Tiu, Ramón V.

PURPOSE The FMS-related tyrosine kinase 3 (FLT3) inhibitor gilteritinib is standard therapy for relapsed/refractory FLT3-mutated ( FLT3 mut ) acute myeloid leukemia (AML) but seldom reduces FLT3 mut burden or induces sustained efficacy. Gilteritinib combines synergistically with the BCL-2 inhibitor venetoclax in preclinical models of FLT3 mut AML. METHODS This phase Ib open-label, dose-escalation/dose-expansion study (ClinicalTrials.gov identifier: NCT03625505 ) enrolled patients with FLT3 wild-type and FLT3 mut (escalation) or FLT3 mut (expansion) relapsed/refractory AML. Patients received 400 mg oral venetoclax once daily and 80 mg or 120 mg oral gilteritinib once daily. The primary objectives were safety, identification of the recommended phase II dose, and the modified composite complete response (mCRc) rate (complete response [CR] + CR with incomplete blood count recovery + CR with incomplete platelet recovery + morphologic leukemia-free state) using ADMIRAL phase III–defined response criteria. RESULTS Sixty-one patients were enrolled (n = 56 FLT3 mut ); 64% (n = 36 of 56) of FLT3 mut patients had received prior FLT3 inhibitor therapy. The recommended phase II dose was 400 mg venetoclax once daily and 120 mg gilteritinib once daily. The most common grade 3/4 adverse events were cytopenias (n = 49; 80%). Adverse events prompted venetoclax and gilteritinib dose interruptions in 51% and 48%, respectively. The mCRc rate for FLT3 mut patients was 75% (CR, 18%; CR with incomplete blood count recovery, 4%; CR with incomplete platelet recovery, 18%; and morphologic leukemia-free state, 36%) and was similar among patients with or without prior FLT3 inhibitor therapy (80% v 67%, respectively). The median follow-up was 17.5 months. The median time to response was 0.9 months, and the median remission duration was 4.9 months (95% CI, 3.4 to 6.6). FLT3 molecular response (< 10 −2 ) was achieved in 60% of evaluable mCRc patients (n = 15 of 25). The median overall survival for FLT3 mut patients was 10.0 months. CONCLUSION The combination of venetoclax and gilteritinib was associated with high mCRc and FLT3 molecular response rates regardless of prior FLT3 inhibitor exposure. Dose interruptions were needed to mitigate myelosuppression.

Abstract Gilteritinib (Gilt), a FLT3 tyrosine kinase inhibitor (TKI), is approved for the treatment of relapsed/refractory (R/R) FLT3-mutated (FLT3 +)acute myeloid leukemia (AML). However, long-term survival is limited by the development of drug resistance mutations in persistent FLT3 + clones. Combination regimens may deepen response and improve outcomes. Venetoclax (Ven), a BCL-2 inhibitor, is approved in combination with hypomethylating agents for newly diagnosed AML not suitable for standard induction therapy. FLT3 + AMLhas been associated with clinical resistance to Ven. Still, FLT3 TKIs + Ven have demonstrated synthetic lethality in preclinical models, prompting this multicenter, open-label, phase 1b trial (NCT03625505) to evaluate Ven + Gilt for R/R AML. Here, we report final response and survival endpoints, and molecular clearance among patients (pts) treated at the recommended phase two dose (RP2D). The study design has been previously described (Daver, et al. ASH 2020, Abstract 333). Pts in the dose expansion cohort received Ven 400 mg + Gilt 120 mg (RP2D) daily in 28-day cycles, following Ven ramp-up. The primary endpoint was mCRc (complete response [CR] + CR with incomplete platelet recovery [CRp] + CR with incomplete blood count recovery [CRi] + morphologic leukemia-free state) to align with the ADMIRAL phase III trial (Perl, et al. NEJM 2019). Baseline co-mutations and serial FLT3 internal tandem duplications (ITD) allelic burden were assessed using the MyAML panel (Invivoscribe, San Diego, CA) and FLT3-ITD MRD assay with sensitivities of 5% and 0.001%, respectively. As of the data cut off of January 31, 2021, 54 pts were treated at the RP2D. Fifty-two pts (as assessed locally) had FLT3 +AML; 41 had FLT3-ITD only, 8 had tyrosine kinase domain only, 3 had both mutations, and 2 were FLT3 wild type (wt). Additional baseline characteristics are in Table 1. Grade 3 or 4 AEs occurred in 51 (94.4%) pts, and 39 (72.2%) pts had serious AEs. Grade 3 or 4 cytopenias occurred in 43 (79.6%) pts. AEs of special interest included tumor lysis syndrome (2 [3.7%]) and QT prolongation (1 [1.9%]). AEs leading to dosing interruptions (Ven, 27 [50%]; Gilt, 26 [48.1%]), reductions (Ven, 3 [5.6%]; Gilt, 4 [7.4%]), and discontinuation (Ven, 7 [13%]; Gilt, 7 [13%]) were reported for both study drugs. There was 1 treatment-emergent death of typhlitis. Among FLT3 + pts with post-baseline assessments (51/52), mCRc was achieved by 38 pts (74.5%; CR/CRp/CRi, 19 [37.3%] pts), with a median follow-up time of 12 mo (range: 0.8 - 20.1). The mCRc in pts with prior TKI (32) or prior Ven (10) use were 78.1% and 60%, respectively. The mOS among all FLT3 +pts was 10 mo (95%CI: 6.6, NE), with a median DoR (mDoR) of 5.4 mo (95% CI: 3.3, 6.6). Pts with FLT3-ITD had a mOS of 10.5 mo (95%CI: 6.8, NE), and a mDoR of 5.6 mo (95% CI: 3.3, 8.3). For the 14 pts who had a transplant, the mOS was not reached (95%CI: 10.0, NE) vs 6.89 mo (95%CI: 3.0, 10.5) for those who did not have a transplant (37). The mOS for pts with prior TKI or Ven was 9.6 (95% CI: 4.3, NE) and 10.5 mo (95% CI: 2.0, NE), respectively, with a mDoR of 9.6 (95% CI: 4.3, NE) and 6.2 mo (95% CI: 2.6, NE), respectively. The 60-day mortality rate was 11.8% (95% CI: 4.4, 23.9). The mCRc for NPM1 + and NPM1wt were 92.3% and 61.1%, respectively. mCRc for DNMT3A + and DMNT3A wt pts were 82.4% and 64.3%, respectively. WT1 + and WT1 wt mCRc were 66.7% and 77.3%, respectively. The mCRc for NPM1 + and DNMT3A + co-mutated pts was 100%. In a post hoc analysis of the 30 analyzable mCRc pts with at least one follow-up MRD assessment, 17 (56.7%) achieved molecular clearance defined as FLT3 allelic burden &lt; 10 -2. The mOS of pts achieving mCRc with FLT3 allelic burden of &lt; 10 -2 vs mCRc with FLT3 allelic burden ≥ 10 -2 (Figure 1) was not reached (95% CI: 9.76, NE) vs 6.83 mo (4.21, NE). Ven + Gilt achieved high mCRc in patients with R/R FLT3 + AML, with or without prior TKI exposure, and an encouraging mOS. FLT3 mutation clearance was seen in a majority of patients and associated with longer OS. Encouraging remission rates were observed across many genotypes and were particularly high among pts with NPM1 + +/- DNMT3A co-mutation. Cytopenias were common but manageable with appropriate Ven or Gilt dosing modifications. Serial NGS molecular data, as well as updated survival data will be presented at the meeting. Figure 1 Figure 1. Disclosures Daver: Hanmi: Research Funding; Abbvie: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; Novimmune: Research Funding; FATE Therapeutics: Research Funding; Glycomimetics: Research Funding; Amgen: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Perl: Actinium: Consultancy; Genentech: Consultancy; Roche: Consultancy; Astellas: Consultancy, Research Funding; Forma: Consultancy; Syndax: Consultancy; Loxo: Consultancy; Fujifilm: Research Funding; Arog: Research Funding; BMS/Celgene: Consultancy; AbbVie: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Onconova: Consultancy; Sumitomo Dainippon: Consultancy. Levis: Amgen, Astellas Pharma, Daiichi-Sankyo, FujiFilm, and Menarini: Honoraria; Astellas and FujiFilm: Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Jazz: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Ritchie: Astellas: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria; Celgene/BMS: Consultancy, Other: travel support, Speakers Bureau; Bristol Myers Squibb: Consultancy, Research Funding; NS Pharma: Research Funding; Incyte: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria; Jazz: Consultancy, Research Funding; Protaganist: Consultancy, Honoraria; ARIAD Pharmaceuticals: Ended employment in the past 24 months, Speakers Bureau; Pfizer: Consultancy, Research Funding. Litzow: Astellas: Research Funding; Omeros: Other: Advisory Board; Pluristem: Research Funding; AbbVie: Research Funding; Amgen: Research Funding; Actinium: Research Funding; Jazz: Other: Advisory Board; Biosight: Other: Data monitoring committee. McCloskey: Jazz: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Smith: AbbVie: Research Funding; Revolutions Medicine: Research Funding; Daiichi Sankyo: Consultancy; FUJIFILM: Research Funding; Astellas Pharma: Consultancy, Research Funding; Amgen: Honoraria. Schiller: Takeda: Research Funding; Trovagene: Research Funding; Tolero: Research Funding; Ono: Consultancy; Novartis: Consultancy, Research Funding; ASH foundation: Other: Chair-unpaid; Pfizer: Current equity holder in publicly-traded company, Research Funding; Incyte: Consultancy; Sanofi: Honoraria, Research Funding, Speakers Bureau; Ariad: Research Funding; Stemline Therapeutics, Inc.: Honoraria, Research Funding, Speakers Bureau; Ono-UK: Consultancy, Research Funding; Karyopharm: Research Funding; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; Onconova: Research Funding; Mateon: Research Funding; Sangamo: Research Funding; Samus: Research Funding; Regimmune: Research Funding; PrECOG: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AstraZeneca: Consultancy; Kaiser Permanente: Consultancy; Cyclacel: Research Funding; MedImmune: Research Funding; Ambit: Research Funding; Agios: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company, Honoraria, Research Funding, Speakers Bureau; Jazz: Consultancy, Honoraria, Research Funding, Speakers Bureau; Elevate: Research Funding; Bio: Research Funding; Pharma: Consultancy; Johnson & Johnson: Current equity holder in publicly-traded company; Biomed Valley Discoveries: Research Funding; Eli Lilly: Research Funding; Sellas: Research Funding; Geron: Research Funding; Genentech-Roche: Research Funding; Gamida Cell Ltd.: Research Funding; FujiFilm: Research Funding; Forma: Research Funding; Delta-Fly: Research Funding; Deciphera: Research Funding; Daiichi-Sankyo: Research Funding; Constellation Pharmaceuticals: Research Funding; Celator: Research Funding; BMS/Celgene: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Astellas: Honoraria, Research Funding, Speakers Bureau; Arog: Research Funding; Actuate: Research Funding; Actinium Pharmaceuticals, Inc: Research Funding; Abbvie: Research Funding; Leukemia & Lymphoma Society: Research Funding; Bluebird Bio: Research Funding; Boehringer-Ingleheim: Research Funding; Cellerant: Research Funding; CTI Biopharma: Research Funding; Janssen: Research Funding; Kura Oncology: Research Funding; Pharmacyclics: Honoraria, Speakers Bureau; Millennium: Research Funding; National Marrow Donor Program: Research Funding; NIH: Research Funding; Onyx: Research Funding; Pharmamar: Research Funding; UC Davis: Research Funding; UCSD: Research Funding; Evidera: Consultancy; NCI: Consultancy; Novartis: Speakers Bureau. Bradley: AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Tiu: Astellas Pharma: Current Employment; Eli Lilly and Company: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Naqvi: Genentech/Roche: Current Employment, Current holder of stock options in a privately-held company. Dail: Genentech/Roche: Current Employment, Current equity holder in publicly-traded company. Siddani: AbbVie: Current Employment, Current holder of stock options in a privately-held company. Wang: AbbVie: Current Employment, Current holder of stock options in a privately-held company. Chyla: AbbVie: Current Employment, Current equity holder in publicly-traded company. Lee: AbbVie: Current Employment, Current holder of stock options in a privately-held company. Altman: Astellas: Consultancy, Other: Advisory Board, Research Funding; AbbVie: Consultancy, Other: Advisory Board, Research Funding; Biosight: Consultancy, Other: Travel fees, Research Funding; Daiichi Sankyo: Consultancy; Kura Oncology: Consultancy; Syros: Consultancy; Theradex: Consultancy, Other: Advisory boards; GlycoMimetics: Other: Participation on an advisory board; ALZ Oncology: Research Funding; Amgen: Research Funding; Aprea: Research Funding; BMS: Research Funding; Boehringer Ingelheim: Research Funding; Fujifilm: Research Funding; Immunogen: Research Funding; Kartos: Research Funding; Kura: Research Funding. OffLabel Disclosure: Venetoclax is a B-cell lymphoma 2 inhibitor approved in combination with azacitidine, or decitabine, or low-dose cytarabine for the treatment of newly-diagnosed acute myeloid leukemia (AML) in adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy. Gilteritinib is a kinase inhibitor indicated for the treatment of adult patients who have relapsed or refractory acute myeloid leukemia (AML) with an FLT3 mutation as detected by an FDA-approved test.

Background: The FMS-like tyrosine kinase 3 (FLT3) inhibitor gilteritinib (Gilt) improves survival compared with standard salvage chemotherapy in relapsed/refractory (R/R) FLT3-mutated (FLT3mut+) acute myeloid leukemia (AML); however, relapses are common and long-term survival remains poor. Combination therapies of FLT3 tyrosine kinase inhibitors (TKIs) with agents that induce apoptosis have demonstrated preclinical synthetic lethality and enhanced cytotoxicity against FLT3mut+ clones. This may delay or prevent drug resistance. We present updated data from the dose-escalation and expansion cohorts of an ongoing, multicenter, open-label, Phase 1b trial (NCT03625505) of Gilt in combination with B-cell lymphoma 2 (BCL-2) inhibitor venetoclax (Ven) in patients (pts) with R/R FLT3mut+ AML. Methods: Pts with R/R AML with ≥1 prior line of therapy and Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 were eligible. The expansion cohort required FLT3mut+ R/R AML at enrollment. Pts received the recommended Phase 2 dose (RP2D) of Ven 400 mg in combination with Gilt 120 mg daily in 28-day cycles, following a 3-day ramp-up of Ven. Pts with prior Gilt were excluded from expansion, and none were enrolled in dose escalation; prior Ven or other FLT3 inhibitor was permitted. Concurrent use of moderate or strong CYP3A4 inhibitor was allowed. Interruptions of Ven or both drugs simultaneously were permitted for management of adverse events (AEs), and subsequent cycles could include dose adjustments to minimize myelosuppression or other drug-related AEs. The primary endpoint was modified composite complete remission (mCRc; complete response [CR] + CR with incomplete platelet recovery [CRp] + CR with incomplete blood count recovery [CRi]) + morphologic leukemia-free state (MLFS). Responses were graded by the International Working Group (IWG) for AML criteria (with adapted CRi criteria as presented in the ADMIRAL trial) for comparison with composite CR (CRc) used in Gilt development. All criteria for response used by IWG were maintained in these response definitions. Secondary endpoints included CR + CR with partial hematologic recovery (CRh) and duration of response (DOR) of mCRc. Results: At data cutoff, April 15, 2020, 39 R/R pts started therapy at the RP2D (internal tandem duplications [ITD] only [n=32]; tyrosine kinase domain [TKD] mutation only [n=5]; both TKD and ITD [n=2]). Median age was 63 years (range 23-85) and the majority had an ECOG status of 1-2 (87.2%). Most pts (n=29; 74.4%) had received ≥2 prior lines of therapy, including ≥1 FLT3 TKI (n=25, 64.1%; midostaurin, n=19; sorafenib, n=5; crenolanib, n=1). Twelve pts (30.8%) had prior stem-cell transplant (SCT); 3 (7.7%) had received prior Ven. Grade ≥3 treatment-emergent AEs (TEAEs) were reported in 37 pts (94.9%), and 28 (71.8%) reported serious AEs. The only Grade 3/4 nonhematologic TEAE reported in &gt;20% of pts was febrile neutropenia (48.7%). Four pts (10.3%) experienced a fatal AE, including colitis, disease progression, multiple organ dysfunction syndrome, and bronchopulmonary aspergillosis (all n=1). AEs leading to Ven and Gilt interruptions occurred in 19 pts (48.7%) and 18 pts (46.2%), respectively, and AEs leading to dose reductions occurred in 2 pts (5.1%) for each treatment. Six pts (15.4 %) and 5 pts (12.8%) discontinued Ven and Gilt, respectively, owing to AEs. mCRc was achieved by 83.8% of pts (n=31/37; Table). With median duration of follow-up of 2.9 (range 0.8−11.0) months in all pts, median event-free survival was 5.1 (95% confidence interval: 2.8, 8.3) months but administrative censoring after short follow-up for a large number of recently enrolled patients limits interpretation; median DOR has not been reached. Eight pts (21.6%), all ITD only, proceeded to SCT. CR + CRh was achieved by 7 pts (18.9%). Conclusions: Ven plus Gilt achieved a very high overall rate of marrow and blood blast elimination and mCRc rate (84%) in this expansion cohort of heavily pretreated FLT3mut+ pts, the majority of whom had prior FLT3 TKI exposure. Using similar response assessment criteria, the high mCRc rate here suggests substantially greater antileukemic activity from Ven plus Gilt compared with single-agent Gilt. Cytopenias were prominent but manageable with dose interruption/modification on subsequent cycles. Nonhematologic toxicities were modest, and the combination was well tolerated. Disclosures Daver: Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Altman:AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Fujifilm: Research Funding; Astellas: Other: Advisory Board, Speaker (no payment), Steering Committee (no payment), Research Funding; Agios, Theradex, Abbvie: Other: Advisory Board; Astellas, Agios: Honoraria, Research Funding; Glycomimetics: Other: Data safety and monitoring committee; Daiichi Sankyo: Other: Advisory Board - no payment but was reimbursed for travel; Kura Oncology: Patents & Royalties: Scientific Advisory Board - no payment accepted; Biosight: Other: No payment but was reimbursed for travel . Levis:Menarini: Honoraria; Amgen: Honoraria; FujiFilm: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria; Astellas: Honoraria, Research Funding. Ritchie:Abbvie: Honoraria; Sierra Oncology: Honoraria; Incyte: Speakers Bureau; Novartis: Honoraria; Jazz pharmaceuticals: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. McCloskey:Amgen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Jazz: Consultancy, Honoraria. Smith:Abbvie: Other: Research Support, Research Funding; Sanofi: Honoraria; Astellas Pharma: Honoraria, Other: Research Support, Research Funding; FujiFilm: Other: Research support, Research Funding; Revolution Medicines: Other: Research Support, Research Funding; Daiichi Sanyko: Consultancy, Honoraria. Schiller:Johnson & Johnson: Current equity holder in publicly-traded company; Novartis: Consultancy, Research Funding; Sangamo: Research Funding; Tolero: Research Funding; Trovagene: Research Funding; Kaiser Permanente: Consultancy; Genentech-Roche: Research Funding; Geron: Research Funding; DeltaFly: Research Funding; Deciphera: Research Funding; Celator: Research Funding; FujiFilm: Research Funding; Ariad: Research Funding; Constellation: Research Funding; Cyclacel: Research Funding; Jazz Pharmaceuticals: Research Funding; Karyopharm: Research Funding; Kite Pharma: Research Funding; Mateon: Research Funding; MedImmune: Research Funding; Astellas Pharma: Honoraria, Research Funding; Actinium: Research Funding; Gamida: Research Funding; Bristol-Myers Squibb: Current equity holder in publicly-traded company, Research Funding; Daiichi Sankyo: Research Funding; Abbvie: Research Funding; Stemline: Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Ono Pharma: Consultancy; Forma: Research Funding; Incyte: Consultancy, Research Funding, Speakers Bureau; Gilead: Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Onconova: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Regimmune: Research Funding; Samus: Research Funding; Agios: Consultancy, Research Funding, Speakers Bureau; AstraZeneca: Consultancy; Sanofi: Speakers Bureau. Bradley:AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Tiu:Astellas Pharma Global Development: Current Employment; Eli Lilly & Company: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Hong:F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Tong:AbbVie, Inc.: Current Employment, Other: may hold stock or other options. Qin:AbbVie: Current Employment, Other: may hold stock or other options. Dilley:AbbVie Inc.: Current Employment, Other: may hold stock or stock options. Perl:Leukemia & Lymphoma Society.: Other; AbbVie Inc, Astellas, Actinium, Bayer HealthCare Pharmaceuticals, Daiichi Sankyo Inc, FUJIFILM Pharmaceuticals USA Inc: Research Funding; AbbVie Inc, Actinium Pharmaceuticals Inc, Astellas, Daiichi Sankyo Inc, FORMA Therapeutics, Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company, NewLink Genetics: Other; AbbVie Inc, Arog Pharmaceuticals Inc, Astellas, Daiichi Sankyo Inc: Consultancy; Astellas, AbbVie Inc, Daiichi Sankyo, Actinium, Forma, Syndax, Loxo: Consultancy, Honoraria. OffLabel Disclosure: Venetoclax is a B-cell lymphoma 2 inhibitor approved in combination with azacitidine, or decitabine, or low-dose cytarabine for the treatment of newly-diagnosed acute myeloid leukemia (AML) in adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy. Gilteritinib is a kinase inhibitor indicated for the treatment of adult patients who have relapsed or refractory acute myeloid leukemia (AML) with an FLT3 mutation as detected by an FDA-approved test.

Abstract Myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) are hematologically diverse stem cell malignancies sharing phenotypic features of both myelodysplastic syndromes and myeloproliferative neoplasms. There are currently no standard treatment recommendations for most adult patients with MDS/MPN. To optimize efforts to improve the management and disease outcomes, it is essential to identify meaningful clinical and biologic end points and standardized response criteria for clinical trials. The dual dysplastic and proliferative features in these stem cell malignancies define their uniqueness and challenges. We propose response assessment guidelines to harmonize future clinical trials with the principal objective of establishing suitable treatment algorithms. An international panel comprising laboratory and clinical experts in MDS/MPN was established involving 3 independent academic MDS/MPN workshops (March 2013, December 2013, and June 2014). These recommendations are the result of this collaborative project sponsored by the MDS Foundation.

Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem-cell disorders, characterized phenotypically by the abnormal accumulation of mature-appearing myeloid cells. Polycythemia vera, essential thrombocythemia, primary myelofibrosis (also known as ‘ BCR-ABL1-negative’ MPNs), and chronic myeloid leukemia (CML) are the primary types of MPNs. After the discovery of the BCR-ABL1 fusion protein in CML, several oncogenic tyrosine kinases have been identified in ‘ BCR-ABL1-negative’ MPNs, most importantly, JAK2V617F mutation. The similarity in the clinical characteristics of the BCR-ABL1-negative MPN patients along with the prevalence of the Janus kinase mutation in this patient population provided a strong rationale for the development of a new class of pharmacologic inhibitors that target this pathway. The first of its class, ruxolitinib, has now been approved by the food and drug administration (FDA) for the management of patients with intermediate- to high-risk myelofibrosis. Ruxolitinib provides significant and sustained improvements in spleen related and constitutional symptoms secondary to the disease. Although noncurative, ruxolitinib represents a milestone in the treatment of myelofibrosis patients. Other types of JAK2 inhibitors are being tested in various clinical trials at this point and may provide better efficacy data and safety profile than its predecessor. In this article, we comprehensively reviewed and summarized the available preclinical and clinical trials pertaining to JAK inhibitors.