Although rare, chronic myeloid leukemia (CML) represents an important paradigm for understanding the molecular events leading to malignant transformation of primitive hematopoietic progenitors. CML was the first cancer to be associated with a defined genetic abnormality, BCR-ABL, that is necessary and sufficient for initiating chronic phase disease as well as the first cancer to be treated with molecular targeted therapy. Malignant progenitors or leukemia stem cells (LSCs) evolve as a result of both epigenetic and genetic events that alter hematopoietic progenitor differentiation, proliferation, survival, and self-renewal. LSCs are rare and divide less frequently, and thus, represent a reservoir for relapse and resistance to a molecularly targeted single agent. On subverting developmental processes normally responsible for maintaining robust life-long hematopoiesis, the LSCs are able to evade the majority of current cancer treatments that target rapidly dividing cells. Enthusiasm for the enormous success of tyrosine kinase inhibitors at controlling the chronic phase disease is tempered somewhat by the persistence of the LSC pool in the majority of the patients. Combined therapies targeting aberrant properties of LSC may obviate therapeutic resistance and relapse in advanced phase and therapeutically recalcitrant CML.
• Presented are results from the phase 2 dose-expansion study of the combination of carfilzomib, lenalidomide, and dexamethasone (CRd).• CRd was well tolerated with robust, rapid, and durable responses.We previously reported a phase 1b dose-escalation study of carfilzomib, lenalidomide, and low-dose dexamethasone (CRd) in relapsed or progressive multiple myeloma where the maximum planned dose (MPD) was carfilzomib 20 mg/m 2 days 1 and 2 of cycle 1 and 27 mg/m 2 days 8, 9, 15, 16, and thereafter; lenalidomide 25 mg days 1 to 21; and dexamethasone 40 mg once weekly on 28-day cycles. Herein, we present results from the phase 2 dose expansion at the MPD, focusing on the 52 patients enrolled in the MPD cohort. Median follow-up was 24.4 months. In the MPD cohort, overall response rate (ORR) was 76.9% with median time to response of 0.95 month (range, 0.5-4.6) and duration of response (DOR) of 22.1 months. Median progression-free survival was 15.4 months. ORR was 69.2% in bortezomib-refractory patients and 69.6% in lenalidomide-refractory patients with median DOR of 22.1 and 10.8 months, respectively. A median of 9.5 (range, 1-45) carfilzomib cycles were started with 7.7% of patients requiring carfilzomib dose reductions and 19.2% discontinuing CRd due to adverse events (AEs). Grade 3/4 AEs included lymphopenia (48.1%), neutropenia (32.7%), thrombocytopenia (19.2%), and anemia (19.2%). CRd at the MPD was well tolerated with robust, rapid, and durable responses. This trial was registered at clinicaltrials.gov as #NCT00603447. (Blood. 2013;122(18):3122-3128) IntroductionOver the past 15 years, patients with multiple myeloma (MM) have experienced significant gains in survival, yet nearly all patients will eventually relapse and succumb to their disease.1 Triplet combinations with targeted agents (eg, bortezomib with thalidomide or lenalidomide and dexamethasone) have been shown to improve response rates, disease control, and survival outcomes compared with doublet combinations in patients with MM, including those with advanced or high-risk disease.2-5 These combinations, however, have also been associated with increased toxicity.For instance, in recent phase 1/2 studies, the combination of bortezomib, lenalidomide, and high-dose dexamethasone (RVD) was shown to be highly efficacious in both the newly diagnosed and the relapsed/refractory settings, but there were high rates for some types of adverse events (AEs) that are associated with the individual agents, including neutropenia (lenalidomide) and peripheral neuropathy (bortezomib). 6,7 Similarly, in a recent phase 3 study by the European Group for Blood and Marrow Transplantation (EBMT), the addition of bortezomib to the combination of thalidomide and dexamethasone (VTD) significantly improved the primary end point of time to progression compared with the combination of thalidomide and dexamethasone (TD) alone (19.5 vs 13.8 months; P 5 .001) in patients with relapsed or progressive MM, but was also associated with a higher incidence of grade 3/4 AEs (71% vs 57%; P 5...
Polycythemia Vera (PV) is a myeloproliferative disorder (MPD) that is commonly characterized by mutant JAK2 (JAK2V617F) signaling, erythrocyte overproduction, and a propensity for thrombosis, progression to myelofibrosis, or acute leukemia. In this study, JAK2V617F expression by human hematopoietic progenitors promoted erythroid colony formation and erythroid engraftment in a bioluminescent xenogeneic immunocompromised mouse transplantation model. A selective JAK2 inhibitor, TG101348 (300 nM), significantly inhibited JAK2V617F + progenitor-derived colony formation as well as engraftment (120 mg/kg) in xenogeneic transplantation studies. TG101348 treatment decreased GATA-1 expression, which is associated with erythroid-skewing of JAK2V617F + progenitor differentiation, and inhibited STAT5 as well as GATA S310 phosphorylation. Thus, TG101348 may be an effective inhibitor of JAK2V617F + MPDs in clinical trials.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.