Does ruxolitinib really prolong survival in individuals with myelofibrosis? The never-ending story

Barosi, Giovanni; Gale, Robert Peter

doi:10.1182/bloodadvances.2022007230

Cited by 14 publications

(11 citation statements)

References 19 publications

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“…We have previously argued on the lack of controlled evidence for survival benefit of JAKi in patients with MF, 51,52 a sentiment that is also shared by others 112 . The 3‐year follow‐up information on COMFORT‐2 (ruxolitinib vs.…”

Section: Symptom‐directed Therapymentioning

confidence: 94%

Primary myelofibrosis: 2023 update on diagnosis, risk‐stratification, and management

Tefferi

2023

American J Hematol

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Disease Overview Primary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN) characterized by stem cell‐derived clonal myeloproliferation that is often but not always accompanied by JAK2, CALR, or MPL mutations; additional features include bone marrow reticulin/collagen fibrosis, aberrant inflammatory cytokine expression, anemia, hepatosplenomegaly, extramedullary hematopoiesis (EMH), constitutional symptoms, cachexia, risk of leukemic progression, and shortened survival. Diagnosis Bone marrow examination with cytogenetic and mutation studies provides integrated diagnostic information; presence of JAK2, CALR or MPL mutation is expected but not required. New Classification System The International Consensus Classification distinguishes “prefibrotic” from “overtly fibrotic” PMF; the former might mimic essential thrombocythemia (ET) in its presentation. Approximately 15% of patients with ET or polycythemia vera (PV) might progress into post‐ET/PV MF. Mutations SRSF2, ASXL1, and U2AF1‐Q157 mutations predict inferior survival in PMF; RAS/CBL mutations predict resistance to ruxolitinib therapy. Type 1/like CALR mutation is associated with superior survival. Karyotype Very high‐risk abnormalities include −7, inv (3), i(17q), +21, +19, 12p‐ and 11q‐. Favorable risk abnormalities include normal karyotype or isolated +9, 13q‐, 20q‐, 1q abnormalities and loss of Y chromosome. Risk Stratification Contemporary prognostic systems include GIPSS (genetically‐inspired prognostic scoring system) and MIPSS70+ version 2.0 (MIPSSv2; mutation‐and karyotype‐enhanced international prognostic scoring system). GIPSS is based exclusively on mutations and karyotype; MIPSSv2 includes, in addition, clinical risk factors. Risk‐Adapted Therapy Observation alone is advised for MIPSSv2 “low” and “very low” risk disease (estimated 10‐year survival 56%–92%); allogeneic hematopoietic stem cell transplant (AHSCT) is the preferred treatment of choice for “very high” and “high” risk disease (estimated 10‐year survival 0–13%), as well as in carefully selected patients with intermediate‐risk disease (estimated 10‐year survival 30%). Drug therapy in MF is currently palliative and targets anemia, splenomegaly, and constitutional symptoms. JAK2 Inhibitors Ruxolitinib, fedratinib, and pacritinib are FDA approved and respectfully utilized in patients failing treatment with hydroxyurea, ruxolitinib, or with platelet count <50 × 10 (9)/L. Momelotinib is another JAK2 inhibitor that is poised for approval sometime in 2023 and has shown erythropoietic benefits, in addition to affecting spleen and symptom responses. Other Treatment Modalities Splenectomy is considered for drug‐refractory splenomegaly and involved field radiotherapy for non‐hepatosplenic EMH and extremity bone pain. New Directions New agents, alone or in combination with ruxolitinib, are currently under clinical trial investigation (ClinicalTrials.gov) and preliminary results were presented at the 2022 ASH annual meeting and highlighted in the current review.

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Section: Symptom‐directed Therapymentioning

confidence: 94%

Primary myelofibrosis: 2023 update on diagnosis, risk‐stratification, and management

Tefferi

2023

American J Hematol

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“…The very first step in this regard is to avoid delay in aggressively pursuing ASCT in patients with intermediate/high risk chronic phase or accelerated phase MF, based on the wishful but inaccurate assumption of survival benefit from JAK2 inhibitor (JAKi) therapy. We have previously argued on the lack of controlled evidence for survival effect of JAKi in patients with chronic phase MF, 32,33 a sentiment that is also shared by others 34 . We have since provided additional information on the long‐term outlook of JAKi‐treated patients with MF 35–37 .…”

mentioning

confidence: 77%

“…We have previously argued on the lack of controlled evidence for survival effect of JAKi in patients with chronic phase MF, 32,33 a sentiment that is also shared by others. 34 We have since provided additional information on the long-term outlook of JAKi-treated patients with MF. [35][36][37] The most recently published study in this regard included 183 clinical trial patients with high/intermediate-risk MF receiving ruxolitinib, momelotinib, fedratinib, or other JAKi, and followed for over 10 years; drug discontinuation rate was 97% and 22 patients received ASCT; 5/10-year survival rates were 91%/45% for ASCT vs 47%/19% in those who were not transplanted, respectively.…”

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confidence: 99%

Blast phase myeloproliferative neoplasm: Transplant to the rescue

Tefferi

Bacigalup

2023

American J Hematol

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“…Current data do not provide convincing evidence for survival benefits for JAKi in patients with MF. [58][59][60] We have recently reported longterm survival data among 183 Mayo Clinic trial patients with MF, receiving one of several JAKi, between 2007 and 2013 42 : ruxolitinib…”

Section: Jaki and Survival In Mfmentioning

confidence: 99%

“…Current data do not provide convincing evidence for survival benefits for JAKi in patients with MF 58–60 . We have recently reported long‐term survival data among 183 Mayo Clinic trial patients with MF, receiving one of several JAKi, between 2007 and 2013 42 : ruxolitinib ( N = 50), momelotinib ( N = 79), fedratinib ( N = 23) or BMS‐911543 JAKi ( N = 31); all study patients were followed to death or 2022, during which time 149 (81%) deaths, 27 (15%) leukemic transformations, and 22 (12%) AHSCTs were recorded.…”

Section: Current Hierarchy Of Treatment Choicesmentioning

confidence: 99%

Momelotinib expands the therapeutic armamentarium for myelofibrosis: Impact on hierarchy of treatment choices

Tefferi,

Pardanani,

Gangat

2024

American J Hematol

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The primary objective of treatment in myelofibrosis (MF) is prolongation of life, which is currently accomplished only by allogeneic hematopoietic stem cell transplantation (AHSCT). Determination of optimal timing for AHSCT is facilitated by molecular risk stratification. Non‐transplant treatment options in MF are palliative in scope and include Janus kinase 2 (JAK2) inhibitors (JAKi): momelotinib (FDA approved on September 15, 2023), ruxolitinib (November 16, 2011), fedratinib (August 16, 2019), and pacritinib (February 28, 2022); all four JAKi are effective in reducing spleen size and alleviating symptoms, considered a drug class effect and attributed to their canonical JAK–STAT inhibitory mechanism of action. In addition, momelotinib exhibits erythropoietic effect, attributed to alleviation of ineffective erythropoiesis through inhibition of activin A receptor type‐I (ACVR1). In transplant‐ineligible or deferred patients, the order of treatment preference is based on specific symptoms and individual assessment of risk tolerance. Because of drug‐induced immunosuppression and other toxicities attributed to JAKi, we prefer non‐JAKi drugs as initial treatment for MF‐associated anemia that is not accompanied by treatment‐requiring splenomegaly or constitutional symptoms. Otherwise, it is reasonable to consider momelotinib as the first‐line JAKi treatment of choice, in order to target the triad of quality‐of‐life offenders in MF: anemia, splenomegaly, and constitutional symptoms/cachexia. For second‐line therapy, we favor ruxolitinib, over fedratinib, based on toxicity profile. Pacritinib and fedratinib provide alternative options in the presence of severe thrombocytopenia or ruxolitinib‐resistance/intolerance, respectively. Splenectomy remains a viable option for drug‐resistant symptomatic splenomegaly and cytopenia.

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Does ruxolitinib really prolong survival in individuals with myelofibrosis? The never-ending story

Cited by 14 publications

References 19 publications

Primary myelofibrosis: 2023 update on diagnosis, risk‐stratification, and management

Primary myelofibrosis: 2023 update on diagnosis, risk‐stratification, and management

Blast phase myeloproliferative neoplasm: Transplant to the rescue

Momelotinib expands the therapeutic armamentarium for myelofibrosis: Impact on hierarchy of treatment choices

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