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Management of primary myelofibrosis

Management of primary myelofibrosis
Author:
Ayalew Tefferi, MD
Section Editor:
Richard A Larson, MD
Deputy Editor:
Alan G Rosmarin, MD
Literature review current through: Dec 2022. | This topic last updated: Oct 07, 2022.

INTRODUCTION — Primary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN) associated with bone marrow fibrosis, cytopenias, constitutional symptoms, hepatosplenomegaly, and/or extramedullary hematopoiesis. PMF has the least favorable prognosis among the MPNs, and patients are at risk for premature death due to disease progression, leukemic transformation, thrombo-hemorrhagic complications, and infections. Myelofibrosis that arises after a previous diagnosis of polycythemia vera or essential thrombocythemia is referred to as secondary myelofibrosis. PMF has previously been described by various names, including agnogenic myeloid metaplasia, myelofibrosis with myeloid metaplasia, and chronic idiopathic myelofibrosis.

Management of PMF and secondary myelofibrosis, which is informed by risk stratification and the presence of symptoms, is reviewed in this topic.

Clinical manifestations and diagnosis, assessment of prognosis, and pathogenesis of PMF are presented separately. (See "Clinical manifestations and diagnosis of primary myelofibrosis" and "Prognosis of primary myelofibrosis" and "Pathogenetic mechanisms in primary myelofibrosis".)

PRETREATMENT EVALUATION — Assessment of the goals of care, symptom burden, and medical fitness are important for selecting management of PMF.

Goals of care — Relief of symptoms and improved quality of life are important goals for all patients with PMF. Prolongation of survival with the potential for cure by allogeneic hematopoietic cell transplantation is an appropriate goal for some patients. Establishing the goals of care requires assessment of the burden of disease-related symptoms and determining the individual's prognosis, which are discussed below and separately. (See 'Symptom burden' below and "Prognosis of primary myelofibrosis", section on 'Assessing prognosis in PMF'.)

The goals of care should be discussed by the patient, loved ones, and clinicians at the time of diagnosis, and reassessed periodically through the course of the disease. Mutual understanding of the goals of care is important for optimal selection of therapy and facilitates conversations regarding health care proxies, do-not-resuscitate directives, and end-of-life decisions.

Symptom burden — Most patients with PMF develop troublesome or life-threatening symptoms in the course of their illness. The impact of symptoms on daily function should be evaluated in all patients. We suggest use of a disease-specific tool, such as the MPN-SAF TSS (myeloproliferative neoplasm symptom assessment form total symptom score; MPN-10), to evaluate the symptom burden at baseline and to monitor symptom status in response to therapy [1].

The Eastern Cooperative Oncology Group (ECOG) performance scale (table 1) or Karnofsky performance scale (table 2) can provide general measures of performance status, but these tools do not specifically assess symptoms that are common features of PMF. (See "Clinical manifestations and diagnosis of primary myelofibrosis", section on 'Clinical manifestations'.)

Medical fitness — We suggest assessing medical fitness, including performance status, physiologic condition, and cognition in a manner similar to that for older patients with acute myeloid leukemia. For some patients, it may be helpful to obtain geriatric consultation and/or perform a more comprehensive functional assessment to evaluate medical fitness, as discussed separately. (See "Comprehensive geriatric assessment for patients with cancer" and "Acute myeloid leukemia: Management of medically-unfit adults", section on 'Pretreatment evaluation'.)

We suggest referral to transplantation specialists soon after establishing the diagnosis of PMF in order to evaluate eligibility for allogeneic HCT and to define donor options; age alone should not preclude this evaluation. (See "Determining eligibility for allogeneic hematopoietic cell transplantation".)

RISK STRATIFICATION — Risk stratification enables treatment decisions to be made in the context of the individual's prognosis. There is no consensus regarding the optimal tool for assessing prognosis. The various prognostic models vary in their precision, reproducibility, and classification; importantly, risk categories do not precisely match across models. Our preferred approach for determining prognosis in PMF is described separately. (See "Prognosis of primary myelofibrosis", section on 'Our preferred approach'.)

We suggest a risk-stratified approach to management of PMF that classifies patients according to prognosis (algorithm 1):

●Higher-risk PMF – We consider that higher-risk PMF includes:

•GIPSS:

-High risk

-Intermediate (int)-2: Note that for patients classified as GIPSS int-2, we suggest re-evaluation using MIPSS70+ v2.0, as discussed separately (see "Prognosis of primary myelofibrosis", section on 'Assessing prognosis in PMF')

•MIPSS70+ v2.0:

-Very high risk

-High risk

●Lower-risk PMF – We consider lower-risk PMF to include the following:

•GIPSS:

-Low risk

-Int-1: Note that for patients classified as GIPSS int-1, we suggest re-evaluation using MIPSS70+ v2.0, as discussed separately (see "Prognosis of primary myelofibrosis", section on 'Assessing prognosis in PMF')

•MIPSS70+ v2.0:

-Intermediate risk

-Low risk

-Very low risk

The use of alternative prognostic tools is acceptable in settings where the molecular and/or cytogenetic tests that are used in MIPSS70+ v2.0 and GIPSS are not available. In such settings, higher-risk PMF roughly corresponds to DIPSS and DIPSS-Plus high risk and int-2 risk categories, while lower-risk PMF roughly corresponds to DIPSS-Plus and DIPSS int-1 risk and low risk categories. (See "Prognosis of primary myelofibrosis", section on 'Alternative approaches'.)

MANAGEMENT OF HIGHER-RISK PMF — Patients with higher-risk PMF generally have a poor prognosis and are likely to have disease-associated symptoms. Treatment should be offered to all patients to lessen symptoms and improve the quality of life. Allogeneic transplantation can prolong survival and offers the possibility of cure for patients who are medically eligible.

Classification of patients as having higher-risk PMF is described above (algorithm 1). (See 'Risk stratification' above.)

Transplant eligible — For patients who are eligible for allogeneic hematopoietic cell transplantation (HCT), we suggest transplantation rather than symptom-directed therapy (eg, ruxolitinib, fedratinib, hydroxyurea) (algorithm 2). This suggestion places less emphasis on toxicity of transplantation and greater weight on its potential to relieve symptoms and improve survival. Symptom-directed therapy can lessen symptoms and improve the quality of life, but it has not been proven to prolong survival. Some patients may select observation alone, based on personal preference or advanced age.

Soon after PMF is diagnosed, the patient should be referred to transplant specialists to evaluate suitability for allogeneic HCT and consider donor options. Transplant eligibility varies between institutions, and is generally based on medical fitness and functional performance. There is no specific age above which the risk of transplantation clearly outweighs the benefits in patients with higher-risk PMF, and we do not consider age a barrier to referral. Efficacy of allogeneic HCT results from the conditioning chemotherapy plus a graft-versus-tumor (GVT) effect from allogeneic immune reconstitution. However, allogeneic HCT also causes graft-versus-host disease (GVHD) and substantial treatment-related mortality (TRM). Eligibility for allogeneic HCT is described separately. (See "Determining eligibility for allogeneic hematopoietic cell transplantation", section on 'Impact of individual factors'.)

In retrospective studies, allogeneic HCT for patients with PMF was associated with 30 to 61 percent overall survival (OS) and 24 to 43 percent non-relapse mortality (NRM) at three to five years [2]. As an example, a retrospective analysis of 289 patients reported long-term OS in approximately one-third of patients, but NRM and the probability of survival at five years was influenced by the type of stem cell graft [3]. Most published studies used prognostic scoring systems (eg, DIPSS) that preceded the routine use of molecular data to stratify patients for transplantation [4]; such models correspond imperfectly to current prognostic classification schemes that incorporate both cytogenetic and molecular data. (See "Prognosis of primary myelofibrosis", section on 'Assessing prognosis in PMF'.)

There are no randomized trials of allogeneic HCT versus symptom-based management in PMF. Most comparisons of transplantation versus other approaches in PMF are retrospective studies of younger, highly selected patient populations [5-13]. As an example, a retrospective study of 438 patients <65 years old with PMF reported that, compared with conventional therapies, transplantation was associated with superior survival, but only in those individuals whose prognosis approximates the higher-risk category described in this topic (ie, patients categorized as DIPSS high risk and int-2) [14]. Compared with 255 patients who were treated with conventional therapies, 188 patients who underwent allogeneic HCT had the following relative risk (RR) of death:

●DIPSS high risk: RR 0.37 (95% CI 0.21-0.66)

●DIPSS int-2: RR 0.55 (95% CI 0.36-0.83)

●DIPSS int-1: RR 1.6 (95% CI 0.79-3.2)

●DIPSS low risk: RR 5.6 (95% CI 1.7-19)

Carefully selected older patients with PMF have good outcomes with allogeneic HCT. As an example, a retrospective study of 30 patients (median age: 65 years; range: 60 to 78 years), most of whom received low-intensity conditioning, reported estimated three-year OS and progression-free survival (PFS) of 45 and 40 percent, respectively, with 13 percent day 100 mortality [15].

There is no consensus regarding the optimal source of the stem cell graft or choice of conditioning regimen, and the approach may vary by institution:

●Stem cell graft – We favor either a matched related donor (MRD; ie, HLA-matched sibling) or matched unrelated donor (MUD) as graft source. There is less experience with alternative donor sources in this setting, but grafts from haploidentical family members and umbilical cord blood may achieve similar outcomes and are acceptable donor options. Alternative graft sources, including mismatched MUD donors, haploidentical family members, or umbilical cord blood are discussed separately. (See "Donor selection for hematopoietic cell transplantation".)

Outcomes may be influenced by the stem cell source. In one study, rates of five-year OS were 37, 40, and 30 percent for HLA-matched sibling donors, other HLA-matched related donors, and MUD, respectively; corresponding disease-free survival rates were 33, 22, and 27 percent [3]. NRM was highest for MUD (50 versus 35 and 38 percent for sibling and other related donors).

Engraftment is generally not a problem in most patients with myelofibrosis, despite concern that engraftment might be adversely affected by severely fibrotic marrow. The registry-based study described above reported engraftment in 90 percent of patients [3], and a study that compared outcomes after HCT in 33 patients with severe myelofibrosis with 33 matched controls without myelofibrosis reported no significant difference in engraftment parameters between the groups [16].

●Conditioning regimen – Selection of a conditioning regimen is influenced by patient age. Myeloablative conditioning (MAC) is preferred for patients ≤65 years old, while reduced intensity conditioning (RIC) or nonmyeloablative (NMA) conditioning are preferred for patients >65 years old. (See "Preparative regimens for hematopoietic cell transplantation".)

The choice of conditioning regimen may affect outcomes with HCT for PMF. No prospective studies have directly compared conditioning regimens, but compared with MAC, RIC is associated with lower rates of NRM but higher rates of relapse [15,17-36]. A multicenter study of 233 patients with RIC reported OS and PFS at five years were 47 and 27 percent, respectively, and five-year NRM and relapse/progression were 24 and 48 percent [32]. Another multicenter study of RIC in 103 patients reported one-year NRM was 16 percent, and three-year cumulative rate of relapse was 22 percent; estimated five-year event-free survival (EFS) and OS were 51 and 67 percent, respectively [17].

Our approach is consistent with US National Comprehensive Cancer Network Myelofibrosis guidelines [37] and consensus recommendations for HCT in PMF by the European LeukemiaNet (ELN) and European Blood and Marrow Transplantation Group (EBMT) [38].

Ineligible for transplantation

Selection of therapy — We favor participation in a clinical trial for patients who are not eligible for allogeneic HCT. (See "Determining eligibility for allogeneic hematopoietic cell transplantation", section on 'Impact of individual factors'.)

Outside of a trial, ruxolitinib, fedratinib, pacritinib, or hydroxyurea is acceptable for symptom relief (algorithm 2). Selection of therapy is informed by the nature and severity of symptoms, blood counts, kidney and liver function, clinician experience, and patient preference. Although these agents can provide symptomatic relief, they have not been proven to prolong survival or reduce the risk of leukemic transformation.

In selecting an agent, it is important to note that:

●Ruxolitinib – Ruxolitinib can relieve PMF-related symptoms, but it should not be used in patients with active infections, and it should be used with caution in patients with thrombocytopenia, impaired liver or kidney function, or concurrent use of medications that are strong CYP3A4 inhibitors.

Importantly, patients must be counseled that discontinuation of ruxolitinib can be associated with full relapse of disease symptoms and development of fever, hypotension, hypoxia, and other manifestations of systemic inflammatory response syndrome. (See 'Ruxolitinib' below.)

●Fedratinib – Fedratinib can reduce splenomegaly and other PMF-related symptoms, but treatment is associated with serious and sometimes fatal, Wernicke-like encephalopathy. Serum thiamine level should be repleted before beginning fedratinib, and levels should be checked periodically during treatment. Fedratinib should not be given to patients with severe liver impairment, taking strong or moderate CYP3A4 inducers or dual CYP3A4 and CYP2C19 inhibitors. (See 'Fedratinib' below.)

●Pacritinib – Pacritinib can reduce splenomegaly and improve symptoms in patients with baseline or treatment-emergent thrombocytopenia. It has been associated with cardiovascular events and death or bleeding when used in higher doses. Pacritinib should not be given to patients taking strong or moderate CYP3A4 inducers or with moderate/severe liver dysfunction or limited renal function. (See 'Pacritinib' below.)

●Hydroxyurea – Hydroxyurea is less efficacious than the kinase inhibitors, but it can relieve moderate splenomegaly, thrombocytosis, and leukocytosis. For patients with PMF, hydroxyurea should be given at doses that are lower than those used for other hematologic malignancies, and its use may be limited by cytopenias. (See 'Hydroxyurea' below.)

These agents may precipitate gout and prophylactic allopurinol may be beneficial. Doses, cautions, and outcomes with these agents are discussed below. (See "Tumor lysis syndrome: Prevention and treatment", section on 'Allopurinol'.)

For patients who are symptomatic with anemia only, evaluation and management are discussed below. (See 'Anemia in PMF' below.)

Ruxolitinib — Ruxolitinib is an inhibitor of JAK2, which is commonly mutated in PMF, but its efficacy is independent of JAK2 mutation status, which suggests that it may suppress symptoms and reduce splenomegaly through a more general inhibition of kinases [39-42]. (See "Pathogenetic mechanisms in primary myelofibrosis", section on 'JAK2 mutations'.)

Ruxolitinib treatment and cautions — Prior to initiating therapy, patients should be counseled about the risk of ruxolitinib withdrawal syndrome and screened for tuberculosis, as described below. Dose adjustments are required for renal and hepatic dysfunction and for patients receiving a concomitant strong CYP3A4 inhibitor (table 3) or fluconazole [43]. The initial dose of ruxolitinib is influenced by the platelet count, and should be adjusted based on a complete blood count (CBC) every two to four weeks until blood counts and doses are stabilized, and then as clinically indicated:

●20 mg twice daily for a platelet count >200,000/microL

●15 mg twice daily for a platelet count between 100,000 and 200,000/microL

●5 mg twice daily for a platelet count between 50,000 and <100,000/microL

Ruxolitinib should not be initiated in the setting of an active serious infection, because of reports of serious bacterial, mycobacterial, fungal, and viral infections, which may be linked to its suppressive effect on natural killer cells and dendritic cells [43-51]. All patients should be screened for tuberculosis risk factors (eg, residence or travel in a country with high prevalence, close contact with a person with active tuberculosis, history of active or latent tuberculosis with unknown treatment status). Patients with such risk factors should undergo testing for latent tuberculosis infection prior to starting ruxolitinib, and those with active or latent tuberculosis should be managed in conjunction with a clinician with expertise in the treatment of tuberculosis. Ruxolitinib may increase the risk of herpes zoster reactivation (shingles), and patients should seek early treatment if shingles is suspected. The ruxolitinib label includes a warning regarding potential hepatitis B virus reactivation and rare cases of progressive multifocal leukoencephalopathy (PML) [43]. (See "Diagnosis of pulmonary tuberculosis in adults" and "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis".)

All doses of ruxolitinib should be taken as scheduled; if a dose is missed, the patient should be advised to return to the usual dosing schedule and not to take an additional dose. If after six months of treatment there is no reduction in spleen size or symptom improvement, ruxolitinib should be discontinued on a tapering schedule. However, patients who appear to have ruxolitinib-resistant disease should be questioned carefully to assure that they are taking the medication at the recommended dose and schedule and are avoiding medications or herbal supplements that may impair efficacy (eg, concurrent treatment with a strong CYP3A4 inducer) [43]. Drug discontinuation rates during the various reported treatment trials have ranged from 24 to 51 percent during the first year of treatment and were reported as high as 46 to 89 percent at three years [52-54].

Discontinuation of ruxolitinib can be associated with full relapse of disease symptoms, with clinical findings (eg, fever, hypotension, hypoxia) suggestive of the systemic inflammatory response syndrome [52,55,56]. Suspicion of ruxolitinib withdrawal syndrome should prompt urgent treatment with systemic glucocorticoids (eg, prednisone 20 mg daily for seven days followed by a taper over the second week), and may also require treatment with vasopressors and resumption of ruxolitinib. An alternative myelosuppressive therapy (eg, hydroxyurea) may be necessary to control progressive leukocytosis or increasing blasts during withdrawal of ruxolitinib. (See "Evaluation and management of suspected sepsis and septic shock in adults".)

Ruxolitinib efficacy — Ruxolitinib can relieve debilitating symptoms of PMF in up to half of patients, compared with symptom relief in ≤5 percent in patients treated with placebo. However, ruxolitinib has not been proven to significantly prolong survival or reduce the risk of leukemic transformation in PMF:

●Symptom relief – The efficacy of ruxolitinib for symptom relief was demonstrated in the following phase III trials; both studies included patients with either wild-type or mutant JAK2:

•COMFORT-1 randomly assigned 309 patients with high-risk PMF to ruxolitinib versus placebo [40]. Compared with placebo, at 24 weeks ruxolitinib was more effective for reducing spleen volume by ≥35 percent (42 versus 1 percent, respectively, based on magnetic resonance imaging) and improving the total symptom score by ≥50 percent (46 versus 5 percent). For two-thirds of responding patients, spleen size reduction was sustained for ≥48 weeks. The study drug was discontinued by 11 percent of patients in both arms, and 13 deaths occurred with ruxolitinib group versus 24 with placebo. Anemia and thrombocytopenia were the most common adverse events with ruxolitinib, but rarely led to drug discontinuation.

•In COMFORT-2, 219 high-risk patients were randomly assigned to ruxolitinib versus best available therapy (BAT) [39]. Importantly, for nearly half of the patients in this trial, hydroxyurea was used as BAT despite the fact that 68 percent had already progressed despite hydroxyurea. Ruxolitinib achieved ≥35 percent spleen volume reduction in 28 percent of patients, compared with 5 percent with BAT; spleen reduction was maintained in 73 and 50 percent of subjects at 48 and 144 weeks of continued therapy, respectively [54]. Anemia and thrombocytopenia were common (grade 3 to 4 toxicity in 45 and 13 percent, respectively) with ruxolitinib, but were generally manageable, improved over time, and rarely led to treatment discontinuation.

●Survival – Ruxolitinib has not been proven to prolong survival in PMF. An abstract that presented preliminary data from COMFORT-2 reported that, after median follow-up of 4.3 years, estimated five-year OS with ruxolitinib was 56 percent versus 44 percent with BAT, median survival was not reached versus 4.1 years, and hazard ratio (HR) for survival was 0.67 (95% CI 0.44-1.02) [57]. However, it is important to recognize that the failure of ruxolitinib to achieve a significant survival benefit in either COMFORT-1 or COMFORT-2 may reflect the crossover design of these trials (ie, patients who progressed with placebo or BAT could subsequently receive ruxolitinib) [39,40]. A separate analysis reported that, compared with a historical control of 350 ruxolitinib-naïve patients, 100 PMF patients treated with ruxolitinib in COMFORT-2 had longer survival (5 versus 3.5 years); multivariate analysis indicated that the effect of ruxolitinib was maintained after adjusting for age and prognostic score (HR 0.64, 95% CI 0.4-0.96) [58].

Ruxolitinib is approved by the US Food and Drug Administration (FDA), the European Commission, and Health Canada for treatment of disease-related splenomegaly or symptoms in adult patients with myelofibrosis. Our suggestions are consistent with a consensus statement of the European LeukemiaNet and the Italian Society of Hematology [59].

Fedratinib — Fedratinib is a JAK2-selective kinase inhibitor that has activity against myelofibrosis, but treatment is associated with serious and sometimes fatal Wernicke-like encephalopathy. The risk for a withdrawal syndrome with fedratinib is not well-defined, but caution is warranted if fedratinib is to be discontinued.

Fedratinib treatment and cautions

●Administration – Fedratinib should be administered at 400 mg orally once daily, with or without food, in patients with a platelet count >50,000/microL [60]. Thiamine levels should be measured and repleted prior to starting fedratinib and should be assessed periodically during treatment; if Wernicke-like encephalopathy is suspected, fedratinib must be discontinued immediately and parenteral thiamine given. The initial dose should be reduced for patients receiving strong CYP3A inhibitors or with severe renal impairment, and fedratinib should not be given to patients with severe liver impairment, strong or moderate CYP3A4 inducers or dual CYP3A4 and CYP2C19 inhibitors (table 3). The dose should be reduced for management of fedratinib toxicity (described below).

●Adverse effects (AEs) – Treatment may be associated with cardiovascular conditions, liver toxicity, and rare cases of severe, sometimes fatal, encephalopathy.

Serious and fatal encephalopathy, including Wernicke's encephalopathy, has occurred in patients treated with fedratinib; serious cases were reported in 1.3 percent (8/608) of patients treated in clinical trials and death resulted in 0.16 percent (1/608) of cases [60]. In a clinical trial (described below) that included patients treated with fedratinib 500 mg daily, encephalopathy developed in seven patients; there were no cases of encephalopathy among patients who were treated with 400 mg daily [61]. Fedratinib has also been associated with cardiovascular death, myocardial infarction, stroke, and liver toxicity in some patients.

The risk and/or severity of a fedratinib withdrawal syndrome is not well-defined, but we taper rather than abruptly discontinue fedratinib (as discussed for ruxolitinib, above), except in the setting of suspected encephalopathy. (See "Wernicke encephalopathy", section on 'Clinical manifestations' and 'Ruxolitinib treatment and cautions' above.)

Fedratinib efficacy — Fedratinib was effective for reducing splenomegaly and symptom burden in more than one-third of patients with myelofibrosis in an international, double-blind, placebo-controlled trial [61]. The trial included 289 adults with higher risk PMF, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis who were randomly assigned to treatment with fedratinib 400 mg, fedratinib 500 mg, or placebo for at least six consecutive four-week cycles. Reduction of spleen volume ≥35 percent at week 24 and confirmed four weeks later was achieved in 36, 40, and 1 percent of patients who received 400 mg fedratinib, 500 mg fedratinib, and placebo, respectively. Reduction of total symptom score ≥50 percent at week 24 was achieved in 36, 34, and 7 percent of patients, respectively. Common AEs with fedratinib were anemia, gastrointestinal symptoms, and elevated liver transaminases, serum creatinine, and pancreatic enzymes.

Fedratinib 400 mg daily is approved by the FDA for treatment of higher-risk PMF [62].

Pacritinib — Pacritinib is an inhibitor of JAK2 and FLT3 [63] that is used for myelofibrosis with baseline or treatment-emergent thrombocytopenia. Pacritinib has been associated with cardiovascular events and death and with bleeding.

●Administration – Pacritinib is given at a dose of 200 mg orally, twice daily, with or without food. Strong CYP3A4 inhibitors or inducers are contraindicated; moderate CYP3A4 inhibitors or inducers should be avoided. Pacritinib should be avoided in patients with moderate or severe liver impairment or kidney disease [64].

●Adverse effects (AEs) – AEs include hemorrhage, diarrhea, prolonged QT interval, and thrombosis [64].

●Outcomes – In the phase 3 PERSIST-2 trial, pacritinib was more effective than best available therapy (BAT) for reducing spleen volume and symptom burden in patients with myelofibrosis with thrombocytopenia [65]. Patients with intermediate or high-risk PMF or secondary myelofibrosis with platelets ≤100,000/microL were randomly assigned to pacritinib (200 mg twice daily) versus BAT (eg, ruxolitinib, watchful waiting, hydroxyurea). Compared with BAT, pacritinib was more effective for reducing spleen volume (27 versus 1 percent), reducing spleen volume ≥35 percent (22 percent versus 3 percent), and lessening symptom burden by ≥50 percent (32 versus 14 percent, according to the MPN total symptom score); there was no difference in OS. Hematologic and cardiovascular AEs were comparable between trial arms. An earlier, larger trial (PERSIST-1) that included a higher dose of pacritinib was suspended due to concerns over bleeding and cardiovascular events and deaths.

Pacritinib was granted accelerated approval by the FDA for treatment of intermediate- or high-risk primary or secondary myelofibrosis with platelets <50,000/microL.

Hydroxyurea — Hydroxyurea can relieve moderate splenomegaly and other proliferative manifestations, such as thrombocytosis or leukocytosis. Hydroxyurea is an acceptable treatment option for patients who are ineligible for allogeneic HCT or who are not candidates for ruxolitinib or fedratinib.

Importantly, the starting dose of hydroxyurea for PMF is lower than that used for other myeloproliferative neoplasms, because many patients with PMF have limited bone marrow reserve and cytopenias. We suggest an initial dose of hydroxyurea 500 to 1000 mg every other day, with dose modifications based on results of semiweekly or weekly complete blood counts until doses are stabilized, and then as clinically indicated. Toxicity of hydroxyurea includes cytopenias, mucocutaneous ulcers, diarrhea, peripheral neuropathy, skin cancer, potential teratogenicity, and rare cases of severe (including fatal) pulmonary toxicity [66]. (See "Prognosis and treatment of essential thrombocythemia", section on 'Hydroxyurea'.)

Hydroxyurea may improve splenomegaly, thrombocytosis, leukocytosis, bone pain, fever, and/or pruritus in patients with PMF [67-71]. In one report, 40 percent of patients with PMF treated with hydroxyurea achieved ≥50 percent reduction of splenic mass, with responses that last for an average of one year [71]. In a series that included 69 patients with PMF, response to treatment with hydroxyurea was higher in patients with JAK2 V617F mutation (48 percent) than in patients with wild-type JAK2 (8 percent) [72]. Responses to hydroxyurea in the COMFORT-2 trial were much less frequent, but this likely reflected the clinical trial design, as described above [57]. (See 'Ruxolitinib efficacy' above.)

Alternative symptom-directed treatment — For patients with troublesome symptoms but who are not candidates for transplantation, ruxolitinib, fedratinib, or hydroxyurea, we suggest enrollment in a clinical trial. (See 'Clinical trials' below.)

Other treatments that may be beneficial for symptom relief in PMF include:

●Surgical splenectomy – Surgical splenectomy may be considered for some patients who have mechanical discomfort from splenomegaly, recurrent splenic infarction, transfusion-dependent anemia, refractory thrombocytopenia, hypercatabolic symptoms, portal hypertension, or high output heart failure; however, indications and practices vary by surgeon and institution [73-77]. Splenectomy generally provides short-term relief, but is associated with approximately 10 percent surgical mortality, short-term and long-term complications (eg, intra-abdominal bleeding, subphrenic abscess, sepsis, extreme thrombocytosis, accelerated hepatomegaly, splanchnic thrombosis), and does not improve survival [78]. (See "Elective (diagnostic or therapeutic) splenectomy" and 'Post-splenectomy thrombocytosis or hepatomegaly' below.)

●Splenic irradiation – Splenic irradiation may provide transient benefit (eg, three to six month) for patients who are poor surgical candidates or who have worsening disease, but it is often complicated by nausea and cytopenias [79]. Dose and schedule vary by institution, but it is prudent to treat with small fractions (eg, 0.25 to 0.50 Gy two to four times per week), with modifications based on the clinical situation and frequent blood counts. In a series of 23 patients with PMF, most had an objective reduction in splenic size and symptomatic relief (median duration: six months), but one-third had significant cytopenias, with fatal sepsis or hemorrhage in three patients [80].

●Other approaches – Interferons may provide symptom relief for some patients [81-84]. Other agents (eg, imatinib, bortezomib, bevacizumab, anagrelide) provide little benefit and/or are associated with significant toxicity [81-90].

Follow-up of higher-risk PMF — For patients who have undergone allogeneic HCT, monitoring is discussed separately. (See "Long-term care of the adult hematopoietic cell transplantation survivor".)

For patients who receive symptom-directed therapy with ruxolitinib, fedratinib, or hydroxyurea, we monitor response to therapy using the MPN-10 tool and evaluate for evidence of disease progression and/or complications every three to six months, or as clinically indicated. Evaluation should include a complete blood count, peripheral blood smear, lactate dehydrogenase, uric acid, and liver and renal function tests (see 'Symptom burden' above):

●For patients who have a favorable response to therapy we continue treatment indefinitely (ie, until progression or intolerance)

●For patients with an inadequate response or loss of response to ruxolitinib or fedratinib, it can be continued at the discretion of the clinician or alternative symptom-directed treatment (eg, hydroxyurea, splenectomy) or allogeneic HCT may be considered. We suggest bone marrow examination, including molecular analysis with next generation sequencing (NGS) to test for additional mutations that may herald disease progression. (See 'Relapsed or refractory disease' below.)

LOWER-RISK PMF — For patients with lower-risk PMF (algorithm 1), we suggest treatment that is guided by the nature and severity of symptoms (algorithm 2). Classification of patients as having lower-risk PMF is described above. (See 'Risk stratification' above.)

Symptomatic — There is no consensus regarding the severity of symptoms that warrants treatment for patients with lower-risk PMF. The decision regarding when and how to treat patients in this setting should be individualized and weigh potential benefits of symptom relief against toxicity of therapy. For patients who are symptomatic with anemia only, evaluation and management are discussed below. (See 'Anemia in PMF' below.)

For other symptomatic patients with lower-risk PMF, acceptable treatment options include (see 'Selection of therapy' above):

●Ruxolitinib (see 'Ruxolitinib' above)

●Fedratinib (see 'Fedratinib' above)

●Hydroxyurea (see 'Hydroxyurea' above)

●Alternative approaches (see 'Alternative symptom-directed treatment' above)

We suggest use of the MPN-10 tool to evaluate symptom burden at baseline and to monitor response to treatment. (See 'Symptom burden' above.)

Follow-up of lower-risk patients who are receiving symptom-directed therapy is discussed below. (See 'Follow-up of patients with lower-risk PMF' below.)

Asymptomatic — For asymptomatic lower-risk patients, we suggest observation rather than symptom-directed therapy (eg, ruxolitinib, fedratinib, hydroxyurea) (algorithm 2). Ruxolitinib, fedratinib, and hydroxyurea have not been shown to improve survival in PMF, and the very favorable prognosis in this setting does not warrant the risks of allogeneic HCT. (See "Prognosis of primary myelofibrosis", section on 'Assessing prognosis in PMF'.)

Follow-up of patients with lower-risk PMF — We generally monitor patients with lower-risk PMF for clinical evidence of disease progression and/or complications every three to six months, or as clinically indicated. We monitor symptom burden with the MPN-10 tool, perform a focused history and physical examination, and obtain a complete blood count, peripheral blood smear, lactate dehydrogenase, uric acid, and liver and renal function tests. We do not routinely perform bone marrow examinations unless there are symptoms or signs of disease progression.

Response to treatment is subjective, but assessment may be aided by use of a disease-specific tool (eg, MPN-10) to evaluate the symptom burden at baseline and to monitor symptom status in response to therapy. For patients who are receiving symptom-directed treatment, we manage as follows:

●Adequate response – For patients who have a response to therapy, we continue treatment indefinitely (ie, until progression or intolerance).

●Inadequate response – For patients with an inadequate symptomatic response, loss of response, or disease progression, ruxolitinib or fedratinib can be continued at the discretion of the clinician, or alternative symptom-directed treatment or allogeneic HCT may be considered. Caution must be used if ruxolitinib or fedratinib is to be discontinued, as discussed above. (See 'Ruxolitinib treatment and cautions' above.)

We suggest bone marrow examination for patients with an inadequate response, including molecular testing for higher-risk mutations that may herald disease progression. (See 'Relapsed or refractory disease' below.)

For patients under observation, development of symptomatic splenomegaly, constitutional symptoms, worsening anemia/transfusion requirement, or other findings should prompt reassessment of risk stratification and consideration of symptom management. (See 'Anemia in PMF' below and 'Specific management issues' below and 'Risk stratification' above.)

SPECIFIC MANAGEMENT ISSUES — Most patients with PMF will have troublesome or life-threatening symptoms related to splenomegaly, hepatomegaly, red blood cell transfusion dependence, severe fatigue, or bone pain in the course of their disease. Management of specific aspects of PMF is described in the sections below.

Anemia in PMF — Anemia in PMF is a significant source of impaired quality of life, and may cause fatigue, weakness, exercise intolerance, angina, dizziness, cognitive impairment, or an altered sense of well-being. Anemia in PMF is generally multifactorial and patients should be evaluated for bleeding, hemolysis, and nutritional deficiencies (eg, iron, vitamin B12, folate), and other remediable causes. (See "Clinical manifestations and diagnosis of primary myelofibrosis", section on 'Anemia' and "Diagnostic approach to anemia in adults".)

Transfusion therapy — The mainstay of anemia management in PMF is red blood cell transfusion, but there is no agreed-upon level of hemoglobin that should trigger transfusion, and management varies with patient age, symptoms, medical comorbidities, and institutional practice. Chronic transfusion therapy may be associated with alloimmunization, iron overload, and other complications. Management of transfusion therapy and complications, and adjunctive treatments that may reduce the transfusion requirement are discussed separately and below. (See "Indications and hemoglobin thresholds for red blood cell transfusion in the adult" and 'Adjunctive approaches' below.)

For many transfusion-dependent patients, it is unclear whether the benefit of reducing splenic sequestration (eg, with surgical splenectomy or irradiation) will outweigh the loss of an important site of extramedullary erythropoiesis. As a general rule, we will consider splenectomy only if a nonbleeding patient with PMF chronically requires ≥3 units of red blood cells every two weeks, because we consider that the spleen is not an "effective" source of red blood cell production in that setting. This reasoning is based on typical transfusion requirements in adults with no effective erythropoiesis (eg, severe aplastic anemia or pure red cell aplasia).

Transfusion-dependent anemia is an important indication for treatment of PMF, and anemia may improve in response to treatment that is guided by the risk-stratified approach described above. (See 'Risk stratification' above.)

Adjunctive approaches — For patients who require ongoing transfusions, we often add an adjunctive therapy. There is no consensus about the optimal regimen nor when to add such an approach.

Erythropoiesis-stimulating agents (ESAs; eg, erythropoietin, darbepoetin) have generally not been successful in alleviating anemia associated with PMF [91-94]; most reported responses to ESAs are in patients with PMF who were not requiring transfusion support and/or those with inappropriately low serum erythropoietin levels [95-97].

We suggest initial treatment with danazol, which can improve anemia in about one-third of patients with PMF [98-101]. We begin with danazol 200 mg twice daily, but the dose can be increased to 400 mg twice daily, as tolerated. Treatment should continue for at least three months and, in patients who respond, the dose can be tapered to the minimum effective dose after six months. Danazol is generally well tolerated, but patients may have an increase in liver enzymes (which may improve with dose reduction), headache, or increased muscle mass. The packaging label for danazol carries warnings regarding effects in pregnancy, severe thromboembolic events, and intracranial hypertension.

If treatment with danazol does not reduce the transfusion requirement, we consider prednisone plus thalidomide or lenalidomide, or an investigational therapy in the context of a clinical trial:

●Thalidomide plus prednisone – Thalidomide (50 mg/day orally) plus prednisone (beginning at 0.5 mg/kg orally per day, and tapering over a period of three months) can achieve a response in about one-third of patients [102-104]. Thalidomide is associated with drowsiness, constipation, fatigue, paresthesias, neutropenia, and thrombosis. The label for thalidomide carries warnings regarding severe birth defects and thromboembolic events.

●Lenalidomide plus prednisone – Lenalidomide (various doses and schedules) plus prednisone has improved anemia in one-quarter to one-third of patients, and may also reduce spleen size [105-107]. We generally reserve the use of lenalidomide plus prednisone for patients with PMF who have both anemia and evidence of progressive myeloproliferation (eg, splenomegaly). The label for lenalidomide carries warnings regarding severe birth defects, hematologic toxicity, and thromboembolic events.

Precautions regarding the use of thalidomide and lenalidomide are discussed separately. (See "Overview of angiogenesis inhibitors", section on 'Immunomodulatory drugs (IMiDs)' and "Multiple myeloma: Prevention of venous thromboembolism in patients receiving immunomodulatory drugs (thalidomide, lenalidomide, and pomalidomide)".)

Extramedullary hematopoiesis — Pain or organ dysfunction from extramedullary hematopoiesis (EMH) may occur in the spinal cord, peritoneal and pleural cavities, bone, liver, lung, and other organs. The presentation is similar to clinical manifestations of myeloid sarcoma, and radiation therapy is often successful in the management of symptomatic foci of EMH due to PMF [108-112]. (See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia", section on 'Myeloid sarcoma'.)

Leukemic transformation — Leukemic transformation is the most common cause of death in PMF [4,113,114]. (See "Clinical manifestations and diagnosis of primary myelofibrosis", section on 'Transformation to acute leukemia'.)

There is no standard treatment of leukemic transformation, and participation in a clinical trial is encouraged. No randomized or well-controlled studies have compared therapeutic approaches, and options range from supportive/palliative management to intensive induction chemotherapy followed by allogeneic hematopoietic cell transplantation (HCT). A decision of when and how to treat is influenced by the patient's overall clinical status, goals, and preferences and clinician/institutional approach and experience. (See "Overview of acute myeloid leukemia in adults".)

A single center, prospective study that used intensive acute myeloid leukemia (AML)-like induction therapy followed by allogeneic HCT reported outcomes of 75 consecutive patients with leukemic transformation after PMF and other myeloproliferative neoplasms (MPN) [115]. A total of 38 patients were treated with curative intent (intensive induction therapy, with or without HCT), while the remainder received non-intensive chemotherapy (eg, low dose cytarabine, azacitidine, decitabine) or supportive care. Treatment with curative intent resulted in complete response (CR), CR with incomplete hematologic recovery (CRi), or reversion to chronic phase MPN in 12, 2, and 10 percent, respectively. Patients treated with curative intent had improved median survival (9.4 versus 2.3 months) and two-year overall survival (25.6 versus 3.1 percent) when compared with treatment with non-curative intent. Five among the 17 patients who underwent allogeneic HCT remained alive and free of AML with a median OS of 47 months after initial leukemic transformation.

Retrospective studies that utilized intensive remission induction chemotherapy for leukemic transformation described overall CR rates ranging from 0 to 60 percent, and median survival rates of 3.9 to 9.4 months [114,116-121]. Retrospective studies of patients who underwent allogeneic HCT after induction therapy for leukemic transformation report improved median and overall survival compared with those who did not undergo HCT, but confirmation of these findings awaits more definitive studies [116,118,120].

Lower intensity treatment with azacitidine, decitabine, or ruxolitinib has limited activity in patients with leukemic transformation who are not eligible for HCT. A retrospective, single institution study of six patients treated with decitabine reported a median survival >9 months, reduction in spleen size, and improved symptoms [122]. Treatment with azacitidine of 26 patients with leukemic transformation achieved an overall response rate of 26 percent and median overall survival of eight months [119]. Treatment with ruxolitinib achieved CR/CRi in 3 of 18 patients with leukemic transformation [123].

Post-splenectomy thrombocytosis or hepatomegaly — Thrombocytosis and/or hepatomegaly are common after surgical splenectomy. A retrospective, single-institution study of 314 patients with PMF who underwent splenectomy reported post-operative extreme thrombocytosis (platelet count >106/microL; 5 percent), bleeding (14 percent), thrombosis (10 percent), and accelerated hepatomegaly (10 percent) [74]. Another study of 71 patients described massive hepatomegaly in 24 percent [75].

There is no consensus regarding optimal management of post-splenectomy thrombocytosis and hepatomegaly. Options include platelet pheresis, hydroxyurea, or cladribine [124,125]. (See "Prognosis and treatment of essential thrombocythemia", section on 'Extreme thrombocytosis or bleeding' and 'Hydroxyurea' above.)

After postoperative hemostasis has been achieved, we consider treatment with short-term anticoagulation (eg, one month of therapeutic anticoagulation with low molecular weight heparin) to minimize the risk of splanchnic vein thrombosis, but this decision should be individualized.

Relapsed or refractory disease — The choice of therapy for patients with relapsed or refractory PMF should take into consideration prior therapies, the quality and duration of response to prior therapy, the severity of symptoms, and the patient's preferences and performance status. We encourage patients with relapsed or refractory disease to participate in clinical trials. (See 'Clinical trials' below.)

Outside of a clinical trial, fedratinib may provide relief of symptoms and/or reduction of spleen volume for patients who are resistant or refractory to ruxolitinib. In the JAKARTA2 study, nearly one-third of patients who were ruxolitinib-resistant, -refractory, or -intolerant had ≥35 percent decrease in spleen volume and ≥50 percent reduction in symptom score; grade ≥3 anemia and thrombocytopenia were reported in 38 and 22 percent, respectively [126]. Treatment and cautions regarding fedratinib are discussed above. (See 'Fedratinib treatment and cautions' above.)

SECONDARY MYELOFIBROSIS — Secondary myelofibrosis refers to myelofibrosis that develops after polycythemia vera (PV) or essential thrombocythemia (ET). Our approach to evaluation and management of secondary myelofibrosis follows the suggestions for PMF.

Diagnostic criteria for secondary myelofibrosis are presented separately. (See "Clinical manifestations and diagnosis of primary myelofibrosis", section on 'Secondary myelofibrosis (post-PV or post-ET)'.)

SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The coronavirus 2019 (COVID-19) pandemic has increased the complexity of cancer care. Important issues include balancing the risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. Additionally, immunocompromised patients are candidates for a modified vaccination schedule (figure 1), other preventive strategies (including pre-exposure prophylaxis), and the early initiation of COVID-directed therapy. These issues and recommendations for cancer care during the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)

CLINICAL TRIALS — Often, there is no better therapy to offer a patient than enrollment onto a well-designed, scientifically valid, peer-reviewed clinical trial. Additional information and instructions for referring a patient to an appropriate research center can be obtained from the United States National Institutes of Health (www.clinicaltrials.gov).

Current approaches include novel agents and therapies used for other conditions. As an example, imetelstat is an investigational antisense oligonucleotide directed against telomerase. In a pilot study, imetelstat resulted in an at least partial response in 7 of 33 patients with advanced myelofibrosis (median time to response 3.5 months, median duration of response 18 months) [127]. Four patients had a complete response with reversal of bone marrow fibrosis. The most common toxicity was myelosuppression, which resulted in dose reductions in 67 percent of patients. While common, elevations in liver enzymes were usually reversible.

SOCIETY GUIDELINE LINKS — Our approach is consistent with consensus recommendations for hematopoietic cell transplantation in PMF by the European LeukemiaNet (ELN) and European Blood and Marrow Transplantation Group (EBMT) [38] and US National Comprehensive Cancer Network Myelofibrosis guidelines [37].

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Myeloproliferative neoplasms".)

SUMMARY AND RECOMMENDATIONS

●Description – Primary myelofibrosis (PMF) is a myeloproliferative neoplasm associated with bone marrow fibrosis, cytopenias, constitutional symptoms, hepatosplenomegaly, and/or extramedullary hematopoiesis. Patients are at risk for premature death due to disease progression, leukemic transformation, thrombo-hemorrhagic complications, and infections.

●Pretreatment

•Discussion of goals of care (see 'Goals of care' above)

•Evaluation of baseline symptom burden (see 'Symptom burden' above)

•Assessment of medical fitness, including performance status, physiologic fitness, and cognition (see 'Medical fitness' above)

●Risk-stratification – Patients are classified as having higher-risk versus lower-risk PMF. Details of classification and prognostic instruments are presented separately. (See "Prognosis of primary myelofibrosis", section on 'Assessing prognosis in PMF'.)

●Management – Management is stratified according to PMF risk status, eligibility for allogeneic hematopoietic cell transplantation (HCT), and symptom burden (algorithm 1):

•Higher-risk, HCT-eligible – For patients with higher-risk PMF who are eligible for transplantation, we suggest HCT, rather than symptom-directed therapy (eg, ruxolitinib, fedratinib, pacritinib, hydroxyurea) (algorithm 2) (Grade 2B). (See 'Transplant eligible' above.)

•Higher-risk, ineligible for HCT – For patients with higher-risk PMF who are not candidates for transplantation, we favor a clinical trial; other options include ruxolitinib, fedratinib, pacritinib, or hydroxyurea for relief of symptoms (algorithm 2). (See 'Ineligible for transplantation' above.)

•Lower-risk, symptomatic – For patients with lower-risk PMF, we suggest symptom-directed treatment, rather than transplantation (algorithm 2) (Grade 2B). (See 'Symptomatic' above.)

•Lower-risk PMF, no symptoms – For asymptomatic patients with lower-risk PMF, we suggest observation rather than symptom-directed treatment (algorithm 2) (Grade 2B). (See 'Asymptomatic' above.)

●Selection of treatment – The choice of therapy for symptom relief is influenced by severity of symptoms, comorbid illnesses, other medications, and platelet count. The kinase inhibitors, ruxolitinib, fedratinib, and pacritinib, should be used with caution in patients with liver or kidney dysfunction, administration of CYP3A4 activators or inhibitors, and thrombocytopenia; however, pacritinib is approved for treatment of patients with platelets <50,000/microL.

Options include:

•Ruxolitinib – (See 'Ruxolitinib' above.)

•Fedratinib – (See 'Fedratinib' above.)

•Pacritinib – (See 'Pacritinib' above.)

•Hydroxyurea – (See 'Hydroxyurea' above.)

•Splenectomy or splenic irradiation – (See 'Alternative symptom-directed treatment' above.)

●Other management – Management of anemia, extramedullary hematopoiesis, leukemic transformation, post-splenectomy thrombocytosis, and relapsed/refractory PMF is discussed above. (See 'Specific management issues' above.)

ACKNOWLEDGMENT — The editors of UpToDate acknowledge the contributions of Stanley L Schrier, MD as Section Editor on this topic, his tenure as the founding Editor-in-Chief for UpToDate in Hematology, and his dedicated and longstanding involvement with the UpToDate program.

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  75. Barosi G, Ambrosetti A, Buratti A, et al. Splenectomy for patients with myelofibrosis with myeloid metaplasia: pretreatment variables and outcome prediction. Leukemia 1993; 7:200.
  76. Lafaye F, Rain JD, Clot P, Najean Y. Risks and benefits of splenectomy in myelofibrosis: an analysis of 39 cases. Nouv Rev Fr Hematol 1994; 36:359.
  77. Barbui T, Barosi G, Birgegard G, et al. Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet. J Clin Oncol 2011; 29:761.
  78. Tefferi A, Mesa RA, Nagorney DM, et al. Splenectomy in myelofibrosis with myeloid metaplasia: a single-institution experience with 223 patients. Blood 2000; 95:2226.
  79. Pardanani A, Brown P, Neben-Wittich M, et al. Effective management of accelerated phase myelofibrosis with low-dose splenic radiotherapy. Am J Hematol 2010; 85:715.
  80. Elliott MA, Chen MG, Silverstein MN, Tefferi A. Splenic irradiation for symptomatic splenomegaly associated with myelofibrosis with myeloid metaplasia. Br J Haematol 1998; 103:505.
  81. Gilbert HS. Long term treatment of myeloproliferative disease with interferon-alpha-2b: feasibility and efficacy. Cancer 1998; 83:1205.
  82. Radin AI, Kim HT, Grant BW, et al. Phase II study of alpha2 interferon in the treatment of the chronic myeloproliferative disorders (E5487): a trial of the Eastern Cooperative Oncology Group. Cancer 2003; 98:100.
  83. Kiladjian JJ, Chomienne C, Fenaux P. Interferon-alpha therapy in bcr-abl-negative myeloproliferative neoplasms. Leukemia 2008; 22:1990.
  84. Tefferi A, Elliot MA, Yoon SY, et al. Clinical and bone marrow effects of interferon alfa therapy in myelofibrosis with myeloid metaplasia. Blood 2001; 97:1896.
  85. Tefferi A, Mesa RA, Gray LA, et al. Phase 2 trial of imatinib mesylate in myelofibrosis with myeloid metaplasia. Blood 2002; 99:3854.
  86. Cortes J, Giles F, O'Brien S, et al. Results of imatinib mesylate therapy in patients with refractory or recurrent acute myeloid leukemia, high-risk myelodysplastic syndrome, and myeloproliferative disorders. Cancer 2003; 97:2760.
  87. Barosi G, Gattoni E, Barbui T, et al. A phase I study of the proteasome inhibitor bortezomib in patients with myelofibrosis (abstract). Blood 2007; 110:1036A.
  88. Mesa RA, Verstovsek S, Rivera C, et al. Bortezomib therapy in myelofibrosis: a phase II clinical trial. Leukemia 2008; 22:1636.
  89. Mesa RA, Silver RT, Verstovsek S, et al. Single agent bevacizumab for myelofibrosis: results of the Myeloproliferative Disorders Research Consortium Trial. Haematologica 2013; 98:1421.
  90. Yoon SY, Li CY, Mesa RA, Tefferi A. Bone marrow effects of anagrelide therapy in patients with myelofibrosis with myeloid metaplasia. Br J Haematol 1999; 106:682.
  91. Tefferi A, Silverstein MN. Recombinant human erythropoietin therapy in patients with myelofibrosis with myeloid metaplasia. Br J Haematol 1994; 86:893.
  92. Rodríguez JN, Martino ML, Diéguez JC, Prados D. rHuEpo for the treatment of anemia in myelofibrosis with myeloid metaplasia. Experience in 6 patients and meta-analytical approach. Haematologica 1998; 83:616.
  93. Mohr B, Herrmann R, Huhn D. Recombinant human erythropoietin in patients with myelodysplastic syndrome and myelofibrosis. Acta Haematol 1993; 90:65.
  94. Huang J, Tefferi A. Erythropoiesis stimulating agents have limited therapeutic activity in transfusion-dependent patients with primary myelofibrosis regardless of serum erythropoietin level. Eur J Haematol 2009; 83:154.
  95. Aloe Spiriti M, Latagliata R, Avvisati G, et al. Erythropoietin treatment of idiopathic myelofibrosis. Haematologica 1993; 78:371.
  96. Cervantes F, Alvarez-Larrán A, Hernández-Boluda JC, et al. Erythropoietin treatment of the anaemia of myelofibrosis with myeloid metaplasia: results in 20 patients and review of the literature. Br J Haematol 2004; 127:399.
  97. Cervantes F, Alvarez-Larrán A, Hernández-Boluda JC, et al. Darbepoetin-alpha for the anaemia of myelofibrosis with myeloid metaplasia. Br J Haematol 2006; 134:184.
  98. Lévy V, Bourgarit A, Delmer A, et al. Treatment of agnogenic myeloid metaplasia with danazol: a report of four cases. Am J Hematol 1996; 53:239.
  99. Cervantes F, Alvarez-Larrán A, Domingo A, et al. Efficacy and tolerability of danazol as a treatment for the anaemia of myelofibrosis with myeloid metaplasia: long-term results in 30 patients. Br J Haematol 2005; 129:771.
  100. Shimoda K, Shide K, Kamezaki K, et al. The effect of anabolic steroids on anemia in myelofibrosis with myeloid metaplasia: retrospective analysis of 39 patients in Japan. Int J Hematol 2007; 85:338.
  101. Cervantes F, Hernández-Boluda JC, Alvarez A, et al. Danazol treatment of idiopathic myelofibrosis with severe anemia. Haematologica 2000; 85:595.
  102. Elliott MA, Mesa RA, Li CY, et al. Thalidomide treatment in myelofibrosis with myeloid metaplasia. Br J Haematol 2002; 117:288.
  103. Mesa RA, Elliott MA, Schroeder G, Tefferi A. Durable responses to thalidomide-based drug therapy for myelofibrosis with myeloid metaplasia. Mayo Clin Proc 2004; 79:883.
  104. Mesa RA, Steensma DP, Pardanani A, et al. A phase 2 trial of combination low-dose thalidomide and prednisone for the treatment of myelofibrosis with myeloid metaplasia. Blood 2003; 101:2534.
  105. Tefferi A, Cortes J, Verstovsek S, et al. Lenalidomide therapy in myelofibrosis with myeloid metaplasia. Blood 2006; 108:1158.
  106. Quintás-Cardama A, Kantarjian HM, Manshouri T, et al. Lenalidomide plus prednisone results in durable clinical, histopathologic, and molecular responses in patients with myelofibrosis. J Clin Oncol 2009; 27:4760.
  107. Mesa RA, Yao X, Cripe LD, et al. Lenalidomide and prednisone for myelofibrosis: Eastern Cooperative Oncology Group (ECOG) phase 2 trial E4903. Blood 2010; 116:4436.
  108. Steensma DP, Hook CC, Stafford SL, Tefferi A. Low-dose, single-fraction, whole-lung radiotherapy for pulmonary hypertension associated with myelofibrosis with myeloid metaplasia. Br J Haematol 2002; 118:813.
  109. Koch CA, Li CY, Mesa RA, Tefferi A. Nonhepatosplenic extramedullary hematopoiesis: associated diseases, pathology, clinical course, and treatment. Mayo Clin Proc 2003; 78:1223.
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  111. Tefferi A, Jiménez T, Gray LA, et al. Radiation therapy for symptomatic hepatomegaly in myelofibrosis with myeloid metaplasia. Eur J Haematol 2001; 66:37.
  112. Neben-Wittich MA, Brown PD, Tefferi A. Successful treatment of severe extremity pain in myelofibrosis with low-dose single-fraction radiation therapy. Am J Hematol 2010; 85:808.
  113. Cervantes F, Dupriez B, Passamonti F, et al. Improving survival trends in primary myelofibrosis: an international study. J Clin Oncol 2012; 30:2981.
  114. Mesa RA, Li CY, Ketterling RP, et al. Leukemic transformation in myelofibrosis with myeloid metaplasia: a single-institution experience with 91 cases. Blood 2005; 105:973.
  115. Kennedy JA, Atenafu EG, Messner HA, et al. Treatment outcomes following leukemic transformation in Philadelphia-negative myeloproliferative neoplasms. Blood 2013; 121:2725.
  116. Tam CS, Nussenzveig RM, Popat U, et al. The natural history and treatment outcome of blast phase BCR-ABL- myeloproliferative neoplasms. Blood 2008; 112:1628.
  117. Passamonti F, Rumi E, Arcaini L, et al. Leukemic transformation of polycythemia vera: a single center study of 23 patients. Cancer 2005; 104:1032.
  118. Noor SJ, Tan W, Wilding GE, et al. Myeloid blastic transformation of myeloproliferative neoplasms--a review of 112 cases. Leuk Res 2011; 35:608.
  119. Thepot S, Itzykson R, Seegers V, et al. Treatment of progression of Philadelphia-negative myeloproliferative neoplasms to myelodysplastic syndrome or acute myeloid leukemia by azacitidine: a report on 54 cases on the behalf of the Groupe Francophone des Myelodysplasies (GFM). Blood 2010; 116:3735.
  120. Cherington C, Slack JL, Leis J, et al. Allogeneic stem cell transplantation for myeloproliferative neoplasm in blast phase. Leuk Res 2012; 36:1147.
  121. Takagi S, Masuoka K, Uchida N, et al. Allogeneic Hematopoietic Cell Transplantation for Leukemic Transformation Preceded by Philadelphia Chromosome-Negative Myeloproliferative Neoplasms: A Nationwide Survey by the Adult Acute Myeloid Leukemia Working Group of the Japan Society for Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant 2016; 22:2208.
  122. Mascarenhas J, Navada S, Malone A, et al. Therapeutic options for patients with myelofibrosis in blast phase. Leuk Res 2010; 34:1246.
  123. Eghtedar A, Verstovsek S, Estrov Z, et al. Phase 2 study of the JAK kinase inhibitor ruxolitinib in patients with refractory leukemias, including postmyeloproliferative neoplasm acute myeloid leukemia. Blood 2012; 119:4614.
  124. Tefferi A, Silverstein MN, Li CY. 2-Chlorodeoxyadenosine treatment after splenectomy in patients who have myelofibrosis with myeloid metaplasia. Br J Haematol 1997; 99:352.
  125. Faoro LN, Tefferi A, Mesa RA. Long-term analysis of the palliative benefit of 2-chlorodeoxyadenosine for myelofibrosis with myeloid metaplasia. Eur J Haematol 2005; 74:117.
  126. Harrison CN, Schaap N, Vannucchi AM, et al. Fedratinib in patients with myelofibrosis previously treated with ruxolitinib: An updated analysis of the JAKARTA2 study using stringent criteria for ruxolitinib failure. Am J Hematol 2020; 95:594.
  127. Tefferi A, Lasho TL, Begna KH, et al. A Pilot Study of the Telomerase Inhibitor Imetelstat for Myelofibrosis. N Engl J Med 2015; 373:908.
Topic 4531 Version 106.0

References

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2 : Hematopoietic Cell Transplantation as Curative Therapy for Patients with Myelofibrosis: Long-Term Success in all Age Groups.

3 : Outcome of transplantation for myelofibrosis.

4 : New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment.

5 : Allogeneic bone marrow transplantation for agnogenic myeloid metaplasia. French Society of Bone Marrow Transplantation.

6 : Allogeneic hematopoietic stem cell transplantation for myelofibrosis.

7 : Allogeneic marrow transplantation for myeloproliferative disorders other than chronic myelogenous leukemia: review of forty cases.

8 : Allogeneic bone marrow transplantation for primary myelofibrosis.

9 : Allogeneic bone marrow transplantation for primary myelofibrosis.

10 : Hematopoietic cell transplantation for adult patients with myelodysplastic syndromes and myeloproliferative disorders.

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12 : Retrospective study of allogeneic haematopoietic stem-cell transplantation for myelofibrosis.

13 : Myelofibrosis with myeloid metaplasia: clinical and haematological parameters predicting survival in a series of 133 patients.

14 : Impact of allogeneic stem cell transplantation on survival of patients less than 65 years of age with primary myelofibrosis.

15 : Allogeneic haematopoietic cell transplantation for myelofibrosis in 30 patients 60-78 years of age.

16 : Relevance of marrow fibrosis in bone marrow transplantation: a retrospective analysis of engraftment.

17 : Allogeneic stem cell transplantation after reduced-intensity conditioning in patients with myelofibrosis: a prospective, multicenter study of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation.

18 : MPD-RC 101 prospective study of reduced-intensity allogeneic hematopoietic stem cell transplantation in patients with myelofibrosis.

19 : Allogeneic haematopoietic stem cell transplantation for myelofibrosis: a report of the SociétéFrançaise de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC).

20 : Different outcome of allogeneic transplantation in myelofibrosis using conventional or reduced-intensity conditioning regimens.

21 : Allogeneic blood cell transplantation following reduced-intensity conditioning is effective therapy for older patients with myelofibrosis with myeloid metaplasia.

22 : Dose-reduced conditioning regimen followed by allogeneic stem cell transplantation in patients with myelofibrosis with myeloid metaplasia.

23 : Pilot study of reduced-intensity conditioning followed by allogeneic stem cell transplantation from related and unrelated donors in patients with myelofibrosis.

24 : Allogeneic hematopoietic stem-cell transplantation with reduced-intensity conditioning in intermediate- or high-risk patients with myelofibrosis with myeloid metaplasia.

25 : Allogeneic hemopoietic SCT for patients with primary myelofibrosis: a predictive transplant score based on transfusion requirement, spleen size and donor type.

26 : Impact of JAK2V617F mutation status, allele burden, and clearance after allogeneic stem cell transplantation for myelofibrosis.

27 : The outcome of allo-HSCT for 92 patients with myelofibrosis in the Nordic countries.

28 : Risk models predicting survival after reduced-intensity transplantation for myelofibrosis.

29 : Clearance of the Janus kinase 2 (JAK2) V617F mutation after allogeneic stem cell transplantation in a patient with myelofibrosis with myeloid metaplasia.

30 : Relapse of postpolycythemia myelofibrosis after allogeneic stem cell transplantation in a polycythemic phase: successful treatment with donor lymphocyte infusion directed by quantitative PCR test for V617F-JAK2 mutation.

31 : Allogeneic hematopoietic stem cell transplantation in patients with polycythemia vera or essential thrombocythemia transformed to myelofibrosis or acute myeloid leukemia: a report from the MPN Subcommittee of the Chronic Malignancies Working Party of the European Group for Blood and Marrow Transplantation.

32 : Reduced-intensity hematopoietic cell transplantation for patients with primary myelofibrosis: a cohort analysis from the center for international blood and marrow transplant research.

33 : Allogeneic hematopoietic cell transplantation following reduced intensity conditioning for treatment of myelofibrosis.

34 : Outcome of allogeneic stem cell transplantation following reduced-intensity conditioninig regimen in patients with idiopathic myelofibrosis: the g.I.T.m.o. Experience.

35 : Improved outcomes using tacrolimus/sirolimus for graft-versus-host disease prophylaxis with a reduced-intensity conditioning regimen for allogeneic hematopoietic cell transplant as treatment of myelofibrosis.

36 : Outcome after Transplantation According to Reduced-Intensity Conditioning Regimen in Patients Undergoing Transplantation for Myelofibrosis.

37 : Outcome after Transplantation According to Reduced-Intensity Conditioning Regimen in Patients Undergoing Transplantation for Myelofibrosis.

38 : Indication and management of allogeneic stem cell transplantation in primary myelofibrosis: a consensus process by an EBMT/ELN international working group.

39 : JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis.

40 : A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis.

41 : JAK inhibitor in CALR-mutant myelofibrosis.

42 : Impact of mutational status on outcomes in myelofibrosis patients treated with ruxolitinib in the COMFORT-II study.

43 : Impact of mutational status on outcomes in myelofibrosis patients treated with ruxolitinib in the COMFORT-II study.

44 : The JAK-inhibitor ruxolitinib impairs dendritic cell function in vitro and in vivo.

45 : An opportunistic infection associated with ruxolitinib, a novel janus kinase 1,2 inhibitor.

46 : Reactivation of hepatitis B virus infection following ruxolitinib treatment in a patient with myelofibrosis.

47 : Disseminated tuberculosis in a patient treated with a JAK2 selective inhibitor: a case report.

48 : Bilateral toxoplasmosis retinitis associated with ruxolitinib.

49 : Progressive multifocal leukoencephalopathy associated with ruxolitinib.

50 : Ruxolitinib is a potent immunosuppressive compound: is it time for anti-infective prophylaxis?

51 : Cytomegalovirus Retinitis in a Patient Who Received Ruxolitinib.

52 : Long-term outcome of treatment with ruxolitinib in myelofibrosis.

53 : Long-term outcomes of 107 patients with myelofibrosis receiving JAK1/JAK2 inhibitor ruxolitinib: survival advantage in comparison to matched historical controls.

54 : Three-year efficacy, safety, and survival findings from COMFORT-II, a phase 3 study comparing ruxolitinib with best available therapy for myelofibrosis.

55 : Serious adverse events during ruxolitinib treatment discontinuation in patients with myelofibrosis.

56 : Ruxolitinib withdrawal syndrome leading to tumor lysis.

57 : Long-Term Efficacy and Safety in COMFORT-II, a Phase 3 Study Comparing Ruxolitinib with Best Available Therapy for the Treatment of Myelofibrosis: 5-Year Final Study Results

58 : Impact of ruxolitinib on the natural history of primary myelofibrosis: a comparison of the DIPSS and the COMFORT-2 cohorts.

59 : Which patients with myelofibrosis should receive ruxolitinib therapy? ELN-SIE evidence-based recommendations.

60 : Which patients with myelofibrosis should receive ruxolitinib therapy? ELN-SIE evidence-based recommendations.

61 : Safety and Efficacy of Fedratinib in Patients With Primary or Secondary Myelofibrosis: A Randomized Clinical Trial.

62 : Safety and Efficacy of Fedratinib in Patients With Primary or Secondary Myelofibrosis: A Randomized Clinical Trial.

63 : Comprehensive kinase profile of pacritinib, a nonmyelosuppressive Janus kinase 2 inhibitor.

64 : Comprehensive kinase profile of pacritinib, a nonmyelosuppressive Janus kinase 2 inhibitor.

65 : Pacritinib vs Best Available Therapy, Including Ruxolitinib, in Patients With Myelofibrosis: A Randomized Clinical Trial.

66 : Pacritinib vs Best Available Therapy, Including Ruxolitinib, in Patients With Myelofibrosis: A Randomized Clinical Trial.

67 : Management of polycythaemia vera, essential thrombocythaemia and myelofibrosis with hydroxyurea.

68 : Reversal of myelofibrosis by hydroxyurea.

69 : Management of myelofibrosis with intermittent hydroxyurea.

70 : Splenic irradiation in the treatment of patients with chronic myelogenous leukemia or myelofibrosis with myeloid metaplasia. Results of daily and intermittent fractionation with and without concomitant hydroxyurea.

71 : Efficacy and tolerability of hydroxyurea in the treatment of the hyperproliferative manifestations of myelofibrosis: results in 40 patients.

72 : The presence of JAK2V617F in primary myelofibrosis or its allele burden in polycythemia vera predicts chemosensitivity to hydroxyurea.

73 : Splenectomy in patients with agnogenic myeloid metaplasia: an analysis of 321 published cases.

74 : Palliative goals, patient selection, and perioperative platelet management: outcomes and lessons from 3 decades of splenectomy for myelofibrosis with myeloid metaplasia at the Mayo Clinic.

75 : Splenectomy for patients with myelofibrosis with myeloid metaplasia: pretreatment variables and outcome prediction.

76 : Risks and benefits of splenectomy in myelofibrosis: an analysis of 39 cases.

77 : Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet.

78 : Splenectomy in myelofibrosis with myeloid metaplasia: a single-institution experience with 223 patients.

79 : Effective management of accelerated phase myelofibrosis with low-dose splenic radiotherapy.

80 : Splenic irradiation for symptomatic splenomegaly associated with myelofibrosis with myeloid metaplasia.

81 : Long term treatment of myeloproliferative disease with interferon-alpha-2b: feasibility and efficacy.

82 : Phase II study of alpha2 interferon in the treatment of the chronic myeloproliferative disorders (E5487): a trial of the Eastern Cooperative Oncology Group.

83 : Interferon-alpha therapy in bcr-abl-negative myeloproliferative neoplasms.

84 : Clinical and bone marrow effects of interferon alfa therapy in myelofibrosis with myeloid metaplasia.

85 : Phase 2 trial of imatinib mesylate in myelofibrosis with myeloid metaplasia.

86 : Results of imatinib mesylate therapy in patients with refractory or recurrent acute myeloid leukemia, high-risk myelodysplastic syndrome, and myeloproliferative disorders.

87 : A phase I study of the proteasome inhibitor bortezomib in patients with myelofibrosis (abstract)

88 : Bortezomib therapy in myelofibrosis: a phase II clinical trial.

89 : Single agent bevacizumab for myelofibrosis: results of the Myeloproliferative Disorders Research Consortium Trial.

90 : Bone marrow effects of anagrelide therapy in patients with myelofibrosis with myeloid metaplasia.

91 : Recombinant human erythropoietin therapy in patients with myelofibrosis with myeloid metaplasia.

92 : rHuEpo for the treatment of anemia in myelofibrosis with myeloid metaplasia. Experience in 6 patients and meta-analytical approach.

93 : Recombinant human erythropoietin in patients with myelodysplastic syndrome and myelofibrosis.

94 : Erythropoiesis stimulating agents have limited therapeutic activity in transfusion-dependent patients with primary myelofibrosis regardless of serum erythropoietin level.

95 : Erythropoietin treatment of idiopathic myelofibrosis.

96 : Erythropoietin treatment of the anaemia of myelofibrosis with myeloid metaplasia: results in 20 patients and review of the literature.

97 : Darbepoetin-alpha for the anaemia of myelofibrosis with myeloid metaplasia.

98 : Treatment of agnogenic myeloid metaplasia with danazol: a report of four cases.

99 : Efficacy and tolerability of danazol as a treatment for the anaemia of myelofibrosis with myeloid metaplasia: long-term results in 30 patients.

100 : The effect of anabolic steroids on anemia in myelofibrosis with myeloid metaplasia: retrospective analysis of 39 patients in Japan.

101 : Danazol treatment of idiopathic myelofibrosis with severe anemia.

102 : Thalidomide treatment in myelofibrosis with myeloid metaplasia.

103 : Durable responses to thalidomide-based drug therapy for myelofibrosis with myeloid metaplasia.

104 : A phase 2 trial of combination low-dose thalidomide and prednisone for the treatment of myelofibrosis with myeloid metaplasia.

105 : Lenalidomide therapy in myelofibrosis with myeloid metaplasia.

106 : Lenalidomide plus prednisone results in durable clinical, histopathologic, and molecular responses in patients with myelofibrosis.

107 : Lenalidomide and prednisone for myelofibrosis: Eastern Cooperative Oncology Group (ECOG) phase 2 trial E4903.

108 : Low-dose, single-fraction, whole-lung radiotherapy for pulmonary hypertension associated with myelofibrosis with myeloid metaplasia.

109 : Nonhepatosplenic extramedullary hematopoiesis: associated diseases, pathology, clinical course, and treatment.

110 : Nonhepatosplenic extramedullary hematopoiesis: associated diseases, pathology, clinical course, and treatment.

111 : Radiation therapy for symptomatic hepatomegaly in myelofibrosis with myeloid metaplasia.

112 : Successful treatment of severe extremity pain in myelofibrosis with low-dose single-fraction radiation therapy.

113 : Improving survival trends in primary myelofibrosis: an international study.

114 : Leukemic transformation in myelofibrosis with myeloid metaplasia: a single-institution experience with 91 cases.

115 : Treatment outcomes following leukemic transformation in Philadelphia-negative myeloproliferative neoplasms.

116 : The natural history and treatment outcome of blast phase BCR-ABL- myeloproliferative neoplasms.

117 : Leukemic transformation of polycythemia vera: a single center study of 23 patients.

118 : Myeloid blastic transformation of myeloproliferative neoplasms--a review of 112 cases.

119 : Treatment of progression of Philadelphia-negative myeloproliferative neoplasms to myelodysplastic syndrome or acute myeloid leukemia by azacitidine: a report on 54 cases on the behalf of the Groupe Francophone des Myelodysplasies (GFM).

120 : Allogeneic stem cell transplantation for myeloproliferative neoplasm in blast phase.

121 : Allogeneic Hematopoietic Cell Transplantation for Leukemic Transformation Preceded by Philadelphia Chromosome-Negative Myeloproliferative Neoplasms: A Nationwide Survey by the Adult Acute Myeloid Leukemia Working Group of the Japan Society for Hematopoietic Cell Transplantation.

122 : Therapeutic options for patients with myelofibrosis in blast phase.

123 : Phase 2 study of the JAK kinase inhibitor ruxolitinib in patients with refractory leukemias, including postmyeloproliferative neoplasm acute myeloid leukemia.

124 : 2-Chlorodeoxyadenosine treatment after splenectomy in patients who have myelofibrosis with myeloid metaplasia.

125 : Long-term analysis of the palliative benefit of 2-chlorodeoxyadenosine for myelofibrosis with myeloid metaplasia.

126 : Fedratinib in patients with myelofibrosis previously treated with ruxolitinib: An updated analysis of the JAKARTA2 study using stringent criteria for ruxolitinib failure.

127 : A Pilot Study of the Telomerase Inhibitor Imetelstat for Myelofibrosis.