is no current trial within the network. UKALL XII patients should be discussed with the
trial co-ordinators.
• If there is still curative intent then transplant options will be considered if possible and the
patient should be discussed with the transplant centre prior to a decision to give further
treatment as this may influence the choice of therapy.
• HyperCVAD(Koller, Kantarjian et al. 1997) for B cell ALL and hyper-CVAD/CLAEG for T cell
ALL followed by transplant is the recommended option. CNS prophylaxis in the form of
intrathaecal therapy with 12 mg MTX on day 2 and 8 with each course of Hyper CVAD and for
CLAEG protocol IT MTX 12 mg instead of triple therapy stated in the protocol. (Level 2 and 4)
• Use of autologous PBSCs collected in first CR may depend on the duration of remission.
• See below for a discussion of the use of Imatinib in this setting for Ph+ve cases.
• These cases need discussion at an MDT incorporating transplant advice (see above).
Relapse has a very poor prognosis, particularly if it occurs less than a year from treatment
end. If there is no transplant option then further chemotherapy can be considered as for
refractory cases (see above).
The UKALL group is looking into using Hyper-CVAD+ Campath for these patients.
Imatinib in relapsed/refractory Ph+ve cases
Monotherapy in relapsed/refractory cases can achieve CRs in up to a third of patients although these
are not durable. Imatinib can be a useful agent in re-establishing short term remission prior to
transplant. Post transplant relapses can also be managed in this way. The place of Imatinib in these
circumstances should be discussed at an appropriate MDT (see above). CNS prophylaxis must be
considered in the context of the treatment schedule agreed at the MDT. (Level 1)
CNS leukaemia at diagnosis
• The UKALL12 protocol can be followed for all patients. This consists of weekly IT MTX until
clear then radiotherapy, depending on whether they are proceeding to transplant. (Level 2)
• As an alternative to IT MTX, IT Depocyte should be considered.
• For CNS + BM relapse consider* IT + Salvage therapy (hyper-CVAD) (level 2)
• For Solitary CNS relapse consider* IT + Salvage therapy (as above) (Level 2)
All above salvage treatments should be consolidated with a transplant modality
(*Consider radiotherapy for CNS disease if no transplant option)
Special issues in prophylaxis
Fungal infection – continues to be a particular hazard. Prophylaxis must be with a minimum of oral
fluconazole (itraconazole may be better but is not proven). Serious consideration should be given to
prophylactic amphotericin B i.v. at a dose of 0.25-0.5mg/kg on alternate days (no standard dose has
been established). A regional document on fungal therapy/ prophylaxis is imminent and will
supersede this guideline.
Please note that there is a drug-drug interaction between itraconazole and vincristine which
lead to increased vincristine neurotoxicity.
PCP – Prophylaxis is required and is standard (example : septrin 960mg bd orally 3x a week or
pentamidine nebulised 300mg monthly or 150mg 2 weekly if poorly tolerated – the latter requires
approved apparatus and room ventilation, and must be discussed with local microbiology colleagues).
Asparaginase thrombophilia – monitor according to UKALL XII protocol.
Guidelines for the Management of Haematological Malignancies
17. PRECURSOR CELL LYMPHOBLASTIC LEUKAEMIA IN ADULTS
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18 MYELODYSPLASTIC SYNDROMES
Diagnostic Criteria
Typical Cases
• Hypercellular marrow in the presence of cytopenia
• Erythroid series shows nuclear budding or bridging, vacuolation of late erythroblasts,
multinuclear cells, asynchronous haemoglobinisation.
• Myeloid series shows abnormal granulation, pseudo-Pelger change, maturation asynchrony,
increased numbers of CD34+ myeloblasts, usually >3.5% by flow cytometry. The blasts
should have the phenotype CD34+, CD45+, CD117+, CD15-.
• Megakaryocytes are cytologically abnormal with micro forms and nuclear lobe separation.
• Single lineage dysplasia in the appropriate clinical context is sufficient for a diagnosis of MDS
(WHO classification)
Variants
• Any of the above features in a hypocellular marrow. Increased bone marrow fibrosis and an
excess of blasts are most useful to differentiate from aplastic anaemia.
• 5q- as sole cytogenetic abnormality often with increased abnormal megakaryocytes +/-
increased platelets and anaemia.
• Refractory anaemia with ring sideroblasts - requires >15% ring sideroblasts and 3 months)
•

mainstay of treatment, but selected groups may benefit from chemotherapy and other specific
treatment.(Bowen, Culligan et al. 2003)
Anaemia
• RBC transfusion should be considered in any patient with symptomatic anaemia.
• Iron chelation with s/c desferrioxamine should be considered principally in stable transfusiondependent
patients with low/INT-1 IPSS score (predicted survival > 4 yrs)(especially pure
sideroblastic anaemia [WHO RARS], pure refractory anaemia [WHO RA] and 5q- syndrome).
Initiate iron chelation at serum ferritin >1000 mcg/l, with annual eye and ear assessment.
There is no evidence for benefit from IV desferal given at the same time as blood
transfusion.Desferrioxamine remains chelator of choice if tolerant and effective. Alternatives
are Deferiprone(This is not licensed for these indications and it need a weekly full blood count
and should be initiated only if the baseline neutrophils > 1.5 x 109/l), Deferasirox and
Combination of Deferiprone daily plus Desferrioxamine 3 x /week
Erythropoietin (EPO) +/- G-CSF can reduce transfusion requirements in selected patients. This will
become increasingly important as blood supplies fall. But this should be restricted to patients with
Serum EPO < 500 IU/l and Low transfusion requirement (≤ 2 units / month)
A randomised phase 3 controlled trial is likely to be open in late 2007
Immunosuppression with ALG or cyclosporin can be beneficial in hypoplastic MDS, but also in normoor
hyper-cellular low-risk groups (IPSS INT-1 or less). ALG should only be used in patients

• Both the degree of thrombocytopenia and platelet dysfunction can contribute to bleeding
problems. In the absence of bleeding or fever, the threshold for platelet transfusion is 10 x
10 9 /l.
• Antifibrinolytics and danazol may be useful in some patients.
• Trial of AMG531 for low/Int-1 MDS with platelets < 50 x 10 9 /l open in Leeds.
Chemotherapy and Stem Cell transplantation
• Non-intensive: patients aged >60 years with >10% blasts should be offered therapy within the
AML16 non-intensive trial. Low dose oral melphalan should be considered for elderly patients
(>75 years) with hypocellular RAEB / AML with a normal karyotype. 5-azacytidine (Vidaza)
has been reported as achieving haematological responses in up to 35% of patients with MDS,
and complete remissions in 6%; responses are similar with 5-aza-2- deoxycytidine
(Decitabine/Dacogen). (Level 1)
• Intensive: patients aged >60 years with >10% blasts should be offered therapy within the
AML16 intensive trial. Patients 10% blasts and/or INT-2/ High risk disease
should be considered for intensive AML induction chemotherapy.They will be eligible for the
NCRI AML17 study. For such patients now treat per AML15 until AML17 open. (Level 2) In
patients

19 CHRONIC MYELOID LEUKAEMIA
Diagnostic Criteria
Chronic phase CML
• t(9;22) as part of a single or complex translocation, or BCR-ABL transcript must be present in
every case
• Maximally cellular marrow with left shifted, myeloid series, monolobated megakaryocytes and
suppressed erythroid series
• 20% basophils in marrow or blood, associated
with clinical progression or refractory to treatment.
• Blast crisis (BC): >20% myeloid blasts or >5% lymphoid blasts or solid extramedullary tumour
deposit consisting mainly of blasts.
Essential Investigations
• Full blood count with manual differential.
• Full examination with documentation of liver and spleen size. Ultrasound scanning of the
abdomen to more accurately document spleen size may be considered.
• Routine biochemistry to include U&Es, LFTs, calcium, LDH and urate.
• Bone marrow aspirate and trephine with sample sent for cytogenetics
• Bone marrow and peripheral blood sample for RT-PCR
• All newly diagnosed patients should have a Hasford or New CML (Euro) score measured. This
can be calculated using a simple web based programme found at www.pharmacoepi.de.
• A full family history, in particular paying attention to potential sibling donor details, should be
taken. As early as possible after diagnosis, tissue typing of the patient and siblings should be
arranged. This should be mandatory in all patients under the age of 65.
Primary Therapy (Oscier, Fegan et al. 2004)
Patients in Chronic Phase (CP)
• All new patients should be offered entry into the SPIRIT study (Level1)
• All patients are to be considered for stem cell harvest. However, in practice this should only be
carried out in patients who may be eligible for studies assessing the role of autografting in
CML, or in whom a backup for allogeneic transplantation may be required.
• In patients with symptoms of leucostasis consideration may be given to therapeutic
leucopheresis in addition to buffy coat stem cell collection.
• All patients should be well hydrated and receive allopurinol 300-600 mg daily.
• Initial cytoreductive therapy should be with Imatinib (400 mg daily). (Level 1)
Rarely, patients may be encountered who are intolerant of Imatinib. Treatment options in such cases
should be discussed with the MDT lead for leukaemia,as new trials will become available in the next
near future investigating new targeted therapies.
Patients in Accelerated Phase (AP)
• Patients presenting in the accelerated phase of CML should receive Imatinib 600mg daily,
which is associated with a reported progression-free survival rate of 67% at 12 months, and
overall survival of 66% at 36 months.
Patients in Blast Crisis (BC)
Guidelines for the Management of Haematological Malignancies
19. CHRONIC MYELOID LEUKAEMIA
48

• Patients presenting in blast crisis present a difficult management problem. The best responses
have been reported to Imatinib 600mg daily, with reported 12 month survival rates of 32%.
Major cytogenetic responses have been reported in 16% of patients, and complete
cytogenetic responses in 7%.
NICE do not recommend continued use of Imatinib in patients presenting in CP who progress to AP or
BC after exposure to the drug. Management of such cases should be discussed with the MDT lead for
leukaemia. For patients in BC, options include acute leukaemia type therapy (as for AML or ALL
depending on phenotype) or autologous stem cell transplantation.
Patients in AP and BC mayalso be eligible for new trials of alternative targeted therapies(see above).
Further Management of Chronic Myeloid Leukaemia Patients on Imatinib
Imatinib is well tolerated by the majority of patients.
• Side effects include mild allergic type rashes, which may respond to simple anti-histamines.
• Severe dermatological reactions have been documented which may require steroid therapy or
in some cases the discontinuation of Imatinib.
• Arthralgia is seen in 60% of patients and usually responds to simple treatment with nonsteroidals.
• Fluid retention may be troublesome and occurs in the majority of cases often just as simple
peri-orbital oedema. More severe oedema is often quite refractory to diuretic therapy and may
require dose reduction or discontinuation.
• Neutropenia is usually easily managed by the addition of GCSF to the regimen and may allow
dose escalation.
• Patients in whom there is no documented haematological or cytogenetic response may benefit
from dose escalation of up to 800 mg per day. Again the addition of GCSF may be helpful in
maintaining dose levels.
• The combination with α-interferon has been tried and has produced cytogenetic responses in
patients not achieving this with α-interferon alone. The most experience has been with once
weekly PEG-Intron in doses up to 1µg/kg/week in the PISCES study.
Management of Chronic Myeloid Leukaemia Patients who are resistant or intolerant to Imatinib
• In chronic phase for treatment failure new tyrosine kinase inhibitors like Nilotinib or
Dasatinib(Talpaz, Shah et al. 2006) should be tried before considering Allogenic stem cell
transplant if appropriate.
• For suboptimal response the options are either dose escalation of Imatinib to 600-800mg or
changing to new tyrosine kinase inhibitors should be considered before offering Allogenic
stem cell transplant.(Hughes, Deininger et al. 2006)
• For accelerated phase and blast crisis new tyrosine kinase inhibitors and Allogenic stem cell
transplant are the options.
Monitoring of Response to Imatinib(Goldman 2005; Baccarani, Saglio et al. 2006)
• All patients should have baseline bone marrow examination with cytogenetic analysis and
peripheral blood sample for quantitative RT-PCR.
• Peripheral blood monitoring should be done every 3 months. Bone marrow investigation will
be advised for patients with inadequate response. 10ml of EDTA blood is required.
At 3 months:
If 1 log reduction not achieved (>5.5%) then that is unsatisfactory response. Bone marrow
cytogenetics and peripheral blood PCR at 6 months.
If 2 log reduction is achieved (0.55% or less), this is probably equivalent to a complete
cytogenetic response.
Then continue 3 monthly PB assessment.
At 12 months of therapy
If at least 3 log reduction (>0.055% or less) is achieved then it is considered as a major
molecular response bone marrow cytogenetics should be performed with peripheral blood
Guidelines for the Management of Haematological Malignancies
19. CHRONIC MYELOID LEUKAEMIA
49

PCR analysis on patients who have not achieved major molecular response after 12 months
of therapy. (Hughes, Kaeda et al. 2003)
Bone marrow should also be performed on patient who have > 2-5 fold rise, confirmed on
repeat sample (Mutation screening will also be performed)
Management of CML in Pregnancy (Fitzgerald, Rowe et al. 1986; Lipton, Derzko et al. 1996)
There is little in the way of large published series about the management of chronic myeloid leukaemia
in pregnancy. However, a number of the concerns that are associated with myeloproliferative
disorders (MPD) in pregnancy will also apply to CML.
• There is little evidence that pregnancy itself adversely affects the natural course and
prognosis of CML but any haematological disorder that may lead to hyperleucocytosis and
possibly thrombocytosis is likely to affect fertility, and may lead to an adverse outcome of the
pregnancy itself because of thrombotic or bleeding complications. This is certainly true in
primary thrombocythaemia (PT) where first trimester abortion is the most frequent
complication but increased perinatal mortality and premature delivery are also observed.
• Placental infarction due to thrombosis is the most consistent event.
• As regards management, it is desirable that some attempt to control the white cell count (and
perhaps platelet count) in pregnancy should be attempted. Hydroxyurea is teratogenic in
animals and one stillbirth and one malformed infant have been reported after exposure in
pregnancy. It should generally be avoided, but there are several well documented cases of
successful outcomes in PT with hydroxyurea given throughout pregnancy.
• Alternative treatments include α-interferon, which has been well documented as being safe in
the management of PT in pregnancy, and leucopheresis. This is the most common therapeutic
manoeuvre cited in the literature with good control of the white cell count and a successful
outcome for mother and baby in all reported cases.
Based on the published evidence, a reasonable recommendation for the management of CML in first
chronic phase diagnosed in pregnancy would be as follows:
1. Initial leucopheresis to control the white cell count, together with allopurinol and aspirin
therapy, especially if there is associated thrombocytosis.
2. Instigation of α-interferon therapy to maximum tolerated dose to control the white cell count
with intermittent leucopheresis to keep the white cell count below 20 x10 9 /l and platelets below
400 x10 9 /l until delivery.
3. No particular precautions need to be taken at delivery, assuming stable peripheral blood
parameters, and normal vaginal delivery should be possible.
The management of accelerated phase or blast crisis occurring in pregnancy is much more difficult.
• Either of these situations should warrant consideration of early termination of pregnancy and
the introduction of Imatinib therapy, but it is possible that hydroxyurea may control the
situation at least until the baby is of a great enough gestational age to deliver safely. This
policy would be associated with a relatively low risk of foetal abnormality.
• More specific therapy, including bone marrow transplantation could then be considered
following parturition.
• The potential role, if any, of Imatinib in managing CML in pregnancy is unknown at present.
Animal data does suggest that it is teratogenic in rats at doses of 100 mg/kg or more. It is
unlikely that any meaningful data will emerge regarding its use in this situation for some time.
Bone Marrow Transplantation
Bone marrow transplantation remains the only proven curable treatment for patient with chronic
myeloid leukaemia. However, the emergence of Imatinib has led to a reappraisal of the appropriate
timing of BMT.
• The excellent outcomes in young patients (

A more difficult decision concerns older patients and all patients in whom an unrelated donor
transplant is being considered.
• Recent strategies presented at the American Society of Haematology advocate starting all
such patients on Imatinib with close monitoring of their haematological, cytogenetic and
molecular responses.
• There is some evidence that those patients not achieving a major cytogenetic response at six
months of therapy are at particular risk of disease progression and these then should be
considered for transplantation.
• In those who do achieve a major cytogenetic response, Imatinib should be continued with 6
monthly bone marrow cytogenetic analysis.
• In those who do achieve a major cytogenetic response or satisfactory reduction in BCR-ABL,
Imatinib should be continued with 3monthly PB quantitative RT-PCR.analysis.
A significant rise in BCR-ABL (2 fold) should lead to BM examination. Patients in CCR who are then
documented as having a cytogenetic relapse, and have a transplant option (autologous or allogeneic),
should then be then considered for the transplant procedure.
Autologous transplantation
The role of autologous transplantation in CML is not established.
• It may be useful in re-establishing a short-lived second CP in patients progressing to blast
crisis. The attempted harvesting of buffy coat cells in Imatinib treated patients achieving a
CCR may be considered within the context of a clinical trial.
Guidelines for the Management of Haematological Malignancies
19. CHRONIC MYELOID LEUKAEMIA
51

20 CHRONIC MYELOPROLIFERATIVE
DISORDERS
Diagnostic Guidelines
JAK2 tyrosine kinase mutations can be detected by PCR. Mutations are found in the majority of
patients with PRV, about a third with ET and IMF. (Baxter, Scott et al. 2005; James, Ugo et al. 2005;
Kaushansky 2005; Kralovics, Passamonti et al. 2005; Levine, Wadleigh et al. 2005)
Investigation should follow the following algorithm:
Suspected
Myelofibrosis
Investigation of Suspected Chronic Myeloproliferative Disorder
Increased HCT +
WBC or Platelets
Raised EPO level – stop
investigating for CMPD
Negative
JAK 2 PCR
RCM?? Monitor?
Bone Marrow
EDTA sample to HMDS with FBC and ferritin
PCR done on basis of FBC
Guidelines for the Management of Haematological Malignancies
20. CHRONIC MYELOPROLIFERATIVE DISORDERS
Positive
Diagnosis of
CMPD
JAK 2 testing outside these indications is not
interpretable
Raised platelets, no
Fe def, no cause
52

Diagnostic Criteria
With the exceptions listed below all cases will be reported using the generic term 'chronic
myeloproliferative disorder'.
The diagnosis can only be made on a trephine biopsy and will not be made where only aspirate
smears are available.
Typical Cases
• Marrow shows normal or increased cellularity
• Trilineage expansion with hyperlobated or clustered megakaryocytes
• If any suspicion of CML this should be excluded by PCR
• Blasts 5% require repeat marrow within one month to assess progression to
acute leukaemia
Variant
Chronic Idiopathic Myelofibrosis: increased reticulin/ fibrosis, sometimes with new bone formation with
appropriate clinical and peripheral blood features
Essential Investigations
• FBC – Hb is more sensitive than HCT
• Red cell mass (if Hct is normal/ high normal)
• Bone marrow aspirate & trephine biopsy (see diagnostic guidelines)
• Ultrasound abdomen
• CRP, ESR or PV
• U&E, LFT
• EPO
• Ferritin
Primary Therapy of Essential Thrombocythaemia (Level 1)
Patients should be assessed as to the risk of thrombosis according to the criteria laid down in the
NCRI PT1 trial documentation.
• Low risk → aspirin
• Intermediate risk → randomise to either aspirin or aspirin & myelosuppressive therapy
• High risk → hydroxyurea & aspirin
• Anagrelide should be considered for those with intolerance to or side effects of hydroxyurea.
• Aspirin 75 mg long term
• Allopurinol prophylaxis
• Vascular complications may require input from a vascular surgeon who should be member of
the leukaemia MDT.
Therapy of Polycythaemia
• Refer to BCSH Guidelines.
Therapy of Idiopathic Myelofibrosis (Level 1)
• Hydroxyurea for: ↑platelets, ↑WBCs or hypermetabolic symptoms
• Splenic irradiation for: hypermetabolic symptoms, leucopenia, symptomatic splenomegaly or
unfit for splenectomy
• Splenectomy for: symptomatic splenomegaly, hypersplenism, trauma or rupture
• α-interferon or thalidomide may be efficacious in some cases
• Allopurinol prophylaxis
Guidelines for the Management of Haematological Malignancies
20. CHRONIC MYELOPROLIFERATIVE DISORDERS
53

21 Reporting Pathological specimens from
haemato-oncology patients
21.1 Introduction
These guidelines are designed to ensure Network compliance with measures 1C-120, (designated
haematologists for the whole of the Network) 1C-121 (a single agreed list of named designated
consultant haematopathologists for the Network) 1C-122 (there should be a final integrated report on
the pathological diagnosis for each haemato-oncolgy patient) and 1C-123 (the NSSG should agree
and produce the network-wide pathology guidelines for haemato-oncology.
21.2 Network Policy
The network policy is that all peripheral blood immunophenotyping, all bone marrow aspirates and
trephines and all solid tissue specimens from patients with suspected haematological malignancy at
primary diagnosis and subsequent follow up should be referred to the Haematological Malignancy
Diagnostic Service at Leeds Teaching Hospital NHS Trust. There they will be reported by the
designated haemato-pathologists for the YCN/HYCCN combined Network. Haematology MDT’s in the
YCN/HYCCN will only make treatment plans based upon diagnoses confirmed by HMDS. HMDS
designated pathologists will be core members of all of the Networks haematology MDT’s.
21.3 Designated Pathologists
The designated consultant pathologists within the HMDS laboratory are:
Name MDT membership
Dr Andrew Jack Leeds, Hull, Mid Yorkshire
Dr Roger Owen Leeds, Bradford
Dr David Swirsky Leeds, Hull, Bradford, York
Dr Reuben Tooze Leeds
It is the policy within the HMDS laboratory that all specimens are reported independently by two
pathologists from the above list. The names of both pathologists appear on the report. Where the
reporters disagree the matter is resolved by discussion or where necessary by obtaining a third
opinion. An audit file is keep with details of all cases where there was an initial difference of opinion
between reporters. This is available through the HILIS systems and is regularly reviewed by the
reporting team.
A report is issued when results of morphology, flow cytometry and immunocytochemistry are available.
The results of FISH, cytogenetics or molecular studies are added later and an amended report is
issued. The will be authorised by one of the designated pathologists or by a principal grade clinical
scientist.
Reporting times are continually monitored and reviewed by the reporting team. These are available for
inspection through the HILIS system.
Guidelines for the Management of Haematological Malignancies
21. REPORTING PARHOLOGICAL SPECIMENS FROM HAEMATO-ONCOLOGY PATIENTS
54

21.4 Reporting Standards
All specimens are reported in accordance with the HMDS Standard Operating Procedure. This
specifies the criteria that are required for each diagnosis and specifies the diagnostic terms that are
permitted. The SOP is based on the WHO classification of Haematological Malignancies but in a
number of instances more rigorous criteria have been adopted. The permitted diagnostic terms are
based on ICD-O3 codes. (The relevant code is stated in the report). The SOP is available to users on
line at www.hmds.org.uk (link to diagnostic criteria) or in paper format.
21.5 Expected Reporting Times
Reporting times are continually monitored and available on the HILIS systems. The target time for a
bone marrow aspirate and trephine biopsy (excluded molecular and cytogenetic investigations) is 2.5
working days, and unfixed lymph node is 4 working days and a referred tissue block is 3 working days.
21.6 Investigation Protocols
In addition to morphological reporting HMDS provides the following modalities of investigation;
Flow Cytometry
• Wide range of 4 and 6 colour test covering all aspects of primary diagnosis
• Minimal residual disease monitoring applicable to a range of haematological malignancies
Immunocytochemistry
• Comprehensive range of around 50 antibodies applicable to paraffin and resin embedded
specimens
• Multi-colour techniques are currently being evaluated for routine use.
FISH
• Interphase FISH on smears, sections and isolated nuclei covering all clinically relevant
abnormalities in lymphoproliferative disorders.
PCR
• Clonality studies
• RT-PCR for balanced translocation
• DNA PCR for translocations
• Mutational analysis
• Quantitative PCR
• Chimerism studies.
Metaphase cytogenetics is carried in the Department of Genetics but results are integrated with the
final HMDS report.
In general, specimens are referred to HMDS for investigation of a clinical problem rather than for a
specific test. All specimens are investigated according to preset protocols. All specimens are screened
on receipt by a consultant or senior scientist and assigned to a screening category on the HILIS. This
maps to the relevant set of investigation and these are automatically requested and progress tracked.
The matrix used is available at www.hmds.org.uk. Additional investigation can be ordered manually
where indicated.
21.7 Procedure For Referral Of Specimen
Guidelines for the Management of Haematological Malignancies
21. REPORTING PARHOLOGICAL SPECIMENS FROM HAEMATO-ONCOLOGY PATIENTS
55

Specimens should be referred to HMDS using the request form, copies of which can be downloaded
from the HMDS website. It is particularly important that full patient ID is provided including the NHS
number. It is essential that appropriate labelling is attached where HIV or other infection hazards are
suspected.
21.8 Specimen Types Handled By HMDS
• Any type of tissue specimen
• Peripheral blood
• Bone marrow aspirate and trephine biopsies
• Effusion and CSF specimens.
21.9 Collection And Transport Of Tissue Specimens
It is strongly recommended that tissue specimens, especially lymph node biopsies, should be sent
unfixed to the HMDS laboratory to facilitate the widest and most effective range of investigations. This
should be done in all cases where a haematological malignancy is suspected. Where the diagnosis is
subsequently found to be a metastatic tumour the report and tissue blocks will be forward to the
appropriate specialist pathologist.
Unfixed specimens should be wrapped in a piece of sterile gauze that has been soaked in
isotonic saline. The specimen should be sent by taxi, or dedicated hospital transport. The
specimens should arrive within 4 hours of removal from the patient.
In cases where the tissue has been processed locally and haematological malignancy is subsequently
suspected the tissue block should be referred to HMDS. The specimens can be sent by hospital
transport or 1st class mail or equivalent.
21.10 Urgent And Out Of Hours Specimens
A 24 hour service is provided and a full reporting service is available out of hours when there is a
defined and urgent clinical need; this is usually a requirement to commence chemotherapy
immediately. A senior member of the clinical team must discuss this with the HMDS consultant on call,
who can be contacted via the laboratory (0113 2067851) or the switchboard at St James’s University
Hospital (Bexley Wing).
The laboratory is staffed from 8am to 8pm Monday to Friday and 9-12am on Saturday. If unfixed
specimen are likely to arrive after 5pm or at weekends the HMDS BMS on call should be informed by
contacting the laboratory or through St James’s University Hospital (Bexley Wing), even if an urgent
report is not required.
21.11 Transmission Of Reports
Reports will be sent to:
• The referring clinician and/or pathologist
• The local Haemato-oncology MDT
• The Haematology Network data centre at Health Sciences, University of York
• Cancer Registry.
Paper reports are despatched by routine mail for all specimens. Some centres have opted to receive
bulk email delivery of reports.
Guidelines for the Management of Haematological Malignancies
21. REPORTING PARHOLOGICAL SPECIMENS FROM HAEMATO-ONCOLOGY PATIENTS
56

All members of Haemato-oncology MDTs can have on line access to reports through the HILIS
system.
An alert email is sent to the relevant MDT when a new diagnosis of malignancy is made.
21.12 References
1. Haematological Malignancy Diagnostic Service (HMDS) website is www.hmds.org.uk
These guidelines were drafted by Dr Russell Patmore and Dr Andrew Jack.
They were agreed by the YCN and H&YCCN Pathology Groups and the Site Specific Group of the
YCN and H&YCCN and the locality MDTs.
Version 1.0 Produced by Dr Russell Patmore and Dr Andrew Jack, Aug 2008
Responsible for review; YCN Pathology Group
Guidelines for the Management of Haematological Malignancies
21. REPORTING PARHOLOGICAL SPECIMENS FROM HAEMATO-ONCOLOGY PATIENTS
57

22 Facilities necessary for provision of
intensive chemotherapy (NICE 2003)
22.1 Facilities
• Provision for direct admission to the ward or unit.
• Specific beds in a single dedicated ward within the hospital with the capacity to treat the
planned volumes of work.
• In-patient unit that minimises airborne microbial contamination
• For isolation: a number of single rooms with en-suite facilities.
• All patients receiving induction therapy or other high-dose chemotherapy should be housed in
single rooms with en-suite facilities.
• Designated area for out-patient care that reasonably protects the patient from transmission of
infectious agents, and can provide, as necessary, for patient isolation, long duration
intravenous infusions, multiple medications, and/ or blood component transfusions.
• Full haematology and blood transfusion laboratories on site.
• Rapid availability of blood counts and blood products including products such as
• CMV seronegative and gamma-irradiated blood components.
• Central venous (Hickman) or Portacath catheter insertion must be available by a committed
and experienced specialist.
• Central venous catheters and pumps (portable and static)
• On-site facilities for emergency computed tomography (CT) scanning.
• Cytotoxic drug reconstitution centralised at the pharmacy.
22.2 Staffing
• Consultant-level specialist medical staff should be available at any time of the day or night.
This level of cover demands at least three consultants, all full members of a single
haematology MDT and providing in-patient care at a single site. Levels of staffing must comply
with the EU working time directive.
• Specialist registrars and staff grade doctors providing cover should be working in
haematology/oncology and part of the unit. They should be involved in looking after these
patients during the normal working day. They should be familiar with, and have received
formal instruction in, the unit protocols.
• A nurse/patient ratio satisfactory to cover the severity of the patients’ clinical status.
• The level of staffing required for neutropenic patients is equivalent to that in a high
dependency unit.
• At least one trained specialist nurse* on the ward at all times, able to deal with indwelling
venous catheters, recognise early symptoms of infection, and respond appropriately to
potential crisis situations.
∗ There is no universally agreed definition of specialist nurse in this context. However the term is understood to cover nurses
with sufficient experience (i.e. at least a year of experience as a qualified nurse in haematology and/or oncology), and usually
formal academic qualifications including ENB, diploma courses with specialist modules in oncology or haematology, or locally
organised university validated courses or specialist degree courses in haematology/oncology and palliative care.
• Consultant microbiological advice must be available at all times. There must be ready access
to specialist laboratory facilities for the diagnosis of fungal or other opportunistic pathogens.
• A consultant clinical oncologist must be available for consultation, although radiotherapy
facilities need not be on site.
• On-site advice from a specialist oncology pharmacist
• Access to staff (e.g. data manager) to support entry of patients into the local portfolio of
National Cancer Research Network (NCRN) clinical trials.
Guidelines for the Management of Haematological Malignancies
22. FACILITIES NECESSARY FO PROVISION OF INTENSIVE CHEMOTHERAPY
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22.3 Clinical Support
• On-site access to bronchoscopy, intensive care and support for patients with renal failure.
• Written policies for all procedures, including infection prevention and control, insertion of
indwelling venous catheters, high dose therapy and/or immunosuppressive agent
administration (including intrathecal chemotherapy), and blood component transfusion.
• Participation in network based audit of process and outcome.
Guidelines for the Management of Haematological Malignancies
22. FACILITIES NECESSARY FO PROVISION OF INTENSIVE CHEMOTHERAPY
59

23 Care Pathways for Teenagers and Young
Adults with a Haematological Malignancy
in Yorkshire and the Humber and East
Coast Cancer Networks
Working group:
Sally Burnell, Gordon Cook, Di Gilson, Pete Hillmen, Sally Kinsey, Ian Lewis
Sue Morgan, Lisa Newton, Russell Patmore, Julie Watson and Nicola Walden.
Introduction
The care of Teenagers and Young Adults (TYA) with cancer is receiving much attention nationally and
within Cancer Networks. It was agreed that a group of interested individuals from the Yorkshire and
Humber and East Coast Cancer Networks haemato-oncology group would work with members of TYA
Service (TYAS) in Leeds to produce a discussion document with suggestions for how care might be
delivered for TYA with haematological malignancy.
Background
Two important documents will have an impact on the way that we should care for TYA with cancer
within hospitals.
The first is the ‘Children in Hospital NSF’(DOH 2003), which lays out benchmarks of care for children
and teenagers under the age of 19 years, i.e. up to one day short of their
19th birthday, in hospital.
In brief this document states that children and young people:
• are vulnerable individuals, yet have their own rights
• have a right to education, recreation and full information
• should be treated in a suitable environment by professionals who have:
- an understanding around issues of consent
- offer a choice in their care
- can offer appropriate support.
• should be treated by multidisciplinary teams:
- With knowledge of the issues of child protection
- using evidence based practice
- providing co-ordination of services.
The second is the NICE Guidance for ‘Improving Outcomes for Children and Young People with
Cancer’.(NICE 2005) This is currently in draft form and is out for second consultation. This document
is very likely to have an impact on the way in which Cancer Centres and Units function with regard to
young people. As with other areas of cancer care covered by improving outcomes guidance (IOG), it is
very likely that this will lead to Peer Review in the near future.
The guidance covers children from birth to young people in their late teens and early twenties
presenting with malignant disease.
The underlying principles of the draft document are that services must be age appropriate, safe, and
effective and deliver care as near to the patients home as possible. The document contains the
following guidance that is likely to impact on TYA Services:
• Age appropriate facilities:
- All young people under the age of 19 years must be cared for in age appropriate facilities.
- All young people 19 years and older should have unhindered access to age appropriate
facilities and support when needed.
Guidelines for the Management of Haematological Malignancies
24. GUIDELINES FOR CONVENTIONAL CYTOGENETIC ANALYSIS IN ADULT PATIENTS WITH HAEMATOLOGICAL
MALIGNANCIES
60

• Principle treatment centres must be established for the care of children and TYA with
associated referral pathways. They should be able to provide a sustainable range of services
for this group of patients and their families.
• MDT Cancer Centres providing care for TYA should ensure that the skills and experience
represented in the MDT are appropriate to the age related needs.
• Treatment based, clear evidence of the best outcomes The choice of paediatric or adult
protocol for the treatment and care of teenagers and young adults should be based on clear
evidence of the best outcomes
• Development of appropriate care pathways Partnerships between age appropriate
facilities, such as teenage units, and tumour specific services, which may be primarily located
with an adult setting, are required. Care should be delivered throughout the patient pathways
through MDT’s. This group would benefit from the development of clear ‘signposts’ to the most
appropriate care pathways based on need
• Peer Review All sites delivering cancer therapy in this age group will be subject to peer
Review
• Trials TYA should be offered entry to any clinical research trial for which they are eligible, and
adequate resources should be provided to support such trials. If there is no, relevant trial
open, TYA should be treated according to agreed treatment and care protocols based on
expert advice. Resources should be provided to monitor and evaluate outcomes.
• Cancer registry The issues related to the registration of cancers in 15-24 year olds and the
potential value of a dedicated register within the structure of the National Cancer Registry
should be addressed urgently.
• Psychosocial support TYA should all be offered:
- the advice and support of a social worker
- support from psychologists with expertise in young people with clear routes of referral
- access to an age appropriate MDT
- peer support
- sibling and family support
• Long term follow up There should be robust and appropriate surveillance of survivors for
long term effects of treatment
• Palliative care Special provision is required. This will often entail the development of
partnerships between child and adult services. These patients require individual packages of
care provided by a multidisciplinary, multi-agency service.
• Bereavement support All families should have access to a specialist bereavement support,
and ongoing support following death for an appropriate period.
• Child protection All services for children and TYA must demonstrate robust child protection
arrangements, regardless of the setting in which care is delivered. All staff whose work brings
them into contact with children (i.e. 16 years and under) should be Criminal Records Bureau
checked. All staff should have a full understanding about the rights and needs of children and
TYA’s.
Principles underlying suggested care pathways
• It seems unlikely that the IOG for children and young people will be prescriptive about the
details of how services should be developed, but there will be a need to develop clear
pathways of care.
• Once the Guidance is finalised, its recommendation will have to be adopted as they will be
assessed as a part of the Peer Review process.
• An effective collaboration needs to be developed between the TYA MDT and paediatric and
adult haematology services as haematological malignancies are the commonest cancers in
this age group of patients.
• A Cancer Network based service should be developed to ensure that the patient receives the
optimum care.
• The patient’s care should be at the centre of any service that is configured by the Cancer
Network.
• It is recognised that occasionally there may be conflicting management strategies between
adult and paediatric practices for a specific disease entity. Ideally in this situation, a
multidisciplinary meeting with all relevant staff who could potentially be involved in the
patient’s care should be set up to discuss the treatment options. The decision about the
patient’s management should be based on the biology of the disease, available evidence and
Guidelines for the Management of Haematological Malignancies
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the possibility of trial entry. The relevant teams should then agree who will be responsible for
the patient’s care and this decision should be based on the expertise available to manage the
patient.
• It is essential to develop close links between the TYA service and the adult haemato-oncology
services throughout the Network. A starting point is to establish robust referral routes for TYA
with haematological malignancy.
• The next phase of this work will be to develop clear guidelines to facilitate the transition of
care for children and younger adolescents from paediatric to adult services as they become
adults.
• It will be necessary to evaluate the efficacy of any care pathways that are established.
Suggested care pathways for discussion
The aim of care pathways that may be developed is to deliver patient centred care.
To start this process we have outlined some suggestions for patterns of care and referral for
discussion:
Age: 16 years and under
Place of Care: treated as children and referred to St James’s University Hospital.
Treatment Team: Paediatric haematologist and paediatric oncology MDT and TYA Service as
appropriate.
Protocol: Paediatric.
Age: 17 – 18 years
Number of patients in 2004 from networks: 7
Place of Care: There is an expectation that patients requiring in patient chemotherapy will be treated
in the Teenage Cancer Unit, SJUH. Patients requiring outpatient chemotherapy will be managed using
a shared care arrangement with chemotherapy and supportive care delivered locally or in the Teenage
Cancer Unit dependant on the patient’s needs and the facilities available to meet those needs. The
patients will be reviewed at a MDT meeting in Leeds. The patient will visit the Teenage Cancer Unit,
SJUH and choose whether to have their chemotherapy delivered locally or in Leeds.
Treatment Team: To be decided after discussion with the referring Consultant, paediatric
haematologist and TYA Service.
Protocol: Jointly discussed between referring consultant and paediatric haematologist/oncologist. The
protocol should be chosen considering the biology of the particular haematological malignancy.
Age: 19 – 25 years.
Number of patients per year from networks: 16
Place of Care: Adult Haematology Unit, unless it is considered that patient would benefit from the
Teenage Cancer Unit because of maturity and circumstances, when the patient could then be given a
choice.
Treatment Team: Adult haemato-oncology with psycho-social support from the TYA Service.
Protocol: For most patients adult protocols will be used but the protocol should be chosen
considering the biology of the particular haematological malignancy. For patients with cancers that
occur most commonly in the paediatric age group, management should be jointly discussed between
referring consultant and paediatric haematologist/oncologist.
To facilitate care:
• Each young person and their family should have a ‘key worker’ who would maintain close
liaison between all Consultants and Clinical Nurse Specialists involved in the patients care.
They would be responsible for the co-ordination of the supportive care. The key worker may
be a member of the TYAS or local team. This will be a named person and agreed by the
TYAS, local team and MDT.
• Each young person would have a named Consultant from his/her locality and from the TYA
unit or adult haematology services in Leeds as appropriate.
• For patients from any locality receiving treatment in Leeds, the consultant responsible for the
patient’s care, i.e. adult or paediatric haematologist/oncologist, will be determined by the
patient’s age and treatment protocol being used.
• Each young person would have a named Clinical Nurse Specialist from his/her locality and
from the TYA unit.
Guidelines for the Management of Haematological Malignancies
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• It is envisaged that relevant staff from the patient’s local haemato-oncology service and TYA
unit would attend MDT meetings where the patient’s management is being discussed.
• It would be helpful, where feasible, for staff from the patients’ localities to visit patients having
inpatient treatment in Leeds and vice versa.
Other Developments
A nine bedded young people’s unit, with a 3 bed Day Care area and consulting room is planned for the
new Oncology Building, along side Adult services, when it opens in 2007/8. The position of this Unit is
central to the other Wards and it is anticipated that it will be used for those patients aged 18 years +.
However, this has yet to be formalised. There is a vision that the young people would be cared for on
a day–to-day basis by a multidisciplinary team combing the expertise of the TYAS and tumour site
specialists.
An NCRI/N group has just been given the go-ahead which will assess the epidemiology of TYA
malignancy, set up a national register, and promote the participation of TYA into Clinical Trials. This
national initiative has been led by a team from Leeds.
23.1 Leeds Teenage And Young Adult Service
REFERRAL CRITERIA
Aged between 13 and 24 years with a diagnosis of a haematological or solid tumour malignancy.
AIMS
• To communicate with the patient/family within 2 working days of referral. The patient/families
are contacted and a meeting is arranged to discuss any issues with which they may need
help. This may be in the form of psychosocial support and/or financial, educational,
employment or relationship advice, facilitating access to professionals who are able to answer
any questions about their disease and treatment.
• To liaise with the professionals who are caring for the patient, to help with any developing
issues. To be the ‘Key Worker’ where necessary.
• To offer a place of contact for any help, either practical or social, five days a week.
• To offer visits from the team whilst the patient is hospitalised.
• To attend outpatient appointments with the patient, to help explain any difficult issues or for
moral support, if required.
• To be their advocate
• To access a local network of young people with cancer and their families.
• To offer bereavement follow-up to the family, where necessary. This may include attending the
funeral to represent the hospital, home visits and, if necessary, return visits to the hospital to
discuss any unresolved issues with the medical staff. There is also a bereavement support
group for families, partners and friends.
Contacts:
• Sue Morgan Macmillan Clinical Nurse Specialist in TYA
• Sally Burnell Oncology Nurse Specialist for TYA
• Simon Pini Learning Mentor - Emma Maltby Memorial Trust
• Sarah Horvath Social Worker – Sargent Cancer Care
• Sarah Grant Candlelighters’ Activity Co-ordinator
• To be appointed in May ‘05 Macmillan Clinical Psychologist
Tel: 0113 2066204/5/6
Email: tya.service@leedsth.nhs.uk
Guidelines for the Management of Haematological Malignancies
24. GUIDELINES FOR CONVENTIONAL CYTOGENETIC ANALYSIS IN ADULT PATIENTS WITH HAEMATOLOGICAL
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24 Guidelines for conventional cytogenetic
analysis in adult patients with
haematological malignancies
These proposals have been developed following an extensive audit of previous practice which was
precipitated by a large backlog of specimens and unacceptable reporting times.
These guidelines follow a number of basic principles
• Cytogenetics should only be performed in patients with an established diagnosis when it is
considered that it will produce relevant information that will guide therapy.
• Cytogenetics are of limited value in establishing/ confirming a diagnosis. The primary
exceptions to this are CML and APML where the diagnosis relies upon the demonstration of a
specific chromosomal translocation. In most instances cytogenetics is used to demonstrate
prognostically relevant abnormalities only.
• It is not good practice to base a diagnosis entirely on the karyotype. If an abnormal karyotype
is seen in a patient with equivocal pathology or a poor quality specimen then a repeat
assessment is indicated.
• When it is necessary to look for specific abnormalities it may be more appropriate to use
alternative techniques such as FISH and PCR as they have a higher pick up rate but are also
cheaper and less time consuming.
24.1 B-cell lymphoproliferative disorders including myeloma
The key points to consider are:
• The incidence of abnormal karyotypes is very low.
• Conventional karyotyping frequently misses key abnormalities such as the t(11;14) and
t(14;18).
• FISH studies are now routinely used to demonstrate the following abnormalities when
required: trisomy 12, del 13q, del 17p, del 11q, t(11;14) and t(14;18).
Conventional karyotyping is not therefore indicated in these patients.
24.2 Chronic myeloproliferative disorders
The key points are:
• The incidence of abnormal karyotypes is very low.
• No evidence for the t(9;22) by karyotyping or RT-PCR in the retrospective audit.
Conventional karyotyping and RT-PCR analysis for the t(9;22) is not indicated in these patients.
24.3 Acute lymphoblastic leukaemia
The incidence of karyotypic abnormalities in this setting is high but in most cases their significance is
unclear. The t(9;22) is the exception but this can be demonstrated by RT-PCR analysis.
Conventional karyotyping is not indicated, but all cases should be assessed by RT-PCR for the
t(9;22).
Guidelines for the Management of Haematological Malignancies
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24.4 Acute Myeloid leukaemia
There are a number of key factors to consider in this setting:
• Cytogenetic analysis should be performed in all patients in whom intensive/ curative therapy is
envisaged. In older patients, as Low dose Ara-C ineffective in older AML with adverse
karyotype, it can be done but karyotype is not mandatory for AML16
• Cytogenetic analysis has strong prognostic value in morphological remission setting
(Bloomfield JCO 2004) as 12% patients in morphological CR had residual abnormal
cytogenetics which indicates poorer prognosis.
• Relapse karyotype is very frequently different from diagnostic karyotype and this influences
response to relapse therapy .So karyotype is important in relapse
• The prognostically relevant balanced translocation is demonstrable by RT-PCR and
immunofluorescence in the case of the t(15;17).
• Internal tandem duplications (ITD) of Flt3 have a considerable impact on outcome. This is now
routinely evaluated in all younger patients with AML.
It is therefore proposed that conventional karyotyping is a minimum diagnostic criterion for the initial/
diagnostic evaluation of patients aged 70 years or less, and that this is supplemented by PCR for the
balanced translocations and Flt3 ITD. It is useful in assessing the remission status and at relapse and
also in patients who is to be started on Low dose Ara-C.
24.5 Myelodysplastic syndromes
The key points to consider are:
• The WHO criteria for the diagnosis of MDS are based upon morphological assessment and
cytogenetics (for 5q- MDS) [WHO revision conference in Feb 2007]
• Adverse karyotype may have greater significance than blast count in determining the overall
outcome [Haase ASH 2006]
• It is very important to identify the 5q- given success of Lenalidomide therapy
• An IPSS score cannot be produced without karyotype which is the gold standard
prognostication system and the management of MDS is guided by IPSS score
• Preliminary data suggest that chr 7 abnormalities respond to DMT inhibitors and DMT
inhibitors produce karyotypic response in complex / adverse karyotypic patients
It is therefore proposed that all patients with morphological diagnosis of MDS must have a cytogenetic
analysis.
24.6 Chronic myeloid leukaemia
The key points are:
• The t(9;22) is demonstrable by FISH and RT-PCR as well as karyotyping.
• Conventional karyotyping on bone marrow aspirate specimens remains the conventional
means to evaluate response in Imatinib and interferon treated patients, although it is
envisaged that interphase FISH on peripheral blood will supersede this in due course.
• The role RT-PCR in the assessment of Imatinib treated patients has not been established.
It is therefore proposed that:
• Patients will be assessed at presentation by cytogenetics and RT-PCR.
• Bone marrow cytogenetics will be used to assess response to Imatinib and interferon.
• RT-PCR analysis is used to monitor residual disease following allogeneic transplant only. It is
not currently available for the assessment of patients receiving Imatinib or interferon.
Guidelines for the Management of Haematological Malignancies
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25 AUDIT & DATA COLLECTION PROTOCOL
Background
The network group is obliged to carry out a systematic audit of its activities. Audit should be
systematic and cover the main components of diagnosis and treatment of patients within the network.
A network audit group will be established to oversee all audit processes and to prepare an annual
report for the main network group.
Diagnostic Audit
Audit Standards
1. The HMDS diagnostic standard operating procedure. This is reviewed annually. This is
published at www.hmds.org.uk, in booklet form and summarised in the main guidelines.
2. Reporting time: continuously monitored on HILIS database.
Audit Process
1. All specimens sent to HMDS are dual reported. Differences are resolved by consensus. All
discrepancies are logged on HILIS database.
2. All revised diagnosis following MDT meetings are to be logged.
3. External audit arranged annually and report made available to Audit group.
Audit Outcome
Audit group will review changes to diagnostic SOP.
Audit group will consider patterns in diagnostic discrepancies and make recommendations.
Therapeutic Audit
Audit Standard
• Regional Guidelines for the treatment of patients with leukaemia and lymphoma.
Audit Process
1. A copy of all MDT annotations will be sent to HMDS. These will be stored securely.
2. Treatment and prognostic data will be entered on the Network Group database by completing
the appropriate form or direct on line entry.
3. HMDS listing of all new patients in the network.
Audit Outcome
The audit group will report on:
1. The proportion of patients in each diagnostic category who are reviewed at an MDT meeting.
2. How many MDT meetings meet the IOG specification for membership and highlight systematic
deficiencies e.g. absence of radiological support.
3. The proportion of patients treated according to the regional guidelines.
4. Discordance between treatment plan at MDT and actual treatment given.
In 3 and 4 the group will decide on a suitable sample size e.g. 10% of randomly selected new patients.
5. Problems in applying guidelines or where changes in actual practice suggest need for
revision.
Guidelines for the Management of Haematological Malignancies
25. AUDIT AND DATA COLLECTION PROTOCOLS
66

Data Collection
The network is obliged to collect a dataset on all patients. This information is needed for the purposes
of clinical audit and service development. The database may be used for research under the
conditions specified below.
Process of data collection
• With the consent of the network, the LRF Epidemiology Unit at the University of York will
manage data collection.
• All new patients will be identified at diagnosis through the HILIS system at HMDS. A record
will be generated automatically on the regional database.
• Datasets will be determined by the audit and data collection group.
• Data to be collected will be defined using a standard operating procedure.
Access to Data
• Access to data will comply with NHS regulation and the Data Protection Acts.
• All data will be held on a secure server within the NHS network using NHSIA standards.
• Consultant members of the network and those directly involved in data collection will have full
access to the database. Access for others will be reviewed by the audit and data collection
group.
Use of the Database for Research
• All research studies will use a parallel database from which the patient name and other unique
identifiers have been removed.
• All research material – tissue specimens, computer files, etc- will be linked to the research
database by a code number assigned automatically. It will not be possible for researchers to
trace the patient ID using the code in the main open database.
• Consent will be required to use any information or tissue specimens for research. A network
wide system for managing consent will be established.
• All studies will need ethics and management approval.
• The audit and data collection group will review all studies.
Composition of the Audit and Data Collection Group
1. The group will have one member from each MDT, the chair and deputy chair (who may also
represent a MDT) of the network group, one member from HMDS, one member from the LRF
Epidemiology Unit and a consultant clinical oncologist. If a member of the group cannot
attend the MDT, another consultant should represent him/ her.
2. Meetings will be held every three months following the main network meeting.
The group will prepare an annual network audit report covering all the above topics, to be circulated to
the main group. If the audit identifies an area of practice in which one MDT is significantly divergent
from the group as a whole, all members of that MDT or department will be invited to comment before
inclusion in a report and their responses included alongside the data in the final report.
The group will be responsible for supervising the process of revision of these guidelines.
Guidelines for the Management of Haematological Malignancies
25. AUDIT AND DATA COLLECTION PROTOCOLS
67

26 Chemotherapy Regimens
Refer to network protocols.
No dose capping at 2m2, except in clinically obese patients. In this situation ideal body weight should
be used.
Surface area calculation is:
SA = √ (Ht (cm) x Wt (Kg)/3600)
Allopurinol need only be given with first courses of chemo therapy.
26.1 The International Prognostic Index (IPI)
The IPI describes a predictive model for patients with non-Hodgkin’s lymphoma based on 5 clinical
features at presentation.
FEATURE SCORE 0 SCORE 1
Age ≤ 60 years > 60 years
Ann Arbor Stage I/ II III/ IV
Serum LDH Normal Elevated
Extranodal site ≤ 1 site > 1 site
Performance status 0, 1 2-4
An age-adjusted index for patients aged < 60 years of age is also described, based on stage, LDH
and performance status. Patients can be divided into four prognostic categories based on these
factors:
Guidelines for the Management of Haematological Malignancies
26. CHEMOTHERAPY REGIMES
Number of risk factors
IPI risk group All patients Age adjusted IPI
Low-risk 0,1 0
Low/intermediate-risk 2 1
High/intermediate-risk 3 2
High-risk 4,5 3
68

27 FLIP Index for Follicular Lymphoma (FLIPI)
Score 1 for each of the following:
• Age > 60 years
• Hb 4
FLIPI Risk Group Score
Good 0-1
Intermediate 2
Poor ≥ 3
Guidelines for the Management of Haematological Malignancies
27. FLIP INDEX FOR FOLLICULAR LYMPHOMA
69

28 ANN ARBOR STAGING CLASSIFICATION
FOR NHL
Stage Area of involvement
I One lymph node region
IE One extralymphatic (E) organ or site
II Two or more lymph node regions on the same side of the diaphragm
IIE One extralymphatic organ or site (localised) in addition to criteria for stage II
III Lymph node regions on both sides of the diaphragm
IIIE One extralymphatic organ or site (localised) in addition to criteria for stage III
IIIS Spleen (S) in addition to criteria for stage III
IIISE Spleen and one extralymphatic organ or site (localised) in addition to criteria for stage III
IV One or more extralymphatic organs with or without associated lymph node involvement (diffuse or
disseminated); involved organs should be designated by subscript letters (P, lung; H, liver; M,
bone marrow)
A = asymptomatic
B = symptomatic unexplained fever of ≥38.6ºC [101.5oF];
unexplained, drenching night sweats; or
loss of > 10% body weight within the previous 6 months.
Guidelines for the Management of Haematological Malignancies
28. ANN ARBOR STAGING CLASSIFICATION FOR NHL
70

29 BINET DISEASE STAGE FOR CLL
STAGE ORGAN ENLARGEMENT* Hb**(g/dl) Platelets (x10 9 /l)
A 0, 1 or 2 areas ≥10 ≥100
B 3, 4 or 5 areas ≥10 ≥100
C Not considered

30 INTERNATIONAL HODGKIN LYMPHOMA
PROGNOSTIC SCORE:
1. Age >45 years
2. Male
3. Stage IV
4. Hb

31 ECOG PERFORMANCE STATUS
Grade ECOG
0 Fully active, able to carry on all pre-disease performance without restriction
1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a
light or sedentary nature, e.g., light house work, office work
2 Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and
about more than 50% of waking hours
3 Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours
4 Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair
5 Dead
Guidelines for the Management of Haematological Malignancies
31. ECOG PERFORMANCE STATUS
73

32 KARNOFSKY PERFORMANCE STATUS
SCALE
The Karnofsky Performance Scale Index allows patients to be classified as to their functional
impairment. This can be used to compare effectiveness of different therapies and to assess the
prognosis in individual patients. The lower the Karnofsky score, the worse the survival for most
serious illnesses.
DEFINITIONS RATING (%) CRITERIA
Normal no complaints; no evidence of
100
disease.
Able to carry on normal activity and to work; no Able to carry on normal activity; minor
90
special care needed.
signs or symptoms of disease.
Normal activity with effort; some signs
80
or symptoms of disease.
Cares for self; unable to carry on
70
Unable to work; able to live at home and care for
most personal needs; varying amount of assistance 60
needed.
Guidelines for the Management of Haematological Malignancies
32 Karnofsky performance status scale
50
40
normal activity or to do active work.
Requires occasional assistance, but is
able to care for most of his personal
needs.
Requires considerable assistance and
frequent medical care.
Disabled; requires special care and
assistance.
Severely disabled; hospital admission
30 is indicated although death not
Unable to care for self; requires equivalent of imminent.
institutional or hospital care; disease may be Very sick; hospital admission
progressing rapidly.
20 necessary; active supportive
treatment necessary.
Moribund; fatal processes progressing
10
rapidly.
0 Dead
74

33 WEBSITES
UK Websites
HMDS www.hmds.org.uk
BSH www.b-s-h.org.uk
BCSH Guidelines www.BCSHguidelines.com
Lymphoma Association www.lymphoma.org.uk
UK Myeloma Foundation www.ukmf.org.uk
CancerBACUP www.cancerhelp.org.uk
Cancer Research UK www.cancerresearchuk.org
Leukaemia Research Fund www.leukaemia-research.org.uk
BNLI Details NCRI Trials www.ncrn.org.uk
BNLI CRC and UCL Cancer Trials Centre
222 Euston Road
London
NW1 2DA
Tel: 020 7679 8060
Fax: 020 7679 8061
Contact person: Paul Smith
Tel: 020 7679 8062
Overseas Websites
Lymphoma Research Foundation www.lymphoma.org
Lymphoma Foundation Canada www.lymphoma.ca
NHLBCELL www.NHLBCELL.org
Lymphoma Information Network www.lymphomainfo.net
Oncolink www.oncolink.com
Guidelines for the Management of Haematological Malignancies
33 Website
75

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35 Appendices
DRAFT
Haematological Malignancies
NSSG
Date Approved:
Review Date:
Imaging Guidelines
Developed by the Network Imaging Group
Chairperson : Dr G Avery
Guidelines for the Management of Haematological Malignancies
35. Appendices
81

Introduction
‘A Guideline is not a rigid constraint upon clinical practice, but a concept of good practice
against which the requirements of the individual patient can be considered’. (RCR, 1990).
It therefore remains the responsibility of the practising Clinicians to interpret the application
of guidelines, taking into account local service constraints and the needs and wishes of the
patients.
This Guidance is based on the recommendations contained in:
1. Yorkshire Cancer Network and Humber and Yorkshire Coast Cancer Network –
Guidelines for the Management of Haematological Malignancies, Version 2 -
published 2006.
2. The Royal College of Radiologists – Recommendations for Cross-Sectional
Imaging in Cancer Management, Issue 2 – published August 2006.
Lymphoma
Diagnosis and Staging
All patients with lymphoma should be imaged for staging. Routine staging should include the
chest, abdomen and pelvis. The neck should be scanned if there are neck nodes at
presentation.
There is one exception in cutaneous lymphomas. When a histological diagnosis of Mycosis
Fungoides has been made a CT scan should only be carried out under the following
circumstances:
• In Sezary syndrome
• In CD30 negative large cell CTCL
• With clinically or pathologically involved glands
• Prior to chemotherapy or radiotherapy.
CT is the main staging technique, with MRI the investigation of choice for suspected CNS,
musculoskeletal and marrow involvement.
Assessment of Treatment
CT is used to monitor the response to treatment; usually this will be requested to be
performed after 3-4 cycles of chemotherapy and depending upon the response further imaging
after 6 or 8 cycles.
The scan should include chest, abdomen and pelvis. Neck disease can usually be assessed
clinically during treatment.
In young patients with Hodgkin’s Disease where disease at staging is confined to the
mediastinum, reassessment examinations limited to the thorax are adequate between courses
of chemotherapy with imaging of the chest, abdomen and pelvis at the end of treatment or
pre-autograft.
Follow-up
There are no guidelines for routine imaging.
Guidelines for the Management of Haematological Malignancies
35. Appendices
82

CT:
Routine staging should include the chest, abdomen and pelvis. The neck should be scanned if
there are neck nodes at presentation.
The scan should be performed to the standards within the document - The Royal College of
Radiologists – Recommendations for Cross-Sectional Imaging in Cancer Management.
Local policy is that all scans will be performed with oral and intravenous contrast, whether for
initial diagnosis/staging or monitoring of treatment.
Information of help in evaluating the CT scans:
Lymph node size at various anatomic sites:
short axis diameter, upper limits of normal
Site Group Short axis size (mm)
Head and Neck Facial
Cervical
Guidelines for the Management of Haematological Malignancies
35. Appendices
Not visible
10(

Bulky disease should only be reported if there is a mass > 10cm maximum diameter on the
CT scan.
Local agreement is for splenic size to be measured in the craniocaudal dimension.
A residual mass is generally defined as a post-treatment mass greater than 1 cm in diameter,
but in Hodgkin’s lymphoma and non-Hodgkin’s lymphoma a residual mass is classified as a
nodal mass 1.5 cm in diameter or greater.
Cheson BD, Horning SJ, Coiffier B, et al. Report of an international workshop to standardize
response criteria for non-Hodgkin’s lymphomas. NCI Sponsored International Working
Group. J Clin Oncol 1999; 17: 1244.
WHO criteria – Definitions of objective response
Complete response (CR) Disappearance of all known disease
Partial response (PR) 50% or more decrease in total tumour load(single or
multiple lesions, bidimesional or unidimensional
measurement)
No change (NC) 50% decrease or 25% increase not established
Progressive disease (PD) 25% or more increase in the size of measurable lesion
or appearance of new lesions
The RECIST (Response Criteria in Solid Tumours) criteria are designed to be used in clinical
trials, for further discussion on the use of these in reporting please see:
The Royal College of Radiologists – Recommendations for Cross-Sectional Imaging in
Cancer Management, Issue 2.
The vast majority of current clinical trials use RECIST as the standard. A practical approach
is summarised below:
• Unidimensional assessment.
• Measurement of up to ten lesions to determine response
• Note that no measurements are necessary if a new metastatic lesion is seen, as this is
unequivocal disease progression.
If a patient is within a clinical trial which requires a change to the routine performance of the
investigation or the scan to be reported against specific criteria it is the responsibility of the
referring clinician to discuss and agree the scanning protocols (including frequency,
techniques, coverage and reporting) with the radiology department prior to the trial
commencing.
MRI:
This is the investigation of choice for suspected involvement of CNS, musculoskeletal and
marrow. Examinations should be performed to local protocols and with reference to the
guidance issued by the Royal College of Radiologists.
PET-CT
PET-CT has not been routinely included in the guidelines for the management of lymphoma
in the Humber and Yorkshire Coast Cancer Network. All cases in which it is thought that a
PET-CT scan would affect clinical management should be discussed at the MDT.
Guidelines for the Management of Haematological Malignancies
35. Appendices
84

Multiple Myeloma and Related Disorders
All patients with suspected plasma cell disorders require a skeletal survey.
The UK Myeloma forum and the Nordic Myeloma Study Group have issued
recommendations for the use of imaging in Myeloma:
Guidelines on the diagnosis and management of multiple myeloma 2005 British Journal of
Haematology
Vol. 132 Issue 4 Page 410 February 2006
Alastair Smith, Finn Wisloff, Diana Samson, the UK Myeloma Forum, Nordic Myeloma
Study Group and British Committee for Standards in Haematology.
Their recommendations are as follows:
• Skeletal survey should be part of the staging procedure of newly diagnosed myeloma
patients and should include a postero-anterior (PA) view of the chest, antero-posterior
(AP) and lateral views of the cervical spine (including and open-mouth view), thoracic
spine, lumbar spine, humeri and femora, AP and lateral view of the skull and AP view
of the pelvis. In addition, any symptomatic areas should be specifically visualised
with appropriate views (grade C recommendation; level IV evidence).
• CT should be used to clarify the significance of ambiguous plain radiographic
findings, such as equivocal lytic lesions, especially in parts of the skeleton that are
difficult to visualise on plain radiographs, such as ribs, sternum and scapulae (grade B
recommendation; level III evidence).
• CT should also be used to examine symptomatic areas of the skeleton where no
pathological lesion is found on the skeletal survey (grade B recommendation; level
III).
• CT or MRI is indicated to delineate the nature and extent of soft tissue disease and
these two imaging techniques can give complementary information (grade B
recommendation; level III evidence).
• Tissue biopsy may be guided where appropriate by CT scanning (grade B
recommendation; level III evidence).
• MRI is the technique of choice for investigation of patients with a neurological
presentation suggestive of cord compression (grade B recommendation; level IIB
evidence).
• MRI of the whole spine should be performed in patients with an apparently solitary
plasmacytoma of bone irrespective of site of the index lesion (grade C
recommendation; level IV evidence).
• Bone scintigraphy has no place in the routine investigation of myeloma (grade C
recommendation; level IV evidence).
Guidelines for the Management of Haematological Malignancies
35. Appendices
85

• DEXA scanning has no role in the routine management of myeloma (grade C
recommendation; level IV evidence).
Leukaemia, Myelodysplastic and Myeloproliferative Syndromes/Disorders
Acute Myeloid Leukaemia and Precursor Cell Lymphoblastic Leukaemia in Adults
All patients require a Chest x-ray at time of diagnosis
Chronic Myeloid Leukaemia
Ultrasound of the abdomen should be considered to document spleen size
Chronic Myeloproliferative Disorders
Ultrasound of the abdomen to assess spleen and liver
Management of systemic fungal infection in immunocompromised patients
There are separate guidelines for the management of suspected fungal infections, produced by
Dr Ali, Consultant Haematologist at Hull and East Yorkshire NHS Trust, from which the
following advice has been taken:
1 A normal CXR does not exclude SFI.
2 Patients with one or more host factors consistent with SFI ( IFICG/MSG
diagnostic criteria and nodules on plain CXR should receive antifungal
therapy, and should be investigated further.
3 Patients with one or more host factors consistent with SFI ( IFICG-MSG
diagnostic criteria should receive antifungal therapy if the CT halo sign is seen,
unless there is an alternative explanation for its presence.
4 Patients with one or more host factors consistent with SFI (IFICG-MSG
diagnostic criteria should receive antifungal therapy if cavitation and or the air
crescent sign are seen on CT.
5 Any patient should have an immediate CT scan if they have one or more host
factors consistent with SFI and clinical or microbiological criteria which would
support a diagnosis of probable or possible SFI ( IFICG/MSG diagnostic
criteria.
6 Where IPA (invasive pulmonary aspergillosis) is suspected, HRCT should be
undertaken with slices of 1 mm (1 mm collimation), either at regular 1 cm
intervals, or through suspicious lesions detected previously on CT.
7 Axial and coronal CT of the sinuses and surrounding structures should be
undertaken immediately on clinical suspicion of sinus infection.
Guidelines for the Management of Haematological Malignancies
35. Appendices
86

Host factor, Microbiological and clinical criteria for invasive fungal infection in patients with cancer or recipient of
haematopoietic stem cell
36 Type of criteria 37 Criteria
38 Host Factors 1. Neutropenia (10 days)
2. Persistent fever>96 hours refractory to broad spectrum
antibacterial treatment
3. Temp >38 or 10days
b. The use of immunosuppressive agents in previous30
Guidelines for the Management of Haematological Malignancies
35. Appendices
days
c. Proven or probable IFI during previous episode of
neutropenia
d. Coexistence of symptomatic AIDS
4. Signs and symptoms indicating graft-versus- host disease
39 Microbiological 1. +ve culture of mould from sputum or BAL
2. +ve culture or finding of cytologic/direct microscopic
evaluation for mould from sinus aspirate
3. +ve result for Aspergillus antigen in BAL fluid, CSF, or >2
blood samples
4. +ve result for cryptococcal antigen in blood sample
5. +ve findings of cytologic or direct microscopic examination for
fungal element in sterile body fluid sample
6. +ve result for Histoplasma capsulatum antigen in blood, urine,
or CSF
7. 2 +ve results of culture of urine samples for yeasts in absence of
urinary catheter
8. +ve result of blood culture for Candida
Clinical
Lower respiratory tract infection
Major
Minor
Sinonasal infection
Major
Minor
CNS infection
Major
Minor
Disseminated fungal infection
Chronic disseminated candidiasis
Any of the following new infiltrates on CT:
•1 Halo sign
•2 Air-crescent sign
•3 Cavity within area of consolidation
Symptoms of lower respiratory tract infection (cough, chest pain,
haemoptysis, dyspnoea); physical finding of pleural rub; any new
infiltrate or pleural effusion
Suggestive radiological evidence of invasive fungal infection in sinuses
Upper respiratory symptoms (nasal discharge, stuffiness) nose ulceration;
periorbital swelling; maxillary tenderness; black necrotic lesion or
perforation of hard palate
Radiological evidence suggesting CNS infection
Focal neurological symptoms and signs; mental changes; meningeal
irritation findings; abnormalities in CSF biochemistry
Popular or nodular skin lesions without any other explanation; intraocular
findings suggestive of haematogenous fungal chorioretinitis or
endophthalmitis
Small, peripheral, target-like abscesses in liver and/or spleen
demonstrated by CT, MRI or US as well as elevated alkaline phosphatase
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