N. Vey

Treatment of myelodysplastic syndromes with 5q deletion before the lenalidomide era; the GFM experience with EPO and thalidomide

Anemia in MDS with 5q deletion was generally considered, until the advent of lenalidomide, unresponsive to available treatments. We analyzed erythroid response to erythropoetin (EPO) or darbepoetin (DAR) and thalidomide in MDS with 5q deletion treated by French centers (GFM) and in whom karyotype was successfully performed. Of 345 patients treated with EPO or DAR+/-G-CSF, 48 had 5q deletion. The response rate was 46% (31% major, 15% minor) according to International Working Group (IWG) 2000 criteria versus 64% in patients without 5q deletion (p=0.03). According to IWG 2006 criteria, the response rate in patients with 5q deletion was 39% versus 52% in patients without 5q deletion (p=0.10). Mean duration of response was 14 months versus 25 months (IWG 2000) and 13 months versus 27 months (IWG 2006) in 5q deletion and non-5q deletion patients (p=0.019 and 0.003, respectively). Of 120 MDS treated with thalidomide, all of whom had successful cytogenetic analysis, 37% of the 24 patients with 5q deletion responded (IWG 2000 criteria, 20% major, 17% minor) with a mean duration of 9.5 months, versus 32% (18% major, 14% minor) in MDS without 5q deletion and a mean response duration of 9 months (p=NS). Our results confirm that response rates to EPO or DAR and thalidomide are clearly inferior to those obtained with lenalidomide.

Allogeneic stem cell transplantation improves the outcome of adults with t(1;19)/E2A-PBX1 and t(4;11)/MLL-AF4 positive B-cell acute lymphoblastic leukemia: results of the prospective multicenter LALA-94 study.

Adult patients with acute lymphoblastic leukemia (ALL) and t(1;19)/E2A-PBX1 or t(4;11)/MLL-AF4 have a poor outcome. We have evaluated the impact of an intensified post-remission therapy using a high-dose chemotherapy course followed by allogeneic or autologous SCT on the outcome of 58 patients with t(1;19)/E2A-PBX1 (E2A group, n=24) or t(4;11)/MLL-AF4 (MLL group, n=34) treated in the LALA-94 multicenter prospective study. Patients in the MLL group had higher WBC counts and more frequent DIC. CR rates achieved by MLL and E2A groups were similar to other B-cell ALL (87, 82 and 86% respectively). While in CR, patients with a donor were assigned to alloSCT (n=22), the remaining patients with were randomized between autoSCT (n=15) or chemotherapy (n=8). Five-year overall survival was 31 and 45% for E2A and MLL groups, respectively. In both groups, DFS was higher in the alloSCT arm as compared to autoSCT and chemotherapy arms. The results of this study show that chemotherapy intensification did not overcome the poor prognosis of adults with t(1;19)/E2A-PBX1. Allogeneic SCT should thus be offered in first CR to patients with t(1;19)/E2A-PBX1 or t(4;11)/MLL-AF4. New therapeutic approaches are needed for patients without donor.

Prognostic significance of monosomal karyotype in higher risk myelodysplastic syndrome treated with azacitidine.

Prognostic significance of monosomal karyotype in higher risk myelodysplastic syndrome treated with azacitidine

Is there a role for all-trans retinoic acid in combination with recombinant erythropoetin in myelodysplastic syndromes? A report on 59 cases.

Erythropoiesis-stimulating agents (ESAs) remain the first-line treatment of anemia in lower risk myelodysplastic syndromes (MDS) without 5q deletion. A preliminary report suggested that adding all-trans retinoic acid (ATRA) to ESAs may improve their erythroid response, particularly in patients with high endogenous erythropoietin (EPO) level, and may improve other cytopenias. We conducted a prospective multicenter study of EPO-β and ATRA in anemic MDS patients with marrow blasts <10% and either previous ESA failure or relapse, endogenous EPO >500u2009U/l or other cytopenia(s) (absolute neutrophilic count <1.0u2009G/l or platelets <50u2009G/l). A total of 59 patients were evaluable after 12 weeks of treatment. The erythroid response rates according to IWG 2000 and 2006 criteria, respectively, were as follows: overall: 49 and 36%; patients with previous ESA failure (n=28): 43 and 32%; patients with endogenous EPO >500u2009U/l (n=18): 11 and 19%; patients transfused >2 red blood cells units/month (n=28) 43 and 39%. Only one neutrophil, but no platelet response, and no major side effect were observed. EPO-β–ATRA combination appears a possible therapeutic option in anemia of MDS having failed an ESA alone, but not in patients with high endogenous EPO level, and does not improve neutropenia and thrombocytopenia.

Early death in acute promyelocytic leukemia (APL) in French centers: a multicenter study in 399 patients

Early death in acute promyelocytic leukemia (APL) in French centers: a multicenter study in 399 patients

Effectiveness and tolerance of low to very low dose thalidomide in low-risk myelodysplastic syndromes.

Effectiveness and tolerance of low to very low dose thalidomide in low-risk myelodysplastic syndromes J. Tamburini a,∗, C. Elie b, S. Park a, O. Beyne-Rauzy c, M. Gardembas d, C. Berthou e, B. Mahe f, L. Sanhes g, A. Stamatoullas h, N. Vey i, A. Aouba j, B. Slama k, B. Quesnel l, A. Vekhoff n, J.J. Sotto m, D. Vassilief a, C. Al-Nawakil a, P. Fenaux o, F. Dreyfus a, D. Bouscary a, for the “Groupe Francophone des Myelodysplasies, GFM” a Department of haematology Hopital Cochin, France b Department of biostatistiques universite Paris 5, France c Department of Hematology Odile; Hopital Purpan, Toulouse, France d Department of Hematology Martine; Centre Hospitalier d’Angers, France e Department of Hematology Christian; Hopital de Brest, France f Department of Hematology Centre hospitalier de Nantes, France g Department of Hematology Centre Hospitalier de Perpignan, France h Department of Hematology Aspasia; Centre Hospitalier de Rouen, France i Department of HematologyInstitut Paoli Calmette, Marseille, France j Hopital Cochin, Paris, internal medicine, France k Department of Hematology Centre Hospitalier d’Avignon, France l Department of Hematology Centre Hospitalier de Lille, France m Department of Hematology Centre Hospitalier de Grenoble, France n Department of Hematology Hopital Hotel Dieu, Paris, Hematology, France o Department of Hematology Hopital Avicenne, Bobigny, France

Does addition of erythropoiesis stimulating agents improve the outcome of higher-risk myelodysplastic syndromes treated with azacitidine?

We studied a retrospective cohort of 282 higher-risk MDS treated with azacitidine, including 32 patients who concomitantly received an ESA for a median of 5.8 months after azacitidine onset. Forty-four percent of ESA and 29% of no-ESA patients reached HI-E (p=0.07); 48% and 20% achieved transfusion independence (p=0.01). Median OS was 19.6 months in the ESA and 11.9 months in the no-ESA groups (p=0.04). Addition of an ESA significantly improved OS (p=0.03) independently of azacitidine schedule and duration, and of our proposed azacitidine risk score (Blood 2011;117:403-11). Adding an ESA to azacitidine in higher-risk MDS should be studied prospectively.

Molecular characterization of acute erythroid leukemia (M6-AML) using targeted next-generation sequencing.

Molecular characterization of acute erythroid leukemia (M6-AML) using targeted next-generation sequencing

Drug response profiling can predict response to ponatinib in a patient with t(1;9)(q24;q34)-associated B-cell acute lymphoblastic leukemia

Tyrosine kinase inhibitor (TKI)-based targeted therapy has significantly modified the outcome for patients with chronic myeloid leukemia (CML) in chronic phase. However, resistance remains a major concern in blastic phase of CML and in Philadelphia chromosome positive B-cell acute lymphoblastic leukemia (Ph+ B-ALL). Second- and third-generation TKIs have been developed to overcome resistance to first generation drugs, but selecting the appropriate drug has become a challenge. nVarious tests are available to determine a patient’s disease status in CML including the mechanisms of resistance when involved, but clinical experience is limited in ALL, especially those with poorly defined ABL1 rearrangements. Here, we report a case of nALL associated with a t(1;9)(q24;q34) RCSD1-ABL1 rearrangement. We show how ex vivo drug response profiling (DRP) may help choose among various therapeutic options.

Outcome of patients treated for myelodysplastic syndromes with 5q deletion after failure of lenalidomide therapy

While lenalidomide (LEN) is the standard of care for the lower-risk myelodysplastic syndromes (MDS) patients with deletion 5q, 35% will not respond to or do not tolerate the drug. Moreover, most of the patients will lose their response after a few years. Defining the outcome of patients with LEN failure and determining the impact of subsequent therapies is therefore important to develop alternative strategies. Based on an international collaboration, we were able to compile a total of 392 patient cases of lower-risk MDS patients with 5q deletion and to analyze their outcome after failure of lenalidomide. The median survival following LEN failure was 23 months. We observed a negative impact on survival of advanced age, higher bone marrow blast count at LEN initiation, progression after LEN failure, and unfavorable cytogenetics. Among the treatment strategies, we observed a relatively prolonged survival of patients treated subsequently with hypomethylating agents and only a limited impact on survival of allogeneic transplantation. In conclusion, our work stresses the relatively short survival of this group of patient and defines the expected baseline for the needed future investigations in this group of patients.While lenalidomide (LEN) is the standard of care for the lower-risk myelodysplastic syndromes (MDS) patients with deletion 5q, 35% will not respond to or do not tolerate the drug. Moreover, most of the patients will lose their response after a few years. Defining the outcome of patients with LEN failure and determining the impact of subsequent therapies is therefore important to develop alternative strategies. Based on an international collaboration, we were able to compile a total of 392 patient cases of lower-risk MDS patients with 5q deletion and to analyze their outcome after failure of lenalidomide. The median survival following LEN failure was 23 months. We observed a negative impact on survival of advanced age, higher bone marrow blast count at LEN initiation, progression after LEN failure, and unfavorable cytogenetics. Among the treatment strategies, we observed a relatively prolonged survival of patients treated subsequently with hypomethylating agents and only a limited impact on survival of allogeneic transplantation. In conclusion, our work stresses the relatively short survival of this group of patient and defines the expected baseline for the needed future investigations in this group of patients.