Mohamad Cherry

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is incurable with conventional therapies. Limited retrospective data have shown durable remissions after haematopoietic cell transplantation (HCT) [allogeneic (allo) or autologous (auto)]. We conducted a multicentre retrospective study in BPDCN patients treated with allo-HCT and auto-HCT at 8 centres in the United States and Canada. Primary endpoint was overall survival (OS). The population consisted of 45 consecutive patients who received an allo-HCT (n = 37) or an auto-HCT (n = 8) regardless of age, pre-transplant therapies, or remission status at transplantation. Allo-HCT recipients were younger (50 (14-74) vs. 67 (45-72) years, P = 0·01) and had 1-year and 3-year OS of 68% [95% confidence interval (CI) = 49-81%] and 58% (95% CI = 38-75%), respectively. Allo-HCT in first complete remission (CR1) yielded superior 3-year OS (versus not in CR1) [74% (95% CI = 48-89%) vs. 0, P < 0·0001]. Allo-HCT outcomes were not impacted by regimen intensity [3-year OS for myeloablative conditioning = 61% (95% CI = 28-83%) vs. reduced-intensity conditioning = 55% (95% CI = 28-76%)]. One-year OS for auto-HCT recipients was 11% (95% CI = 8-50%). These results demonstrate efficacy of allo-HCT in BPDCN, especially in patients in CR1. Pertaining to auto-HCT, our results suggest lack of efficacy against BPDCN, but this observation is limited by the small sample size. Larger prospective studies are needed to better define the role of HCT in BPDCN.

Abstract Introduction: Gilteritinib is a novel, potent, highly-selective oral fms-like tyrosine kinase 3 (FLT3)/AXL inhibitor. Once-daily single-agent gilteritinib doses of ≥80 mg/day elicited antileukemic responses in FLT3 mutation-positive (FLT3mut+) subjects with relapsed/refractory AML (Perl AE, et al. Lancet Oncol. 2017). We examined the safety/tolerability and antitumor activity of gilteritinib plus front-line intensive chemotherapy in newly diagnosed AML patients. Methods: This ongoing open-label, dose-escalation/expansion phase 1 study (NCT02236013) assesses the safety/tolerability and antitumor effects of gilteritinib combined with 7+3 induction and high-dose cytarabine consolidation, and as single-agent maintenance therapy in subjects aged ≥18 years with newly diagnosed AML (excluding core-binding factor translocations). Dose escalation followed a 3+3 design; successive cohorts of 3-6 subjects received 40, 80, 120, or 200 mg/day gilteritinib. Subjects received ≤2 cycles of a 7+3 induction regimen (cytarabine 100 mg/m2/day, Days 1-7 plus idarubicin 12 mg/m2/day, Days 1-3 [dose-escalation and dose-expansion cohorts], and once-daily gilteritinib on Days 4-17 [Schedule 1]). After completion of the dose-expansion cohort using Schedule 1, a new cohort of patients were enrolled. In this cohort of six patients, gilteritinib administration was changed to Days 8-21 (Schedule 2) in preparation for phase 3 studies and daunorubicin 90 mg/m2/day, administered on Days 1-3, was used as an alternative anthracycline to idarubicin. During consolidation, subjects received cytarabine (1.5 g/m2 every 12 hours, Days 1, 3, and 5) and once-daily gilteritinib (Days 1-14) at the induction dose for ≤3 cycles. Subjects in the dose-expansion cohort received gilteritinib at the recommended expansion dose established during dose escalation. Transplantation was allowed for responding subjects. After consolidation or transplantation with stable engraftment, subjects received maintenance therapy with once-daily gilteritinib (28-day cycles; ≤26 cycles). Results: As of July 2, 2018, 62 subjects have been enrolled; 60 are included in the safety analysis set. Most subjects were male (66.7%; median age, 59.5 years [range, 23-77]) and 32 (53.3%) had FLT3 mutations (FLT3-ITD, n=23). During dose-escalation, two subjects in the 40 mg/day cohort who had received gilteritinib on Days 1-14 experienced dose-limiting toxicities (DLTs; neutropenia, thrombocytopenia, decreased ejection fraction). After the gilteritinib induction schedule change, no more DLTs occurred at this dose. Two subjects in the 200 mg/day cohort experienced DLTs (neutropenia, neutropenic enterocolitis). The maximum tolerated dose and the recommended expansion dose were established at 120 mg/day. Grade ≥3 adverse events (AEs) in ≥10% of patients were febrile neutropenia (63.3%), thrombocytopenia (18.3%), decreased platelet count (16.7%), neutropenia (15.0%), bacteremia (10.0%), sepsis (10.0%), and decreased white blood cell count (10.0%). Serious drug-related AEs in &gt;1 subject were febrile neutropenia (n=9), small intestinal obstruction, lung infection, sepsis, and decreased ejection fraction (all n=2). The end-of-treatment investigator-reported rate of composite complete remission (CRc) for response evaluable FLT3mut+ subjects receiving gilteritinib 120 mg on Schedule 1 (n=17) was 100%. The CRc rate in FLT3mut+ subjects receiving Schedule 2 induction with daunorubicin was also 100% (Table). Enrollment in the Schedule 2 cohort receiving idarubicin is ongoing; the two subjects in this cohort have not been assessed for response. Among subjects who received ≥80 mg/day gilteritinib (n=47), CRc rates for FLT3mut+ subjects were 88.9% (n=24/27). Median overall survival has not been reached. Median disease-free survival was 297 days (95% CI: 112, not reached). Assessment of minimum residual disease in FLT3-ITD patients using a next-generation sequencing-based assay is ongoing; results will be available at the time of presentation. Conclusions: Gilteritinib can be safely combined with intensive chemotherapy, and given as single-agent maintenance therapy in subjects with newly diagnosed AML. Treatment was well tolerated. High response rates were observed in FLT3mut+ subjects after treatment with either idarubicin or daunorubicin in combination with two different gilteritinib administration schedules. Disclosures Pratz: Millenium/Takeda: Research Funding; AbbVie: Consultancy, Research Funding; Agios: Research Funding; Astellas: Consultancy, Research Funding; Boston Scientific: Consultancy. Altman:Astellas Pharma: Other; Agios: Other: Payment to the institution to conduct the trial ; Epizyme: Other: payment to the institution to conduct clinical trial work; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other: payment to the institution to conduct clinical trial work; Cyclacel: Other: payment to the institution to conduct clinical trial work; Celator: Other: payment to the institution to conduct clinical trial work; Ariad: Other: payment to the institution to conduct clinical trial work; Bayer: Other: payment to the institution to conduct clinical trial work; Genetech: Other: Payment to the institution to conduct clinical trial work; FujiFilm: Other: payment to the institution to conduct clinical trial work; Incyte: Other: payment to the institution to conduct clinical trial work; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: payment to the institution to conduct clinical trial work; Boeringer Ingelheim: Other: payment to the institution to conduct clinical trial work; Syros: Membership on an entity's Board of Directors or advisory committees; GSK: Other: payment to the institution to conduct clinical trial work; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Immune Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Cruz:Takeda: Speakers Bureau. Jurcic:Kura Oncology: Research Funding; Forma Therapeutics: Research Funding; Celgene: Research Funding; Daiichi-Sankyo: Research Funding; Incyte: Consultancy; Actinium Pharmaceuticals, Inc: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Syros Pharmaceuticals: Research Funding; Genetech: Research Funding; AbbVie: Consultancy, Research Funding; Astellas: Research Funding. Lin:Jazz Pharmaceuticals: Honoraria. Perl:AbbVie: Membership on an entity's Board of Directors or advisory committees; Actinium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Arog: Consultancy; NewLink Genetics: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy. Podoltsev:Pfizer: Membership on an entity's Board of Directors or advisory committees; Astellas Pharma: Research Funding; LAM Therapeutics: Research Funding; Astex Pharmaceuticals: Research Funding; Genentech: Research Funding; Boehringer Ingelheim: Research Funding; Sunesis Pharmaceuticals: Research Funding; Daiichi Snakyo: Research Funding; Celator: Research Funding; Celgene: Research Funding; Pfizer: Research Funding. Schiller:bluebird bio: Research Funding; Astellas Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding. Liu:Astellas Pharma: Employment. Bahceci:Astellas Pharma: Employment.

PURPOSE Gilteritinib is a type 1 FLT3 inhibitor active as monotherapy for relapsed or refractory FLT3-mutated AML. We investigated the safety, tolerability, and efficacy of gilteritinib incorporated into intensive induction and consolidation chemotherapy, and as maintenance therapy for adult patients with newly diagnosed, non–favorable-risk AML. METHODS In this phase IB study (2215-CL-0103; ClinicalTrials.gov identifier: NCT02236013 ), 103 participants were screened and 80 were allocated to treatment. The study was divided into four parts: dose escalation, dose expansion, investigation of alternate anthracycline and gilteritinib schedule, and continuous gilteritinib during consolidation. RESULTS After dose escalation, 120 mg gilteritinib once daily was chosen for further study. There were 58 participants evaluable for response at this dose, 36 of whom harbored FLT3 mutations. For participants with FLT3-mutated AML, the composite complete response (CRc) rate was 89% (83% were conventional complete responses), all achieved after a single induction cycle. The median overall survival time was 46.1 months. Gilteritinib was well-tolerated in this context although the median time to count recovery during induction was approximately 40 days. Longer time-to-count recovery was associated with higher trough levels of gilteritinib, which, in turn, were associated with azole use. The recommended regimen is gilteritinib at a dose of 120 mg once daily from days 4 to 17 or 8 to 21 of a 7 + 3 induction with either idarubicin or daunorubicin and from day 1 continuously with high-dose cytarabine consolidation. Maintenance therapy with gilteritinib was well-tolerated. CONCLUSION These results demonstrated the safety and tolerability of gilteritinib incorporated into an induction and consolidation chemotherapy regimen, and as single-agent maintenance therapy for patients with newly diagnosed FLT3-mutant AML. The data herein provide an important framework for the design of randomized trials comparing gilteritinib with other FLT3 inhibitors.

Abstract Duvelisib, a potent δ‐ and γ‐PI3K inhibitor, is a potential therapeutic for hematologic malignancies. Rituximab and bendamustine have demonstrated activity in non‐Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Combining duvelisib with either rituximab alone or rituximab and bendamustine may improve response rates and remission durability. We conducted this Phase one study in relapsed/refractory NHL and CLL patients. During expansion, each arm enrolled to disease‐specific cohorts to assess efficacy. Arm one received rituximab 375 mg/m 2 IV weekly for two 4‐week cycles plus duvelisib until progression/intolerance. Arm two received rituximab 375 mg/m 2 IV Day one, bendamustine 90 mg/m 2 IV (NHL patients) or 70 mg/m 2 IV (CLL patients) Days one‐two for six cycles, plus duvelisib until progression/intolerance. Duvelisib doses of 50 mg and 75 mg BID were tested during dose escalation. Forty‐six patients (27 NHL, 19 CLL) were treated. The adverse events of the drug combinations were consistent with single agent toxicities. The most common AEs were neutropenia (47.7%), fatigue (41.3%), and rash (41.3%). A duvelisib expansion dose of 25 mg BID was chosen based on the monotherapy phase one study, IPI‐145‐02, which confirmed that dose for further clinical development. Overall response rate was 71.8%. Median progression‐free survival was 13.7 months. Median overall survival has not been reached, but 30‐month overall survival probability was 62%. Duvelisib combined with rituximab, or bendamustine and rituximab did not appear to increase toxicities beyond the known safety profile of the individual agents. Further study is needed to determine if these combinations improve efficacy.