Sections

Treatment

Approach Considerations

Historically, therapy for primary myelofibrosis was mainly supportive. Patients received transfusions as needed. Thrombocytosis could be managed with hydroxyurea and other palliative agents. Low-risk, asymptomatic patients may be observed without intervention. Patients with milder disease may still be treated with supportive therapies. Four Janus kinase (JAK) inhibitors are approved by the US Food and Drug Administration (FDA) for the treatment of myelofibrosis. Other pharmacologic therapies have been used.

Patients with refractory splenomegaly may be candidates for splenectomy. Involved-field radiotherapy is most useful for patients with the following^[1]:

Post-splenectomy hepatomegaly
Non-hepatosplenic extramedullary hematopoiesis
Primary myelofibrosis–associated pulmonary hypertension
Extremity bone pain

Patients with high or intermediate-2 risk disease, according to the Dynamic International Prognostic Scoring System–plus (DIPSS-plus; see Overview/Prognosis), or those with high-risk mutations such as ASXL1 or SRSF2, should be considered for hematopoietic stem cell transplantation (HSCT). An international working group has published consensus recommendations on the use of HSCT in primary myelofibrosis.^[26]

JAK Inhibitors

The following Janus-associated kinase (JAK) inhibitors are approved for the treatment of myelofibrosis:

Ruxolitinib (Jakafi)
Fedratinib (Inrebic)
Pacritinib (Vonjo)
Momelotinib (Ojjaara)

Ruxolitinib

Ruxolitinib (Jakafi), a JAK1/JAK2 inhibitor, is the first chemotherapeutic agent to be approved by the US Food and Drug Administration (FDA) for the treatment of myelofibrosis. The 2011 approval was based on the results of the COMFORT-I and COMFORT-II trials. A gain-of-function mutation (VG17F) in JAK2 is present in approximately 50% of all patients with myelofibrosis and contributes to the pathophysiology of the disease. Thus, inhibition of this target is a potential therapeutic option.

In the COMFORT-1 trial, patients with intermediate-2 or high-risk myelofibrosis were randomized to either ruxolitinib (either 15 mg or 20 mg PO bid) or placebo. The primary endpoint was the proportion of patients with 35% or higher reduction in spleen volume at week 24 of therapy, assessed by MRI or CT. The primary endpoint response rate was 41.9% for ruxolitinib compared with 0.7% for placebo. The most common adverse events of any grade were abdominal pain (10.3% vs 41.1%), thrombocytopenia (34.2% vs 9.3%), fatigue (25.2% vs 33.8%), anemia (31% vs 13.9%), diarrhea (23.2% vs 21.2%), and peripheral edema (18.7% vs 22.5%).

The COMFORT-II trial was a randomized phase III study that compared the efficacy and safety of ruxolitinib with best available therapy in patients with intermediate-2 or high-risk primary myelofibrosis, post-polycythemia vera-myelofibrosis, or post-essential thrombocythemia–myelofibrosis, and palpable splenomegaly. The primary endpoint was the proportion of patients achieving at least 35% reduction in spleen volume at week 48 as determined by MRI. The response rate was 28% for ruxolitinib compared with 0% for the control arm. The most common adverse events were thrombocytopenia, anemia, diarrhea, and edema.

A double-blind placebo-controlled trial by Verstovsek et al randomized patients with intermediate-2 or high-risk primary myelofibrosis to twice-daily oral ruxolitinib (n=155) or placebo (n=154). The primary endpoint was the proportion of patients achieving at least 35% reduction in spleen volume at week 24 as determined by MRI, which was reached in 41.9% of patients in the ruxolitinib group as compared with 0.7% in the placebo group. This reduction in spleen volume was maintained for 48 weeks in 67% of the patients. Anemia and thrombocytopenia were the most common adverse events, with 2 patients in ruxolitinib group having transformation to acute myeloid leukemia.^[27]

A clinical trial by Harrison et al also found reductions in splenomegaly and other disease-related symptoms, improvements in quality of life, and modest toxic effects with oral ruxolitinib versus the best available therapy.^[28]

Fedratinib

Another JAK inhibitor, fedratinib (Inrebic), was approved in 2019 for adults with intermediate-2 or high-risk primary myelofibrosis (as well as for myelofibrosis secondary to polycythemia vera or essential thrombocythemia). The efficacy of fedratinib was investigated in JAKARTA (NCT01437787), a double-blind, randomized, placebo-controlled trial in 289 patients with intermediate-2 or high-risk myelofibrosis, post–polycythemia vera myelofibrosis, or post–essential thrombocythemia myelofibrosis with splenomegaly. Patients were randomized to receive fedratinib 500 mg (N=97) or 400 mg (n=96) or placebo (n=96) once daily for at least 6 cycles.

Follow-up magnetic resonance imaging or computed tomography scanning showed that of the 96 patients treated with the recommended dose (400 mg) of fedratinib, 35 (37%) achieved a 35% or greater reduction in spleen volume, compared with 1 of 96 patients who received placebo (P < 0.0001). The median duration of spleen response was 18.2 months for the fedratinib 400 mg group. In addition, 40% of patients who received 400 mg experienced a 50% or greater reduction in myelofibrosis-related symptoms, compared with only 9% of patients receiving placebo.^[29]

Pacritinib

In March 2022, the FDA approved pacritinib (Vonjo), the first treatment for adults with myelofibrosis and severe thrombocytopenia (platelet count < 50 × 10⁹/L). Pacritinib is an oral JAK inhibitor that inhibits JAK2 and FLT3, as well as CSFIR and IRAK1.

Approval was based on the PERSIST-1 and PERSIST-2 phase III trials and the phase II PAC203 trial. The PERSIST-1 trial randomized 327 patients to receive pacritinib or the best available therapy (BAT) until disease progression or unacceptable toxicity. At week 24, 19% of the pacritinib-treated arm achieved the primary endpoint of spleen volume reduction (SVR) ≥35% compared with 5% in the BAT arm.^[30]

PERSIST-1 led to PERSIST-2, which randomized 311 patients with myelofibrosis and platelet count ≤100 × 10⁹/L to receive pacritinib 400 mg once daily, pacritinib 200 mg BID, or BAT (including ruxolitinib). Pacritinib at either dosage was more effective for SVR ≥35% compared with BAT (18% vs 3%, respectively) but twice-daily pacritinib was also significantly more effective for producing a ≥50% reduction in total symptom score (TSS), compared with BAT.^[31]

A pacritinib dose of 200 mg twice daily also proved preferable in PAC203, a dose-finding study that enrolled 161 patients with primary myelofibrosis who had received prior ruxolitinib. Participants were randomized to receive 100 mg daily, 100 mg BID, or 200 mg BID. At Week 24, SVR ≥35% rates were highest with 200 BID (9.3%, versus 0% with 100 mg daily and 1.8% with 100 mg BID), particularly in patients with baseline platelet counts < 50 × 10⁹/L (17%; 4 of 24). Reduction in the 7-component TSS by ≥50% through week 24 was similar across doses (100 mg daily, 7.7%; 100 mg BID, 7.3%; 200 mg BID, 7.4%).^[32]

Momelotinib

In September 2023, the FDA approved momelotinib (Ojjaara) for the treatment of intermediate- or high-risk myelofibrosis, including primary myelofibrosis or secondary myelofibrosis (post–polycythemia vera and post–essential thrombocythemia), in adults with anemia. Momelotinib is a once-a-day, oral JAK1/JAK2 and activin A receptor type 1 (ACVR1) inhibitor.

Approval was based on the MOMENTUM study and a subpopulation of adult patients with anemia from the SIMPLIFY-1 phase III trial. The MOMENTUM trial randomized 195 patients to receive momelotinib or danazol for 24 weeks. The proportion of patients who reported a reduction in total symptom score of 50% or more was 25% in the momelotinib group versus 9% in the danazol group (P=0.0095).^[33]

SIMPLIFY-1 was a multicenter, randomized, double-blind, phase III study that compared the safety and efficacy of momelotinib versus ruxolitinib in 432 patients with myelofibrosis who had not received prior treatment with a JAK inhibitor. Momelotinib met the primary end point of noninferiority for spleen response but not the key secondary end point of symptomatic improvement; however, more patients achieved transfusion independence with momelotinib than with ruxolitinib, and objective laboratory measures of anemia (eg, hemoglobin, serum iron, transferrin saturation) also favored momelotinib.^[34]

Pemigatinib

Pemigatinib (Pemazyre) is an orally bioavailable inhibitor of the fibroblast growth factor receptor (FGFR) types 1, 2, and 3 (FGFR1/2/3). It inhibits FGFR 1/2/3 phosphorylation and signaling, and decreases cell viability in cancer cell lines with activating FGFR amplifications and fusions. It is indicated for relapsed or refractory myeloid/lymphoid neoplasms (MLNs) in adults with FGFR1 rearrangement.

Approval was based on the phase 2 FIGHT-203 clinical trial. Study participants included patients with documented MLNs with an 8p11 translocation on conventional cytogenetics and/or an FGFR1 rearrangement on break-apart fluorescence in situ hybridization (FISH) testing.^[35]

In patients with chronic phase in the marrow with or without extramedullary disease (EMD) (N = 18), the complete response (CR) rate was 78%. The median time to response of CR was 104 days (range, 44 to 435 days). The median duration of CR was not reached. In patients with blast phase in the marrow with or without EMD (N = 4), 2 patients achieved a CR. For all patients (N = 28, including 3 patients without evidence of morphologic disease) the complete cytogenetic response rate was 79% (22/28; 95% CI: 59, 92).^[35]

Other Chemotherapeutics

Older chemotherapeutics have mainly been used as cytoreductive therapy to control leukocytosis, thrombocytosis, or organomegaly. Hydroxyurea is the preferred agent, but other drugs (eg, interferon, cladribine) have also been used. Busulfan has been used, but it is not a preferred agent in view of the lesser toxicity of hydroxyurea. Patients with primary myelofibrosis are especially prone to developing myelotoxicity with these agents, which should therefore be used with caution.

Interferon alfa is a viable alternative to hydroxyurea therapy, especially in young patients (< 45 y), who have a long life expectancy. Response rates of 50% have been observed, with improvement in splenomegaly and blood cell counts. Results are best in patients with elevated counts.^[36]

Aggressive chemotherapy to induce remissions has been used; however, despite aggressive chemotherapy, hematologic remissions are rare and do not change the overall course of the disease.

Androgens and corticosteroids

These agents have been used to treat patients with severe anemia and are administered to improve symptoms and to decrease transfusional requirements. Approximately 30% of patients respond to therapy.

Thalidomide with prednisone

Studies using low-dose thalidomide (50 mg) and prednisone showed reduced adverse effects in comparison with higher doses of thalidomide. Some patients develop a significant increase in WBC or platelet counts, usually in the first 4-8 weeks, and may require additional cytoreductive therapy.^{[37, 38, 39, 40, 41, 42, 43, 44]}

In a study in which low-dose thalidomide and prednisone were administered to 21 symptomatic patients suffering from myelofibrosis with myeloid metaplasia, an objective clinical response was demonstrated in 13 (62%) patients, all improvements in anemia.^[37]Among 10 patients who were dependent on erythrocyte transfusions, seven (70%) improved and four (40%) became transfusion independent. Among 8 patients with thrombocytopenia (platelet count < 100 × 10⁹/L), 6 (75%) experienced a 50% or higher increase in their platelet count. In four of 21 patients (19%), spleen size decreased by more than 50%.

Lenalidomide is a thalidomide analogue that is much more potent than thalidomide. It is approved for treatment of multiple myeloma and for patients with 5q- syndrome myelodysplastic syndrome. A study of 68 patients with symptomatic myelofibrosis and myeloid metaplasia revealed overall response rates of 22% for anemia, 33% for splenomegaly, and 50% for thrombocytopenia.^[45]

High-dose chemotherapy

This modality, combined with autologous transplantation, has been shown to slow disease progression. In a small study, evidence of improvement in fibrosis was noted.

Investigational drugs

Drugs being studied for myelofibrosis include the following:

Pomalidomide
Everolimus
Farnesyl transferase inhibitors ^{[46, 47]}
Tyrosine kinase inhibitors ^[22]
Vascular endothelial growth factor inhibitors ^{[48, 49]}
Telomerase inhibitors ^[50]

Pomalidomide

Although thalidomide and lenalidomide can alleviate anemia in myelofibrosis, their use is limited by their respective potential to cause peripheral neuropathy and myelosuppression. Pomalidomide is a second-generation thalidomide analogue with reduced toxicity and enhanced anticancer and immunological activity.

A study by Tefferi et al found pomalidomide to be effective against myelofibrosis-associated anemia. The investigators conducted a phase II, randomized, multicenter, double-blind, adaptive study of 4 treatment arms of pomalidomide, including pomalidomide at a dose of 2 mg/day plus placebo, pomalidomide at a dose of 2 mg/day plus prednisone, pomalidomide at a dose of 0.5 mg/day plus prednisone, and prednisone plus placebo.^[51]Pomalidomide was administered for as many as 12 treatment cycles lasting 28 days. During the first 3 cycles, prednisone (30 mg/d) was administered via a tapering dose schedule. Of 84 patients with myelofibrosis-associated anemia who were randomized, response in anemia was documented in 20 patients, including 15 who became transfusion independent.

The response rates were 23%, 16%, 36%, and 19%, respectively. With or without pomalidomide, the response was durable (range, 3.2-16.9+ mo) and was significantly better in patients without leukocytosis (37% vs 8%; P =.01). The presence of JAK2 V617F and the cytogenetic status did not affect the response. Toxicities of grade 3 or higher were infrequent and included neutropenia (9%, 16%, 5%, and 5%, respectively), thrombocytopenia (14%, 16%, 9%, and 5%, respectively), and thrombosis (9%, 5%, 0%, and 0%, respectively).

Everolimus

In addition to dysregulated JAK/STAT signaling, activation of the AKT/mTOR pathway occurs in myelofibrosis. Guglielmelli et al conducted a phase 1/2 study with everolimus, an mTOR inhibitor, in 39 high-risk or intermediate-risk subjects with primary or post–polycythemia vera/post–essential thrombocythemia myelofibrosis.^[52]Responses were evaluated in 30 patients of phase 2. No dose-limiting toxicity was observed in doses of as much as 10 mg/d. The most common toxicity was grade 1-2 stomatitis. Rapid and sustained splenomegaly reduction of more than 50% and more than 30% was observed in 20% and 44% of subjects, respectively.

A total of 69% and 80% of patients experienced complete resolution of systemic symptoms and pruritus, respecitvely. Response in leukocytosis, anemia, and thrombocytosis occurred in 15%-25% of patients. Clinical responses were not associated with reduced JAK2 V617F burden, circulating CD34⁺ cells, or cytokine levels, whereas CCDN1 mRNA and phospho-p70S6K level, known targets of mTOR, and WT1 mRNA were identified as possible biomarkers associated with response.

Splenectomy

Splenectomy may be considered for patients with massive splenomegaly. Indications include abdominal pain and discomfort, symptomatic portal hypertension, severe thrombocytopenia, and need for frequent red blood cell transfusions.^[53]

Patients with primary myelofibrosis who require surgery are best treated under the supervision of an experienced hematologist, because splenectomy in these patients has been associated with a significant risk of perioperative morbidity and mortality. Perioperative morbidity—principally infections, hemorrhage, and thrombosis—has been reported in approximately 30% of cases. Perioperative mortality—principally from infection and hemorrhage—averages approximately 8%.^[53]

Tefferi et al created a prognostic model to help identify patients with myelofibrosis who are likely to benefit from splenectomy, using four risk factors found to be associated with shorter survival after splenectomy^[54]:

Age > 65 years
Leukocyte count > 25 × 10 ⁹/L
Circulating blasts ≥ 5%
Need for red blood cell transfusion

Risk categories and 3-year and median postsplenectomy survival were as follows:

Low risk (0-1 risk factors): 47% and 2.9 years
Intermediate risk (2 risk factors): 11% and 1.3 years
High risk (3-4 risk factors): 0% and 0.3 years

Prior to splenectomy, obtain CBC and platelet counts, and order studies to assess for subclinical DIC. Consider patients with significant thrombocytosis for cytoreductive therapy to decrease platelet counts to the reference range. Patients with primary myelofibrosis who experience problems with bleeding may require platelet transfusions and infusions of cryoprecipitate, based on coagulation parameters.

Patients with primary myelofibrosis may develop marked hepatomegaly and thrombocytosis after splenectomy, which may be minimized by close monitoring and the appropriate use of cytoreductive therapy. Aplastic crises do not occur following splenectomy, because bone marrow continues to be the predominant site of hematopoiesis.

Splenectomy is reportedly associated with a higher rate of transformation to acute myeloid leukemia (AML). In one study, leukemic transformation occurred in 26.4% of splenectomized patients, conpared with 11.4% of nonsplenectomized patients.^[53]

Radiation Therapy

Radiation may be used to treat symptomatic extramedullary hematopoiesis. This therapy is also beneficial for bone pain resulting from tumors or periostitis.

Splenic radiation is beneficial to patients with symptomatic splenomegaly or splenic infarction, although the effects are usually temporary (median duration, 6 mo).^[55]

After splenic irradiation, prolonged pancytopenia may occur (25% of patients). In addition, splenectomy after splenic irradiation is associated with a very high risk of intra-abdominal hemorrhage. Accordingly, reserve splenic irradiation only for patients in whom surgery is contraindicated.

Stem Cell Transplantation

Allogeneic stem cell transplantation (SCT) is a potentially curative therapy in patients with primary myelofibrosis. Long-lasting, complete remissions have been reported. Regression of marrow fibrosis occurs following successful allogeneic transplantation.

Patients with hemoglobin values below 10 g/dL, karyotypic abnormalities, osteomyelosclerosis, and older age appear to have poorer outcomes. The 1-year mortality rate for persons receiving human leukocyte antigen (HLA)-identical sibling transplants is approximately 30%.

A study of long-term outcome of allogeneic SCT in patients with myelofibrosis, which included 837 patients with primary myelofibrosis, found that of patients who were disease-free 2 years after SCT, disease-free survival at 10 years was 64% (60-68%) and overall survival was 74% (71-78%). Older age, male sex, and no graft versus host disease (GVHD) in the the first 2 years after SCT were associated with a significantly higher risk of mortality; older age, reduced-intensity conditioning, male sex, donor other than an HLA-matched related donor, and no earlier GVHD were associated significantly with lower disease-free survival.^[56]

An analysis of the outcomes of 438 patients < 65 years old at diagnosis of primary myelofibrosis who received allogeneic SCT (n = 190) or conventional therapies (n = 248) found that non–ruxolitinib-treated patients with intermediate-2 or high-risk disease were likely to benefit from allogeneic SCT, whereas patients with low-risk disease had a higher risk of death and nontransplant approaches should be considered. Individual counseling was suggested for intermediate-1 risk patients.^[57]

A panel of 23 experts appointed by the European LeukemiaNet and European Blood and Marrow Transplantation Group developed a consensus recommendation that patients with intermediate-2 risk or high-risk disease and age < 70 years should be considered as candidates for allogeneic SCT.^[26]The panel recommended that patients with intermediate-1 risk disease and age < 65 years be considered as candidates if they present any of the following:

Refractory, transfusion-dependent anemia
Greater than 2% of blasts in peripheral blood
Adverse cytogenetics

Newer, nonmyeloablative transplantations may improve the overall outcome by decreasing the early mortality observed after conventional high-dose chemotherapy–based transplantation regimens. Salit et al reported that treatment with ruxolitinib prior to SCT is well tolerated and may improve outcome in transplanted patients.^[58]

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Media Gallery

Primary myelofibrosis. Peripheral smear shows teardrop red blood cells (RBCs) and a leukoerythroblastic picture with nucleated RBC precursors and immature myeloid cells. Courtesy of Wei Wang, MD, and John Lazarchick, MD, Department of Pathology, Medical University of South Carolina.
Bone marrow biopsy from a patient with primary myelofibrosis shows extensive fibrosis. Courtesy of Wei Wang, MD, and John Lazarchick, MD, Department of Pathology, Medical University of South Carolina.
Reticulin stain on a bone marrow biopsy from a patient with primary myelofibrosis shows extensive fibrosis. Courtesy of Wei Wang, MD, and John Lazarchick, MD, Department of Pathology, Medical University of South Carolina.
Extramedullary hematopoiesis in the spleen of a patient with primary myelofibrosis. Courtesy of Wei Wang, MD, and John Lazarchick, MD, Department of Pathology, Medical University of South Carolina.

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Author

Asheesh Lal, MBBS, MD Physician, Department of Internal Medicine, Lexington Medical Center

Asheesh Lal, MBBS, MD is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences

Disclosure: Nothing to disclose.

Additional Contributors

Karen Seiter, MD Professor, Department of Internal Medicine, Division of Oncology/Hematology, New York Medical College

Karen Seiter, MD is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, American Society of Hematology

Disclosure: Received honoraria from Novartis for speaking and teaching; Received consulting fee from Novartis for speaking and teaching; Received honoraria from Celgene for speaking and teaching.

Acknowledgements

Author: Asheesh Lal, MBBS, MD, Physician, Department of Internal Medicine, Lexington Medical Center.

Asheesh Lal is a member of the following medical societies: American Society of Clinical Oncology and American Society of Hematology.

Editors: Karen Seiter, MD, Professor, Department of Internal Medicine, Division of Oncology/Hematology, New York Medical College; Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference; Emmanuel C Besa, MD, Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University.

Primary Myelofibrosis Treatment & Management

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