Abstract: BACKGROUND: Few therapeutic options are currently available for patients (pts) with severe aplastic anemia (SAA) refractory to antithymocyte globulin (ATG) plus ciclosporine (CsA) and not eligible for allogeneic stem cell transplantation. It has recently been reported that eltrombopag (ELT), a TPO receptor agonist, is efficient to improve tri-lineage blood counts in this setting. However, real-life use of this drug is still largely unknown. In pts with SAA refractory to ATG, physicians can accede to ELT in France through a compassionate use program. We took advantage of this program to assess the efficacy and safety of ELT in SAA pts. PATIENTS AND METHODS: The French National Reference Center for Aplastic Anemia conducted this study in pts who received ELT for the treatment of SAA. Latest guidelines were used to define disease severity, treatment indication, and response rates (Marsh et al, BJH 2014). The diagnosis of SAA was confirmed by marrow biopsy and Camita criteria for all pts. Pts were eligible if they received at least 2 months of ELT alone or in combination with other treatment in case of relapsed/refractory disease or front-line therapy for pts not eligible to the association of ATG and CsA. Pts were identified through a national e-mailing on behalf of the French reference center for SAA and the French Society of Hematology. All data presented here were collected at the reference date of June 26th, 2016. The study was conducted according to Helsinki's Declaration. RESULTS: Forty-six pts (male, 54%) who received ELT between July 2012 and February 2016 were identified in 17 French centers. Indications for ELT were relapsed/refractory SAA in 35 pts (76%) after 1 (49%), 2 (29%) or 3 (9%) courses of CsA+ATG. Eleven pts considered unfit for ATG also received the drug as first line therapy. The characteristics of the pts according to ELT indications are shown in Table 1. Median age at time of ELT initiation was 61 years [IQR 40 to 70]. 44 pts had idiopathic SAA including 17 (37%) with a detectable PNH clone (median size 7%). Two pts (4%) with dyskeratosis congenita also received ELT. ELT was introduced 17 months [8-50] after the initial diagnosis of SAA and with a median of 6 months [3-14] after the last course of immunosuppressive therapy. The maximal dose was 150 mg/day [100-150] for a median duration time of 6 months [4-12]. At last follow-up 22(48%) pts were still on treatment, 4(9%) pts stopped because of good hematological response, 1(2%) and 15(33%) after limited toxicity and failure to improve hematological status. Before treatment, median neutrophils count was 790/mm3 [500-1215] and pts received a median number of 4 red blood cells packs [2-4] and 3 platelets apheresis units [2-4] every month. Neutrophils counts were 765 [515-1475], 1100 [600-1800] , 1200 [670-1915] and 1200/mm3 [757-2300] at 1, 3, 6 months and at last follow-up respectively. The rates of transfusion independence for both red cells and platelets were 7%, 33%, 46% and 46% at 1, 3, 6 months and at last follow-up. In pts achieving transfusion independence, hemoglobin and platelets level improved of 3 gr/dL [1.4, 4.5] and 42 G/L [11, 100] , respectively. The rate of transfusion independence was not different among first line and refractory pts (p=0,5). We did not observe any response in the 2 patients with dyskeratosis congenita. No factor associated with hematological response to ELT was identified. Liver toxicity (cytolysis) occurred in 11 pts (1 grade 3 that required withdrawal of the treatment and 10 grade 1 who responded to dose reduction). 2 pts had a grade 2 intestinal toxicity which improved after dose reduction. Other side effects where related to SAA (28% infections, 13% hemorrhages). Bone marrow karyotype analysis after ELT was done in twelve pts (26%) (median time 14 months [5-22] after ELT start). In 10 pts the karyotype was normal, in one, trisomy 8 was identified (already seen at SAA diagnosis), and karyotype was a failure in 1 pt. CONCLUSION: We report here the first real-life multicenter study about the use of ELT in SAA. In a particular severe pts population with no other treatment possibility, we confirm a 40% rate of hematological improvement with transfusion independence. Some of the pts who were not eligible to ATG plus CsA (comorbidities) also received ELT first line with similar response rates. Elderly pts unfit for ATG may thus benefit from this treatment which at the best should be given through prospective clinical trials. Table 1 Table 1. Disclosures Ades: Celgene, Takeda, Novartis, Astex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Terriou:Novartis: Consultancy; amgen: Consultancy. Peffault de Latour:Alexion: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Research Funding.

Abstract: Background & aims The only curative treatment of CML to date, remains allogeneic stem cell transplantation (Allo-SCT) despite some observations of non-detectable disease recurrence after tyrosine kinase inhibitor (TKI) cessation. The scope of allogeneic stem cell transplant for chronic phase (CP-) CML remains debatable and it seems interesting to retrospectively analyse the settings of this procedure in such patients since the introduction of TKI within the therapeutic arsenal of this disease. Methods We retrospectively analysed the registry of the Francophone society of stem cell transplantation and cellular therapy (SFGM-TC) from 2002 to 2014, for patients being in CP at diagnosis and at transplant. All data were captured according to thefrench regulations and were collected after signed up informed consent for each patient. All patients were transplanted for different degrees of resistance or severe recurrent intolerance to TKI(s). We segmented the observation period into two parts: 2002-2006 (Imatinib era) and 2006-2014, once second generation TKI were available in our country (TKI2 era). All patients were in CP-CML at diagnosis and first chronic phase at transplant. Second transplants for the same patient were excluded from this analysis. Results From 2002 to 2014 the proportion of transplants for CML dramatically decreased form 7.1% to 〈 3% of totalallo-SCT performed in the country. Nevertheless, between 2002 and 2014, 191 transplants were performed for CP-CML, 121 during the first period and 70 during the second period. Interestingly, age at transplant is 36 (26-43) for IM period and older, 44 (26-55) years for TKI2 period; with a sex ratio of 1.08 and 1.3 respectively (p=ns). The median interval between diagnosis and transplant was 19 (1.4-197) months for IM period and much longer thereafter[32 (6.6-194) months, p 〈 0.001]. The source of cells varied a lot with 71% of BM, 25.5% PBSC and 3.5% CB for IM period, 37% BM, 56% PBSC and 7% CB for TKI2 period (p 〈 0.001), whereas the proportion of MAC versus RIC remained stable (88.5%/11.5% versus 81%/19%, p=0.262). The use of TBI as a part of the conditioning regimen was drastically reduced during the second period: 37% IM era, 14% TKI2 era (p 〈 001). While ABO match did not differ, the use of unrelated donors largely increased in the second period (66% versus 46%, p=0.015), with less identical sibling donors used (33% versus 52%) in this last period. The proportion of sex match did not differ with a majority of male to male transplants (28% and 37%; p=ns) performed in both groups. The majority of patients wereGratwohlscore 3 in IM period andGratwohlscore 4 in the second period. Overall, the cumulative incidence of grade 2-4 acute GVHD was 32%, 41.3% and 44% at 1,2 and 3 months respectively, and the overall cumulative incidence of chronic GVHD was 26%, 40%, 45%, 50% at 1, 2, 5, and 10 years. The TRM rates were not different between the 2 periods: 22.4%, 23%, 26.65% and 27.8% at 1, 2, 5 and 10 years for IM period and 16.2%, 19.7%, 22.4% and 27.8% at 1, 2, 5 years for TKI2 period (NR 10 year for this period, p=0.508).The overall (OS) and relapse-free survival (RFS) rates according to the two periods are shown in Figure 1, with only a trend in the improvement of OS and RFS in the TKI2 period (log-rank tests, p=0.601 and 0.651 respectively).Gratwohlscore efficiently segregated patients for OS (overall p value = 0.002) and RFS (p=0.007). Multivariate analysis adjusted on OS identified only age (HR=1.02, p=0.05), and a related donor as a favourable variable on outcome (HR=0.53, p=0.031) with no significant influence of age, interval diagnosis-allo-SCT, source of donor cells, and type of conditioning regimen. Conclusion Allo-SCT still remains a curative treatment of CP-CML despite significant toxicities over time and the picture of this procedure in the therapeutic arsenal has dramatically changed over the last decade due to multiple therapeutic options offered now. Despiteallo-SCT of patients with longer diseases histories, probably more co-morbidities, there is an encouraging trend in the improvement of OS and RFS. Figure 1 OS and RFS for CP-CML according to the engraftment period. Figure 1. OS and RFS for CP-CML according to the engraftment period. Figure 2 Figure 2. Disclosures Nicolini: BMS: Consultancy, Honoraria; Ariad: 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, Research Funding. Coiteux:Novartis, BMS, ARIAD: Speakers Bureau. Michallet:Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Astellas Pharma: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria. Peffault De Latour:Novartis: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding.

Abstract: Anthracyclines and cytarabine are cornerstones for intensive chemotherapy in acute myeloid leukemia (AML). The goals of this study were to comprehensively assess deviations from theoretical doses and the impact of body‐surface area (BSA) on patients’ characteristics, physicians’ strategy, dose adjustment, and clinical outcome. Methods The GOELAMS 2001 phase III trial included 823 AML patients below 60 years of age. In the course of treatment, anthropomorphic parameters and chemotherapy doses were prospectively registered. Results Very high BSA (≥2.15 m 2 ) was the factor most significantly associated with the physician's decision to reduce chemotherapy doses during induction and postremission therapy. Despite similar AML characteristics and therapeutic strategies, the very high BSA group exhibited a significantly worse survival (5‐years OS of 27%) compared to the low (BSA≤1.5 m 2 ), intermediate (1.5 m 2 〈 BSA≤2.0 m 2 ), or high (2 m 2 〈 BSA 〈 2.15 m 2 ) BSA groups (46%, 47%, 56%, respectively) ( P =.009). In the very high BSA group, dose capping was associated with worse overall survival, although not significantly ( P =.09). Conclusion The presence of a very high BSA is the main reason prompting physicians to reduce chemotherapy doses in adult AML. Furthermore, these patients display a poor outcome and could benefit from full doses calculated on actual BSA.

Abstract: Background Inhibitory Killer Immunoglobulin-like Receptors (KIR) negatively regulate Natural Killer (NK) cell-mediated killing of HLA class I-expressing tumors. Lack of KIR-HLA class I interactions has been associated with antitumor efficacy and increased survival in patients (pts) with AML in CR after haploidentical stem cell transplantation from KIR-mismatched donors(Ruggeri, Blood 2007). IPH2101, a fully human mAb designed to enhance antitumor effects of NK cells by blocking the major inhibitory HLA-C-specific KIR can be safely administered in elderly pts with AML (Vey, Blood 2012). Lirilumab is a 2nd generation anti-KIR mAb currently evaluated in multiple indications and combinations with encouraging preliminary results in combination with nivolumab in pts with squamous cell carcinoma of the head and neck (Leidner, SITC 2016). Here we report the results of a phase 2 trial with lirilumab as single agent in the maintenance therapy of elderly pts with AML in first CR. The objectives of this randomized phase 2 study were to determine if lirilumab could improve leukemia free survival (LFS) and to assess two dose schedules predicted from the phase 1 dose-escalation trial (Vey, ASCO 2015) to be associated with either continuous (CONT) or intermittent (INT) full KIR occupancy. Methods EFFIKIR was a randomized double-blind 3-arm placebo controlled trial (NCT01687387). Eligible pts were: aged 60 to 80 yrs, diagnosed with non-APL AML, in CR1 following standard induction (1 to 2 cycles) and consolidation (1 to 2 cycles) and had: ECOG performance status of 0-1, adequate hematologic, liver and renal function. Pts were randomly allocated to receive placebo or lirilumab given at either 0.1 mg/kg q 12 weeks (INT) or 1mg/kg q 4 weeks (CONT) according to a minimization algorithm adjusting for center, primary vs. secondary AML, number of consolidation cycles (1 vs. 2) and cytogenetics. Pts were to receive up to 2 yrs of therapy. The primary endpoint was LFS by independent central review. Results Between November 2012 and July 2014, 153 pts were randomized and 152 pts were treated; Pts characteristics are depicted in Table 1. All had received 7+3 induction therapy. Most pts (81%) received 2 cycles of consolidation prior to inclusion. Consolidation chemotherapy consisted of intermediate-dose single agent cytarabine (IDAC) in 53%, and 5+1 in 47% of the pts, according to the recommendations of the ALFA and FILO cooperative groups, respectively. Median time since diagnosis was 4.9 months (mo) [2.8-15.5]. Median time between CR or the last consolidation and randomization were 3.3 [1.1-5.9] and 1.5 mo [0.3-3.5], respectively. The 3 arms were well balanced apart from a slight trend in favor of the placebo arm for lower age, better ECOG, and use of IDAC as consolidation. In March 2015, based upon DSMB recommendation, treatment of pts in CONT was discontinued in light of an excess of early relapses. Mean number of treatment cycles administered was 14.7, 8.8 and 13.8 in the INT, CONT and placebo arms respectively and only 6 pts had one cycle postponed in the lirilumab arms. Major reasons for study discontinuation were relapse (63%) and adverse events (AE) (10%). AE rate was analyzed by taking into account the exposure across pts in each arm. Slightly more AE rate of G1-G2 asthenia, diarrhea and pruritus was observed in CONT arm. Occurrence of hematological disorders did not differ between the 3 arms. 17 pts (11%) experienced second primary malignancies across the 3 arms. PK/PD results were in line with the model predictions: transient full KIR occupancy lasting 7-28 days for the majority of the INT arm pts and permanent full occupancy in the CONT arm. Lirilumab is not significantly immunogenic and does not induce major modifications in peripheral blood NK and T cell subsets. With a median follow-up of 36.6 mo [33.4; 38.2], 108 pts experienced relapses and 2 pts died before relapse. LFS results are presented in Table 2. Conclusions Single agent lirilumab administered for up to 24 cycles was well tolerated. Lirilumab did not result in a statistically significant improvement of LFS in the challenging setting of maintenance in AML in elderly pts. Immune-pharmacological studies will be presented. Potential hypotheses relevant for AML and lirilumab monotherapy (e.g. dosage/schedule optimization, partial desensitization by continuous KIR blockade leading to an impaired immunosurveillance by NK cells) for the non-significant trends will be discussed. Disclosures Recher: Novartis, Celgene, Jazz, Sunesis, Amgen: Consultancy; Celgene, Sunesis, Amgen, Novartis: Research Funding. Pautas: Pfizer: Honoraria. Rousselot: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sunesis: Honoraria; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; BMS: Research Funding. Castaigne: Pfizer: Honoraria, Research Funding. Jourdan: NOVARTIS: Consultancy, Honoraria. Gardin: Sunesis: Honoraria; AbbVie: Honoraria; Celgene: Honoraria. Delannoy: Innate Pharma: Honoraria. Beautier: Innate Pharma: Employment, Equity Ownership. Paturel: Innate Pharma: Employment, Equity Ownership. Andre: Innate Pharma: Employment, Equity Ownership. Zerbib: Innate Pharma: Employment, Equity Ownership. Dulphy: Celgene: Research Funding; Innate Pharma: Research Funding; Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees. Olive: Imcheck Therapeutics: Other: Cofunder; GSK: Research Funding; Innate Pharma: Research Funding. Pigneux: Pfizer: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Sunesis: Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biogaran: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Dombret: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travels, Accommodations, Research Funding, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travels, Accommodations, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharma.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sunesis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: 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; Cellectis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Menarini: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Chugai/Roche: Consultancy.

Abstract: Kim et al . recently measured the structure factor of deeply supercooled water droplets (Reports, 22 December 2017, p. 1589). We raise several concerns about their data analysis and interpretation. In our opinion, the reported data do not lead to clear conclusions about the origins of water’s anomalies.