Myeloproliferative neoplasms (MPN) that have evolved into accelerated or blast phase disease (MPN-AP/BP) have poor outcomes with limited treatment options and therefore represent an urgent unmet need. We have previously demonstrated in a multicenter, phase 1 trial conducted through the Myeloproliferative Neoplasms Research Consortium that the combination of ruxolitinib and decitabine is safe and tolerable and is associated with a favorable overall survival (OS). In this phase 2 trial, 25 patients with MPN-AP/BP were treated at the recommended phase 2 dose of ruxolitinib 25 mg twice daily for the induction cycle followed by 10 mg twice daily for subsequent cycles in combination with decitabine 20 mg/m2 for 5 consecutive days in a 28-day cycle. Nineteen patients died during the study follow-up. The median OS for all patients on study was 9.5 months (95% confidence interval, 4.3-12.0). Overall response rate (complete remission + incomplete platelet recovery + partial remission) was 11/25 (44%) and response was not associated with improved survival. We conclude that the combination of decitabine and ruxolitinib was well tolerated, demonstrated favorable OS, and represents a therapeutic option for this high-risk patient population. This trial was registered at www.clinicaltrials.gov as #NCT02076191.

Effective treatment of chronic myelogenous leukemia (CML) largely depends on eradication of CML leukemic stem cells (LSCs). We recently showed that CML LSCs depend on Tcf1 and Lef1 factors for self-renewal. Using a connectivity map we identified prostaglandin E1 (PGE1) as a small molecule that partly elicited the gene expression changes in LSCs caused by Tcf1/Lef1 deficiency. Although it has little impact on normal hematopoiesis, we found that PGE1 treatment impaired the persistence and activity of LSCs in a pre-clinical murine CML model and a xenograft model of transplanted CML patient CD34+ stem/progenitor cells. Mechanistically, PGE1 acted on the EP4 receptor and repressed Fosb and Fos AP-1 factors in a β-catenin-independent manner. Misoprostol, an FDA-approved EP4 agonist, conferred similar protection against CML. These findings suggest that activation of this PGE1-EP4 pathway specifically targets CML LSCs, and that combination of PGE1/misoprostol with conventional tyrosine-kinase inhibitors could provide effective therapy for CML.

The prognosis of elderly patients (pts) with acute lymphoblastic leukemia (ALL) remains poor, and novel therapeutic approaches are clearly needed. CD19 is expressed on the majority of precursor-B ALLs and represents an attractive therapeutic target. The anti-CD19 bi-specific engager antibody blinatumomab has demonstrated significant activity in both relapsed/refractory ALL and minimal residual disease (MRD) positive ALL. Therefore, we evaluated blinatumomab as a single agent in the upfront treatment of newly diagnosed elderly pts with Philadelphia chromosome (Ph) negative B-lineage ALL to determine response rates and overall survival (OS). Methods: Pts were treated at National Clinical Trial Network sites from June 2015 to September 2017. The primary objective of the study was to estimate 3-year OS. An IND was approved by the FDA and the protocol was approved by a central institutional review board. Eligibility: age > 65 years, newly diagnosed Ph negative B-lineage ALL with adequate organ function and no evidence of central nervous system (CNS) disease. Pts received blinatumomab for induction at standard dosing for 1-2 cycles until attainment of complete response (CR) or CR with incomplete count recovery (CRi) (defined below). Pts then received 3 cycles of blinatumomab post-remission therapy followed by 18 months of maintenance POMP (prednisone, vincristine, 6-mercaptopurine, methotrexate). A total of 8 doses of intrathecal methotrexate were administered as CNS prophylaxis. Cytogenetic risk was ascribed by NCCN 2018 criteria and bone marrow samples were analyzed for the presence of the Ph-like signature. MRD was assessed centrally by 8 color flow cytometry pre-treatment, on Day 35 of induction cycle 1, and on Day 35 of re-induction (if applicable). Response was assessed at the completion of 1-2 cycles of blinatumomab. CR was defined as < 5% marrow blasts with no evidence of extramedullary disease and recovery of counts [absolute neutrophil count (ANC) > 1000/uL, platelets >100,000/uL]. CRi was defined the same as CR but ANC < 1000/ uL and/ or platelets ≤ 100,000/ uL. OS was measured from day of registration on trial until the date of death. Disease-free survival (DFS) was measured from the date the pt achieved CR/ CRi until relapse or death. Toxicities were graded according to NCI CTCAE version 4.0. Results: Of 31 pts enrolled, 29 were eligible. The median age was 75 years (range 66 - 84), 22 (76%) were male, median baseline white blood count was 3.7 x 103/uL (range 0.3 - 7,100), and median bone marrow blast count percentage was 86.5% (range 30-100). Three pts received hydroxyurea or steroids prior to treatment initiation. Cytogenetic risk at diagnosis was: poor (34% of pts; n=10), standard (55% of pts; n=16), good (3% of pts; n=1) and unknown (7% of pts, n=2). Testing for the Ph-like signature is being completed. The most common Grade 3-5 non-hematologic toxicities related to treatment during induction were hyperglycemia (14%), dyspnea (10%), febrile neutropenia (10%), hypertension (10%), and lung infection (7%). One pt developed Grade 3 cytokine release syndrome and 1 developed Grade 3 neurotoxicity. No pts died during the first 28 days of treatment. The overall response rate (CR + CRi) was 66% (all CRs). Thirteen of the 19 responders have available MRD data post-treatment. Of these, 12 pts (92%) achieved MRD negativity, all at Cycle 1 Day 35. One pt required 2 cycles of blinatumomab to achieve CR. One pt proceeded to allogeneic hematopoietic stem cell transplant. The median follow-up time is 1 year and median duration on trial is 170 days (6 pts are still on maintenance therapy). OS estimated by Kaplan Meier at 6 months is 79% (95% CI 58%-90%) and at 1 year is 65% (95% CI 43%-80%). DFS estimated at 6 months is 68% (95% CI 43%-84%) and at 1 year is 56% (95% CI 31%-75%). No baseline features including CD19 expression (by percentage or mean-fluorescent intensity) or presence of a CD19 negative subpopulation were associated with response. Conclusions: Blinatumomab was well tolerated and effective in the treatment of newly diagnosed elderly patients with Ph negative B-lineage ALL. Further follow up will determine the durability of these responses. Disclosures Advani: Pfizer: Honoraria, Research Funding; Amgen: Research Funding; Novartis: Consultancy; Glycomimetics: Consultancy. Wieduwilt:Leadiant: Research Funding; Merck: Research Funding; Shire: Research Funding; Reata Pharmaceuticals: Equity Ownership; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding. Park:Adaptive Biotechnologies: Consultancy; Pfizer: Consultancy; AstraZeneca: Consultancy; Novartis: Consultancy; Kite Pharma: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Shire: Consultancy. Stock:Jazz Pharmaceuticals: Consultancy. Erba:Immunogen: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Agios: Consultancy, Speakers Bureau; Takeda/Millenium: Research Funding; Amgen: Research Funding; Novartis: Consultancy, Speakers Bureau; Juno: Research Funding; Juno: Research Funding; Celgene: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Takeda/Millenium: Research Funding; Incyte: Consultancy, Speakers Bureau; MacroGenics: Consultancy; Jazz: Consultancy, Speakers Bureau; MacroGenics: Consultancy; Agios: Consultancy, Speakers Bureau; Immunogen: Consultancy, Research Funding; Amgen: Research Funding; Agios: Consultancy, Speakers Bureau; Astellas: Research Funding; MacroGenics: Consultancy; Takeda/Millenium: Research Funding; Seattle Genetics: Consultancy, Research Funding; MacroGenics: Consultancy; Novartis: Consultancy, Speakers Bureau; Amgen: Research Funding; Novartis: Consultancy, Speakers Bureau; Janssen: Research Funding; Celgene: Consultancy, Speakers Bureau; Immunogen: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Janssen: Research Funding; Jazz: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Amgen: Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Pfizer: Consultancy, Other: grant; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Astellas: Research Funding; Pfizer: Consultancy, Other: grant; Celgene: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding; Incyte: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Pfizer: Consultancy, Other: grant; Incyte: Consultancy, Speakers Bureau; Juno: Research Funding; Jazz: Consultancy, Speakers Bureau; Pfizer: Consultancy, Other: grant; Astellas: Research Funding; Seattle Genetics: Consultancy, Research Funding; Takeda/Millenium: Research Funding; Immunogen: Consultancy, Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Juno: Research Funding; Jazz: Consultancy, Speakers Bureau.

PURPOSE Chemotherapy outcomes in older patients with Philadelphia (Ph) chromosome–negative B-acute lymphoblastic leukemia (ALL) are very poor. Here, we evaluated blinatumomab as induction and consolidation therapy followed by prednisone, vincristine, 6-mercaptopurine, and methotrexate (POMP) maintenance chemotherapy in this patient population. PATIENTS AND METHODS Patients were treated at National Clinical Trial Network sites. Eligibility criteria included age ≥ 65 years and newly diagnosed Ph chromosome–negative B-ALL. Patients received blinatumomab as induction for one-two cycles until attainment of response (complete remission (CR) and CR with incomplete count recovery). Patients then received three cycles of consolidation with blinatumomab followed by 18 months of POMP maintenance chemotherapy. Eight doses of intrathecal methotrexate were administered as central nervous system prophylaxis. RESULTS Twenty-nine eligible patients were enrolled. The median age was 75 years, and the median bone marrow blast count at diagnosis was 87%. Cytogenetic risk was poor in 10 patients (34%), and five of 14 patients (36%) tested had the Ph-like ALL gene signature. Nineteen patients (66%; 95% CI, 46 to 82) achieved CR. Kaplan-Meier 3-year disease-free survival and overall survival estimates were 37% (95% CI, 17 to 57) and 37% (95% CI, 20 to 55), respectively. CONCLUSION Blinatumomab was well tolerated and effective in the treatment of older patients with newly diagnosed Ph chromosome–negative B-ALL, including patients with poor-risk cytogenetics. The 3-year disease-free survival and overall survival results are encouraging and suggest that this approach should be further explored.

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