Category Archives: Myelofibrosis

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

Prognostic Scores Validated for Additional Mutations in Secondary Myelofibrosis

Posted on by

July 11, 2024

An article in the American Journal of Hematology reported an in-depth characterization of clinical and molecular differences between primary and secondary myelofibrosis (MF). Researchers also found that two newer prognostic scores, the Mutation-Enhanced International Prognostic Scoring System 70 (MIPSS70) and MIPSS70+ v2.0, stratified risk in patients with secondary MF more accurately than the myelofibrosis secondary to polycythemia vera and essential thrombocythemia prognostic model (MYSEC-PM). These two scores also are the first to account for additional mutations besides SRSF2 status in patients with secondary MF.

Several prognostic scores have been developed for patient risk stratification and appropriate treatment allocation in primary MF. These include the IPSS, Dynamic IPSS (DIPSS), and DIPSS-plus. Studies have highlighted the prognostic significance of molecular alterations in primary MF, particularly mutations in High Molecular Risk (HMR) genes such as ASXL1, EZH2, IDH1/2, SRSF2, and U2AF1. Consequently, these genetic and molecular alterations were incorporated into the latest prognostic scores, including MIPSS70, MIPSS70-plus, and MIPSS70+ v2.0.

“As opposed to primary MF, few studies explored mutations prognosis significance in secondary MF,” explained Matteo Guerra and colleagues. “The MYSEC-PM was specifically developed for secondary MF and displays a more accurate prognostic performance than IPSS and DIPSS. However, no molecular prognostic models accounting for additional mutations in SMF have yet been described.”

Read more

Observational MOST Trial Reveals Progression Trends in Low-Risk Myelofibrosis

Posted on by

July 11, 2024

Author(s):Jax DiEugenio

Findings from the prospective, observational MOST trial (NCT02953704) showed that 58.5% of patients with low- or intermediate-1–risk myelofibrosis enrolled in cohort A (n = 205) met at least 1 criterion for disease progression after a median follow-up of less than 53 months, which was a higher rate than investigators expected, according to Aaron Gerds, MD.

Cohort A included patients with low-risk or intermediate-1–risk disease, where patients were considered to have intermediate-1–risk myelofibrosis based on age only. Cohort B (n = 27) featured patients with intermediate-1–risk disease with other Dynamic International Prognostic Scoring System (DIPSS) risk factors beyond age.

Findings presented at the 2024 EHA Congress showed that of the 120 patients in cohort A who experienced disease progression, 64 (53.3%) met 1 criterion for progression, 27 (22.5%) met 2 criteria, and 29 (24.2%) met at least 3 disease progression criteria. The most common progression criteria met in cohort A included a hemoglobin level of less than 10 g/dL (47.5%) and a platelet count of less than 100 x 109/L (31.7%). For Cohort B, 25 patients (92.6%) met 1 progression criterion, 1 patient (3.7%) met 2 progression criteria, and 1 patient (3.7%) met 3 progression criteria.

Read more

Myelofibrosis management in routine clinical practice with a focus on patients with cytopenias: recommendations from a global consensus group

Posted on by

Steffen Koschmieder, Prithviraj Bose, Martin H. Ellis, Vikas Gupta, Jean-Jacques Kiladjian, John Mascarenhas, Vikram Mathews, Francesco Passamonti & Claire Harrison

Leukemia (2024)

Myelofibrosis (MF) is a Philadelphia chromosome (BCR::ABL1)-negative myeloproliferative neoplasm, a hallmark of which is progressive deposition of fibrotic tissue in bone marrow [1]. Clinical manifestations of MF often include splenomegaly, cytopenias (such as severe anemia), and extramedullary hematopoiesis [1]. The Janus kinase inhibitor (JAKi) therapies ruxolitinib (RUX) and fedratinib (FED) have demonstrated significant clinical efficacy in splenic volume reduction and symptom improvement, but they may induce treatment-related anemia and thrombocytopenia [2,3,4,5,6,7,8,9]. Other JAKi options include pacritinib (PAC), which received FDA approval in 2022 for patients with MF and severe thrombocytopenia (platelet count <50 × 109/l), and momelotinib (MMB), which received FDA and EMA approval in 2023/2024, respectively, for patients with MF and anemia [10,11,12]. Clinical trials with JAKis in MF are summarized in reference [1].

National and international guidelines exist for the management of MF; however, a need remains for practical guidance applicable in everyday clinical practice, especially for patients experiencing cytopenias or potential failure of current therapy. The landscape is further complicated by the availability of multiple prognostic tools for MF; as such, clinicians may find disease prognostication challenging and confusing. Additionally, to maximize clinical applicability of trial data, inclusivity of eligibility criteria in the context of the real-world MF patient population should be considered.

Recognizing these significant challenges, an international expert consensus group was established to provide best practice recommendations for healthcare professionals, intending to supplement, but not replace, existing guidelines.

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

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