ALBERT

Description: Background: Standard chemotherapies for relapsed or refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) are often unsuccessful. Pre-treatment ("priming") with hypomethylating agents such as decitabine has been shown to sensitize AML cells to chemotherapeutics, prompting a phase 1/2 study (NCT01729845) of MEC preceded by decitabine priming (d/MEC) in relapsed/refractory AML/MDS. Methods: Patients ≥18 years with relapsed/refractory AML or high-risk MDS (〉10% blasts) requiring first or subsequent salvage therapy were eligible if they had adequate organ function and a treatment-related mortality (TRM) score of

Description: Background: Because infections are a major cause of morbidity and mortality after AML induction chemotherapy, patients typically remain hospitalized for monitoring and rapid antimicrobial therapy until hematopoietic recovery. With declining early mortality and improved oral antimicrobials, interest in moving post-induction care to the outpatient setting has emerged. In the 5-year period since completing a prospective phase 2 trial evaluating an Early Hospital Discharge (EHD) strategy, EHD following AML-like induction chemotherapy has become routine at our institution. In recent retrospective analyses, we found 〉80% of EHD patients required hospital readmission, primarily for neutropenic fever. Still, the EHD strategy was safe and reduced healthcare resource utilization, and EHD patients spent 〉70% of their post-chemotherapy time as outpatients. Here, we investigated differences in the pattern of infectious complications between patients managed as outpatients following induction chemotherapy and those who remain hospitalized until hematopoietic recovery. Methods: We retrospectively identified all adults ≥18 years with untreated AML/high-grade myeloid neoplasms (≥10% blasts in blood/ bone marrow) who started intensive induction chemotherapy ("7+3" or a regimen of similar/higher intensity) at our institution from 8/1/2014-7/31/2018. Patients were considered "EHD" if they were discharged from the hospital

Description: Background: No approved treatment options are available to HR-MDS pts after HMA therapy. Study 04-21 (“ONTIME” trial) was a Phase III, randomized, controlled study of the efficacy and safety of rigosertib, a novel small molecule inhibitor of PI3-kinase and PLK pathways, in a heterogeneous population of MDS pts who had relapsed after, failed to respond to, or progressed during administration of HMAs. The study was conducted at 87 sites in the United States and 5 European countries. Methods:From Dec 2010 to Aug 2013, 299 HR-MDS pts [7 days, mostly due to unrelated adverse events (AEs). No obvious differences between rigosertib and BSC were found in the incidence of AEs (rigosertib, 99%; BSC, 85%) or of ≥ Grade 3 AEs (rigosertib, 79%; BSC, 68%). In the rigosertib arm, AEs reported by ≥ 20% of pts, irrespective of severity or causality, were nausea (35%), diarrhea (33%), constipation (31%), fatigue (30%), fever (27%), anemia (22%), and peripheral edema (21%). Rigosertib had low myelotoxicity, consistent with previous clinical experience. Conclusions:Although the primary endpoint in this Phase III study of rigosertib vs BSC in pts with HR-MDS did not reach statistical significance in the ITT population, encouraging rigosertib treatment-related improvement in OS was noted in several subgroups of MDS pts, including those with “primary HMA failure and in patients in the IPSS-R Very High Risk category. CIV therapy with rigosertib had a favorable safety profile in this orphan population of elderly pts with MDS. Figure 1 Figure 1. Figure 2 Figure 2. Figure 3 Figure 3. Disclosures Fenaux: Celgene: Research Funding; Janssen: Research Funding; Novartis: Research Funding. Sekeres:Celgene Corp.: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees. Roboz:Novartis: Consultancy; Agios: Consultancy; Celgene: Consultancy; Glaxo SmithKline: Consultancy; Astra Zeneca: Consultancy; Sunesis: Consultancy; Teva Oncology: Consultancy; Astex: Consultancy. Wilhelm:Onconova Therapeutics, Inc: Employment, Equity Ownership. Wilhelm:Onconova Therapeutics, Inc: Employment. Azarnia:Onconova Therapeutics, Inc: Employment. Maniar:Onconova Therapeutics, Inc: Employment.

Description: Background: Optimal treatment for medically less fit adults with acute myeloid leukemia (AML) remains uncertain. Retrospective data suggest intensive therapy may lead to better outcomes in these patients. However, these findings must be interpreted cautiously because of the possibility of selection bias and other confounders. Ideally, the optimal treatment intensity is defined via randomized trial but whether patients and their physicians are amenable to such a study is unknown. We therefore designed a trial (NCT03012672) to 1) evaluate the feasibility of randomization between intensive and non-intensive therapy in this population and 2) examine the impact of treatment intensity on response rate and survival. We used CLAG-M as high-dose cytarabine-based intensive induction therapy. Rather than selecting different classes of drugs in the 2 treatment arms- which may have different modes of action and therefore confound the question of treatment intensity - we used reduced-dose ("mini") CLAG-M as the non-intensive comparator. Methods: Adults ≥18 years were eligible if they had untreated AML or high-grade myeloid neoplasms (≥10% blasts in blood or marrow) and were medically less fit as defined by having a "treatment related mortality" (TRM) score of ≥13.1, corresponding to a 〉10-15% 28-day mortality with intensive chemotherapy. Left ventricular ejection fraction ≤45% was the only organ function exclusion. Patient-physician pairs were first asked if they were amenable to randomized treatment allocation. If so, they were randomized 1:1 to mini- vs. regular-dose CLAG-M. If not, in order to evaluate our secondary endpoints, the patient or physician could choose the treatment arm and still enroll on study. Patients and physicians then completed surveys elucidating their decision-making processes. Up to 2 induction courses were given with mini- vs. regular-dose CLAG-M: cladribine 2 or 5 mg/m2/day (days 1-5), cytarabine 100 or 2,000 mg/m2/day (days 1-5), G-CSF 300 or 480µcg/day for weight

Description: Introduction: Many patients with newly diagnosed acute myeloid leukemia (AML) or myelodysplastic syndrome with 10-19% blasts (MDS-EB2) do not enter complete remission (CR) following initial induction chemotherapy. At an academic referral center, such patients often stay to receive additional treatment, or return to their home communities for further care. For patients and providers alike, the decision about whether to stay or go after initial treatment failure is often fraught. To better inform such decision-making, in this retrospective single-center analysis, we compared covariate-adjusted survival for patients who elected to stay for further treatment at our center and those who returned to their home communities for subsequent care. Methods: We included adults ≥ age 18 years of age with newly-diagnosed AML or MDS-EB2 treated at our institution between January 2012 and May 2018 who failed to enter CR (〈 5% morphologic bone marrow blasts) or CR with incomplete hematologic recovery (CRi) after their first cycle of induction chemotherapy. We excluded patients who died before they could begin re-induction therapy. Patients who stayed at our institution for additional treatment are referred to as the "stay" group (n=86); patients who left are considered the "go" group (n=35). Multivariable Cox regression analysis was used to account for other measured covariates possibly influencing survival. Results: The go group was older and had a higher median treatment-related mortality (TRM) score (Table 1), the latter predictive of the probability of death within the first 28 days of initial induction therapy. Forty-seven percent of stay patients received high-intensity re-induction (containing cytarabine at individual doses ≥1g/m2) while 50% received low-intensity treatment (e.g. azacitidine, decitabine, or low-dose cytarabine). Twenty-nine percent of go patients received treatment (mostly low-intensity) in the community setting, while 63% received supportive care only. The stay patients had a median of 2 subsequent hospitalizations (range 0-12) and spent a median of 27 days hospitalized after initial treatment failure (range 0-124). Survival was longer in the stay group compared to the go group (median 8.3 vs. 1.8 months, p

Description: The median age at diagnosis of MDS is 72 years (yrs), and conventional HCT is not an option for many patients (pts). The primary benefit of nonmyeloablative conditioning regimens is a reduction in acute post-HCT morbidity and mortality. However, this benefit may be offset by an increase in post-HCT relapse. To address these issues, we performed a retrospective review of data from 172 pts over age 40 yrs with a diagnosis of MDS or tAML as determined by WHO criteria who underwent HCT between January 1998 and December 2003. Data were analyzed as of July 28, 2004. One hundred thirty two pts were conditioned with a myeloablative regimen of targeted (800–900 ng/ml) busulfan (starting dose 1mg/kg every 6 hours for 16 doses) and cyclophosphamide (120mg/kg) with or without thymoglobulin. Forty pts selected for a nonmyeloablative regimen because of age or comorbid illnesses were conditioned with 2 Gy TBI with or without fludarabine, 30mg/m2/day for three days. The median age was 52 (40–65) yrs for the myeloablative group, and 62 (40–73) yrs for the nonmyeloablative group. The majority of pts in the nonmyeloablative group had progressed to tAML (55%) and had high risk disease by IPSS (55%). The WHO distribution (highest at any time) was as follows: myeloablative/nonmyeloablative- 34%/55% with tAML, 29%/22% with refractory anemia with excess blasts (RAEB-1/2), and 37%/22% with refractory anemia with or without ringed sideroblasts (RA/RARS). The IPSS distribution (highest at any time) was as follows: myeloablative/nonmyeloablative-26%/55% high, 23%/30% int-2, 41%/15% int-1, and 11%/0% low risk. All pts received HCT from HLA-matched related (50% of myeloablative, 65% of nonmyeloablative) or unrelated donors. There were no differences between the two groups with regards to gender distribution, donor CMV status, recipient CMV status, duration of disease prior to HCT, primary or secondary etiology of MDS, or source of stem cells. Overall survival (OS) [46%/31%], relapse free survival (RFS) [40%/28%], and non-relapse mortality [37%/37%] did not differ significantly between myeloablative/nonmyeloablative pts. There was a trend towards improved RFS in pts with RA/RARS (p=0.16) who received myeloablative HCT, and a trend towards improved RFS in pts with tAML who received nonmyeloablative HCT (p=0.14). Among pts with more advanced disease (RAEB-1/2 or tAML) given myeloablative/nonmyeloablative HCT there were 39%/87% who received induction chemotherapy (IC) pre-HCT and 59%/85% given IC achieved a CR. Post-HCT OS and RFS were similar for pts who achieved CR following IC regardless of conditioning regimen used. Thus, while there was a trend towards superior survival with myeloablative HCT in pts with RA/RARS and with nonmyeloablative HCT in pts with tAML, in this retrospective review there were no significant differences between results obtained with myeloablative and nonmyeloablative conditioning regimens. Furthermore, even though most nonmyeloablative pts had high risk disease, there was no significant difference in RFS between the two groups suggesting that a graft vs. tumor effect was more important than conditioning intensity in preventing relapse in pts with high risk MDS or tAML in CR after IC. This raises the question of whether nonmyeloablative HCT should be considered in all pts with high risk MDS or tAML who achieve a CR with IC.

Description: Introduction: Patients (pts) with higher-risk myelodysplastic syndrome (HR-MDS) and those who fail to respond to or relapse/progress after treatment with hypomethylating agents (HMA) have limited therapeutic options and poor prognosis. PD-L1 expression is upregulated in HR-MDS pts (compared with lower-risk MDS pts) and in those who fail HMA therapy. Combining inhibition of the PD-L1/PD-1 pathway with azacitidine may improve outcomes in MDS. Methods: We conducted a Phase Ib trial of the anti-PD-L1 monoclonal antibody atezolizumab, with or without azacitidine, in HMA-failure and HMA-naive MDS pts (NCT02508870). The primary objective was to determine the safety and tolerability of atezolizumab as a single agent or in combination with azacitidine. An initial safety evaluation was performed in three cohorts. Cohort A1 (10 pts) consisted of HMA-failure HR-MDS pts treated with atezolizumab alone (1200mg IV q3w). Cohort B1 (11 pts) consisted of HMA-failure HR-MDS pts treated with atezolizumab (840mg IV q2w) in combination with azacitidine (75mg/m2 qd for 7 days q4w) for 6 cycles, followed by atezolizumab maintenance alone (1200mg IV q3w). Cohort C1 (6 pts) consisted of HMA-naive HR-MDS pts treated with atezolizumab (840mg IV q2w) in combination with azacitidine (75mg/m2 qd for 7 days q4w). If atezolizumab alone or in combination with azacitidine was deemed safe and tolerable in Cohorts A1 and B1, an additional 1:1 randomization into two cohorts of 30 pts each (Cohorts A2 and B2) was planned. If the combination of atezolizumab and azacitidine was found to be safe and tolerable in Cohort C1, an additional expansion cohort (Cohort C2) of 14 pts with HMA-naive HR-MDS was planned. Primary endpoints included determining the safety and tolerability of atezolizumab-based regimens in HR-MDS and defining the recommended Phase II dose for the combination. Results: As of January 2018, 42 HR-MDS pts had been treated with atezolizumab-based regimens: Cohort A, 10 pts; Cohort B, 11 pts; Cohort C, 21 pts. Median age for the entire pt cohort was 76 years (range: 63−89). Median treatment duration for Cohorts A, B, and C was 4.2, 5.5, and 5.8 months, respectively. The overall response rate for Cohorts A, B, and C was 0%, 9% (hematologic improvement [HI]: 9%), and 62% (CR, 14%; mCR, 19%; mCR + HI, 10%; HI, 19%), respectively. All pts in Cohorts A and B have discontinued therapy, with a median overall survival (OS) of 5.9 months and 10.7 months, respectively. For pts in Cohort C, 8/21 pts remain on therapy, and median OS has not been reached. Grade 3−5 adverse events (AEs) in 〉10% of pts were primarily hematologic; grade 3−5 febrile neutropenia occurred in 29% of all pts and was particularly common in pts receiving the atezolizumab-azacitidine combination (Cohorts B [36%] and C [33%] compared with Cohort A [10%]; Table 1). In Cohort A, 70% (7/10) of pts died, as did 64% (7/11) of pts in Cohort B and 29% (6/21) of pts in Cohort C. Median time to death was 160 days (Cohort A), 299 days (Cohort B), and 53 days (Cohort C). Timing and causes of death were different in the three cohorts. Causes of death were more commonly from disease progression in Cohorts A and B, while serious AEs accounted for all deaths in Cohort C (Table 2). In addition, deaths within 3 months occurred in 10%, 18%, and 29% of pts in Cohorts A, B, and C, respectively. The high early death rate compared with historical controls observed in HMA-naive HR-MDS patients (Cohort C) led to early termination of the study prior to completing recruitment. Biomarker assessment demonstrated PD-L1 expression on variable proportions of AML blasts in samples from all pts analyzed. However, PD-L1 expression was not associated with clinical response (Figure). Conclusions: Combination of atezolizumab plus azacitidine in HMA-naive HR-MDS pts had an unfavorable safety profile, which led to early termination. Limited responses were observed with atezo-based regimens (with or without azacitidine) in HMA-failure HR-MDS pts, without excessive or unexpected toxicity. Better understanding of the reasons associated with the differential toxicity profile observed between HMA-naive versus HMA-failure HR-MDS pts will be crucial for potential future developments of this combination. Disclosures Gerds: Incyte: Consultancy; Celgene: Consultancy; CTI Biopharma: Consultancy; Apexx Oncology: Consultancy. Khaled:Daiichi: Consultancy; Alexion: Consultancy, Speakers Bureau; Juno: Other: Travel Funding. Lin:Jazz Pharmaceuticals: Honoraria. Pollyea:AbbVie: Consultancy, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Curis: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees. Dail:Genentech: Employment, Equity Ownership. Green:Genentech: Employment. Ma:Genentech: Employment. Medeiros:Genentech: Employment, Equity Ownership. Phuong:Genentech Inc: Employment, Equity Ownership, Other: Ownership interests PLC. Wenger:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership, Other: Ownership interests PLC. Yan:Roche: Employment.

Description: We showed previously that the presence of aberrant marrow myeloblasts, as determined by flow cytometry immediately pre-transplant had predictive value for post-transplant outcomes in patients undergoing hematopoietic cell transplantation (HCT) for Myelodysplastic Syndrome (MDS). The characteristics of phenotypically abnormal myeloblasts in MDS include decreased expression of CD45, presence of non-lineage lymphoid antigens including CD56, and differences in the intensity of various myeloid antigens in comparison to healthy controls. In the present study, the bone marrow aspirates of 156 patients with MDS were analyzed before HCT for the presence of abnormal myeloblasts with the aim of determining whether myeloid dyspoiesis by flow cytometry was predictive of post-transplant outcomes, specifically in patients who were considered good risk by currently accepted criteria. All patients received ”myeloablative” conditioning, which in most patients (78%) consisted of busulfan (targeted) and cyclophosphamide followed by HLA-identical related (52%), HLA-matched unrelated (39%), or alternative donor (9%) stem cell infusions. In agreement with our initial report, patients with severe flow scores (≥4) had an increased hazard of relapse (HR=2.7, 95% CI_1.1–6.3, p=0.017) in comparison to patients with normal flow scores. In addition, even among patients with less than 5% marrow myeloblasts, dyspoietic characteristics of the blasts, as assessed by flow cytometry criteria were associated with an increased hazard of relapse (HR=4.0, 95% CI 1.4–12.1, p=0.013) as compared to patients without dyspoiesis by flow. The cumulative incidence of relapse in MDS patients with flow cytometrically normal marrow myeloblasts was 11.7%, compared to 28.1% in patients with less than 5% but phenotypically aberrant myeloblasts; the latter was not different from a relapse incidence of 31.4% in patients with 5% or more abnormal marrow myeloblasts. Furthermore, patients with intermediate-1 risk disease by the International Prognostic Scoring System, who showed flow cytometric aberrancies were at significantly increased risk of relapse (HR=4.2, p=0.01) in comparison to patients with intermediate-1 risk disease and no or mild dyspoiesis by flow cytometry. Thus, the presence of dyspoietic changes was more relevant than the proportion of marrow myeloblasts in predicting the risk of relapse, suggesting that flow cytometry is a powerful tool to select high risk patients from cohorts of patients who by established criteria would be considered to have good risk MDS.

Description: Abstract 2622 Background: Acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS with 10–19% blasts) are associated with higher mortality in the elderly population. This poor outcome is in part attributed to therapy resistance and therefore, using combinations of agents with different mechanisms of action may improve outcomes. The nitrogen mustard Bendamustine combines unique alkylating characteristics with putative anti-metabolite activity while Idarubicin inhibits DNA and RNA synthesis by intercalation between DNA base pairs. In this single-arm adaptive phase I/II dose-escalation trial, we assessed increasing doses of Bendamustine in combination with a uniform dose of Idarubicin. We used a Bayesian approach to determine whether there was a dose of Bendamustine which, together with Idarubicin can provide a complete response (CR) rate of at least 40%, with minimal ( 50. Methods: Eligible patients were age 350 with untreated AML or high-risk MDS, had an ECOG performance status 40% was also

Description: Background Treatment outcomes for older patients with newly diagnosed AML remain poor. TST is an oral aminopeptidase inhibitor that has anti-neoplastic activity in a variety of malignancies, including AML. Phase I/II monotherapy studies in patients with relapsed AML and MDS have shown TST to have adequate safety and promising efficacy. Pre-clinical AML blast proliferation assays have demonstrated synergy between TST and both cytarabine and hypomethylating agents. For this reason, we performed a randomized, open-label Phase II trial using TST in combination with intermediate-dose cytarabine or decitabine in patients with untreated AML or high-risk MDS (i.e. RAEB-2). Methods Patients ≥60 years old with untreated AML or high risk MDS were randomized to receive TST 120 mg daily by mouth days 1-21 with 5 days of either cytarabine 1 g/m2/day IV or decitabine 20 mg/m2/day IV delivered every 35 days. Patients received up to three 35-day cycles if they had at least stable disease with an acceptable toxicity profile following the initial course. Patients who did not achieve a complete remission (CR) or CR with incomplete blood count recovery (CRi) after 3 cycles of therapy were taken off study; patients who obtained CR/CRi were eligible to receive up to 2 additional cycles (maximum of 5). The primary objective was to determine the rates of CR and 4 month survival using TST in combination with either cytarabine or decitabine for older patients with untreated AML or high-risk MDS. Results A total of 26 patients have been treated, with 14 receiving TST/cytarabine and 12 receiving TST/decitabine. The median age was 69 (range, 60-83), and 22 patients (85%) presented with an ECOG performance status of 1. Nineteen patients (73%) had AML and 7 (27%) had MDS RAEB-2. Nineteen patients (73%) had intermediate-risk and 7 (27%) had adverse-risk disease by European Leukemia Net criteria. Fourteen patients (54%) had secondary AML/MDS or antecedent hematologic disorder. The median duration of treatment was 3 months. The overall CR/CRi rate was 54%, with 10 patients (39%) achieving a CR and 4 patients (15%) achieving a CRi. Five patients required 3 cycles, four patients required 2 cycles and five patients required 1 cycle of therapy to achieve maximal disease response. CR/CRi was attained in 3 patients with adverse cytogenetics and 4 additional patients with FLT3 mutations. Of the 14 patients who achieved a CR/CRi (54%), 7 were treated on each of two study arms. Nine of the 14 patients who achieved a CR/CRi were referred for allogeneic hematopoietic cell transplantation (HCT), 3 patients deferred HCT, and 1 patient died of sepsis in CRi 133 days after starting induction. Ten patients were taken off study after a median of 2 cycles due to lack of response or disease progression. With a median follow-up of 5.7 months (range, 0.5-13.4), 21 patients (81%) lived longer than 4 months. Five (19%) of the 26 patients died within 4 months of starting therapy. Of these five patients, three died of sepsis on subsequent salvage protocols, one with a history of myeloproliferative disorder died of splenic infarct within 15 days of starting therapy and a fifth patient died at age 83 during cycle 2 of unknown cause. Eight patients (31%) were treated completely as outpatients without requiring hospitalization, and 15 patients (58%) were hospitalized at some point during treatment for febrile neutropenia. There were no Grade 3-4 non-hematologic toxicities requiring withdrawal from the study. Conclusions These results demonstrate that TST at 120 mg daily in combination with cytarabine or decitabine resulted in a 54% CR/CRi rate in 26 older patients with untreated AML or high-risk MDS. This approach was well tolerated as predominantly outpatient therapy and may warrant further study in a controlled trial. Disclosures: Wang: Cell Therapeutics, Inc.: Employment. Myint:Cell Therapeutics, Inc: Employment. Singer:Cell Therapeutics, Inc: Employment, Equity Ownership.