Tag Archives: mpn

Younger Patients With PV May Benefit From Earlier Treatment With Cytoreductive Therapies

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Laura Joszt, MA

Although patients younger than age 60 with polycythemia vera (PV) are typically not treated with cytoreductive therapy due to treatment toxicity concerns, this may result in an undertreatment of patients as there is no clear evidence that the risk of toxicity exceeds the potential benefit of treatment, according to a study published in Blood Advances.1

PV causes an overproduction of blood cells in the bone marrow, which leads to high numbers of circulating red blood cells.2 This thickens the blood, which may not flow through smaller blood vessels properly. Although PV can be diagnosed at any age, it most often occurs in people over the age of 60 years.2

For most patients, phlebotomy is the standard treatment, and it may be the only treatment needed for years. However, additional treatment to suppress the formation of blood cells in the bone marrow may be needed. Cytoreductive therapies, such as interferons, hydroxyurea, ruxolitinib, and anagrelide, may be needed, particularly for high-risk patients.3

Currently, cytoreductive therapies are not routinely recommended by the European LeukemiaNet or National Comprehensive Cancer Network for patients with PV younger than 60 years who don’t have a history of thrombosis, a high symptom burden, or an intolerance to phlebotomy.

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Retrospective Study Shows HSCT Consolidation After Blast Reduction Improves OS in Chronic Phase–Reverted MPN

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Ashling Wahner

Patients with myeloproliferative neoplasms in accelerated or blast phase (MPN-AP/BP) who revert to chronic phase (cMPN) after blast-reduction therapy, as well as those with complete response (CR) or CR with incomplete hematologic recovery (CRi) after blast reduction, experience improved overall survival (OS) outcomes after hematopoietic stem cell transplant (HSCT) consolidation therapy, according to findings from a single-center, retrospective analysis evaluating outcomes with intensive and nonintensive blast-reduction strategies in patients with MPN-AP/BP, which were published in Blood Advances.1

This study, which used clinically relatable response criteria developed at the Princess Margaret Cancer Centre, as well as the European LeukemiaNet (ELN) 2022 acute myeloid leukemia (AML) response criteria, found that patients who received intensive blast-reduction therapy achieved a best overall response rate (ORR) of 77% (n = 62/81) vs 39% (n = 21/54) in those who received nonintensive therapy. CR/CRi and cMPN reversions were observed in 24 and 38 patients in the intensive group and 4 and 17 patients in the nonintensive group, respectively.

Although allogeneic HSCT is the only therapy associated with long-term survival improvements for patients with MPN-AP/BP, this treatment strategy is typically reserved for patients who have achieved disease control. Other blast-reduction strategies include induction chemotherapy, as well as hypomethylating agents (HMAs)—such as azacitidine (Vidaza)—as monotherapy or in combination with agents such as venetoclax (Venclexta).2

“However, the optimal blast-reduction strategy and depth of disease clearance required before HSCT are unknown,” lead study author Marta B. Davidson, MD, PhD, FRCPC, of the Princess Margaret Cancer Centre in Toronto, Ontario, Canada, and coauthors, wrote in the paper.1 “Moreover, a lack of standardized response criteria to evaluate the treatment of MPN-AP/BP poses challenges for understanding treatment efficacy between reported studies.”

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Pegylated Interferons Have Promise but Also Unmet Potential in MPNs

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Jared Kaltwasser

Pegylated interferons are a meaningful therapeutic option for the treatment of myeloproliferative neoplasms (MPNs), but a new review article says more research is needed to better understand the ideal usage of the therapy.

The report was published in Therapeutic Advances in Hematology.

Study investigators said several interferon products are currently available to treat patients with MPNs, but they said the short half-life of interferons and the risk of (AEs) effects have limited their usage. Pegylation can help overcome those issues, they said.

“Many of these shortcomings were addressed by covalently binding polyethylene glycol to the interferon structure, which increases the stability, prolongs activity, and reduces immunogenicity of the molecule,” the authors wrote.

More research is needed to better understand when and in whom pegylate interferon therapy is most effective | Image Credit: Iamnee – stock.adobe.com

They said current National Comprehensive Cancer Network guidelines call for pegylated interferons to be used for polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Currently, there are 2 pegylated interferons available for patients with MPNs, they said: peginterferon alfa-2a (Pegasys; pharma&) and ropeginterferon alfa-2b-njft (BESREMi; PharmaEssentia). Both medications are recommended as cytoreductive therapies for PV, the investigators said.

Next-Generation JAK Inhibitors Signal the Future of Myelofibrosis Treatment Advances

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Ashling Wahner

Newer-generation JAK inhibitors are increasingly adept at controlling symptoms in patients with myelofibrosis and may recapture treatment response in patients who have progressed on prior ruxolitinib (Jakafi), according to Joseph G. Jurcic, MD.

“Using drugs that target all these particular abnormalities can result in symptom and spleen improvement, and in some, a reduction in cytokines and allelic burden,” Jurcic said in an interview with OncLive®.

In the interview, Jurcic discussed the benefits and limitations of several JAK inhibitors for patients with myelofibrosis, highlighting the treatment advances that have been made since the introduction of ruxolitinib to the treatment paradigm, considerations for the use of fedratinib (Inrebic), and the potential advantages of pacritinib (Vonjo) for patients with anemia.

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Rusfertide Treatment Strengthens Response and Decreases Erythrocytosis Among Patients With Polycythemia Vera

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Jordan Kadish

03/22/2024

According to findings from the international phase 2 REVIVE trial published in The New England Journal of Medicine, treatment with rusfertide, a peptide mimetic of the master iron regulatory hormone hepcidin, strengthened responses and decreased erythrocytosis among patients with polycythemia vera (PV). Patients who received rusfertide demonstrated a mean hematocrit of less than 45% during the dose-finding period.

Marina Kremyanskaya, MD, PhD, Icahn School of Medicine at Mount Sinai, New York, New York, and coauthors stated, “Polycythemia vera is a chronic myeloproliferative neoplasm characterized by erythrocytosis,” or a high concentration of red blood cells in the blood. “The safety and efficacy of rusfertide in patients with phlebotomy-dependent polycythemia vera are unknown,” they added.

To expand on the available research, the study authors aimed to assess the efficacy of rusfertide among patients with polycythemia vera. The primary end point was a response, which was characterized by the hematocrit control, absence of phlebotomy, and finishing the trial regimen during part 2. The modified Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) patient diary was utilized to assess patient-reported outcomes of symptoms.

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Dr Raajit Rampal Highlights Emerging Therapies in MPNs

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March 22, 2024

By Laura Joszt, MA

Interferons have been used for decades to treat myeloproliferative neoplasms (MPNs), and new emerging therapies, such as the Janus kinase (JAK) inhibitor ruxolitinib, are expanding the therapeutic armamentarium, said Raajit Rampal, MD, PhD, hematologic oncologist, associate attending physician, Memorial Sloan Kettering Cancer Center.

What is the importance of interferons as a treatment for MPNs, and what role do they play?

Interferons have been used now for decades in MPNs, and they demonstrate clinical efficacy, certainly in essential thrombocytopenia, in polycythemia vera, and there is data for prefibrotic myelofibrosis.1 Now there are a number of different interferons. There were interferons that were given 3 times a week, and pegylated interferon, which is what we use most often, and now there’s ropeginterferon, which is every 2 weeks as a treatment.

What the interferons can do, for sure, is that they can reduce blood counts. So, for people with the polycythemia or with essential thrombocytopenia, we can get a reduction in the blood counts in the majority of patients. What is also interesting is that—and as has been known now for a number of years—the allele burden, particularly of JAK2, can decrease over time with the treatment with interferons, which at least would suggest to us that you may be depleting part of the clone that causes the disease. So, there are certainly a number of important clinical benefits of interferons, but even potentially biological effects.

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The Role of DNA Repair (XPC, XPD, XPF, and XPG) Gene Polymorphisms in the Development of Myeloproliferative Neoplasms

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by , , , , , and  

Abstract

Background and Objectives: Several polymorphisms have been described in various DNA repair genes. Nucleotide excision DNA repair (NER) detects defects of DNA molecules and corrects them to restore genome integrity. We hypothesized that the XPC, XPD, XPF, and XPG gene polymorphisms influence the appearance of myeloproliferative neoplasms (MPNs). Materials and Methods: We investigated the XPC 1496C>T (rs2228000, XPC Ala499Val), XPC 2920A>C (rs228001, XPC Lys939Gln), XPD 2251A>C (rs13181, XPD Lys751Gln), XPF-673C>T (rs3136038), XPF 11985A>G (rs254942), and XPG 3507G>C (rs17655, XPG Asp1104His) polymorphisms by polymerase chain reaction–restriction fragment length polymorphism analysis in 393 MPN patients [153 with polycythemia vera (PV), 201 with essential thrombocythemia (ET), and 39 with primary myelofibrosis (PMF)] and 323 healthy controls. Results: Overall, we found that variant genotypes of XPD 2251A>C were associated with an increased risk of MPN (OR = 1.54, 95% CI = 1.15–2.08, p = 0.004), while XPF-673C>T and XPF 11985A>G were associated with a decreased risk of developing MPN (OR = 0.56, 95% CI = 0.42–0.76, p < 0.001; and OR = 0.26, 95% CI = 0.19–0.37, p < 0.001, respectively). Conclusions: In light of our findings, XPD 2251A>C polymorphism was associated with the risk of developing MPN and XPF-673C>T and XPF 11985A>G single nucleotide polymorphisms (SNPs) may have a protective role for MPN, while XPC 1496C>T, XPC 2920A>C, and XPG 3507G>C polymorphisms do not represent risk factors in MPN development.

Momelotinib for myelofibrosis: our 14 years of experience with 100 clinical trial patients and recent FDA approval

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Ayalew Tefferi & Animesh Pardanani

Momelotinib is an ATP-competitive small molecule inhibitor of Janus kinase proteins (JAKi), including JAK1, JAK2, JAK3, and TYK2; its other clinically relevant targets include activin A receptor type 1 (ACVR1), also known as activin receptor like kinase 2 (ALK2) [1]. Momelotinib was recently approved (September 15, 2023) for use in anemic patients with high/intermediate risk myelofibrosis (MF), including primary (PMF) [2] and secondary variants, the latter emerging from antecedent polycythemia vera (post-PV) [3] or essential thrombocythemia (post-ET) [4]. All three MF variants belong to the broader category of myeloproliferative neoplasms (MPNs), which are characterized by the presence of JAK-STAT activating mutations (JAK2, CALR or MPL) and predominantly megakaryocytic myeloproliferation with variable degrees of bone marrow fibrosis [5]. Patients with MF face premature death with 10-year survival estimates ranging from >80% in very low-risk diseases to <5% in very high-risk diseases [6]. In addition, the clinical course of the disease in MF is complicated by progressive anemia, extramedullary hematopoiesis with marked splenomegaly and hepatomegaly, constitutional symptoms, and cachexia. Causes of death in MF include disease transformation into acute myeloid leukemia [7].

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Disease-, Age-, Genomic-Specific Factors Increase Risk of ET, PV, PrePMF Developing Into Overt MF

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Laura Joszt, MA

The risk of essential thrombocytopenia (ET), polycythemia vera (PV), and prefibrotic primary myelofibrosis (PrePMF) developing into overt myelofibrosis (MF) increases with age, the accumulation of mutations, and the activation of proliferative pathways, which identifies new targets for therapeutic intervention.

The findings, based on an analysis of the mutational landscape of more than 1700 genes and the gene expression of various cells from patients with myeloproliferative neoplasms (MPNs), was published in Clinical Cancer Research.1

ET, PV, PMF, and MF are all part of a group of diseases MPNs, in which a mutation in the bone marrow causes too many red blood cells, white blood cells, or platelets.2 In addition to being the most common MPNs, ET, PV, and PMF share the presence of mutations in either Janus kinase 2 (JAK2), calreticulin (CALR), and/or MPL.3 ET and PV are less aggressive forms of MPN, but they still can progress to MF. According to the Leukemia & Lymphoma Society, Pre-PMF will likely progress to PMF, “suggesting that more regular observations for pre-fibrotic PMF patients is warranted.”3

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A phase I trial of pevonedistat in combination with ruxolitinib for the treatment of myelofibrosis

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March 13, 2024

Tim Kong, Nicole Gaudin, Karyn Gordon, Maggie J. Cox, Amy W. Zhou, and Stephen T. Oh

Abstract

Janus kinase 2 (JAK2) inhibitors such as ruxolitinib have become standard-of-care therapy for patients with myeloproliferative neoplasms (MPNs); however, activation of alternate oncogenic pathways including nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) has limited durable response as single-agent therapy. With the rationale of targeting both pathways, we conducted a phase I dose escalation trial of pevonedistat in combination with ruxolitinib for the treatment of patients with myelofibrosis (NCT03386214). The primary objective was to assess the safety and tolerability of combination therapy with additional objectives of treatment efficacy and alterations of biomarkers. There were no dose-limiting toxicities observed with most adverse events being limited to grades 1/2. In secondary measures, anemia response was observed in two patients. Pro-inflammatory cytokines and iron parameters were longitudinally assessed, which revealed suppression of interleukin-6 and interferon-gamma in a dose-dependent manner across a subset of patients. These results suggest that combination therapy targeting both JAK2 and NFκB may hold clinical merit for MPN patients.