12th Congress of the European Hematology ... - Haematologica

12 th Congress of the European Hematology Association
from 42 g/L to 25 g/L) Electrophysiological study showed features of sensorimotor
neuropathy with axonal injury. Cerebrospinal fluid (CSF)
examination revealed meningeal lymphoplasmocytic cell infiltration (40
cells/mm 3 with 96% lymphoplasmocytes ; protein level of 1,81g/l). Magnetic
resonance imaging of the lumbar spine suggested infiltration of
nerve roots. Intravenous chemotherapy with high dose of methotrexate
was interrupted because of acute renal toxicity; subsequent four cycles
of intravenous chemotherapy with cytosine arabinoside and dexamethasone
were ineffective. Intrathecal liposomal cytarabine (DepoCyte ® )
was then administrated according to the induction and consolidation
treatment schedule (9 injections). Clinical improvement as well as normalization
of CSF cellularity (2/mm 3 ) and disappearance of electrophysiological
signs of neuropathy were obtained at the end of the DepoCyte ®
treatment. Following this good neurological response, the patient
received six courses of purin analogues (fludarabin ® ) to achieve a better
response on systemic disease. One year later, the patient remained
asymptomatic (monoclonal Ig M is 8 g/L and CSF is normal). In conclusion,
use of intrathecal depot liposomal cytarabine may be a well-tolerated
and appropriate treatment of meningeal infiltration by low-grade
lymphoma such as waldenström’s macroglobinemia. In combination
with a systemic treatment, one can expect to potentiate this drug’effect.
1135
MULTIPLE MOLECULAR MECHANISM MAY ACCOUNT FOR RESISTANCE TO IMATINIB
IN RESISTANT CELL LINES
F. Pane, 1 N. Esposito, 2 B. Izzo, 2 F. Quarantelli, 2 I. Colavita, 2
T. Buonomo, 2 V. Roberti, 2 S. Soverini, 3 J.V. Melo, 4 G. Martinelli, 3
R. Martinelli, 2 M. Ruoppolo, 2 F. Pane1 1 Hematology, NAPOLI, Italy; 2 CEINGE, NAPLES, Italy; 3 Hematology/Oncology,
BOLOGNA, Italy; 4 Imperial College, LONDON, United Kingdom
Imatinib mesylate, given its high activity against chronic myeloid
leukemia (CML), is the current first-line therapy for the treatment of this
disease. However, a part of patients in chronic-phase CML and even
more in advanced-phase, demonstrate primary resistance to imatinib or
develop secondary resistance during treatment. In addition, imatinib is
able to induce molecular remission only in a limited proportion of CML
patients who achieve a complete cytogenetic remission. Therefore, a second
level of resistance to the treatment in patients may be considered
minimal residual of Ph + cells. The best known cause of resistance is point
mutations in the Abl kinase domain. Others putative mechanisms include
genomic amplification of BCR-ABL and modulation of drug efflux or
influx from the cells. However, in a sizeable number of patients the resistance
mechanisms are still unknown. In this study we investigate imatinib-sensitive
and -resistant cells derived from the original Kcl22 line. In
these cells the resistance is innate and is not associated to mutations of
Abl catalytic domain. The aim of our work is the study of the complex
intracellular pathway of signal transduction and gene expression involved
in the molecular mechanisms of resistance to imatinib. To this aim, we
combined a proteomics and a gene expression profile approach. On one
hand, we studied by 2D-DIGE technology the protein expression both
in sensitive and resistant KCL22 cells to the imatinib. On the other hand,
we studied the pattern of gene expression in the same cells by microarrays
technology. Using Agilent microarray analysis we detected differential
expression of 256 genes, many of these are associates to imatinibresistant
phenotype. Among genes down regulated in Kcl22r, there are
phosphatase like SHP1 and DUSP6. They negatively regulate JAK/STAT
and MAP Kinase signalling pathway which are associated with cellular
proliferation and differentiation. Interestingly we also found down
expression of the heat shock protein like HSP70-1B, HSP27 and HSP70-
2; these molecules stabilize the structure of intracellular proteins and
mediate the folding of newly translated proteins. The HSP70 protein has
been recently shown to stabilize the inactive form of the oncogenic SHP-
2 phosphatase. 2D-DIGE analysis detected 27 proteins whose levels are
highly different in the couple of Ima- resistant and sensitive Kcl22 cell
lines. Among these, Annexin A1 a protein involved in several cellular
functions such as trafficking, exocytosis, apoptosis and cellular differentiation,
seems to be implicated in the resistance to different drugs used
in chemotherapy, including imatinib. These data indicate that the activation
of alternative pathway(s), independently of Bcr/Abl kinase activity,
may help CML cell to escape from imatinib action and may, therefore,
correlate with disease progression.
418 | haematologica/the hematology journal | 2007; 92(s1)
1136
RADIOIMMUNOTHERAPY WITH 90Y IBRITUMOMAB TIUXETAN IN
REFRACTORY/RELAPSED FOLLICULAR NON-HODGKIN LYMPHOMA RESULTS IN AN
SPANISH CENTER
A. Rubio-Martinez, 1 M.J. Agustín, 2 V. Recasens, 3 L. Lopez-Gomez, 4
M. Perella, 5 G. Pérez-Lungmus, 3 T. Baringo, 6 P. Giraldo3 1 Hospital U Miguel Servet, ZARAGOZA, Spain; 2 Clinical Pharmacy. HU
Miguel Servet, ZARAGOZA, Spain; 3 Haematology Department. HU Miguel
Servet, ZARAGOZA, Spain; 4 Haematology Department. H Royo Villanova,
ZARAGOZA, Spain; 5 Haematology Department. H Barbastro, BARBASTRO.
HUESCA, Spain; 6 Nuclear Medicine. HU Miguel Servet, ZARAGOZA, Spain
Background. We are present our experience on the therapy with 90Y
ibritumomab tiuxetan (90Y-IT) in an every day clinical practice protocol
applied to refractory/relapsed Follicular non Hodgkin Lymphoma
(NHLF), since commercial availability in Spain. Methods. Observational
retrospective analysis of the efficacy and safety of 90Y-IT. Patients: 18
NHLF Period of study: september 2005 to december 2006. Variables:
age, gender, time from diagnosis, number of previous schedulles, FLIPI,
relapsed and stage at baseline, haemoglobine, leucocytes, platelets,.
bone-marrow infiltration 90Y-IT was applied according an establish
coordinate and uniform protocol. The effectiveness endpoints was evaluated
by type of response: CR, PR, F, relapsed free survival (RFS) and
overall survival (OS) and safety. Results. 18 patients were included, three
of them were from other hospitals. M/F, 9/9; mean age 57.6 y (37-77);
ECOG 0-1, 73.3%. Mean time from diagnosis: 4.2 y. 85% grade 1, 10%
grade 2, 5% grade 3 NHLF. FLIPI distribution was: low-risk 53.1%, intermediate-risk
15.5% and high-risk 31.4%. Mean of previous schedules
3(1-7), administered dose 0.4 mCi/kg (12) and 0.3 mCi/kg (6). OR 85%.
With a maximum follow-up time of 15 months, only 1 grade 3 NHLF
relapsed at 5 months. Median OS has not been achieved. Safety: non
immediate adverse events were appeared. Grade 2-3 neutropenia (nadir:
+4±7 week; mean: 1.1×10 9 /L range: 0.4-2.2), G-CSF were administered
in 4 patients, grade 3-4 trombocytopenia (nadir: +4±8 week; mean:
70×10 9 /L; range: 7-162), 3 patients required red blood cell packet (12 U)
and 5 required platelet transfusions (40 U). Mean time to normalized
blood parameters 20 days (range: 7-60). In two patients a neoplasia of
colon and prostate were diagnosed in two and 4 months after received
90Y-IT and were considered as not related it. Any patient requires hospitalization.
Conclusions. Despite the limitations of the small number of
cases, our experience with 90Y-RIT for NHLF patients treated in an every
day clinical practice setting are similar to that obtained in clinical trials
1137
REFRACTORY ANAEMIA WITH RINGED SIDEROBLASTS ASSOCIATED
WITH THROMBOCYTOSIS: RESULTS FROM A SPANISH MULTICENTRIC STUDY
J.M. Raya, 1 J.M. Raya, 2 L. Florensa, 2 A. Domingo, 2 L. Arenillas, 2
E. Alonso, 2 G. Letamendi, 2 M.A. Piñan, 2 M. Barbon, 2 M. Rozman, 2
G. Gutierrez, 2 E. Luño, 2 C. Sanzo, 2 L. Garcia, 2 A. Lemes, 2 T. Molero, 2
F. Milla, 2 J.T. Navarro, 2 M.J. Muruzabal, 2 J.I. Olalla, 2 L. Yanez, 2 A. Villegas,
2 M. Mateo, 2 M.A. Duran, 2 A. Elosegui, 2 T. Hernandez-Santamaria, 2
M. Ardanaz, 2 L. Hernandez-Nieto, 2 S. Woessner2 1 Hospital Universitario de Canarias, LA LAGUNA - TENERIFE; 2 Spanish
Hematocytology Group, LA LAGUNA - TENERIFE, Spain
Introduction. Refractory anaemia with ringed sideroblasts associated with
marked thrombocytosis (RARS-MT) constitutes a provisional entity
among unclassifiable myelodysplastic/myeloproliferative disorders (WHO
classification, 2001). A platelet (Plt) count above 600 ×10 9 /L is necessary
for its diagnosis. Our aim was to analyze the clinical and analytical features
of a group of patients with RARS-MT, and to compare with those
of patients with RARS associated with not-marked thombocytosis (RARSnMT,
Plt between 400 and 600×10 9 /L). Methods. We retrospectively
reviewed RARS cases associated with thrombocytosis, differentiating
RARS-MT and RARS-nMT. Philadelphia chromosome and BCR/ABL
fusion gene were excluded prior to diagnosis. Analyzed data included
main features at presentation (clinical, biological and analytical), as well
as clinical course (treatment, complications, survival). The whole studied
data and parameters are described. Result. From 59 patients with RARS
associated with thrombocytosis, collected from 16 Spanish hospitals, 30
cases fulfilled the diagnostic criteria of RARS-MT (74,6±8,2 years; 18 male,
12 female) and 29 were assigned as RARS-nMT (70,2±12,1 years; 16 male,
13 female). The main differences between both groups are expressed in
the Table 1. Main motive for initial consultation in RARS-nMT patients
was anaemic symptoms (50%), while most of patients with RARS-MT