ALBERT

Description: Twenty four patients (pts) with planned autologous stem cell transplantation for lymphoma diseases (Hodgkin’s disease=4; non-Hodgkin’s lymphoma=20) received chemotherapy (CT) (Induction CT=3 and salvage regimen= 21) followed by a fixed single dose (6 mg) administration of Pegfilgrastim (PF) after the last day of CT for peripheral blood stem cell collection (PBSC) (target cell dose of 3 2×106 CD34+/kg). Median age was 53 yrs (24–68) and median weight was 72, 5 kg (45–98). Among the 24 pts, 7 received more than 2 lines of CT regimens. The injection of PF was well tolerated. Median time interval between day 1(D1) of the cycle of CT mobilization and first leukapheresis session was 14 days (10–18) while the median time interval between injection of PF and first leukapheresis session was 9 days (6–13). Stem cell collection was started when the absolute number of circulating CD34+ cells was 〉10×106/L and performed with standard volume leukapheresis. Median CD34+ cells level at D1 of leukapheresis was 35, 5/mm3 (11–320) and interestingly, more than 35 % of pts could reach this median level of CD34+ early after PF injection (around D6). Notably, 22 pts reached the target cell dose in 2 sessions of leukapheresis or less (10 pts after 1 session, 10 other pts after 2 sessions, 2 pts after 3 and 4 sessions respectively). The median number of leukapheresis sessions was 2(1–4) and the median CD34+ cells harvested was 4×106/kg (0,8–26,6). Two pts (DLBCL = 1 and FL = 1) could not reach the level of CD34+ required to start leukapheresis and both became secondary refractory to CT. In univariate analysis, PBSC collection of 〉 4×106/kg was highly correlated with pts who started their collection at D9 of PF administration (P=0,01) and with those presenting a CD34+ cells level 〉 35.5/mm3 at D1 of leukapheresis (P=0,033). White blood cells level higher than 9 G/l was also predictive of circulating CD34+ cells 〉35,5/mm3 (P=0,033). These data suggest that PF may represent an attractive option for PBSC mobilization particularly for pts with lymphoma when optimal compliance of frequent sequential regimens of CT is required. We also emphasize that stem cell mobilization is effective even in pts in second or subsequent salvage CT regimen. Importantly, the circulating CD34+ count should be performed from D6 of PF administration. The presentation will include the updated data.

Description: Karyotype is one of the most important prognosis factor in acute myeloid leukemia. The MLL gene, located at 11q23, is fused to a variety of partner genes through chromosomal translocations and generates the critical leukemogenic fusion proteins. We performed a large retrospective study in 146 adults and children with 11q23/MLL + rearrangement enrolled in 6 clinical trials conducted in France between 1987 and 1998. Prognosis studies were performed in the 110 patients (47 adults and 63 children) who achieved a complete remission. Individual data were registred, including age, blood and marrow count, extramedullary disease and cytogenetics. The kaplan-Meier method was used in survival analysis and the cox proportinal-hazards model was used to analyse the effect of potential prognosis factors on survival. Among 47 adults, 43 % (20/47) carried t(9 ;11), 19% (9/47) carried t(6 ;11), 23% (11/47) carried t(11 ;19), 6% (3/47) carried t(10 ;11) and 8% (4/47) carried another abnormalities involved 11q23/MLL. Estimated 5-year disease-free survival (DFS), overall survival (OS) and relapse rate (RR) were respectively 17%, 21% and 77%. We analysed separately all translocations involved MLL and we found that the only translocation indicating a favorable prognosis was the translocation t(11 ;19). Compared with other translocations involving MLL, the estimated 5-year DFS, OS and RR of patients with a t(11 ;19) were respectively 45 vs 8% (p=.02), 54 vs 11% (p=.006) and 48 vs 84% (p=.04). Relative risk of relapse was 0,29 (95% confidence interval, 0.09 to 0,9 ;p=.03). Among 63 children, 63% (40/63) carried t(9 ;11), 3% (2/63) carried t(6 ;11), 8% (5/63) carried t(11 ;19), 14% (9/63) carried t(10 ;11) and 11% (7/63) carried another MLL rearrangement. Estimated 5-year DFS, OS and RR were respectively 59%, 72% and 36%. Compared with other translocations involving MLL, we found no difference in outcome between patients with t(9 ;11) and those with other rearrangement of MLL. In conclusion, the most common recurrent abnormality in this large study was translocation t(9 ;11) in adults and children. We found that adults patients whose leukemic cells contained the t(11 ;19) have a better outcome compared with those whose leukemic cells contain other 11q23 /MLL alterations. In children, we do not confirm the favorable impact of t(9 ;11) suggested in previous reports.

Description: Dasatinib (Sprycel®, Bristol-Myers Squibb) is a potent multi-targeted kinase inhibitor (TKI) of BCR-ABL and SRC family kinases. Despite a 33% complete hematological response (CHR) rate in a Phase 2 study in patients with Philadelphia positive (Ph+) acute lymphoblastic leukaemia (ALL) intolerant or resistant to imatinib, the median duration of progression-free survival (PFS) was 3.3 months (Ottmann et al. Blood. 2007;110:2309-2315). Second-generation TKI may thus have a place in the management of these patients. As a European consensus has been reached by the EWALL to adopt a common first-line chemotherapeutic schedule for elderly patients (aged 55 years or more) with Ph-positive ALL, this schedule was used here to test the addition of dasatinib. After a prephase with dexamethasone 10 mg/m2 d-7 to d-3, the induction phase consisted in IV injections of vincristine 1 mg combined with 2 days of dexamethasone 40 mg PO repeated weekly for 4 weeks followed by consolidation cycles including methotrexate 1000 mg/m2 IV d1 (500 mg/m2 over 70y) and asparaginase 10,000 UI/m2 IM d2 (5,000 UI/m2 over 70y) for cycles 1, 3 and 5 alternating with cytarabine 1,000 mg/m2/12h IV d1, d3, d5 (500 mg/m2 over 70y) for cycles 2, 4 and 6. Maintenance phase consisted in 6-MP 60 mg/m2/d and methotrexate 25 mg/m2/week orally 1 month every other month and dexamethasone/vincristine in 2 months intervals during the first year and in 3 months intervals during the second year. Dasatinib (provided by Bristol-Myers Squibb) was administered at 140 mg per day (QD) during the induction period in combination with chemotherapy and at 100 mg/d sequentially with the chemotherapy courses during consolidation and maintenance. BCRABL analysis was performed according to the European Leukemia Net recommendations in two centralized laboratories. A total of 22 patients were included from August 2007 to June 2008. Median age was 71 years (range, 61 to 83), sex ratio (M/F) was 0,46, and median follow-up was 5.8 months. The Ph+ chromosome was associated with complex abnormalities in 58% of cases and 84% of the patients were m-BCR. The CHR rate was 95.2% (20 out of 21 evaluable patients). The only case of induction failure was due to death. The rate of complete molecular remission (CMR) after induction was 33% in blood and 28% in bone marrow and MRD level continued to decrease with time. Only one relapse was observed before the consolidation phase. No other relapse occurred for the 13 patients in CHR still in study after a median follow-up of 3.6 months. One patient died during induction from invasive aspergillosis, 3 deaths occurred in CR, 2 before consolidation due to pulmonary embolism and physical deterioration, and one during maintenance from pneumonia. Serious adverse events (SAEs) were reported in 7 out of 22 patients during induction (31.8%) and in 2 out of 13 patients during maintenance and consolidation (15.3%). SAEs consisted in renal failure (n=3, 2 from acute lysis syndrome and 1 tubular necrosis), invasive aspergillosis (n=1), pulmonary embolism (n=2), pneumonia (n=1), atrial arythmia (n=2), pleural effusion (n=1), microangiopathy (n=1), cytolytic hepatitis (n=1) and physical deterioration (n=1). Eight patients discontinued the study after induction (35%). Primary reasons for discontinuation were SAEs (n=4), death (n=3) and relapse (n=1). The EWALL-PH-01 protocol is highly effective with a 95.2% RCH rate in elderly patients with Ph-positive ALL. Of importance, responses appeared to be durable and MRD level was decreasing over time. An expected 40% rate of SAEs was observed in this elderly population. Reduced doses of therapy are now applied for patients over 70y (20 mg for dexamethasone, 100 mg/d for dasatinib).

Description: Abstract 844 Introduction: intensive chemotherapy (IC) in AML post-MDS (here AML) or High Risk-MDS (here MDS) is associated with lower CR rate, shorter response duration and poor overall survival compared to de novo AML. Upfront treatment of MDS with AZA delays time to AML evolution and prolongs overall survival (OS). The low toxicity profile of AZA should also allow its use in IC responders in an outpatient setting. Preliminary results with this approach by the Nordic MDS group in 23 pts (ASH 2008, abstr n°223) showed its feasibility. We used it in AML or MDS patients (pts), who had achieved response after IC. Methods: Inclusion criteria were: (1) de novo MDS patients and IPSS int-2 or high risk (including CMML if WBC 23 cycles in 4 of them) and 2 (0-11) in CRi or PR pts. Median follow-up was 24 months (m). Median DFS was 6.5 m and 18-m DFS was 20% (95% CI 9-35); median and 18 month OS from response were 15 m and 43% (95% CI 27-58), respectively. 18-m-DFS and OS were 30 % (95% CI 13-48) and 56% (95% CI 35-72), in the 33 CR pts (median OS 24m), compared to O% and 17% (95% CI 3-41), in the 11 PR/CRi pts, ( P= .0001 and .04, respectively) . 21 of the 33 CR pts had relapsed and 3 had CR duration 〉24 months. None of the pts in CRi/PR after IC improved their response with AZA. Only initial response to IC (ie CR vs CRi/PR), but not cytogenetics (normal vs. others), diagnosis at IC onset (MDS vs AML), % bone marrow blasts (using 20 or 30 % cut-off), age or time from MDS diagnosis to treatment, significantly predicted DFS or OS in this cohort. AZA dosing in CR patients was escalated in 9 pts but had to be reduced in 6 other pts, due to GI tract intolerance (n=1) and cytopenias (n=5). Only 2/33 CR pts, developed severe infection or febrile neutropenia while in persistent response, compared to 4/11 pts in CRi or PR (including 1 fatal case). We finally compared outcome of the 22 AML study pts in CR to that of 46 similar AML post MDS pts from our ALFA group elderly AML 9803 study (Gardin, Blood 2007), in which pts in CR received DNR/IDA–AraC post-remission therapy. Cumulative incidence of relapse did not differ between the present AZA cohort in AML patients and the ALFA cohort (18-m CIR at 41% (95% CI 18-63) and 25% (95% CI 13-40), respectively; P=0.92). OS from CR was also identical between the 2 cohorts (18-m OS of 56% (95% CI 31-76) and 54% (95% CI 37-69), respectively; P=0.84) Conclusion: In this study, post–CR therapy with AZA alone was associated with a 30% DFS rate and 56% OS at 18m and a median OS of 24m, while pts in CRi or PR did not benefit from AZA. Although selection biases may exist between cohorts, DFS and OS of AML post MDS in CR were identical to those observed in similar pts treated after CR by anthracyclin and AraC consolidation. Hematological toxicity of AZA, however, was minimal. Combinations of AZA with other drugs may be of further interest in those patients at high–risk of relapse. Disclosures: Gardin: Celgene: Consultancy, Honoraria, Research Funding. Off Label Use: azacitidine as post-remission therapy in AML patients. Dombret:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Fenaux:Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Ortho Biotech: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Cephalon: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

Description: Background: LEN is very effective for the anemia of lower risk MDS with del 5q. A patient named program was launched by the French health agency (AFSSAPS) to use LEN in low and int 1 risk MDS with del 5q and transfusion dependence (〉 2 RBC units/2 months). Methods: Patients received 10 mg of LEN/day, 3 weeks on, 1 week off. Hematological response (IWG 2006) was assessed after 8, 16 and 32 weeks of treatment. G-CSF use was recommended in case of grade 3 neutropenia, in order to avoid dose reduction, especially during the first 16 weeks of treatment. Results: 71 pts from 35 centers were evaluable for response as of Aug 1st, 2008. Median age was 75 [range 43–93], 68% females, median interval from diagnosis to LEN treatment 28.6 months (range 1–235). At inclusion, 32 pts had del 5q syndrome, 10 RA, 13 RARS, 2 RCMD-RS and 14 RAEB-1. IPSS was low in 43% and int-1 in 57%. Del 5q was isolated, with 1 additional and 〉 1 additional abn in 76%, 15% and 9% pts respectively. 23 pts were untreated, while 48 had previously received EPO. Median transfusion requirement was 4 units/2 months. 50/71 (69%) pts achieved erythroid response (IWG 2006), of whom 48 (67%) achieved transfusion independence (TI). Median time to TI was 12 weeks (range 8 – 32). TI was achieved in 76%, 62%, 68%, 70% and 50% pts with IPSS low, IPSS int 1, isolated del 5q, del 5q+1abn, del5q + 〉1abn, resp, and 70% and 65% of EPO pretreated and EPO naive pts (p=NS). Grade III-IV neutropenia and thrombocytopenia were seen in 86% and 26% pts resp, leading to transient discontinuation followed by reduction of LEN dosing in 55%pts. Of the 19 pts who received GCSF, 3 (16%) required transient LEN discontinuation due to neutropenia compared to 15 (28%) of the 52 who did not receive GCSF (p=0.3). Apart from neutropenia and thrombocytopenia, grade III–IV side effects were Lyell’s syndrome (n=1), deep venous thrombosis (n=3) Quincke’s oedema (n=1), No patient died from sepsis due to neutropenia or bleeding due to thrombocytopenia. With a still short median follow up on treatment (28 weeks), no relapse had occurred. 1 pt (RAEB 1 with 7% of blasts, isolated del 5q and IPSS INT-1 at inclusion who had achieved TI) progressed to AML at week 48. Conclusion: Our results confirm on a very multicenter basis the efficacy of LEN on the anemia of lower risk MDS with del 5q,. The use of G-CSF during the early treatment phase may somewhat reduce the proportion of early LEN discontinuation due to neutropenia.

Description: Acute myeloid leukemias (AMLs) carrying 11q23/MLL reciprocal translocations are usually associated with a bad prognosis. However, this AML subtype constitutes a heterogeneous group and the major factor influencing prognosis seems to be the MLL partner involved in the translocations. We thus performed a large retrospective study in 191 patients, including 102 adult and 89 children, prospectively enrolled in 11 different trials conducted in France between 1987 and 2002 (BGMT 87, BGMT 91, BGMT 95, LAM 2001, LAM-SA-2002, Alfa 9801, Alfa 9802, Alfa 9000, Goelam02, LAME89–91, LAME2000). Patients with MLL were not included. All patients received induction treatment with cytarabine and an anthracycline followed by an intensive consolidation with either high-dose cytarabine (HDAC) based chemotherapy or autologous or allogeneic stem cell transplantation. Results in 102 adults: Median age was 37,7 years (range 19–79). The majority of patients (56%) had AML-M5 according to FAB classification. 38% carried t(9;11), 20% carried t(6;11), 20% carried t(11;19), 7% carried t(10;11) and 15% carried various other reciprocal translocations. Overall CR rate was 86%. At 5-year, estimated disease-free survival (DFS) and overall survival (OS) were 20% and 25%, respectively. Only patients with t(11;19) indicated a relatively favorable outcome with a 5-year DFS and OS of 42% and 50%, respectively. This outcome was significantly better than for patients with any other translocation (p=.001). In patients with t(9;11) or other various translocation, 5-year DFS and OS were 20% and 25%, respectively. In patients with t(6 ;11), 5-year DFS and OS were 0%. The prognosis was no modified by a presentation with complex karyotype or by the type of consolidation received (HDAC, autologous, or allogeneic transplantation). Results in 89 children: Median age was 1,8 years (range 0,09–16,3). The majority of children (56%) had AML-M5 according to FAB classification. 58% carried t(9;11), 15% carried t(10;11), 9% carried t(11;19), 7% carried t(1;11) and 11% carried various other translocations including t(11 ;17), t(4 ;11) or t(6 ;11). Overall CR rate was 89%. At 5 years, estimated DFS and OS were 60% and 65%, respectively. In children with a t(9;11) translocation, 5-year DFS and OS were 72% and 78%, respectively. This outcome was significantly better than for patients with any other translocation (p=.013). In children with t(10;11) or t(11;19), 5-year DFS and OS were 47% and 50%, respectively. In those with other various translocations, 5-year DFS and OS were 18% and 13%, respectively. As in adults, the prognosis was not modified by a presentation with complex karyotype or by the type of consolidation received (HDAC, autologous or allogeneic transplantation). Conclusion: The prognosis of patients with a translocation involving MLL is heterogeneous with a better outcome for adults with t(11;19) and for children with t(9;11). Data of this study shows that adults with t(11;19) might be considered as intermediate cytogenetic risk. In contrast, the prognosis of t(6;11) in adults and children is extremely poor and this group should be regarded as very high risk. In adults and children, prognosis of these translocations is no modified by complex karyotype or by the type of post-remission treatment received (HDAC, autologous or allogeneic transplantation). The t(9;11) translocation is the most common recurrent one but with a different prognosis in adults as compared to children, which might be related to a different drug-resistance profile.

Description: Abstract 2764 Poster Board II-740 Background: LEN is particularly effective on anemia of lower risk MDS with del 5q (List et al, NEJM, 2006). A compassionate program (ATU) of LEN in low and int 1 risk MDS with del 5q and transfusion dependence was opened by the French health agency between Jan and Sept 2007. Methods: Patients (pts) received 10 mg of LEN/day, 3 weeks on, 1 week off. Response was assessed after 8, 16, 32, and 48 weeks according to IWG 2006 criteria. After the first months of the program, G-CSF use was recommended in case of grade 3-4 neutropenia in order to avoid dose reduction. Results: 95 pts from 35 centers were enrolled. Median age was 73 [42–92], M/F 25/70, median interval from diagnosis to LEN was 29 months (range 1–234). Median follow-up after inclusion was 16 months. At inclusion (WHO classification), 41 pts had del 5q syndrome, 8 RA, 9 RARS, 2 RCMD-RS, 10 RCMD, 1 CMML and 24 RAEB-1. IPSS was low in 29/95 (31%) and int-1 in 66/95 (69%). Del 5q was isolated, with 1 additional and 〉 1 additional abn in 75/95 (79%), 13/95 (14%), and 6/95 (6%) pts respectively (resp). 62 pts had previously received an erythropoietic stimulating agent (ESA). Median transfusion requirement was 4 units/2 months and platelet count 〈 100G/L and ANC 〈 1G/L present in 9.5% and 12.6%, resp. 62/95 pts (65%) achieved erythroid response, including 60 (63%) transfusion independence (TI). Median time to TI was 16 weeks. TI was achieved in 49/75 (65%), 7/13 (54%) and 4/6 (67%) pts with isolated del 5q, del 5q+1abn, del5q + 〉1abn, resp (p=0.5). Complete, partial and no cytogenetic response were observed in 20%, 40%, 40% pts resp. TI rate was not significantly influenced by concomitant G-CSF (n=25) vs no G-CSF (72% vs 60%, p=0,34), previous ESA vs no ESA (61 vs 73%, p=0.13), interval from diagnosis2 years (69 vs 59%, p=0.5) or IPSS low vs Int-1 (52% vs 66.7%, p=0.36) but there was a trend for higher TI rate in pts with baseline platelets 〉100 G/l vs 13 g/dl, 5/31 (16%) developed DVT, compared to 1/29 (3%) with maximum Hb level