Category Archives: Research

Efficacy of a JAK2/mTOR Inhibitor Combination in Controlling Acute Graft-vs-Host Disease

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By The ASCO Post Staff
Posted: 8/8/2024

Adding a Janus kinase 2 (JAK2) inhibitor to standard immunosuppressive drugs may not improve prevention of acute graft-vs-host disease in patients with hematologic malignancies undergoing treatment with allogeneic hematopoietic cell transplantation, according to a recent study published by Pidala et al in Blood.

Background

Hematopoietic cell transplantation may offer a potential cure in patients with hematologic malignancies; however, between 10% and 20% of patients who receive stem cells from a donor through allogeneic hematopoietic cell transplantation develop acute graft-vs-host disease within the first 100 days following transplant. This condition occurs when a donor’s immune cells identify the patient’s cells as foreign and attack them. Apart from disease recurrence, graft-vs-host disease can be life threatening and greatly impact a patient’s quality of life posttransplant.

While JAK inhibition is often effective in treating graft-vs-host disease—the JAK1/2 inhibitor ruxolitinib is indicated for the treatment of refractory graft-vs-host disease—the researchers conducting the recent trial addressed whether JAK inhibitors could have a role in graft-vs-host disease prophylaxis. JAK2 inhibitors are capable of turning off the JAK2 gene—which promotes inflammation and contributes to the development of graft-vs-host disease.

“JAK inhibitors are active in treating [graft-vs-host disease] that does not respond to steroids,” explained senior study author Brian Betts, MD, Vice Chair of Strategic Initiatives for Transplant & Cellular Therapy at the Roswell Park Comprehensive Cancer Center. “But the question over the past 10 years has been whether JAK inhibition could prevent [graft-vs-host disease],” he added.

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Cardiovascular Risk in Philadelphia-Negative Myeloproliferative Neoplasms: Mechanisms and Implications—A Narrative Review

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by Samuel Bogdan Todor, Cristian Ichim, Adrian Boicean, and Romeo Gabriel Mihaila

Abstract

Myeloproliferative neoplasms (MPNs), encompassing disorders like polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are characterized by clonal hematopoiesis without the Philadelphia chromosome. The JAK2 V617F mutation is prevalent in PV, ET, and PMF, while mutations in MPL and CALR also play significant roles. These conditions predispose patients to thrombotic events, with PMF exhibiting the lowest survival among MPNs. Chronic inflammation, driven by cytokine release from aberrant leukocytes and platelets, amplifies cardiovascular risk through various mechanisms, including atherosclerosis and vascular remodeling. Additionally, MPN-related complications like pulmonary hypertension and cardiac fibrosis contribute to cardiovascular morbidity and mortality. This review consolidates recent research on MPNs’ cardiovascular implications, emphasizing thrombotic risk, chronic inflammation, and vascular stiffness. Understanding these associations is crucial for developing targeted therapies and improving outcomes in MPN patients.

Underreporting of Patient-Reported Outcomes Seen in Blood Cancer Trials

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Caleb Rans, PharmD

The incorporation of patient-reported outcomes (PROs) in clinical trials provides a means for researchers to measure health-related quality of life (HRQOL) and patient-specific outcomes. When evaluating subjective symptoms, for example, patients are usually the most reliable source of feedback. Consequently, PROs are seen as the gold standard for assessing subjective symptoms.1

According to the authors, PROs are not often collected or reported in solid tumor trials, but less is known about RCTs focusing on blood cancers.2

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Prospective Study to Evaluate Fedratinib Plus Nivolumab in Myelofibrosis

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Andrea S. Blevins Primeau, PhD, MBA

A single-arm, phase 2 study of fedratinib, a selective JAK2 inhibitor, plus nivolumab is planned for patients with myelofibrosis (MF) who had a suboptimal or no response to a JAK inhibitor was initiated, according to a report published in the Annals of Hematology.

“This study will provide new findings that may contribute to advancing the treatment landscape for MF patients with suboptimal responses and limited alternatives,” the researchers wrote in their report. Currently, 23 of 30 planned patients are enrolled in the study and recruitment is expected to be completed by December 2024.

The open-label FRACTION trial will treat patients with MF from 9 academic centers in Germany, who will receive 400 mg of fedratinib daily in 28-day cycles, followed by 240 mg of nivolumab every 2 weeks beginning in cycle 2. Treatment will be given until progressive disease, relapse, death, or study discontinuation.

This study will provide new findings that may contribute to advancing the treatment landscape for MF patients with suboptimal responses and limited alternatives.

The primary efficacy endpoints will be response rate within 12 treatment cycles and RCT independency. Secondary endpoints will include safety, incidence of leukemic transformation, clinical benefit, duration of response, progression-free survival, overall survival, and disease burden. Molecular analyses will also serve as exploratory endpoints for the study.

Patients with MF primary or secondary MF are eligible if they had a suboptimal or no response to a JAK inhibitor, which is defined by persistent symptoms, splenomegaly, cytopenia, or hyperproliferation. Patients who have received a prior immune checkpoint inhibitor or history of uncontrolled autoimmune disease are not eligible for the study.

Disclosures: This research was supported in part by Celgene/Bristol Myers Squibb. Please see the original reference for a full list of disclosures.

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High Neutrophil Ratio as a Thrombosis Predictor in Myeloproliferative Neoplasms

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July 24, 2024

The following is a summary of “Predictive significance of high neutrophil ratio for thrombosis in myeloproliferative neoplasms: JSH-MPN-R18 subanalysis,” published in the July 2024 issue of Hematology by Nagaharu et al.

A nationwide study was conducted to identify clinical features of thrombosis in patients with myeloproliferative neoplasms to inform risk-based treatment strategies.

Researchers conducted a retrospective study to determine which complete blood count (CBC) parameters predicted thrombosis in patients with myeloproliferative neoplasms.

They investigated patients from JSH-MPN-R18, focusing on essential thrombocythemia (ET; n = 1152) and polycythemia vera (PV; n = 456). Using Welch’s T-test, the CBC parameters were compared with those with or without thrombotic events. Statistical analyses were conducted with R software.

The results showed that 74 patients with ET experienced thrombotic events. In multivariate analysis, patients with ET and thrombosis had a slightly but significantly higher neutrophil ratio compared to those without thrombosis (P<0.05). The absolute neutrophil count (aNeu) emerged as a valuable predictor for thrombosis in patients with low-risk according to the revised International Prognostic Score of Thrombosis for ET. Among patients with PV, those with thrombosis had notably higher hematocrit and aNeu levels than those without thrombosis. Additionally, the neutrophil ratio was slightly but significantly higher in patients with ET with thrombosis, potentially reflecting a greater JAK2 V617F allelic frequency, though was not detailed in JSH-MPN-R18.

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Dr Watts on the Investigation of INCB057643 in Advanced Myelofibrosis and MPN

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July 24, 2024

Author(s): Justin M. Watts, MD

Justin M. Watts, MD, associate professor of medicine, Division of Hematology, chief, Leukemia Section, University of Miami Sylvester Comprehensive Cancer Center, discusses the design of a phase 1 trial (NCT04279847) investigating INCB057643 in patients with advanced myelofibrosis and other myeloid neoplasms, and highlights how this agent could address unmet needs in patients with relapsed/refractory myeloproliferative neoplasms (MPNs).

INCB057643 is an oral small molecule BET inhibitor that most selectively targets BRD-4, he begins. The agent is being evaluated in a phase 1 dose-escalation and -expansion study of patients with advanced myelofibrosis, including those with relapsed/refractory myelofibrosis and patients who are suboptimal responders to ruxolitinib (Jakafi), Watts details. Patients in the former group received the BET inhibitor as a monotherapy; those in the latter cohort received the agent as an add-on therapy, he explains.

Findings from the study were reported at the 2024 ASCO Annual Meeting, and demonstrated that INCB057643 when used as a monotherapy (n = 28) or in combination with ruxolitinib (n = 16), was generally well tolerated at doses ranging from 4 mg to 10 mg.

The maximum tolerated dose of the agent was established at 10 mg per day, Watts continues. INCB057643 monotherapy is currently being evaluated in a dose-expansion phase, with the combination regimen being assessed in the dose escalation phase at 8 mg, he reports. Watts notes that 8 mg is likely to be the optimal dose of INCB057643 when administered alongside ruxolitinib. During the dose expansion phases, different dosing of the BET inhibitor is permitted based on a patient’s platelet count, Watts says. This cohort includes both patients with myelofibrosis and those with essential thrombocythemia who have progressed on standard therapy, he states.

Initially, the dose escalation phase of the trial included a cohort of patients with myelodysplastic syndromes (MDS) and MDS/MPN overlap syndrome, Watts expands. However, the study’s focus has since shifted exclusively to patients with advanced myelofibrosis due to the significant unmet needs present in this patient population, Watts says. Many patients with advanced myelofibrosis have progressed on multiple lines of therapy or are completely intolerant or refractory to JAK inhibition, he explains. Accordingly, enhancing their response to therapy, reducing toxicities, decreasing spleen size beyond what can be achieved with ruxolitinib alone, and concurrently addressing anemia could benefit these patients, Watts concludes.

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Pelabresib/Ruxolitinib Data Underscore Need for Novel End Points in Myelofibrosis Trials

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July 15, 2024

Author(s): Jax DiEugenio

Although a 35% reduction in spleen volume (SVR35) and a 50% reduction in total symptom score (TSS50) have been established as key end points in clinical trials evaluating therapies for the treatment of patients with myelofibrosis, integrating end points such as overall survival (OS) and progression-free survival (PFS) as key objectives in future studies could help guide drug development and measure any disease-modifying properties of treatments, according to Aaron Gerds, MD.

“[Findings] from [the phase 3] MANIFEST-2 [NCT04603495] and TRANSFORM-1 [NCT04472598] trials are a wakeup call for the field that we need to move beyond SVR35 and TSS50 [as clinical trial end points in myelofibrosis]. We have drugs that are good at making patients’ symptoms better; however, we need are drugs that truly modify the disease course in a meaningful way,” Gerds explained.

Updated data from the MANIFEST-2 presented at the 2024 ASCO Annual Meeting showed that patients with myelofibrosis who received frontline pelabresib (CPI-0610) plus ruxolitinib (Jakafi; n = 214) experienced an SVR35 rate of 65.9% at week 24 compared with 35.2% for those given ruxolitinib plus placebo (n = 216). Notably, updated data showed that in patients who experienced an SVR35 at any time, 13.4% of patients in the experimental arm lost that response vs 27.8% of patients in the placebo arm.1

Additionally, the TSS50 rates at week 24 were 52.3% for pelabresib plus ruxolitinib vs 46.3% for placebo plus ruxolitinib, translating to a numerical improvement that was not statistically significant (difference, 6.0%; 95% CI, –3.5% to 15.5%; nominal P = .216).

Notably, 40.2% of patients in the pelabresib arm experienced both SVR35 and TSS50 at week 24 compared with 18.5% of patients in the placebo arm.

In an interview with OncLive®, Gerds an assistant professor of medicine, Hematology, and Medical Oncology at Cleveland Clinic Taussig Cancer Institute in Ohio, detailed prior data from MANIFEST-2 presented at the 2023 ASH Annual Meeting;2 expanded on updated data presented at the 2024 ASCO Annual Meeting; and emphasized the need to look beyond current end points in clinical trials evaluating treatments for patients with myelofibrosis.

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Ropeginterferon alfa-2b shows anti-polycythaemia vera activity without causing clinically significant anaemia

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Keita Kirito, Albert Qin, Shanshan Suo, Rongfeng Fu, Daoxiang Wu, Toshiaki Sato, Oleh Zagrijtschuk, Kazuya Shimoda, Norio Komatsu & Jie Jin

July 11, 2o24

Polycythaemia vera (PV) is a Philadelphia chromosome-negative myeloproliferative neoplasm (MPN) that, in most cases, harbour the Janus kinase 2 gene (JAK2) driver mutation JAK2V617F [1]. PV is characterised by an over-production of blood cells with increased haematocrit levels, which is a risk factor for thrombotic events (TEs) and cardiovascular mortality [1, 2]. Low-dose aspirin and phlebotomy are usually recommended for patients with low-risk PV (i.e., no history of thrombosis and age ≤60 years). The National Comprehensive Cancer Network (NCCN) recommends ropeginterferon alfa-2b (BESREMi®) as a preferred cytoreductive treatment for patients with low- or high-risk PV [3].

Ropeginterferon alfa-2b is a novel polyethylene glycol (PEG)-conjugated recombinant proline-interferon alpha (IFN-a) with a favourable in vivo pharmacokinetic (PK) profile [4, 5]. Ropeginterferon alfa-2b has demonstrated substantial anti-PV clinical activity, including complete haematologic response (CHR; defined as a haematocrit <45% without phlebotomy, a platelet count ≤ 400 × 109/L, and a white blood cell count ≤10 × 109/L) and a reduction in the JAK2V617F allele burden [6,7,8,9]. Ropeginterferon alfa-2b injection is approved for adult patients with PV at an initial dose of 100 µg (or 50 µg for patients already receiving cytoreductive therapy) with 50 µg incremental intrapatient increases in the dose up to a maximum recommended dose of 500 µg every two weeks. It can take several months to reach the plateau dose level [6]. An alternative dosing regimen with a higher starting dose of 250 µg and simpler intrapatient dose escalation to 500 µg every two weeks with flexible dose adjustment according to tolerability was explored as a treatment option. This regimen controlled PV effectively, as defined by the CHR, and was associated with a shorter time to achieve a CHR [8, 9]. In this report, we aimed to examine the data from the approved slow-dose titration and exploratory higher starting dose regimens focusing on the dynamics of haemoglobin (Hgb) and the occurrence of anaemia. Anaemia is important in the context of PV treatment for several reasons. First, patients who undergo frequent phlebotomy may suffer from symptomatic iron deficiency, leading to anaemia [10]. Anaemia and symptoms can negatively affect the patient well-being and should be avoided in patients with PV and MPNs. The symptoms include headache, insomnia, concentration difficulties, dizziness, restless legs and may coincide and potentiate the disease-related symptoms of the underlying MPN [11,12,13]. Commonly used agents in the PV treatment cause anaemia in substantial numbers of cases ranging from 18% with hydroxyurea (HU) [14] to 72% with ruxolitinib [11, 15]. Anaemia is symptomatic in many cases and may limit the treatment dose or lead to treatment interruption if uncontrolled or severe cases are present. Association between venous thromboembolism and iron-deficiency anaemia has also been shown [16]. Thus, having an agent that can effectively control the elevated haematocrit without excessively suppressing the normal erythropoiesis is a major therapeutic advantage.

An important question regarding ropeginterferon alfa-2b in this context is whether the control of haematocrit is commonly accompanied by clinically significant anaemia, i.e., at the ≥grade 3 level or at the moderate, grade 2 level, but the anaemia is persistent and unmanageable. We therefore performed a retrospective analysis of the effect of ropeginterferon alfa-2b on Hgb levels at various time points or on the occurrence of anaemia with the data available from our two prospective clinical studies in patients with PV.

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Immunofluorescence microscopy on the blood smear identifies patients with myeloproliferative neoplasms

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July 17, 2024

Carlo Zaninetti, Leonard Vater, Lars Kaderali, Carl C. Crodel, Tina M. Schnöder, Jessica Fuhrmann, Leonard Swensson, Jan Wesche, Carmen Freyer, Andreas Greinacher & Florian H. Heidel

Myeloproliferative neoplasms (MPN) are a group of clonal stem cell disorders with heterogeneous clinical presentation [1]. Due to the risk of severe thromboembolic complications and disease progression, the early recognition of an MPN prior to the appearance of clinical complications is clearly warranted to facilitate early pharmacologic intervention [2,3,4]. Detection of the somatic mutations by genotyping has become an essential part of the diagnostic work-up of suspected subjects, as well as of the risk stratification after the diagnosis of MPN has been confirmed [5]. However, in many parts of the world molecular testing is barely affordable.

We have established an immunofluorescence microscopy (IF)-based method for platelet phenotyping on the peripheral blood smear [6]. This method has been proven to be highly efficient in the diagnosis of diverse hereditary platelet disorders by recognizing disease-specific changes of cell structures, including alterations of leukocytes and red blood cells (RBC) [7, 8]. Major advantages of this approach are the need of small amounts of blood (<100 μL) and the possibility to send the blood films by regular mail even long distances.

It is well-known that morphology of peripheral blood cells is also often altered in MPN [9, 10]. However, due to different methods and the heterogeneity of the patients’ populations, results are difficult to compare.

In the present study, we aimed at assessing platelet phenotype using our IF method in a cohort of patients diagnosed with MPN. The study has been registered in the German Clinical Trials Register (DRKS-ID: DRKS00032588). Three German reference centers for diagnosis and treatment of MPN took part in the study: Internal Medicine C, University Medicine Greifswald; Internal Medicine 2, University Hospital Jena; and Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Germany. The study protocol was approved by the institutional review boards of all centers. Patients or their legal guardians signed written informed consent to the investigation, which was conducted according to the Declaration of Helsinki. Healthy controls were enrolled among blood donors at the Institute for Transfusion Medicine, University Medicine Greifswald, Germany.

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Ph- MPN in Adolescent and Young Adult Patients

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June 26, 2024

Elizabeth L. Courville, MD

England JT, Szuber N, Sirhan S, et al. Clinical features and long-term outcomes of a pan-Canadian cohort of adolescents and young adults with myeloproliferative neoplasms: a Canadian MPN group study. Leukemia. 2024;38(3):570-578.

The classical BCR:: ABL1-negative myeloproliferative neoplasms (Ph- MPNs) polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) are typically diseases of older adults, with a median age at diagnosis within the sixth decade of life. In two large case series from cancer centers in the United States, adolescent and young adult (AYA) patients were reported to account for 11 to 12% of the Ph- MPNs evaluated.1,2  The data on AYA patients with Ph- MPNs is less robust than that available for their older counterparts, and this patient population may not be represented in cohorts used to develop prognostic scoring systems.

Recently, James T. England, MD, MSc, and colleagues investigated the clinical features and long-term outcomes of a cohort of 609 patients (17 pediatric patients aged <18 years and 592 patients aged 18-45 years) with Ph- MPNs from across eight participating centers in Canada. Initial diagnoses are shown in Figure 1. Clinical features from the current study cohort are compared with those of a 2018 Mayo Clinic AYA cohort1  (Table). The patients were diagnosed between 2000 and 2022, with MPN driver mutation analysis performed in 89% and next-generation sequencing (NGS) of clinically relevant myeloid genes performed in 48%. More than one-third of patients (211) had NGS testing first performed during initial disease phase, with a median time from diagnosis of 3.9 years (range, 0-29 years). Sixty-four patients had NGS first performed during the post-ET/post-PV secondary myelofibrosis (SMF) phase, while 19 had NGS first performed during the accelerated phase (AP)/blast phase (BP) of disease. Non-MPN driver mutations were detected in a higher proportion of patients evaluated during disease progression (secondary myelofibrosis or elevated blasts) than during initial disease phase, including more frequent high molecular risk (HMR) mutations (Figure 2). Mutations defined as HMR included pathogenic and likely pathogenic variants in ASXL1, EZH2, IDH1/2, SRSF2, TP53, and U2AF1Q157. Among those patients with NGS testing performed during the initial disease phase, additional mutations were most frequently detected in those with overt PMF (26%).

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