David Watkins - The Royal Marsden

The Royal Marsden 

Principles of chemotherapy in 

the management of lymphoma 

Dr David Watkins 

Senior Clinical Research Fellow 

at the GI and Lymphoma Unit

Lymphoma outcomes 

100 

% Survival 

80 

60 

40 

one-year 

five-year 

NHL 

England & Wales 

20 

0 

1971-1980 1981-1990 1991-1999 

100 

one-year 

five-year 

% Survival 

80 

60 

40 

Hodgkin lymphoma 

England & Wales 

20 

0 

1971-80 1981-90 1991-99


What has resulted in the improved lymphoma 

outcomes displayed in these figures 

1. Better diagnostic/staging procedures 

2. Better supportive measures (management of toxicities) 

3. Formation of multidisciplinary teams 

4. More effective cytotoxic agents 

5. Conformal radiotherapy


What has resulted in the improved lymphoma 

outcomes displayed in these figures 

1. Better diagnostic/staging procedures 

Available of CT and PET imaging, Histological classification 

2. Better supportive measures (management of toxicities) 

GSCF, Antibiotics, Antiemetics, Tumour lysis, Specialist nurses 

3. Formation of multidisciplinary teams 

Medical/Clinical Oncology, Haematology, Radiology, Pathology 

4. More effective cytotoxic agents 

Limited advances ABVD and CHOP both developed in the 70’s 

5. Conformal radiotherapy


Defining treatment strategies 

• Heterogeneous disease 

- Curative & palliative paradigms 

• Optimal management is heavily dependant on; 

- Correct pathological classification 

- Correct staging 

• Excision biopsy for ‘specialist’ histopathological evaluation 

- Requires assessment of tissue architecture 

• Histological classification is complicated…. 

- Non-Hodgkin Lymphoma 

- Hodgkin Lymphoma

The Royal Marsden

The Royal Marsden

Precursor B-cell lymphoma 

Non-Hodgkin Lymphoma 

Small lymphocytic lymphoma 

Lymphoplasmacytic lymphoma 

Splenic marginal zone lymphoma 

Hairy cell leukaemia 

Plasma cell neoplasms 

Extranodal marginal zone B-cell lymphoma of mucosa-associated 

lymphoid tissue (MALT lymphoma) 

Nodal marginal zone B-cell lymphoma 

Follicular lymphoma (grades 1, 2, 3a and 3b) 

Diffuse follicle centre lymphoma 

Mantle cell lymphoma 

Diffuse large B-cell lymphoma 

Mediastinal (thymic) large B-cell lymphoma 

Intravascular large B-cell lymphoma 

Primary effusion lymphoma 

Burkitt lymphoma 

Hodgkin Lymphoma 

Nodular Sclerosing (Classical) 

Mixed-cellularity subtype 

Lymphocyte-rich or Lymphocytic predominance 

Lymphocyte depleted 

Unspecified 

Cytogenetic 

Abnormality 

t(14;18) 

t(8;14) 

Chromosomal Abnormalities 

Histology 

Follicular 

DLBC 

Burkitt 

lymphoma 

Oncogene 

bcl-2 

c-myc 

B-cell proliferations of 

uncertain malignant potential 

Precursor T- and NK-cell 

lymphomas 

Mature T-cell and NK-cell 

lymphomas 

Lymphomatoid granulomatosis 

Post-transplant lymphoproliferative disorder, polymorphic 

Precursor T lymphoblastic lymphoma 

Blastic NK-cell lymphoma 

T-cell prolymphocytic leukaemia 

T-cell large granular lymphocytic leukaemia 

t(11;14) 

t(11;18) 

Mantle cell 

lymphoma 

MALT 

lymphoma 

Cyclin-D1 

Unknown 

Aggressive NK-cell leukaemia 

Adult T-cell lymphoma/leukaemia 

Extranodal NK-/T-cell lymphoma, nasal type 

Enteropathy-type T-cell lymphoma 

Hepatosplenic T-cell lymphoma 

Subcutaneous panniculitis-like T-cell lymphoma 

Mycosis fungoides 

Peripheral T-cell lymphoma unspecified 

Angioimmunoblastic T-cell lymphoma 

Anaplastic large cell lymphoma


Lymphoma classification 

Indolent 

Indolent 

Non-Hodgkin lymphoma 

– Diffuse large B cell lymphoma 31 % 

– Follicular lymphoma 22 % 

– (MALT) lymphoma; nodal/extra nodal marginal zone lymphoma 9 % 

– Small lymphocytic lymphoma/B-CLL 7 % 

– Mantle cell lymphoma 6 % 

– Peripheral T cell lymphoma, unspecified 4 % 

– Mediastinal (thymic) large B cell lymphoma 3 % 

– Burkitt lymphoma 2 % 

– Anaplastic large cell lymphoma 2 % 


― Nodular Sclerosing 

– Mixed-cellularity subtype 

– Lymphocyte depleted 

– Lymphocyte-rich or Lymphocytic predominance 

~15% of all lymphomas


Lymphoma work-up 

• CT – Neck, Thorax, Abdo, Pelvis 

• PET/CT 

- More sensitive than CT imaging 

- Role in staging and response assessement 

• Bone marrow aspiration and trephine 

• Bloods 

- LDH, paraproteins, β2 microglobulin, HIV, Hep B,C 

• Lumbar puncture 

- In patients considered at risk of CNS involvement


Chemotherapy naming conventions 

Chemotherapy treatment often involves a combination of 

cytotoxic drugs &/or antibody therapy 

R-CHOP 

R ituximab 

C yclophosphamide 

H ydroxydaunorubicin (doxorubicin) 

O ncovin (vincristine) 

P rednisolone 

CVP 


V incristine 

P rednisolone 

Gem-P 

Gem Gemcitabine 

P latinium (Cisplatin) 

Methyl Prednisolone 

CODOX-M / IVAC 

C cyclophosphamide 


Do xorubicin 

M ethotrexate 

I fosphamide 

V P-16 (etoposide) 

A ra-C (Cytarabine) 

ABVD 

A driamycin (doxorubicin) 

B leomycin 

V inblastine 

D acarbazine (DTIC)


Treatment defined by stage and intent


Curative strategy for limited stage disease 

Radiotherapy 

Chemotherapy 

Achieving cure with 

lowest long-term 

toxicity


Curative strategy for advanced disease 

Radiotherapy 

Chemotherapy 

Maximising cure at 

expense of higher 

long-term toxicity


Balancing Risks vs Benefits 

In addition to disease stage, clinical features allow an 

assessment of risk of treatment failure 

Lower Risk 

Risk of treatment failure 

Higher Risk 

DLBC 

Hodgkin 

Follicular 

International Prognostic Index 

Hasenclever index 

Follicular Lymphoma IPI


Balancing Risks vs Benefits 

The aim is to be able to tailor treatment accordingly 

Lower Risk 

Risk of treatment failure 

Higher Risk 

DLBC 

R-CHOP 

CODOX-M/IVAC 

Hodgkin 

ABVD 

BEACOPP 

Follicular Watch and Wait 

R-CHOP 

Treatment toxicities 

Methods to better select patients and individualise treatment are 

under ongoing evaluation


What is the most likely diagnosis 

25 yr old women presents with a 6/52 history of R 

cervical lymphadenopathy and 1/52 history of chest 

tightness. Otherwise well. 

1. DLBC lymphoma with pulmonary involvement 

2. Follicular lymphoma 

3. Hodgkin lymphoma with mediastinal nodal mass 

4. Hodgkin lymphoma with pulmonary involvement


What is the most likely diagnosis 

25yr old women presents with a 6/52 history of R 

cervical lymphadenopathy and 1/52 history of chest 

tightness. Otherwise well. 

–3. Hodgkin lymphoma with mediastinal nodal mass – 

- Bulky stage IIA disease, ~90% 5yr survival 

Management Priorities 

1. Achieve curative outcome 

2. Minimise long-term morbidity 

3. Consider fertility preservation



Hodgkin lymphoma is the 

third most common cancer 

diagnosis in people aged 15-29 

years 

Chemotherapy related 

toxicities may significantly 

impact on later life 

Pulmonary toxicities 

Infertility/early menopause 

Bone density 

Cardiac toxicities 

Secondary malignancies 

Psychological impact



ABVD 

Adriamycin (doxorubicin) 

Bleomycin 

Vinblastine 

Dacarbazine 

Given by IV injection on 

day 1 and day 15 

Repeated every 28 days



ABVD 

Adriamycin (doxorubicin) 

Bleomycin 

Vinblastine 

Dacarbazine 

Given by IV injection on 

day 1 and day 15 

Repeated every 28 days 

Developed in the 1970’s and remains the standard of care 

Response usually rapid. CT imaging undertaking every 2 cycles 

Stage I/IIA 

Typical treatment would consists of 2 - 4 cycles of ABVD followed by 

radiotherapy to sites of disease involvement 

Survival rates of 90-95% 

Stage IIB-IV 

Typical treatment would consists of 6-8 cycles of ABVD and possible 

radiotherapy to bulky sites 

~30% will suffer disease relapse with 5 years survival rates of 80-90%



ABVD side effects 

– Neutropenic sepsis 

– Congestive cardiac failure 

– Pulmonary fibrosis 

– Thromboembolism 

– Infertility – ABVD carries a low risk of causing infertility 

– Teratogenic - Contraception 

– Early Menopause 

– Numbness or tingling in hands or feet 

– Fevers and chills


ABVD specific toxicities 

Vinblastine 

- Peripheral and autonomic neuropathy 

Doxorubicin 

-High risk of congestive cardiomyopathy 

with cummulative dose of doxorubicin 

> 550 mg/m² (50mg/m 2 per cycle) 

Bleomycin 

- Associated with risk of pulmonary fibrosis 

- Risk factors: Cumulative dose 

Age 

Poor renal function 

Pulmonary disease 

Lung radiotherapy


Fertility preservation 

Men 

Sperm Cryopreservation 

Women 

Egg/Embryo/ovarian tissue cryo preservation 

- Eggs collected after ovulation induction. This process 

requires 3-4 weeks. 

- The risk and benefits in each individual case needs to be 

discussed. 

Need to consider the potential for more intensive 

chemotherapy treatments if primary chemotherapy fails


Other Hodgkin lymphoma regimens 

BEACOPP 

B leomycin 

E toposide 

A driamycin (doxorubicin) 



P rocarbazine 

P rednisolone 

More effective than ABVD in high-risk patients 

Also more toxic, associated with 

- Infertility 

- Increase rate of secondary malignancies 

Concerns relating to toxicity have limited widespread use


Risk of second malignancies 

Relative risk 

Time at risk 

Sites at risk 

Chemotherapy 

alone 

2.0 

(95%CI 1.7-2.4) 

Peaks 5-9 years 

Nil > 15 years 

Lung 

NHL 

Leukeamia 

Combined 

modality 

3.9 

(95%CI 3.5-4.4) 

0-4 years to 

> 20 years 

In addition 

Colon 

NM Skin 

Breast 

Leukaemia risk and all-malignancies risk increased strongly with 

number of cycles of alkylating chemotherapy


Novel approaches in Hodgkin lymphoma 

Current standard of care 

6-8 cycles ABVD 

All patient receive 

therapy based on clinical 

factors, 

as a result: 

Proportion over-treated 

Proportion under-treated


Novel approaches in Hodgkin lymphoma 

Currently under investigation: RATHL study 

6-8 cycles ABVD 

2 cycles ABVD 

PET 

scan 

Stage IIB-IV 


All patient receive 

identical therapy, 

as a result: 

Proportion over-treated 

Proportion under-treated 

PET +ve 

PET -ve 

Randomised 

BEACOPP 

ABVD x4 

AVD x4


R-CHOP 

High grade NHL / DLBC 

Given by IV injection 

with oral prednisolone 

R ituximab 

(d1-5) 


Repeated every 21 days 



P rednisolone 

CHOP developed in the 1970’s 

Rituximab (anti- CD20 antibody) 

demonstrated benefit in 2002 

R-CHOP-21 current standard of care

R-CHOP specific toxicities 

R-CHOP R ituximab side effects 




P rednisolone 

Flu-like symptoms 

Low blood pressure 

Allergic reactions 

Flushing 

Haemorrhagic cystitis 

Infertility / premature menopause 

Congestive cardiac failure 

Tingling in hands or feet 

Constipation 

Gastritis 

Increased appetite 

Raised blood sugar 

Fluid retention 

Behavioural changes 

Neutropenic sepsis 

Nausea and vomiting 

Tiredness 

Skin & nail changes 

Thromboembolism 

Hair loss 

Mucositis 

Altered taste 

Specialist nurses play a 

crucial role in the 

outpatient management 

of lymphoma patients


How confident are you managing patients 

receiving cytotoxic chemotherapy 

1. I rarely review patients receiving chemotherapy but may on 

occasion contact the hospital team for advice 

2. I feel confident in managing patients and know when to refer to 

the hospital 

3. I am often uncomfortable reviewing patients on chemotherapy 

and struggle to get advice from the hospital teams 

4. I discuss a significant proportion of cases with the hospital team


High grade NHL / DLBC lymphoma 

Treatment plan dependant on risk factors: 

- Disease bulk 

- International prognostic index 

Stage I/IIA 

3 cycles (R) –CHOP plus involved field radiotherapy 

or 

6-8 cycles R-CHOP 

Stage II-IV 

6-8 cycles R-CHOP +/- radiotherapy 

Possible intrathecal chemotherapy for CNS prophylaxis


Developments in DLBC lymphoma 

Delivery of CHOP chemotherapy every 14 days has been 

shown to be more effective than delivery every 21 days 

It is not currently known if R-CHOP 14 is better than R- 

CHOP 21 

Stage IIB - IV 

Randomise 

6x 

R-CHOP-14 

8x 

R-CHOP-21


Risk adjusted treatment strategies in DLBC 

Studies are examining the use of more intensive chemotherapy regimens in 

patients at higher risk for relapse 

Aim to reduce relapse risk but only expose a limited number of patients to 

increased toxicity 

International prognostic index 

Age (>60) 

Ann Arbor stage 

(III/IV) 

Performance Status (≥2) 

Serum LDH 

(>ULN) 

Number of extranodal sites (>1) 

Lower risk 

Stage II - IV 

Higher risk patients 

Stage III/IV 

6-8x 

R-CHOP-21 

R- CODOX-M 

IVAC


Management of relapsed disease 

– Bone marrow transplantation often considered 

– Non-cross resistant chemotherapy regimens may be 

utilised to re-induced remission prior to bone marrow 

transplant 

– Platinum based 

- Gem- P (gemcitabine, cisplatin, methylprednisolone) 

- ESHAP (etoposide, methylprednisolone, cytarabine, cisplatin) 

- DHAP (dexamethasone, cisplatin, cytarabine) 

– Ifosfamide based 

- IVE (Ifosfamide, etoposide, epirubicin) 

- ICE (ifosfamide, etoposide, carboplatin) 

- IVAC (ifosfamide, etoposide, cytarabine)


Low Grade NHL 

– Considered incurable (some exclusions; stage 1 and MALT) 

– Often indolent behaviour with slowly progressing disease and 

median survival ~10-12 years 

– May develop transformation to high-grade disease 

– Treatment of low-grade lymphoma often less intense including 

observation alone 

– Patients will receive multiple lines of therapy during the course 

of their lives. Treatment aims; 

- Delay symptomatic decline (maximise PFS) 

- Minimise treatment morbidity (ie hospital stays)


Treating follicular lymphoma – systemic therapy 

Common regimens 

- R-CVP 

1 st line NICE guidance 

Symptomatic stage III/IV disease 

- R-CHOP + maintenance rituximab 

- Rituximab 

- Chlorambucil +/- rituximab 

- FC-R (fludarabine, cyclophosphamide & rituximab) 

Radioimmunotherapy – Zevalin (Ibritumomab tiuxetan) 

Allogeneic transplantation 

- Can produce durable remissions in multiply relapsed patients


Maintenance rituximab in follicular lymphoma 

The use of maintenance rituximab significantly delays the time to 

disease progression 

2 nd Line 

Rituximab intravenously 

once every 3 months 

until relapse or for a 

maximum of 2 years 

NICE approved 2008 

1 st Line 

Rituximab intravenously 

once every 2 months 

until relapse or for a 

maximum of 2 years 

0 6 12 18 24 30 36 42 48 54 60


Rituximab 

Which of the following statements regarding rituximab 

is false 

1. Rituximab improves survival in DLBC lymphoma 

2. Rituximab is associated with a depletion of B cells 

3. Rituximab can cause neutropenia 

4. Patients on rituximab should not receive the seasonal 

flu vaccine

Summary 

 

 

 

Rituximab has had a major influence on the treatment of low- and 

high-grade NHL 

Current studies are examining the optimal use of chemotherapy 

regimens attempting to limits patients exposure to excess toxicity 

- Molecular predictors 

Novel targeted agents continue to be evaluated 

- Temsirolimus: Targets mTOR, a protein involved in cell growth and proliferation 

- Brentuximab: Anti- CD30 antibody, a protein expressed in Hodgkin 

lymphoma and anaplastic large cell lymphoma 

- Bendamustine: Conventional cytotoxic agent showing high response rates 

in indolent and mantle cell lymphoma 

- Lenolidomide: A derivative of thalidomide approved to treat myeloma under 

evaluation in lymphoma.

David Watkins - The Royal Marsden

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