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PURPOSE Multiple myeloma (MM) is characterized by copy number abnormalities (CNAs), some of which influence patient outcomes and are sometimes observed only at relapse(s), suggesting their acquisition during tumor evolution. However, the presence of micro-subclones may be missed in bulk analyses. Here, we use single-cell genomics to determine how often these high-risk events are missed at diagnosis and selected at relapse. MATERIALS AND METHODS We analyzed 81 patients with plasma cell dyscrasias using single-cell CNA sequencing. Sixty-six patients were selected at diagnosis, nine at first relapse, and six in presymptomatic stages. A total of 956 newly diagnosed patients with MM and patients with first relapse MM have been identified retrospectively with required cytogenetic data to evaluate enrichment of CNA risk events and survival impact. RESULTS A total of 52,176 MM cells were analyzed. Seventy-four patients (91%) had 2-16 subclones. Among these patients, 28.7% had a subclone with high-risk features (del(17p), del(1p32), and 1q gain) at diagnosis. In a patient with a subclonal 1q gain at diagnosis, we analyzed the diagnosis, postinduction, and first relapse samples, which showed a rise of the high-risk 1q gain subclone (16%, 70%, and 92%, respectively). In our clinical database, we found that the 1q gain frequency increased from 30.2% at diagnosis to 43.6% at relapse (odds ratio, 1.78; 95% CI, 1.58 to 2.00). We subsequently performed survival analyses, which showed that the progression-free and overall survival curves were superimposable between patients who had the 1q gain from diagnosis and those who seemingly acquired it at relapse. This strongly suggests that many patients had 1q gains at diagnosis in microclones that were missed by bulk analyses. CONCLUSION These data suggest that identifying these scarce aggressive cells may necessitate more aggressive treatment as early as diagnosis to prevent them from becoming the dominant clone.

Background Tyrosine kinase inhibitors (TKI) can be safely discontinued in chronic phase chronic myeloid leukemia (CP‐CML) patients who had achieved a sustained deep molecular response. Based on the results of discontinuation trials, recommendations regarding patient selection for a treatment‐free remission (TFR) attempt had been proposed. The aims of this study were to evaluate the rate of patients eligible for TKI discontinuation and molecular recurrence‐free survival (MRFS) after stop according to recommendations. Methods Over a 10‐year period, newly diagnosed CP‐CML patients and treated with first‐line TKI in the nine French participating centers were included. Eligibility to treatment discontinuation and MRFS were analyzed and compared according to selection criteria defined by recommendations and first‐line treatments. Results From January 2006 to December 2015, 398 patients were considered. Among them, 73% and 27% of patients received imatinib or either second or third generation tyrosine kinase inhibitors as frontline treatment, respectively. Considering the selection criteria defined by recommendations, up to 55% of the patients were selected as optimal candidates for treatment discontinuation. Overall 95/398 (24%) discontinued treatment. MRFS was 51.8% [95% CI 41.41–62.19] at 2 years and 43.8% [31.45–56.15] at 5 years. Patients receiving frontline second‐generation TKI and fulfilling the eligibility criteria suggested by recommendations had the lowest probability of molecular relapse after TKI stop when compare to others. Conclusion One third of CP‐CML patients treated with TKI frontline fulfilled the selection criteria suggested by European LeukemiaNet TFR recommendations. Meeting selection criteria and second‐generation TKI frontline were associated with the highest MRFS., Tyrosine kinase inhibitors (TKI) can be safely discontinued in chronic phase chronic myeloid leukemia patients who had achieved a sustained deep molecular response. Several recommendations regarding the optimal selection of the patients before stop have been proposed. Based on these recommendations, we estimate that one third of the patients treated with frontline TKI will meet these criteria. Moreover, patients treated with frontline second generation TKI and selected as optimal candidate according to these recommendations have the highest probability of molecular recurrence‐free survival when compared to others.

Background: Tyrosine Kinase Inhibitors (TKIs) discontinuation in patients who had achieved a deep molecular response (DMR) offer now the opportunity of prolonged treatment-free remission (TFR). Patients and Methods: Aims of this study were to evaluate the proportion of de novo chronic-phase chronic myeloid leukemia (CP-CML) patients who achieved a sustained DMR and to identify predictive factors of DMR and molecular recurrence-free survival (MRFS) after TKI discontinuation. Results: Over a period of 10 years, 398 CP-CML patients treated with first-line TKIs were included. Median age at diagnosis was 61 years, 291 (73%) and 107 (27%) patients were treated with frontline imatinib (IMA) or second- or third-generation TKIs (2&ndash, 3G TKI), respectively. With a median follow-up of seven years (range, 0.6 to 13.8 years), 182 (46%) patients achieved a sustained DMR at least 24 months. Gender, BCR-ABL1 transcript type, and Sokal and ELTS risk scores were significantly associated with a higher probability of sustained DMR while TKI first-line (IMA vs. 2&ndash, 3G TKI) was not. We estimate that 28% of CML-CP would have been an optimal candidate for TKI discontinuation according to recent recommendations. Finally, 95 (24%) patients have entered in a TFR program. MRFS rates at 12 and 48 months were 55.1% (95% CI, 44.3% to 65.9%) and 46.9% (95% CI, 34.9% to 58.9%), respectively. In multivariate analyses, first-line 2&ndash, 3G TKIs compared to IMA and TKI duration were the most significant factors of MRFS. Conclusions: Our results suggest that frontline TKIs have a significant impact on TFR in patients who fulfill the selection criteria for TKI discontinuation.

In multiple myeloma (MM), among the anomalies associated with shorter survival, it should be noted recurrent copy number variations (CNV), such as del(17p13), del(1p32), or 1q gains. These abnormalities are considered secondary, thus acquired during the course of the disease. Although they can be observed from diagnosis, they are only detected at the time of relapses in some patients. It is now clearly demonstrated that MM is a molecular subclonal disease, with the coexistence of different subclones of varying size. As in other cancers, it has also been shown that these different subclones can vary in size according to the different relapses, suggesting that an unnoticed minor subclone at diagnosis could become the major one at the time of relapse. Although subclonality has been largely reported at the mutational level, little is known about this phenomenon at the CNV level. Since a few CNV are associated with a poor outcome, and assuming they will impact the disease course, it would be clinically highly valuable to track these abnormalities at the time of diagnosis in minor subclones. Here, we report the first analysis at the single cell level of CNV of tumor cells from 81 patients with MM analyzed at the time of diagnosis, relapse or pre-symptomatic stages. A total of 52,176 single MM cells were analyzed. The number of analyzable tumor cells was variable from patients to patients, due to heterogeneity in the sample cellularity, but also variability in cell capture rate for the single cell analysis. The mean number of analyzable cells was 656 MM cells per patient (range=83-5192). To avoid possible false positive cases, we arbitrarily defined a subclone by at least 10 cells presenting the same CNV. In these 81 patients, at least one subclone was detected in 74 of them (91%). In this cohort, a subclonal high-risk CNV (not detected on the routine assessment) was observed in 19 patients (23.5%). We had the opportunity to also analyze at single cell level residual MM cells from one patient at the end of induction therapy, and early relapse. This patient displayed a 1q gain subclone at diagnosis (16 % of the analyzed cells), not detected in the bulk analysis. At the post-induction time (thus before high-dose melphalan and autologous stem cell transplantation), 70 % of the 202 analyzable tumor cells presented this high-risk feature. This patient did relapse only 18 months after diagnosis and at this time, 92% of the cells harbored the 1q gain (Figure 1). To address the question whether these high-risk subclonal features may impact outcome as soon as diagnosis, we explored our database. We found that 1q gains are observed in 34.1% of patients (1891/5539) at the time of diagnosis. When analyzing patients at relapse, 46.3% of them displayed a 1q gain (622/1341), thus a 12% increase. This increasing frequency reflects clonal selection of minor subclones already present at diagnosis but not detectable by conventional technique (found in comparable proportions), rather than actual acquisition after diagnosis during evolution of the disease. We then looked at the prognostic impact of 1q gain in patients displaying this CNV at diagnosis versus those presenting it only at the time of first relapse. Interestingly, the PFS and OS) curves were totally superimposable, suggesting that this subclonal 1q gain present from diagnosis in these latter patients impacts survival, possibly through early expansion. In order to go further in the molecular consequences of these high-risk subclones, we did perform single cell RNA-sequencing in 63 of the 81 patients. 1q gains defined specific subclones in the MM cells expression analyses from affected patients. Based on the expression of CDC28 protein kinase regulatory subunit 1B (CKS1B), located at 1q21, we found that high expression was restricted to specific subclones. In conclusion, our study highly suggests that high-risk CNVs are not acquired after, but are present from the diagnosis, and selected by the treatment. These findings may have implications in high-risk definition and patient's management, by reinforcing the therapeutic strategy in these patients as soon as the first line therapy to prevent the clonal selection of these aggressive subclones. Whether this finding could be extended to cancer in general but also in some pre-malignant stages is possible, but needs to be explored. Figure 1 Figure 1. Disclosures Perrot: GSK: 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; BMS Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria; Sanofi: Honoraria, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Leleu: Carsgen Therapeutics Ltd: Honoraria; Celgene: Honoraria; Gilead Sciences: Honoraria; Janssen-Cilag: Honoraria; Karyopharm Therapeutics: Honoraria; Merck: Honoraria; Mundipharma: Honoraria; Novartis: Honoraria; Oncopeptides: Honoraria; Pierre Fabre: Honoraria; Roche: Honoraria; Sanofi: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria; Takeda: Honoraria, Other: Non-financial support; AbbVie: Honoraria. Manier: Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene - Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: 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, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Macro: Sanofi: Honoraria; GSK: Honoraria; Takeda: Honoraria, Other: Travel accomodation, Research Funding; Janssen: Honoraria, Other: Travel accomodation, Research Funding; Celgen/BMS: Honoraria. Mohty: Novartis: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria; Adaptive Biotechnologies: Honoraria; Bristol Myers Squibb: Honoraria; Astellas: Honoraria; Sanofi: Honoraria, Research Funding; Takeda: Honoraria; Gilead: Honoraria; Pfizer: Honoraria; Jazz: Honoraria, Research Funding. Munshi: Novartis: Consultancy; Takeda: Consultancy; Bristol-Myers Squibb: Consultancy; Janssen: Consultancy; Oncopep: Consultancy, Current equity holder in publicly-traded company, Other: scientific founder, Patents & Royalties; Abbvie: Consultancy; Amgen: Consultancy; Karyopharm: Consultancy; Celgene: Consultancy; Adaptive Biotechnology: Consultancy; Legend: Consultancy; Pfizer: Consultancy.

Objectives To assess the reduction of transfusions rate in transfusion-dependent patients with low-risk myelodysplastic syndrome (MDS) with iron overload treated with deferasirox. Methods Prospective observational study. Primary endpoint was reduction in transfusion requirements (RTR) at 3 months, (assessed on 8-week period). Secondary endpoints were hematologic improvement according to International Working Group (IWG) 2006 criteria at 3, 6, and 12 months. Results Fifty-seven patients were evaluable. After 3 months of chelation, no effect was seen on transfusion requirement (5.9 packed red blood cells (PRBC) vs 5.8 before chelation). According to the Kaplan-Meier analysis, the probability of RTR at 3, 6, and 12 months was assessed as 3.5%, 9.1%, and 18.7%, respectively. Median duration of RTR was 182 days. However, during the 12-month follow-up after deferasirox initiation, 17 patients (31.5%) achieved minor erythroid response [HI-E] according to IWG criteria, 10 of whom having achieved Hb improvement at month 12. Conclusion After 3 months of treatment, deferasirox had no impact on transfusion requirement in regularly transfused patients with low-risk MDS. However, deferasirox could induce 31% of erythroid response during the 12-month follow-up period thus suggesting that iron chelation therapy with deferasirox may induce an effect on hematopoiesis in a subset of patients with MDS and iron overload.

International audience; no abstract

The response definitions proposed by the European Leukemia Net (ELN) have been recently modified. We evaluated the new criteria for de novo imatinib (400 mg/d) chronic phase chronic myeloid leukemia (CP-CML) patients. Response status according to the 2009 and 2013 criteria were determined in 180 unselected patients. Outcome of the subgroups of patients were then compared. The 180 patients were classified as optimal responders (OR2009; n = 113, 62.7%), suboptimal responders (SOR2009; n = 47, 26.1%) and failures (FAIL2009; n = 20, 11.1%) according to the 2009 ELN criteria and optimal responders (OR2013; n = 77, 42.7%), warnings (WAR2013; n = 59, 32.7%), and failures (FAIL2013; n = 44, 24.4%) according to the 2013 ELN criteria. No difference in terms of outcome was observed between OR2009 patients who became WAR2013 when compared with OR2013 patients. When compared with FAIL2009 patients, SOR2009 patients who became WAR2013 had better EFS, FFS, PFS, and OS. No difference was observed in PFS or OS in SOR2009 patients who became FAIL2013. The 2013 ELN response status criteria have improved patients classification in terms of response status. However, in our patient population this improvement is related to a better definition of failure rather than that of optimal response for CP-CML patients treated with IM frontline therapy. Am. J. Hematol. 90:37–41, 2015. © 2014 Wiley Periodicals, Inc.

Introduction. Cases series of patients with FIP1L1-PDGFRA (F/P)-associated chronic eosinophilic leukemia (F/P+ CEL) are scarce and of small sample-size. Low-dose imatinib mesylate (IM) is highly effective in this setting. Although successful treatment discontinuation has been reported, approximately 40% of the patients subsequently relapse. To date, no predictor of relapse after IM discontinuation has yet been evidenced. Methods. We conducted a French multicentric retrospective of patients diagnosed with F/P+ CEL between 2003-2019. Weight loss was defined as a 10% weight loss over the course of the disease's history. Complete (CHR) and partial (PHR) hematological responses were defined as a normalization of the absolute eosinophil count (AEC) and as a reduction in peripheral blood eosinophilia by at least 50% from baseline, respectively. Relapses were defined as the recurrence of eosinophilia, with or without evidence of F/P-gene transcript, but without any other explanation. Complete molecular response (CMR) was defined as a negative RT-PCR and/or RQ-PCR assay for F/P rearrangement. A backward stepwise logistic regression model was used to identify factors associated with relapse after IM discontinuation. Results. One hundred and fifty F/P+ CEL patients (145 males; mean (SD) age at diagnosis: 49 (+/-12 years) were included, among which 26 (17%) did not report any symptom. The main involved organs were the spleen (n=65, 43%), skin (n=47, 31%), heart (n=27, 18%), lungs (n=36, 24%), central nervous system (n=14, 9%), and bones/joints (n=8, 5%). Four (2,6%) patients showed features of vasculitis, involving the skin (n=2) and the CNS (n=2). The mean peak AEC was 10.3 G/L (+/-6 G/l). Besides eosinophilia, the most frequent associated complete blood count (CBC) abnormalities were thrombocytopenia (n=43, 28%), anemia (n=37, 24%), hyperleukocytosis (n=33, 22%) and monocytosis (n=25, 16%). Forty-seven (31%) patients had normal CBC besides eosinophilia. Bone marrow karyotype was normal in 91% (when tested, n=94). Serum vitamin B12 and tryptase (mean: 2386 (+/-1435) pmol/L and 34 (+/-20) µg/L) levels were elevated in 74 (94%) and 44 (79%) of patients respectively, whereas CRP and IgE levels were elevated in 31 (26%) and 12 (14%) each. None of the 37 (25%) patients that received first-line glucocorticoid therapy achieved CHR. All but 3 patients received IM (daily starting dose: 100 (n= 102; 72%), 200 (n=13; 9%) or 400 mg (n=20; 14%)), of whom 100% and 99% achieved CHR and CMR (when tested: n=84), respectively. The mean follow-up (FU) was 80 (+/- 56) months, with overall survival at 1, 5 and 10 years of 99%, 95% and 84% (reaching 100%, 98% and 89% in the 147 IMB-treated patients) respectively. Overall, 8 (5%) patients died during FU, including untreated patients with acute myeloblastic leukemia transformation (n=2) and a single patient with massive cerebral infarction. Eight patients relapsed during IM tapering, all of which were successfully treated when higher doses of IM were resumed. After a median [IQR] of 44 [27-72] months of IM treatment, 46 (32%) patients eventually discontinued IM, amongst whom 19 (41%) relapsed after a median of 10[4-23] months (42% of relapses defined by PCR). In multivariate analysis, weight loss (HR: 5,02 95%CI[1,9 - 28,04]; p =0,004), the time between onset of eosinophilia and IM initiation (HR 1,02 [1,00 - 1,03]; 0,01) and duration of IM treatment prior to discontinuation (HR: 0,97 [0,95-0,99]; p=0,01) were independent factors of relapse (Table 1). Conclusion. This large cohort further confirms that F/P+ CEL almost exclusively affects male patients, with spleen, skin, heart and lung involvements being the most frequent. While glucocorticoids never lead to the normalization of CBC parameters, IM is highly effective and treated patients carry an excellent prognosis. After IM discontinuation, although 60% of patients maintain CHR overtime, 40% subsequently relapse, with weight loss, time between onset of eosinophilia and IM initiation and duration of IM treatment prior to discontinuation being significant but moderate independent factors of relapse. Disclosures Nicolini: Incyte Biosciences: Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Sun Pharma Ltd: Consultancy. Tavitian:Novartis: Membership on an entity's Board of Directors or advisory committees. Huguet:Novartis: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Incyte Biosciences: Honoraria; Amgen: Honoraria; Servier: Honoraria; Jazz Pharmaceuticals: Honoraria. Jardin:Servier: Honoraria; janssen: Honoraria; celgene: Honoraria; roche: Honoraria; amgen: Honoraria.

Sustained imatinib treatment in chronic myeloid leukemia patients can result in complete molecular response allowing discontinuation without relapse. We set out to evaluate the frequency of complete molecular response in imatinib de novo chronic phase chronic myeloid leukemia patients, to identify base-line and under-treatment predictive factors of complete molecular response in patients achieving complete cytogenetic response, and to assess if complete molecular response is associated with a better outcome. A random selection of patients on front-line imatinib therapy (n=266) were considered for inclusion. Complete molecular response was confirmed and defined as MR 4.5 with undetectable BCR-ABL transcript levels. Median follow up was 4.43 years (range 0.79–10.8 years). Sixty-five patients (24%) achieved complete molecular response within a median time of 32.7 months. Absence of spleen enlargement at diagnosis, achieving complete cytogenetic response before 12 months of therapy, and major molecular response during the year following complete cytogenetic response was predictive of achieving further complete molecular response. Patients who achieved complete molecular response had better event-free and failure-free survivals than those with complete cytogenetic response irrespective of major molecular response status (95.2% vs. 64.7% vs. 27.7%, P=0.00124; 98.4% vs. 82.3% vs. 56%, P=0.0335), respectively. Overall survival was identical in the 3 groups. In addition to complete cytogenetic response and major molecular response, further deeper molecular response is associated with better event-free and failure-free survivals, and complete molecular response confers the best outcome.

Purpose to evaluate the relevance of the 2013 ELN response status criteria for de novo imatinib (400 mg/d) chronic phase chronic myeloid leukemia (CP-CML) patients. Patients and Methods Response status according to the 2009 and 2013 criteria were determined in 180 unselected patients. Outcome of the subgroups of patients were then compared. Results One hundred and eighty patients were included in this study. The median age at diagnosis was 58.1 years (range, 19.8-88.9) and 112 (62.2%) were male. Sokal risk scores were low in 50 patients (27.7%), intermediate in 74 (41.1%), high in 38 (21.1%) and unknown in 18 patients (10%). Ten patients (5.5%) had clonal evolution at diagnosis. With a median follow up of 5.4 years, the 180 patients were classified as optimal responders (OR2009) (n=113, 62.7%), suboptimal responders (SOR2009) (n=47, 26.1%) and failures (FAIL2009) (n=20, 11.1%) according to the 2009 ELN criteria and optimal responders (OR2013) (n=77, 42.7%), warnings (WAR2013) (n=59, 32.7%) and failures (FAIL2013) (n=44, 24.4%) according to the 2013 ELN criteria. All the patients classified as failures according to the 2009 criteria were classified as failures by the 2013 criteria. Results are presented in table 1. No difference was observed in event-free (EFS), progression-free (PFS) and overall (OS) survivls between OR2009 and SOR2009 or between OR2013 and WAR2013. PFS and OS were not different between SOR2009 and FAIL2009 whereas a significant difference was observed between WAR2013 and FAIL2013 in PFS and OS (p=.003 and p=.024 respectively). No difference in terms of outcome was observed between OR2009 patients who became WAR2013 when compared to OR2013 patients. When compared to FAIL2009 patients, SOR2009 patients who became WAR2013 had better EFS, FFS, PFS and OS. No difference was observed in PFS or OS in SOR2009 patients who became FAIL2013. Conclusion The 2013 ELN response status criteria have improved patients classification in terms of response status. However this improvement is related to a better definition of failure rather than that of optimal response for CP-CML patients treated with IM frontline therapy. Disclosures: Etienne: Ariad Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity’s Board of Directors or advisory committees. Dulucq:Novartis: Membership on an entity’s Board of Directors or advisory committees. Nicolini:Ariad Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Teva: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Mahon:Novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity’s Board of Directors or advisory committees; Ariad Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees.

Background:Long-term blood transfusions remain the mainstay of supportive care in patients with low-risk myelodysplastic syndromes (MDS). Blood transfusions can result in iron overload, which can lead to impaired organ function, significant morbidity and mortality. Although debate exists around its use in patients with MDS, iron chelation therapy is recommended in patients with low-risk MDS to prevent iron-overload toxicities and to improve survival. In addition, hematologic improvement has been reported during chelation therapy (Jensen PD 1996, Gattermann N 2012). Here we report results from a prospective, observational study that evaluated a hematologic response to deferasirox in a large population of regularly transfused patients with low- or intermediate-1-risk MDS. Methods:inclusion criteria: Transfusion-dependent (at least 4 packed red blood cells (PRBC)/8 weeks) adult patients with IPSS low- or intermediate-1-risk MDS who had initiated or had been receiving chelation therapy for less than 3 months. Primary endpoint was reduction in transfusion requirements at 3 month, (i.e. the number of PRBC received during the 8 weeks before deferasirox initiation compared with the 8 weeks before month 3). Secondary endpoints included: hematologic improvement (HI; IWG 2006 criteria for erythroid [HI-E], platelet [HI-P] and neutrophil [HI-N]) at 3, 6 and 12 months, duration of response, serum ferritin levels and safety. Results: 70 patients were included, 57 were evaluable. Most exclusions (19%) were related to a low level of transfusion before inclusion. Median age was 78.3 years. The cytologic subtypes were: sideroblastic anemia, 31.6%; refractory anemia, 19.3%; refractory anemia with excess blasts-1, 17.5%; refractory cytopenia with multilineage dysplasia, 17.5%; 5q syndrome, 10.5%; unclassified SMD, 3.6%. Median time since diagnosis was 2.79 years (33 months). Before inclusion, 87% patients had received a treatment for MDS (erythropoiesis-stimulating agents, 72%; lenalidomide, 17%;G-CSF, 16%; azacitidine, 7%; thalidomide: 2%). Patients received a median of 5.8 ± 2.8 PRBC during the 8 weeks before inclusion. The mean number of PRBC received per month during the 6 months before inclusion was 2.11. The median serum ferritin level at inclusion was 1 543 ng/ml.The mean number of PRBC received in the whole population post inclusion (eight weeks before month 3) was 5.9, which was not significantly different from the number of PRBC given during the 8 weeks before inclusion (5.8). However at 3 months, 4 patients had a positive effect on transfusion requirement. At 6 and 12 months, positive effect occurred in 3 and 4 additional patients, respectively. 10 patients achieved HI-E during the study and according to Kaplan-meier analysis, the probability of HI-E was 12.7% at 6 months and 24.2% at 1 year. During the study, 17 patients (32%) achieved an erythroid response, i.e positive effect on transfusion requirement and/or HI-E; 19% had an erythroid response at month 12. Median duration of erythroid response was 123 days. 3.5%, 10%, 21% of patients had received a concomitant treatment with deferasirox at 3, 6, and 12 months, respectively. However,deferasirox was the sole specific treatment received in 12/17 patients with erythroid response. 27 patients experienced adverse events (AEs) related to deferasirox, among them 4 patients with grade > 2 . 32 patients underwent deferasirox dosing modifications, and 20 patients had discontinued treatment by 3 months ( median duration of treatment 11.3 months). In patients receiving deferasirox for more than 9 months, the median serum ferritin level at 12 months was 1 438 ng/ml . In contrast, the median serum ferritin level at 12 months was 2247 ng/ml in the whole group. There were no predictive factors of erythroid response (cytologic classification, time since diagnosis, level of ferritin at inclusion, the number of PRBC transfused before inclusion), but the number of responders was low. Conclusions: After 3 months of treatment, deferasirox had no impact on transfusion requirement in regularly transfused low risk MDS patients. However, deferasirox could induce 19% of specific erythroid response at 12 months. These results suggest that iron chelation therapy with deferasirox may induce an effect on hematopoiesis in a small subset of patients with MDS and iron overload. Disclosures Rose: Genzyme, Novartis, Celgene: Honoraria, Research Funding. Beyne-Rauzy:Celgene, Novartis: Honoraria. Dreyfus:Novartis: Honoraria.

Abstract 3754 Background Imatinib (IM) has dramatically improved the prognosis of chronic myeloid leukaemia (CML) patients. Some of them will achieve a so-call complete molecular remission (CMR) that allows when it is sustained treatment discontinuation without relapse. Aims Aims of this study were i) to evaluate the frequency of CMR in IM de novo CML-CP patients, ii) to identify baseline and ongoing predictive factors of CMR in patients who had achieved a complete cytogenetic response (CCyR) on IM therapy, iii) to assess if achieving a CMR with IM frontline therapy is associated with a better event and progression-free survival. Methods Unselected CML chronic phase patients under frontline IM therapy were considered. CMR was defined as undetectable BCR-ABL transcript with sensitivity of at least 4·5 log on two consecutive analyses at least two months apart. Event-free survival (EFS) referred to survival without loss of complete hematologic response, loss of complete CCyR, detection of a BCR-ABL domain kinase point mutation associated with a high level of IM resistance, progression to accelerated or blastic phase, death of any cause on or off therapy, off treatment for toxicity. Progression-free survival (PFS) referred to survival without events previously described with the exception of treatment cessation for toxicity. EFS and PFS and overall survival were measured from the date of the first CCyR on therapy to the date of event. Among patients who failed to achieve a CMR, patients with a follow-up lower than the observed median time to CMR and without any reported event were excluded for the identification of predictive factors of CMR and survival studies . Results 266 patients diagnosed with CML-CP and treated with IM frontline were included between July 2000 and June 2010. The median age was 56 years (range 17–89), 160 (60%) were male. 86% of the patients received an initial IM daily dose of 400 mg. Sixty-five (24%) patients had IM dose increase to at least 600 mg. The median follow-up was 4,43 years (range 0.79–10 .8). At the time of the analysis 88 (33%) patients had stopped IM. Two hundred and thirty three patients achieved a CCyR while on IM. Among them, 35 (13%) had a CCyR without major molecular response (MMR), 133 (50%) a CCyR with MMR without CMR, 65 (24%) a CCyR with CMR. The median time to CMR was 32.7 months (range 2.6 to 87.9). Forty six out of the 65 patients (70%) were still in CMR at the last follow-up with a median duration of CMR of 35.4 months (range, 4.1 to 91.5 months). For patients who achieved a CMR, the probability of remaining in CMR at two years is 68%. Twelve out of 35 patients of the CCyR+MMR- group, 41 out of 133 patients of the CCyR+MMR+CMR- group had a follow-up below the observed median time to CMR and without any reported event during follow-up were excluded for the identification of CMR predictive factors and survival studies. In multivariate analysis, spleen enlargement below the costal margin at diagnosis was negatively associated with the achievement of a CMR (HR:0.354 CI95%:0.192–0.654; p=0.0009) while shorter time from IM start to the first CCyR (CCyR before or after 12 months, HR:0.5; IC95%:0.27–0.95; p=0.034) and MMR (before or after 12 months; HR:0.2147;IC95%:0.092–0.5; p=0.00038) were strongly associated with the probability of achieving a CMR. Patients who achieved a CMR had a better EFS and PFS than those with CCyR irrespective of MMR status (95.2% vs 64.7% vs 27.7% p=0.00124; 98.4% vs 82.3% vs 56% p=0.0335) (figures 1a and 1b). Overall survival was not different between the 3 groups. Conclusion This study points out that once patients achieve a CCyR on IM therapy, achieving a further deeper molecular response is associated with a better EFS and PFS, CMR confering the best outcome. Disclosures: Etienne: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Nicolini:Novartis Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; ARIAD: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teva: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mahon:Novartis Pharma: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy.