Abstract: The value of pretransplant splenectomy in patients with myelofibrosis (MF) is subject to debate, since the procedure may preclude subsequent allogeneic hematopoietic cell transplantation (allo‐HCT). To determine the impact of pretransplant splenectomy on the incidence of allo‐HCT, we conducted a comprehensive retrospective study of all patients with MF for whom an unrelated donor search had been initiated via the French bone marrow transplantation registry (RFGM) between 1 January 2008 and 1 January 2017. Additional data were collected from the patients' medical files and a database held by the French‐Language Society for Bone Marrow Transplantation and Cell Therapy (SFGM‐TC). We used a multistate model with four states (“RFGM registration”; “splenectomy”; “death before allo‐HCT”, and “allo‐HCT”) to evaluate the association between splenectomy and the incidence of allo‐HCT. The study included 530 patients from 57 centers. With a median follow‐up time of 6 years, we observed 81 splenectomies, 99 deaths before allo‐HCT (90 without splenectomy and nine after), and 333 allo‐HCTs (268 without splenectomy and 65 after). In a bivariable analysis, the hazard ratio [95% confidence interval (CI)] for the association of splenectomy with allo‐HCT was 7.2 [5.1‐10.3] in the first 4 months and 1.18 [0.69‐2.03] thereafter. The hazard ratio [95% CI] for death associated with splenectomy was 1.58 [0.79‐3.14]. These reassuring results suggest that splenectomy does not preclude allo‐HCT in patients with MF.

Abstract: Abstract 2841 Introduction: Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) characterized by bone marrow fibrosis, splenomegaly, cytopenias and constitutional symptoms. Ruxolitinib was recently approved by the FDA for the treatment of MF in the USA; its approval in Europe is still pending. However, EU patients may access to ruxolitinib through compassionate programs. In France, health authorities opened a compassionate patient-named program (Authorization for Temporary Utilization [ATU] program. Methods: 241 French patients (pts) with MF, including primary (PMF), post-polycythemia vera (PPV) and post-essential thrombocythemia (PET) MF were granted ruxolitinib therapy through ATU program, independently of their JAK2 mutational status, between April 15, 2011 and May 31, 2012. Physicians were asked to provide information on disease characteristics, treatment history, constitutional symptoms, spleen size, platelet and neutrophils count, as well as the ruxolitinib dose prescribed and adverse events (AE). Request forms had to be submitted at the time of initial application and every 3 months upon drug resupply or in case of treatment discontinuation. This analysis has been performed based on data available at baseline (n= 241), after 3 months (n= 101), 6 months (n= 57), 9 months (n= 21) and 12 months (n= 4). Results: In the entire cohort, 138 pts were men and 103 women. Median age was 68.3 years. 51.5% of pts had PMF, 22.8% PPV-MF and 23.8% PET-MF. 99.2% of pts had received ≥1 lines of therapy for MF prior to ruxolitinib (hydroxyurea: 56%; pipobroman: 15.4%; iMIDs: 13.7%; interferons: 13.7%; erythropoietins: 6.6%; spleen irradiation: 6.6%; anagrelide: 5.8%; corticosteroids: 4.9%). Despite these therapies, 93.7% had constitutional symptoms and 94.2% of patients presented a palpable splenomegaly (median 15 cm below costal margin) at inclusion. Efficacy: According to the baseline platelet count, ruxolitinib therapy was initiated at 15 mg BID in 132 pts (54.8%) or 20 mg BID in 103 pts (42.7%), or other doses in a minority of pts (n=6). Among the pts who were evaluable after 3 and 6 months of therapy, 96.5% and 90% presented a mean reduction in the spleen size (by palpation) by 47.2% and 46% from baseline, respectively. Constitutional symptoms resolved in 65.3% and 70.2% of pts at the aforementioned time points, respectively. In pts who completed 9 months follow-up (n=21), benefits in spleen size reduction and symptoms resolution were durable (95% and 71.4%). Safety: Since the beginning of the ruxolitinib ATU program, 83 pts presented at least one AE, including 27 pts with serious AE (SAE), with or without causal relationship to ruxolitinib therapy. AE, all grades, were essentially hematologic abnormalities (51.6%), gastro-intestinal 6.3%, cardiac 3.1%, musculoskeletal 3.1%, hepatic 2.3%, infection 2.3%. Dose adjustments were reported in 60 pts, mainly due to thrombocytopenia (n=36) and anemia (n=13). However, no patient discontinued ruxolitinib therapy because of cytopenia. Treatment was discontinued in 11 patients after a median duration of 2.6 months (range 0.3–7.9 months). Reasons for discontinuation were death (n=6), AE (n=2), inefficacy (n=2), and patient decision (n= 1). Conclusion: In this large, unselected population of heavily pretreated MF pts, ruxolitinib therapy appeared to be effective in treating both constitutional symptoms and splenomegaly, in line with previously reported efficacy in clinical trials. The safety profile seems also comparable. Comprehensive data and updated follow-up of the cohort will be presented. Disclosures: Off Label Use: compassionate use of ruxolitinib for myélofibrosis in France (indication not yet approved by EMEA). Rey:Novartis: Consultancy. Nicolini:novartis, Bristol myers Squibb, Pfizer, Ariad and Teva: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Recher:Celgène, Genzyme, Sunesis, Jansen-Cilag: Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel to ASH Other. Ranta:Novartis: Membership on an entity's Board of Directors or advisory committees. Legros:Novartis, Bristol Myers-Squibb: Research Funding, Speakers Bureau, Travel to meeting Other. Viallard:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dupriez:novartis: Membership on an entity's Board of Directors or advisory committees. Coiteux:Novartis, Bristol Myers-Squibb: Speakers Bureau. Demory:Novartis: Honoraria. Giraudier:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ugo:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Travel to ASH Other. Kiladjian:Incyte: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Roy:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel to ASH Other.

Abstract: Abstract 440 Background: The JAK2V617F mutation is found in a small proportion of MDS, especially in RARS-T and occasionally in other MDS subtypes, but the overall impact of JAK2V617F on MDS characteristics and outcome remains unclear. Method: Diagnostic and follow up data on MDS patients (pts) with known JAK2V617F mutation status were collected from 19 centers of the Groupe Francophone des Myélodysplasies (GFM) and the French Intergroup of MPN (FIM). MDS post MPN and CMML were excluded. Patient characteristics and outcome according to JAK2V617F status were analyzed by univariate analysis. Survival analysis with Cox model matched on age, IPSS score and sex according to JAK2 status was also made. Analysis was performed using STATA 10.0 software. Result: 161 cases were collected, including 65 JAK2V617F mutated (JAK2 pos) and 96 unmutated (JAK2 neg) cases. Median age was 75 years and M/F ratio 1.2 in JAK2 pos vs 71 years (p=NS) and 1 (p=NS) in JAK2 neg pts, respectively (resp). WHO 2008 distribution was RA (8%), RARS (12%), RARS-T (41%), CRDM (15%), RAEB-1 (11%), RAEB-2 (5%), 5q- (3%), unclassified (5%) in JAK2 pos pts and RA (25%), RARS (9%), RARS-T (1%), CRDM (14%), RAEB-1 (28%), RAEB-2 (19%), 5q- (1%), unclassified (3%) in JAK2 neg pts, resp (p & lt;0.001). Hb (median 103 vs 98 g/L, p=NS) and MCV (98 vs 98 fL, p=NS) were similar in JAK2 pos and JAK2 neg pts resp but WBC (median 7.3 vs 4.4 G/L, p & lt;0.001), ANC (4.85 vs 2.1 G/L, p & lt;0.001) and platelets counts (541 vs 160 G/L p & lt;0.001) were higher in JAK2 pos than in JAK2 neg pts. Conversely, marrow blasts % was significantly lower in JAK2 pos than in JAK2 neg pts (median 2% vs 4%, p & lt;0.001). Karyotype was abnormal in 40% JAK2 pos pts (10% +8, 17% del5q, 7% −7/del7q, 3% del20q) and in 35% JAK2 neg pts (3% +8, 5% del5q, 2% −7/del 7q, 3% del20q) (p=NS). Unfavorable karyotypes (complex and −7/del7q) were seen in 9% JAK2 pos and 13% JAK2 neg pts (p=NS). IPSS was low or int-1 in 93% JAK2 pos and in 82% JAK2 neg pts (p=0.056). Median follow up was 44 months [8-350] in JAK2 pos and 62 months [25-182] in JAK2 neg pts. Progression to AML occurred in 6% JAK2 pos and in 20% JAK2 neg pts (p & lt;0.001). 5-year OS was 88% in JAK2 pos and 57.8% in JAK2 neg pts (p & lt;0.001). When the analysis was performed after exclusion of RARS-T (n=133) median age was 74 years and M/F 1.1 in JAK2 pos vs 70 years (p=NS) and 0.7 (p=NS) in JAK2 neg pts resp. Hb (median 103 vs 98 g/L, p=NS) and MCV (102.5 vs 98 fL, p=NS) remained similar in JAK2 pos and JAK2 neg pts, resp. WBC (median 6.4 vs 4.4 G/L, p & lt;0.001), ANC (3.88 versus 2.1 G/L, p=0.001) and platelet counts (268 versus 156 G/L p & lt;0.001) were still higher in JAK2 pos than in JAK2 neg pts. Marrow blasts % was still significantly lower in JAK2 pos than in JAK2 neg pts (median 2% vs 4%, p=0.016). IPSS was low and int-1 in 88% JAK2 pos and in 82% JAK2 neg pts (p=NS). Progression to AML occurred in 9.7% JAK2 pos and in 20% JAK2 neg pts (p=NS). 5 year OS was 92.2% in JAK2 pos and 57.6% in JAK2 neg pts (p=0.0052). When survival analysis was matched on age, IPSS and sex, JAK2 mutation was associated with better OS both in the whole population (p=0.011) and after excluding RARS-T (p=0.028). Finally, in JAK2 pos RARS-T pts (n=27) no AML progression was seen, and 5-year OS was 84.9%. Conclusion: We found JAK2V617F mutation in MDS to be associated with higher WBC, ANC and platelet counts, lower % marrow blasts, less progression to AML and better survival than JAK2V617F neg MDS. This positive prognostic impact persisted after exclusion of RARS-T. However, our results will require confirmation in a prospective study. Disclosures: Fenaux: CELGENE, JANSSEN CILAG, AMGEN, ROCHE, GSK, NOVARTIS, MERCK, CEPHALON: Honoraria, Research Funding.

Abstract: Abstract 3378 Chronic Myelogenous Leukemia (CML) originates in the Philadelphia chromosome, a reciprocal translocation creating the fusion oncogene BCR-ABL. In 1–2% of CML cases, breakpoints fall outside the M-BCR gene on chromosome 22, leading to the synthesis of a variety of atypical BCR-ABL transcripts [shortened: e1a2 (m-BCR), e6a2, e8a2, b2a3 (e13a3), b3a3 (e14a3), or elongated transcripts: e19a2 (m-BCR)] and to the synthesis of different molecular weight BCR-ABL proteins that might have different tyrosine kinase activities. Thus, clinical phenotypes and BCR-ABL inhibition by tyrosine kinase inhibitors might be different and lead to different prognostic features. We retrospectively analysed at the national level, the clinical characteristics and the responses to imatinib (IM) of 63 patients with CML harbouring atypical BCR-ABL transcripts: 22 e1a2 [Group 1 (G1)] , 20 e19a2 [Group 2 (G2)], 5 e8a2 [Group 3 (G3)] , 4 e6a2 [Group 4 (G4)], 5 b2a3 [Group 5 (G5)] , and 3 b3a3 [Group 6 (G6)] BCR-ABL transcripts. The general characteristics of the patients and their best response to IM are depicted in Table 1: Table 1 Group 1(e1a2) Group 2 (e19a2) Group 3 (e8a2) Group 4 (e6a2) Group 5 (b2a3) Group 6 (b3a3) n 22 20 5 8 5 3 M/F 7/15 6/14 4/1 4/4 5/0 0/3 Median age (years) 70 69 43 57 62 47 CP/AccP/MBC 20/0/2 17/1/2 5/0/0 4/1/3 4/1/0 2/1/0 Sokal (L/H/I/Ukn)* 6/8/2/4 1/3/9/4 3/1/0/1 1/2/1/0 1/2/0/1 0/2/0/0 Leukocytes (G/l, median) 60.85 28.3 55 28.4 93 82.4 Hemoglobin (g/dl, median) 12 10.2 11.7 10.95 11.1 10.2 Platelets (G/l, median) 303 848 253 259 167 363 Monocytes (G/l median) 4.8 0.8 2.34 0.05 1.08 0.825 Additional Clonal Abnormalities at diag (% of patients) 20 28 0 29 25 0 IM duration (median, years) 1.55 1.38 1.58 0.8 1.13 1.42 Interval Diagnosis-IM (median, years) 1.31 1.48 1 1.17 0.87 1.66 Best response to IM* No response 20 0 0 0 0 0 CHR (%) 13 32 0 0 0 0 Minor CyR (%) 47 0 0 0 0 0 PCyR (%) 0 10 20 10 25 67 CCyR (%) 13 32 60 50 0 0 MMR (%) 7 26 20 40 75 33 Follow-up since diag (median, years) 3.24 1.57 1.6 3.82 1.5 1.68 (CP states for Chronic phase, AccP for accelerated phase, MBC for myeloid blast crisis, L for Low, I for intermediate, H for High, Ukn for Unknown, * For CP patients only) Surprisingly, e1a2 and e19a2 transcripts seem significantly more frequent in females than in males conversely to typical BCR-ABL transcripts (p=0.01) and occurring more often in the elderly (p=0.05). The majority of the patients presented with typical cytological CML features, however, a significant monocytosis was observed in e1a2 and e8a2 atypical transcripts (p=0.0002). The median time on IM and the interval between diagnosis and IM were not statistically different between the 6 groups. Overall, there was no significant difference in the (hematologic, cytogenetic, molecular) responses to IM, but e1a2 transcripts seem less sensitive to this agent. The overall survival since diagnosis or since IM initiation was not different between atypical transcripts (p=0.55 and p=0.73 respectively), however, the progression-free survival (PFS) since diagnosis with e1a2 transcripts was significantly worse than for all other atypical transcripts (p=0.02) as shown in Figure 1: The PFS since IM initiation was somewhat worse for e1a2 transcripts, but close to significance (p=0.09), but the follow-up is not very long yet. Fifteen patients among 63 had second generation TKIs (TKI2), 7 in group 1, 3 in group 2, 1 in groups 3, 4, 5, and 2 in group 6. Only one patient (b3a3 transcript) developed a MBC being on IM. Two patients developed a T315I BCR-ABL mutation (1 e1a2, and 1 e6a2). Two patients got allo-transplanted (1 e1a2 alive and well at last follow-up, 1 e19 a2 died from GVHD). In conclusion, atypical BCR-ABL transcripts induce a particular molecular and subsequent clinical phenotypes, particularly e1a2 transcripts showing in this study poor prognosis features. The response of atypical BCR-ABL transcripts to IM might vary from that what it is for classical M-BCR transcripts, but a longer follow-up is needed. Disclosures: No relevant conflicts of interest to declare.

Abstract: Background: The Philadelphia chromosome negative myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF) all have a time dependent risk of progression to either an advanced myelofibrotic state (post ET/PV MF) and/or to acute myeloid leukemia. The impact of disease duration upon the MPN symptom burden is not well understood, nor are the precise mechanisms of disease progression. We sought to better understand the impact of disease duration on MPN symptom burden. Methods: Symptom burden data was collected utilizing the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) amongst MPN patients, collected at the time of an office visit in an international cohort of MPN patients as previously described (Scherber et. al.). Symptom burden assessment was a previously validated 27-item symptom burden questionnaire scored on a 0-10 scale (0= as good as it can be, 10 = as bad as it could be). The patient or provider was asked to report the time since MPN diagnosis. MPN duration was determined to be early if the diagnosis was established between 0 to 5 years ago, intermediate if the diagnosis was established between 6 to 10 years ago, and late if the diagnosis was established 11 years ago or more. Anemia was defined as a red blood cell count less than 10 g/dL, leukopenia was defined as a white blood cell count was below 4 x 109, and thrombocytopenia if the platelet count was below 150 x109. Statistical significance was calculated using ANOVA f-test and chi squared. Results: Patient demographics and disease burden: A total of 1443 patients responded to the survey, including 592 (41%) ET, 549 (38%) PV, and 302 (21%) MF patients, including 181 (60%) primary MF, 67 (22%) post-ET MF, and 54 (18%) post-PV MF. Among MF patients, mean duration of MPN diagnosis was 9 years, and mean duration MF diagnosis was 4.7 years. Among respondents, 757 fit criteria for early disease duration, 353 fit criteria for intermediate disease duration, and 333 fit criteria for late disease duration. Respondent mean age was 62 years and approximately half of respondents were female (55%). Patients with longer diagnosis duration tended to be older (p=0.009) and were most likely to have anemia (0.02), leukopenia (p=0.01), or thrombocytopenia (p=0.03). These individuals were also most likely to have a history of hemorrhage (p=0.007) or require red blood cell transfusions (p 〈 0.001). Combined cohort symptom burden: On average among the combined cohort of ET, PV and MF patients, symptoms tended to worsen with time with this effect being significant for symptom items of fatigue (BFI, p 〈 0.04), concentration (p=0.007), insomnia (p=0.02), sexual difficulties (p=0.002), cough (p=0.03), night sweats (p=0.002), and pruritus (p=0.02). Symptoms of early satiety (p=0.004), concentration difficulties (p=0.01), insomnia (p=0.03), sexual difficulties (p=0.02), cough (p=0.01), and night sweats (p= 〈 0.001) had significantly higher prevalence in those with longer disease duration. Similarly, the total calculated MPN-10 score (p=0.008) and quality of life assessment (0.03) demonstrated worsened outcomes with time (Table 1). No significant differences in symptoms for the combined cohort were observed among individuals diagnosed 0 to 1 years ago compared to those with a diagnosis established between 2 and 5 years ago. Symptom burden in MPN subtypes. When evaluating specific MPN types, patients with essential thrombocythemia experienced significantly greater sexual difficulties over time (p=0.03). The severity (p=0.01) and incidence (p=0.03) of pruritus and incidence of night sweats (p 〈 0.001) were significantly increased over time for individuals with PV. For those with MF, the severity (p= 0.01) and incidence (p=0.009) of cough also significantly increased with longer diagnosis duration. Discussion Overall, significant worsening in symptom burden can be recognized over time for individuals diagnosed with MPNs. Diagnosis may not necessarily correlate with disease duration as the timing of diagnosis may be delayed from onset of disease. Given the intent of this abstract to evaluate changes with disease duration, we did not investigate correlations between symptom burden and cytopenias. We do know that risk factors for survival in the MPNs include older age and thrombosis, however, disease duration should be investigated as an alternative marker of burden in future survival studies. Disclosures Harrison: CTI Biopharma: Consultancy, Honoraria, Speakers Bureau; Shire: Speakers Bureau; Gilead: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau; Sanofi: Honoraria, Speakers Bureau. Kiladjian:Incyte Corporation: Consultancy; Novartis: Other: Travel grant; Research Funding paid to institution (Hôpital Saint-Louis et Université Paris Diderot); Novartis: Consultancy. Zweegman:Celgene: Research Funding; Janssen: Research Funding; Takeda: Research Funding. Barbui:Novartis: Speakers Bureau. Etienne:Novartis: Consultancy, Honoraria, Other: Congress Travel/Accomodations, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; ARIAD: Consultancy, Honoraria, Speakers Bureau. te Boekhorst:CTI Biopharma: Consultancy; Novartis: Consultancy. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Other: Research Funding paid to institution (University of Florence), Research Funding; Shire: Speakers Bureau; Baxalta: Membership on an entity's Board of Directors or advisory committees. Mesa:Novartis. Research- incyte, Gilead, cti, Genentech, promedior, NS Pharma: Consultancy.