ALBERT

Description: BACKGROUND: Invasive fungal infections (IFIs) including invasive candidiasis(IC), pulmonary invasive aspergillosis (IA) and other fungal species as mucor mycosis (IM), remain a major clinical problem in neutropenic patients receiving intensive chemotherapy for acute myeloid leukemia (AML) due to their high morbidity and mortality. DESIGN: We performed a prospective observational study on antifungal (AF) prophylaxis used in a prospective clinical trial of intensive chemotherapy within the Acute Leukemia French Association (ALFA 0702 study, ClinicalTrials.gov Identifier: NCT00932412). A total of 677 AML patients from 34 different centers were included, 45% were males, and median age was 46 years (18-60). Prognosis according to cytogenetics was favorable in 23% of patients, intermediate in 53% and unfavorable in 18%. All patients received daunorubicine and aracytine intensive induction chemotherapy. The trial protocol recommended posaconazole suspension as AF prophylaxis at the dose of 200 mg three times a day from day 4 after induction chemotherapy and until neutrophils recovery. Patients were considered evaluable for this study if they received posaconazole for a minimum duration of 7 days and not later than 10 days after the beginning of the induction chemotherapy. IFI were classified by the local investigators and were reviewed later by an independent expert according to the EORTC classification (possible, probable and proven), scanner images were requested for further investigations when needed. The objective of this study was to describe the IFI prophylaxis strategies used in the different centers, to calculate the cumulative incidence of IFI according to different strategies, and to evaluate the overall survival and IFI related mortality. RESULTS: Among the 677 patients, 383 (57%) received posaconazole as AF prophylaxis for a median duration of 25 days (7-253). Posaconazole was introduced after a median time of 3 days after the beginning of the chemotherapy. We distinguished 4 groups, Group 1: patients without any prophylaxis (n = 203, 30%), Group 2: posaconazole alone (n=241, 36%), Group 3: posaconazole plus other prophylaxis (n=142, 21%), and Group 4: patients receiving other prophylaxis (n= 91, 13%). Overall, there were 72 IA [34 (47%) possible, 38 (53%) probable/proven], 17 IC (all probable/proven) and 7 IM [1 possible, 6 probable/proven]. The median delay between posaconazole prophylaxis and IFI occurrence was 22 days (7-50) for IA, 18 days (15-60) for IC and 26 days (13-28) for IM compared to 10 days (3-180), 8 days (3-32) and 21 days (10-32) in case of other prophylaxis. The cumulative incidence of IFI was 2.4% at 10 days (IA: 2.4%, IC : 0%, IM : 0%), 11,2% at 30 days (IA: 8.4%, IC: 2%, IM: 0.7%), 14.2% at 60 days ( IA: 10.6%, IC : 2.5%, IM : 1%), and 14.2% at 100 days (IA:10.6%, IC : 2.5%, IM : 1%). When considering the prophylaxis groups, the cumulative incidence of probable/proven IA at day 60 was 8.37% for Group 1; 4.7% for Groups 2 and 3 combined and 3.3% for Group 4 (Figure 1). After a median follow-up of 27.5 months (0.4- 73.4), 418 patients are alive and 259 (38.3%) died with 5.4% from IFI. Concerning the overall survival, the results were analyzed according to the presence or absence of IFI and AF prophylaxis (Figure 2) we observed a better survival without any IFI whatever the AF prophylaxis was and in case of AF prophylaxis there was an improvement of 2-years survival after chemotherapy induction. Concerning the global mortality and the IFI related mortality, the results were analyzed according to the prophylactic groups and the timing of prophylaxis, the multivariate analysis showed the negative impact of 2 factors on the mortality at day 100: Unfavorable cytogenetics: HR= 3.34 (1-11.20) p=0.05 and presence of IFI: HR = 5.63 (2.62-12.08) p

Description: Introduction : TP53 mutated (TP53m) MDS and AML have very poor outcome irrespective of the treatment received, including 40% responses (20% CR) with azacitidine (AZA) with short response duration and a median overall survival (OS) of about 8 months (Bejar, Blood 2014). APR-246 is a prodrug spontaneously converted to methylene quinuclidinone (MQ), a Michael acceptor that binds covalently to cysteines in mutant p53, leading to protein reconformation that reactivates its pro apoptotic and cell cycle arrest functions. The combination of AZA and APR 246 showed promising results in a phase Ib study in TP53m MDS (Sallman, ASH 2018). We report interim results of a GFM phase 2 study of AZA+ APR-246 in TP53m MDS and AML, conducted in parallel with a similar US MDS consortium study. Patients and Methods : The study included hypomethylating agent (HMA) naïve and not previously allografted intermediate, high or very high IPSS-R TP53m MDS and AML adult patients. Patients received APR-246 4500 mg IV /d (6 hour infusions) (days 1-4) followed by AZA 75 mg/m²/d (days 4-10) in 28 day cycles. Response (primary endpoint, assessed by IWG 2006 for MDS and ELN criteria for AML) was evaluated after 3 and 6 cycles in the intent to treat (ITT) population, ie all patients who had received any protocol treatment, and in patients who had at least a blood and bone marrow evaluation after cycle 3 (evaluable population). Allo-SCT, when possible, was proposed after 3 to 6 cycles, and treatment with reduced APR 246 and AZA doses could be continued after allo-SCT. Results : 53 patients were enrolled between Sept 2018 and July 2019 in 7 GFM centers, with a median age of 73 years (range 44-87), and M/F: 28/25. 34 patients had MDS (including 74% very high IPSS-R) and 19 had AML. IPSS-R cytogenetic risk was very poor in 30/34 MDS, and unfavorable in 18/19 AML, complex in 89% of the patients. Median baseline mutated TP53 VAF was 21% (range 3-76). Nineteen of the 53 patients had been included at least 7 months before date of analysis (25 July 2019), had received protocol treatment and were thus potentially evaluable for response after 6 treatment cycles (ITT population). One of them died after only one cycle from an unrelated cause (cerebral ischemic stroke), and 2 during the third cycle (from bleeding and sepsis, respectively). In the remaining 16 patients (evaluable population per protocol), the response rate was 75% including 9 (56%) CR, 3 (19%) marrow CR or stable disease with hematological improvement (HI), and 4 treatment resistance. In the ITT population, the response rate was 63%, including 47% CR, and 16% stable or marrow CR+ HI. Among CR patients, complete cytogenetic CR and negative NGS for TP53 mutation (VAF cutoff of 2%) were achieved in 7/9 (78%) and 8/8 (100%), respectively. So far, 1 patient has undergone allo-SCT. All 53 patients had received at least one treatment cycle, and no increased myelosuppression, compared with AZA alone, was apparent. Treatment related AEs observed in ≥ 20% of patients were febrile neutropenia in 19 (36%) and neurological AEs in 21 (40%) of the patients. The latter, reviewed with a neurological team, were mainly grade 1 or 2 and consisted of ataxia (n=13), sometimes associated with cognitive impairment (n=4), suggesting a cerebellar origin. Other patients experienced acute confusion (n=4), isolated dizziness (n=3) and facial paresthesia (n=1). Neurological AEs reached grade III in 3 cases (1 acute confusion, 2 ataxia). Occurrence of neurological AEs was correlated with lower glomerular filtration rate at treatment onset (p

Description: A high proportion of Ph-positive Acute Lymphoblastic Leukemia (Ph+ ALL) patients still undergo relapses despite the use of Tyrosine Kinase Inhibitors (TKIs) in addition to chemotherapy as frontline therapy. In this leukemia subtype, the role of BCR-ABL1 kinase domain (KD) mutations as a driver of resistance to TKIs has already been documented by previous studies and such mutations have been reported in up to 80% of the patients at relapse. Next-generation sequencing (NGS) has been proposed to characterize these mutations with a higher sensitivity than Sanger. We report here a prospective study aiming at detecting potentially resistant cell populations by NGS in Ph+ ALL patients enrolled in the GRAAPH 2014-trial. Between March 2016 and February 2019, 156 patients aged 18 to 59 years with newly diagnosed Ph+ and/or BCR-ABL1 positive ALL have been included in the GRAAPH 2014 trial (NCT02619630). BCR-ABL1 isoforms were E1A2 69%, B2A2/B3A2 29%, atypical 2%. After a prephase of steroid, treatment consisted of 4 blocks of chemotherapy + nilotinib. 118 patients (76%) underwent allogeneic or autologous stem cell transplantation (SCT). 22 medullary relapses were recorded within a median time of 9 months (range, 2 - 35). Blood and marrow samples harvested at diagnosis, after each treatment block, before and 3 months after SCT, and at relapse, were sequenced if BCR-ABL1/ABL1 ratio were above 0.001. Mutated BCR-ABL1 transcripts were detected by sequencing the KD of BCR-ABL1 transcripts by NGS with a limit of detection (LOD) of 0.03. T315I allele specific oligonucleotide (ASO) droplet digital RT-PCR (ddRT-PCR) with a LOD of 0.0005 was also performed at diagnosis on a subset of 63 patients, including 5 who have subsequently developed a T315I clone. NGS. At diagnosis, no KD mutation was found by NGS in pretreatment samples of 137 patients. During follow-up (FU), only 12 mutations were found by NGS in 7 out of the 88 patients tested (81, 45, 30, 20, 19, 9 after block 1, 2, 3, 4, before and 3 months after SCT, respectively). Mutations were T315I (N=6), Y253H (N=1), E255K (N=2), E255V (N=1), Q252H (N=1), Y253F (N=1). At relapse, 16 mutations were identified by NGS in 12 patients out of the 17 tested (71%). Mutations were T315I (N=7), Y253H (N=n=3), F359V (N=2), E255K (N=1), E255V (N=1), Q252H (N=1), Y253F (N=1). More than 1 mutated clone were present in 2 patients (E255V+T315I+F359V and Y253H+F359V), and a compound mutation was found in 1 patient (Q252H/Y253F). Out of the 7 patients found mutated during FU, 5 have relapsed with a rapid expansion (1 to 3 months) of the mutated clone. One patient harboring a sub-clonal (10%) E255K at MRD1 has relapsed 9 months later without any detectable mutation. One patient identified with 3 mutated clones (E255K 10%, E255V 10%, T315I 80%) underwent SCT and has not relapsed so far. We failed to anticipate expansion of any mutated clone in the 7 remaining patients found mutated at relapse. T315I ASO ddRT-PCR on diagnostic samples. Low-level T315I mutated BCR-ABL1 transcripts (0.00051 to 0.0013) were detected in 14 out of 63 patients (24%) tested. Only one has expanded a T315I clone later on. In the context of the GRAAPH 2014 trial, 71% of the 17 relapses tested so far were associated with BCR-ABL1 KD mutations. Expansion of the mutated clone could have been characterized before the onset of hematological relapses in only 5 out of 12 patients (42%). Unfortunately in these cases, lags between first detection and relapse were very short (1 to 3 months). On the contrary, occurrences of relapses associated with expansion of KD-mutated clones could not have been anticipated in 58%. All mutations identified, including T315I, F359V, E255K/V and Y253F/H, Q252H/Y253F are known for conferring resistance to nilotinib. NGS is a valuable method for KD mutation detection in Ph+ ALL. It allows a quantitative characterization of KD mutations at relapse. However in our hands and in the context of an intensive therapy combining chemotherapy, nilotinib and SCT, its enhanced sensitivity as compared to Sanger (3% vs 20%) does not translate into the capacity of anticipating expansion of KD-mutated clones. Moreover, in this study, NGS did not detect any mutation in pre-therapeutic samples while T315I mutated BCR-ABL1 transcripts were found at low-level in 24% of these samples by ddRT-PCR. However it should be emphasized that when detected, low-level T315I mutated sub-clones present at diagnosis failed to expand in most instances. Disclosures Cayuela: Incyte: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Chalandon:Pfizer: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Incyte Biosciences: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Rousselot:Pfizer: Research Funding. Thomas:PFIZER: Honoraria; ABBVIE: Honoraria; INCYTE: Honoraria; DAICHI: Honoraria. Huguet:Amgen: Honoraria; Servier: Honoraria; Jazz Pharmaceuticals: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Incyte Biosciences: Honoraria; Novartis: Honoraria. Chevallier:Incyte: Consultancy, Honoraria; Jazz Pharmaceuticals: Honoraria; Daiichi Sankyo: Honoraria. Boissel:NOVARTIS: Consultancy. Vey:Novartis: Consultancy, Honoraria; Janssen: Honoraria. Berthon:PFIZER: Other: DISCLOSURE BOARD; JAZZPHARMACEUTICAL: Other: DISCLOSURE BOARD; CELGEN: Other: DISCLOSURE BOARD.

Description: Context. The prognostic value of gene mutations in older AML patients (pts) treated intensively remains unclear. Only one study has explored the role of mutation patterns determined by NGS in older AML pts prospectively treated with various chemotherapies in years 2000-2010 (Eisfeld Leukemia 2018). Methods. Pts older than 60y enrolled in the ALFA-1200 trial (NCT01966497) between 09/2012 and 06/2016 were sequenced with a 37-gene myeloid panel. Pts received one 7+3 course followed by 2 intermediate-dose cytarabine courses. Pts with non-favorable risk were eligible for allogeneic stem cell transplantation (SCT). Variable selection for multivariate analyses was performed by lasso penalized regression including age, gender and log(WBC) as covariates. Results. Sequencing was done in 471 (93%) of the 509 enrolled pts. Median age and WBC count were 68y and 5.3x109/L, respectively (resp). CR (including CRp) was achieved in 341 (72%) pts and 90 underwent RIC-SCT in first CR. With a median follow-up of 25.4 months, median OS was 20.7 months. Pts had a median of 3 mutations (range 1-10). The 17 mostly frequently mutated genes (≥5% of pts, by decreasing frequency: DNMT3A, NPM1, TET2, ASXL1, FLT3, SRSF2, IDH2, RUNX1, NRAS, IDH1, STAG2, BCOR, TP53, PTPN11, U2AF1, EZH2 and KRAS) were retained for prognostic analyses. Genes belonging to a common pathway (eg. NRAS and KRAS) may have divergent prognostic values, preventing biology-informed grouping of mutations. Cytogenetic risk (derived from ELN 2017, Döhner Blood 2017, not considering gene mutations) was favorable (fav), intermediate (int), adverse (adv) and missing in 3%, 72%, 18% and 7% resp. Because of the few pts with fav cytogenetics in our cohort, pts were further grouped into non-adv and adv cytogenetics. CR rates and median OS were 75.6% vs 56.6% and 24.8 vs 9.5 months in pts with non-adv and adv cytogenetics, resp (both p

Description: Introduction Isolated trisomy 8 is a frequent cytogenetic abnormality in MDS, but hematological characteristics of MDS with isolated trisomy 8 have not been reported in detail. Patients and Methods This was a retrospective analysis of cases of MDS with isolated trisomy 8 diagnosed in 6 French centers of the Groupe Francophone des Myélodysplasies (GFM) between 2003 and 2013. Only patients with isolated trisomy 8 diagnosed as MDS or MPN/MDS (other than CMML) according to WHO were eligible, excluding AML, well characterized MPN (PV, ET) and CMML. Myeloproliferative (MP) features were defined by repeated presence (in the absence of infection) of one of the following: WBC 〉 10G/L, circulating immature granulocytes (myelemia ) 〉 2%, or palpable splenomegaly. Results 103 patients with isolated trisomy 8 were identified, with a median age of 75 years, and M/F 1.7. At diagnosis, median WBC count was 4.1 G/L, with WBC ≥ 10 G/L in 13 patients (12.6 %), myelemia ≥ 2% in 27 patients (26.2 %), palpable splenomegaly in 9 patients (8.7 %). WHO diagnosis included 20 RA, 2 RARS, 22 RCMD, 1 RCMD-RS, 1 RCUD, 21 RAEB-1, 18 RAEB-2, 7 MDS-U, 10 MDS/MPN, 1 hypoplastic MDS. IPSS was intermediate 1 (72.2 %), intermediate 2 (19.6 %), high (8.2 %) ; IPSS-R was low (37.1 %), intermediate (29.9 %), high (22.7 %), very high (10.6 %). MP features were found in 50 patients (48.5 %): 31 at diagnosis, 19 during evolution (in patients without MP features at diagnosis). Bone marrow morphological features could be reviewed in 15 MP cases, showing hypercellular marrow in 60 % cases, granulocytic hyperplasia (E/G

Description: Introduction As clinical trials for relapsed Acute Myeloid Leukaemia (AML) patients do not accurately reflect the daily clinical reality, data regarding the outcome of these patients is scarce. We thus conducted a retrospective analysis to quantify the prospects of salvage treatment of primary refractory or first-relapse AML patients and to assess the contribution of allograft and intensive treatment regimens with respect to major risk groups in a real-life setting. Methods We performed a retrospective analysis of 163 patients diagnosed from 2005-2012, in 5 haematological centres in the north of France (Lille, Amiens, Roubaix, Valenciennes and Lens). We considered every patient in that time frame who was treated following an intensive pathway. Statistical analysis as performed using Kaplan-Meier survival analysis and logrank test in the SPSS software Results The mean age at diagnosis was 45 (range 16-70 years) and the median age at relapse was 48 (ranging 17-70 years). The median time from diagnosis to relapse was 8 months. 20.6% of patients were considered primary refractory (relapse within 60 days from diagnosis). The median overall survival was 28 months (95% CI was 17-38 months). There was no statistically significant survival difference between primary refractory patients and first relapsed patients. Unsurprisingly, survival was significantly (p

Description: Abstract 309 Background: The granulomonocytic (GM) hyperplasia of CMML has been attributed to GM-CSF hypersensitivity triggered by mutations in the CBL/RAS pathway according to the prevailing model in juvenile myelomonocytic leukemias (Kotecha Cancer Cell 2008). Recurrent mutations affecting epigenetic (eg TET2 and ASXL1) and splicing (eg SRSF2) machineries, or cytokine signaling (N/KRAS, CBL, JAK2) are present in most CMML cases, but none is specific of CMML. In 224 CMML patients (pts), we found TET2 (58%), SRSF2 (47%) and ASXL1 (38%) to be the most frequently mutated genes; only 66 (35%) cases had mutations in cytokine signaling genes (CBL, N/KRAS, JAK2, FLT3, KIT) (abstract submitted). We analyzed the differentiation of CD34+populations from genetically annotated CMML pts to address the mechanisms of GM hyperplasia in CMML. Methods: CD34+ populations (hematopoietic stem cells [HSC]; multipotent [MPP]; common myeloid [CMP] and granulomonocytic progenitors [GMP] defined by the CD34/CD38/CD90/CD123/CD45RA panel; Majeti Cell Stem Cell 2007) from 28 genetically annotated CMML and TET2 mutated MPN (n=8) or MDS (n=5) cases were cloned and genotyped for each mutation identified in mature CD14+ cells, and differentiated in vitro. Results: Early clonal dominance, with at least one mutation in 〉 75% of HSC/MPP clones, was found in all cases. In 18/19 pts with ≥2 mutations, a linear succession of mutations was found, with signaling mutations often following TET2 or ASXL1 mutations. Contrasting with the dominance of first events in HSC/MPP, second events reached clonal dominance in GMP, suggesting that they provide a selective advantage during the early steps of myeloid differentiation. We next analyzed the clonogenicity of peripheral blood (PB) CD34+ cells in the presence of GM-CSF (10 ng/mL) in 20 CMML cases and 4 controls. GM-CSF hypersensitivity (clonogenicity 〉 mean+2SD of controls) was found in 7 (35%) cases. A mutation in a signaling gene was found in 6/7 pts (1 homozygous JAK2, 1 homozygous CBL, 4 heterozygous N/KRAS mutations), compared to 3/13 in pts without GM-CSF hypersensitivity (2 JAK2, 1 CBL, all heterozygous; P=.02) Median WBC was 29.2 and 11.4 G/L in pts with and without GM-CSF hypersensitivity, respectively (P=.08). The proportion of GMP in bone marrow (BM) CD34+cells was not significantly different in 33 CMML pts compared to 15 age-matched controls. Clonogenicity of GMP was similar in CMML and controls, except for a trend toward increased clonogenicity in pts with mutations in signaling genes. In contrast, the proportion of MPP and CMP was higher in CMML than in controls (P

Description: Background: Clofarabine has been shown as effective as single-agent or in combination with cytarabine in various populations of AML patients. Nevertheless, two randomized studies failed to demonstrate prolonged survival when compared to low-dose cytarabine in older AML patients (Burnett, 2013) or intermediate-dose cytarabine (IDAC) in patients aged 55y or more with relapsed/refractory AML (Faderl, 2012). As this was likely due to excessive toxicity and poor compliance in these difficult-to-treat populations, we made the hypothesis that a more apparent benefit might be observed during post-remission therapy. We thus randomly assessed the role of CLARA combination (clofarabine + IDAC) versus high-dose cytarabine (HiDAC) as consolidation cycles in younger AML patients. Methods: Between 2009 and 2013, 713 patients aged 18-60y old with de novo AML (CBF-AML excluded) were enrolled in the ALFA-0702 trial by 33 French centers. They received a timed-sequential induction with daunorubicin (60 mg/m2, day 1-3; 35 mg/m2, day 8-9), cytarabine (500 mg/m2 CI, day 1-3; 1 g/m2/12h bolus, day 8-10) and G-CSF priming. A first salvage with idarubicin and HiDAC may be proposed to patients not achieving CR/CRp after this first course. Patients in CR/CRp with non-favorable AML (according to ELN classification) or those who needed the salvage (late CR/CRp) were eligible for: 1) allogeneic stem cell transplantation (SCT) if they had a sibling or fully matched unrelated donor; or 2) randomization for consolidation with three HiDAC (3 g/m2/12h cytarabine, day 1/3/5; G-CSF priming) or CLARA (30 mg/m2 clofarabine, day 2-6; 1 g/m2/12h cytarabine, day 1-5; G-CSF priming) cycles if no identified donor. Primary endpoint was relapse-free survival (RFS), patients receiving allogeneic SCT in first CR/CRp after randomization (late donor identification) being censored at SCT time. Secondary endpoints were cumulative incidence of relapse (CIR) and death in first CR/CRp (CID), overall survival (OS), and safety. Anticipating a 35% SCT rate in randomized patients, 230 patients should be randomized to demonstrate a 20% gain in 2-year RFS. A sensitivity analysis without SCT censoring was planned. Results: Among 468 CR/CRp patients of interest (465/552 non-favorable AML + 3/161 favorable AML with late CR/CRp), 221 were randomized between HiDAC (n=114) and CLARA (n=107) consolidation and 247 were not randomized for the following reasons: 181 had an identified donor for SCT; 19 had favorable ELN genotype even if no evidence of normal karyotype; and 47 were negatively selected (13 early relapses, 1 early death, 18 AEs, 15 drop-out). The ITT analysis was conducted in these 221 eligible patients (median age, 48y; 136 intermediate-risk, 85 unfavorable-risk; 18 late CR/CRp; without imbalances between randomization arms), the remaining 9 randomized patients having non-eligibility criteria (6 favorable-risk AML and 3 not in CR/CRp). Among these patients, the rate of SCT in first CR/CRp was higher than anticipated (50%; 55 patients in each arm). With a median follow-up of 37.4 months and SCT censoring, 2-year RFS was 52.1% (40-68) in the CLARA arm versus 30.5% (20-46) in the HiDAC arm (HR, 0.62 [0.39-0.99]; p= 0.042). This was due to a lower CIR in the CLARA arm (44.0 versus 67.7%; p= 0.023) with similar CID (3.9 versus 1.9%, p= 0.60). At 2 years, OS was 68.1% (56-82) in the CLARA arm versus 49.8% (38-66) in the HiDAC arm (p= 0.18). Interestingly, the gain in CIR and RFS was observed in both intermediate- and unfavorable-risk groups and persisted after adjustment on AML risk and age. As expected, these gains were lower when not censoring at SCT (2-year RFS, 57.8 versus 45.6%; p= 0.12). In the 110 randomized patients allografted in first CR/CRp, no differences in post-SCT outcome were observed according to randomization arm. In Mantel-Byar time-dependent analysis, longer RFS was observed after SCT in the HiDAC arm (HR, 0.45; p= 0.004), while not in the CLARA arm (HR, 0.71; p= 0.26). Finally, CLARA cycles were associated with higher hematologic toxicity, more infections and more liver toxicities than HiDAC cycles, especially after cycle 1. Conclusions: As compared to HiDAC, clofarabine-based consolidation improved RFS in younger patients with intermediate- and unfavorable-risk AML in first CR/CRp. CLARA combination might thus become a new standard for post-remission therapy in these patients, especially in those who may not benefit from allogeneic SCT. Disclosures Off Label Use: CLOFARABINE is not currently approved for this indication.. De Botton:Agios pharmaceuticals: Research Funding. Vey:Janssen: Honoraria; Roche: Honoraria; Celgene: Honoraria. Dombret:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: Abstract 1713 Abstract Title: Is azacitidine (AZA) really effective in higher risk MDS patients with chromosome 7 abnormalities (Abn 7)? Results of a retrospective study from the GFM and GESMD registries. Background: Cytogenetic alterations are the most discriminative prognostic variables in MDS, complex karyotype and abnormalities of chromosome 7 (Abn 7) having the poorest outcome. However, prognosis of isolated 7q- and to a lesser extent isolated −7 appears to be less severe than that of complex karyotypes at least in patients not receiving drugs with a potential effect on survival (Schanz et al, JCO, 2012, Cordoba et al, Cancer, 2012). It has been suggested in relatively small patients series that Abn 7 may be associated with relatively favorable response to AZA in MDS. We analyzed the outcome of a large series of higher risk MDS with Abn 7 treated with AZA. Methods: Between 2005 and 2011, higher risk MDS pts were treated with AZA (75 mg/m2/d during 7 or less often 5 days / 4 weeks, scheduled for at least 6 cycles), in compassionate programs (prior to AZA approval by EU) or within AZA label (since 2008) and included in the French and Spanish MDS registries. We retrospectively analyzed, in those series, the outcome of pts with Abn 7. Results: 123 pts with Abn 7 having received at least one cycle of AZA, including 82 (66%) de novo MDS and 69 males (55%), with a median age of 70y (range 33–89) were analyzed. At diagnosis, according to WHO 2008, 52% pts (n=65) had RAEB2, 16% (n=20) had RAEB1 and 10% (n=13) had AML with 20–30% marrow blasts (RAEB-T according to FAB). IPSS was high in 51% (n=64), int-2 in 43% (n=55), and not available (but at least int-2) in the remaining 25 pts. Karyotype distribution was: monosomy 7 (−7) (isolated or with 1 other abnormality, non complex −7) in 33 patients (27%), 7q- (isolated or with 1 other abnormality, non complex 7q-) in 19 patients (16%), del(7p) (isolated or with 1 other abn) in 1 patient (1%), and 69 patients (56%) had complex karyotype (〉= 3 abn) with −7 or 7q-. Among 106 patients with this information available, 74% (n=78) were RBC and/or PLT transfusion dependent (TD). 86% (n=108) of the patients received the conventional 7 day schedule of AZA, the remaining 14% receiving reduced daily dosing or 5 day cycles. The median number of cycles administered was 5 (1–32). Among 110 patients with available information the overall response rate (IWG 2006 criteria) was 32% (35/110), including 12% CR and 20% SD with HI. Among non responders, 12% died prior to evaluation, 33% were in SD and 23% progressed. Among transfusion dependent patients, 16% became RBC transfusion independent (12 of 73 TD patients with available information). The overall response rate was 30% in pts with complex karyotype with −7 or 7q-, 33% in pts with non complex −7 and 31% in pts with non complex 7q- (p=0.1 for complex vs non complex Abn 7). At the time of last follow up, 66 patients (53%) had relapsed or progressed and 102 (83%) had died. Median event free survival(considering death, relapse or progression as events ) at 1 and 2 years was 32 and 8%, respectively. Median OS at 1 and 2 years was 40%, and 18%, respectively. OS was better for patients with response after 4–6 cycles (OS at 1 year 64%) when compared with SD (1y OS 47%) or progression (1y OS 12%), p

Description: L-asparaginase (L-ASP) is an important drug in the treatment of acute lymphoblastic leukemia (ALL) demonstrating efficacy in a broad range of patients. However the toxicity profile, including allergy, has been a major drawback. There is an unmet medical need for patients who cannot receive L-ASP current formulations, especially due to allergy. E-Coli L-Asparaginase encapsulated into red blood cells (RBC/L-ASP) is a new product under development with the aim of improving the tolerability of this enzyme. Asparagine is actively transported through the membrane of red blood cells (RBC) where it is hydrolyzed by the encapsulated L-ASP, the erythrocytes acting as “bioreactors”. In addition, the RBC membrane shields against the anti-L-ASP antibody then avoiding binding to encapsulated L-ASP. Clinical trials have demonstrated a reduction in allergy with encapsulated L-ASP, and the enzyme activity is sustained even in presence of anti-L-ASP antibodies. Four patients, who were not able to receive any current L-ASP due to allergy, were enrolled in an Expanded Access Program (# NCT02197650) allowing to receive RBC/L-ASP: Patient 1: 48 year old, female, with T-cell ALL Ph-, normal karyotype, without neuro-meningeal infiltration, without extra-medullar localization. Treated according to GRAALL-2005 protocol. In complete remission (CR) after induction therapy, with negative MRD. During consolidation therapy, a grade 3 allergy (anaphylaxis) was observed after 6 injections of native E-Coli L-ASP. For late intensification, the patient was switched to Erwinia and after 3 injections a grade 3 allergy occurred. This patient was switched to RBC/L-ASP (150IU/Kg) receiving 2 injections to complete the late intensification phase with no occurrence of allergy. To date this patient is treated by radiotherapy which will be followed by the maintenance therapy. Patient 2: 30 year old, male, with T-cell ALL Ph-, normal karyotype, without neuro-meningeal infiltration, with extra-medullar localization (cutaneous and renal involvement). Treated according to GRAALL-2005 protocol, corticosensitive and chemosensitive. In CR after induction therapy, with negative MRD after 35 and 70 days. During consolidation phase, a grade 3 allergy (anaphylaxis) was observed after 8 injections of native E.Coli L-ASP. The patient was switched to Erwinia and after 2 injections a grade 2 allergy was observed. For late intensification this patient received RBC/L-ASP (150IU/Kg) at day 2 and at day 15. No allergy occurred. The patient remains in CR and has initiated maintenance therapy. Patient 3: 9 year old, male, with relapsing B-cell ALL Ph-, with hyperdipliody, without neuro-meningeal infiltration, with no extra-medullar localization. Treated according to INTREALL 2010 protocol UKALL R3 arm. In CR after re-induction therapy, with negative MRD on day 35. Grade 1 L-ASP related allergy was observed after 17 injections of native E-coli L-ASP. Erwinia was initiated and a grade 1 allergy observed after 5 injections. Peg-ASP then resulted in a grade 1 allergy after 1 injection. This patient received RBC/L-ASP (150IU/Kg) at day 6 and at day 41 of the consolidation phase. A grade 1 allergy was observed in hours following the first administration. One dose of hydrocortisone and an anti histamine treatment for 2 days resulted in full resolution. 35 days later, the patient received a second injection with prophylactic anti allergic treatment. No allergy occurred. 21 days later the patient died due to bacterial infection with ARDS. Patient 4: 3 year old, male, with T-cell ALL Ph-, with no extramedullary localization, treated in the VHR group of EORTC 58081 protocol (poor prednisone response to the prephase). In CR at the end of induction (Ia), with negative MRD after induction and consolidation (