Tag Archives: JAK inhibitor

JAK Inhibitors Diversify the Field of Myelofibrosis Symptom and Spleen Management

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October 8, 2024

Author(s): Ashling Wahner

Fact checked by: Courtney Flaherty

The wealth of JAK inhibitors available for managing myelofibrosis invites the development of increasingly personalized treatment plans based on individual patient needs and disease characteristics, according to Idoroenyi Amanam, MD.

“We’ve come a long way since ruxolitinib [Jakafi] was FDA approved,” Amanam said in an interview with OncLive®. “We have a better understanding of which patients benefit from JAK inhibitors, and we are clearer on the shortcomings of JAK inhibitors.”

In the interview, Amanam discussed how JAK inhibitors measure up against other available therapies in myelofibrosis; patient characteristics that are most likely to indicate benefit with JAK inhibitors; and which of these agents he is likely to choose based on patients’ platelet counts, symptom burden, and treatment history.

For instance, Amanam highlighted the importance of pacritinib (Vonjo) in the myelofibrosis treatment paradigm. Pacritinib was approved by the FDA in 2022 for the treatment of select adult patients with intermediate- or high-risk myelofibrosis with thrombocytopenia based on findings from the phase 3 PERSIST-2 trial (NCT02055781), in which 29% patients who received the agent achieved a spleen volume reduction (SVR) of at least 35%. Among patients who received best available therapy, the SVR rate was 3%.1

He also explained the role of momelotinib (Ojjaara) for patients with anemia. Momelotinib was FDA-approved in 2023 for the treatment of adult patients with intermediate- or high-risk myelofibrosis and anemia based on data from the phase 3 MOMENTUM trial (NCT04173494).2 In MOMENTUM, 25% of patients who received momelotinib (n = 32/130) experienced a Myelofibrosis Symptom Assessment Form 4.0 total symptom score reduction of at least 50% vs 9% of those who received danazol (Danocrine; n = 6/65), translating to a treatment difference of 16% (95% CI, 6%-26%; P < .0095).3

Amanam is an assistant professor in the Division of Leukemia in the Department of Hematology & Hematopoietic Cell Transplantation at City of Hope in Duarte, California.

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Janus kinase inhibitor monotherapy and combination therapies for myelofibrosis: what’s the current standard of care?

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Mahesh Swaminathana, Akhil Jain, Sungchul Daniel Choi & Naveen Pemmaraju
Received 10 Jun 2024, Accepted 23 Sep 2024, Published online: 03 Oct 2024

ABSTRACT

Introduction

JAK inhibitors (JAKi) have changed the treatment paradigm of myelofibrosis (MF). Currently, 4 JAKis are approved in the US as monotherapy (mono) to treat patients with MF. JAKis are also being studied in combination (combo) with novel agents. Herein, we review some of the key studies that evaluated JAKi as mono and combo in MF.

Areas covered

We performed a Pubmed search for ‘JAK inhibitors’ and ‘myelofibrosis’ from 1/2010 to 12/2023. For mono, we included only the unique phase II/III studies of the approved JAKi. Selective studies that evaluated JAKi in combo with the novel agents were also included.

Expert opinion

JAKis aim to provide clinical benefit to patients via spleen size reduction and MPN symptom improvement. In order to potentially increase clinical benefit for patients with MF, several novel agents are being partnered with ruxolitinib (RUX) with the ongoing hypothesis to augment greater measures of MF disease modification. The novel agents are either ‘added-on’ to RUX or as a combo in JAKi naïve patients. Also, the mutant-targeting era of therapies is now beginning with novel CALR-mutated, novel JAK2 V617F mutation-specific and type II JAK2i in the initial stages of drug development, representing a new approach to treatment.

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Choosing the Right JAK Inhibitor for Effective Myelofibrosis Treatment

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By Jordyn Sava
Fact checked by Sabrina Serani

With 4 JAK inhibitors approved in the US and additional agents in development, it is an exciting time for the field of myeloproliferative neoplasms (MPNs). Now, experts face the challenge of determining which treatment is best for each patient.

Ruxolitinib (Jakafi), an established JAK inhibitor, was first approved by the FDA in 2011,1 showing clear survival benefits. This was followed by the FDA approvals of fedratinib (Inrebic) in 2019,2 pacritinib (Vonjo) in 2022,3 and momelotinib (Ojjaara) in 2023.4

“Each [JAK inhibitor has] their place depending on the patient’s blood counts and other clinical factors,” explained Prithviraj Bose, MD, in an interview with Targeted OncologyTM.

With multiple JAK inhibitors available to choose from, a tailored approach ensures that each patient’s specific disease characteristics and comorbidities are considered to maximize efficacy and minimize toxicity during treatment.

In the interview, Bose, professor in the Department of Leukemia at MD Anderson Cancer Center, discussed the multiple JAK inhibitors available for the treatment of patients with MPNs.

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Dr Amanam on Criteria for Selecting a JAK Inhibitor in Myelofibrosis

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September 23, 2024

Author(s): Idoroenyi Amanam, MD

Idoroenyi Amanam, MD, assistant professor, Division of Leukemia, Department of Hematology & Hematopoietic Cell Transplantation, City of Hope, discusses the criteria for selecting JAK inhibitors in the treatment of patients with myelofibrosis.

Ruxolitinib (Jakafi) was the first JAK inhibitor approved for the treatment of myelofibrosis by the FDA in 2011. Amanam notes that this approval was initially based on the agent’s demonstrated benefits in reducing splenomegaly and improving symptom burden, two critical factors that influence treatment outcomes in myelofibrosis. Since then, 3 additional JAK inhibitors have received FDA approval for the treatment of select patients with myelofibrosis: fedratinib (Inrebic) in 2019, pacritinib (Vonjo) in 2022, and momelotinib (Ojjaara) in 2023.

Amanam emphasizes that the ideal candidates for JAK inhibitors are patients experiencing significant symptom burden and splenomegaly. Patients presenting with myelofibrosis, particularly those with moderate to severe spleen enlargement and a high burden of disease-related symptoms, are likely to derive the most benefit from JAK inhibition, he continues.

Conversely, patients who are not experiencing splenomegaly or any symptom burden may have limited therapeutic gain from JAK inhibitors, and the use of these agents in these patients may expose them to unnecessary risks of adverse effects (AEs), he says. The most commonly reported AEs from JAK inhibitor treatment are cytopenias, such as anemia, thrombocytopenia, and leukopenia, Amanam notes.

To avoid these potential toxicities, Amanam stresses the importance of thorough patient evaluation and symptom assessment when considering JAK inhibitors, as the absence of these key criteria can reduce the overall efficacy of treatment and increase the potential for unnecessary AEs.

In clinical practice, Amanam explains the importance of personalized treatment strategies based on individual patient characteristics and risk profiles, prioritizing those who meet the established clinical benchmarks for symptom relief and splenic volume reduction.

Although JAK inhibitors can offer significant symptomatic relief for appropriately selected patients, they are not universally beneficial for all patients with myelofibrosis and should be used judiciously to optimize clinical outcomes, he concludes.

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SOHO State of the Art Updates and Next Questions | Choosing and Properly Using a JAK Inhibitor in Myelofibrosis

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Michael J. Hochmanm, Colin A. Vale, Anthony M. Hunter

Abstract

Myelofibrosis (MF) is a chronic myeloid neoplasm characterized by myeloproliferation, bone marrow fibrosis, splenomegaly, and constitutional symptoms related to pro-inflammatory cytokine signaling. Biologically, MF is characterized by constitutive activation of JAK-STAT signaling; accordingly, JAK inhibitors have been rationally developed to treat MF. Following the initial approval of ruxolitinib in 2011, three additional agents have been approved: fedratinib, pacritinib, and momelotinib. As these therapies are non-curative, allogeneic stem cell transplantation remains a key treatment modality and patients with MF who are deemed candidates should be referred to a transplant center. This potentially curative but toxic approach is typically reserved for patients with higher-risk disease, and JAK inhibitors are recommended in the pre-transplant setting. JAK inhibitors have proven effective at managing splenomegaly and constitutional symptoms and should be started early in the disease course in patients presenting with these clinical manifestations; asymptomatic patients may initially be followed with close surveillance. Drug-related myelosuppression has been a challenge with initial JAK inhibitors, particularly in patients presenting with a cytopenic phenotype. However, newer agents, namely pacritinib and momelotinib, have proven more effective in this setting and are approved for patients with significant thrombocytopenia and anemia, respectively. Resistance or disease progression is clinically challenging and may be defined by several possible events, such as increasing splenomegaly or progression to accelerated or blast phase disease. However, with multiple JAK inhibitors now approved, sequencing of these agents appears poised to improve outcomes. Additionally, novel JAK inhibitors and JAK inhibitor-based combinations are in clinical development.

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

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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.

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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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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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Momelotinib Improves Anemia in JAK Inhibitor-Naive Myelofibrosis

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Sabrina Serani

Treatment with momelotinib (Ojjaara) delivered benefits to anemia among patients with myelofibrosis who were naive to JAK inhibitors, regardless of their baseline hemoglobin level. Further, momelotinib provided significant anemia benefits compared with ruxoltinib (Jakafi), according to an analysis from the phase 3 SIMPLIFY-1 study (NCT01969838).

SIMPLIFY-3 randomized 432 patients with myelofibrosis who had not received JAK inhibitors toreceive momelotinib or ruxolitinib.In patients who were anemic and received momelotinib, mean hemoglobin levels increased by weeks 2 to 4 of treatment, and hemoglobin levels remained stable among patients who were not anemic.

Comparatively, patients who were anemic and nonanemictreated with ruxolitinib experienced an initial decrease in mean hemoglobin. This decrease stabilized after weeks 4 to 6 as patients received red blood cell transfusions. Patients receiving ruxolitinib were permitted to cross over to the momelotinib group, and mean hemoglobin levels increased after this change.

The study also evaluated patients at different levels of anemia. Among patient who were mildly anemic, with ahemoglobin levelbetween 10 and 12 g/dL, 90.4% of patients were transfusion-free at baseline, 93.9% of these patients remained transfusion-free while receiving momelotinib. Four patients who were not transfusion-free at baseline became transfusion-free while on treatment. In contrast, patients who were mildly anemic in the ruxolitinib arm became more dependent on transfusion; 50% of patients who were transfusion-free at baseline required a transfusion while on ruxolitinib.

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A new mouse model highlights the need for better JAK inhibitors in myeloproliferative neoplasms

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Charles E. de Bock

The discovery that the gain of function JAK2 V617F mutation is present in myeloproliferative neoplasms (MPNs) has led to numerous clinical trials assessing the efficacy of JAK inhibitors. Most notably, ruxolitinib, a combined JAK1/2 selective inhibitor, has gained approval in patients with myeolofibrosis (MF), and additional JAK2 inhibitors including fedratinib, pacritinib, and momelotinib also under evaluation for patients with MF. However, while these inhibitors demonstrate some clinical benefit, they do not adequately reduce the mutant clone fraction. 1 , 2 Consequently, a critical question for the field has been whether the lack of a durable response is attributed to either (i) the inability of current JAK inhibitors to completely block the pathway or (ii) the possibility that mutant clones are not entirely dependent on this activated pathway.

To address these two possibilities, a new study from the laboratory of Ross Levine, published in Cancer Discovery,developed an innovative mouse model of Jak2 V617F alone or in combination with Tet2 loss. The novel aspect of this mouse model lies in the ability to control the expression and genetic deletion of Jak2 V617F allele from mutant clones upon development of MPN. To do so, it utilizes two orthogonal site‐specific recombinases which exert precise control over the temporal expression and deletion of the Jak2 V617F allele.

The mouse model uses the well‐established Cre recombinase that recognises short nucleotide target sequences called Lox sites, in conjunction with the relatively new Dre recombinase which recognizes short nucleotide sequences called Rox sites. Importantly, the strategic arrangement and orientation of these sequences can lead to either flipping or deletion of the intervening DNA sequence. In this context, Dre recombinase is employed to initiate the expression of the Jak2 V617F allele. Subsequently, a modified CreER recombinase, translocated to the nucleus upon tamoxifen treatment, can delete the Jak2 V617F allele (Figure 1A). This intricate mouse model provided a powerful tool for comparing the durability of response between JAK inhibitors and the genetic loss of Jak2 V617F in the context of MPNs.

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