ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Myelofibrosis (MF): Management of primary MF and secondary MF

Myelofibrosis (MF): Management of primary MF and secondary MF
Author:
Ayalew Tefferi, MD
Section Editor:
Richard A Larson, MD
Deputy Editor:
Alan G Rosmarin, MD
Literature review current through: Jan 2024.
This topic last updated: Dec 19, 2023.

INTRODUCTION — Primary myelofibrosis (PMF) and secondary myelofibrosis are BCR::ABL1-negative myeloproliferative neoplasms that cause bone marrow fibrosis and associated clinical findings.

Patients typically experience abdominal pain/fullness from splenomegaly, symptoms related to anemia and other cytopenias, constitutional symptoms, and they may have thrombosis or bleeding, manifestations of extramedullary hematopoiesis, and/or findings related to transformation to acute myeloid leukemia.

The goals of management of myelofibrosis are to relieve symptoms, prevent complications, and prolong survival. Prognosis is generally poor.

●Primary MF – PMF was previously called agnogenic myeloid metaplasia, myelofibrosis with myeloid metaplasia, and chronic idiopathic myelofibrosis. Most cases are associated with mutation of JAK2, CALR, or MPL genes. Some patients present with a prefibrotic form of PMF that evolves to severely symptomatic overt fibrotic MF; contemporary classification schemes distinguish between early/prefibrotic PMF and overt fibrotic PMF [1,2].

●Secondary MF – Secondary MF refers to MF that evolves from either polycythemia vera (PV) or essential thrombocythemia (ET).

Management of PMF and secondary MF is discussed 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 — Patients with primary myelofibrosis (PMF) and secondary myelofibrosis should be evaluated clinically for related symptoms and assessed for medical fitness, including suitability for hematopoietic cell transplantation (HCT).

PMF and secondary MF must be distinguished from other conditions that are associated with marrow fibrosis, as discussed separately. (See "Clinical manifestations and diagnosis of primary myelofibrosis", section on 'Differential diagnosis'.)

Clinical and laboratory testing

●Clinical

•History – Duration and severity of anemia-related symptoms, prior transfusions, blood loss, and hemolysis; recurrent or severe infections; and bleeding or bruising are noted. Medications, nutritional deficiencies, kidney or thyroid dysfunction, autoimmune disorders, and other conditions that can contribute to cytopenias should be evaluated.

We encourage use of the myeloproliferative neoplasms symptom assessment total symptom score (MPN-SAF TSS) to evaluate the symptom burden at baseline and to monitor symptom status with treatment [3].

•Examination – Documentation of spleen and liver size, bruising, and evidence of infections.

●Laboratory

•Hematology – Complete blood count and differential leukocyte count

•Chemistry – Serum electrolytes, glucose, blood urea nitrogen, creatinine, liver function tests, uric acid, lactate dehydrogenase

●Imaging – Computed tomography (CT) of abdomen and pelvis to document the size of liver and spleen

Medical fitness — We assess medical fitness by performance status and comorbidities.

●Performance status – The Eastern Cooperative Oncology Group (ECOG) performance scale (table 1) or Karnofsky performance scale (table 2) can provide general measures of performance status.

●Comorbid conditions – Significant heart, lung, liver, or kidney disease can affect tolerance for treatment used for MF. We assess comorbid conditions as described for evaluating patients with acute leukemia. (See "Acute myeloid leukemia: Management of medically unfit adults", section on 'Medical fitness'.)

For some patients, it may be helpful to obtain geriatric consultation and/or perform a more comprehensive functional assessment to evaluate fitness, as discussed separately. (See "Comprehensive geriatric assessment for patients with cancer".)

●Eligibility for hematopoietic cell transplantation – We suggest referral to transplantation specialists soon after establishing the diagnosis of MF to evaluate eligibility for allogeneic HCT and to define donor options.

Many centers limit allogeneic HCT to patients ≤70 years without major comorbid illnesses, as described separately. (See "Determining eligibility for allogeneic hematopoietic cell transplantation".)

RISK STRATIFICATION — Treatment of MF is guided by prognosis, as assessed by clinical and/or pathologic features using a mutation-based model.

Prognostic models — Commonly used prognostic models for PMF include:

●GIPSS – Genetically Inspired Prognostic Scoring System (calculator 1) [4]

●MIPSS70+ v2.0 – Mutation-enhanced International Prognostic Scoring System plus karyotype, version 2.0 (calculator 2) [5]

Use of other prognostic models, such as DIPSS (Dynamic International Prognostic Scoring System) [6] or DIPSS-Plus (table 3) [7], is acceptable where neither cytogenetics nor molecular analysis is available. Precision and reproducibility of various models differ, and prognostic categories do not match precisely across models. There is no consensus, but further details of prognostic assessment and models are presented separately. (See "Prognosis of primary myelofibrosis", section on 'Our preferred approach'.)

Prognostic classification — We classify both primary MF (PMF) and secondary MF (algorithm 1) as follows:

●Higher-risk PMF – Any of the following:

•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 – Any of 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

Where molecular and/or cytogenetic data are not available, we use DIPSS-Plus or DIPSS as follows (see "Prognosis of primary myelofibrosis", section on 'Alternative approaches'):

●Higher risk – High risk and int-2 risk

●Lower risk – Int-1 risk and low risk

For assessing prognosis in secondary MF, DIPSS-Plus was superior to MYSEC, a model designed to assess prognosis in secondary MF that uses only limited genetic information [8].

HIGHER-RISK MF — Patients with higher-risk MF have a poor prognosis and are likely to have significant disease-associated symptoms. Risk stratification of primary MF (PMF) (algorithm 1) is discussed above. (See 'Risk stratification' above.)

Management is guided by eligibility for allogeneic hematopoietic cell transplantation (HCT). Many institutions limit allogeneic HCT to patients ≤70 years without major medical comorbidities, but criteria may vary.

Our approach is consistent with guidelines of the United States National Comprehensive Cancer Network Myelofibrosis guidelines [9] and European LeukemiaNet (ELN)/European Blood and Marrow Transplantation Group (EBMT) [10].

Transplant-eligible patients — For transplant-eligible patients with higher-risk MF, we suggest allogeneic HCT rather than symptom-directed therapy (algorithm 2). This suggestion places greater weight on the potential for prolonged survival with transplantation than on its substantial toxicity; while symptom-directed therapy can lessen symptoms and improve quality of life, it has not been shown to prolong survival.

The decision to pursue allogeneic HCT should be made by shared decision making that weighs transplantation-associated risks against the expected survival without transplantation and is aligned with the patient's values and preferences. A donor search should be initiated soon after diagnosis of MF. Details of eligibility for allogeneic transplantation are presented separately. (See "Determining eligibility for allogeneic hematopoietic cell transplantation".)

No randomized trials have directly compared allogeneic HCT with symptom-based management for PMF. Studies that compare approaches should be interpreted with caution because most transplantation studies are retrospective analyses of younger, highly selected patient populations [11-19].

●Transplantation versus symptom-based management

A retrospective international study reported that among 183 patients <65 years with higher-risk PMF, allogeneic HCT was associated with better survival than symptom-based management [20]. Compared with symptom-based treatments, the relative risk (RR) of death was lower with transplantation for patients who had DIPSS (Dynamic International Prognostic Scoring system) high-risk score (RR 0.37 [95% CI 0.21-0.66]) and DIPSS intermediate (int)-2 score (RR 0.55 [95% CI 0.36-0.83]). There was no survival advantage for transplantation in patients with lower-risk PMF.

●Transplantation outcomes – Allogeneic HCT is associated with long-term survival in approximately one-half and nonrelapse mortality (NRM) in at least one-quarter of patients with PMF [21,22].

•A retrospective study of 4142 patients with MF who underwent allogeneic HCT reported 58 percent three-year overall survival (OS), 22 percent relapse, and 29 percent NRM; 23 percent of patients had extensive chronic graft-versus-host disease (GVHD) [23]. The median age was 59 years, and nearly one-half of patients received grafts from matched unrelated donors.

•Carefully selected older patients can have good outcomes with allogeneic HCT. A study of 556 patients ≥65 years who were transplanted for MF reported 40 percent five-year OS, 37 percent NRM, and 25 percent relapse [24]. A retrospective study of 30 patients (median 65 years; range 60 to 78 years) reported 45 percent three-year OS and 40 percent progression-free survival (PFS), with 13 percent day 100 mortality; most received low-intensity conditioning [25].

Pretransplant spleen management — We attempt to control massive splenomegaly (eg, >15 cm below the costal margin) prior to transplantation. No studies have prospectively compared approaches for controlling massive splenomegaly before transplantation, and the preferred method varies among experts.

●Ruxolitinib – Among 551 patients who underwent allogeneic HCT for MF, 277 received pretransplant ruxolitinib [26]. There was no difference in NRM based on use of pretransplant ruxolitinib (22 percent for both cohorts), but day 45 neutrophil engraftment was higher in ruxolitinib-treated patients (94 versus 85 percent). Patients with an ongoing spleen response to ruxolitinib at transplantation had better two-year event-free survival (EFS; 69 versus 54 percent) and lower risk of relapse (8 versus 19 percent).

Other studies also suggest that pretransplant exposure to ruxolitinib is safe [27-32].

●Splenectomy – Pretransplant splenectomy was not associated with a survival difference among 1195 patients who underwent allogeneic HCT for PMF [33]. Splenectomy in 202 patients was associated with lower NRM (hazard ratio [HR] 0.64 [95% CI 0.44-0.93]) but increased risk of relapse (HR 1.43 [95% CI 1.01-2.02]); as a result, there was no difference in survival. However, OS was increased in patients who were splenectomized for massive splenomegaly (palpable spleen length ≥15 cm; HR 0.44 [95% CI 0.28-0.69]).

There was no difference in survival, NRM, or relapse based on pretransplant splenectomy among 85 consecutive patients who were transplanted for MF [34]. The 39 patients who underwent pretransplant splenectomy had faster hematologic recovery, but one-half had surgical or postsurgical morbidities (mostly thrombosis or hemorrhage), including two who required intensive care. Another study reported that splenectomy could be safely performed before HCT [35].

●Radiation therapy – There was no difference in survival among 17 patients who received splenic radiation therapy (RT) within three months of transplantation compared with 48 unirradiated patients who underwent lower-intensity conditioning allogeneic HCT for MF, but platelet engraftment was slower in the RT group [36].

Splenectomy and radiation therapy to control symptomatic splenomegaly are discussed below. (See 'Splenectomy/splenic irradiation' below.)

Conditioning regimen — Patient age may influence the choice of conditioning regimen.

Myeloablative conditioning (MAC) is generally preferred for patients ≤65 years, while reduced intensity conditioning (RIC) or nonmyeloablative (NMA) conditioning are generally used to lessen morbidity for older patients (eg, >65 years). (See "Preparative regimens for hematopoietic cell transplantation".)

No prospective studies have directly compared conditioning regimens, but compared with MAC, RIC is generally associated with less NRM and more relapses.

●In a study of 2224 patients who underwent allogeneic HCT for MF, outcomes were similar for 781 patients who received MAC compared with 1443 who received RIC [37]. Although patients receiving MAC were younger (median 53 versus 58 years), outcomes were similar, including five-year OS (53 versus 51 percent), five-year NRM (35 versus 34 percent), time to engraftment, and grade 2 to 4 acute GVHD. Compared with MAC, there were trends toward higher rates of five-year relapse (23 versus 20 percent) and extensive chronic GVHD (31 versus 27 percent) with RIC.

●A multicenter study of 233 patients who underwent RIC allogeneic HCT reported 47 percent five-year OS and 27 percent five-year PFS; rates of NRM and relapse/progression at five years were 24 and 48 percent, respectively [38].

●In a multicenter study of 103 patients who underwent RIC allogeneic HCT, five-year OS was 67 percent and five-year EFS was 51 percent; one-year NRM was 16 percent, and the three-year cumulative rate of relapse was 22 percent [39].

●Other studies have reported similar outcomes with allogeneic HCT for MF [25,38-57].

Graft source — Transplantation outcomes may be influenced by the stem cell source.

Grafts from a matched related donor (MRD; ie, human leukocyte antigen [HLA]-matched sibling) or matched unrelated donor (MUD) are preferred, but haploidentical family members or umbilical cord blood are acceptable alternative donor sources.

●In a study of 289 patients who were transplanted for MF, rates of five-year OS were 37, 40, and 30 percent for HLA-matched sibling donors, other HLA-matched related donors, and MUDs, respectively; corresponding disease-free survival rates were 33, 22, and 27 percent [58]. NRM was highest for MUDs (50 versus 35 and 38 percent for sibling and other related donors).

●Haploidentical donor grafts have been used successfully in allogeneic HCT for PMF, with outcomes that were similar to those with matched donor sources [59].

Despite severely fibrotic marrow, engraftment is generally not a problem in most patients with MF. A registry-based study reported engraftment in 90 percent of transplanted patients [58]. Another study reported no significant difference in engraftment parameters for 33 patients transplanted for severe MF compared with 33 matched controls without MF [60].

Alternative graft sources, including mismatched MUDs, haploidentical family members, or umbilical cord blood, are discussed separately. (See "Donor selection for hematopoietic cell transplantation".)

Ineligible for transplantation — Preferred management for patients who are not eligible for transplantation is guided by the nature and severity of symptoms.

Asymptomatic higher-risk patients — For patients with no significant symptoms related to MF, we suggest observation while monitoring for development of symptoms rather than initiating treatment.

There is no evidence that treatment of asymptomatic patients alters the natural history of higher-risk MF, and observation avoids adverse effects (AEs) associated with treatment.

For patients who subsequently develop symptoms, management is guided by the nature of the symptoms, as described in the sections that follow.

Anemia only — For patients with anemia but no symptomatic splenomegaly or constitutional symptoms, we suggest red blood cell (RBC) transfusions and adjunctive methods to lessen transfusion requirements (algorithm 2), rather than initial treatment with a Janus kinase inhibitor (JAKi), to avoid JAKi toxicity.

●Transfusions – RBC transfusions provide prompt relief of symptomatic anemia and can improve quality of life. However, chronic transfusion therapy may be associated with fluid overload, transfusion reactions, and/or alloimmunization, and heavily transfused patients may develop iron overload.

The threshold for transfusion varies with age, symptoms, and medical comorbidities. Although there is no consensus, many centers transfuse asymptomatic patients with hemoglobin ≤8 g/dL, especially to prevent complications in patients with significant cardiovascular, pulmonary, or neurologic comorbidities. (See "Indications and hemoglobin thresholds for RBC transfusion in adults".)

Because most patients with MF require ongoing RBC transfusions, we use adjunctive methods to reduce transfusion needs. There is no consensus, but acceptable choices include:

●Danazol – Danazol is a synthetic androgen that improves anemia in one-third of patients with PMF [61-64].

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; in responsive patients, 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.

●Erythropoiesis-stimulating agents – The erythropoiesis-stimulating agents (ESAs), epoetin alfa and darbepoetin alfa, have only modest benefits for patients with MF.

ESAs generally do not significantly alleviate anemia associated with MF [65-68]. Most reported responses to ESAs are in patients with PMF who were not requiring transfusion support and/or those with low serum erythropoietin levels [69-71].

Administration and AEs of ESAs are discussed separately. (See "Myelodysplastic syndromes/neoplasms (MDS): Management of hematologic complications in lower-risk MDS", section on 'Anemia'.)

●Other options – For patients whose anemia-related symptoms and transfusion requirements do not respond adequately to danazol or ESAs, one of the following options may be beneficial:

•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 [72-74]. 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 congenital anomalies, hematologic toxicity, and thromboembolic events.

•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 approximately one-third of patients [75-77]. Thalidomide is associated with drowsiness, constipation, fatigue, paresthesias, neutropenia, and thrombosis. The label for thalidomide carries warnings regarding severe congenital anomalies 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".)

Luspatercept, a transforming growth factor (TGF)-beta antagonist that can reduce transfusion dependence in patients with lower-risk myelodysplastic syndromes/neoplasms (MDS) and thalassemia, is under investigation for management of anemia in patients with MF. Luspatercept is not currently approved by the US Food and Drug Administration (FDA) or the European Medicines Agency (EMA) for treatment of MF-associated anemia. Treatment with luspatercept is discussed separately. (See "Myelodysplastic syndromes/neoplasms (MDS): Management of hematologic complications in lower-risk MDS", section on 'Luspatercept'.)

For patients with ongoing RBC transfusion needs despite the above treatments, we manage as discussed below. (See 'Splenomegaly or other symptoms with anemia' below.)

Splenomegaly only — For patients with symptomatic splenomegaly and no associated anemia, we suggest hydroxyurea (algorithm 2) rather than a JAKi, based on efficacy and little toxicity.

Hydroxyurea is generally associated with clinical improvement in one-quarter to one-half of patients with MF and is well tolerated. Although JAKi therapy can effectively reduce symptoms associated with splenomegaly, it is associated with more AEs than hydroxyurea.

Administration, toxicity, and outcomes with hydroxyurea are discussed below. (See 'Hydroxyurea' below.)

Patients who do not have an adequate response to hydroxyurea should be treated as discussed below. (See 'Splenomegaly or other symptoms with anemia' below.)

Splenomegaly or other symptoms with anemia — We stratify treatment of patients with symptomatic splenomegaly and anemia according to the platelet count.

Adequate platelets — For patients with symptomatic splenomegaly, anemia, and platelets ≥50,000/microL (≥50 x 109/L), we suggest ruxolitinib or momelotinib (algorithm 2), rather than other agents. Ruxolitinib is a JAKi, while momelotinib is both a JAKi and an inhibitor of activin A receptor type 1 (ACVR1).

Outcomes were similar in a trial of 432 transplant-ineligible, JAKi-naïve patients with higher-risk PMF or symptomatic lower-risk PMF who were randomly assigned to ruxolitinib versus momelotinib [78]. After 24 weeks of treatment, ≥35 percent spleen volume reduction (SVR) was seen in 29 percent of patients treated with ruxolitinib and 27 percent of patients treated with momelotinib. Ruxolitinib more effectively reduced symptoms (42 versus 28 percent), while more patients who received momelotinib became transfusion independent at week 24 (67 versus 49 percent). The most common grade ≥3 hematologic abnormalities in both groups were thrombocytopenia and anemia. Momelotinib was associated with grade ≥3 infections in 7 percent of patients and neuropathy in 10 percent (all grade ≤2), while ruxolitinib was associated with 3 percent grade ≥3 infections and 5 percent peripheral neuropathy (all grade ≤3).

Ruxolitinib is approved by the FDA and the EMA for patients with MF. Momelotinib is approved by the FDA for adults with intermediate- or high-risk MF with anemia.

Administration, toxicity, and outcomes of other studies with these agents are presented below. (See 'Ruxolitinib' below and 'Momelotinib' below.)

<50,000 platelets/microL — For patients with symptomatic splenomegaly, anemia, and platelets <50,000/microL, we suggest treatment with pacritinib (algorithm 2).

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

Pacritinib was more effective than best available therapy (BAT) for relieving symptoms in patients with MF with thrombocytopenia in the phase 3 PERSIST-2 trial [79]. Patients with higher-risk PMF or secondary MF and platelets ≤100,000/microL were randomly assigned to pacritinib 200 mg twice daily versus BAT (eg, ruxolitinib, watchful waiting, hydroxyurea). There was no difference in OS, but pacritinib achieved better ≥35 percent SVR (22 versus 3 percent) and ≥50 percent reduction of symptom burden (32 versus 14 percent, using the myeloproliferative neoplasm [MPN] total symptom score). 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, cardiovascular events, and deaths.

Where pacritinib is not available, treatment with reduced doses of another JAKi may be tolerable.

LOWER-RISK MF — We treat patients with lower-risk primary MF (PMF) according to MF-associated symptoms.

Risk stratification for patients with MF (algorithm 1) is discussed above. (See 'Risk stratification' above.)

Asymptomatic — For asymptomatic patients with lower-risk MF, we suggest observation rather than symptom-directed therapy or allogeneic hematopoietic cell transplantation (HCT). Symptom-directed therapy has not been shown to improve survival in patients with MF, and the favorable prognosis for patients with lower-risk MF does not warrant the risks of allogeneic HCT. (See "Prognosis of primary myelofibrosis", section on 'Assessing prognosis in PMF'.)

Symptomatic — For symptomatic patients with lower-risk MF, we suggest symptom-directed treatment rather than allogeneic HCT. Transplant-related morbidity and mortality outweigh the potential prolongation of survival in this group of patients, who have a generally favorable prognosis.

The choice of management is guided by the nature and severity of symptoms, as described above for patients who are ineligible for HCT (algorithm 2). (See 'Ineligible for transplantation' above.)

There was no survival advantage for patients transplanted for lower-risk PMF according to results from a retrospective international study [20]. For patients with DIPSS (Dynamic International Prognostic Scoring System) intermediate (int)-1 score, overall survival (OS) did not differ with symptom-based management (75 patients) compared with allogeneic HCT (38 patients). However, for patients with DIPSS-low score, OS was superior for 125 patients treated with conventional therapy compared with 22 who underwent transplantation (relative risk 5.6 [95% CI 1.7-19]).

MONITORING — Monitoring is guided by prognostic classification, treatment, and concerns of the clinician and patient.

For patients who receive symptom-directed therapy, we monitor the response to treatment, evidence of disease progression/complications, and symptom burden (using the myeloproliferative neoplasm [MPN]-10 tool [3]).

We schedule visits every three to six months or as clinically indicated. Evaluation should include a complete blood count, peripheral blood smear, lactate dehydrogenase (LDH), uric acid, and liver and renal function tests.

For patients who are receiving treatment, further management is guided by the response to therapy:

●Adequate response – For patients who have a favorable response to therapy (eg, symptom relief, reduced transfusion needs), we continue treatment indefinitely (ie, until progression or intolerance).

●Inadequate response – For patients with an inadequate response to treatment, loss of response, or disease progression while receiving treatment, treatment can be continued or switched to another agent. We generally repeat a bone marrow examination in this setting to test for additional mutations that may herald disease progression.

For patients receiving ruxolitinib, the dose should be tapered to avoid a potentially dangerous rebound syndrome, as described below. (See 'Ruxolitinib' below.)

Management of patients with an inadequate response is discussed below. (See 'Relapsed/refractory MF' below.)

Follow-up for patients who underwent allogeneic HCT is discussed separately. (See "Long-term care of the adult hematopoietic cell transplantation survivor".)

TREATMENTS

Ruxolitinib — Ruxolitinib is a Janus kinase inhibitor (JAKi). JAK2 is commonly mutated in primary MF (PMF), but ruxolitinib efficacy is independent of JAK2 mutation status, which suggests that it may suppress symptoms and reduce splenomegaly through a more general inhibition of kinases [80-83]. (See "Pathogenetic mechanisms in primary myelofibrosis", section on 'JAK2 mutations'.)

●Administration – Ruxolitinib should not be used in patients with an active infection, 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. Prior to initiating therapy, patients should be counseled about the risk of ruxolitinib withdrawal syndrome and screened for tuberculosis.

The initial dose of ruxolitinib is guided by the baseline platelet count:

•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

Dose adjustments are required for renal and hepatic dysfunction and for patients receiving a concomitant strong CYP3A4 inhibitor (table 4) or fluconazole [84]. The dose should be adjusted according to blood counts every two to four weeks until blood counts and doses are stabilized, and then as clinically indicated.

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.

The dose of ruxolitinib can be adjusted according to relief of symptoms.

If there is no reduction in spleen size or symptom improvement after six months of treatment, 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/schedule and are avoiding medications or herbal supplements that may impair efficacy (eg, concurrent treatment with a strong CYP3A4 inducer) [84].

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 MF.

●Toxicity – Patients must be counseled that abrupt discontinuation of ruxolitinib can be associated with a full relapse of disease symptoms and development of fever, hypotension, hypoxia, and other manifestations of systemic inflammatory response syndrome.

•Infections – 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 [84-92].

All patients should be screened for tuberculosis risk (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). Such patients 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. Herpes zoster vaccination should be considered. (See "Vaccination for the prevention of shingles (herpes zoster)".)

The ruxolitinib label includes a warning regarding potential hepatitis B virus reactivation and rare cases of progressive multifocal leukoencephalopathy (PML) [84]. (See "Diagnosis of pulmonary tuberculosis in adults" and "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis".)

•Ruxolitinib withdrawal syndrome – Discontinuation of ruxolitinib can be associated with a full relapse of disease symptoms, with clinical findings (eg, fever, hypotension, hypoxia) suggestive of the systemic inflammatory response syndrome [93-95].

Suspicion of ruxolitinib withdrawal syndrome should prompt urgent treatment with systemic glucocorticoids and may also require treatment with vasopressors and resumption of ruxolitinib. We give prednisone 20 mg daily for seven days followed by a taper over the second week. Hydroxyurea or another myelosuppressive therapy 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 can be associated with substantial weight gain, which may be due to the inhibition of JAK/STAT signaling downstream of the leptin receptor [96].

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 [93,97,98].

●Outcomes – Ruxolitinib can relieve debilitating symptoms of PMF in up to one-half of patients, but it has not been shown to significantly prolong survival or reduce the risk of leukemic transformation in PMF.

•COMFORT-1 randomly assigned 309 patients with high-risk PMF to ruxolitinib versus placebo [81]. Compared with placebo, at 24 weeks ruxolitinib was more effective for ≥35 percent spleen volume reduction (SVR; 42 versus 1 percent) and ≥50 percent improvement of the total symptom score (TSS; 46 versus 5 percent). SVR was sustained for ≥48 weeks for two-thirds of responding patients. There were 13 deaths in the ruxolitinib group versus 24 with placebo, and the rate of drug discontinuation was the same (11 percent) in both trial arms. Anemia and thrombocytopenia were the most common adverse effects (AEs) with ruxolitinib but rarely led to drug discontinuation.

•In COMFORT-2, 219 patients with higher-risk MF were randomly assigned to ruxolitinib versus best available therapy (BAT) [80]. Importantly, for nearly one-half of the patients in this trial, hydroxyurea was used as BAT, even though 68 percent had already progressed on hydroxyurea. Ruxolitinib achieved ≥35 percent SVR 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 [98]. Anemia and thrombocytopenia were common (grade 3 to 4 in 45 and 13 percent of patients, respectively) with ruxolitinib but were generally manageable, improved over time, and rarely led to treatment discontinuation. A separate analysis reported that, compared with a historical control of 350 ruxolitinib-naïve patients, 100 patients with PMF treated with ruxolitinib in COMFORT-2 had longer survival (5 versus 3.5 years); after adjusting for age and prognostic score, multivariate analysis found the survival advantage with ruxolitinib was maintained (hazard ratio [HR] 0.64, 95% CI 0.4-0.96) [99].

Momelotinib — Momelotinib is both a JAKi and an inhibitor of activin A receptor type 1 (ACVR1).

●Administration – Momelotinib 200 mg once daily by mouth.

Momelotinib is approved by the FDA for treatment of MF.

●Toxicity – Primarily cytopenias, infections, hepatotoxicity, cardiovascular events, thrombosis, and peripheral neuropathy.

●Outcomes – Momelotinib effectively achieved SVR and reduced transfusion burden and other symptoms in patients with MF and platelets ≥50,000/microL in a phase 3 trial (described above) [78]. (See 'Adequate platelets' above.)

Fedratinib — Fedratinib is a JAK2-selective kinase inhibitor that has activity against MF, but treatment is associated with serious and potentially fatal Wernicke-like encephalopathy.

●Administration – Thiamine levels should be measured and repleted prior to starting fedratinib and should be assessed periodically during treatment to avoid serious Wernicke-like encephalopathy. Fedratinib should only be used in patients with platelet counts >50,000/microL.

Fedratinib is administered 400 mg orally once daily, with or without food.

Fedratinib should not be given to patients with a platelet count ≤50,000/microL, severe liver impairment, strong or moderate CYP3A4 inducers, or dual CYP3A4 and CYP2C19 inhibitors (table 4). The initial dose should be reduced for patients receiving strong CYP3A inhibitors or with severe renal impairment, and the dose should be reduced for management of fedratinib toxicity, as described below.

If Wernicke-like encephalopathy is suspected, fedratinib must be discontinued immediately and parenteral thiamine given.

Fedratinib is approved by the FDA for treatment of higher-risk PMF in adults with platelets >50,000/microL. The label has a warning about the risk of encephalopathy.

●Toxicity – Treatment may be associated with cardiovascular conditions, liver toxicity, and rare cases of severe, sometimes fatal, encephalopathy.

•Encephalopathy – Serious and fatal encephalopathy, including Wernicke 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 [100]. 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 [101]. Fedratinib has also been associated with cardiovascular death, myocardial infarction, stroke, and liver toxicity in some patients.

•Withdrawal syndrome – The risk and/or severity of a fedratinib withdrawal syndrome is not well defined, but we taper the dose, rather than abruptly discontinuing it, except when encephalopathy is suspected. (See "Wernicke encephalopathy", section on 'Clinical manifestations'.)

●Outcomes – Fedratinib reduced splenomegaly and symptoms in more than one-third of patients in an international, double-blind, placebo-controlled trial of 289 adults with higher risk PMF, post-polycythemia vera MF, or postessential thrombocythemia MF [101]. Patients were randomly assigned to fedratinib 400 mg, fedratinib 500 mg, or placebo for ≥6 consecutive four-week cycles. SVR ≥35 percent at week 24 was achieved in 36, 40, and 1 percent of patients who received 400 mg fedratinib, 500 mg fedratinib, and placebo, respectively. Reduction of TSS by ≥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.

Pacritinib — Pacritinib is an inhibitor of JAK2 and FMS-like tyrosine kinase 3 (FLT3) [102] that is used for treating MF in patients with baseline or treatment-emergent thrombocytopenia. Pacritinib has been associated with cardiovascular events and bleeding.

●Administration – Pacritinib is given 200 mg twice daily by mouth, 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 [103].

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

●Toxicity – Includes hemorrhage, diarrhea, prolonged QT interval, and thrombosis.

●Outcomes – In the phase 3 PERSIST-2 trial, pacritinib was more effective than BAT for SVR and reducing symptom burden in patients with MF with thrombocytopenia [79]. Patients with intermediate- or high-risk PMF or secondary MF with platelets ≤100,000/microL were randomly assigned to pacritinib 200 mg twice daily versus BAT (eg, ruxolitinib, watchful waiting, hydroxyurea). There was no difference in overall survival (OS) between trial arms, but compared with BAT, pacritinib was more effective for ≥35 percent SVR (22 versus 3 percent), ≥50 percent reduction of TSS (32 versus 14 percent), and reducing transfusion requirements. 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.

Hydroxyurea — Hydroxyurea can relieve moderate splenomegaly and other proliferative manifestations (eg, thrombocytosis, leukocytosis, constitutional symptoms) in patients without significant anemia.

Hydroxyurea is also acceptable for symptom management in patients who are ineligible for allogeneic hematopoietic cell transplantation (HCT) or who are not candidates for a JAKi.

●Administration – We initiate hydroxyurea 500 to 1000 mg every other day. Note that this dose is lower than what is used for other myeloproliferative neoplasms because many patients with MF have cytopenias with limited bone marrow reserves.

The dose should be modified based on semiweekly or weekly blood counts until doses are stabilized, and then as clinically indicated.

Hydroxyurea is not labeled for treatment of MF by the FDA or the EMA.

●Toxicity – Includes cytopenias, mucocutaneous ulcers, diarrhea, peripheral neuropathy, skin cancer, potential teratogenicity, and rare cases of severe (including fatal) pulmonary toxicity.

●Outcomes – Hydroxyurea was associated with clinical improvement or partial response in 28 percent of 69 patients with PMF [104]. In another report, 40 percent of patients with PMF treated with hydroxyurea achieved ≥50 SVR, with responses that lasted for an average of one year [105].

Splenectomy/splenic irradiation

●Surgical splenectomy – Surgical splenectomy can relieve mechanical discomfort from marked splenomegaly, but it is associated with substantial morbidity and mortality. Splenectomy can provide relief for selected patients with recurrent splenic infarction, transfusion-dependent anemia, refractory thrombocytopenia, hypercatabolic symptoms, portal hypertension, or high-output heart failure.

Surgical 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 [106]. (See "Elective (diagnostic or therapeutic) splenectomy" and 'Postsplenectomy thrombocytosis or hepatomegaly' below.)

In transfusion-dependent patients, it is unclear if reducing splenic sequestration with splenectomy outweighs the loss of an important site of extramedullary erythropoiesis. We generally offer surgical splenectomy only if a nonbleeding patient with MF chronically requires ≥3 units of red blood cells (RBCs) every two weeks; we consider that the spleen is not an effective source of RBC production in that setting, based on typical transfusion requirements in adults with no effective erythropoiesis (eg, severe aplastic anemia or pure red cell aplasia).

●Splenic irradiation – Splenic irradiation can provide transient benefit (eg, three to six months) for patients with worsening symptoms who are poor surgical candidates, but it is often complicated by nausea and cytopenias [107]. Abscopal effects of the splenic irradiation can lead to significant myelosuppression and profound thrombocytopenia [108].

The preferred dose and schedule vary by institution, but it is prudent to treat with small fractions (eg, 0.25 to 0.5 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 [109].

SPECIFIC MANAGEMENT ISSUES — Management of other aspects of MF is described in the sections below.

Extramedullary hematopoiesis — Pain or organ dysfunction from extramedullary hematopoiesis 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 primary MF (PMF) [110-114]. (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 [115-117]. (See "Clinical manifestations and diagnosis of primary myelofibrosis", section on 'Transformation to acute leukemia'.)

There is no standard treatment of leukemic transformation. Participation in a clinical trial is strongly encouraged.

Treatment options include intensive induction with acute myeloid leukemia (AML)-like therapy, lower-intensity treatments (eg, hypomethylating agents, venetoclax), and palliative care. Some patients seek allogeneic hematopoietic cell transplantation (HCT). A decision of when and how to treat leukemic transformation is influenced by overall clinical status, fitness, institutional approach, and patient preference. (See "Acute myeloid leukemia in adults: Overview".)

●Intensive treatments – A prospective study that used intensive AML-like induction therapy followed by allogeneic HCT reported outcomes of 75 consecutive patients with leukemic transformation after PMF and other myeloproliferative neoplasms (MPNs) [118]. For 38 patients treated with intensive induction therapy (with or without subsequent HCT), the median survival was longer (nine versus two months) and two-year overall survival (OS) was better (26 versus 3 percent) compared with treatment with noncurative intent. Among the 17 patients who underwent allogeneic HCT, 5 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 complete remission (CR) in 0 to 60 percent and a median OS of four to nine months [117,119-124]. Retrospective studies of patients who underwent allogeneic HCT after induction therapy for leukemic transformation report improved survival compared with those who did not undergo HCT [119,121,123].

●Lower-intensity therapy – Azacitidine, decitabine, and Janus kinase inhibitor (JAKi) therapy have limited activity in patients with leukemic transformation who are transplant candidates. A single-institution study of six patients treated with decitabine reported a median survival >9 months, reduced spleen size, and improved symptoms [125]. Treatment with azacitidine of 26 patients with leukemic transformation achieved an overall response rate of 26 percent and median OS of eight months [122]. Treatment with ruxolitinib achieved CR in 3 of 18 patients with leukemic transformation [126].

Management of AML with lower-intensity treatments is discussed separately. (See "Acute myeloid leukemia: Management of medically unfit adults".)

Postsplenectomy 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 postoperative platelet count >106/microL (5 percent), bleeding (14 percent), thrombosis (10 percent), and accelerated hepatomegaly (10 percent) [127]. Another study of 71 patients described massive hepatomegaly in 24 percent of patients [128].

There is no consensus management for postsplenectomy thrombocytosis and hepatomegaly. Options include platelet pheresis, hydroxyurea, or cladribine [129,130]. (See "Essential thrombocythemia: Treatment and prognosis", section on 'Acquired von Willebrand syndrome' and 'Hydroxyurea' above.)

After postoperative hemostasis has been achieved, we consider 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/REFRACTORY MF — Management of relapsed or refractory (r/r) MF should consider severity of symptoms, prior treatments, duration of response, and patient preference. We encourage patients with r/r MF to participate in clinical trials.

For patients who remain symptomatic after symptom-based treatment, we suggest momelotinib or fedratinib, based on improved symptom control and acceptable toxicity. For patients who were previously treated with momelotinib, we treat with fedratinib.

●Momelotinib – A phase 3 trial (MOMENTUM) of momelotinib versus danazol in symptomatic and anemic patients (124 with primary MF [PMF] and 71 with secondary MF) who were previously treated with a Janus kinase inhibitor (JAKi) reported similar overall survival (OS) in both trial arms, but momelotinib achieved better symptom control [131]. Compared with danazol, momelotinib achieved superior symptom reduction (≥50 percent improvement of total symptom score [TSS]; 25 versus 9 percent) and transfusion independence (31 versus 20 percent). Momelotinib was associated with less grade ≥3 anemia and similar levels of thrombocytopenia (<50 x 109/L), nonhematologic toxicity, and fatal adverse effects (AEs; 12 versus 17 percent with danazol). More patients in the danazol group discontinued treatment early.

Another phase 3 trial (SIMPLIFY­2) reported that momelotinib achieved similar outcomes as best available therapy (BAT) in 156 symptomatic, ruxolitinib-treated patients [132]. Patients were randomly assigned (2:1) to momelotinib (104 patients) versus BAT (52 patients; 89 percent received ruxolitinib and others received chemotherapy, steroids, other standard interventions, or no treatment). The trial arms achieved similar rates of ≥35 percent spleen volume reduction (SVR; 7 percent with momelotinib and 6 percent with BAT), serious AEs (35 versus 23 percent, respectively), and treatment-related mortality (6 versus 8 percent, respectively).

Administration of momelotinib is discussed above. (See 'Momelotinib' above.)

●Fedratinib – In the JAKARTA2 study, nearly one-third of patients who were ruxolitinib resistant, refractory, or intolerant had ≥35 percent SVR and ≥50 percent reduction in TSS; grade ≥3 anemia and thrombocytopenia were reported in 38 and 22 percent, respectively [133].

Administration of fedratinib is discussed above. (See 'Fedratinib' above.)

SOCIETY GUIDELINE LINKS — Our approach is consistent with consensus recommendations for hematopoietic cell transplantation in primary MF by the European LeukemiaNet (ELN) and European Blood and Marrow Transplantation Group (EBMT) [10] and United States National Comprehensive Cancer Network Myelofibrosis guidelines [9].

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 – Myelofibrosis (MF) refers to a myeloproliferative neoplasm (MPN) characterized by bone marrow fibrosis, cytopenias, constitutional symptoms, hepatosplenomegaly, and/or extramedullary hematopoiesis. Patients are at risk for premature death from disease progression, leukemic transformation, thrombohemorrhagic complications, and infections.

•Primary MF – A category of BCR::ABL1-negative MPN

•Secondary MF – MF that arose from another type of MPN

●Evaluation – Symptoms and medical fitness are assessed prior to treatment. (See 'Pretreatment evaluation' above.)

●Risk stratification – Patients are classified according to clinical features, pathologic findings, and/or mutation status (algorithm 1) as described above (see 'Risk stratification' above):

•Higher risk

•Lower risk

Management of MF is guided by the risk category, symptoms, and medical fitness.

●Higher-risk MF, transplant-eligible patients – For patients with higher-risk MF who are eligible for transplantation, we suggest allogeneic hematopoietic cell transplantation (HCT) rather than symptom-directed therapy (algorithm 2) (Grade 2C). (See 'Transplant-eligible patients' above.)

Allogeneic HCT is generally limited to patients ≤70 years with major comorbid illnesses. Pretransplant management of symptomatic splenomegaly and selection of a conditioning regimen and graft source are discussed.

●Higher-risk MF, not eligible for hematopoietic cell transplantation – Management is guided by the nature and severity of symptoms.

•Asymptomatic – For patients with no significant symptoms related to MF, we suggest observation while monitoring for development of symptoms rather than initiating treatment (Grade 2C). (See 'Asymptomatic higher-risk patients' above.)

•Anemia only – For patients with anemia only (ie, no symptomatic splenomegaly or other proliferative symptoms), we suggest transfusion therapy plus adjunctive approaches to reduce transfusion burden (algorithm 2) rather than a Janus kinase inhibitor (JAKi) (Grade 2C). Examples of such approaches include danazol or an erythropoiesis-stimulating agent. (See 'Anemia only' above.)

•Splenomegaly without anemia – For symptomatic splenomegaly or other proliferative symptoms without anemia, we suggest hydroxyurea (algorithm 2) rather than a JAKi (Grade 2C). (See 'Splenomegaly only' above.)

•Splenomegaly with anemia and platelets ≥50,000/microL – For symptomatic splenomegaly, anemia, and adequate platelets, we suggest ruxolitinib or momelotinib (algorithm 2) rather than other treatments (Grade 2B). (See 'Adequate platelets' above.)

•Splenomegaly with anemia and platelets <50,000/microL – For symptomatic splenomegaly, anemia, and low platelets, we suggest pacritinib (algorithm 2) (Grade 2B). (See '<50,000 platelets/microL' above.)

●Lower-risk MF – Management of patients with lower-risk MF is guided by symptoms:

•Asymptomatic – For asymptomatic patients with lower-risk MF, we suggest observation rather than systemic treatments (Grade 2C). (See 'Asymptomatic' above.)

•Symptomatic – Management of symptomatic patients with lower-risk MF is guided by the nature of symptoms, as discussed for higher-risk patients. (See 'Ineligible for transplantation' above.)

●Treatments – Administration, toxicity, and outcomes with drugs used for symptom-based management of MF are discussed above. (See 'Treatments' above.)

●Special management issues – Management of extramedullary hematopoiesis, leukemic transformation, and postsplenectomy thrombocytosis is discussed above. (See 'Specific management issues' above.)

●Relapsed/refractory MF – For persistent symptoms after prior treatment, we suggest either momelotinib or fedratinib (Grade 2C); for those with prior exposure to momelotinib, we offer fedratinib. (See 'Relapsed/refractory MF' 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.

  1. Arber DA, Orazi A, Hasserjian RP, et al. International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data. Blood 2022; 140:1200.
  2. Khoury JD, Solary E, Abla O, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia 2022; 36:1703.
  3. Emanuel RM, Dueck AC, Geyer HL, et al. Myeloproliferative neoplasm (MPN) symptom assessment form total symptom score: prospective international assessment of an abbreviated symptom burden scoring system among patients with MPNs. J Clin Oncol 2012; 30:4098.
  4. Tefferi A, Guglielmelli P, Nicolosi M, et al. GIPSS: genetically inspired prognostic scoring system for primary myelofibrosis. Leukemia 2018; 32:1631.
  5. Tefferi A, Guglielmelli P, Lasho TL, et al. MIPSS70+ Version 2.0: Mutation and Karyotype-Enhanced International Prognostic Scoring System for Primary Myelofibrosis. J Clin Oncol 2018; 36:1769.
  6. Passamonti F, Cervantes F, Vannucchi AM, et al. A dynamic prognostic model to predict survival in primary myelofibrosis: a study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment). Blood 2010; 115:1703.
  7. Gangat N, Caramazza D, Vaidya R, et al. DIPSS plus: a refined Dynamic International Prognostic Scoring System for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status. J Clin Oncol 2011; 29:392.
  8. Shide K, Takenaka K, Kitanaka A, et al. Nationwide prospective survey of secondary myelofibrosis in Japan: superiority of DIPSS-plus to MYSEC-PM as a survival risk model. Blood Cancer J 2023; 13:110.
  9. National Comprehensive Cancer Network. https://www.nccn.org/professionals/physician_gls/pdf/mpn_blocks.pdf (Accessed on November 29, 2018).
  10. Kröger NM, Deeg JH, Olavarria E, et al. Indication and management of allogeneic stem cell transplantation in primary myelofibrosis: a consensus process by an EBMT/ELN international working group. Leukemia 2015; 29:2126.
  11. Guardiola P, Esperou H, Cazals-Hatem D, et al. Allogeneic bone marrow transplantation for agnogenic myeloid metaplasia. French Society of Bone Marrow Transplantation. Br J Haematol 1997; 98:1004.
  12. Deeg HJ, Gooley TA, Flowers ME, et al. Allogeneic hematopoietic stem cell transplantation for myelofibrosis. Blood 2003; 102:3912.
  13. Przepiorka D, Giralt S, Khouri I, et al. Allogeneic marrow transplantation for myeloproliferative disorders other than chronic myelogenous leukemia: review of forty cases. Am J Hematol 1998; 57:24.
  14. Singhal S, Powles R, Treleaven J, et al. Allogeneic bone marrow transplantation for primary myelofibrosis. Bone Marrow Transplant 1995; 16:743.
  15. Creemers GJ, Löwenberg B, Hagenbeek A. Allogeneic bone marrow transplantation for primary myelofibrosis. Br J Haematol 1992; 82:772.
  16. Benesch M, Deeg HJ. Hematopoietic cell transplantation for adult patients with myelodysplastic syndromes and myeloproliferative disorders. Mayo Clin Proc 2003; 78:981.
  17. Guardiola P, Anderson JE, Bandini G, et al. Allogeneic stem cell transplantation for agnogenic myeloid metaplasia: a European Group for Blood and Marrow Transplantation, Société Française de Greffe de Moelle, Gruppo Italiano per il Trapianto del Midollo Osseo, and Fred Hutchinson Cancer Research Center Collaborative Study. Blood 1999; 93:2831.
  18. Lissandre S, Bay JO, Cahn JY, et al. Retrospective study of allogeneic haematopoietic stem-cell transplantation for myelofibrosis. Bone Marrow Transplant 2011; 46:557.
  19. Visani G, Finelli C, Castelli U, et al. Myelofibrosis with myeloid metaplasia: clinical and haematological parameters predicting survival in a series of 133 patients. Br J Haematol 1990; 75:4.
  20. Kröger N, Giorgino T, Scott BL, et al. Impact of allogeneic stem cell transplantation on survival of patients less than 65 years of age with primary myelofibrosis. Blood 2015; 125:3347.
  21. Ali H, Bacigalupo A. 2021 Update on allogeneic hematopoietic stem cell transplant for myelofibrosis: A review of current data and applications on risk stratification and management. Am J Hematol 2021; 96:1532.
  22. Deeg HJ, Bredeson C, Farnia S, et al. Hematopoietic Cell Transplantation as Curative Therapy for Patients with Myelofibrosis: Long-Term Success in all Age Groups. Biol Blood Marrow Transplant 2015; 21:1883.
  23. McLornan D, Eikema DJ, Czerw T, et al. Trends in allogeneic haematopoietic cell transplantation for myelofibrosis in Europe between 1995 and 2018: a CMWP of EBMT retrospective analysis. Bone Marrow Transplant 2021; 56:2160.
  24. Hernández-Boluda JC, Pereira A, Kröger N, et al. Allogeneic hematopoietic cell transplantation in older myelofibrosis patients: A study of the chronic malignancies working party of EBMT and the Spanish Myelofibrosis Registry. Am J Hematol 2021; 96:1186.
  25. Samuelson S, Sandmaier BM, Heslop HE, et al. Allogeneic haematopoietic cell transplantation for myelofibrosis in 30 patients 60-78 years of age. Br J Haematol 2011; 153:76.
  26. Kröger N, Sbianchi G, Sirait T, et al. Impact of prior JAK-inhibitor therapy with ruxolitinib on outcome after allogeneic hematopoietic stem cell transplantation for myelofibrosis: a study of the CMWP of EBMT. Leukemia 2021; 35:3551.
  27. Robin M, Porcher R, Orvain C, et al. Ruxolitinib before allogeneic hematopoietic transplantation in patients with myelofibrosis on behalf SFGM-TC and FIM groups. Bone Marrow Transplant 2021; 56:1888.
  28. Shahnaz Syed Abd Kadir S, Christopeit M, Wulf G, et al. Impact of ruxolitinib pretreatment on outcomes after allogeneic stem cell transplantation in patients with myelofibrosis. Eur J Haematol 2018; 101:305.
  29. Stübig T, Alchalby H, Ditschkowski M, et al. JAK inhibition with ruxolitinib as pretreatment for allogeneic stem cell transplantation in primary or post-ET/PV myelofibrosis. Leukemia 2014; 28:1736.
  30. Hanif A, Hari PN, Atallah E, et al. Safety of ruxolitinib therapy prior to allogeneic hematopoietic stem-cell transplantation for myeloproliferative neoplasms. Bone Marrow Transplant 2016; 51:617.
  31. Shanavas M, Popat U, Michaelis LC, et al. Outcomes of Allogeneic Hematopoietic Cell Transplantation in Patients with Myelofibrosis with Prior Exposure to Janus Kinase 1/2 Inhibitors. Biol Blood Marrow Transplant 2016; 22:432.
  32. Ali H, Tsai NC, Synold T, et al. Peritransplantation ruxolitinib administration is safe and effective in patients with myelofibrosis: a pilot open-label study. Blood Adv 2022; 6:1444.
  33. Polverelli N, Mauff K, Kröger N, et al. Impact of spleen size and splenectomy on outcomes of allogeneic hematopoietic cell transplantation for myelofibrosis: A retrospective analysis by the chronic malignancies working party on behalf of European society for blood and marrow transplantation (EBMT). Am J Hematol 2021; 96:69.
  34. Robin M, Zine M, Chevret S, et al. The Impact of Splenectomy in Myelofibrosis Patients before Allogeneic Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant 2017; 23:958.
  35. Bossard JB, Beuscart JB, Robin M, et al. Splenectomy before allogeneic hematopoietic cell transplantation for myelofibrosis: A French nationwide study. Am J Hematol 2021; 96:80.
  36. Bales JR, Kim HT, Portillo R, et al. Splenic irradiation prior to allogeneic hematopoietic cell transplantation for patients with myelofibrosis. Bone Marrow Transplant 2023; 58:459.
  37. McLornan D, Szydlo R, Koster L, et al. Myeloablative and Reduced-Intensity Conditioned Allogeneic Hematopoietic Stem Cell Transplantation in Myelofibrosis: A Retrospective Study by the Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant 2019; 25:2167.
  38. Gupta V, Malone AK, Hari PN, et al. Reduced-intensity hematopoietic cell transplantation for patients with primary myelofibrosis: a cohort analysis from the center for international blood and marrow transplant research. Biol Blood Marrow Transplant 2014; 20:89.
  39. Kröger N, Holler E, Kobbe G, et al. 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. Blood 2009; 114:5264.
  40. Rondelli D, Goldberg JD, Isola L, et al. MPD-RC 101 prospective study of reduced-intensity allogeneic hematopoietic stem cell transplantation in patients with myelofibrosis. Blood 2014; 124:1183.
  41. Robin M, Tabrizi R, Mohty M, et al. Allogeneic haematopoietic stem cell transplantation for myelofibrosis: a report of the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC). Br J Haematol 2011; 152:331.
  42. Merup M, Lazarevic V, Nahi H, et al. Different outcome of allogeneic transplantation in myelofibrosis using conventional or reduced-intensity conditioning regimens. Br J Haematol 2006; 135:367.
  43. Devine SM, Hoffman R, Verma A, et al. Allogeneic blood cell transplantation following reduced-intensity conditioning is effective therapy for older patients with myelofibrosis with myeloid metaplasia. Blood 2002; 99:2255.
  44. Hessling J, Kröger N, Werner M, et al. Dose-reduced conditioning regimen followed by allogeneic stem cell transplantation in patients with myelofibrosis with myeloid metaplasia. Br J Haematol 2002; 119:769.
  45. Kröger N, Zabelina T, Schieder H, et al. Pilot study of reduced-intensity conditioning followed by allogeneic stem cell transplantation from related and unrelated donors in patients with myelofibrosis. Br J Haematol 2005; 128:690.
  46. Rondelli D, Barosi G, Bacigalupo A, et al. Allogeneic hematopoietic stem-cell transplantation with reduced-intensity conditioning in intermediate- or high-risk patients with myelofibrosis with myeloid metaplasia. Blood 2005; 105:4115.
  47. Bacigalupo A, Soraru M, Dominietto A, et al. Allogeneic hemopoietic SCT for patients with primary myelofibrosis: a predictive transplant score based on transfusion requirement, spleen size and donor type. Bone Marrow Transplant 2010; 45:458.
  48. Alchalby H, Badbaran A, Zabelina T, et al. Impact of JAK2V617F mutation status, allele burden, and clearance after allogeneic stem cell transplantation for myelofibrosis. Blood 2010; 116:3572.
  49. Abelsson J, Merup M, Birgegård G, et al. The outcome of allo-HSCT for 92 patients with myelofibrosis in the Nordic countries. Bone Marrow Transplant 2012; 47:380.
  50. Alchalby H, Yunus DR, Zabelina T, et al. Risk models predicting survival after reduced-intensity transplantation for myelofibrosis. Br J Haematol 2012; 157:75.
  51. Ruiz-Argüelles GJ, Garcés-Eisele J, Reyes-Núñez V, et al. Clearance of the Janus kinase 2 (JAK2) V617F mutation after allogeneic stem cell transplantation in a patient with myelofibrosis with myeloid metaplasia. Am J Hematol 2007; 82:400.
  52. Benjamini O, Koren-Michowitz M, Amariglio N, et al. 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. Leukemia 2008; 22:1961.
  53. Lussana F, Rambaldi A, Finazzi MC, et al. 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. Haematologica 2014; 99:916.
  54. Snyder DS, Palmer J, Stein AS, et al. Allogeneic hematopoietic cell transplantation following reduced intensity conditioning for treatment of myelofibrosis. Biol Blood Marrow Transplant 2006; 12:1161.
  55. Patriarca F, Bacigalupo A, Sperotto A, et al. Outcome of allogeneic stem cell transplantation following reduced-intensity conditioninig regimen in patients with idiopathic myelofibrosis: the g.I.T.m.o. Experience. Mediterr J Hematol Infect Dis 2010; 2:e2010010.
  56. Snyder DS, Palmer J, Gaal K, et al. 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. Biol Blood Marrow Transplant 2010; 16:281.
  57. Robin M, Porcher R, Wolschke C, et al. Outcome after Transplantation According to Reduced-Intensity Conditioning Regimen in Patients Undergoing Transplantation for Myelofibrosis. Biol Blood Marrow Transplant 2016; 22:1206.
  58. Ballen KK, Shrestha S, Sobocinski KA, et al. Outcome of transplantation for myelofibrosis. Biol Blood Marrow Transplant 2010; 16:358.
  59. Raj K, Eikema DJ, McLornan DP, et al. Family Mismatched Allogeneic Stem Cell Transplantation for Myelofibrosis: Report from the Chronic Malignancies Working Party of European Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant 2019; 25:522.
  60. Soll E, Massumoto C, Clift RA, et al. Relevance of marrow fibrosis in bone marrow transplantation: a retrospective analysis of engraftment. Blood 1995; 86:4667.
  61. 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.
  62. 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.
  63. 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.
  64. Cervantes F, Hernández-Boluda JC, Alvarez A, et al. Danazol treatment of idiopathic myelofibrosis with severe anemia. Haematologica 2000; 85:595.
  65. Tefferi A, Silverstein MN. Recombinant human erythropoietin therapy in patients with myelofibrosis with myeloid metaplasia. Br J Haematol 1994; 86:893.
  66. 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.
  67. Mohr B, Herrmann R, Huhn D. Recombinant human erythropoietin in patients with myelodysplastic syndrome and myelofibrosis. Acta Haematol 1993; 90:65.
  68. 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.
  69. Aloe Spiriti M, Latagliata R, Avvisati G, et al. Erythropoietin treatment of idiopathic myelofibrosis. Haematologica 1993; 78:371.
  70. 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.
  71. 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.
  72. Tefferi A, Cortes J, Verstovsek S, et al. Lenalidomide therapy in myelofibrosis with myeloid metaplasia. Blood 2006; 108:1158.
  73. 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.
  74. 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.
  75. Elliott MA, Mesa RA, Li CY, et al. Thalidomide treatment in myelofibrosis with myeloid metaplasia. Br J Haematol 2002; 117:288.
  76. 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.
  77. 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.
  78. Mesa RA, Kiladjian JJ, Catalano JV, et al. SIMPLIFY-1: A Phase III Randomized Trial of Momelotinib Versus Ruxolitinib in Janus Kinase Inhibitor-Naïve Patients With Myelofibrosis. J Clin Oncol 2017; 35:3844.
  79. Mascarenhas J, Hoffman R, Talpaz M, et al. Pacritinib vs Best Available Therapy, Including Ruxolitinib, in Patients With Myelofibrosis: A Randomized Clinical Trial. JAMA Oncol 2018; 4:652.
  80. Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med 2012; 366:787.
  81. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med 2012; 366:799.
  82. Passamonti F, Caramazza D, Maffioli M. JAK inhibitor in CALR-mutant myelofibrosis. N Engl J Med 2014; 370:1168.
  83. Guglielmelli P, Biamonte F, Rotunno G, et al. Impact of mutational status on outcomes in myelofibrosis patients treated with ruxolitinib in the COMFORT-II study. Blood 2014; 123:2157.
  84. ruxolitinib. United States prescribing information. Revised July 2014. http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/202192s006lbl.pdf (Accessed on August 04, 2014). (Accessed on January 03, 2019).
  85. Heine A, Held SA, Daecke SN, et al. The JAK-inhibitor ruxolitinib impairs dendritic cell function in vitro and in vivo. Blood 2013; 122:1192.
  86. Wysham NG, Sullivan DR, Allada G. An opportunistic infection associated with ruxolitinib, a novel janus kinase 1,2 inhibitor. Chest 2013; 143:1478.
  87. Caocci G, Murgia F, Podda L, et al. Reactivation of hepatitis B virus infection following ruxolitinib treatment in a patient with myelofibrosis. Leukemia 2014; 28:225.
  88. Colomba C, Rubino R, Siracusa L, et al. Disseminated tuberculosis in a patient treated with a JAK2 selective inhibitor: a case report. BMC Res Notes 2012; 5:552.
  89. Goldberg RA, Reichel E, Oshry LJ. Bilateral toxoplasmosis retinitis associated with ruxolitinib. N Engl J Med 2013; 369:681.
  90. Wathes R, Moule S, Milojkovic D. Progressive multifocal leukoencephalopathy associated with ruxolitinib. N Engl J Med 2013; 369:197.
  91. Heine A, Brossart P, Wolf D. Ruxolitinib is a potent immunosuppressive compound: is it time for anti-infective prophylaxis? Blood 2013; 122:3843.
  92. von Hofsten J, Johnsson Forsberg M, Zetterberg M. Cytomegalovirus Retinitis in a Patient Who Received Ruxolitinib. N Engl J Med 2016; 374:296.
  93. Tefferi A, Litzow MR, Pardanani A. Long-term outcome of treatment with ruxolitinib in myelofibrosis. N Engl J Med 2011; 365:1455.
  94. Tefferi A, Pardanani A. Serious adverse events during ruxolitinib treatment discontinuation in patients with myelofibrosis. Mayo Clin Proc 2011; 86:1188.
  95. Dai T, Friedman EW, Barta SK. Ruxolitinib withdrawal syndrome leading to tumor lysis. J Clin Oncol 2013; 31:e430.
  96. Mollé N, Krichevsky S, Kermani P, et al. Ruxolitinib can cause weight gain by blocking leptin signaling in the brain via JAK2/STAT3. Blood 2020; 135:1062.
  97. Verstovsek S, Kantarjian HM, Estrov Z, et al. Long-term outcomes of 107 patients with myelofibrosis receiving JAK1/JAK2 inhibitor ruxolitinib: survival advantage in comparison to matched historical controls. Blood 2012; 120:1202.
  98. Cervantes F, Vannucchi AM, Kiladjian JJ, et al. Three-year efficacy, safety, and survival findings from COMFORT-II, a phase 3 study comparing ruxolitinib with best available therapy for myelofibrosis. Blood 2013; 122:4047.
  99. Passamonti F, Maffioli M, Cervantes F, et al. Impact of ruxolitinib on the natural history of primary myelofibrosis: a comparison of the DIPSS and the COMFORT-2 cohorts. Blood 2014; 123:1833.
  100. fedratinib. US Food and Drug Administration. Revised August, 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212327s000lbl.pdf (Accessed on October 06, 2022).
  101. Pardanani A, Harrison C, Cortes JE, et al. Safety and Efficacy of Fedratinib in Patients With Primary or Secondary Myelofibrosis: A Randomized Clinical Trial. JAMA Oncol 2015; 1:643.
  102. Singer JW, Al-Fayoumi S, Ma H, et al. Comprehensive kinase profile of pacritinib, a nonmyelosuppressive Janus kinase 2 inhibitor. J Exp Pharmacol 2016; 8:11.
  103. pacritinib. United States prescribing information. Revised February 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/208712s000lbl.pdf (Accessed on May 09, 2022).
  104. Sirhan S, Lasho TL, Hanson CA, et al. The presence of JAK2V617F in primary myelofibrosis or its allele burden in polycythemia vera predicts chemosensitivity to hydroxyurea. Am J Hematol 2008; 83:363.
  105. Martínez-Trillos A, Gaya A, Maffioli M, et al. Efficacy and tolerability of hydroxyurea in the treatment of the hyperproliferative manifestations of myelofibrosis: results in 40 patients. Ann Hematol 2010; 89:1233.
  106. 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.
  107. 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.
  108. Mesa RA. How I treat symptomatic splenomegaly in patients with myelofibrosis. Blood 2009; 113:5394.
  109. 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.
  110. 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.
  111. Koch CA, Li CY, Mesa RA, Tefferi A. Nonhepatosplenic extramedullary hematopoiesis: associated diseases, pathology, clinical course, and treatment. Mayo Clin Proc 2003; 78:1223.
  112. Hoffman R. Agnogenic myeloid metaplasia (ch.63). In: Hematology: Basic Principles and Practice, 3rd ed, Hoffman R, Benz EJ Jr, Shattil SJ, et al. (Eds), Churchill Livingstone, New York 2000.
  113. Tefferi A, Jiménez T, Gray LA, et al. Radiation therapy for symptomatic hepatomegaly in myelofibrosis with myeloid metaplasia. Eur J Haematol 2001; 66:37.
  114. 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.
  115. Cervantes F, Dupriez B, Passamonti F, et al. Improving survival trends in primary myelofibrosis: an international study. J Clin Oncol 2012; 30:2981.
  116. Cervantes F, Dupriez B, Pereira A, et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood 2009; 113:2895.
  117. 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.
  118. Kennedy JA, Atenafu EG, Messner HA, et al. Treatment outcomes following leukemic transformation in Philadelphia-negative myeloproliferative neoplasms. Blood 2013; 121:2725.
  119. 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.
  120. Passamonti F, Rumi E, Arcaini L, et al. Leukemic transformation of polycythemia vera: a single center study of 23 patients. Cancer 2005; 104:1032.
  121. Noor SJ, Tan W, Wilding GE, et al. Myeloid blastic transformation of myeloproliferative neoplasms--a review of 112 cases. Leuk Res 2011; 35:608.
  122. 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.
  123. Cherington C, Slack JL, Leis J, et al. Allogeneic stem cell transplantation for myeloproliferative neoplasm in blast phase. Leuk Res 2012; 36:1147.
  124. 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.
  125. Mascarenhas J, Navada S, Malone A, et al. Therapeutic options for patients with myelofibrosis in blast phase. Leuk Res 2010; 34:1246.
  126. 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.
  127. Mesa RA, Nagorney DS, Schwager S, et al. 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. Cancer 2006; 107:361.
  128. 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.
  129. 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.
  130. 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.
  131. Verstovsek S, Gerds AT, Vannucchi AM, et al. Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis (MOMENTUM): results from an international, double-blind, randomised, controlled, phase 3 study. Lancet 2023; 401:269.
  132. Harrison CN, Vannucchi AM, Platzbecker U, et al. Momelotinib versus best available therapy in patients with myelofibrosis previously treated with ruxolitinib (SIMPLIFY 2): a randomised, open-label, phase 3 trial. Lancet Haematol 2018; 5:e73.
  133. 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.
Topic 4531 Version 111.0

References

1 : International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data.

2 : The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms.

3 : Myeloproliferative neoplasm (MPN) symptom assessment form total symptom score: prospective international assessment of an abbreviated symptom burden scoring system among patients with MPNs.

4 : GIPSS: genetically inspired prognostic scoring system for primary myelofibrosis.

5 : MIPSS70+ Version 2.0: Mutation and Karyotype-Enhanced International Prognostic Scoring System for Primary Myelofibrosis.

6 : A dynamic prognostic model to predict survival in primary myelofibrosis: a study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment).

7 : DIPSS plus: a refined Dynamic International Prognostic Scoring System for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status.

8 : Nationwide prospective survey of secondary myelofibrosis in Japan: superiority of DIPSS-plus to MYSEC-PM as a survival risk model.

9 : Nationwide prospective survey of secondary myelofibrosis in Japan: superiority of DIPSS-plus to MYSEC-PM as a survival risk model.

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

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

12 : Allogeneic hematopoietic stem cell transplantation for myelofibrosis.

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

14 : Allogeneic bone marrow transplantation for primary myelofibrosis.

15 : Allogeneic bone marrow transplantation for primary myelofibrosis.

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

17 : Allogeneic stem cell transplantation for agnogenic myeloid metaplasia: a European Group for Blood and Marrow Transplantation, SociétéFrançaise de Greffe de Moelle, Gruppo Italiano per il Trapianto del Midollo Osseo, and Fred Hutchinson Cancer Research Center Collaborative Study.

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

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

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

21 : 2021 Update on allogeneic hematopoietic stem cell transplant for myelofibrosis: A review of current data and applications on risk stratification and management.

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

23 : Trends in allogeneic haematopoietic cell transplantation for myelofibrosis in Europe between 1995 and 2018: a CMWP of EBMT retrospective analysis.

24 : Allogeneic hematopoietic cell transplantation in older myelofibrosis patients: A study of the chronic malignancies working party of EBMT and the Spanish Myelofibrosis Registry.

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

26 : Impact of prior JAK-inhibitor therapy with ruxolitinib on outcome after allogeneic hematopoietic stem cell transplantation for myelofibrosis: a study of the CMWP of EBMT.

27 : Ruxolitinib before allogeneic hematopoietic transplantation in patients with myelofibrosis on behalf SFGM-TC and FIM groups.

28 : Impact of ruxolitinib pretreatment on outcomes after allogeneic stem cell transplantation in patients with myelofibrosis.

29 : JAK inhibition with ruxolitinib as pretreatment for allogeneic stem cell transplantation in primary or post-ET/PV myelofibrosis.

30 : Safety of ruxolitinib therapy prior to allogeneic hematopoietic stem-cell transplantation for myeloproliferative neoplasms.

31 : Outcomes of Allogeneic Hematopoietic Cell Transplantation in Patients with Myelofibrosis with Prior Exposure to Janus Kinase 1/2 Inhibitors.

32 : Peritransplantation ruxolitinib administration is safe and effective in patients with myelofibrosis: a pilot open-label study.

33 : Impact of spleen size and splenectomy on outcomes of allogeneic hematopoietic cell transplantation for myelofibrosis: A retrospective analysis by the chronic malignancies working party on behalf of European society for blood and marrow transplantation (EBMT).

34 : The Impact of Splenectomy in Myelofibrosis Patients before Allogeneic Hematopoietic Stem Cell Transplantation.

35 : Splenectomy before allogeneic hematopoietic cell transplantation for myelofibrosis: A French nationwide study.

36 : Splenic irradiation prior to allogeneic hematopoietic cell transplantation for patients with myelofibrosis.

37 : Myeloablative and Reduced-Intensity Conditioned Allogeneic Hematopoietic Stem Cell Transplantation in Myelofibrosis: A Retrospective Study by the Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplantation.

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

39 : 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.

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

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

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

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

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

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

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

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

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

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

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

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

52 : 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.

53 : 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.

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

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

56 : 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.

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

58 : Outcome of transplantation for myelofibrosis.

59 : Family Mismatched Allogeneic Stem Cell Transplantation for Myelofibrosis: Report from the Chronic Malignancies Working Party of European Society for Blood and Marrow Transplantation.

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

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

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

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

64 : Danazol treatment of idiopathic myelofibrosis with severe anemia.

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

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

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

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

69 : Erythropoietin treatment of idiopathic myelofibrosis.

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

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

72 : Lenalidomide therapy in myelofibrosis with myeloid metaplasia.

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

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

75 : Thalidomide treatment in myelofibrosis with myeloid metaplasia.

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

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

78 : SIMPLIFY-1: A Phase III Randomized Trial of Momelotinib Versus Ruxolitinib in Janus Kinase Inhibitor-Naïve Patients With Myelofibrosis.

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

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

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

82 : JAK inhibitor in CALR-mutant myelofibrosis.

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

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

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

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

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

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

89 : Bilateral toxoplasmosis retinitis associated with ruxolitinib.

90 : Progressive multifocal leukoencephalopathy associated with ruxolitinib.

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

92 : Cytomegalovirus Retinitis in a Patient Who Received Ruxolitinib.

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

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

95 : Ruxolitinib withdrawal syndrome leading to tumor lysis.

96 : Ruxolitinib can cause weight gain by blocking leptin signaling in the brain via JAK2/STAT3.

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

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

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

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

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

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

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

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

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

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

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

108 : How I treat symptomatic splenomegaly in patients with myelofibrosis.

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

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

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

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

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

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

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

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

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

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

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

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

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

122 : 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).

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

124 : 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.

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

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

127 : 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.

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

129 : 2-Chlorodeoxyadenosine treatment after splenectomy in patients who have myelofibrosis with myeloid metaplasia.

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

131 : Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis (MOMENTUM): results from an international, double-blind, randomised, controlled, phase 3 study.

132 : Momelotinib versus best available therapy in patients with myelofibrosis previously treated with ruxolitinib (SIMPLIFY 2): a randomised, open-label, phase 3 trial.

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

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟