Abstract
Cyclin-dependent kinases (CDKs) control cell cycle progression in proliferating cells and are commonly dysregulated in acute leukemias. Inactivation or repression of the INK4 inhibitors p16 or p15 leading to over-activity of CDK4/6 has been described in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). There is compelling data that several subtypes of leukemia may rely predominantly on activation of the CDK4/6 pathway for survival and be exquisitely sensitive to its inhibition. CyclinD-CDK4/6 axis is a downstream effector of FLT3 signaling and pharmacologic inhibition with a selective CDK4/6 inhibitor led to G1 cell-cycle arrest, and reduced proliferation (Wang 2007). An RNAi screen in an MLL leukemia cell line identified CDK6 as critical for its survival and pharmacologic inhibition using a CDK4/6 inhibitor demonstrated growth arrest and differentiation (Placke 2014). Inhibition of the Cyclin D3-CDK4/6 axis has also been shown to be important in T-cell ALL (Sawai 2012).
We designed an investigator-initiated phase I clinical trial to study the safety and feasibility of the oral CDK4/6 inhibitor palbociclib (palbo) alone (during cycle 1) and then in rational combinations (cycle 2 onward). Patients aged >/= 15 yrs, with R/R AML or R/R ALL and adequate organ function were eligible. There were 3 combination arms: (A) sorafenib 400mg PO BID on D1-28, (B) decitabine 20 mg/m2 IV on D8-17, and (C) dexamethasone (dex) 40mg on D1-4 & 11-14. Patients were assigned to an arm at enrollment by physician choice; only R/R ALL pts were eligible for arm C. During cycle 1 (28 days) all patients received palbo 125mg PO on D1-28. Hydrea was allowed for proliferative disease. Starting cycle 2, pts continued palbo along with their assigned combination (A,B, or C). The primary endpoint was safety and secondary endpoints included efficacy & biomarker analysis.
Twelve R/R pts, with a median of 4 (range, 2-11) prior therapies, were enrolled: 10 (83%) with AML, 1 (8%) with B-ALL, and 1 (8%) with T-ALL. The median age was 48 yrs (17-86) and pts received a median of 2 (2-4) cycles of therapy on protocol. Figure 1 summarizes the baseline patient characteristics and mutational landscape. Single-agent palbociclib was well tolerated. All pts had myelosuppression related to their disease. Drug related non-heme adverse events (AEs) included fatigue (G2), diarrhea (G2), and nausea (G1). Non-heme AEs on the trial, regardless of attribution, are summarized in Table 1. 6 pts (50%) had progressive disease or died prior to starting cycle 2. Of the 6 pts who proceeded to the combination cycle, 1 (17%) went on arm A, 3 (50%) went on arm B, and 2 (33%) went on arm C. No DLTs have been observed with the combinations. Two AML pts treated with decitabine + palbo had >50% reduction in bone marrow blasts. A T-ALL pt treated with dex + palbo had significant decrease in bulky extramedullary disease. One patient treated with sorafenib + palbo has had decline in peripheral blasts, but is too early for objective response assessment.
Palbo is well tolerated, but has minimal single-agent activity in non-MLL rearranged R/R acute leukemia. Combinations with palbociclib appear to be feasible and show early signs of response in pts with R/R acute leukemias. Further investigation will continue with combination strategies in this difficult population. Pharmacodynamic analysis of patient samples is ongoing.
Kadia:Takeda: Consultancy; Celgene: Research Funding; Celgene: Research Funding; Abbvie: Consultancy; Novartis: Consultancy; Jazz: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; BMS: Research Funding; Novartis: Consultancy; Jazz: Consultancy, Research Funding; Takeda: Consultancy; BMS: Research Funding; Pfizer: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Abbvie: Consultancy. Konopleva:Stemline Therapeutics: Research Funding; abbvie: Research Funding; cellectis: Research Funding; Immunogen: Research Funding. Wierda:Genentech: Research Funding; AbbVie, Inc: Research Funding. Bose:Pfizer, Inc.: Research Funding; Blueprint Medicines Corporation: Research Funding; Celgene Corporation: Honoraria, Research Funding; Astellas Pharmaceuticals: Research Funding; Incyte Corporation: Honoraria, Research Funding; Constellation Pharmaceuticals: Research Funding; CTI BioPharma: Research Funding. Jabbour:novartis: Research Funding. Pemmaraju:plexxikon: Research Funding; celgene: Consultancy, Honoraria; cellectis: Research Funding; stemline: Consultancy, Honoraria, Research Funding; novartis: Research Funding; samus: Research Funding; abbvie: Research Funding; daiichi sankyo: Research Funding; Affymetrix: Research Funding; SagerStrong Foundation: Research Funding. Jain:Pfizer: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Celgene: Research Funding; Abbvie: Research Funding; Pharmacyclics: Research Funding; ADC Therapeutics: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Genentech: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Research Funding; BMS: Research Funding; Infinity: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Pfizer: Research Funding; Abbvie: Research Funding; Incyte: Research Funding; Servier: Research Funding; Verastem: Research Funding; Celgene: Research Funding; Cellectis: Research Funding; Adaptive Biotechnologioes: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cortes:novartis: Research Funding. Ravandi:Jazz: Honoraria; Jazz: Honoraria; Abbvie: Research Funding; Macrogenix: Honoraria, Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Macrogenix: Honoraria, Research Funding; Seattle Genetics: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Sunesis: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Orsenix: Honoraria; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Orsenix: Honoraria; Sunesis: Honoraria; Bristol-Myers Squibb: Research Funding; Abbvie: Research Funding; Xencor: Research Funding; Xencor: Research Funding.
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