ALBERT

Description: Despite recent advancements, approximately 50% of patients with acute myeloid leukemia (AML) do not respond to induction therapy (primary induction failure, PIF) or relapse after

Description: Background.Treatment of APL in the elderly with conventional ATRA-anthracycline based CT regimens is associated, like in younger patients, with very few relapses, but high death rates (CR rate of 87.3%, 10-year CIR of 9.3%, 21.7% deaths in CR, and a 10-year OS of 58% in patients aged〉 65 years in our previous APL trials ;Blood 2010 115:1690). Recent results have shown that, in standard risk APL, ATRA+ATO combinations (without CT) are at least as effective as classical ATRA + CT regimens while being less myelosuppressive (Lo Coco, NEJM 2014; Burnett, Lancet Oncol, 2015) thus constituting a very appealing approach for elderly patients. However, when our APL 2006 trial started, the feasibility of treatment of APL without CT was unknown. Furthermore, access to ATO still remains limited for frontline treatment of APL in most countries. We present results of APL 2006 trial, where we combined ATO to ATRA and reduced CT in patients aged older than 70 with standard risk APL (baseline WBC 70 years with WBC 1 G/L and platelets〉 50G/l after the first consolidation course was 16.2 and 11.9 days in the original vs 5.6 and 4.0 days in the amended protocol (p

Description: Background: In standard risk APL, ATRA+ATO combinations (without CT) are at least as effective as classical ATRA + anthracycline based chemotherapy (CT) while being less myelosuppressive (Lo Coco, NEJM 2014, Burnett, Lancet Oncol, 2015). In high risk APL (WBC〉 10G/l), it is still unclear if CT can be avoided or greatly reduced, but addition of ATO to ATRA + CT reduces relapses (Powell, Blood 2010). In a randomized trial (APL2006 trial) in high-risk APL patients (pts) who received ATRA + CT induction treatment, we evaluated the addition of ATO to CT during consolidation. Methods: Between 2006 and 2015, newly diagnosed APL pts 10 G/L, after an induction of ATRA 45mg/m2/d until CR with Idarubicin (Ida) 12 mg/m2/dx3 and AraC 200mg/m2/dx7, were randomized for consolidation between CT and CT+ATO. The CT group (standard group) received a first consolidation with Ida 12 mg/m2/dx3 and AraC 200mg/m2/dx7, a second consolidation with Ida 9 mg/m2/dx3 and AraC 1g/m2/12h x4d, and 2-year maintenance with intermittent ATRA and continuous 6 MP + MTX. The CT+ATO group received the same treatment except that ATO 0.15 mg/Kg/d d1 -25 was added during both consolidation courses. After a first interim analysis in Sept 2010, based on 81 pts, AraC was deleted from consolidation cycles of the CT+ ATO group. The primary endpoint was EFS from CR achievement. Results: 211 pts 10 G/L were included (after the exclusion of 8 diagnostic errors) in 58 centers. 95.7% achieved CR, 3.3% had early death and 1% resistant leukemia. 193 pts were randomized for consolidation, 97 in the CT and 96 the CT+ ATO groups. Pre-treatment characteristics were well balanced between the 2 groups. 7 pts (3 CT vs 4 CT+ATO) had relapsed (5-year cumulative incidence of relapse (CIR) of 2.5% vs 3.9%; p= 0.39) and 9 pts had died in CR :7 (7.8%), 2 (5.1%), 0 (0%) in the CT, CT (with AraC) + ATO, CT (without AraC) + ATO groups respectively (p=0.04). Causes of death in CR were bleeding (n=5), infection (n=2), previous cancer relapse (n=2). One patient in the CT+ATO arm developed AML/MDS. 5-year OS was 93% vs 94% (p=0.56) and 5-year EFS was 89% vs 93% (p=0.47) in the CT and CT+ATO groups, respectively. Omission of AraC (after the amendment) in the CT+ATO group did not increase CIR (5 year CIR 5.3% with and 3.3% without AraC, p=0.57). In the CT, CT (with AraC) + ATO, CT (without AraC) + ATO groups respectively, median time to ANC〉1 G/L after consolidation 2 was 22, 25 and 19 days (p50G/l was 24, 26 and 20 days (p

Description: Abstract 439 Background: TET genes have been implicated in DNA demethylation in mammals (Thalihani, Science, 2009; Ito, Nature 2010) and the TET2 gene is mutated in 15–22% of MDS and AML (Kosmider et al. Blood 2009, Nibourel et al. Blood 2010). Azacitidine (AZA) is a hypomethylating agent providing about 50% of responses in MDS and AML with low blast count (Lancet Oncol 2009, JCO 2010). Routine clinical and biological variables can predict OS with AZA, but are poor predictors of response to AZA (Itzykson et al. ASH 2009, and other abstract submitted to ASH 2010), while no consensus genetic predictor of response has been reported so far. Methods: In consecutive MDS (including RAEB-t and CMML) and AML post MDS (with 〉30% blasts) (AML/MDS) patients treated by AZA in 6 centers, we prospectively sequenced the TET2 gene from PBMC or BMNC DNA samples stored prior to AZA onset. Standard PCR and sequencing procedures were performed as previously described (Delhommeau et al, NEJM 2009), allowing detection of mutations in the entire coding sequence of the TET2 gene (exons 3 to 11). Patients were to receive AZA at the FDA/EMEA approved schedule (75mg/m2/d, 7d/4 weeks). Patients (pts) having received ≥ 1 cycle of AZA and who had bone marrow evaluation after ≥ 4 cycles, or who died or progressed before completion of 4 cycles were considered evaluable (the last 2 groups were considered as treatment failures). Responses were scored according to IWG 2006 criteria for MDS and to Cheson et al. (JCO 2003) for AML. Results: The study population included 103 pts: F/M: 36/67; median age 72 (range 43–91). Diagnosis at AZA onset was MDS in 89 (RAEB-1 n=20, RAEB-2 n=43, RAEB-t n=23, CMML-1 n=2, CMML-2 n=1; IPSS int-1 in 13, int-2 in 38, high in 36, undetermined in 2) and AML/MDS in 14 pts; 29 pts had previously been treated by LD AraC or intensive chemotherapy (IC). Cytogenetics according to IPSS was favorable in 48, intermediate in 20, unfavorable in 31, unknown in 4. 78 pts received the approved and 25 (24%) a reduced AZA schedule (mostly 75 mg/m2 for 5 days every 4 weeks). Median number of cycles was 7 [range 1–39] and median follow-up was 18.2 months. 21 TET2 mutations were found in 17 (17%) pts, including 12 frameshift (all inducing a premature STOP codon), 6 non sense and 3 missense mutations. Predicted TET2 protein length was preserved in 3, and truncated in 14 pts, respectively. Patients with mutated (MUT) TET2 had similar age, diagnosis, BM blast %, neutrophil and platelet counts as those with wild type (WT) TET2 (all p〉0.3), but less frequent unfavorable cytogenetics (6% vs 37%, p=0.02) and a trend for higher WBC (p=0.12), lower Hb (p=0.11) and more pretreatment by LD AraC or IC (47% vs 24%, p=0.08) than WT TET2 pts. The 2 groups received AZA at similar schedules (p=0.4) for a median of 6 [1-39] cycles (TET2 WT) or 11 [4-34] cycles (TET2 MUT, p=0.01). Ten WT pts (vs 0 MUT) received

Description: Abstract 1653 Poster Board I-679 Background The immune system is involved in AML control and Natural Killer (NK) cells are among the most promising effectors. The therapeutic potential of NK cells has been revealed by the Killer Immunoglobulin Receptor (KIR) mismatch allogeneic transplant model where the anti-leukemic effect of the graft, is due to unleashed NK cells towards AML blasts, as suggested by enhanced in vitro lytic activity of KIR-HLA mismatched donor NK cells against recipient blasts (Miller et al. 2005; Ruggeri et al. 2002). Receptors involved in the function of NK cells against AML blasts have been identified (Pende et al., 2005). Some of these receptors are altered in AML patients at diagnosis and might be involved in the immune escape of AML blasts (Costello et al., 2002). However, the status of NK cells during early stages of patient's chemotherapy (CT) treatment is unknown. The present study monitored status of NK cells during early stages following patient's remission after CT that may be critical for their long lasting clinical response, and results might provide new targets for immunotherapy. Methods We enrolled 20 elderly patients (60 to 80 years old) with non promyelocytic AML in first CR following induction and pre-consolidation CT with normal renal and hepatic functions. Patient peripheral NK, gd T and CD8 T cells were analyzed before consolidation CT and every other week after treatment for 8 weeks. 6-colors flow cytometry was performed to investigate the expression of MHC receptors (CD158a, b, e, i, CD85j and NKG2A), activating receptors (NKp30, NKp46, NKG2D, CD16, DNAM-1, 2B4) as well as their differentiation status (perforin and granzyme expression). Their function, as determined by cytotoxicity (51Cr release and CD107 expression) and cytokine production (intracellular staining of IFN-g), was analyzed using purified NK cells stimulated by K562, or in redirected assays using NKp30, NKp46 and CD16 mAbs. Results NK cell counts were depressed away from the induction and pre-consolidation CT as compared to NK cell counts of age-matched controls (ctl) (95±107 NK/μL vs 229±91 NK/μL respectively); they were further depressed during the first 2 weeks post-consolidation CT (55±57 NK/μL), but were back to pre-consolidation CT level at 4 weeks (105±102 NK/μL). In contrast, CD8 T cells and gd T cells counts were normal even at early times post-CT. Expression of 2B4 was depressed at all time points. In contrast, NKp30 expression was lower at diagnosis and close to ctl level post-consolidation CT (p=0.0003) and NKp46 expression increased after CT (p

Description: Abstract 3996 Background: AZA significantly improves OS in higher-risk MDS (including RAEB-t/AML) compared to conventional treatments (AZA 001 trial, Lancet Onc, 2009), but prognostic factors of response and OS to AZA remain largely unknown. We designed a prognostic score for OS in a cohort of AZA treated higher-risk MDS in a patient-named compassionate program (French ATU), and validated it in patients from the AZA 001 trial. Methods: Between Sept 2004 and Jan 2009, prior to AZA approval in Europe, IPSS int-2/high risk MDS (including RAEB-t) not previously treated with intensive chemotherapy (IC), allo SCT, or a hypomethylating agent were included in a compassionate program (ATU), and received AZA (planned schedule 75 mg/m2/d ×7 d every 28 d for ≥4 cycles). Independent prognostic factors of OS were individualized in a Cox model. A prognostic score was then developed based on those factors. After validation of the score as a continuous variable, pts were grouped in three distinct risk categories. We subsequently tried to validate this score in the 175 higher risk MDS pts treated with AZA at the same schedule in AZA 001 trial (4 of the 179 pts randomized to AZA in that trial did not start AZA). Results: The ATU cohort included 282 pts with de novo (74%) or therapy related (t) (26%) higher-risk MDS (IPSS int-2 in 54% high in 43%, at least int-2 in 2%). ECOG PS ≥2, RBC transfusion dependence ≥4 units/8 weeks and circulating blasts were present in 21%, 46% and 46% of pts respectively (resp). Cytogenetic risk was good, int, and poor in 31%, 17% and 47% (unknown in 5%). 10% pts had previously been treated with LD araC for their MDS. Multivariate analysis of survival retained PS ≥2 (HR= 2.0 [95% CI: 1.4–2.9]), RBC transfusion dependence ≥4 units/8 weeks (HR=1.9 [1.4-2.6]), presence of circulating blasts (HR=2.0 [1.5-2.7]), and IPSS cytogenetic risk (intermediate: HR=1.4 [0.8-2.3], poor: HR=3.0 [2.0-4.3]) as independent prognostic factors (all p

Description: Abstract 1868 Aim: Erythropoiesis stimulating agents (ESA) or lenalidomide (in case of del 5q) are the usual first line treatments of anemia of low/int-1 IPSS (lower) risk MDS. After their failure, IST with ATG+/−CsA is among the approaches considered, with 30 to 50% erythroid response (Sloand, JCO 2008; Lim, Leukemia 2007, and others), including durable red cell transfusion independence (RBC-TI). In multivariate analysis, predictors of response to IST in MDS include low/Int-1IPSS (especially int-1 without excess blasts due to presence, in addition of anemia, of thrombocytopenia or intermediate (int) karyotype) and, depending on studies, age ≤60 y and HLA DR-15 positivity. Pts with those good prognostic factors were however overrepresented in several MDS series treated with IST and analysis of the first 400 pts included in the European LeukemiaNet lower risk MDS registry found only 2 pts treated with IST (De Witte, personal communication). We reviewed the characteristics and outcome of MDS pts treated with IST in our centre and assessed the frequency of low/int-1 MDS pts potentially candidates to IST, based on published prognostic factors, in the Groupe Francophone des Myélodysplasies (GFM) patient database. Methods: From Jan 2004 to Feb 2010, we treated in our center 12 MDS by IST. From mid 2003 to end of 2008, 1311 MDS pts with IPSS scoring, were entered into the GFM registry. We computed in this registry the frequency of pt subsets potentially good candidates to IST based on age, having anemia with low/int-1 IPSS, or int-1 with 65 y responded. With a median follow-up of 21.5 months (6-68), erythroid response was ongoing after 17, 21, 44, 47 and 62 months, respectively. Three NR pts died at 11, 16 and 18 months (one Int-2 pt with RAEB and +8, from AML progression, and 2 pts from marrow failure). In the GFM database, pts with transfusion dependent anemia and IPSS low or int-1, and IPSS int-1 with

Description: Introduction: Acute myeloid leukemia (AML) in the elderly is a therapeutic challenge, and global evaluation of comorbidity, performance status, fitness and frailty is crucial for therapeutic decision of treatment intensity. Accurately predicting risks and benefits of available therapies is particularly difficult, as it relies on subjective criteria, no geriatric scores being validated so far. The aim of this study was to evaluate the impact of a standardized geriatric assessment at diagnosis in a prospective cohort of newly diagnosed AML in elderly patients, and to investigate correlations between geriatric scores and overall survival. Methods: All patients aged ≥ 70 years with newly diagnosed AML were prospectively included in this cohort. They all benefited from an exhaustive geriatric assessment in addition to standard AML workup, including ADL, IADL, ECOG, comorbidities, nutritional status (assessed by BMI and mini-MNA), cognitive impairment (mini-COG, mini-GDS), quality of life (QLQ-C30), functional scales (physical, role, emotional, cognitive and social functioning), symptom scales (fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, financial difficulties) and frailty criteria (physical activity, energy visual scale, mobility, nutrition). Patients were treated according to international guidelines, with intensive chemotherapy, hypomethylating agents, subcutaneous low-dose cytarabine, palliative oral chemotherapy or best supportive care only, according to physician choice. The impact of geriatric scores on 6-months overall survival was analyzed. Results: Between 2010 and 2015, 94 patients were enrolled, including 61.7% of males and 38.3% of females. Median age was 75.5 years (70-96). Initial median leucocytes, neutrophils, hemoglobin, and platelets counts were respectively 4.7 G/L (0.4-174), 1.3 G/L (0.1-5.4), 9.3 g/dL (5.3-13.2), 51 G/L (5-520). Median bone marrow blasts percentage was 55% (20-96). Cytogenetics was favorable, intermediate and adverse in 18%, 62% and 20% respectively. Intensive chemotherapy was chosen in 57.4% of patients, and low intensity or palliative approach in 42.6% of patients. Patients spent a median of 30.5 days in hospital (0-119), received a median of 12 (0-44) red blood cells units and 2 (0-33) platelets units. Global geriatric assessment of patients is reported in Table 1. By univariate analysis, prognostic factors associated with a reduced survival were high dementia risk (HR=3.63, 95% CI=1.4-9.3, p=0.004), high ECOG score (HR=2.1, 95% CI=1.1-4, p=0.02) and high risk of denutrition (HR=3.43, 95% CI=1.33-8.9, p=0.007), while intensive chemotherapy was associated with a better outcome (HR=0.45, 95% CI=0.2-0.9, p=0.014). Multivariate analysis identified high risk of denutrition as independently associated with reduced survival (HR=3.08, 95% CI=1.17-8.11, p=0.02). Intensive chemotherapy treatment tended to impact prognosis but was not statistically significant (HR=0.54, 95% CI=0.27-1.01, p=0.08). Conclusions: In a prospective cohort of newly diagnosed AML elderly patients, an exhaustive standardized geriatric assessment at diagnosis identified high risk patients for mortality. The most relevant prognostic factor was nutritional status, which correlated with overall survival. Other geriatric scores and scales did not impact prognosis, which highlights the difficulty of global evaluation in this population. Patients treated with intensive chemotherapy tended to have a better outcome. Disclosures No relevant conflicts of interest to declare.

Description: Background : although azacitidine (AZA) is an established frontline therapy for HR-MDS, approximately 40% of the patients fail to respond and virtually all of the responders will ultimately relapse. We previously reported the poor outcome of patients who failed AZA treatment for whom a median survival of 6 months is expected (Prebet, J Clin Oncol. 2011;29(24):3322). Overexpression of SMO a member of the hedgehog pathways has been observed in HR-MDS. Preclinical data have shown the activity of hedgehog pathway inhibitors and suggested synergism with Hypomethylating agents (HMA) (Zou, PLoSONE 2015; 10(8):e0136843). To harness potential synergism, we designed an add-on trial in which sonidegib (LDE-225), an oral inhibitor, was added to AZA in patients who failed AZA monotherapy. Patients and methods: Eligible patients should have IPSS Int-2 or HR-MDS or AML, (to have 10% to 30% marrow blasts), have received a minimum of 6 cycles of AZA monotherapy and to have failed to achieve a response to AZA (defined as CR, CRi, PR or HI as per IWG criteria) in the absence of marrow progression or have relapsed after achieving a response. Patients were scheduled to receive sonidegib daily from day 1 to 28 of 28-day cycles while continuing on AZA at the maximum previously tolerated dose (ie 50 to 75 mg/m²/d for 5-7 days). Two sonidegib dose levels were evaluated in the phase 1 part of the trial (400 and 800 mg/d) according to a classical 3+3 scheme. Results: 23 patients, median age 76, were included in the study. One withdrew consent before starting the study treatment and is not included in the analysis. Characteristics of the remaining 22 patients are summarized in the Table. At the 800 mg/d dose level, 3 pts experienced DLT (grade 4 ASAT elevation (1 pt); grade 4 CPK elevation (2 pts)). The recommended dose for the expansion phase was 400 mg/d and no DLT was observed. 19 patients received 400 mg/d. Pts received a median of 3.5 cycles [IQR 2 ; 5], and 5 pts (23 %) received ≥ 6 cycles. All of them were withdrawn from study: 5 (26%) for disease progression (including 1 pt who progressed before starting cycle 1 and did not received treatment), 5 (26%) for death (all due to infection in the context of active disease) and 9 for miscellaneous reasons. 25 SAEs were reported including 23 infections, 1 intra cranial hemorrhage and 1 urinary retention. The most frequent non-hematologic toxicity was infection that occurred in 16/22 (73%) pts. In addition, 243 non hematologic toxicities of any grade were recorded in 20 pts for a total of 83 cycles, all but 3 of grade 1-2, including GI, cutaneous and musculo-skeletal toxicities and fatigue. Hospitalization was required in 45% of the pts. Only 3 responses were observed (1 CR, 1 marrow CR and 1 PR). Response durations were 1, 9 and 15 months .With a median follow-up of 23 months, 13 pts have died and the median overall survival is 6.8 months. Conclusion Sonidegib at the dose of 400 mg/d can be given in combination with azacitidine with an acceptable toxicity. With a response rate of only 13%, our results indicate that the addition of sonidegib failed to reverse resistance to azacitidine in pts with higher risk MDS. This contrasts with the positive effect of the combination of glasdegib, another hedgehog pathway inhibitor with cytarabine in pts with AML and MDS (Cortes, Blood 2016 128:99). Besides potential differences in drug potency, our results may highlight the difficulty to identify active agents in the difficult-to-treat patient population selected after HMA therapy failure. The recommended dose-schedule of AZA-sonidegib established here could be used for further investigation in previously untreated patients. Table. Table. Disclosures No relevant conflicts of interest to declare.