Ofran, Yishai

Abstract Background We performed a prospective study evaluating a baseline GA battery and clinical outcomes in fit older adults (age ≥60 years) with AML and normal cardiac and renal function in the recent E-A NCTN E2906 phase 3 study. A patient-reported outcomes (PRO) assessment of Depression, Activities of Daily Living (ADL), Cognitive Function, Social Support (SS) domains, and comorbidity was performed at study registration to evaluate the prevalence of vulnerabilities and their impact on overall survival (OS) and 30-day induction mortality rates (IM) in this cohort selected for fitness to receive IC. Methods E2906 study design and results have been presented previously [n=727, age ≥60 years, randomized 1:1 to ‘standard 7&3‘ & high dose cytarabine (Arm A) vs. single agent clofarabine (CLO, Arm B), as remission induction (Step 1) and consolidation (Step 2)]. There was no difference in composite complete remission (CCR, 50%) or IM (8.5%), and CLO was inferior for OS. A baseline GA was a key secondary protocol objective, offered to all patients, and n=532 (73%) participated. We assessed Geriatric Depression Scale (GDS, none vs. any depressive symptoms, n=524); cognitive screen using Mini-Mental Exam Section (MMES, score 8/8 vs. <8, n=516); ADL & Instrumental ADL (iADL), (need for assistances vs. not n=526); a Medical Outcomes Study SS Survey (MOS-SS, measured as per unit increase, n=527); a Comorbidity survey ( ≤4 vs. ≥5 patient-reported comorbidities, n=530), patient-reported prescription medications use (PM, 0-3 vs. ≥4, n=519); and a survey of Sexual Desire (n=491) and Sexual Activity (n=477) within 4 weeks of AML diagnosis. Association of GA domains with OS, IM, and achievement of CCR was evaluated using the Chi-squared, Fisher's exact, and Wilcoxon rank sum test. Survival analysis was performed using the Cox proportional hazards models, adjusted for treatment arm. All p-values are 2-sided. Results The median age among those participating in GA battery was 67 yrs (range 60-85), including 38% age ≥70. There were 42% females, and ECOG performance status was 0 (28%), 1 (54%), 2 (16%), or 3 (2%). Central Cytogenetic review was classified (ELN2017) as Favorable (3%), Intermediate (66%), and Adverse (31%) risk. There was a notable rate of GA scores outside ‘normal’ clinical cutoff, including Depression (GDS 31%), cognitive and functional impairment [MMSE (37%), ADL (25%) and iADL (32%)], ≥5 Comorbidities (23%), and ≥4 PM's (44%). 81% & 76%, respectively, reported no sexual activity and low/none sexual desire. MOS-SS tended to be high in this cohort [mean (SD) score 87 (17)]. We observed a significant association of GA domains with OS & IM. For OS, absence of depressive symptoms [GDS, Hazard Ratio (HR) 0.79, 95% confidence Intervals (CI) 0.64-0.97, p=0.025)], MMES 8/8 (HR 0.78, 95%CI 0.64-0.96, p=0.016), requiring no assistance with ADLs (HR 0.65, 95%CI 0.52-0.82, p<0.001) and iADLs (HR 0.69, 95%CI 0.57-0.85, p<0.001), and ≤4 Comorbidities (HR 0.68, 95%CI 0.54-0.84, p=0.001) were significant for superior OS; use of ≥4 PM's was associated with inferior OS (HR 1.32, 95%CI 1.09-1.61, p=0.005). There was no association of sexual activity/desire, BMI ≥30 kg/m2, or MOS-SS with OS. IM was significantly higher among those with any depression symptoms (GDS, p=0.005), any ADL (p=0.010) or iADL (p=0.013) impairment, ≥5 comorbidities (p=0.037) and ≥4 PM's (p=0.001); there was no association with MOS-SS or MMES. There was no significant association of GA scores with cytogenetic risk group or with CCR rates. Only ADL independence (p=0.048), and possibly Comorbidity ≤4 (p=0.071), were associated with proceeding to Step 2. Conclusions In this large prospective cohort of fit older adults with AML selected to receive IC, we observed high rates of PRO-assessed GA vulnerability, which was significantly associated with inferior OS and higher IM rates, and (for ADL impairment) lower rates of proceeding to consolidation therapy. This suggests that functional and cognitive impairments are prevalent and can significantly impact outcome even in fit older adults. Despite potential long-term OS advantages of IC previously observed in E2906, efforts to systematically recognize those at higher risk based on GA PROs are needed to help identify patients who may be more appropriate for study of lower intensity treatment options to mitigate impact on IM and OS. SImilarly we plan to evaluate the potential benefit of GA-driven supportive care to improve patients' outcomes.

Background There is limited prospective or comparative data evaluating the HRQoL impact of intensive chemotherapy (IC) in older adults (age ≥60 years) with AML. In the recent EA E2906 phase 3 study of '7&3' (daunorubicin & cytarabine) vs. clofarabine (CLO), a putative lower intensity therapy, we incorporated a prospective patient-reported outcomes (PRO) assessment of HRQoL and fatigue to understand treatment impact from the patients' (pts) perspective. Methods E2906 study design and results have been presented previously [n=727, med. age 68 years (range 60-86), randomized 1:1 to ‘standard’ ‘7&3‘ & high dose cytarabine (Arm A) vs. single agent CLO (Arm B), as remission induction (Step 1) and consolidation (Step 2), respectively]. There was no difference in composite complete remission (CCR, 50%) or 30-day mortality rates (8.5%), and in primary analysis CLO was inferior for Overall Survival. HRQoL was a key secondary protocol endpoint. PROs assessed HRQoL and leukemia-specific symptoms and concerns using Functional Assessment of Cancer Therapy-Leukemia scale (FACT-Leu), & Fatigue using FACT-Fatigue subscale. PROs were administered at prespecified time points: (1) Baseline; (2) Cycle 1 at nadir (approx. Day 15); (3) End of Step 1 restaging (approx. D 40); (4) Beginning of Step 2 (1 st consolidation, approx. D 45); and (5) 2 nd cycle consolidation/End Step 2 (approx. D 60). The FACT-Leu Trial Outcome Index ( TOI) was calculated by summing physical well-being, functional well-being, and leukemia-specific concerns subscales to create a single composite score. Higher TOI scores correspond to better HRQoL. The primary endpoint was to evaluate TOI difference from randomization to day 30 after induction therapy between arms, evaluated using Wilcoxon rank sum test. We also compared Clinically Meaningful differences (CMiD) in TOI (defined as patient change ≥½ standard deviation from baseline TOI) between arms, using the X2 test. Pts not completing at least 2 assessment forms (including baseline) were excluded. Testing of constructs of Physical Well-being (PWB), Functional, Leukemia & Fatigue scales demonstrated high Cronbach's a values (a >0.7) except for PWB (a=0.672) at a single time point (End of Step 2). Results Baseline TOI was available for n=489, and 364 pts (n=182 each Arm) were evaluable in this planned analysis. Evaluating CMiD during Cycle 1 induction, pts in Arm B were less likely to experience ‘Worse’ TOI score (32% vs. 40.7%, Arm A), more likely to maintain stable TOI scores (49.1% vs. 39%, Arm A), and had a similar proportion of ‘Better’ TOI scores (20.3%, A vs. 18.9%, B) although differences were not significant (p=0.1389). Conversely in cycle 1 consolidation, more patients in Arm A experienced Better TOI (45.1% vs. 29.2%, Arm B), fewer had stable TOI (45.1% vs. 58.3%, Arm B), and rates of ‘Worse’ TOI were similar (9.8%, A vs 12.5%, Arm B), again differences were not significant (p=0.2616). There was no difference in Fatigue scores between Arms (p=0.49). We evaluated whether TOI and Fatigue scores could predict the ability to complete protocol therapy. In univariate analysis baseline TOI (p=0.0059) and Fatigue (p=0.0057) were associated with Step 1 completion, however on multivariate analysis (adjusting for age, sex, and Arm) were no longer significant [TOI, Odds Ratio (OR) 1.03 (0.98-1.08, p=0.27); Fatigue, OR 1.03 (0.96-1.11, p=0.42)]. There was a borderline association of TOI with Step 2 completion [TOI OR 1.10 (1.00-1.23, p=0.06)]. Using a multivariable linear mixed effects model, we observed similar and significant changes in TOI scores in both Arms, demonstrating the effect of IC & CLO on HRQoL (Figure). Comparing to baseline, TOI scores decreased significantly at C1 induction nadir (-4.0873, p<0.0001), and increased by 5.0762 (p=0.0004) at end Step 1, by 6.9047 at cycle 1 consolidation (p<0.0001), and by 11.4601 (p<0.0001) at end Step 2. Differences were mainly apparent in those who achieved CCR, and there was significant attrition in PRO responses in non-CCR pts. Conclusions Older adults experienced significant improvement in HRQoL after nadir regardless of therapy, and those achieving CCR report significantly higher scores. We did not observe differences in leukemia specific HRQoL or fatigue between treatment Arms (7&3 vs. CLO). Patient-reported HRQoL & Fatigue was not predictive of completion of protocol therapy. These results serve as a benchmark for expectations with IC in older adults.

Abstract Introduction: Allogeneic stem cell transplantation (alloSCT) is the most effective post remission anti-leukemia strategy. However, the associated toxicity is a barrier for its routine adoption as standard of care in older adults. Studies of AML patients who underwent alloSCT are mainly retrospective as randomized controlled trials comparing transplantation to non-transplantation are very difficult to conduct. We herein present prospective data from a randomized controlled phase III study, E2906, designed to compare two intensive chemotherapy arms. Patients who achieved remission and had a donor were to proceed to alloSCT after induction or first consolidation, at investigator discretion. Non-transplanted patients received 2 cycles of consolidation and then underwent a second randomization between observation and decitabine maintenance. Herein are reported all patients who received alloSCT either on protocol during first remission (CR1) or at other post induction time-points. Patients and Methods: Enrolled to E2906 study were 727 AML patients age 60 years and over. AlloSCT was performed in 166 patients, of whom 71 received alloSCT as part of the study and 95 received alloSCT off protocol. 105 patients (66/71 on protocol, 39/95 off protocol) received alloSCT at CR1/CRi1/LFS1 (CR: 92, CRi: 9 LFS: 4). Patients were followed for a median of 33.6 months from diagnosis and 29.1 months from transplant. No patients received decitabine maintenance prior to alloSCT. Overall survival (OS) is defined as the time from allo transplant to death from any cause, with follow-up censored at the date of last contact. Disease free survival (DFS) is defined as the time from alloSCT transplant to relapse or death of any cause. The censored follow-up time for patients without relapse or death information is the date of last contact. Kaplan-Meier estimates were used to estimate OS and DFS. DFS and OS were compared between subgroups using log rank tests. A cumulative incidence analysis, with death without prior relapse as competing events, was performed to evaluate the subgroup effect on time to relapse after transplant. Results: Patient characteristics of those who received alloSCT at CR1/CRi1/LFS1 are similar to the general distribution of AML patients eligible for intensive chemotherapy. Median age was 66 years, 52% were male and 88% with ECOG PS of 0-1. Cytogenetic data were available for 85 patients of whom 26% presented with unfavorable cytogenetics. Minimal residual disease (MRD) status prior to alloSCT was available for 44 patients of whom 19 (43%) achieved a MRD negative state. Long-term OS and DFS rates for all 105 patients who underwent alloSCT at CR1/CRi1/LFS1 are encouraging (Figure 1). OS and DFS at two years were 56.4% and 53.6% and 49.4%, 45.6% and 42.9%, 39% at 3 and 4 years, respectively. Age above or below 65 years, gender, induction regimen (3+7 or clofarabine) and MRD status prior to transplantation had no impact on outcome. Survival curves by intermediate or adverse cytogenetic risk are not significantly different. The numbers of patients with CRi1 or LFS1 are too small to compare with patients in CR1. Nevertheless, 36/38 patients that were alive and remain in first remission at the time of data cutoff, are patients who achieved CR1 and only 2/38 are patients transplanted at CRi1 or LFS1. Notably, the non-relapse mortality (NRM) was not significantly different for patients less or over 65 years. NRM at 6 months and 2 years for patients over and under 65 years of age were 4.4%, 8.4% and 15.6%, 24.0% respectively. Relapse during the first year post alloSCT is the main barrier for longer survival, particularly in patients with adverse cytogenetics and MRD positivity prior to transplantation (Figure 2). Conclusions: Fit older patients, including those over age 65, who undergo an alloSCT in CR1, can expect a 4-year survival of 43% with an acceptable NRM rate. The NRM was, surprisingly, not higher than for a typically younger cohort of AML. Relapse within one year after transplant is the major limitation to prolonged survival and this finding reflects the biology of the leukemia in these patients. In this patient population, novel post remission strategies should either be complimentary to alloSCT or competitive with updated outcome of alloSCT. Figure 1 Figure 1. Disclosures Ofran: Medison Israel: Consultancy; Janssen: Consultancy; Pfizer: Consultancy; Astellas: Consultancy; AbbVie: Consultancy. Claxton: Astellas: Other: Clinical Trial; Novartis: Research Funding; Astex: Research Funding; Cyclacel: Research Funding; Daiichi Sankyo: Research Funding; Incyte: Research Funding. Tallman: Syros: Membership on an entity's Board of Directors or advisory committees; Kura: Membership on an entity's Board of Directors or advisory committees; NYU Grand Rounds: Honoraria; Innate Pharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Biosight: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Oncolyze: Membership on an entity's Board of Directors or advisory committees; KAHR: Membership on an entity's Board of Directors or advisory committees; Orsenix: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Rafael Pharmaceuticals: Research Funding; Glycomimetics: Research Funding; Biosight: Research Funding; Orsenix: Research Funding; Abbvie: Research Funding; Mayo Clinic: Honoraria; UC DAVIS: Honoraria; Northwell Grand Rounds: Honoraria; NYU Grand Rounds: Honoraria; Danbury Hospital Tumor Board: Honoraria; Acute Leukemia Forum: Honoraria; Miami Leukemia Symposium: Honoraria; New Orleans Cancer Symposium: Honoraria; ASH: Honoraria; NCCN: Honoraria. Melnick: Constellation: Consultancy; Epizyme: Consultancy; Daiichi Sankyo: Research Funding; Sanofi: Research Funding; Janssen Pharmaceuticals: Research Funding; KDAC Pharma: Membership on an entity's Board of Directors or advisory committees. Levine: Prelude: Membership on an entity's Board of Directors or advisory committees; Ajax: Membership on an entity's Board of Directors or advisory committees; Zentalis: Membership on an entity's Board of Directors or advisory committees; Mission Bio: Membership on an entity's Board of Directors or advisory committees; QIAGEN: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; Lilly: Honoraria; Morphosys: Consultancy; Janssen: Consultancy; Incyte: Consultancy; Astellas: Consultancy; Imago: Membership on an entity's Board of Directors or advisory committees; Auron: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Celgene: Research Funding; Roche: Honoraria, Research Funding; C4 Therapeutics: Membership on an entity's Board of Directors or advisory committees; Isoplexis: Membership on an entity's Board of Directors or advisory committees. Lazarus: Bristol Myer Squibb: Membership on an entity's Board of Directors or advisory committees. Luger: Syros: Honoraria; Agios: Honoraria; Daiichi Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria; Brystol Myers Squibb: Honoraria; Acceleron: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Onconova: Research Funding; Celgene: Research Funding; Biosight: Research Funding; Hoffman LaRoche: Research Funding; Kura: Research Funding. Foran: gamida: Honoraria; aptose: Research Funding; syros: Honoraria; boehringer ingelheim: Research Funding; kura: Research Funding; takeda: Research Funding; abbvie: Research Funding; trillium: Research Funding; revolution medicine: Honoraria; certara: Honoraria; actinium: Research Funding; OncLive: Honoraria; pfizer: Honoraria; servier: Honoraria; bms: Honoraria; novartis: Honoraria; taiho: Honoraria; sanofi aventis: Honoraria; h3bioscience: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding. Litzow: Jazz: Other: Advisory Board; AbbVie: Research Funding; Omeros: Other: Advisory Board; Amgen: Research Funding; Actinium: Research Funding; Astellas: Research Funding; Pluristem: Research Funding; Biosight: Other: Data monitoring committee.

BackgroundCXCR4 mediates the retention and survival of acute myelogenous leukemia blasts in bone marrow and contributes to their resistance to chemotherapy. The authors evaluated a combination of the high‐affinity CXCR4 antagonist BL‐8040 with high‐dose cytarabine (HiDAC) chemotherapy in a phase 2a study of patients with relapsed and refractory AML.MethodsForty‐two patients received treatment with BL‐8040 monotherapy for 2 days followed by a combination of BL‐8040 with HiDAC for 5 days. Six escalating BL‐8040 dose levels were investigated (0.5, 0.75, 1.0, 1.25, 1.5, and 2.0 mg/kg), and 1.5 mg/kg was selected as the dose for the expansion phase (n = 23).ResultsBL‐8040 in combination with HiDAC was safe and well tolerated at all dose levels. Clinical response was observed with BL‐8040 doses ≥1.0 mg/kg. The composite response rate (complete remissions plus complete remissions with incomplete hematologic recovery of platelets or neutrophils) was 29% (12 of 42) in all patients and 39% (9 of 23) in the 1.5‐mg/kg phase. The median overall survival was 8.4 months for all patients, 10.8 months in the 1.5‐mg/kg phase, and 21.8 months for responding patients in the 1.5‐mg/kg cohort. Two days of BL‐8040 monotherapy triggered the mobilization of blasts into peripheral blood, with significantly higher mean fold‐changes in responders versus nonresponders. This was accompanied by a decrease in bone marrow blasts.ConclusionsThe current results demonstrate the efficacy of CXCR4 targeting with BL‐8040 and support continued clinical development in acute myelogenous leukemia.

Background: Relapse remains the most common cause of treatment failure after intensive induction and consolidation (CONS) therapy in older adults with AML. We therefore performed a prospective randomized phase II study to determine the safety and impact on DFS (relapse or death) and OS of DAC maintenance using an abbreviated 3-day schedule administered every 4 weeks for 1 year (per Lubbert et al, Haematologica 97:393, 2012) vs. Observation (OBS) after intensive AML therapy, conducted in the large multi-center E-A E2906 Phase III trial in patients (pts) age ≥60 yrs. Methods: The design and primary clinical results for E2906 (n=727) have been reported previously (Foran et al, ASH #217a, 2015), demonstrating superior OS following 'Standard' 7&3 (Daunorubicin 60mg/m2) induction and intermediate dose Ara-C consolidation (CONS) vs. single agent Clofarabine (CLO, provided by SANOFI), despite similar CR/CRi (CR with incomplete CBC recovery) and induction mortality rates. All CR/CRi pts after induction (n=311) were assigned to 2 cycles CONS with either Ara-C (1.5g/m2 x 12 doses; 6 doses if age >/=70 yrs), or single agent CLO, based on induction randomization. Ongoing CR/CRi after recovery from CONS was confirmed with restaging BM biopsy, and eligible pts offered participation in the 'Step 3' maintenance study, a 1:1 randomization (stratified by induction therapy, cytogenetic risk group, age <70 yrs) to either OBS vs. DAC (20mg/m2IV Days 1-3, q4 wks) for 1 year. DAC could be held for up to 4 weeks for delayed hematologic recovery, but dose reductions were not permitted per protocol, and DAC was not continued beyond 12 months. Patients in both arms were evaluated with CBC q4 weeks for 1 year, and surveillance BM biopsy every 3 months (or at the time of suspected clinical relapse) for 2 years. 'Step 3' was designed as a phase II pilot randomized study, with target accrual n=172, allowing 90% power to detect 36% reduction in DFS Hazard Ratio (HR) with DAC maintenance for 1 year (using protocol-specified 1-sided log-rank test significance level of 0.1), assuming 140 events & 2 years of follow-up from randomization. However, further accrual to E2906 was suspended in 2/2015 by independent DSMC due to superior OS observed with standard Arm, so that 'Step 3' completed only 70% of target accrual. P-values reported are two-sided by convention unless specified otherwise. Results: 'Step 3' total accrual was n=120 (of 172 planned) (DAC 61, OBS 59), with median age 69 yrs (range 60-85), and groups were very well balanced for baseline clinical characteristics; most pts had Intermediate risk cytogenetics (74.2%) and ECOG performance status (PS)=0/1 (96%). The median number of DAC cycles received was 6 (range 0-13), and analysis was 'intention-to-treat'. The median follow-up is 49.8 months. There were 90 DFS events (47 OBS, 43 DAC), with 82 deaths (46 OBS, 36 DAC). Univariate DFS and OS are shown in Figure, with associated two-sided p-values; using protocol-prespecified one-sided significance level of 0.1, OS was significant (one-sided p=0.06) for DAC v. OBS, and there was a statistical trend favoring DFS (one-sided p=0.11), particularly for CLO pts (Table). We also performed multivariate Cox model (after adjustment for ECOG PS, sex, secondary AML, and baseline hematologic parameters) which confirmed superior HR for DFS (one-sided p=0.10) & OS (one-sided p=0.07), per statistical design. FLT3-ITD status is available for n=96 pts, and 84 were FLT3-ITD-negative (46 OBS, 38 DAC). Importantly, we observed a significant association of DAC maintenance with superior OS in the large FLT3-ITD-neg subgroup (p=0.039) (Figure). DAC was generally well tolerated apart from grade 3 febrile neutropenia (9%) and reversible grade 4 cytopenias, with no grade 5 events. Conclusions: In this randomized phase II study, DAC maintenance for 1 year after intensive AML therapy was associated with improved HR for OS and a trend for DFS, using protocol-specified statistical design. Furthermore there was a significant impact on OS for the FLT3-ITD-negative population. We acknowledge limitations based on incomplete accrual due to early termination of the parent E2906 study, and inherent to the phase 2 design of this E2906 endpoint, but results suggest an important impact of DAC maintenance on survival. These data strongly support a definitive phase III randomized study of DAC maintenance, particularly focused on the large intermediate risk FLT3-ITD-negative subgroup. Disclosures Foran: Agios: Honoraria, Research Funding. Claxton:Daiichi Sankyo Co. and Ambit Biosciences Corp, Astellas Pharma, Novartis Pharmaceuticals, Incyte Corporation, Cyclacel Pharmaceuticals, Inc, Celegene Corporation, Medimmune, Inc, Merck Sharp & Dohme Corp., Gilead Sciences, Inc.: Research Funding. Lazarus:Pluristem Therapeutics, Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Speakers Bureau; Genentech: Speakers Bureau; Biosight: Membership on an entity's Board of Directors or advisory committees; Actinium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Adaptive Biotechnologies: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Honoraria, Speakers Bureau; Teva Pharmaceuticals: Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL Behring: Consultancy. Rowe:BioSight: Consultancy. Altman:Cancer Expert Now: Consultancy; Glycomimetics: Consultancy, Honoraria, Other: Data Safety and Monitoring Committee; prIME Oncology: Speakers Bureau; PeerView: Speakers Bureau; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Theradex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; France Foundation: Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Biosight: Other: US Lead. Luger:Ariad: Research Funding; Agios: Honoraria; Biosight: Research Funding; Seattle Genetics: Research Funding; Pfizer: Honoraria; Onconova: Research Funding; Kura: Research Funding; Jazz: Honoraria; Genetech: Research Funding; Daichi Sankyo: Honoraria; Cyslacel: Research Funding; Celgene: Research Funding. Al-Kali:Astex Pharmaceuticals, Inc.: Research Funding. Zheng:Pfizer: Research Funding. Pratz:AbbVie: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Millenium/Takeda: Research Funding; Boston Biomedical: Consultancy; Astellas Pharma: Consultancy, Research Funding. Powell:Jazz Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding; Janssen: Research Funding; Novartis: Consultancy, Speakers Bureau; Rafael Pharmaceuticals: Consultancy, Research Funding. Tallman:Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: 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, Research Funding; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biosight: Research Funding; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; UpToDate: Patents & Royalties; Cellerant: Research Funding; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees. Off Label Disclosure: Use of maintenance Decitabine in AML

Abstract Background: Persistence of minimal residual disease (MRD) after induction, consolidation and salvage therapies is an independent poor prognostic marker in AML. The bone marrow (BM) microenvironment is a protective niche that promotes chemotherapy resistance of leukemia cells. This residual subset of chemotherapy-resistant cells present during remission eventually contributes to the leukemia relapse/persistence. Adhesion of AML cells to BM stroma is dependent on the CXCR4 receptor binding to its ligand CXCL12. High levels of CXCR4 expression correlate with poor survival in AML. It is postulated that blocking the CXCL12/CXCR4 axis will dislodge AML cells from the protective microenvironment and, when combined with chemotherapy, may improve the response to therapy. BL-8040 (BKT140) is a short peptide which inhibits the binding of CXCR4 to CXCL12, resulting in mobilization of leukemic blasts from the BM to the peripheral blood (PB). BL-8040 has strong affinity for the CXCR4 receptor with long receptor occupancy and as a single agent induces differentiation and apoptosis of leukemia cells in preclinical models. A clinical trial assessing the safety and efficacy of BL-8040 in combination with cytarabine (Ara-C) for the treatment of relapsed/refractory AML patients was recently completed (NCT01838395). Here we report results from correlative studies done on samples from patients who participated in this trial. Objective: To assess BL-8040 single agent anti leukemia effects in relapsed/refractory AML. Method: Patients received a once daily SC dose of BL-8040 monotherapy on days 1-2 followed by the same dose of BL-8040 plus Ara-C (1.5g/m2 for patients ≥60; 3g/m2 for patients <60) per day on days 3-7. Six dose levels of BL-8040 (0.5 - 2.0 mg/kg) were tested. PD parameters such as mobilization of leukemic blasts and induction of differentiation and apoptosis were assessed after monotherapy with BL-8040 using frequent PB sampling and BM aspirates at baseline and on day 3 prior to Ara-C administration. Results: 45 patients (including 3 receiving compassionate use BL-8040) with a median age of 61 yrs were treated. The majority of patients had poor risk disease with 24% secondary AML and 17% with prior allogeneic stem-cell transplantation. Most patients were heavily pretreated with 19% relapsing after a short first remission (CR1 ≤12 months), 17% had ≥2 relapses and 45% refractory to 1-2 inductions. The CR+CRi rate was 38% in subjects receiving BL-8040 dose ≥1.0 mg/kg (n=39). Ongoing follow-up (FU) of responding patients (expansion phase; N=19) shows median EFS of 9.3 months (range 4.3-12.8 months). At the time of this analysis 10/19 patients are alive with a FU range of 0.96 - 12.8 months. FACS analysis revealed that BL-8040 monotherapy triggered an average 4.3-fold increase of immature AML blasts (CD45+Low/CD34+/CD117+/HLA-DR+) in PB (i.e., mobilization). Response to treatment was associated with more robust mobilization of AML blasts following BL-8040 monotherapy (responders 9.5 vs non-responders 1.7 fold median). Preferential mobilization of AML blasts over normal cells (4.7 fold vs. 1.4 fold, respectively) was confirmed by FISH analysis in a subset of patients with informative cytogenetic abnormalities. Induction of granulocytic differentiation of immature leukemia progenitors (2.5 fold) in the BM following BL-8040 monotherapy was noted. Finally, induction of AML blasts apoptosis (40% increase) by BL-8040 alone was evident by FACS in day 3 (pre-araC) bone marrow biopsies. Conclusions: The data demonstrate that sustained blockade of the CXCR4-CXCL12 axis with BL-8040 is safe and well tolerated and when given in combination with Ara-C improves the response rate achieved historically with Ara-C alone. In addition, treatment with BL-8040 as a single agent rapidly and efficiently induces mobilization, differentiation and cell death of AML blasts. This selective effect on chemotherapy-resistant cells may be translated into reduction of residual disease arguing for incorporation into front-line trials and such studies are ongoing. Disclosures Foran: Millennium Pharmaceuticals, Inc.: Research Funding; medscape: Honoraria; karyopharm: Honoraria; pfizer: Honoraria; novartis: Honoraria; boehringer ingelheim: Research Funding; agios: Research Funding; Cellerant: Research Funding. DiPersio:Incyte Corporation: Research Funding. Peled:Biokine Therapeutics: Employment. Abraham:Biokine Therapeutics Ltd: Employment. Pereg:BioLineRx Ltd: Employment. Vainstein:BioLineRx Ltd.: Employment. Oberkovitz:BioLineRx Ltd.: Employment. Aharon:BioLineRx Ltd.: Employment. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

Abstract Background: The bone marrow (BM) niche protects acute myeloid leukemia (AML) cells from chemotherapy. BM homing of AML cells is dependent on CXCR4 and its ligand CXCL12; high levels of CXCR4 expression correlate with poor survival in AML. It is postulated that blocking the CXCL12/CXCR4 axis with a potent CXCR4 antagonist will disrupt the interaction of the leukemic blasts with the BM and augment the anti-leukemic effect of chemotherapy. BL-8040 (BKT140) is a short synthetic peptide which inhibits the binding of CXCR4 to CXCL12, resulting in the mobilization of leukemic blasts from the bone marrow to the peripheral blood. BL-8040 also inhibits CXCR4/CXCL12 mediated pro-survival ERK/Akt signaling and alters balance of pro/anti-apoptotic Bcl-2 proteins. BL-8040 has strong affinity for the CXCR4 receptor with long receptor occupancy, and, in contrast to other CXCR4 inhibitors, as a single agent induces apoptosis of leukemia cells ex-vivo in clinical samples. A clinical trial assessing the safety and efficacy of BL-8040 in combination with cytarabine (Ara-C) for the treatment of adult relapsed/refractory AML patients is currently ongoing (NCT01838395). Objective: To assess the safety, efficacy and pharmacodynamics/pharmacokinetic parameters of BL-8040 in combination with Ara-C in first or second relapse and refractory AML patients. Method: The study includes a dose escalation phase (3+3 design) followed by an expansion phase. Each patient receives a once daily SC dose of BL-8040 monotherapy on days 1-2 followed by the same dose of BL-8040 plus Ara-C (1.5 g/m2 for patients ≥60; 3 g/m2 for patients <60) on days 3-7. Five dose levels of BL-8040 (0.5, 0.75, 1, 1.25 and 1.5 mg/kg) have been tested. Extensive pharmacodynamic parameters such as CXCR4 expression on the leukemic cells, receptor occupancy, mobilization of leukemic cells and induction of apoptosis are being assessed after monotherapy with BL-8040 using peripheral blood sampling (PB) and BM aspirates at baseline and on day 3 prior to Ara-C administration. Clinical response to treatment is evaluated by BM biopsy on day 30 (-/+ 2). Results: Twenty two patients (median age, 61 y; range, 43-74 y) with relapsed/refractory AML were treated during the escalation phase. BL-8040 was escalated up to 1.5 mg/kg (recommended phase 2 dose) without reaching the MTD. Combination of BL-8040 with Ara-C was safe and well tolerated at all doses tested. Only one SAE (Sweet Syndrome) was reported as possibly related to study drug. The primary treatment related AEs were transient injection site and systemic reactions. The composite complete remission including complete remission (CR) and complete remission with incomplete blood count recovery (CRi) rate was 38% in subjects receiving BL-8040 doses of 1 mg/kg and higher (n=16). Two days of BL-8040 monotherapy triggered an average 40.2-fold (range 1.0-350.9) mobilization of immature AML progenitors (CD45+Low/CD34+/CD117+/HLA-DR+) from the BM to the PB. Moreover, a significant apoptotic effect on the immature leukemia progenitors in the BM following 2 days of BL-8040 monotherapy was noted. Flow cytometric evidence of apoptosis by BL-8040 was corroborated by an increase in cleaved caspase 3 positive blasts in day 3 bone marrow biopsies. In addition, BL-8040 treatment resulted in a median decrease of 57.7% (range, -10.4% to -96.2%) in the number of BM Leukemia progenitor cells (CD45+Low/CD34+/CD117+/HLA-DR+ out of total CD45+/CD34+ normal/progenitor cells) compared with the baseline biopsy. This decrease was accompanied with a 3.1 fold increase in granulocytes in the day 3 BM biopsy supporting differentiation effect. Finally, long receptor occupancy (up to 24 hours post dosing) was confirmed by FACS analysis measuring surface CXCR4 staining. Pharmacokinetics analysis confirmed dose incremental BL-8040 exposure with a short plasma half-life. Conclusions: The current data demonstrate that sustained blockade of the CXCR4-CXCL12 axis with BL-8040 has potent anti leukemic activity and in combination with Ara-C may improve the response typically achieved in this advanced AML population. Mechanistically, BL-8040 was able to induce apoptosis of leukemic progenitor cells, overcoming the stroma protection, inducing mobilization and differentiation. Disclosures Rowe: BioLineRx Ltd.: Consultancy; Amgen: Consultancy; BioSight Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Uy:Novartis: Research Funding. Altman:Seattle Genetics: Consultancy; Novartis: Consultancy; Spectrum: Consultancy; Astellas: Consultancy; Ariad: Consultancy; BMS: Consultancy. Peled:Biokine Ltd.: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; BiolineRX: Consultancy, Research Funding. Pereg:BioLineRx: Employment. Vainstein:BioLineRx: Employment. Aharon:BioLineRx: Employment. Pemmaraju:Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Cortes:Teva: Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; BerGenBio AS: Research Funding; Novartis: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy.