Tag Archives: mf

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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Real-World Data for Pacritinib Show Improvement in Thrombocytopenia, Anemia in Myelofibrosis

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September 10, 2024

Author(s): Jax DiEugenio

Fact checked by: Chris Ryan

Pacritinib (Vonjo) generated improvements in thrombocytopenia and anemia in patients with myelofibrosis treated in the real-world setting, according to data from a retrospective study presented at the 2024 SOHO Annual Meeting.1

Findings showed that patients with a platelet count below 100 x 109/L at baseline (n = 74) experienced an early increase in platelet count following treatment initiation that was maintained throughout the observation period. Additionally, an early increase in median hemoglobin was reported in all patients, and this increase was sustained throughout the observation period. Patients with hemoglobin level of less than 8.0 g/dL at the start of treatment (n = 35) experienced a hemoglobin increase of nearly 1 g/dL by day 30.

Notably, patients who received prior treatment with ruxolitinib (Jakafi; n = 69) experienced an increase in platelet counts and hemoglobin levels following initiation of pacritinib. At baseline, the median platelet count and median hemoglobin level in this population was 91.0 x 109/L and 8.7 g/dL, respectively. At day 360, the median platelet count and median hemoglobin were 97.0 x 109/L and 10.4 g/dL, respectively.

“In addition to spleen and symptom benefits observed in previous clinical trials, real-world outcomes demonstrate stability or improvement in thrombocytopenia and/or anemia in patients with myelofibrosis treated with pacritinib,” lead study author Michael Marrone, PhD, MPH, and colleagues, wrote in a poster presentation of the data. Marrone is an assistant professor in the College of Medicine, Department of Public Health Sciences, at the Medical University of South Carolina in Charleston.

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Managing Ruxolitinib-Associated Liver Toxicity in Patients With Myelofibrosis Requires a Nuanced Approach

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September 4, 2024

William J. Hogan, MBBCh, MRCPI

Key Points:

  • Ruxolitinib plays an important role in the treatment of symptomatic myelofibrosis, but its associated toxicities and adverse withdrawal effects can pose a challenge.
  • Myelofibrosis is linked with hepatic dysfunction, and ruxolitinib—despite its associated risks of hepatic transaminitis—may limit inflammation and progressive fibrosis, with liver injury resolution reported after treatment.
  • Overall, management of liver injury related to ruxolitinib depends on the cause and severity.

 

Question: In patients with myelofibrosis, how do you manage liver toxicity from ruxolitinib use beside dose de-escalation?

Answer: Ruxolitinib is a small-molecule JAK1/2 inhibitor that has an established role in the treatment of patients with symptomatic myelofibrosis, hydroxyurea-resistant polycythemia vera, and acute and chronic graft-versus-host disease. It has a potent anti-inflammatory effect that can provide very useful palliation of constitutional symptoms and splenomegaly in patients with myelofibrosis via inhibition of the JAK 1 and 2 pathways, which are involved in the production of inflammatory cytokines and hematopoietic growth factors.1-3 Common toxicities include myelosuppression, hepatic transaminitis, diarrhea, fatigue, headache, and peripheral edema. In patients with advanced myelofibrosis or florid inflammatory states, sudden withdrawal can lead to a systemic inflammatory response syndrome that can precipitate cardiopulmonary decompensation in frail patients, especially those with tenuous cardiopulmonary function, and corticosteroid prophylaxis or treatment may be required.4

In a mouse model of liver injury using carbon tetrachloride, JAK1/2 expression was implicated in progression of liver fibrosis. Inhibition of JAK1/2 downregulates downstream signaling, reduces progression to fibrosis, and even accelerates fibrosis reversal by inhibiting proliferation, migration, and activation of hepatic stellate cells in vitro.5 Myelofibrosis is associated with hepatic dysfunction by several mechanisms, including infiltration by hematopoietic stem cells (ie, extramedullary hematopoiesis [EMH]), portal vein thrombosis, and obliterative portal venopathy. EMH may respond favorably to ruxolitinib, and liver injury resolution after ruxolitinib treatment has been reported in patients with severe liver compromise related to myelofibrosis.6 These findings suggest that the drug may be able to reduce the consequences of inflammation—limiting progressive fibrosis in some circumstances—and may be of durable benefit in selected patients. A retrospective review of patients with liver injury and underlying myeloproliferative disorders treated with ruxolitinib and evaluated by biopsy demonstrated a variety of etiologies7; however, it is not always easy to determine how much is related to the underlying disease versus drug effects based on the biopsy findings, and this distinction is predominantly a clinical decision.

Liver toxicity typically manifests as mild hepatic transaminitis and can be exacerbated by drug–drug interactions. The incidence of hepatic transaminitis has been reported to be between 25% and 50%. Typically, these elevations are mild and self-limited, with < 1.5% of patients having values > 5 times the upper limit of normal. The drug is metabolized in the liver predominantly via the CYP3A4 pathway, and liver injury may be the result of the production of a toxic intermediate. Drug–drug interactions, such as with azole antifungals, can increase the effective exposure and enhance the potential for toxicity. Because suppression of intracellular signaling impairs immune response, suppression of viral replication may be impaired, increasing the potential for reactivation of quiescent viruses. This has been reported with reactivation of hepatitis B, resulting in clinically meaningful liver injury in patients who are at risk. It appears that the risk of viral reactivation with transaminitis and hyperbilirubinemia is greater in patients with HBsAg positivity, but reactivation has also been reported in those with anti-HBc. Efficacy with entecavir has been reported in treating viral reactivation and prophylaxis, so a nucleoside analog such as entecavir or tenofovir should be considered in patients who are at high risk.8-10

Management of liver injury related to ruxolitinib depends on the cause and severity. Identifying contributing causes, such as drug–drug interactions and prior viral hepatitis exposure and excluding other hepatotoxins are the initial imperative. Prior viral exposure with reactivation should be treated or prophylaxed when applicable. For mild transaminase elevations without hyperbilirubinemia, monitoring or temporary dose reduction may be appropriate. In more significant liver injury, dose interruption may be necessary. Consideration of an alternative JAK inhibitor may occasionally be warranted, as there does not appear to be significant evidence to suggest cross-reactivity between ruxolitinib and other JAK inhibitors. Of note, a retrospective review of liver injury occurring in patients with myeloproliferative neoplasms receiving ruxolitinib suggested a variety of potential etiologies, including those unrelated to the drug itself (EMH), in addition to obstructive portal vein apathy and drug-induced liver injury.

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Talazoparib Plus Pacritinib Aims to Improve the Limitations of Second-Line Therapy in MPNs

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September 5, 2024

Author(s): Caroline Seymour

Fact checked by:Kristi Rosa

The combination of talazoparib (Talzenna) and pacritinib (Vonjo) could provide more than symptom burden relief for patients with myeloproliferative neoplasms (MPNs) who have become unresponsive to frontline JAK2 inhibition with ruxolitinib (Jakafi), according to Peter Abdelmessieh, DO, MSC.

The regimen is under study in a phase 1 trial (NCT06218628) at Fox Chase Cancer Center and is supported by earlier work published in Blood showing the synergistic disease-modifying activity of the regimen.1

To be eligible for enrollment, patients must have received a diagnosis of histologically or cytologically confirmed primary myelofibrosis, post-polycythemia vera-myelofibrosis, post-essential thrombocythemia-myelofibrosis, chronic myelomonocytic leukemia, polycythemia vera, or essential thrombocytosis according to the 2008 World Health Organization criteria. Patients must also have at least 2 symptoms with a score of 3 or greater or a total score of 12 or greater, according to the Myelofibrosis Symptom Assessment Form v4.0; intermediate-2 or high-risk myelofibrosis according to the Dynamic International Prognostic Scoring System Plus; and a baseline QTc less than 0.47 seconds per Bazett formula.

Additionally, patients must have prior exposure to a JAK2 inhibitor for at least 12 weeks with documented disease progression or have new, palpable splenomegaly measuring at least 5 cm below the left costal margin in patients who had no evidence of splenomegaly before the start of any frontline JAK2 inhibitor.2

“Second-line treatment for patients with this disease is an unmet need along with the need to investigate other possible pathways that might be effective in this disease. The tool shed is essentially barren for clinicians outside of JAK2 inhibitors,” Abdelmessieh said in an interview with OncLive®.

In the interview, Abdelmessieh, an assistant professor in the Department of Bone Marrow Transplant and Cellular Therapies at Fox Chase Cancer Center, in Philadelphia, Pennsylvania, discussed the basis for the phase 1 trial in patients with MPNs.

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Momelotinib May Improve Survival and Quality of Life in MF

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August 30, 2024

Leonardo Jaimes

Momelotinib appears to positively impact quality of life and overall survival in patients with myelofibrosis (MF), according to a recently published study in Frontiers in Oncology.

Most MF cases are associated with JAK or CALR mutations, which lead to an uncontrolled proliferation of stem cells and a decrease in the production of red blood cells (RBCs) and thrombocytes, the researchers noted.

Stem cell transplantation is currently the only curative alternative available for patients with MF. The advent of JAK inhibitors represented a significant advancement in symptom management, but patients often observed decreased efficacy after 3 years.

Anemia is largely responsible for the decrease in quality of life seen in patients with MF and represents an important cause of treatment discontinuation, as some of the treatments used in MF can contribute to the development of anemia.

“Anemia in MF is a complex condition resulting from factors such as displacement of erythropoietic tissue by fibrotic stroma, suboptimal environments in extramedullary sites, and splenomegaly-induced RBC sequestration,” the authors wrote.

Momelotinib is an effective JAK1/2 inhibitor that can successfully treat anemia in patients with MF, decreasing the need for transfusions. It can also prevent hepcidin synthesis, which in turn leads to increased iron circulation and increased erythropoiesis.

The effectiveness of momelotinib is supported by the results of the MOMENTUM trial; the double-blind included almost 200 patients who received either momelotinib or danazol to treat MF-associated anemia.  Results showed that patients who received were significantly less likely to require blood transfusions and have better Total Symptom Score than their counterparts.

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A randomized, double-blind, placebo-controlled phase 3 study to assess efficacy and safety of ropeginterferon alfa-2b in patients with early/lower-risk primary myelofibrosis

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Ghaith Abu-Zeinah, Albert Qin, Harinder Gill, Norio Komatsu, John Mascarenhas, Weichung Joe Shih, Oleh Zagrijtschuk, Toshiaki Sato, Kazuya Shimoda, Richard T. Silver & Ruben Mesa

Abstract

Primary myelofibrosis (PMF) is the most aggressive of the myeloproliferative neoplasms and patients require greater attention and likely require earlier therapeutic intervention. Currently approved treatment options are limited in their selective suppression of clonal proliferation resulting from driver- and coexisting gene mutations. Janus kinase inhibitors are approved for symptomatic patients with higher-risk PMF. Additionally, most ongoing clinical studies focus on patients with higher-risk disease and/or high rates of transfusion dependency. Optimal treatment of early/lower-risk PMF remains to be identified and needs randomized clinical trial evaluations. Pegylated interferon alfa is recommended for symptomatic lower-risk PMF patients based on phase 2 non-randomized studies and expert opinion. Ropeginterferon alfa-2b (ropeg) is a new-generation pegylated interferon-based therapy with favorable pharmacokinetics and safety profiles, requiring less frequent injections than prior formulations. This randomized, double-blind, placebo-controlled phase 3 trial will assess its efficacy and safety in patients with “early/lower-risk PMF”, defined as pre-fibrotic PMF or PMF at low or intermediate-1 risk according to Dynamic International Prognostic Scoring System-plus. Co-primary endpoints include clinically relevant complete hematologic response and symptom endpoint. Secondary endpoints include progression- or event-free survival, molecular response in driver or relevant coexisting gene mutations, bone marrow response, and safety. Disease progression and events are defined based on the International Working Group criteria and well-published reports. 150 eligible patients will be randomized in a 2:1 ratio to receive either ropeg or placebo. Blinded sample size re-estimation is designed. Ropeg will be administered subcutaneously with a tolerable, higher starting-dose regimen. The study will provide important data for the treatment of early/lower-risk PMF for which an anti-clonal, disease-modifying agent is highly needed.

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Triple-Negative Myelofibrosis Associated With Decreased Survival, Aggressive Clinical Behavior and Shorter Duration of Response to Ruxolitinib

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August 14, 2024

Amber Denham

According to recently published research in Clinical Lymphoma, Myeloma & Leukemia, triple-negative myelofibrosis (TN-MF) was found to be continually associated with decreased survival, enhanced aggressive clinical behavior with higher rates of leukemic transformation, and a shorter duration of response to ruxolitinib.

“Myelofibrosis is the most aggressive subtype among classical BCR::ABL1 negative myeloproliferative neoplasms…Triple-negative myelofibrosis accounts for only 5% [to] 10% of cases and carries the worst outcomes,” explained lead study author Luis Aguirre, MD, Dana-Farber Cancer Institute, Harvard Medical School, Cambridge, Massachusetts, and colleagues. They added, “Little has been described about this subset of disease…identification of features of interest and assessment of treatment response are areas in need of further investigation.”

Researchers evaluated baseline clinical and molecular parameters from 626 patients with myelofibrosis who presented to the H. Lee Moffitt Cancer Center in Tampa, Florida, between 2003 and 2021. These data were compared based on the presence or absence of the 3 classical phenotypic driver mutations.

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Cardiovascular Risk in Philadelphia-Negative Myeloproliferative Neoplasms: Mechanisms and Implications—A Narrative Review

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by Samuel Bogdan Todor, Cristian Ichim, Adrian Boicean, and Romeo Gabriel Mihaila

Abstract

Myeloproliferative neoplasms (MPNs), encompassing disorders like polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are characterized by clonal hematopoiesis without the Philadelphia chromosome. The JAK2 V617F mutation is prevalent in PV, ET, and PMF, while mutations in MPL and CALR also play significant roles. These conditions predispose patients to thrombotic events, with PMF exhibiting the lowest survival among MPNs. Chronic inflammation, driven by cytokine release from aberrant leukocytes and platelets, amplifies cardiovascular risk through various mechanisms, including atherosclerosis and vascular remodeling. Additionally, MPN-related complications like pulmonary hypertension and cardiac fibrosis contribute to cardiovascular morbidity and mortality. This review consolidates recent research on MPNs’ cardiovascular implications, emphasizing thrombotic risk, chronic inflammation, and vascular stiffness. Understanding these associations is crucial for developing targeted therapies and improving outcomes in MPN patients.

Donor Type Impacts Survival in MF Cell Transplantation

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Leonardo Jaimes

Patients with myelofibrosis (MF) who receive hematopoietic cell transplantation (HCT) from a matched sibling donor appear to have better overall survival (OS) than those who receive transplants from other donor types, according to a recently published study in Blood Advances.

“Understanding the impact of donor type is crucial not only to improve the clinical outcomes with HCT but also to establish the donor pool with viable options and eventually improve access to HCT,” the authors wrote.

HCT is currently the only disease-modifying therapy available for MF, the study team noted. The outcome after transplantation is diverse and dependent on several disease- and patient-associated factors, they added. According to recent research, donor type could also influence the prognosis of patients with MF after HCT. One study showed that patients with matched sibling donors had a better OS than the rest.

However, previous research has not taken the impact of posttransplantation cyclophosphamide for graft versus host disease prophylaxis into consideration, the researchers noted. Furthermore, no patients in previous studies had received vHLA-haploidentical donor grafts, they continued.

Therefore, the authors aimed to assess the impact of donor type in OS, considering the factors above and using the Center for International Blood and Bone Marrow Transplant Research registry data for HCTs done between 2013 and 2019. The study included over 1000 patients who received HCTs for MF.

Results showed that similarly to previous findings, matched sibling transplants were associated with better overall survival and lower graft failure than the rest. However, OS was only superior to the rest in the first 90 days after transplant. There was no significant difference in OS among patients who received mismatched unrelated, matched unrelated, and haploidentical donor transplants.

Despite the findings, the authors remarked that HCTs should not be delayed in the search for fully matched donors and highlighted the need for solutions regarding graft failure.

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Prospective Study to Evaluate Fedratinib Plus Nivolumab in Myelofibrosis

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Andrea S. Blevins Primeau, PhD, MBA

A single-arm, phase 2 study of fedratinib, a selective JAK2 inhibitor, plus nivolumab is planned for patients with myelofibrosis (MF) who had a suboptimal or no response to a JAK inhibitor was initiated, according to a report published in the Annals of Hematology.

“This study will provide new findings that may contribute to advancing the treatment landscape for MF patients with suboptimal responses and limited alternatives,” the researchers wrote in their report. Currently, 23 of 30 planned patients are enrolled in the study and recruitment is expected to be completed by December 2024.

The open-label FRACTION trial will treat patients with MF from 9 academic centers in Germany, who will receive 400 mg of fedratinib daily in 28-day cycles, followed by 240 mg of nivolumab every 2 weeks beginning in cycle 2. Treatment will be given until progressive disease, relapse, death, or study discontinuation.

This study will provide new findings that may contribute to advancing the treatment landscape for MF patients with suboptimal responses and limited alternatives.

The primary efficacy endpoints will be response rate within 12 treatment cycles and RCT independency. Secondary endpoints will include safety, incidence of leukemic transformation, clinical benefit, duration of response, progression-free survival, overall survival, and disease burden. Molecular analyses will also serve as exploratory endpoints for the study.

Patients with MF primary or secondary MF are eligible if they had a suboptimal or no response to a JAK inhibitor, which is defined by persistent symptoms, splenomegaly, cytopenia, or hyperproliferation. Patients who have received a prior immune checkpoint inhibitor or history of uncontrolled autoimmune disease are not eligible for the study.

Disclosures: This research was supported in part by Celgene/Bristol Myers Squibb. Please see the original reference for a full list of disclosures.

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