Category Archives: Myelofibrosis

Ruxolitinib Could Be Useful in MF Care

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Leonardo Jaimes, MD

Ruxolitinib appears to produce durable responses and minimal adverse effects in patients with myelofibrosis (MF) in a real-world setting, according to a recently published study in Cancer.

Since its US Food and Drug Administration approval over a decade ago, the JAK1/JAK2 inhibitor ruxolitinib has become one of the most commonly used drugs for the management of MF-associated symptoms, the study team noted. Its approval is based on the results from the COMFORT study, which included only intermediate-2 and high-risk patients, they continued.

“However, intermediate-1 risk patients may carry a significant burden of disease and are increasingly treated with ruxolitinib in the real-life setting. Moreover, in some European countries (e.g., Germany) approval of ruxolitinib is not restricted to higher risk patients but rather to those with symptomatic disease (even when intermediate-1 or low risk),” the authors wrote.

Given the lack of studies investigating the effectiveness and safety of ruxolitinib in an intermediate-1 risk patient population and the small cohorts and short follow-up times used in previous studies, the research team aimed to assess the drug in a real-world clinical practice context.

The retrospective study included data from over 1000 patients with MF who had received ruxolitinib since 2013. Approximately 56% of the patients were intermediate risk-1.

The authors observed a 26% spleen response rate after six months of ruxolitinib in the intermediate risk-1 population and a 68% symptom response rate. Both rates were slightly inferior in patients with intermediate risk-2.

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Hypomethylating Agents Show Promise in Myelofibrosis Progression After alloHCT

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Andrea S. Blevins Primeau, PhD, MBA

Donor chimerism was restored with hypomethylating agent (HMA) treatment among some patients with myelofibrosis (MF) who relapsed after allogeneic hematopoietic cell transplantation (alloHCT), according to a small retrospective published in the journal Transplantation and Cellular Therapy.

These data suggest that HMA “is an option for patients in the future,” the researchers wrote in their report. “By promoting restoration of donor chimerism and clearance of pre-alloHCT somatic mutations, HMAs offer a capable therapeutic strategy for improving outcomes in this challenging patient population.”

In the single-center, retrospective study, the researchers analyzed data from the electronic health records of 12 patients with MF who relapsed after alloHCT between 2020 and 2023 and were subsequently treated with an HMA.

The median age of the cohort was 61 years and 33% of patients had primary MF, 41.7% had post-essential thrombocythemia MF, and 25.0% had post-polycythemia vera MF.

There were 92% of patients with disease classified as intermediate-2/high-risk by the Dynamic International Prognostic Scoring System (DIPSS) and 83% were considered high or very high risk by the Molecular International Prognostic Scoring System (MIPSS70+). There were 66.7%, 25.0%, and 16.7% of patients with JAK2, MPL, or CALR driver mutations, respectively, at diagnosis.

After transplantation, 99.9% of patients achieved donor chimerism at day 30 and 96.6% at day 100. Patients relapsed after alloHCT within a median of 282.5 days (range, 96-2388 days). The median donor chimerism before initiating an HMA was 57.82%.

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Shear Wave Elastography Distinguishes Myelofibrosis From Other MPNs

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Sep 25, 2024

 

Liver and spleen shear-wave elastography helped distinguish patients with myelofibrosis from healthy controls and those with essential thrombocytopenia, according to findings published in the Journal of Ultrasound. This suggests that the technique may help diagnose myeloproliferative neoplasms.

Researchers added that liver stiffness and spleen stiffness appeared to be linked with bone marrow fibrosis.

“Vibration-controlled transient elastography (VCTE) has proven to be a valuable tool in providing prognostic and staging information in patients with liver disease, greatly reducing the need for liver biopsy,” Vito Sansone, MD, Student, and colleagues wrote. “Spleen stiffness, similarly, has proven useful as a surrogate marker of portal hypertension. To date, however, the role of any of these techniques in the work-up of MPNs has not been established. …This study aims to investigate if values of liver and spleen stiffness measured with shear-wave elastography could help to differentiate MPNs from healthy controls and if there are significant differences in values of liver stiffness and spleen stiffness.”

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New Trial Sets Out to Test Treatment for Early Primary MF

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Özge Özkaya, MSc, PhD

A new randomized, double-blind, placebo-controlled, phase 3 clinical trial assessing the safety and efficacy of ropeginterferon alfa-2b, a new-generation pegylated interferon-based therapy, in patients with early and lower-risk primary myelofibrosis (MF) is now open.

The trial aims to recruit 150 such patients who are at least 18 years of age and will receive either up to 500 μg of subcutaneous ropeginterferon alfa-2b or a placebo every 2 weeks until 56 weeks.

The primary endpoints of the trial include clinically relevant complete hematologic response as measured by platelet count, white blood cell count, hemoglobin levels in peripheral blood, absence of thrombotic events, and no progression to acute myeloid leukemia, and symptom endpoint.

Secondary endpoints include bone marrow response, event-free survival or progression-free survival, molecular response in driver or relevant coexisting gene mutations, and safety.

“The study will provide important data for the treatment of early/lower-risk [primary] MF for which an anti-clonal, disease-modifying agent is highly needed,” the researchers wrote in an article that they published in the journal Annals of Hematology, which contains the details of the trial design.

The trial is not yet recruiting participants. It is estimated to start in October 2024 and be completed in August 2027.

Previous research has shown that ropeginterferon alfa-2b has favorable pharmacokinetics and safety profiles and requires less frequent injections than previous formulations of pegylated interferon alfa, the researchers noted.

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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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Rovadicitinib Bests Hydroxyurea in Myelofibrosis

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Erin Clancy

The JAK2 inhibitor rovadicitinib proved more effective than hydroxyurea in patients with JAK inhibitor-naïve, intermediate-2 or high-risk myelofibrosis in a phase 2 trial presented at the ESMO Congress 2024.

These results “support the use of rovadicitinib as a new treatment option” for these patients, said study presenter Ling Pan, of West China Hospital, Sichuan University, in Chengdu, China.

The trial (NCT05020652) enrolled 105 patients with intermediate-2 or high-risk primary, post-polycythemia vera, or post-essential thrombocythemia myelofibrosis. All patients had received no prior JAK inhibitor treatment and had palpable splenomegaly.

Patients were randomly assigned 2:1 to receive rovadicitinib at 15 mg twice daily plus placebo (n=72) or hydroxyurea at 0.5 g twice daily plus placebo (n=35). Baseline characteristics were well balanced between the arms.

Treatment continued for 24 weeks, at which point patients who achieved a spleen volume reduction of 35% or greater (SVR35) maintained treatment as assigned. Those who had not achieved SVR35 by week 24 received open-label rovadicitinib at 15 mg twice daily until treatment termination criteria were met.

At week 24, the SVR35 rate was 58.33% in the rovadicitinib arm and 22.86% in the hydroxyurea arm (P =.0006). The best spleen response rate during the study period was 63.89% with rovadicitinib and 31.43% with hydroxyurea (P =.0017).

The proportion of patients who achieved a 50% or greater reduction in total symptom score at week 24 was 61.11% with rovadicitinib and 45.71% with hydroxyurea (P =.136). The best symptom response rate during the study period was 77.78% with rovadicitinib and 54.29% with hydroxyurea (P =.0136).

Eighteen patients who initially received hydroxyurea but switched to rovadicitinib after week 24 were included in the safety analysis, so 90 patients were evaluable in the rovadicitinib arm and 35 patients were evaluable in the hydroxyurea arm.

The rate of treatment-emergent adverse events (TEAEs) was 97.78% in the rovadicitinib arm and 100% in the hydroxyurea arm. The rate of grade 3 or higher TEAEs was 51.11% and 77.14%, respectively. The rate of serious TEAEs was 31.11% and 40.00%, respectively.

The most common grade 3 or higher hematologic TEAEs (in the rovadicitinib and hydroxyurea arms, respectively) were platelet count decrease (20.00% and 17.14%) and anemia (28.89% and 60.00%). The most common grade 3 or higher non-hematologic TEAE was hyperkalemia (6.67%) in the rovadicitinib arm and weight gain (2.86%) in the hydroxyurea arm.

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Patients With Lower-Risk Myelofibrosis May Respond to Jakafi

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By Darlene Dobkowski, MA
Fact checked by Ashley Chan

Responses to treatment with Jakafi (ruxolitinib) were more frequent and durable in patients with intermediate-1 risk (low-risk) myelofibrosis, according to findings from a real-world study.

In addition, patients with intermediate-2 (high-risk) myelofibrosis had lower rates of toxicity from Jakafi treatment, as shown in findings from the study published in the journal Cancer.

After six months of treatment with Jakafi, spleen response rates were observed in 26.8% of patients, with symptom response rates in 67.9% of patients with intermediate-1 risk myelofibrosis.

“Splenomegaly (enlarged spleen) and symptoms may be extremely burdensome also in lower-risk patients, with approximately 40% of such patients starting [Jakafi] with a large splenomegaly and a high symptom score,” the study authors wrote. “This finding again supports how the clinical phenotype of [myelofibrosis] should guide the medical therapeutic approach, without being influenced by the prognostic risk category, which, in contrast, is essential instead for the transplant decision.”

Predictors of responses at six months after initiating treatment with Jakafi included no cytopenia (a condition with a lower-than-normal number of blood cells, which can include hemoglobin levels, platelets and white blood cells), no high-molecular-risk mutations and blasts less than 1%. Out of all these factors, high-molecular-risk mutations continued to have a significant association with responses.

According to The Leukemia & Lymphoma Society, blasts are immature blood cells that are a result of mutated stem cells multiplying uncontrollably. They do not mature into healthy blood cells, nor do they function as such. Abnormal blasts, over time, can surpass the bone marrow’s production of normal healthy blood cells.

At the start of the study, 595 of the 1,055 patients (56.2%) with myelofibrosis had intermediate-1 risk according to two different scoring systems used to classify risk (Dynamic International Prognostic Scoring System and Myelofibrosis Score With Constitutional Symptoms – Peripheral Myeloid Immaturity). Both of these scoring systems take into account certain factors like hemoglobin levels, platelet count, spleen size and symptoms.

The spleen was palpable (meaning that it is enlarged and could be felt through the abdominal wall) at the lower edge of the rib cage at less than 5 centimeters in 5.9% of patients, between 5 and 10 centimeters in 47.4% and greater than 10 centimeters in 39.7%. Of note, 54.1% of patients were highly symptomatic.

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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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Ruxolitinib Stands Out Among JAK2 Inhibitors for Myelofibrosis

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By Targeted Oncology Staff

In this virtual tumor board discussion, experts review the case of a 68-year-old woman diagnosed with primary myelofibrosis. The discussion focuses on recent data and emerging insights to guide clinical decision-making and explore the latest advances in treatment strategies for this challenging disease.

Prithvira J. Bose, MD: What are the first steps you would take for this patient, and how do you view multidisciplinary collaboration?

Julie Huynh-Lu, PA-C: Specific to [The University of Texas] MD Anderson [Cancer Center], the role of the physician assistant or nurse practitioner in the leukemia department is to evaluate the patient. Aside from doing a review of systems, I go over the myeloproliferative neoplasms [MPN] questionnaire with the patients to review any changes in their score. Whether they have started therapy or not, [we determine whether they] need to be on therapy based on their answers.

I do a physical assessment of the patient checking their spleen. We don’t order ultrasounds or CT scans on patients unless we’re unable to palpate due to pain in that area. I’ll measure the spleen size every time the patient comes in with a tape measure.

Having a second set of eyes evaluating the patient [is key] because some questions that I may ask, someone else may not—or the physician may ask questions that I may not know [to ask]. Collaboration among nurses, physician assistants or nurse practitioners, and physicians in compiling patient information ensures the best care for the patient.

We are lucky to have the MPN10 form in the Epic system on our flow sheet, and patients can fill out this form before they check in for their appointment. If they were unable to fill it out, I can go into that flow sheet, ask those questions, and fill it out with them. Then, the score [generates] for each patient.

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Donor Source Does Not Impact Survival for HCT in Myelofibrosis

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Vicki Moore, PhD

For patients with myelofibrosis (MF) who received hematopoietic cell transplantation (HCT), a study showed that overall survival (OS) outcomes at 3 months were similar whether haploidentical or matched unrelated donor (MUD) HCT was used. Study results were published in the journal Blood Advances.

The study was based on data obtained from the Center for International Blood and Marrow Transplant Research (CIBMTR) registry. This analysis of donor trends included data for adults in the registry who received an initial HCT between January 2013 and December 2019 for primary or post-essential thrombocythemia or post-polycythemia vera MF. The study’s primary endpoint was OS.

There were 1597 HCTs identified over the study period. Among these, in 2013 there were 117 HCTs performed, while in 2019 this number had risen to 371. Additionally, the proportion of HCTs that involved haploidentical donors rose from 3% of total HCTs in 2013 to 19% in 2019.

Overall, 1032 patients met eligibility criteria for inclusion in further analyses for this study. Patients whose HCT involved mismatched unrelated donors (MMUDs; 64 patients) had a median age at HCT of 59.3 years, while patients with matched sibling donors (MSDs; 298 patients) had a median age at HCT of 61.4 years, patients with haploidentical donors had a median age of 62.5 years (119 patients), and patients with MUDs had a median age of 63 years (551 patients).

The median follow-up period was 46.5 months (range, 3.7-99.7) in this study. In univariate analyses, the 3-year OS rates were estimated to be 68.8% (95% CI, 63.3-74.1) for recipients of MSD-HCT, 59% (95% CI, 49.7-67.9) for recipients of haploidentical HCT, 61.3% (95% CI, 57.1-65.4) for recipients of MUD-HCT, and 55.2% (95% CI, 42.7-67.4) for recipients of MMUD-HCT (P =.03).

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