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Immune suppression, exhaustion, and senescence are frequently seen throughout disease progression in acute myeloid leukemia (AML). We conducted a phase II study of high-dose cytarabine followed by pembrolizumab 200 mg i.v. on day 14 to examine whether PD-1 inhibition improves clinical responses in relapsed/refractory (R/R) AML. Overall responders could receive pembrolizumab maintenance up to 2 years. Among 37 patients enrolled, the overall response rate, composite complete remission (CRc) rate (primary endpoint), and median overall survival (OS) were 46%, 38%, and 11.1 months, respectively. Patients with refractory/early relapse and those receiving treatment as first salvage had encouraging outcomes (median OS, 13.2 and 11.3 months, respectively). Grade ≥3 immune-related adverse events were rare (14%) and self-limiting. Patients who achieved CRc had a higher frequency of progenitor exhausted CD8+ T cells expressing TCF-1 in the bone marrow prior to treatment. A multifaceted correlative approach of genomic, transcriptomic, and immunophenotypic profiling offers insights on molecular correlates of response and resistance to pembrolizumab. Significance: Immune-checkpoint blockade with pembrolizumab was tolerable and feasible after high-dose cytarabine in R/R AML, with encouraging clinical activity, particularly in refractory AML and those receiving treatment as first salvage regimen. Further study of pembrolizumab and other immune-checkpoint blockade strategies after cytotoxic chemotherapy is warranted in AML. See related commentary by Wei et al., p. 551. This article is highlighted in the In This Issue feature, p. 549

Targeted busulfan dosing helps limit chemotherapy-related toxicity and optimize disease outcomes in hematopoietic stem cell transplantation (HCT). The objective of this study was to evaluate busulfan exposure from a pharmacokinetic (PK)-guided dosing strategy using a test dose. This retrospective evaluation included adult patients who underwent HCT at our institution with busulfan-based myeloablative (>9 mg/kg) conditioning between January 2014 and October 2015. A weight-based test dose of 0.8 mg/kg was used with PK assessments to predict area under the curve (AUCpred) achieved with weight-based dosing, with a target AUC of 4800 µM*minute (AUCtarget). PK from the test dose was then used to calculate a PK-guided first myeloablative busulfan dose. PK assessments were also done after the first dose to assess if the goal area under the curve (AUC) had been achieved (AUCfirst). A PK-guided first dose resulted in achievement of target AUC with target ranges of ±10% in 50% of patients, ±15% in 75%, and ±20% in 94%. This was an improved rate of target achievement compared with the 33%, 44%, and 63% of patients who achieved the desired AUC for these respective target ranges when using weight-based dosing (P = .12, .004, and

Background Despite increasing donor options for allogeneic transplantation, including matched/mismatched related donors, matched unrelated donors and cord blood units, a proportion of patients do not find a donor. This is especially relevant in patients from racial/ethnic minorities. Post-transplant cyclophosphamide (PTCY) has successfully overcome barriers related to HLA-mismatching in the related donor setting. We hypothesized that transplantation with a mismatched unrelated donor (MMUD) using PTCY would be feasible and associated with high engraftment and acceptable GVHD incidence. Methods We performed a prospective Phase II study of MMUD bone marrow (BM) transplantation with PTCY for patients with hematologic malignancies. Patients with a suitable HLA matched related or URD were excluded. Patients received a fresh BM graft, followed by PTCY on days +3, +4, Sirolimus/MMF starting on Day+5. Matching for 4-7/8 at HLA-A, -B, -C, and –DRB1 was permitted. We enrolled 80 patients (40 full intensity conditioning [FIC]; 40 reduced intensity conditioning [RIC]) at 11 transplant centers in the U.S. between Dec 2016 and March 2019. Regimen intensity was at the center's discretion. Results Characteristics are shown in Table 1. Importantly, 48% of patients were non-white/Hispanic, 55% had an HCT-CI >2 and 34% had a KPS of 1 HLA allele, 59% were under 30. Overall survival and non-relapse mortality at 100 days were 92% and 5% in the FIC arm, and 90% and 7.5% in the RIC arm (Table 2). Neutrophil recovery was 98% in both arms, with no primary graft failure in the FIC arm, and 7.5% in the RIC arm. Peripheral blood donor chimerism was >75% at all timepoints. Acute GVHD grade III-IV at day 100 was relatively high at 25% in the FIC arm but very low at 2.6% in the RIC arm. Viral reactivations were high (Table 3). Conclusion These early (day 100) results of our prospective study show high rates of engraftment with acceptable rates of GVHD in recipients of MMUD transplantation with PTCY, despite a high degree of HLA mismatch. An important finding is that ethnic minorities represent almost 50% of the study population, showing that this approach expands access to patients in need of potentially curative therapy. BK and HHV-6 virus reactivation/infection were common, the clinical significance of which requires further study. Understanding the risks for and impact of graft failure and acute GVHD is being studied as follow up continues.

Nelarabine is a prodrug of 9-β-arabinofuranosylguanine (ara-G) and a member of the purine nucleoside analogs. In cells, ara-G is phosphorylated to ara-G triphosphate (ara-GTP), which competes with ...

Autologous stem cell transplantation remains a mainstay of therapy for diseases such as multiple myeloma and relapsed lymphoma. The use of plerixafor has been shown to augment the ability to collect adequate stem cells, but the optimal use of this agent when used with chemotherapy is not yet clear. We utilized an algorithm-based approach with the addition of plerixafor to 54 patients undergoing chemomobilization with reduced-dose etoposide who had a less than optimal preapheresis CD34+ cell count. We used a CD34+ precount of 20 cells/μL as a threshold to initiate stem cell apheresis. Ninety-four percent of patients were successfully collected and proceeded to transplantation. Fourteen of 51 (28%) patients who successfully collected required plerixafor to augment stem cell yield. Of the patients who successfully collected, 94% (89% of the entire population) were able to collect in 2 or fewer days. Compared with previous data from our institution, the rate of patients collecting > 4 × 106 CD34+ cells/kg in a single collection was increased from 39% to 69%. The safety profile of this approach was acceptable. The use of this algorithm-based method to determine when and whether to add plerixafor to chemomobilization was shown to be a successful and cost-effective approach to stem cell collection.

Background: Despite recent advances in the therapeutic armamentarium for AML, outcomes remain dismal for patients (pts) with relapsed/refractory (R/R) AML. Response rates with high dose cytarabine (HiDAC) salvage chemotherapy are approximately 20%. Multiple immune aberrations in AML lead to immune suppression, exhaustion, and senescence. Programmed Death-1 (PD-1), a co-inhibitory receptor (IR) on immune cells, suppresses immune activation and is exploited by leukemic cells to evade immune surveillance. PD-1 and other IRs are up-regulated during disease progression. We hypothesized that pembrolizumab, a monoclonal antibody targeting PD-1, after HiDAC would stimulate a T-cell mediated anti-leukemic immune response. Methods: Eligibility for this study included R/R AML 18-70 years, ECOG PS 0-1 and adequate organ function. Treatment consisted of HiDAC (60 years: 1.5 gm/m2 IV Q12hours days 1-5) followed by pembrolizumab 200 mg IV on day 14. The primary objective of this study was to estimate the overall complete remission (CR + CRi) rate. Secondary objectives included assessment of safety, durability of CR, overall survival (OS) and biomarker correlates of response. Overall responders were eligible to receive maintenance phase pembrolizumab 200 mg IV Q3weeks for up to 2 years until progression. Allogeneic stem cell transplant (alloSCT) was permissible before or after maintenance phase. Results: Thirty-seven pts were enrolled and evaluable (Table 1). Sixteen (43%) pts had refractory disease and 16 (43%) pts had relapsed AML with CR1 duration 3: n=1), AST elevation (32%; Grade >3: n=1), fatigue (27%), alkaline phosphatase elevation (24%), and maculopapular rash (19%; Grade >3: n=2). Grade >3 immune-related adverse events (iRAE) were rare (maculopapular rash: n=2, AST/ALT increase: n=2, right upper quadrant pain with lymphocytic infiltrate in liver: n=1) and self-limiting. Five (14%) pts required steroid administration for grade 2 hyperbilirubinemia (n=1), grade 3 ALT elevation (n=1), grade 3 AST elevation with liver biopsy revealing no evidence of iRAE (n=1), grade 3 bilirubin subsequently deemed to be a delayed hemolytic transfusion reaction (n=1), and grade 3 systolic dysfunction without evidence of myocarditis by endomyocardial biopsy or cardiac MRI (n=1). Sixty-day mortality was 3% (1/37) due to progressive AML. Median time to full neutrophil (>1x109/L) and platelet (>100x109/L) recovery was 32 and 31 days, respectively. The overall response (ORR: CR+CRi+PR+MLFS) and composite CR (CR+CRi) rates were 46% [29%,63%] and 38% [22%,55%], respectively, meeting the primary endpoint of the study. Notably, 13/28 (46%) pts receiving HiDAC + pembrolizumab as their first salvage regimen achieved CR/CRi. Two pts refractory to HiDAC (administered within past 6 months) achieved CR including one pt who was refractory to HiDAC salvage 1 month prior to enrollment and ultimately achieved CR without evidence of minimal residual disease. Nine (24%) pts received an alloSCT. There were no instances of Grade >3 acute GVHD or veno-occlusive disease post-alloSCT. Nine (24%) pts received maintenance phase pembrolizumab (median # of cycles = 3; range: 1-12) for CR (n=8) or PR (n=1). Seven out of 9 pts relapsed/progressed after maintenance phase. Median follow-up among survivors, and median OS, event-free survival and disease-free survival was 7.8 months, 8.9 months [6.0,13.1], 6.9 months [4.2,11.5], and 5.7 months [1.9,7.3], respectively. Conclusions: Pembrolizumab can be safely administered after HiDAC salvage in R/R AML. Severe iRAE's were uncommon despite administration after cytotoxic chemotherapy. The addition of pembrolizumab to HiDAC led to an encouraging overall CR rate meeting the primary endpoint of the study. Immunogenomic biomarker analyses consisting of B cell receptor amplicon sequencing, RNA-seq of blasts and CD8+ T cells, CD8+ T cell receptor repertoire, whole exome sequencing and flow cytometry analyses are ongoing to determine predictors of response. These results warrant further investigation of IR blockade and other immunomodulatory therapeutic strategies after intensive cytotoxic chemotherapy in AML. Disclosures Zeidner: Takeda: Research Funding; Merck: Research Funding; AsystBio Laboratories: Consultancy; Pfizer: Honoraria; Tolero: Honoraria, Research Funding; Daiichi Sankyo: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Agios: Honoraria; AbbVie: Honoraria. Vincent:Pharmacyclics: Research Funding; Merck: Research Funding. Foster:Bellicum Pharmaceuticals: Research Funding; Macrogenics: Research Funding; Celgene: Research Funding; Daiichi Sankyo: Consultancy. Coombs:Dedham Group: Consultancy; Covance: Consultancy; Cowen & Co.: Consultancy; Octopharma: Honoraria; H3 Biomedicine: Honoraria; Loxo: Honoraria; Pharmacyclics: Honoraria; Medscape: Honoraria. Webster:Pfizer: Consultancy; Amgen: Consultancy; Genentech: Research Funding. DeZern:Astex Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy. Smith:Jazz: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Agios: Consultancy. Levis:Amgen: Consultancy, Honoraria; Astellas: Consultancy, Research Funding; FUJIFILM: Consultancy, Research Funding; Menarini: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; Daiichi Sankyo Inc: Consultancy, Honoraria; Agios: Consultancy, Honoraria. Luznik:Merck: Research Funding, Speakers Bureau; Genentech: Research Funding; AbbVie: Consultancy; WindMiL Therapeutics: Patents & Royalties: Patent holder. Serody:Merck: Research Funding; GlaxoSmithKline: Research Funding. Gojo:Amphivena: Research Funding; Amgen Inc: Consultancy, Honoraria, Research Funding; Juno: Research Funding; Merck: Research Funding; Jazz: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. OffLabel Disclosure: Pembrolizumab is investigational for AML.

Background: Outcomes remain dismal for patients (pts) with relapsed/refractory (R/R) AML. Programmed Death-1 (PD-1), an inhibitory receptor on T and B cells, suppresses immune activation. We hypothesized that administration of pembrolizumab, a monoclonal antibody targeting PD-1, after high dose cytarabine (HiDAC) salvage chemotherapy would stimulate a T-cell mediated anti-leukemic immune response leading to improved efficacy in R/R AML. Methods: We are conducting a multicenter phase II study of HiDAC ( Results: To date, 26 pts are evaluable for safety and response (Table 1). Grade ≥3 immune-related adverse events have been rare and self-limiting. The overall CR rate is 35%. Of the 9 CR pts, 5 (56%) had no evidence of minimal residual disease (MRD) by standard monitoring. Notably, 2/3 primary refractory pts with inv(3) cytogenetics achieved CR and underwent SCT. Additionally, 1 pt with relapsed AML with most recent treatment refractory to HiDAC salvage achieved CR with no evidence of MRD. Five pts received maintenance pembrolizumab: 3 relapsed (median duration of CR = 2.8 months; range: 2-5.7 months), 1 proceeded to SCT after 2 cycles, and 1 initially achieved a partial remission (PR) and had stable disease for 12 cycles of maintenance pembrolizumab before progressing. Four pts received a SCT in CR (n=3) and morphologic leukemia free state (MLFS) (n=1). Grade II acute graft-versus host disease (GVHD) and moderate chronic GVHD was seen in 2/4 (50%) pts, respectively. With a median follow up of 10.8 months to date, median overall survival is 10.5 months (range: 1.8-20.8 months). We performed B cell receptor amplicon sequencing, T cell receptor (TCR) amplicon sequencing from CD8+ T cells, and RNA-seq from enriched blasts and non-blast fractions in bone marrow (BM) from 3 CR and 3 non-responders (NR) prior to HiDAC. From the BM blast enriched fraction, expression of innate immune genes such as NLRP12, C3, S100A9, S100A12 and CD14 correlated with response. Gene Set Enrichment Analysis (GSEA) demonstrated that CR correlated with expression of genes in the Toll Pathway, Lysosome pathway, and adaptive immune system while NRs were associated with expression of the PAR1 and GATA3 pathways. From the non-blast BM population, CR correlated with expression of cell-cycle genes such as CCNE1, CCNB2, E2F2, KIF18B and CDKN3. Not surprisingly, GSEA revealed that expression of cell cycle pathways correlated with response. CR correlated with increased expression of B cell metagenes and the inverse IPRES signature in the non-blast BM fraction. As previously reported, there was a significant increase in peripheral blood (PB) TCR diversity in CR pts. CR was also significantly associated with the abundance and richness of the non-blast BM fraction of the B cell heavy and both light chains suggesting that a broader immune response at baseline may be critical for response to HiDAC and pembrolizumab. Finally, CR correlated with increased expression of CD300E, CCR7, CCR4, CCR8 and CCL7 in PB CD8+ T cells suggesting that migration of monocytes, T and B cells is associated with response. Conclusions: Our findings demonstrate that pembrolizumab is well tolerated after HiDAC in an ongoing study in R/R AML. An encouraging response rate has been seen in a high-risk patient population without apparent additive toxicity post-SCT. Our RNA-seq and amplicon sequencing data indicate that biomarkers of response are present prior to therapy. Increased expression of innate immune genes expressed by leukemic blasts and cell cycle genes by the non-blast fraction correlated with response to therapy. Additionally, CR was associated with increased measures of B and T cell diversity and immune cell migration. Further immunogenomic biomarker correlates are ongoing to determine predictors of response to pembrolizumab after HiDAC in R/R AML. Disclosures Zeidner: Tolero: Honoraria, Other: Travel Fees, Research Funding; Asystbio Laboratories: Consultancy; Merck: Research Funding; Takeda: Other: Travel fees, Research Funding; Rafael Pharmaceuticals: Other: Travel Fees; Celgene: Honoraria. Vincent:Merck: Research Funding. Foster:Celgene: Research Funding; Macrogenics: Research Funding; Pfizer: Research Funding; Shire: Honoraria. Coombs:Incyte: Other: Travel fees; AROG: Other: Travel fees; DAVA Oncology: Honoraria; Abbvie: Consultancy; H3 Biomedicine: Honoraria. Luznik:WIndMIL Therapeutics: Equity Ownership, Patents & Royalties. Gojo:Merck inc: Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Serody:Merck: Research Funding.

Purpose Event-free survival following all-trans-retinoic acid (ATRA) –based therapy for acute promyelocytic leukemia (APL) averages 70% at 5 years. While arsenic trioxide (ATO) can induce remissions in 95% of relapsed patients, few studies have addressed the integration of ATO into the primary management of APL. This study examines the efficacy of a single cycle of ATO-based consolidation therapy in a treatment regimen designed to decrease exposure to other cytotoxic agents. Patients and Methods After induction with ATRA and daunorubicin (DRN), untreated patients with APL received 3 days of cytarabine and DRN followed by 30 doses of ATO beginning on day 8. Molecular remitters received 2 years of risk-based maintenance therapy. Results Forty-one of 45 patients receiving induction therapy achieved remission; four patients died (one before treatment was initiated). Thirty-seven patients received consolidation and maintenance; of these one patient relapsed (CNS) and one died in remission during maintenance therapy (hepatic sickle cell crisis). With a median follow-up of 2.7 years, estimated disease-free survival was 90%; overall survival for all patients was 88%. Despite a total anthracycline dose of only 360 mg/m2, cardiac ejection fraction decreased by ≥ 20% in 20% of patients. Conclusion These data, combined with other recent studies using ATO in the primary management of APL, demonstrate the important role that ATO can play in the primary management of this curable disease. Future studies should continue to focus on reducing the toxicity of treatment without increasing the relapse rate.

In a single-center study, we analyzed the outcomes of 66 patients with advanced hematological malignancies receiving two reduced-intensity conditioning regimens for allogeneic transplantation: fludarabine and low-dose TBI (flu/TBI, n=25), or fludarabine, antithymocyte globulin and BU (flu/ATG/BU, n=41). The selection criteria were based on the hypothesis that flu/TBI patients were expected to achieve autologous recovery in the event of non-engraftment. Sixty-three patients (95%) engrafted. Regimen-related mortality at day 100 and 1 year was 6 and 15%, respectively. With median follow-up of 50.4 months, survival did not differ by regimen. Multivariate analysis confirmed that the type of regimen did not affect relapse. In patients achieving full donor chimerism by day 30, those conditioned with flu/TBI showed greater overall survival (P=0.02). Engraftment failure occurred in two patients (3%), both of whom received flu/TBI. We conclude that conditioning with flu/TBI or flu/ATG/BU yields comparable survival and remission outcomes. By contrast to our hypothesis, patients receiving flu/TBI who subsequently failed engraftment did not achieve autologous recovery. Yet, rapid attainment of full donor chimerism after flu/TBI is associated with greater survival than after flu/ATG/BU. Further, larger prospective randomized studies are required to define the advantage of one regimen over the other.

Background Ruxolitinib, a Janus kinase 1 and 2 inhibitor, demonstrated improvements in spleen volume, symptoms, and survival over placebo and best available therapy in intermediate-2 or high-risk myelofibrosis patients with baseline platelet counts ≥100 × 109/L in phase III studies. The most common adverse events were dose-dependent anemia and thrombocytopenia, which were anticipated because thrombopoietin and erythropoietin signal through JAK2. These events were manageable, rarely leading to treatment discontinuation. Because approximately one-quarter of MF patients have platelet counts

Introduction: AML pts have a poor prognosis with conventional chemotherapy regimens. Early lymphocyte recovery (ELR) following intensive timed sequential therapy (TST) induction is characterized by a dysfunctional immunosuppressive state. Pomalidomide (Pom), a small molecule immunomodulatory agent (IMiD), has direct effects on T cell co-stimulation by promoting the ubiquitination of Aiolos, an IL-2 transcriptional repressor. We hypothesized that the administration of Pom at the time of ELR after induction TST may influence T cell differentiation and enhance an anti-leukemia immune effect. Methods: A multicenter phase 1 dose escalation study was conducted to determine the safety and tolerability of Pom after intensive induction TST in newly diagnosed AML and HR-MDS pts 18-65 years. Core-binding factor AML was excluded. All pts received induction chemotherapy with AcDVP16: cytarabine 667 mg/m2/day IV continuous infusion days 1-3, daunorubicin 45 mg/m2/day IV days 1-3, etoposide 400 mg/m2/day IV days 8-10. Pom was administered at the assigned dose and schedule after day 14 and within 3 days of the total white blood cell count (WBC) reaching >0.2x109/L above nadir, defined as ELR. Three dose levels were planned (2 mg, 4 mg and 8 mg) within 2 cohorts: 10 days of Pom and 21 days of Pom, in a traditional 3+3 dose escalation design. Results: 25 pts were enrolled on this study January 2014-June 2016 across 3 institutions (Table 1). Pom administration occurred at a median of 21 days after AcDVP16 induction. There were no dose-limiting toxicities (DLTs) in the first cohort of Pom x 10 days within each dose level- 2 mg (n=3), 4 mg (n=3) and 8 mg (n=7). There were no DLTs seen at 4 mg x 21 days (n=7). Two DLTs were seen at Pom 8 mg x 21 days (Grade 3 ALT increase and Grade 3 hypoxia, respectively). Thus, Pom 4 mg x 21 days will be further expanded. Nine (36%) pts discontinued Pom early (median duration = 5 days) due to: grade 3 rash (n=3), physician discretion (decreased WBC: n=1, fever and increased creatinine: n=1), grade 3 ALT increase (n=1), grade 3 hypoxia (n=1), disease progression (n=1), and pt preference (n=1). Adverse events (AEs) possibly associated with Pom that were seen in >1 pt included fever (n=8), rash (n=7), AST/ALT increase (grade 1: n=4, grade 3: n=1), mucositis (n=2), and fatigue (n=2). All of these AEs were self-limiting with supportive care and/or discontinuation of Pom. 60-day mortality was 0%. A complete remission (CR) was achieved in 18 pts and 1 achieved CR with incomplete platelet recovery (CRp) with a combined CR + CRp = 19/25 (76%). Among pts with adverse-risk AML, 5/6 (83%) achieved CR. One pt achieved a partial remission and 5 pts were refractory to treatment. Of the 19 CRs, 15 had no evidence of minimal residual disease by cytogenetics, FISH, or flow cytometry. Among pts who completed a course of Pom (10 days or 21 days), 14/16 (88%) achieved CR. As previously reported, a dramatic decrease of Aiolos expression via flow cytometry in T cell subsets was observed in vivo for the duration of POM treatment with doses > 2 mg, but the effect was lost after Pom was stopped. Figure 1 displays the pattern of cytokine production of CD4+ T cells visualized with pie charts, and shows a significantly different subset composition at ELR in Pom-treated pts compared to the same pts at full recovery (p=0.02), and compared to control AML pts at the same time point (p=0.004). Furthermore, there was a significant increase in TNF-α production (p=0.009) and the combination of TNF-α and IL-2 production (p=0.03) in stimulated CD4+ T cells during Pom treatment, which was reduced to baseline values after Pom was discontinued at full recovery (Figure 1: data analysis performed with the SPICE software). Conclusions: Pom can be safely administered at the time of ELR after intensive induction TST. Fever and rash are the most common AEs seen after Pom administration. Inhibition of Aiolos and consequent increase in both IL-2 and TNF-α expression, as measured by flow cytometry, appear to be reliable markers of Pom-induced T cell modulation in vivo. Planned expansion of the cohort of 4 mgx 21 days will allow further evaluation of safety and activity of Pom in AML. Expression of Cytokines in CD4+ T Cells Expression of Cytokines in CD4+ T Cells Disclosures Zeidner: Takeda: Research Funding; Merck: Research Funding; Agios: Honoraria; Otsuka: Consultancy; Tolero: Research Funding. Zeidan:Celgene: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Ariad: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Smith:Celgene: Consultancy, Other: member of DSMB. Levis:Millennium: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding. Foster:Celgene: Research Funding.

Background: Relapsed or refractory acute lymphoblastic leukemia (ALL) remains challenging to treat with an extremely poor prognosis. Salvage chemotherapy regimens can achieve complete remission (CR) rates of 30-50%, but CRs are not durable without hematopoietic stem cell transplant (HSCT). Outcomes in untreated adolescents and young adults have improved with the use of pediatric chemotherapy regimens, but data on the use of pediatric chemotherapy regimens in relapsed/refractory adult ALL is lacking. We chose to retrospectively examine the outcomes of adult patients with relapsed ALL at our institution treated with the CCG-1941 pediatric salvage protocol (Gaynon PS, et al. J Clin Oncol 2006). Methods: We conducted a single-center retrospective cohort study of patients aged 18 and older with relapsed/refractory ALL who were treated with the CCG-1941 protocol. Patients received induction with vincristine, dexamethasone, ifosfamide, etoposide, PEG-asparaginase, and methotrexate, as well as intrathecal methotrexate, cytarabine, and hydrocortisone prophylaxis, followed by intensification and continuation phases. This regimen was offered to relapsed/refractory patients who, in the judgement of treating physician, were likely to tolerate multiagent chemotherapy. All adult patients who received this regimen between 2006 and 2015 were included in the analysis. Outcomes of interest were: the CR rate, duration of remission (DOR), toxicity, 30-day mortality, and the rate of patients undergoing HSCT. Results: Between January 2006 and April 2015, 15 patients aged 20-54 (median 31) with first relapse (n=12) or refractory (n=3) ALL were treated with the CCG-1941 regimen. Baseline patient characteristics are described in the Table 1. Seven patients (47%) had alterations to the induction protocol. The majority of these modifications were reduction or omission of PEG-asparaginase or vincristine. All patients experienced infectious complications, most commonly neutropenic fever (n= 12, 80%, 95% CI 52-96). There was one death due to infection, which occurred during an intensification phase. Two patients had grade 3 pancreatitis and two patients had hemorrhage (one grade 2, and one grade 5). 30-day mortality was 7% (95% CI 0-32) due to one fatal intracranial hemorrhage. Median length of hospitalization for induction was 28 days (range 10-61). Twelve patients (80%, 95% CI 52-96) achieved CR, and six of these patients received 1-2 cycles of intensification or continuation. Among the remaining 6 CR patients, one proceeded immediately to HSCT, two received other consolidation, two had early relapse, and one was lost to follow up. Six patients proceeded directly to HSCT, and one more underwent HSCT after receiving subsequent therapies for relapsed disease. The DOR was 81% at 6 months, 54% at 12 months, 36% at 18+ months and 18% at 24 months. One patient has been followed for 63 months and has not recurred. Median follow-up for survivors was 16 months (range 3.6-63). Conclusions: The CCG-1941 regimen appears to be tolerable and efficacious in adult patients with relapsed/refractory ALL. This regimen has been previously reported only in children. Despite the regimen's toxicities, a substantial proportion of patients underwent subsequent stem cell transplantation. Such salvage therapies remain important options for patients with T-ALL and for those B-ALL patients who are not candidates for, or who have failed phenotype-specific immunotherapies. Further prospective, multicenter study is warranted for use of pediatric salvage regimens in the adult patient population. Disclosures Foster: Celgene: Research Funding.

Introduction: Salvage chemotherapy regimens for patients with relapsed/refractory acute myeloid leukemia (AML) are associated with complete response rates of 30 - 60%. Determining the superiority of one treatment over another is difficult due to the lack of comparative data. There are no data comparing treatments with cladribine and clofarabine based salvage regimens to each other. Therefore, we conducted a retrospective study of GCLAC (clofarabine 25 mg/m2 IV days 1-5, cytarabine 2 gm/m2 IV days 1-5, and G-CSF) and CLAG (cladribine 5 mg/m2 IV days 1-5, cytarabine 2 gm/m2 IV days 1-5, and G-CSF). Methods: We identified 41 consecutive patients with pathologically diagnosed relapsed or refractory AML who received either GCLAC or CLAG between 2011 and 2014. The primary outcome was the complete response rate (CRp or CR) as defined by the International Working Group. Secondary outcomes included the percentage of patients who underwent allogenic stem cell transplant, relapse free survival (RFS), and overall survival (OS). Fisher's exact and Wilcoxon Rank Sum tests were used to compare patient characteristics and response rates. The Kaplan Meier method and Log Rank tests were used to evaluate RFS and OS. Results: We found no significant differences in the baseline characteristics of patients treated with GCLAC (n=22) or CLAG (n=19) including age, race, gender, organ function, or cytogenetic risk group (table 1). There were also no significant differences in the percentage of relapsed patients (36% vs. 21%), the average duration of the previous remission (28.6 vs. 19.4 months) or in their previous therapy. An anthracycline-based "7+3" regimen was given to 82% of the GCLAC patients and to 90% of the CLAG patients. The outcomes with these two regimens were also not significantly different. Patients treated with GCLAC had a 64% CR/CRp rate compared with 47% for CLAG patients (p= 0.36). 45% GCLAC patients underwent allogeneic stem cell transplant compared with 26% of CLAG patients (p= 0.32). The median RFS on GCLAC and CLAG respectively was 1.59 years [0.41, non-estimable (NE)] and 1.03 years [0.49, 1.03], (p= 0.75). The median OS was 1.03 years [0.52, NE] and 0.70 years [0.28, 1.11], (p= 0.08). Given the similarities of these regimens, we combined the data sets to compare the OS for patients with refractory AML to relapsed AML. The OS for patients with refractory AML was not significantly worse than patients with relapsed AML (0.94 years [0.36, 1.3] vs.1.11 years [0.46, not evaluable]; p=0.49). Conclusion: We find no significant differences in outcomes using GCLAC or CLAG for relapsed/refractory AML patients. The trends in outcome that favored GCLAC are likely explained by trends in patient populations (e.g. longer first remission for GCLAC patients). Since our results are similar to the published reports describing these regimens, we feel the choice of regimen can be based on other considerations such as cost. We do find the efficacy of both regimens in refractory AML to be encouraging. However, we recognize that overall survival of one year is not acceptable and that most relapsed/refractory patients should be entered into clinical trials. Table 1.Baseline CharacteristicsGCLAC (n=22)CLAG (n=19)p ValueAge (years)54.75 ± 11.552.9 ± 12.50.69Race (C vs Non C)18 (82%)12 (63%)0.21Gender (M)11 (50%)11 (58%)0.76Risk group Favorable4 (19%)2 (11%)0.48 Int-12 (10%)4 (22%) Int-27 (33%)3 (17%) Adverse8 (38%)9 (50%)Salvage attempt 120 (91%)15 (79%)0.39 >12 (9%)4 (21%)Relapse vs Refractory Relapse8 (36%)4 (21%)0.32Primary Refractory14 (64%)15 (79%)OutcomesGCLAC (n=22)CLAG (n=19)p ValueCRp or CR14 (64%)9 (47%)0.36Transplant9 (45%)5 (26%)0.32Median RFS (years)1.59 (0.41,NE)1.03 (0.49, 1.03)0.75Median OS (years)1.03 (0.52, NE )0.70 (0.28, 1.11)0.083RelapseRefractoryp ValueOS (years) of relapse vs refractory patients*1.11 (0.46, NE)0.94 (0.36, 1.34)0.49*All GCLAC and CLAG patients combined Disclosures Foster: Celgene: Research Funding.

6630 Background: Ruxolitinib (RUX) has demonstrated clinical benefit as therapy for MF. This study explores the safety and efficacy of RUX in pts with MF and low PC, where clinical data are limited. Methods: In this phase II study, pts with intermediate-1 to high-risk MF, and PC of 50–100x109/L started RUX at 5 mg BID. Doses could be increased in 5 mg QD increments every 4 weeks (wks) beginning at wk 4. Doses were decreased or held for PC 9/L and 9/L respectively. Assessments: Total Symptom Score (TSS, using the modified MF Symptom Assessment Form v2.0, and comprised of scores from 0=absent to 10=worst imaginable for night sweats, itching, bone/muscle pain, early satiety, abdominal discomfort and pain under left ribs); Patient Global Impression of Change (PGIC, a 7-point scale ranging from “very much improved” to “very much worse”); spleen size by palpation and by MRI (data not yet available); and safety. Results: At the time of analysis, 23 pts had completed ≥4 wks on study. At baseline: mean PC=72x109/L; high (4%), intermediate-2 (52%) and intermediate-1 (44%) risk group; mean spleen length=16.6 cm; mean TSS=25.5. At the time of analysis, 4%, 40%, 26%, 26% and 4% of pts were receiving RUX 5 mg QD, 5 mg BID, 5 mg AM/10 mg PM, 10 mg BID, and 10 mg AM/15 mg PM, respectively. At wk 4 (all pts on 5 mg BID), mean TSS improved 14%; 13% had ≥50% improvement. At wk 8 (52% on 5 mg AM/10 mg PM), mean TSS improved 23%; 30% had ≥50% improvement. Mean spleen length reduction of 22% (wk 4) and 27% (wk 8) was observed, and PGIC scores of “much improved” or “very much improved” were reported in 35% (wk 4) and 39% (wk 8) of pts. There were no Grade 4 PC, no dose holds for AEs and no discontinuations; 1 pRBC transfusion-dependent pt had Grade 4 anemia. Three pts experienced a total of 4 SAEs (fever; hypnagogic dreams; and spleen pain/pneumonitis) which resolved while on treatment. Conclusions: Effects on spleen size, PGIC, and TSS, even over the first weeks at low doses, are superior to those observed in the placebo group in the COMFORT-I study. These preliminary findings suggest a dosing strategy starting with 5 mg BID RUX with subsequent dose optimization may be efficacious and well tolerated in MF pts who have low platelets.

Current strategies for the treatment of patients with acute promyelocytic leukemia provide event-free survival of 75 – 85%. Most multicenter studies have used large doses of anthracyclines and multiple cycles of treatment. Based on the extremely high efficacy of arsenic trioxide (ATO) as single agent re-induction therapy, we conducted a Phase II study which minimized anthracycline exposure and treatment duration in newly diagnosed APL patients. The study design was modified from a previous trial which successfully used a single cycle of consolidation chemotherapy (Am. J. Heme.2005;79:119–27). All patients received ATRA for 60 days with daunorubicin (DRN, 60 mg/m2/dose IV) on days 4, 6, 8 unless urgent cytoreduction was required. Consolidation, begun between days 60 and 67, consisted of cytarabine 0.667 gm/m2/day IV continuous infusion days 1 – 3, DRN 60 mg/m2/dose IV days 1 – 3, and ATO 0.15 mg/kg IV for 30 doses, administered five days per week beginning on day 8 of consolidation on an outpatient basis. A second module of ATO was planned for patients with a positive qualitative rt-PCR for PML-RARα (sensitivity 1/10000) following recovery from consolidation. Patients whose initial WBC was < 10,000 per microliter proceeded to ATRA maintenance given for 15 days every three months for 8 cycles. Patients with WBC counts greater than 10,000 per microliter also received 6-mercaptopurine and methotrexate as part of the maintenance regimen. Forty-five patients received induction therapy. Median age was 50; relapse risk categories (Sanz et al. Blood. 2000;96:1247–1253): Low, 36%; Intermediate, 29%; High, 32%. Four patients expired during induction. Of the 41 remaining patients, 4 patients withdrew consent prior to consolidation due to difficulty traveling to the treatment center. 27/31 patients tested following induction achieved molecular remission at that time point (qualitative rt-PCR). 37 patients received consolidation therapy. No patients expired during consolidation, and no patients required a second module of ATO therapy. Only two events have been recorded in patients who underwent consolidation treatment: one patient with Hemoglobin SC disease expired during maintenance therapy due to intrahepatic sickle crisis, possibly related to methotrexate administration, while one patient developed central nervous system relapse. The table compares overall, event free- and disease-free survival of this series to three recent series, including the ATO-containing arm of C9810. Although median follow-up of the current series is shorter, to date the results are comparable to these three studies which employed more extensive therapy. No cases of secondary MDS or AML have been reported to date. Echocardiographic monitoring pre- and post-induction therapy in 24 patients revealed a decrement in ejection fraction post-induction of ≥ 10% in nine patients, including > 20% in three patients to EF values of 20 – 30%, with biopsyproven anthracycline-induced cardiomyopathy documented by biopsy in two patients, indicating possible cardiac sensitization by ATRA to anthracycline. These data suggest that the inclusion of ATO in primary APL management may allow further minimization of conventional cytotoxic chemotherapy without compromising cure rates, and demonstrate the critical need to determine the minimum curative therapy for APL patients. Series Total anthracycline dose administered (mg/m2 DRN equivalent)a Age (median) Sanz Relapse risk: High (percent) Follow- up (years, median) Overall survival Disease- Free Survival Event- Free Survival a Daunorubicin= 1. Mitoxantrone = 2.5. Idarubicin = 5. b nr indicates not reported c Selected based on Sanz risk score 90.5 92.9 83.6 Current 360 50 32 1.8 86 87 77 C9710 ATO arm 500 nrb 24 2.4 82 84 nr PETHEMA LPA99 525 – 625c 37 25 5.4 APL2000 Ara-C arm 495 43 46 5.2 90.5 nr 85.6

Bone marrow (BM) is the accepted source for monitoring post-therapy minimal residual disease (MRD) in APL. PB is easier and less painful to obtain but variable, sometimes contradictory evidence has been presented for its efficacy in MRD monitoring. In this study, PB vs BM monitoring, as well as conventional, qualitative RT-PCR (C-PCR) vs Q-PCR were directly and prospectively compared for their effectiveness as part of an intensive MRD monitoring schedule applied as a safety measure to an investigative Phase II trial (J0422) designed to test the efficacy of minimizing chemotherapy exposure and treatment duration. This trial consisted of one cycle of induction with all-trans retinoic acid (ATRA) and daunorubicin, followed by consolidation with single-agent arsenic trioxide (ATO), followed by a maintenance phase of intermittent ATRA alone or with 6-mercaptopurine and methotrexate for patients (pts) with a presenting white blood cell count (WBC) of >10,000 WBC/uL. The MRD monitoring schedule was as follows: BM and PB after the induction and consolidation treatment modules (modules 1 & 2), then, PB every month and BM every 3 months during 2 years of maintenance therapy. C-PCR and Q-PCR were performed according to published procedures for monitoring the APL-specific fusion gene PML-RARα by the BIOMED-1 Concerted Action and the North American Cooperative Oncology Groups, respectively. Criteria for positive assays were: C-PCR, confirmed visualization of an appropriate-sized gel band after conventional, double-nested PCR amplification; Q-PCR, demonstration of a CT value 10,000 (7 pts), suggesting an association of pretreatment WBC with a difference in the initial dynamics of treatment response. After module-2 consolidation, 0 pts were positive by C-PCR and 3 by Q-PCR (1 BM & PB, 1 BM-only, 1 PB-only). During maintenance at the 3 mo shared BM/PB checkpoints, 0 C-PCR and 5/114 Q-PCR assays were positive (2 BM & PB, 1 BM-only, 2 PB-only), distributed among 3 pts. At monthly PB-only checkpoints, an additional 12/252 assays were positive by Q-PCR, none in a progressive pattern suggestive of impending molecular relapse. Overall, 1 – 3 Q-PCR assays were positive in 9 patients during the maintenance and follow-up periods. Among 8 pts who completed 24 mo maintenance, only 1/6 positive Q-PCR assays occurred at >12 mo, suggesting continued reduction of MRD during first 12 mo of maintenance therapy. No C-PCR assays were positive beyond module-1. In 1 exceptional pt, excluded from the above maintenance analysis, the Q-PCR assays became recurrently positive in BM and/or PB after 6 mo maintenance at a level below the criterion for molecular relapse (normalized quotient relative to the housekeeping gene GAPDH, NQGAPDH, ≥10−5). After 18 mo, the C-PCR became repeatedly positive in PB but not BM with Q-PCRs positive (2 BM & PB, 1 PB-only at shared checkpoints) in the NQGAPDH 4×10−7 to 4×10−6 range, which was associated with relapse in the central nervous system but not the BM. These results indicate that molecular monitoring of PB or BM was equally effective in detecting MRD and that Q-PCR was a more critical measure of MRD than C-PCR on protocol J0422 after single-cycle ATO-based consolidation therapy. The results further suggest that PB monitoring may be more effective in detecting extramedullary relapse, a relatively increasing cause of disease relapse with improved overall therapy for APL.