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Purpose:Carfilzomib is a novel generation proteasome inhibitor. The Carmysap trial demonstrated that twice-weekly KMP (carfilzomib, melphalan, prednisone) might challenge the MPV (melphalan, prednisone, bortezomib) standard. We sought to study KMP weekly, allowing to increase carfilzomib's dose with maintained efficacy and improved safety profile.Patients and Methods:IFM2012-03, a phase I multicenter study of KMP weekly in elderly patients with newly diagnosed multiple myeloma (eNDMM), aimed to determine the MTD of carfilzomib. Carfilzomib was given intravenously at 36, 45, 56, and 70 mg/m2/day on days 1, 8, 15, and 22 with melphalan and prednisone, for nine 35-day induction cycles, followed by carfilzomib maintenance for 1 year. Three dose-limiting toxicities (DLT) determined MTD at the lower dose.Results:Thirty eNDMMs were treated, 6 per cohort at 36, 45, and 56 mg/m2 and 12 at 70 mg/m². There was one DLT at 36 mg/m2 (lymphopenia), one at 45 mg/m2 (lysis syndrome), two at 56 mg/m2 (cardiac insufficiency and febrile neutropenia), and two at 70 mg/m2 (vomiting and elevated liver enzymes). The safety profile was acceptable; however, specific attention must be paid to the risk of cardiovascular events, especially for elderly patients. The overall response rate was 93.3%, with 46.6% complete response.Conclusions:The MTD dose of carfilzomib was 70 mg/m2 in this KMP weekly study in eNDMM. Response rates, and especially CR rate, were remarkable in this population, and would benefit from being assessed in a larger-scale study. The IFM2012-03 study demonstrated that the MTD of carfilzomib weekly is 70 mg/m2 in eNDMM, and 56 mg/m2 for patients older than 75 years. Carfilzomib used weekly in combination has a good efficacy and safety profile in eNDMM.

Supplementary tables 1 to 5

Supplementary Figure 1. Complementary survival curves for the whole cohort (n=30). (A) Event Free Survival (EFR); (B) Time to new treatment (TTNT); (C) Duration of response (DOR). Supplementary Figure 2. Progression Free Survival and Overall Survival according to cytogenetic risk (n=30). (A) PFS according to cytogenetic risk; (B) OS according to cytogenetic risk.

International audience

Immunosuppressive treatment is a disease-modifying therapy for lower-risk myelodysplastic syndromes (MDS). However, IST is relatively rarely used and long-term outcomes of patients are seldom reported. We retrospectively studied outcomes of 20 patients with lower-risk non del 5q MDS with transfusion dependency, with horse or rabbit antithymocyte globulin ± ciclosporine A, and frontline eltrombopag in two of them. IPSS-R was low, intermediate and high in 30%, 55% and 10% of the patients, respectively. Fifty-five percent of the patients had hypocellular bone marrow (BM). Baseline mutations were detected in 31.5% of the patients and were more frequent in patients with normo/hypercellular MDS than in patients with hypocellular MDS. Transfusion independence rate for both red blood cells (RBC) and platelets was achieved in 45% of patients. RBC transfusion duration ≤6 months, B-cell counts >0.2 G/L and, marginally, BM blasts ≤2% were associated with higher transfusion independence rate. Age and cellularity did not influence the response rate. Median transfusion independence duration was 53 months. Cumulative incidence of progression to a more aggressive myeloid disease was 0 in patients without baseline mutations and 33% in patients with baseline mutations (P = .008). Median progression-free and overall survival after treatment onset and median overall survival after loss of transfusion independence were 45.5 months, 68 months and not reached, respectively. In conclusion, antithymocyte globulin ± ciclosporine A results in durable responses in MDS, irrespective of age, in patients with lower-risk disease without B-cell lymphopenia and treated early in the course of the disease.

Carfilzomib is a novel generation proteasome inhibitor. The Carmysap trial demonstrated that twice-weekly KMP (carfilzomib, melphalan, prednisone) might challenge the MPV (melphalan, prednisone, bortezomib) standard. We sought to study KMP weekly, allowing to increase carfilzomib's dose with maintained efficacy and improved safety profile., info:eu-repo/semantics/published

Background - Reports of patients with secondary acute promyelocytic leukemia (APL) have increased in recent years, particularly for those who received treatment with mitoxantrone, and retrospective studies have suggested that their characteristics and outcomes were similar to those of patients with de novo APL. Methods - The authors investigated patients with de novo and secondary APL who were included in the ongoing APL-2006 trial. Patients with secondary APL who were included in that trial also were compared with a previous retrospective cohort of patients with secondary APL. Results - In the APL-2006 trial, 42 of 280 patients (15%) had secondary APL. Compared with the retrospective cohort, patients with secondary APL in the APL-2006 trial had a lower incidence of prior breast carcinoma (35.7% vs 57%; P = .03) and a higher incidence of prior prostate carcinoma (26.2% vs 4.7%; P Conclusions - Although the incidence of secondary APL appears to be stable over time, evolving strategies for the treatment of primary cancers have reduced its occurrence among breast cancer patients but have increased its incidence among patients with prostate cancer. The current results confirm prospectively that patients with secondary APL have characteristics and outcomes similar to those of patients with de novo APL.

Background. New standards with increasing efficacy that are also characterized with improving the quality of life are needed for elderly myeloma patients. Although MPT and MPV regimens are remarkable in terms of efficacy, quality of life while on treatment with these 2 regimens remain an issue. The Carmysap twice weekly carfilzomib-based phase 2 study has demonstrated that Carfilzomib at the MTD of 36mg/m² might challenge bortezomib in the VMP standard. However, it has become routine practice to use bortezomib on a weekly schedule, with maintained efficacy and an improved safety profile. We sought to demonstrate that Carfilzomib Weekly plus Melphalan and Prednisone will prove strongly efficacious with acceptable safety profile and quality of life to newly diagnosed elderly multiple myeloma (eNDMM). Methods . IFM2012-03 (also called carmysap weekly) is a phase 1/2 multicenter open label single arm study to determine MTD during the phase 1 part and VGPR+CR rate during the phase 2 part of the study. The inclusion/exclusion criteria of interest were eNDMM (65 and older), with symptomatic and measurable disease, with absolute neutrophils ≥1 G/L, untransfused platelet count ≥75 G/L, hemoglobine ≥8.5 g/dL and clairance creatinine ≥ 30ml/min. We report herein the phase 1 part of the study which last cohort was completed at ASH abstract deadline. For the phase 1 part of the study, each cohort was 6 patients based, and started at 36mg/m² of carfilzomib on days 1, 8, 15, 22 using IV, 30 minutes infusion, route followed by a 13-day rest period per 35-days cycles, melphalan given at 0.25mg/kg/j and oral prednisone 60mg/m², both on days 1 to 4. The subsequent cohorts' doses for carfilzomib were 45, then 56 and finally 70mg/m². 9 cycles were planned as induction followed by a maintenance phase of weekly carfilzomib monotherapy given at 36mg/m² weekly for one year. The MTD was determined when ˃2 DLTs were observed. DLTs were considered during cycle 1 if any hematologic toxicity of grade 4 intensity or preventing administration of 2 or more of the 4 carfilzomib doses of the first treatment cycle, grade ≥3 febrile neutropenia, grade ≥3 gastrointestinal toxicities, any other grade ≥3 nonhematologic toxicity considered related to CMP by the principal investigator, grade ≥ 3 peripheral neuropathy persisting for more than 3 weeks after discontinuation of study drugs. Results. 26 NDMM patients recruited, 24 treated in the study, 6 per cohort at 36 mg/m² carfilzomib +MP, then 45 then 56, and finally at 70mg/m² which cohort cycle 1 is up and running. The median age was 74 with 10 patients older than 75 and sex ratio M/F 65. There was a DLT at 36 mg/m² carfilzomib (grade 4 lymphopenia), one at 45 (lysis syndrome complicated with grade 4 renal insufficiency, two at 56 (cardiac insufficiency grade 3 and febrile neutropenia grade 3). At ASH deadline, all patients from cohort 36 of carfilzomib have completed induction and maintenance up to cycle 6, 5/6 of cohort 45 have completed induction and started the maintenance phase, 5/6 of cohort 56 have completed cycle 6 of induction and pursue within the induction phase, and finally all patients from cohort 70 of carfilzomib are undergoing cycle 1. There are 22 SAE reported for a total of 171 cycles administered of carfilzomib +MP. So far, 3 patients (out of 24) have stopped treatment, including the 2 patients with DLTs, lysis syndrome and cardiac failure, and one patient that presented with pulmonary hypertension later in the disease course on cycle 5 of the 56mg/m² carfilzomib +MP cohort. And, an extra 3 patients have had Carfilzomib dose reduction, 2 patients at 36 from 45 and one at 45 from 56, for neutropenia grade 4, thrombocytopenia grade 4, and Dyspnea grade 3, respectively. Conclusion. The MTD of weekly carfilzomib in the combination to Melphalan and Prednisone could be determined at 70mg/m² in elderly NDMM, demonstrating the good safety profile of carfilzomib in this regimen and fragile population. The complete dataset of the entire study will be updated at ASH with response rate, survival and safety profile. Disclosures Leleu: Chugai: Honoraria; LeoPharma: Honoraria; Pierre Fabre: Honoraria; BMS: Honoraria; Novartis: Honoraria; TEVA: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Karlin:Janssen: Honoraria; BMS: Honoraria; Amgen: Honoraria; Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria. Fitoussi:Sandoz: Membership on an entity's Board of Directors or advisory committees. Moreau:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Background. Progression by serum free light chain (sFLC) test without or preceding progression with intact immunoglobulin (Ig) is called light chain escape. This event alone is not considered a progression for patients with Multiple Myeloma (MM) according to International guidelines, although it is often considered a progression in real life and by clinical trials' investigators. We therefore sought to determine whether light chain escape would be a predictor of relapse and thus question a possible need to modify the current criteria for progression according to the International Myeloma Working Group (IMWG). Material and method. We have reviewed 325 (323 for analysis) patients that presented with a progression in the IFM/DFCI2009 phase 3 study (Attal et al. NEJM 2017). Among these 323 patients, 260 had initial tumor bulk measurement with intact Ig by serum protein electrophoresis test (SPEP; Ig ≥ 10 g/L) and 63 light chain MM (Ig < 10 g/L) measured using urine protein electrophoresis (UPEP). All progressions were validated in the central laboratory of CHU de Nantes (Dr T. Dejoie) and followed IMWG recommendations. sFLC increase was determined by absolute increase ≥ 100 mg/L and ≥ 25% from nadir value of the difference between involved and uninvolved FLC (ΔiFLC). Light chain escape was defined as sFLC increase without progression by SPEP (Ig increase ≥ 5 g/L and ≥ 25%) or UPEP (increase ≥ 200 mg/24h and ≥ 25%). Results. Among the 260 patients with intact Ig at diagnosis, 3 (1.15%) patients presented a light chain escape: progression by sFLC test without progression by SPEP. In parallel, 228 patients (87.7%) progressed by SPEP, of whom 18/228 (6.25%) showed a sFLC increase preceding the increase of intact Ig, with a median delay of 63 days. Among the 63 light chain MM, 6 (9.5%) patients presented a light chain escape: progression by sFLC test without progression by UPEP. Interestingly, 6 other patients (9.5%) progressed by SPEP even though Ig was < 10 g/L at diagnosis. Of the remaining 46 patients, 38 (60.3%) showed sFLC increase before progression by UPEP. Finally, 8 patients (12.7%) progressed but with intact Ig pauci-secreting MM meeting none of the M spike based progression criteria. Median time from iFLC nadir to ΔiFLC ≥ 100 mg/L was 280 days for light chain MM, 496 days for intact Ig MM, and 651 days for light chain escape. Median time from ΔiFLC ≥ 100 mg/L to follow-up visit to assess progression was 402 days light chain MM, 536 days for intact Ig MM, and 713 days for light chain escape. Overall, 9 (3%) patients had true light chain escape with progression by sFLC test without any other progression criteria. In parallel, in 56 (17%) patients, sFLC increase preceded progression to MM by standard test (SPEP or UPEP). Still the vast majority of patients had a regular relapse using the standard markers for progression. Conclusion. Based on a large study of patients treated into a phase 3 clinical trial with centralized assessment of response and progression, we showed that 20% of patients had progression by sFLC without meeting standard progression markers, of whom 3% had true light chain escape and 17% early light chain increase. Even though true light chain escape seems to be a rare phenomenon, analysis of sFLC test could help to avoid delayed or missed diagnosis of progression in 20% of patients in this clinical trial. This data should be confirmed in another database to assess whether a modification in the progression criteria in MM International guidelines should be proposed. Disclosures Hulin: Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Roussel:Amgen: Consultancy; Celgene: Consultancy; Takeda: Consultancy. Hebraud:Amgen: Consultancy; Janssen: Consultancy, Other: Lecture fees; travel and accommodation for congress, Research Funding; Sanofi: Consultancy; Takeda: Consultancy; Celgene: Consultancy, Other: Lecture fees, Research Funding. Karlin:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support. Belhadj:Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Decaux:Celgene: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Amgen: Honoraria. Garderet:Amgen: Consultancy; Takeda: Consultancy; Celgene: Consultancy. Facon:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Oncopeptides: Membership on an entity's Board of Directors or advisory committees. Avet-Loiseau:Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Moreau:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Attal:Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janseen: Consultancy, Research Funding; Sanofi: Consultancy. Leleu:Karyopharm: Honoraria; Gilead: Honoraria; Incyte: Honoraria, Other: steering committee membership ; Roche: Honoraria; Sanofi: Honoraria, Other: steering committee membership steering committee membership ; Novartis: Honoraria, Other: steering committee membership ; Amgen: Honoraria, Other: steering committee membership ; Merk: Honoraria, Other: steering committee membership ; Takeda: Honoraria, Other: steering committee membership ; BMS: Honoraria, Other: steering committee membership ; Celgene: Honoraria, Other: steering committee membership ; Janssen: Honoraria, Other.

Myeloproliferative diseases (MPDs) represent the commonest cause of splanchnic vein thrombosis (SVT), including Budd-Chiari syndrome (BCS) and portal vein thrombosis (PVT), but their diagnosis is hampered by changes secondary to portal hypertension, while their influence in the outcome of SVT remains unclear. We assessed the diagnostic and prognostic value of JAK2 and MPL515 mutations in 241 SVT patients (104 BCS, 137 PVT). JAK2V617F was found in 45% of BCS and 34% of PVT, while JAK2 exon 12 and MPL515 mutations were not detected. JAK2V617F was found in 96.5% of patients with bone marrow (BM) changes specific for MPD and endogenous erythoid colonies, but also in 58% of those with only one feature and in 7% of those with neither feature. Stratifying MPD diagnosis first on JAK2V617F detection would have avoided BM investigations in 40% of the patients. In BCS, presence of MPD carried significantly poorer baseline prognostic features, required hepatic decompression procedures earlier, but had no impact on 5-year survival. Our results suggest that JAK2V617F testing should replace BM investigations as initial test for MPD in patients with SVT. Underlying MPD is associated with severe forms of BCS, but current therapy appears to offset deleterious effects of MPD on the medium-term outcome.

International audience; Background - Reports of patients with secondary acute promyelocytic leukemia (APL) have increased in recent years, particularly for those who received treatment with mitoxantrone, and retrospective studies have suggested that their characteristics and outcomes were similar to those of patients with de novo APL.Methods - The authors investigated patients with de novo and secondary APL who were included in the ongoing APL-2006 trial. Patients with secondary APL who were included in that trial also were compared with a previous retrospective cohort of patients with secondary APL.Results - In the APL-2006 trial, 42 of 280 patients (15%) had secondary APL. Compared with the retrospective cohort, patients with secondary APL in the APL-2006 trial had a lower incidence of prior breast carcinoma (35.7% vs 57%; P = .03) and a higher incidence of prior prostate carcinoma (26.2% vs 4.7%; P Conclusions - Although the incidence of secondary APL appears to be stable over time, evolving strategies for the treatment of primary cancers have reduced its occurrence among breast cancer patients but have increased its incidence among patients with prostate cancer. The current results confirm prospectively that patients with secondary APL have characteristics and outcomes similar to those of patients with de novo APL.

Background. Melphalan plus prednisone and bortezomib combination is the most frequent standard of care used upfront for newly diagnosed elderly myeloma (eNDMM). Despite significant improvements with bortezomib sub-cutaneous administration and weekly schedule, safety profile issues remain with MPV, that only can be resolved with lowering the doses, albeit of the potential loss of efficacy. Carfilzomib (K), a novel generation proteasome inhibitor, has different safety profile with absence of neuropathy. Carmysap, a phase I/II trial of twice weekly Carfilzomib plus MP in eNDMM, demonstrated carfilzomib MTD at 36mg/m2. The safety profile appeared otherwise good for this frail population. We hypothesized that Carfilzomib can be used on a weekly schedule allowing to increase the dose of Carfilzomib given its positive safety profile. Methods. IFM2012-03 (carmysap weekly) is a phase 1/2 multicenter symptomatic eNDMM (65 and older) study to determine MTD during the phase 1 part and VGPR+CR rate (IMWG criteria) during the phase 2 part of KMP (Carfilzomib Weekly Plus Melphalan and Prednisone) regimen. Inclusion criteria required absolute neutrophils ≥1G/L, untransfused platelet count ≥75G/L, hemoglobine ≥8.5g/dL and clairance creatinine ≥30ml/min. Induction comprised nine 5 weeks cycles. K is given 36, 45, 56 and 70 mg/m2 on days 1, 8, 15, 22 IV route in combination to oral Melphalan 0.25mg/kg/j and oral prednisone 60mg/m2, both on days 1 to 4. Maintenance. Carfilzomib. 36 mg/m2 weekly, every two weeks IV route for 1 year. Melphalan and Prednisone is not pursued at maintenance. Analysis is done on ITT. Recruitment was 6 patients per cohort, 3 DLTs defined MTD at the lower N-1 dose. We will report at ASH the results of the phase 1 and 2. Results. 32 NDMM recruited, 30 treated in the study, 6 per cohort at K 36 mg/m², 45, 56, and 70 twice per DSMB request. The median age was 76 with 2/3rd older than 75, sex ratio M/F 1.2, R-ISS 2 and 3 in 80%.There was one DLT at K 36 (grade 4 lymphopenia), one at 45 (lysis syndrome complicated with grade 4 renal insufficiency, two at 56 (cardiac insufficiency grade 3 and febrile neutropenia grade 3) and 2 at 70 (vomiting grade 3 and liver cholestase enzyme grade 3) across the 2 70 cohorts. As a whole for the study, the ORR is 87.5%, with 45.7% at least in CR. At data cut-off, with a median follow-up at 15 months, one patient had progressed and 2 had died of whom one of cardiac dysfunction considered K related at 56. The safery profile appeared well tolerated, however, 22 SAE were reported for a total of greater than 200 cycles administered of KMP. Of particular interest, 19 SAEs were reported across the K 56 and 70 cohorts, 6 of which were cardiovascular origin. Conclusion. IFM2012-03, KMP weekly, Carfilzomib plus Melphalan and Prednisone in elderly NDMM has reached RP2D at 70mg/m2 of K. The SAE signal at the highest dose of K 70 raise concerns on using K 70 in patients older than 75-80 years old, and the DSMB may recommend for these patients to limit the RP2D at 56mg/m2 of K. Updated data for phase 1 and 2 portions will be presented at ASH for the first time. Disclosures Leleu: TEVA: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; LeoPharma: Honoraria; Pierre Fabre: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Karlin:celgene: Consultancy, Honoraria; Bristol: Consultancy; takeda: Consultancy; janssen-cilag: Consultancy, Honoraria; amgen: Consultancy, Honoraria. Meuleman:Celgene: Consultancy; Bristol-Myers-Squibb: Consultancy; Takeda: Consultancy; Amgen: Consultancy. Roussel:AMGEN: Consultancy, Other: lecture fees, Research Funding; sanofi: Other: lecture fees; celgene: Consultancy, Other: lecture fees, Research Funding; janssen: Consultancy, Other: lecture fees; BMS: Other: lecture fees. Decaux:The Binding Site: Other: supply of free light chain assays , Research Funding; SIEMENS: Honoraria, Other: supply of free light chain assays , Research Funding. Hulin:celgene: Honoraria; Bristol: Honoraria; Janssen: Honoraria; Amgen: Honoraria; takeda: Honoraria. Attal:amgen: Consultancy, Research Funding; sanofi: Consultancy; celgene: Consultancy, Research Funding; janssen: Consultancy, Research Funding. Moreau:Celgene: Honoraria; Takeda: Honoraria; Janssen: Honoraria, Speakers Bureau; Amgen: Honoraria; Novartis: Honoraria; Bristol-Myers Squibb: Honoraria. Facon:Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Bristol: Consultancy; Janssen: Consultancy, Speakers Bureau; Karyopharm: Consultancy; Novartis: Consultancy; Millenium/Takeda: Consultancy.

Introduction:Long-term outcome of patients with IPSS low or int 1 (LR) MDS treated by IST with horse or rabbit (hATG or rATG) +/-CsA is not well described and patient selection criteria for such a therapy remain ill-defined in daily practice, including after resistance to erythropoiesis stimulating agents (ESA). Methods: We report the outcome of 15 consecutive LR-MDS patients treated in our institution between 2005 and 2013, with h or rATG (15 mg/kg/d for 5 days and 3.5 mg/kg/d for 5 days, respectively), +/- CsA 2 mg/kg BID for 6 months (m). The use of h or rATG formulation was based on institutional practice and availability. Patients with altered renal function or vascular contra-indication to CsA (mostly due to age) only received ATG. Bone marrow (BM) blasts were counted over 500 cells in cases of very low BM cellularity and over 1,000 cells otherwise. FISH analysis of chromosomes 5 and 7 was performed in case of cytogenetic failure. IST response probability score (ISTRPS) was calculated according to Saunthararajah, Blood 2003. Overall response rate (ORR), including complete response (CR), assessed at 12 m, and progressive disease (PD) were defined according to IWG 2006 criteria. Transfusion independence (TI) was defined as independence from RBC transfusion for at least 8 weeks. Results: Median age was 60 years (y) (range 46-77). Median follow-up was 8.1 y. All patients were RBC-transfusion dependent (RCTD). Median RCTD duration was 4.9 m (0-42). Platelet counts were 2%, P=0.04) and RCTD duration (62.5% if RCTD ≤6 m versus 0 if RTCD >6 m, P=0.02). There was a trend for a higher TI rate with lower platelet counts (P=0.13) and high ISTRPS (P=0.14). By contrast age, using a 60y cut-off, and presence of a DRB15 allele were not predictive of TI (P=0.58 and 0.31) in this cohort. Two relapsed patients were retreated with hATG +CsA and achieved a second durable response (1 CR (45m+) and 1 TI (9m+)). One non-responding patient, who subsequently developed full-blown PNH, responded to CsA and eculizumab. 5-y cumulative incidence of PD and AML were 42% and 6% respectively and median OS was 5.6 y. Median OS was not reached in responders versus 22 m in non-responders (P=0.004 by log-rank test). A single toxic death from a hemorrhagic stroke occurred very early in a patient heavily pretreated for MDS-associated vasculitis. PNH clone expansion and cytogenetic evolution occurred in 2 (both responders) and 3 patients (2 responders). Conclusion: Lower-risk MDS patients responding to IST have a good long-term outcome. After relapse, durable responses to a second course of IST can be achieved. In addition to RCTD ≤6 m, BM blasts ≤2% emerged as an IPSS-R component strongly predicting response to IST. Age >60 y was not associated with worse response. Therefore, IST should be considered as a treatment option for selected lower-risk MDS patients with very low blast counts, irrespective of age. Disclosures Off Label Use: ATG and cyclosporin A are not approved for the treatment of MDS..

Abstract 2171 Background: Our group (JCO, 1992 10:1430; JCO 2003,21:2123) and others have reported tAPL to occur at increased frequency (from 5% of APL between 1984 and 1993 to 22% between 1994 and 2000 in our experience), generally less than 3 years after a primary neoplasm (mainly breast carcinoma) treated with the combination of anthracyclines (anthr) and cyclophosphamide (CY), radiotherapy (RT) and less often VP 16, but our last published series analyzed patients (pts) diagnosed before 2001. In addition, characteristics and outcome of tAPL are considered similar to those of de novo APL, but all reported comparisons were retrospective. We took advantage of our current multicenter APL 2006 trial, which includes both de novo and tAPL, to analyze possible recent changes in etiological factors of tAPL cases, and to prospectively compare them with de novo APL. Methods: In APL 2006 trial, pts 10 G/l, received the same induction treatment, followed by 2 consolidation courses with (randomized) ida+AraC or Ida+AraC+ATO. Pts >70y received the same induction course with reduced dose of Ida and two consolidation courses (Ida+ATO and ATO+ATRA). All patients received 2 y maintenance therapy combining continuous 6MP+ MTX and intermittent ATRA. Results: Between Nov 2006 and March 2010, 280 pts entered the trial, including 42 (15 %) tAPL. By comparison to our tAPL diagnosed before 2001 (JCO 2003, 21, 2123) the primary tumor was less often breast carcinoma (35.7% vs 56.6%, p=0.03), and more often prostate carcinoma (26.2% vs 4.7%; p In APL 2006 trial, characteristics of tAPL were similar to those of de novo APL, with regards to WBC count (21.4% WBC>10 G/l vs. 22.3% in de novo APL, respectively) and M3 variant (14% in the 2 groups). However, tAPL were older (mean 60.2y vs 48.7y in de novo cases, p The CR rate was 97.6% (41/42) in tAPL and 93.4% in de novo APL (p=0.48). The 18-month cumulative incidence of relapse was 0% and 1.2% in tAPL and de novo APL respectively (p=0.43). 18 months OS was 96.4% and 97.0%, respectively (p=0.83, log-rank test). The 18 month rate of death in CR was 3.6% in both tAPL and de novo APL (p=0.97), Conclusion: In this series of recently diagnosed tAPL, by comparison to our tAPL diagnosed before 2001, the primary tumor was less often breast carcinoma and more often another solid tumor (especially prostate). A combination of CT and RT had been less often used, hormone therapy more often, and mitoxantrone had no more been used. Prospective comparison with de novo APL included in the same trial showed tAPL to be characterized by older age and more frequent bcr3 breakpoint, but there were no differences in outcome between the 2 subgroups Disclosures: Fenaux: CELGENE, JANSSEN CILAG, AMGEN, ROCHE, GSK, NOVARTIS, MERCK, CEPHALON: Honoraria, Research Funding.

Abstract 1868 Aim: Erythropoiesis stimulating agents (ESA) or lenalidomide (in case of del 5q) are the usual first line treatments of anemia of low/int-1 IPSS (lower) risk MDS. After their failure, IST with ATG+/−CsA is among the approaches considered, with 30 to 50% erythroid response (Sloand, JCO 2008; Lim, Leukemia 2007, and others), including durable red cell transfusion independence (RBC-TI). In multivariate analysis, predictors of response to IST in MDS include low/Int-1IPSS (especially int-1 without excess blasts due to presence, in addition of anemia, of thrombocytopenia or intermediate (int) karyotype) and, depending on studies, age ≤60 y and HLA DR-15 positivity. Pts with those good prognostic factors were however overrepresented in several MDS series treated with IST and analysis of the first 400 pts included in the European LeukemiaNet lower risk MDS registry found only 2 pts treated with IST (De Witte, personal communication). We reviewed the characteristics and outcome of MDS pts treated with IST in our centre and assessed the frequency of low/int-1 MDS pts potentially candidates to IST, based on published prognostic factors, in the Groupe Francophone des Myélodysplasies (GFM) patient database. Methods: From Jan 2004 to Feb 2010, we treated in our center 12 MDS by IST. From mid 2003 to end of 2008, 1311 MDS pts with IPSS scoring, were entered into the GFM registry. We computed in this registry the frequency of pt subsets potentially good candidates to IST based on age, having anemia with low/int-1 IPSS, or int-1 with Results: The 12 pts treated with IST included 8M/4F. Median age was 63.5 y, (range 47–78, 50% pts older than 65 y). WHO classification was RA =3, RCMD =7, RAEB1 =2; cytogenetics normal /-Y =10; +8 =1; failed =1 pts). IPSS was Int-2 in 1, Int-1 in 10 and ND in 1 pt. All pts were RBC transfusion dependent and 11/12 also had platelets ≤50G/L. Pts received ATG (n=7) or ATG+CsA (n=5). Five (42%) pts, all with RA or RCMD, were responders at 6 months, according to IWG 2006 criteria (4 RBC-TI including 3 CR and one HI-E+ HI-P) and 7 were non-responders (NR). 4/6 DR-15 positive pts responded versus 1/5 DR-15 negative pts.Three of the 6 pts aged >65 y responded. With a median follow-up of 21.5 months (6-68), erythroid response was ongoing after 17, 21, 44, 47 and 62 months, respectively. Three NR pts died at 11, 16 and 18 months (one Int-2 pt with RAEB and +8, from AML progression, and 2 pts from marrow failure). In the GFM database, pts with transfusion dependent anemia and IPSS low or int-1, and IPSS int-1 with Conclusions: We confirm that durable erythroid responses to IST can be obtained in selected int-1 MDS patients, including in some pts aged >65 y. In the GFM data base of # 1300 pts, and based on published prognostic factors, the proportion of potential candidates to IST was very low if the age limit chosen was < 60y, and only slightly increased if the age limit was set to 65 or 70 years. Use of low-dose alentuzumab (Sloand, ASH 2009, abstr n°116), which appears to have less immediate toxicity than ATG (and therefore can be envisaged more easily above 60–65 years) may possibly extend the number of lower risk MDS that may benefit from IST. Disclosures: Off Label Use: ATG ciclosporine.

Abstract 3883 Poster Board III-819 Treatment of peripheral neuropathies (PN) related to IgM monoclonal (MIgM) gammopathy with anti Myelin-Associated-Glycoprotein (MAG) antibodies remains unsatisfactory. Reducing the serum level of the MIgM is likely to be a reasonable goal because of its auto-antibody activity against antigens expressed on peripheral nerve and because of various data, including studies of MIgM and complement deposition along nerve fibers and transfer experiments in animals, which argue in favour of a causal link between the MIgM and the nerve lesions. Rituximab (R) in combination with Fludarabine (F) and/or alkylating agents is considered as a highly effective regimen for achieving excellent remission in Waldenström's macroglobulinemia. It has been poorly evaluated in MIgM anti-MAG antibody-related PN. We retrospectively studied a cohort of 15 patients (pts) who were treated with such association or with R alone. Median age at diagnosis was 64 years (range, 47-84). 13/15 pts had MIgM with kappa-light-chain. All pts had sensory symptoms including 9 with ataxia, and 3 presented with disabling motor involvement. Median INCAT (Inflammatory Neuropathy Course and Treatment) disability score was 4 (range, 2-12). Median MIgM level was 5.9 g/l (range: 1.8-28). In 2 pts, it was not detectable by serum electrophoresis (SEP) but only by serum immunofixation (SIF). No pt had evidence for an associated overt lymphoid proliferation. Anti-MAG antibodies were assessed by immuno-blot and ELISA techniques. Electrophysiologic evaluation showed a demyelinating, axonal or mixed neuropathy in 8, 2 and 5 pts, respectively. Nine pts had been previously treated (7 with alkylating agents alone and 2 with intravenous immunoglobulin infusions) and none had experienced any clinical or biological improvement. Median interval time between PN diagnosis and treatment with R +/- chemotherapy was 25.6 months (range, 1-159). Twelve pts received a combination of R + chemotherapy (7 R + F + Cyclophosphamide (C), 4 R + C or chlorambucil, 1 R + F) and 3 received R alone. Significant and durable clinical improvement (including INCAT disability score) occurred in 7 pts, all treated with R + chemotherapy. Among these responders, 5 had a major reduction (>90%) of the serum MIgM level (including 3 with disappearance of monoclonal component on SEP but not on SIF). On the opposite, neither clinical response nor INCAT disability score improvement was observed in any pt treated with R alone. Electromyography significantly improved in 3 of the 9 evaluable pts, all of whom with concomitant major reduction on the MIgM serum level while on R + chemotherapy. Seven pts experienced drug-induced cytopenias including 4 grade III-IV neutropenia and 1 grade III thrombopenia. Treatment-related infections occurred in 3 pts (2 herpes zoster, 1 cytomegalovirus retinitis). One pt developed parotid adenocarcinoma one year after completion of R+F+C therapy. One pt died from cardiac arrest during a surgical procedure for lithiasic cholecystitis. In conclusion, combination of R, F and alkylating agents in MIgM anti-MAG antibodies-related PN provides high rates of durable clinical improvement, even in first-line refractory pts. Response is most often correlated with significant reduction of the MIgM serum level but does not need its disappearance. R + chemotherapy toxicity is acceptable but adding F implies immunosuppressive consequences that should be carefully evaluated. Although this remains to be formally demonstrated, R + chemotherapy seems to be more effective than R alone. Disclosures: No relevant conflicts of interest to declare.

Abstract 3408 Poster Board III-296 The t(4;14)(p16.3;q32), leading to the ectopic expression of two potential oncogenes, the Multiple Myeloma Set Gene (MMSET) and the Fibroblast Growth Factor 3 (FGFR3), is found in 15% of patients with multiple myeloma (MM) and is associated with a very poor prognosis. We previously shown in patients under 65 years of age that High Dose Therapy followed by Peripheral Blood Stem Cell Transplantation (HDT-PBSCT) provides a high response rate (RR) but a very short median relapse-free survival of only 11 months. In addition, relapses are often aggressive and chemoresistant. Thus, more effective regimen is urgently needed. We prospectively studied 23 t(4;14) MM patients treated with 3 or 4 cycles of a combination of Bortezomib and Dexamethasone (VD) (n=4) or of Bortezomib, Adriamycine and Dexamethasone (PAD) (n=19) as induction treatment before HDT-PBSCT (Melphalan 200 mg/m2). T(4;14) was detected using real time quantitative PCR searching for IGH/MMSET and FGFR3 transcripts. RR, event-free survival (EFS) and overall survival (OS) were evaluated. Median age at diagnosis was 51 years (range, 33-64). Isotype was IgA in 12 (52%) patients. All patients had stage II or III MM. An elevated serum β2m level (>3.5 mg/L) was found in 14 (61%) patients, and a low haemoglobin (Hb) level ( Disclosures: No relevant conflicts of interest to declare.