Tag Archives: mf

Pelabresib Plus Ruxolitinib Significantly Reduces Splenomegaly in Myelofibrosis

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Kristi Rosa

Pelabresib (CPI-0610) plus ruxolitinib (Jakafi) significantly reduced splenomegaly, showed a trend toward a reduction in tumor symptom score (TSS) from baseline, and improved bone marrow fibrosis and anemia at week 24 compared with ruxolitinib alone in JAK inhibitor–naive patients with myelofibrosis, according to updated data from the phase 3 MANIFEST-2 study (NCT04603495) presented at the 2024 ASCO Annual Meeting.1

As previously presented at the 2023 ASH Annual Meeting, the trial met its primary end point when a higher percentage of those who received the doublet (n = 214) experienced a 35% or greater reduction in spleen volume (SVR35) at week 24 vs those given ruxolitinib alone (n = 216), at 65.9% and 35.2%, respectively (difference, 30.4; 95% CI, 21.6-39.3; P < .001).2 The mean percentage change in spleen volume at week 24 in the pelabresib/ruxolitinib arm was -50.6% (95% CI, -53.2% to -48.0%) vs -30.6% (95% CI, -33.7% to -27.5%) in the ruxolitinib-alone arm.

When looking at all responders who achieved SVR35 response, the proportion who lost response at any point in the pelabresib/ruxolitinib arm was 13.4% and more than double in the ruxolitinib-alone arm, at 27.8%. When examining the criteria of loss of SVR35 response plus a spleen volume increase greater than 25% from nadir, this occurred in 9.3% and 14.8% of patients, respectively. Notably, SVR35 response was consistently higher with the doublet vs the monotherapy across all predefined subgroups and across hematologic subgroups.

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Cytopenias/Proliferation Define Outcomes for Patients With Primary MF and MF from Essential Thrombocythemia or PV

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Amber Denham

05/31/2024

According to research presented at the 2024 American Society of Clinical Oncology (ASCO) annual meeting, cytopenias and/or proliferation, rather than JAK2V617F (JAK2) allele burden </≥50%, correlate with the outcomes of patients with primary myelofibrosis (PMF) and patients with MF from essential thrombocythemia or polycythemia vera (PPV/PET-MF). In addition, all patients were noted to display improved survival with ruxolitinib treatment.

Myelodepleted MF, which is characterized by cytopenias, lower JAK2 allele burden, and shorter benefit from JAK-inhibitor ruxolitinib, exhibits worse overall survival (OS) compared to myeloproliferative MF. In addition, lower JAK2 and inferior OS is generally more typical for patients with primary MF (PMF) as compared with patients with MF from essential thrombocythemia or polycythemia vera (PPV/PET-MF).

“We sought to investigate the impact of JAK2 (</≥ 50%), cytopenias and the use of ruxolitinib in outcome of PMF/PPV-PET-MF patients from our center,” explained Julie Braish, MBBCh, The University of Texas MD Anderson Cancer Center, Houston, Texas and colleagues.

To determine these results, study authors retrospectively reviewed the medical charts of 601 patients with JAK2-mutated MF (known JAK2%). Patients were divided based on the absence (-) or presence (+) of cytopenias (hemoglobin < 10 g/dL or platelets < 100 x109/L) and leukocytosis (WBC ≥ 25 x109/L) into: grade 1 = (-)/(-) [absence of both]; grade 2 = (-)/(+) [proliferative]; grade 3 = (+)/(-) [cytopenic]; grade 4 = (+)/(+) [cytopenic and proliferative]) and evaluated overall survival (OS) per JAK2 </≥ 50% and PMF vs PPV/PET-MF. Investigators assessed the tolerance of ruxolitinib ≥3 years by utilizing descriptive statistics, Kaplan-Meier curve with log-rank test and regression analysis for demographics, estimation of OS and its comparison.

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Dr Gerds on Updated Data for Pelabresib Plus Ruxolitinib in JAK Inhibitior–Naive Myelofibrosis

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Author(s): Aaron Gerds, MD

May 31, 2024

Aaron Gerds, MD, assistant professor in medicine, Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, discusses updated efficacy and safety results from the phase 3 MANIFEST-2 trial (NCT04603495) of pelabresib (CPI-0610) plusruxolitinib (Jakafi) in patients with JAK inhibitor–naive myelofibrosis.

Previously reported data from the randomized, double-blind, placebo-controlled trial, showed that the combination of pelabresib and ruxolitinib produced a statistically significant and clinically meaningful improvement in spleen volume reduction of at least 35% (SVR35) from baseline vs placebo plus ruxolitinib in patients with treatment-naive disease.

At the 2024 ASCO Annual Meeting, Gerds and colleagues reported data reaffirming these initial topline results, emphasizing their consistency over time. Among patients who achieved SVR35, 13.4% in the combination arm lost their splenic response compared with 27.8% of patients treated in the placebo arm.

Notably, the proportion of patients achieving both SVR35 and a reduction in tumor symptom score of at least 50% (TSS50) was also evaluated, Gerds states. In the combination therapy group, 40.2% of patients achieved both end points vs 18.5% with ruxolitinib alone, he reports. Gerds posits that the difference in rates of TSS50 may not be as pronounced between the combination therapy and ruxolitinib alone because single-agent ruxolitinib is highly effective in reducing symptoms; however, the higher proportion of patients achieving both end points with the combination therapy is noteworthy, he explains.

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Updated MANIFEST-2 Data With Pelabresib/Ruxolitinib Support Paradigm Shift in Myelofibrosis

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Author(s): Kristi Rosa

May 31, 2024

The addition of pelabresib (CPI-0610) and ruxolitinib (Jakafi) led to a significant and durable reduction in splenomegaly, showed a trend toward reduced tumor symptom score (TSS) from baseline, and improved anemia and bone marrow fibrosis at week 24 vs ruxolitinib alone in JAK inhibitor–naive patients with myelofibrosis, according to updated data from the phase 3 MANIFEST-2 study (NCT04603495) presented at the 2024 ASCO Annual Meeting.1

As previously presented at the 2023 ASH Annual Meeting, the trial met its primary end point when a higher percentage of those who received the doublet (n = 214) experienced a 35% or greater reduction in spleen volume (SVR35) at week 24 vs those given ruxolitinib alone (n = 216), at 65.9% and 35.2%, respectively (difference, 30.4; 95% CI, 21.6-39.3; P < .001).2 The mean percentage change in spleen volume at week 24 in the pelabresib/ruxolitinib arm was -50.6% (95% CI, -53.2% to -48.0%) vs -30.6% (95% CI, -33.7% to -27.5%) in the ruxolitinib-alone arm.

When looking at all responders who achieved SVR35 response, the proportion who lost response at any point in the pelabresib/ruxolitinib arm was 13.4% and more than double in the ruxolitinib-alone arm, at 27.8%. When examining the criteria of loss of SVR35 response plus a spleen volume increase greater than 25% from nadir, this occurred in 9.3% and 14.8% of patients, respectively. Notably, SVR35 response was consistently higher with the doublet vs the monotherapy across all predefined subgroups and across hematologic subgroups.

A strong trend for numerical decrease in absolute change in TSS from baseline at week 24 was observed with the doublet vs the monotherapy, at -15.99 and -14.05, translating to a mean difference of -1.94 points (95% CI, -3.92 to 0.04; P = .0545). A higher proportion of patients who received the combination vs ruxolitinib alone achieved a 50% reduction in TSS (TSS50), at 52.3% vs 46.3% (difference, 6.0; 95% CI, -3.5 to 15.5; P = .216); this difference did not reach statistical significance. A two-fold increase in patients who achieved both SVR35 and TSS50 responses was observed with pelabresib plus ruxolitinib vs ruxolitinib alone, at 40.2% and 18.5%, respectively.

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Azacitidine Plus Ruxolitinib Demonstrates ‘Promising’ Efficacy in Myelofibrosis

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Amber Denham

05/31/2024

Azacitidine in combination with ruxolitinib demonstrates promising efficacy for patients with myelofibrosis (MF), according to long-term follow-up results from a phase 2 clinical trial presented at the 2024 American Society of Clinical Oncology (ASCO) Annual meeting.

The trial included adult patients aged ≥18 years with MF intermediate 1 to 2 or high-risk disease, measured by the Dynamic International Prognostic Scoring System (DIPSS). From March 2013 to October 2021, a total of 61 patients were treated in the trial. Patients had a median age of 66 years (46 to 87). The median hemoglobin was 10.1 g/dl (6.8 to 16.2) and bone marrow blasts 2% (0 to 14%). Overall, 14 (23%) patients had BM blasts ≥5%. Furthermore, JAK2 was mutated in 35 (57%) patients and 38 (62%) patients had intermediate-2 or high-risk DIPSS disease.

Study results showed an International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) response occurred in 44 (72%) patients. A clinical improvement was noted in 37 (61%) patients, including IWG-MRT spleen reduction >50% in 28 (61%) of 46 patients with baseline length ≥5 cm below left costal margin, and 31 (61%) of 51 patients with baseline total symptom score (TSS) >12 having a >50% improvement in TSS 50. In addition, a partial response was seen in 4 patients and cytogenetic complete remission in 3 patients.

With a median follow-up of 93 months, median overall survival (OS) was 46 months (95% confidence interval [CI], 25 to 66), median event-free survival was 33 months (95% CI, 24 to 43), and median duration of any objective response was 43 months (95% CI, 24 to 62). It was noted that disease transformation to AML occurred in 14 (23%) patients with a median time to transformation of 19 months. In addition, 20 (33%) patients received a stem cell transplant (SCT), and 11 (55%) patients had intermediate-2/high-risk DIPPS disease. It was observed that patients in the Intermediate-2/high-risk DIPPS group who received a SCT showed a trend towards improved median OS vs those who did not receive a transplant (38 vs 27 months, P = .2).

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JAK Inhibitor–Based Combinations Could Represent the Next Frontier in Myelofibrosis

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Ryan Scott

In an interview with OncLive® following the Vanderbilt Stem Cell Transplant and Cellular Therapy Symposium, Ashwin Kishtagari, MD, discussed advancements in the treatment of patients with intermediate-risk to high-risk myelofibrosis and highlighted recent data from the 2023 ASH Annual Meeting for combination therapies using JAK inhibitors.

Studies presented at the meeting included the phase 3 TRANSFORM-1 clinical trial (NCT04472598) evaluating navitoclax plus ruxolitinib (Jakafi), as well as the phase 3 MANIFEST-2 trial (NCT04603495) investigating pelabresib (CPI-0610) in combination with ruxolitinib.1,2

Kishtagari, who serves as an assistant professor of medicine in the Department of Hematology and Oncology at Vanderbilt University Medical Center, as well as a clinical research fellow in Bick Lab at Vanderbilt University School of Medicine in Nashville, Tennessee, provided further updates on JAK inhibitors for the treatment of patients with myelofibrosis in another interview with OncLive.

OncLive: How do you see the treatment paradigm for myelofibrosis evolving in the future?

Kishtagari: We have 4 JAK inhibitors which are FDA approved for the treatment of [patients with] myelofibrosis, with the first being ruxolitinib. Fedratinib [Inrebic] was the second agent approved in 2019. Pacritinib [Vonjo] was approved by the FDA in 2022, and momelotinib [Ojjaara]was approved in 2023.

We are moving toward combination therapies because our goal is to have a more significant improvement in splenomegaly response and symptom improvement. The whole field of myelofibrosis is moving toward combination therapy, especially for patients with higher- or intermediate-risk myelofibrosis.

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Sobi to present new myelofibrosis data at the ASCO 2024 Annual Meeting

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WALTHAM, Mass., May 24, 2024 (GLOBE NEWSWIRE) — Sobi North America, the North American affiliate of Swedish Orphan Biovitrum AB (Sobi®), today announced the presentation of three abstracts that highlights data from its myelofibrosis treatment option at the American Society of Clinical Oncology (ASCO) Annual Meeting taking place in Chicago from May 31 – June 4, 2024.

Sobi’s commitment to delivering innovative treatments for people living with hematological diseases is seen in global studies spanning multiple rare disorders, including myelofibrosis.

A retrospective analysis will be presented that demonstrates the efficacy of pacritinib in spleen volume reduction, symptom benefit and red blood cell transfusion response, compared with best available therapy, in patients with myelofibrosis who have both thrombocytopenia and anemia.

An additional retrospective analysis will be presented that shows the substantial symptom benefit pacritinib provides compared with best available therapy or low-dose ruxolitinib, specifically in patients who required red blood cell transfusion at the time of pacritinib initiation. The number of patients experiencing treatment emergent Grade 3 anaemia was similar between pacritinib and BAT groups.

New real-world data will be presented that demonstrates treatment with pacritinib provides stability or improvement in thrombocytopenia and/or anemia in patients with myelofibrosis, regardless of baseline counts, and has favorable overall survival similar to other JAK inhibitor historical controls.

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JAK Inhibitor–Based Combinations Could Represent the Next Frontier in Myelofibrosis

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Ryan Scott

In an interview with OncLive® following the Vanderbilt Stem Cell Transplant and Cellular Therapy Symposium, Ashwin Kishtagari, MD, discussed advancements in the treatment of patients with intermediate-risk to high-risk myelofibrosis and highlighted recent data from the 2023 ASH Annual Meeting for combination therapies using JAK inhibitors.

Studies presented at the meeting included the phase 3 TRANSFORM-1 clinical trial (NCT04472598)evaluating navitoclax plus ruxolitinib (Jakafi), as well as the phase 3 MANIFEST-2 trial (NCT04603495) investigating pelabresib (CPI-0610) in combination with ruxolitinib.1,2

Kishtagari, who serves as an assistant professor of medicine in the Department of Hematology and Oncology at Vanderbilt University Medical Center, as well as a clinical research fellow in Bick Lab at Vanderbilt University School of Medicine in Nashville, Tennessee, provided further updates on JAK inhibitors for the treatment of patients with myelofibrosis in another interview with OncLive.

OncLive: How do you see the treatment paradigm for myelofibrosis evolving in the future?

Kishtagari: We have 4 JAK inhibitors which are FDA approved for the treatment of [patients with] myelofibrosis, with the first being ruxolitinib. Fedratinib [Inrebic] was the second agent approved in 2019. Pacritinib [Vonjo] was approved by the FDA in 2022, and momelotinib [Ojjaara]was approved in 2023.

We are moving toward combination therapies because our goal is to have a more significant improvement in splenomegaly response and symptom improvement. The whole field of myelofibrosis is moving toward combination therapy, especially for patients with higher- or intermediate-risk myelofibrosis.

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Ajax Therapeutics Announces FDA Clearance of IND Application for AJ1-11095, a First-in-Class Type II JAK2 inhibitor, for the Treatment of Myelofibrosis

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– AJ1-11095 is the first Type II JAK2 Inhibitor to ever enter the clinic –

– Phase 1 dose escalation study expected to begin in 2H 2024 –

NEW YORK & CAMBRIDGE, Mass.–(BUSINESS WIRE)–Ajax Therapeutics, Inc., a biopharmaceutical company developing next generation JAK inhibitors for patients with myeloproliferative neoplasms (MPNs), today announced that it has received clearance for its Investigational New Drug (IND) application from the U.S. Food and Drug Administration (FDA) to initiate a Phase 1clinical study of AJ1‑11095, a first-in-class Type II JAK2 inhibitor, for the treatment of patients with myelofibrosis.

“This is an important milestone for our company and our first program to enter the clinic and the first clinical study to ever evaluate a Type II JAK2 inhibitor in patients.”

“We are thrilled to obtain clearance to advance AJ1-11095 into the clinic and excited to bring this innovative new medicine to patients with myelofibrosis,” said Martin Vogelbaum, co-founder and CEO of Ajax Therapeutics. “This is an important milestone for our company and our first program to enter the clinic and the first clinical study to ever evaluate a Type II JAK2 inhibitor in patients.”

“We look forward to the clinical development of AJ1-11095 in myelofibrosis and to initiating our Phase 1 dose escalation study, AJX-101, later this year,” said David Steensma, MD, FACP, Chief Medical Officer at Ajax. “As a first-in-class therapy with a unique mechanism as a Type II inhibitor of JAK2, AJ1-11095 was developed to provide a much-needed new treatment for patients with myelofibrosis by offering the potential for improved efficacy with disease modifying effects compared to existing therapies.”

About AJ1-11095

AJ1-11095 was designed by Ajax, through our collaboration with Schrödinger, to be a next generation JAK2 inhibitor by using structure-based drug design and computational methods at scale to selectively bind the Type II conformation of the JAK2 kinase and to provide greater efficacy with disease modification compared to all currently approved JAK2 inhibitors which bind the Type I conformation of JAK2. Additionally, AJ1-11095 has been shown in preclinical studies to reverse marrow fibrosis, reduce mutant allele burden and maintain efficacy against MPN cells that become resistant to chronic Type I JAK2 inhibition.

About Myelofibrosis

Myelofibrosis (MF) is a rare blood cancer that affects approximately 20,000 patients in the United States. The disease is characterized by spleen enlargement, scarring (fibrosis) in the bone marrow, progressive anemia, and debilitating symptoms, such as fatigue, night sweats, itching, and abdominal discomfort, which can impair a patient’s’ quality of life. The most widely used treatment for MF patients are Type I JAK2 inhibitors which can reduce spleen size and provide symptomatic improvement but have little effect on the underlying cause of disease. Over time, most MF patients stop Type I JAK2 inhibitor therapy. The most common causes for treatment discontinuation include a lack of benefit or loss of response, adverse events, and disease progression, leaving significant unmet treatment needs for these patients.

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Novel Targets Beyond the JAK-STAT Pathway Aim to Push Myelofibrosis Treatment Forward

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Jax DiEugenio

Ongoing research in myelofibrosis continues to focus on agents directed at novel targets with the hope of expanding treatment options beyond the host of JAK inhibitors used in this treatment paradigm, according to Anthony M. Hunter, MD.

“[There are] a lot of novel agents on the horizon [that could] work in combination with JAK inhibitors to hopefully continue to move that bar forward for patients [with myelofibrosis,” said Hunter, who is an assistant professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine and the medical director of the Immediate Care Center at Winship Cancer Institute of Emory University in Atlanta, Georgia.

In an interview with OncLive®, Hunter explained the evolving understanding of the biology of myelofibrosis, detailed the growth of JAK inhibitors being used for the treatment of these patients, and expanded on novel targets and agents currently being tested in clinical trials.

OncLive: How has our understanding of the pathology of myelofibrosis evolved in recent years as more research studies have been conducted?

Hunter: What has been well documented for years now is that the key biologic pathway or cell-signaling pathway actually involved in myeloproliferative neoplasms [MPN] or myelofibrosis is the JAK-STAT pathway. That [understanding] was advanced in 2005 when we found out about the JAK2 mutation in a large percentage of these patients, [and we] subsequently [found out about] the MPL and CALR mutations, as well. We find that in all patients with MPN or myelofibrosis, irrespective of those mutations, we see activation of this JAK-STAT signaling pathway, which has a lot of different effects and we can break those up into effects on hematopoiesis, or how they affect sort of blood cell production.

Then we also see increases in inflammatory cytokine signaling. The JAK/STAT pathway signals through a lot of cytokine and inflammatory receptors, so we see a lot of inflammatory signaling increase in a number of different cytokine levels and in myelofibrosis, which impacts the disease and the symptoms that we see. That has been key to [understanding] the biology [of myelofibrosis] and has led to the development of JAK inhibitors.

We’ve started to move beyond [the JAK-STAT] pathway a little bit, as well. A lot of the research now and new agents that are being explored in clinical trials are largely looking at non–JAK inhibitor agents, combining other pathways such as BET inhibitors, various other signaling molecules, and anti-fibrotic type compounds. All of those have additional roles, along with the JAK-STAT pathway in myelofibrosis.

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