Ruxolitinib for the treatment of myelofibrosis: its clinical potential

Ruxolitinib is an orally bioavailable, selective Janus kinase (JAK) 1 and 2 inhibitor approved for the treatment of myelofibrosis (MF), a bone marrow disease in which the JAK pathway is dysregulated, leading to impaired hematopoiesis and immune function. By inhibiting JAK1 and JAK2, ruxolitinib modulates cytokine-stimulated intracellular signaling. In a phase II clinical trial in patients with MF, ruxolitinib recipients exhibited durable reductions in spleen size, reductions in circulating pro-inflammatory cytokines, improvements in physical activity, weight gain, and alleviation of symptoms (including constitutional symptoms) in patients with and without JAK2 mutation. These findings were confirmed by two phase III clinical MF studies, in which a greater proportion of ruxolitinib recipients achieved a spleen volume reduction of ≥35% from baseline at week 24, compared with placebo in one study (41.9% versus 0.7%; P < 0.0001) and with best available therapy in the other (31.9% versus 0%; P < 0.0001). Alleviation of MF symptoms and improvements in quality of life were also significantly greater in ruxolitinib recipients. Overall survival of patients treated with ruxolitinib was significantly longer than of those receiving the placebo. Owing to risks of potentially serious adverse effects, eg, myelosuppression, ruxolitinib should be used under close physician supervision. Longer follow-up of the phase III MF studies is needed to reach firm conclusions regarding ruxolitinib’s capacity to modify the natural disease course

MOMENTUM: Momelotinib vs danazol in patients with myelofibrosis previously treated with JAKi who are symptomatic and anemic

Hallmark features of myelofibrosis (MF) are cytopenias, constitutional symptoms and splenomegaly. Anemia and transfusion dependency are among the most important negative prognostic factors and are exacerbated by many JAK inhibitors (JAKi). Momelotinib (MMB) has been investigated in over 820 patients with MF and possesses a pharmacological and clinical profile differentiated from other JAKi by inhibition of JAK1, JAK2 and ACVR1. MMB is designed to address the complex drivers of iron-restricted anemia and chronic inflammation in MF and should improve constitutional symptoms and splenomegaly while maintaining or improving hemoglobin in JAKi-naive and previously JAKi-treated patients. The MOMENTUM Phase III study is designed to confirm and extend observations of safety and clinical activity of MMB

Momelotinib long-term safety and survival in myelofibrosis: Integrated analysis of Phase 3 randomized controlled trials

Momelotinib is the first inhibitor of Janus kinase 1 (JAK1) and JAK2 shown to also inhibit activin A receptor type 1 (ACVR1), a key regulator of iron homeostasis, and has demonstrated improvements in splenomegaly, constitutional symptoms, and anemia in myelofibrosis (MF). This long-term analysis pooled data from 3 randomized phase 3 studies of momelotinib (MOMENTUM, SIMPLIFY-1, and SIMPLIFY-2), representing MF disease from early (JAK inhibitor-naive) to late (JAK inhibitor-experienced) stages. Patients in the control arms (danazol in MOMENTUM, ruxolitinib in SIMPLIFY-1, and best available therapy in SIMPLIFY-2) could cross over to receive momelotinib at the end of the 24-week randomized period, and all patients could continue momelotinib treatment after the completion of these studies via an extended access protocol (XAP). Across these studies, 725 patients with MF received momelotinib; 12% remained on therapy for ≥5 years, with a median treatment exposure of 11.3 months (range, 0.1-90.4 months). The most common nonhematologic treatment-emergent adverse event (AE) occurring in ≥20% of patients was diarrhea (any grade, 27% and grade ≥3, 3%). Any-grade thrombocytopenia, anemia, and neutropenia occurred in 25%, 23%, and 7% of patients, respectively. The most common reason for momelotinib discontinuation was thrombocytopenia (4% discontinuation rate). The incidence of AEs of clinical importance (eg, infections, malignant transformation, peripheral neuropathy, and hemorrhage) did not increase over time. This analysis of one of the largest randomized trial databases for a JAK inhibitor to date in MF demonstrated a consistent safety profile of momelotinib without long-term or cumulative toxicity. These trials were registered at www.clinicaltrials.gov as: MOMENTUM (#NCT04173494), SIMPLIFY-1 (#NCT01969838), SIMPLIFY-2 (#NCT02101268), and XAP (#NCT03441113)

The organic arsenic derivative GMZ27 induces PML-RARα-independent apoptosis in myeloid leukemia cells

Arsenic trioxide (ATO) is an inorganic arsenic derivative that is very effective against acute promyelocytic leukemia. However, organic arsenic derivatives (OAD) have a more favorable toxicity profile than ATO. We herein characterized dipropil-S-glycerol arsenic (GMZ27), a novel OAD. GMZ27 had potent antiproliferative activity against human acute myeloid leukemia (AML) cell lines that was higher than that of ATO. In contrast to ATO, GMZ27 only marginally induced maturation of leukemia cells and had no effect on the cell cycle. The anti-leukemia activity of GMZ27 against AML cells was independent of the presence of the PML-RARα fusion protein. GMZ27 dissipates mitochondrial transmembrane potential, and induces cleavage of caspase 9 and activation of caspase 3 without altering the expression levels of (BCL-2), BAX and BCL-xl. GMZ27 induces the formation of intracellular superoxide, a reactive oxygen species (ROS) which plays a major role in the antileukemia activity of this OAD. In addition to ROS generation, GMZ27 concomitantly reduces intracellular glutathione which markedly weakens the cellular antioxidant capacity, thus enhancing the detrimental intracellular effects of ROS production. These results indicate that GMZ27 induces apoptosis in AML cells in a PML-RARα-independent fashion, through the induction of ROS production. This activity provides the rationale for the testing of GMZ27 in patients with AML

Outcome of patients with Philadelphia chromosome-positive chronic myelogenous leukemia post-imatinib mesylate failure

BACKGROUND. The prognosis of patients with chronic myelogenous leukemia (CML) after failure of imatinib mesylate therapy is not well documented. METHODS. The outcome of 420 patients with CML post-imatinib failure (resistance-recurrence in 374; toxicities in 46) were reviewed in relation to survival, overall, and by different therapies. RESULTS. The estimated 3-year survival rates were 72% in 88 patients who progressed in chronic phase, 30% in 130 patients who progressed in accelerated phase, 7% in 156 patients who progressed in blastic phase, and 75% in 37 patients in chronic phase with imatinib intolerance. Survival in chronic phase was better when subsequent therapy was nilotinib or dasatinib vs allogeneic stem cell transplant vs others (estimated 2-year survival rates 100% vs 72% vs 67%; P = .01), but not in accelerated-blastic phase. CONCLUSIONS. Prognosis post-imatinib failure in chronic phase is reasonable; it is poor if the CML phase post-imatinib failure is accelerated or blastic. Cancer 2007. © 2007 American Cancer Society.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/55988/1/22569_ftp.pd

Retrospective analysis of pacritinib in patients with myelofibrosis and severe thrombocytopenia

Thrombocytopenia is common in patients with myelofibrosis (MF) and is a well-established adverse prognostic factor. Both of the approved Janus kinase (JAK) inhibitors, ruxolitinib and fedratinib, can worsen thrombocytopenia and have not been evaluated in patients with severe thrombocytopenia (platelet counts \u3c50×109/L). Pacritinib, a novel JAK2/interleukin-1 receptor-associated kinase 1 inhibitor, has been studied in two phase III trials (PERSIST-1 and PERSIST- 2), both of which enrolled patients with MF and severe thrombocytopenia. In order to better characterize treatment outcomes for this population with advanced disease, we present a retrospective analysis of efficacy and safety data in the 189 patients with severe thrombocytopenia treated in the PERSIST studies. The proportion of patients in the pacritinib group meeting efficacy endpoints was greater than in the BAT group for ≥35% spleen volume reduction (23% vs. 2%, P=0.0007), ≥50% modified Total Symptom Score reduction (25% vs. 8%, P=0.044), and self-reported symptom benefit ( much or very much improved; 25% vs. 8%, P=0.016) at the primary analysis time point (week 24). The adverse event profile of pacritinib was manageable, and dose modification was rarely required. There was no excess in bleeding or death in pacritinib-treated patients. These results indicate that pacritinib is a promising treatment for patients with MF who lack safe and effective therapeutic options due to severe thrombocytopenia

Changes in quality of life and disease-related symptoms in patients with polycythemia vera receiving ruxolitinib or standard therapy

Objectives Polycythemia vera (PV)-related symptoms may not be adequately controlled with conventional therapy. This current analysis of the RESPONSE trial evaluated the effects of ruxolitinib compared with standard therapy on quality of life (QoL) and symptoms in patients with PV who were hydroxyurea resistant/intolerant. Methods In the previously reported primary analysis, ruxolitinib achieved the primary composite endpoint of hematocrit control and ≥35% reduction in spleen volume at Week 32. The current analysis evaluated patient-reported outcomes using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF), the Pruritus Symptom Impact Scale (PSIS), and the Patient Global Impression of Change (PGIC). Results Compared with standard therapy, ruxolitinib was associated with greater improvements in global health status/QoL, functional subscales, and individual symptom scores of the EORTC QLQ-C30. At Week 32, more patients in the ruxolitinib arm (44%) achieved a ≥10-point improvement in global health status/QoL vs. standard therapy (9%). Improvements in MPN-SAF symptom scores were consistent with improvements in EORTC QLQ-C30, PSIS, and PGIC scores. Conclusions Ruxolitinib provides clinically relevant improvements in QoL and ameliorates symptom burden in patients with PV who are hydroxyurea resistant/intolerant

Notch-dependent repression of miR-155 in the bone marrow niche regulates hematopoiesis in an NF-κB-dependent manner

The microRNA miR-155 has been implicated in regulating inflammatory responses and tumorigenesis, but its precise role in linking inflammation and cancer has remained elusive. Here, we identify a connection between miR-155 and Notch signaling in this context. Loss of Notch signaling in the bone marrow (BM) niche alters hematopoietic homeostasis and leads to lethal myeloproliferative-like disease. Mechanistically, Notch signaling represses miR-155 expression by promoting binding of RBPJ to the miR-155 promoter. Loss of Notch/RBPJ signaling upregulates miR-155 in BM endothelial cells, leading to miR-155-mediated targeting of the nuclear factor κB (NF-κB) inhibitor κB-Ras1, NF-κB activation, and increased proinflammatory cytokine production. Deletion of miR-155 in the stroma of RBPJ(-/-) mice prevented the development of myeloproliferative-like disease and cytokine induction. Analysis of BM from patients carrying myeloproliferative neoplasia also revealed elevated expression of miR-155. Thus, the Notch/miR-155/κB-Ras1/NF-κB axis regulates the inflammatory state of the BM niche and affects the development of myeloproliferative disorders

Heterodimeric JAK-STAT Activation as a Mechanism of Persistence to JAK2 Inhibitor Therapy

The identification of somatic activating mutations in JAK21–4 and in the thrombopoietin receptor (MPL)5 in the majority of myeloproliferative neoplasm (MPN) patients led to the clinical development of JAK2 kinase inhibitors6,7. JAK2 inhibitor therapy improves MPN-associated splenomegaly and systemic symptoms, but does not significantly reduce or eliminate the MPN clone in most MPN patients. We therefore sought to characterize mechanisms by which MPN cells persist despite chronic JAK2 inhibition. Here we show that JAK2 inhibitor persistence is associated with reactivation of JAK-STAT signaling and with heterodimerization between activated JAK2 and JAK1/TYK2, consistent with activation of JAK2 in trans by other JAK kinases. Further, this phenomenon is reversible, such that JAK2 inhibitor withdrawal is associated with resensitization to JAK2 kinase inhibitors and with reversible changes in JAK2 expression. We saw increased JAK2 heterodimerization and sustained JAK2 activation in cell lines, murine models, and patients treated with JAK2 inhibitors. RNA interference and pharmacologic studies demonstrate that JAK2 inhibitor persistent cells remain dependent on JAK2 protein expression. Consequently, therapies that result in JAK2 degradation retain efficacy in persistent cells and may provide additional benefit to patients with JAK2-dependent malignancies treated with JAK2 inhibitors