Tag Archives: mf

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

Posted on by

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.

Read more

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

Posted on by

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.

Read more

Dr Klisovic on the Early Use of JAK Inhibitors in Younger Patients With Low-Risk Myelofibrosis

Posted on by

July 15, 2024

Author(s): Rebecca Klisovic, MD

Rebecca Klisovic, MD, chief medical information officer, University Hospitals Seidman Cancer Center, discusses a case study featuring a patient with newly diagnosed myelofibrosis and reviews the optimal JAK inhibitor–based treatment regimen for this patient, as determined by a panel of oncologists at an OncLive® State of the Science Summit™ on hematologic malignancies.

This case study featured a 40-year-old male patient with newly diagnosed myelofibrosis, Klisovic begins. She notes that the discussion about this patient was interesting discussion because the patient was young with low-risk disease. The panel’s conversation centered around the early use of the JAK inhibitor ruxolitinib (Jakafi) to potentially improve this patient’s overall survival outcome, Klisovic details.

Ruxolitinib has demonstrated superiority over placebo and best available therapy in the phase 3 COMFORT-I (NCT00952289) and COMFORT-II studies (NCT00934544). However, it was noted in the conversation that this patient would not have qualified for enrollment in the COMFORT studies due to his low-risk disease status, Klisovic explains. This led to a debate about the appropriateness of initiating treatment earlier rather than later, even in patients who may not otherwise require immediate therapy, according to Klisovic.

Another key question raised was whether ruxolitinib is truly disease-modifying, particularly in a younger patient, Klisovic says. This is a crucial consideration because the long-term benefits of a therapy and its potential for altering the disease course are significant factors in deciding early intervention, she expands.

Additionally, there was a strong recommendation to monitor this patient closely for transplant potential given his age, Klisovic continues. Although this patient’s molecular profile was not presented, discussants highlighted molecular stratification as an important factor for guiding treatment decision-making in similar cases, she states. Klisovic adds that the identification of higher-risk mutations could alter the treatment trajectory and influence whether early intervention or watchful waiting is more appropriate.

Read more

Mascarenhas on the SENTRY Trial Design and Goals

Posted on by

J

By John Mascarenhas, MD

John Mascarenhas, MD, professor, medicine, Icahn School of Medicine, Mount Sinai, director, Center of Excellence for Blood Cancers and Myeloid Disorders, member, The Tisch Cancer Institute, Mount Sinai, discusses the methods, design, and inclusion criteria of the phase 3 SENTRY trial (NCT04562389) for patients with JAK inhibitor treatment-naive myelofibrosis.

SENTRY is a global, multicenter, phase 1/3 study where investigators are assessing the efficacy and safety of selinexor (Xpovio) combined with ruxolitinib (Jakafi) in this patient population.

According to Mascarenhas, the primary end points of phase 3 of the trial include the proportion of patients with spleen volume reduction of greater than or equal to 35% at week 24 (SVR35), and the proportion of patients with a total symptom score reduction of greater than or equal to 50% at week 24 (TSS50), as measured by the myelofibrosis symptom assessment form V4.0.

Read more

Allogeneic HSCT for Myelofibrosis: What to Know as More Patients Receive Treatment

Posted on by

June 25, 2024

Due to new transplant approaches, allogeneic hematopoietic stem cell transplant (HSCT) is now perceived as a safer therapeutic option in patients with myelofibrosis, even among older patients. Authors of a review published in the American Journal of Hematology emphasized the crucial role of early consideration and implementation of HSCT in improving clinical outcomes in this patient population.

Despite the approval of new therapies and “various other exciting non-transplant treatments in development, allogeneic HSCT remains at present the only curative therapy for patients with myelofibrosis,” wrote coauthors Haris Ali, MD, and Andrea Bacigalupo, MD.

The challenges associated with treating myelofibrosis include transplant-related mortality and the risk for relapse after HSCT. The authors aimed to provide a comprehensive review of current clinical data, new transplant platforms, and clinical updates, which can enhance patient outcomes.

“The number of patients undergoing an allogeneic HSCT annually is steadily increasing,” Dr. Ali and Dr. Bacigalupo wrote. “This reflects the fact that HSCT has become safer with the reduction in non-relapse mortality over the years, making the choice of an HSCT more attractive among hematologists caring for [patients with myeloproliferative neoplasms].”

Read more

Outcomes of the Myelofibrosis Symptom Tracking Survey

Posted on by

We would like to thank the 147 patients who responded to a survey that targeted how people with
Myelofibrosis tracked their symptoms and then how they used the information they gleaned from
their tracking. You’ll never guess what we found.

Nearly 65 percent of respondents said they had never tracked their symptoms. When asked why,
a piece of the MF story unfolded. Some people acknowledged that the variability of both the
symptoms and their occurrence made it difficult to track, while others felt that bringing a focus to
their MF and symptoms each day undermined their mental health. A few mentioned that they
made mental notes of their symptoms, had their various doctors tracking symptoms, or just knew
innately when something changed. Several felt that there was no reason to track their symptoms,
this may be due in part to responses to another question that revealed only around 20 percent of
individuals were encouraged by their physician to keep track of their symptoms. Of those that
did track their symptoms, most did so with their own personal pen-and-paper accounting and
used a variety of approaches using numerical scales, happy and sad faces, or a more journaling
style.

After opening this little window into the MF experience. It was hard not to have additional
questions. For example, could symptom tracking be used as both a self-care practice and a tool of
empowerment? Ultimately, the tools and techniques that are most helpful come from the insight
and strength of those who experience MF every day. If symptom tracking is not the best way to
track symptoms to possibly share with your personal health care team, or the team you work with
during a clinical trial, what does work for you? We would love to learn more, and share what we
learn to benefit others. If you have a response to these questions or anything more you would like
to say on this topic, please email us at ngiocondo@mpnadvocacy.com.

Prospective Analysis Highlights Patterns of Progression to Myelofibrosis Following Essential Thrombocythemia Diagnosis

Posted on by

June 17, 2024

Author(s): Caroline Seymour

Most patients with essential thrombocythemia (95.7%; 1184/1237) included in an analysis of the prospective, observational MOST study (NCT02953704) did not experience disease progression to myelofibrosis, but those who did were found to have had longer duration of disease, higher white blood cell counts, and lower hemoglobin levels at enrollment, according to findings presented at the 2024 EHA Congress.1

Of the 4.3% (n = 53) of patients who progressed to myelofibrosis, a pathologic diagnosis of the disease or grade 2 or greater fibrosis was the most common indicator (49.1%; n = 26) of disease progression, followed by new or worsening splenomegaly coupled with a combination of high white blood cell counts and low hemoglobin levels and platelet counts (22.6%; n = 12). Additional indicators were death from myelofibrosis, myelodysplastic syndrome (MDS), or acute myeloid leukemia (AML; 11.3%; n = 6) and circulating blasts above 1% with new or worsening splenomegaly (5.7%; n = 3); patients also met at least 2 progression criteria (11.3%; n = 6).

“These findings and further analyses of MOST data will add insight into disease progression in patients with essential thrombocythemia and facilitate clinical management of this patient population,” lead study author Ruben A. Mesa, MD, FACP, president and executive director of Atrium Health Levine Cancer Institute and Atrium Health Wake Forest Baptist Comprehensive Cancer Center, and vice dean of cancer programs at Wake Forest University School of Medicine in Charlotte, North Carolina, and coauthors wrote in the poster.

Read more

Observational Study Finds Progression Common in Lower-Risk Myelofibrosis

Posted on by

June 14, 2024

Author(s): Sabrina Serani

Among patients with low- or intermediate-risk myelofibrosis (MF), a majority were reported to have disease progression over 4 years, and the rate of progression increased over time, according to findings from the prospective observational MOST study (NCT02953704) presented in a poster session at the 2024 EHA Congress. These findings provide important insight into the rates of disease progression for patients with lower-risk MF, a patient group with limited prospective data available on this topic.

A total of 232 patients with MF were enrolled, with 205 patients considered low or INT-1 risk due to being aged over 65 years alone comprising cohort A and 27 patients considered low or INT-1 risk for factors other than age only being evaluated in cohort B. In cohort A, 58.5% (n = 120) of patients experienced disease progression during the study, with the most common progression criteria being hemoglobin below 10 g/dL (47.5%). Further, 12 patients (10.0%) died due to disease progression and 6 (5%) had leukemic transformation. In cohort B, 29.6% (n = 8) of patients had disease progression during the course of the study.

Laboratory-defined criteria for progression in the MOST study included hemoglobin below 10 g/dL, platelet count below 100 × 109/L, less than 1% blasts, white blood cell count above 25 × 109/L, and leukemic transformation with greater than 20% blasts. Physician-reported criteria for progression were constitutional symptoms (weight loss, fever, sweats), new or worsening splenomegaly, 1 red blood cell transfusion during the study, physician-reported leukemic transformation, and death due to disease progression. The presence of at least 1 criterion was considered disease progression.

Read more

Dr Kishtagari on JAK Inhibitor Selection for Myelofibrosis in the Community Setting

Posted on by

John Mascarenhas, MD

John Mascarenhas, MD, professor, medicine, Icahn School of Medicine, Mount Sinai, director, Center of Excellence for Blood Cancers and Myeloid Disorders, member, The Tisch Cancer Institute, Mount Sinai, discusses phase 3 of the SENTRY (NCT04562389) trial, a global, multicenter, phase 1/3 study evaluating the efficacy and safety of selinexor (Xpovio) when given in combination with ruxolitinib (Jakafi) in patients with JAK inhibitor treatment-naive myelofibrosis.

The study is being conducted in 2 phases. In phase 1, the open-label portion of the study, enrollment has been completed and the safety and recommended dose of selinexor plus ruxolitinib was studied. Phase 1a utilized a standard 3+3 design, and phase 1b was the dose-expansion part. Phase 3 of the trial is enrolling patients with JAK inhibitor treatment-naive myelofibrosis and randomizing them 2:1 to receive the combination therapy of selinexor with ruxolitinib or placebo with ruxolitinib.

In phase 3, the primary end points are the proportion of patients with spleen volume reduction of greater than or equal to 35% at week 24, and the proportion of patients with a total symptom score reduction of greater than or equal to 50% at week 24, as measured by the myelofibrosis symptom assessment form V4.0.

Read more

Safety and efficacy of luspatercept for the treatment of anemia in patients with myelofibrosis

Posted on by

By: Aaron Gerds, Claire Harrison, Jean-Jacques Kiladjian, Ruben Mesa, Alessandro Vannucchi, Rami Komrokji, Prithviaj Bose, Marina Kremyanskaya, Adam Mead, Jason Gotlib, Shelonitda Rose, Fabian Sanabria, Niloufar Marsousi, Ana Giuseppi, Huijing Jiang, Jeanne Palmer , Kelly McCaul, Vincent Ribrag, Francesco Passamonti

Abstract:
The ACE-536-MF-001 trial enrolled patients with myelofibrosis (n = 95) into 4 cohorts: patients in
cohorts 1 and 3A were non-transfusion dependent (NTD) and had anemia; patients in cohorts 2 and 3B
were transfusion dependent (TD); patients in cohort 3A/3B had stable ruxolitinib treatment prior to
and during the study. All patients received luspatercept (1.0-1.75 mg/kg, 21-day cycles). Treatment
was extended if clinical benefit was observed at day 169. The primary endpoint was anemia response
rate (NTD, {greater than or equal to}1.5 g/dL hemoglobin increase from baseline; TD, transfusionindependence) over any 12-week period during the primary treatment period (weeks 1-24). Overall, 14% of patients in cohorts 1 and 3A, 10% in cohort 2, and 26% in cohort 3B met the primary
endpoint. In cohorts 1 and 3A (NTD), 27% and 50% of patients respectively had mean hemoglobin
increase {greater than or equal to}1.5 g/dL from baseline. Among TD patients, ~50% had {greater
than or equal to}50% reduction in transfusion burden. Reduction in total symptom score was observed
in all cohorts, with the greatest response rate seen in cohort 3A. Overall, 94% of patients had
{greater than or equal to}1 adverse event (AE); 47% had {greater than or equal to}1 treatmentrelated AE (TRAE; 11% grade {greater than or equal to}3), most frequently hypertension (18%),
managed with medical intervention. One patient had a serious TRAE leading to luspatercept
discontinuation. Nine patients died on treatment (unrelated to study drug). In most patients,
ruxolitinib dose and spleen size remained stable. In patients with myelofibrosis, luspatercept
improved anemia and transfusion burden across cohorts.

Read more