Primary Myelofibrosis Treatment & Management

Updated: Jan 30, 2017
  • Author: Asheesh Lal, MBBS, MD; Chief Editor: Emmanuel C Besa, MD  more...
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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. 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.

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. [22]

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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 November 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. [23]

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. [24]

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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. [25]

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 side 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. [26, 27, 28, 29, 30, 31, 32, 33]

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. [26] 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. [34]

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

Several new investigational drugs are being studied, including farnesyl transferase inhibitors, [35, 36] tyrosine kinase inhibitors, [20] vascular endothelial growth factor inhibitors, [37, 38] , Janus kinase 2 (JAK2) inhibitors, and telomerase inhibitors. [39]

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. [40] 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).

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 postpolycythemia vera/post-essential thrombocythemia myelofibrosis. [41] 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.

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Splenectomy

Splenectomy may be considered for patients with overt portal hypertension, progressive anemia requiring transfusions, or symptomatic splenomegaly refractory to hydroxyurea. Splenectomy has also been used in patients with severe thrombocytopenia; however, one review reported a lack of a sustained benefit in this situation.

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 operative mortality and morbidity from infections, hemorrhage, and thrombosis. Mortality rates in splenectomized patients of up to 38% have been reported, although other reports estimate the operative mortality rate to be approximately 9%. No clear data are available for optimal preoperative management.

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 AML. A study reported a cumulative transformation rate of 55% in splenectomized patients, compared with 27% in nonsplenectomized patients. Splenectomy was considered to be an independent risk factor for transformation to AML.

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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). [42]

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.

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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%.

An analysis of the outcomes of 438 patients <65 years old at diagnosis of primary myelofibrosis who received allogenic 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 allogenic 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. [43]

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. [22] 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.

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