Safety and Efficacy of Busulphan Based on Dosing Patterns in the Real‐World Management of Myeloproliferative Neoplasms

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March 2025

Ali Mahdi, Alexandros Rampotas, Patrick Roberts, Joanna Stokes

Abstract

Introduction
Myeloproliferative neoplasms (MPNs), such as polycythaemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF), are primarily treated by managing blood counts to reduce the thrombotic risk using cytoreductive agents. Busulphan, an oral alkylating agent, has been historically used for MPN management due to its myelosuppressive effects, but concerns about its risk of leukaemic transformation have limited its use.
Methods
This real‐world retrospective study evaluated the safety and efficacy of busulphan in 115 MPN patients across 13 UK hospitals. Responses in patients with ET and PV only were assessed using European LeukemiaNet (ELN) criteria.
Results
With a median age of 78 years, the overall response rate was 78.1%, with 29% of PV and 18% of ET patients achieving complete responses. Dosing regimens were similarly distributed between repeated single doses of busulphan (31%), courses of treatment lasting 1–4 weeks (30%) and continuous therapy for more than 4 weeks (35%). No cases of disease progression to acute leukaemia or myelofibrosis were recorded during the median follow‐up of 23 months. Adverse events were infrequent, with fatigue and cytopaenia being the most common (4% each).
Conclusion
Busulphan demonstrated a favourable safety profile and is a viable cytoreductive option, particularly for elderly patients who are intolerant to hydroxycarbamide.

Understanding Hematocrit Thresholds in Polycythemia Vera Treatment

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March 19, 2025

Author(s): Maggie L. Shaw, Andrew Kuykendall, MD

In early March, The American Journal of Managed Care® spoke with Andrew Kuykendall, MD, a clinical researcher at Moffitt Cancer Center who focuses on myeloproliferative neoplasms (MPNs), myelodysplastic syndrome/MPN overlap syndromes, and systemic mastocytosis. Kuykendall is an investigator on the phase 3 VERIFY trial (NCT05210790) of the injectable hepcidin mimetic rusfertide (Takeda) to treat polycythemia vera (PV) by enabling patients to achieve and sustain hematocrit control.1 Hematocrit is the measure of the percentage of red blood cells in the body.2

Treatment guidelines in PV currently recommend maintaining hematocrit below 45%, with a higher threshold for men vs women.2 For part 2 of this interview, Kuykendall explains the reasoning behind having different hematocrit thresholds.

In the first part of the interview, Kuykendall discussed how PV manifests and common ways to reduce its negative impact on patient quality of life.

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Optimizing Myelofibrosis Care in the Age of JAK Inhibitors

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Author: Douglas Tremblay, MD

How do you assess a patient’s prognosis at the time that they are diagnosed with myelofibrosis?
In the clinic, we use several scoring systems that have been developed based on the outcomes of hundreds of patients with myeloproliferative neoplasms (MPNs) to try to predict survival from time of diagnosis. Disease features associated with a poor prognosis include anemia, elevated white blood cell count, advanced age, constitutional symptoms, and increased peripheral blasts. Some of these scoring systems also incorporate chromosomal abnormalities as well as gene mutations to further refine prognostication.1

Determining prognosis can be important to creating a treatment plan, particularly to decide if curative allogeneic stem cell transplantation is necessary. However, I always caution patients that these prognostic scoring systems cannot tell the future and that each patient may respond differently to treatment.

How do you monitor for disease progression?
I will discuss with patients how they are feeling in order to determine if there are any new or developing symptoms that could be a sign that their disease is progressing. I will also review their laboratory work looking for changes in blood counts that could be a signal of disease evolution.

For instance, development of anemia or thrombocytopenia may signal worsening bone marrow function or progression to secondary acute leukemia. If there are concerning signs or symptoms, I will then perform a bone marrow biopsy with aspirate that will include assessment of mutations and chromosomal abnormalities to determine if their disease is progressing.

What are the first-line treatment options for a patient newly diagnosed with myelofibrosis, and how do you determine the best course of action?
For patients with myelofibrosis, the first-line treatment options include Janus kinase (JAK) inhibitors, which are effective at improving spleen size and reducing symptom burden. The US Food and Drug Administration (FDA) has approved 4 JAK inhibitors for the treatment of myelofibrosis: ruxolitinib, fedratinib, pacritinib, and momelotinib (Table).2-13 In general, ruxolitinib is the first-line treatment option unless there is thrombocytopenia, in which case pacritinib is more appropriate. In patients with baseline anemia, momelotinib may be the best choice.

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Pelabresib Plus Ruxolitinib Improves Spleen Responses in Myelofibrosis

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By Roman Fabbricatore
Fact checked by Russ Conroy

Pelabresib (CPI 0610) in combination with ruxolitinib (Jakafi) significantly improved spleen responses and elicited robust clinical activity compared with placebo/ruxolitinib in patients with JAK inhibitor-naïve myelofibrosis, according to results from the phase 3 MANIFEST-2 trial (NCT04603495) published in Nature Medicine.1

Efficacy data from the trial revealed that the primary end point of spleen volume reduction of at least 35% at week 24 favored the investigational combination vs the placebo arm: 65.9% vs 35.2%, respectively (difference, 30.4%; 95% CI, 21.6%-39.3%; P <.001). Additionally, the mean percent change at week 24 in the respective arms was –50.6% (95% CI, –53.2% to –48.0%) vs –30.6% (95% CI, –33.7% to –27.5%). Spleen volume response was consistently higher with pelabresib vs placebo across predefined subgroups.

Furthermore, the hemoglobin response rate, defined as a 1.5 g/dl or greater mean increase, occurred in in 10.7% of the pelabresib arm (95% CI, 6.60%-14.90%) vs 6.0% of the placebo arm (95% CI, 2.85%-9.19%). Transfusions were received in the first 24 weeks of treatment in 27.6% and 37.5% of respective arms.

Greater reductions in NF-κB-regulated cytokines (–32.1% [95% CI, –34.9% to –29.2%] vs –19.4% [95% CI, –22.5% to –16.2%]), tumor necrosis factor (TNF; –43.5% [95% CI, –47.0% to –39.8%] vs –26.4% [95% CI, –30.5% to –22.1%]), and interleukin-6 (IL-6; –35.4% [95% CI, –44.2% to –25.2%] vs –14.5% [95% CI, –25.2% to –2.3%]) were seen in the investigational arm vs the placebo arm. Of note, a reduction in IL-8 levels was observed with pelabresib (–14.3% [95% CI, –22.3% to –5.5%]), but an increase was observed in the placebo arm (31.2% [95% CI, 17.5%-46.5%).

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Dr Rampal on ​Emerging Therapies Under Investigation in Myelofibrosis

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March 17, 2025

Author(s): Raajit K. Rampal, MD, PhD

Fact checked by: Ashling Wahner ,Chris Ryan

Raajit Rampal, MD, director of the Center for Hematologic Malignancies and director of the Myeloproliferative Neoplasms Program at Memorial Sloan Kettering Cancer Center, discusses emerging treatments for patients with myelofibrosis.

The therapeutic paradigm for myelofibrosis continues to expand with emerging treatment options, particularly with combination therapies, novel JAK inhibitors, and immunotherapeutic agents, Rampal begins. Among these, pelabresib (CPI-0610), a BET inhibitor, has completed phase 3 trials. Preliminary data from the phase 3 MANIFEST-2 trial (NCT04603495), which were presented in December 2023, demonstrated improved spleen responses and a trend toward better symptom management with the combination of pelabresib and ruxolitinib (Jakafi) vs placebo plus ruxolitinib in patients with JAK inhibitor–naive myelofibrosis. Updated findings from MANIFEST-2 were published in Nature Medicine in March 2025.

Beyond pelabresib, several other agents are currently in phase 3 trials for patients with myelofibrosis, Rampal says. Selinexor (Xpovio), which is currently FDA approved for the treatment of patients with relapsed/refractory multiple myeloma, is being studied in combination with ruxolitinib in patients with myelofibrosis in the phase 3 XPORT-MF-034 trial (NCT04562389). Additionally, navtemadlin (KRT-232), an MDM2 inhibitor, is undergoing clinical evaluation in patients with myelofibrosis. Notably, these trials are ongoing, and no conclusive data are available at this time, Rampal emphasizes.

The development of next-generation JAK inhibitors also represents a promising area of investigation, according to Rampal. These newer inhibitors are anticipated to demonstrate greater potency and selectivity compared with existing agents, though they remain in early-phase clinical trials, he notes.

Rampal states that one of the most exciting advancements in this setting is the emergence of immunotherapies. Calreticulin-targeted antibodies are currently being evaluated in clinical trials, and 2 candidates are in development, he reports. If these agents prove effective, they could significantly alter the treatment paradigm, he concludes.

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Jakafi May Not Associate with Long-Term Benefits in Myelofibrosis Subset

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March 16, 2025

Author(s): Spencer Feldman

Fact checked by: Alex Biese

Among patients with calreticulin (CALR)-mutated myelofibrosis, real-world data reveal insights into those with splenomegaly and/or symptoms requiring therapy with Janus kinase 2 (JAK2) inhibitors.

The findings suggest that while Jakafi (ruxolitinib) shows some initial benefits, CALR-mutated patients may require more targeted and innovative therapeutic approaches for better long-term outcomes, according to study findings published in Annals of Hematology.

“Overall, despite the initial benefits of [Jakafi], CALR-mutated patients may require more innovative therapeutic interventions to achieve optimal outcomes. This further emphasizes the necessity of exploring alternative or adjunctive therapies tailored specifically for CALR-mutated individuals,” lead study author Dr. Francesca Palandri and colleagues wrote in the study.

Palandri is currently an adjunct professor primarily based in the Department of Experimental, Diagnostic and Specialty Medicine at the Università di Bologna, Bologna, Italy. She is also a junior researcher at Azienda Ospedaliero-Universitaria di Bologna, Institute of Hematology, Bologna, Italy.

Patients with CALR mutations began Jakafi with more severe disease, including higher peripheral blast counts, lower hemoglobin levels and worse marrow fibrosis, and after a longer median time from diagnosis (2.6 versus 0.7 years) compared to patients with JAK2 mutations. At six months, spleen responses were numerically lower in CALR-mutated patients, who also had lower rates of symptom responses (56.1% versus 66.7%, respectively). However, CALR-mutated patients experienced lower rates of high white blood cell counts.

Furthermore, in patients with delayed Jakafi initiation, anemia and reduced starting doses correlated with poorer survival. Managing anemia through interventions like danazol, erythropoiesis-stimulating agents, iron chelation and optimized Jakafi dosing may improve outcomes, according to study authors. The study also highlights the potential benefits of alternative JAK2 inhibitors with lower hematological toxicity.

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Topics of Interest in Women With Myeloproliferative Neoplasms

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March 2025

Natasha Szuber, Paola Guglielmelli, Naseema Gangat

Abstract

Overview
Sex and gender have emerged as central modifiers of disease biology, phenotype, and clinical outcomes in myeloproliferative neoplasms (MPNs). This review will uniquely highlight issues affecting women with MPN and articulate their relevant determinants.
Epidemiology and Diagnosis
A higher overall prevalence of MPN has been established in women. The incidence of essential thrombocythemia (ET) predominates, while, conversely, polycythemia vera (PV) and myelofibrosis (MF) are seen in lower frequencies as compared to men. Diagnostic criteria are dictated by sex‐driven physiological variances in hemoglobin and hematocrit levels in PV, mandating separate diagnostic thresholds, respectively: > 16.0 g/dL and > 48% in women vs. > 16.5 and > 49% in men. Genetic Framework and Phenotype Women with MPN harbor fewer acquired somatic mutations and a lower frequency of high‐risk mutations than their male counterparts; lower JAK2V617F driver variant allele frequency and attenuated allele burden kinetics have also been reported. Women with MPN are younger at diagnosis than men and, contingent on subtype, display more indolent disease features. Importantly, validated symptom burden assessments consistently disclose higher scores in women vs. men.
Thrombosis and Outcomes
Women with MPN have a unique thrombotic diathesis with respect to men, more frequently involving the splanchnic venous system in those ultimately diagnosed with PV. Outcomes data depict female sex as a variable associated with more favorable clinical trajectories, including lower rates of MF/leukemic transformation and secondary cancers, as well as improved overall survival rates vis‐à‐vis men. Life‐Cycle Windows, Pregnancy, and Postpartum Potential challenges at each significant life stage will be addressed: puberty, preconception and fertility, and perimenopause; these include issues surrounding oral contraceptives and hormone use. Prospective studies suggest overall favorable maternal and fetal outcomes with pregnancy in women with MPN. Full details on risks and reported outcomes will be discussed, as well as a risk‐adapted approach to management informed by obstetric and thrombosis history. Recommendations include aspirin 81 mg daily in all patients and cytoreduction with interferon‐α in those with antecedent thrombosis, as well as in low‐risk cases with higher‐risk features (e.g., poorly controlled hematocrit and recurrent fetal loss). Antepartum anticoagulation with low molecular weight heparin (LMWH) is recommended in cases with previous venous thromboembolism.
Conclusions and Future Directions
This review highlights female sex and gender as critical drivers of MPN incidence, presentation, and natural history. It further outlines the impact and management of MPN as related to unique female reproductive phases. A sex‐informed lens will be required in order to recalibrate current prognostic tools, a requisite to refining patient counselling and clinical decision‐making in line with precision medicine. Moreover, while several mechanisms underpinning sex‐defined discrepancies have been defined, these mandate further prospective study. Finally, sex and gender‐based differences must be weighted in clinical trials with systematized procedures to correct participation imbalances in favor of sex and gender equity.

 

Risk for Specific Hematologic Cancers Down With GLP-1 Receptor Agonist Use in T2DM

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Publish Date

HealthDay News — For patients with type 2 diabetes (T2D), glucagon-like peptide-1 receptor agonist (GLP-1 RA) use is associated with a reduced risk for developing hematologic cancers compared with insulin and metformin use, according to a research letter published online March 6 in JAMA Network Open.

Omer S. Ashruf, from Northeast Ohio Medical University in Rootstown, and colleagues conducted a retrospective cohort study to compare the risks for hematologic cancers in patients with T2D treated with a GLP-1 RA versus metformin and insulin. The study included patients with T2D prescribed a GLP-1 RA, insulin, or metformin between April 30, 2005, and Oct. 31, 2023 (51,617; 611,115; and 938,602 patients, respectively). Groups were independently matched using a nearest neighbor greedy matching algorithm; 47,716 patients were included in the GLP-1 RA-insulin analysis and 50,590 were included in the GLP-1 RA-metformin analysis.

The researchers found that GLP-1 RA use was associated with significantly lower risks for of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) compared with metformin (hazard ratios, 0.61 and 0.67, respectively). No significant difference was seen in the risk for any other hematologic cancer. GLP-1 RA use was associated with significantly lower risks for myeloid leukemia, lymphoid leukemia, non-Hodgkin lymphoma, MDS, MPN, monoclonal gammopathy, multiple myeloma, and amyloidosis compared with insulin (hazard ratios, 0.39, 0.45, 0.42, 0.19, 0.50, 0.68, 0.49, and 0.52, respectively). GLP-1 RA use was associated with a 54 percent lower risk than that seen with insulin across all hematologic cancers.

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Optimizing Treatment in Patients With Myelofibrosis and Transfusion-Dependent Anemia

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By Clinical Content Hub

In patients with MF, greater anemia severity and transfusion dependency have been linked to worse overall survival and quality of life (QOL). Historically, the only available treatment strategies for MF-related anemia have shown limited efficacy and an increased risk for numerous adverse effects.1,2

In September 2023, the US Food and Drug Administration (FDA) approved momelotinib, an oral inhibitor of JAK1 and JAK2 as well as activin A receptor type 1 (ACVR1), for the treatment of adults with anemia and intermediate or high-risk MF. Momelotinib is currently the only FDA-approved therapy indicated for the treatment of MF patients with anemia.3 In clinical trials, this first-in-class treatment has shown efficacy in treating anemia and other key manifestations of MF.4

Douglas Tremblay, MD, is an assistant professor of medicine at the Icahn School of Medicine at Mount Sinai in New York City, New York, specializing in hematologic malignancies such as myelodysplastic/myeloproliferative overlap syndromes, myeloproliferative neoplasms, and acute myeloid leukemia. He serves as the principal investigator on multiple clinical trials focused on myeloid neoplasms. In this article, Dr Tremblay discusses treatment strategies for MF patients, with a particular focus on those with transfusion-dependent anemia, as well as emerging developments in the MF treatment landscape.

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Impact of treatment for adolescent and young adults with essential thrombocythemia and polycythemia vera

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12 March 2025

Yan Beauverd, Jean-Christophe Ianotto, Kyaw Htin Thaw, Marta Sobas, Parvis Sadjadian, Natalia Curto-Garcia, Lee-Yung Shih, Timothy Devos, Dorota Krochmalczyk, Serena Galli, Maria Bieniaszewska, Ilona Seferynska, Mary Frances McMullin, et al.

Abstract

Essential thrombocythemia (ET) and polycythemia vera (PV) are rare in adolescent and young adult (AYA). These conditions, similar to those in older patients, are linked with thrombotic complications and the potential progression to secondary myelofibrosis (sMF). This retrospective study of ET and PV patients diagnosed before age 25 evaluated complication rates and impact of cytoreductive drugs on outcomes. Among 348 patients (278 ET, 70 PV) with a median age of 20 years, the of thrombotic events was 1.9 per 100 patient-years. Risk factors for thrombosis included elevated white blood cell count (>11 × 109/L) (HR: 2.7, p = 0.012) and absence of splenomegaly at diagnosis (HR: 5.7, p = 0.026), while cytoreductive drugs did not reduce this risk. The incidence of sMF was 0.7 per 100 patient-years. CALR mutation (HR: 6.0, p < 0.001) and a history of thrombosis (HR: 3.8, p = 0.015) were associated with sMF risk. Interferon as a first-line treatment significantly improved myelofibrosis-free survival compared to other treatments or the absence of cytoreduction (p = 0.046). Although cytoreduction did not affect thrombotic event, early interferon use reduced sMF risk. These findings support interferon use to mitigate sMF risk in AYA ET and PV patients.

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