# Background
Myelofibrosis (MF) is a clonal myeloproliferative stem cell disorder characterized by reactive bone marrow fibrosis, extramedullary hematopoiesis, and abnormal cytokine expression leading to systemic symptoms. The purpose of this guideline is to provide a practical approach to diagnosis, investigation and management of myelofibrosis.
Primary myelofibrosis (PMF) is a "BCR-ABL1 negative MPN" categorized alongside polycythemia vera (PV) and essential thrombocytosis (ET) according to current 2016 World Health Organization (WHO) classification (Table 1) 1,2 . Myelofibrosis may arise de novo as primary myelofibrosis (PMF) or develop secondary to either PV or ET, post-PV and post-ET MF, respectively. Clinical manifestations of MF are heterogeneous including: cytopenias, hepatosplenomegaly, constitutional symptoms (night sweats, fevers, and weight loss), chronic fatigue and bone pain. Disease complications include: symptomatic portal hypertension, pulmonary hypertension, non-hepatosplenic extramedullary hematopoesis, bleeding and/or thrombosis and leukemic transformation 3 . Currently, the only curative treatment option is allogeneic stem cell transplant (alloSCT) which is an option in only a selection of patients. As a result, treatment options are to alleviate patient symptoms with novel therapy modalities being investigated.

# Epidemiology
The estimated incidence of myelofibrosis (MF) is 0.1-1.0 per 100,000 worldwide. Reported prevalence ranges 0.5 to 2.7 per 100,000 in Europe to 4 to 6 per 100,000 in the United States 4 . The median age of MF diagnosis is 69 years with < 15% of patients under 50 years old at the time of diagnosis 5 . The causes of MF are largely unknown.

# Signs and Symptoms
Patients with myelofibrosis (MF) can have significant debilitating symptoms and poor quality of life. Symptoms are caused by chronically elevated aberrant cytokine production, myeloproliferation, ineffective erythropoiesis and extramedullary hematopoiesis  . Symptoms of chronic cytokine production include night sweats, muscle and bone pain, pruritus, fever and cachexia. Myeloproliferation leads to progressive cytopenias and results in associated symptoms. Consequently, anemia causes fatigue, weakness, and/or dyspnea; thrombocytopenia results in bruising and bleeding; leukopenia leads to increased susceptibility to infections. Extramedullary hematopoiesis (EMH) leads to hepatosplenomegaly. Splenomegaly causes early satiety and abdominal discomfort and leads to portal hypertension with risks of variceal bleeds and progressive liver dysfunction causing further coagulopathies. Non-hepatosplenic EMH may lead to paraspinal masses with risks of cord compression and pulmonary hypertension 3 .
Guideline Questions 1. What diagnostic and baseline investigations are recommended for adult patients with suspected or confirmed MF? 2. What are the recommended treatment options for MF?

# Search Strategy
This guideline was generated using systematic literature searches of PubMed and MEDLINE databases, ASCO abstracts and proceedings, and ASH abstracts and proceedings. The search included practice guidelines, systematic reviews, meta-analyses, randomized controlled trials and clinical trials. The guidelines were also adapted from the Canadian MPN Group recommendations.

# Target Population
Patients who are 18 years of age who are suspected of, or diagnosed with myelofibrosis.

# Summary of Recommendations
- The diagnosis of Myelofibrosis (MF) requires a bone marrow biopsy. 2. JAK2V617F mutation testing should be performed routinely in patients with MF. 3. If patients do not carry the JAK2V617F mutation, additional screening for driver mutations: CALR and MPL is required. Patients with no driver mutation are considered to be high risk "triple negative". Additional high-risk mutations can be attained via Next generation Sequencing (NGS). MF patients <75 years of age will have NGS testing performed. 4. If significant eosinophilia is present: screen for PDGFRA (FISH), PDGFRB and FGFR1 (conventional karyotype) rearrangements. 5. Prognostic scores should be calculated and documented which includes the IPSS used at time of diagnosis and the DIPSS and/or DIPSS-plus used during the remainder time of disease. If molecular information is available use MIPSS-70. 6. In low risk MF, watchful observation and symptom control is suggested. 7. For isolated anemia consider use of erythropoietin stimulation agents if epo level <125 u/l or if epo levels are elevated Danazol, IMIDS and/or steroids can be used in select patient populations. 8. In Intermediate or High-risk MF, treat symptomatic disease using JAK inhibitor first line therapy.
Ruxolitinib and Fedratinib are both available for use with different side effect profiles and dosing. Drug dose modifications are based on the degree of thrombocytopenia. Thiamine levels are required and supplementation to normal levels is necessary in order to use Fedratinib. Current data supports fedratinib's use post ruxolitinib failure. 9. Second line agents suggested are to use an alternative JAK inhibitor, or Hydroxyurea, Interferonalpha, IMIDs +/-steroids and clinical trials. 10. Allogeneic stem cell transplant (alloSCT) is the only curative treatment in MF. Fit patients with DIPSS Intermediate -2 or higher risk disease are eligible for consideration of allogeneic stem cell transplant. Patients who are transplant eligible should have NGS testing in order to assist with prognostication and alloSCT need (see below). Patients with estimated life survival  20 U PRBCs) or with higher liver iron content based on MRI studies with anticipated longer life survival, such as those going to alloSCT, should receive iron chelation. 13. Splenectomy and splenic radiation are offered in very select palliative cases particularly in the setting of refractory splenomegaly and/or thrombocytopenia. 14. Thromboembolic events should be managed according to accepted management guidelines.
Thromboprophylaxis should be used after surgery and in other high-risk situations.

# Discussion

# Diagnosis
Approximately 30% of patients with myelofibrosis (MF) are asymptomatic at time of diagnosis 9 . Diagnosis of PMF is based on revised 2016 WHO criteria (   The JAK2V617F mutation is an important driver mutation responsible for the pathogenesis of myeloproliferative disorders and is present in 50-60% of patients with PMF or post-ET MF and in 95% of those with post-PV MF  . A JAK2V617F mutation screening should be performed routinely on all patients with suspected MF. Although higher JAK2V617F allele burdens are associated with higher transformation rates and higher allele burden correlates with poorer survival in MF, quantitative assays are not required in MF and do not change clinical management  . Other driver mutations such as thrombopoetin receptor gene (MPL) have been documented in 3-8% of PMF and post ET MF patients, whereas Calreticulin gene (CALR), is present in approximately 50% of PMF and post ET MF patients without either JAK or MPL mutations  . The presence of JAK2V617F, CALR, MPL, trisomy 9, or del13q supports the diagnosis of MF. CALR-mutated patients are less likely to be anemic and/or require transfusions and display less leukocytosis 3 .
Physical examination: Clinical features of MF may include cachexia and physical signs of anemia and thrombocytopenia. Ninety percent of patients with myelofibrosis have an enlarged spleen and hepatomegaly is present in 50% of patients 9 . Assess for clinical signs of portal hypertension.

# Laboratory investigations:
Baseline investigations include: complete blood count with differential (CBCD), peripheral smear, LDH, uric acid, liver panel including liver function (INR, PTT, Bilirubin, Albumin), ferritin and iron studies. Leukoerythroblastosis is present in most cases and with the presence of immature cells from the myeloid and erythroblastic lineages, dacrocytes (tear drop cells) and peripheral myeloid blasts. Additional baseline tests to consider are vitamin B12 level (often elevated in MPNs) and erythropoietin level (when considering treatment of anemic patients). HLA typing is suggested in young patients ( 75 years) who may be eligible for alloSCT. Hepatitis B/C serology and HIV testing are suggested for those patients anticipated to receive immunosuppressive therapy. Consider Quantiferon testing in patients with risk factors.
Bone marrow evaluation: Evaluation of bone marrow histopathology is critical for correct diagnosis of MF. The bone marrow aspirate is often difficult resulting in a "dry tap". The bone marrow biopsy of MF typically reveals megakaryocyte proliferation and atypia, usually with reticulin or collagen fibrosis 21 . A bone marrow (BM) biopsy report should include: age adjusted cellularity, presence of fibrosis (reticulin and collagen stains), evaluation of granulopoiesis with special reference to blast clusters, and characterization of erythropoiesis and megakaryocytes 22 . Overt bone marrow fibrosis might be absent in the setting of prefibrotic PMF. The possibility of prefibrotic primary myelofibrosis, as opposed to ET, should be considered in the presence of persistently increased serum LDH, anemia, leukoerythroblastosis, increased circulating CD34+ cell count, and splenomegaly. ET and prefibrotic PMF are clinically distinct with both overall and leukemia-free survival are significantly worse in prefibrotic PMF 23,24 .
Cytogenetics: Approximately one-third of patients with primary MF present with cytogenetic abnormalities. The most frequent are del(20q), del(13q), trisomy 8 and 9, and abnormalities of chromosome 1 including duplication 1q. Other less frequent lesions include -7  del(7q), del(5q), del(12p), +21 and der(6)t(1;6)(q21;p21.3). A >80% 2-year mortality in PMF was predicted in the setting of monosomal karyotype, inv (3)/i(17q) abnormalities or with any 2 factors: circulating blast >9%, WBC >40 x 10 9 /L, or unfavorable karyotype 25 . Unfavorable karyotypes are incorporated into dynamic prognostic survival models (Table 3) and also result in a higher risk of leukemic transformation  .

# Mutation testing:
Testing for the JAK2V617F mutation should be performed early during the diagnostic workup of suspected MPNs. JAK2V617F negative patients should be screened for mutually exclusive driver mutations CALR and/or MPL. CALR-mutated patients are less anemic and red cell transfusion dependent with less tendency to present with leukocytosis. CALR mutations are associated with younger age, higher platelet counts, lower DIPSS-plus score 3 . In the absence of all 3 driver mutations ("triple negative") disease, consideration of additional molecular mutations is suggested. BCR-ABL1 rearrangement testing should be considered if atypical features are present on the bone marrow biopsy with triple negative disease. PDGFRA and PDGFRB rearrangements should be performed in the setting of eosinophilia given that the presence of these rearrangements is highly sensitive to imatinib therapy.
Triple negative patients, who lack, JAK2, CALR, and MPL mutations have a poor outcome 28,29 . With access to next generation sequencing (NGS) additional mutations can be obtained. It has been found that mutations including: IDH, EZH2, SRSF2 and ASXL1 result in inferior survival 3, . In a study of 570 patients, longest survival was found in CALR +/ASXL-patients (median 10.4 yrs) compared to shortest survival among those with CALR-/ASXL+ status (2.3 years). CALR+/ASXL+ or CALR-ASXLwere considered intermediate with median survival of 5.8 years. The favorable prognostic impact of CALR is limited to type1 or type-1 like variants 28,34 . 

# Prognosis
The clinical course of myelofibrosis (MF) is highly heterogeneous, and the disease can last from months to decades depending on risk status 9 . As the disease evolves, patients become symptomatic from their resultant cytopenias and increasing hepatosplenomegaly with constitutional symptoms.
Complications such as variceal bleeding can occur from resultant portal hypertension as well as having a higher risk of thrombosis. The 10-year survival of PMF patients is 81% lower than that of the general population 35 . Evolution of primary MF to acute myeloid leukemia (AML) occurs at a rate of 8% to 30%  . Other causes of death include: MF progression (18%), thrombosis and cardiovascular complications (13%), infection (11%) or bleeding (5%), and portal hypertension (4%) 9 .
Risk stratification: Various prognostic models have been developed in MF. These models have been validated in only the PMF population but for practical purposes can be used in the setting of secondary MF. The International Prognostic Scoring System (IPSS) estimates prognostic risk at the time of diagnosis of primary myelofibrosis. It was developed by the IWG-MRT and includes 5 variables: age older than 65 years, the presence of constitutional symptoms, hemoglobin level  25  10 9 /L, and 1% or more blasts in the peripheral blood 9 . An IPSS calculator is available online. See Table 3 for IPSS score 9 .
The Dynamic IPSS (DIPSS) is used for re-evaluating survival predictions during the course of the disease and includes additional risk factors not present at diagnosis, such as the acquisition of anemia in particular 26,39 . Subsequently the DIPSS Plus further refines DIPSS by incorporating three additional factors: platelet count <100 x 10 9 /L, red cell transfusion status, and unfavorable karyotype (i.e. complex karyotype or sole or two abnormalities that include: +8, -7/7q-, i(17q), inv (3), -5/-5q-, 12p-, or 11q23 rearrangement with each variable being assigned one point 40 . A DIPSS 26,39 and DIPSS PLUS 40 calculator is available online. See Table 3 for these scores.  

# Risk assessment tools under investigation:
Alternative approaches to MF prognostic risk has been based on specific gene mutations (i.e., ASXL1, EZH2, SRSF2, IDH1, IDH2, CALR, and MPL). Ongoing development of integrated systems for evaluating prognostic risk using molecular and cytogenetic markers in combination with clinical and hematologic findings have been proposed  .

# Mutation-enhanced International Prognostic Scoring System (MIPSS):
The score was derived from a study of 986 PMF patients divided into learning (n=588) and validation (n=398) cohorts. In multivariable analysis, age >60 years, constitutional symptoms, hemoglobin <100g/L, platelets <200x10 9 /L, Triple negative, JAK2 or MPL mutation, ASXL1 and SRSF2 mutation were significant and these variables were subsequently assigned adverse points: 1.5, 0.5, 0.5, 1.0, 1.5, 0.5, 0.5 and 0.5, respectively. Based on this, four distinct risk groups were identified: low (score 0-0.5); intermediate-1 (score 1-1.5); intermediate-2 (score 2-3.5); and high (score 4 or greater). According to the MIPSS up to 67% of patients in the intermediate I category of the IPSS were upstaged to an intermediate II or high-risk MIPSS. The MIPSS also down staged 50% of IPSS high-risk patients. Median survival were 26.4 years, 9.7 years, 6.4 years, and 1.9 years for low, inter mediate-1, Intermediate-11, and high-risk disease, respectively 41 .
A recent prognostic tool was developed for transplant eligible patients with PMF that integrates clinical and mutation data with cytogenetics (MIPSS70-plus) or without cytogenetics (MIPSS70). Risk factors for OS included: hemoglobin 25 x 10 9 /L, platelets <100 x 10 9 /L, circulating blasts  2%, bone marrow fibrosis grade  2, constitutional symptoms and absence of CALR type -1 mutation, and presence of high molecular risk mutations (HMR) (ASXL1, EZH2, SRSF2, IDH1/2) and presence of 2 or more HMR specifically. Three risk categories were delineated for MIPSS70 (see Table 4) with 5-year OS: 95% in low risk (median OS 27.7 years), 70% for intermediate risk (7.1 years) and 29% in high risk 29% (median OS 2.3 years). The MIPSS70-plus model was divided into 4 categories with 5-year OS: 91% in low risk, 66% in intermediate risk, 42% in high risk, and 7% in very high risk. These models remained effective after inclusion of older patients 44 . Calculators are available:  Recently, a personalized MPN prediction model was developed which incorporates genomic and clinical data in order to provide a more personalized risk stratification and prognosis. A total of 2035 patients (63 genomic and clinical variables) were included in the analysis and outcomes correlated with an independent external cohort. The calculator can be found at:  and may assist physicians in providing a more personalized treatment approach for MF 

# Genetics-based Prognostic Scoring System (GPSS):
An alternative genetics-based prognostic scoring system (GPSS) complements the MIPSS. In addition to high-risk mutations and age, the GPSS includes high-risk karyotypes: 5q-, +8, inv(3), i(17q), -7/7q-, 11q or 12p abnormalities, autosomal trisomies (except +9), monosomal and complex non-monosomal karyotypes. High risk GPSS was also associated with higher blast transformation rate (HR 7.4, 95% CI 2.1-26.3) 43 .
All of the above prognostic tools have been derived for primary myelofibrosis but often secondary myelofibrosis is categorized using the same tools. A post-PV and post-ET MF model has been developed: Myelofibrosis Secondary to PV and ET-Prognostic Model (MYSEC-PM) (  

# Treatment
The only curative treatment option for MF patients is allogeneic stem cell transplant (alloSCT). However, due to the associated morbidity and mortality, alloSCT is usually limited to fit patients with high risk features. Current conventional therapies are used for symptom control and target the treatment of the two most prominent symptoms of MF: splenomegaly and anemia 37 . Initiation of treatment is suggested for symptomatic anemia (Hgb persistently <90 g/L) or transfusion dependence (Hgb <80 g/L) and/or for symptomatic splenomegaly or splenomegaly resulting in secondary comorbidities/complications.  Anemia: Prior to initiation of treatment, it is important to rule out secondary causes of anemia. Treatment of anemia is considered for a hemoglobin persistently below 100g/L and is suggested for symptomatic anemia or transfusion dependence. Therapeutic options include erythropoietic stimulating agents (ESAs), androgens and/or immunomodulators (IMiDS) either alone or in combination with low dose steroids 36,37 .
Erythropoietin: Erythropoietin (EPO) is a reasonable treatment option for selected MF patients with anemia and low EPO levels (<125 mU/mL)  . Anemia responses are attained in 23-60% of patients with median duration of response of 12 months 46,47  weeks. If there is no response within 12 weeks, treatment should be discontinued 36 . Careful monitoring of spleen size is required as the use of EPO can result in progressive splenomegaly 37 .
Androgens: Nandrolone, Fluxymesterone, methandrostenolone and oxymetholone have been found to improve anemia in 30-60% of patients. Favorable responses are associated with female gender, prior splenectomy, normal karyotype 36 . Danazol (Cyclomen), is a semisynthestic attenuated androgen associated with less toxicity with a response rate of 40% 49 . Prior to the initiation of treatment, men must be screened for prostate cancer and all patients must have hepatic enzymes and function assessed with baseline ultrasound to rule out presence of hepatic tumors. Initial dosing of Danazol is 600 mg daily and should be maintained  6 months given most responses can only begin at 3-6 months of initiation. Once response is attained, consider dose reductions to maintain response, usually 200 mg/day is sufficient. Routine liver surveillance is required monthly and periodic hepatic ultrasounds are suggested with hepatic toxicity occurring in <20% of patients. Lastly, men require periodic prostate cancer screening and women should be counselled regarding hormonal side effects of treatment 36 .
Immunomodulators: Immunomodulators (IMiDs) include: thalidomide (100 -200 mg/day), lenalidomide (5-10 mg daily) and pomalidomide. IMiDs in combination with low dose steroids is suggested as an alternative to isolated anemia and/or thrombocytopenia treatment in low/int risk MF. Hematologic toxicity is a major side effect and precludes the use of IMiDS and often requires dose reduction and use of concomitant low dose steroids: prednisone (0.5 mg/kg daily for 3 months with taper) 36,37 . Lenalidomide results in 22% anemia response and 10-42% improvement of splenomegaly. Typical dosing of Lenalidomide is 5-10 mg daily for 3 weeks on a 4-week cycle  .
Pomalidomide is a less toxic IMID however, phase 3 studies failed to should a significant improvement in comparison to placebo 53 . Prednisone can be used as single therapy at dosing of 30 mg daily with dose tapering within a few weeks to 15 -20mg daily 36 . agents can be used in combination in setting of severe anemia with or without transfusions.

# Splenomegaly & Constitutional Symptoms
Medical treatment is suggested for patients with symptomatic splenomegaly. Sustained responses are difficult to obtain particularly in the setting of massive splenomegaly. The discovery of the Janus kinase JAK2V617F mutation triggered the development of targeted therapy for myelofibrosis (MF), resulting in approval of the JAK1/2 inhibitor, ruxolitinib (Jakavi  ).

# JAK Inhibitors:
Ruxolitinib: Ruxolitinib is an oral JAK1/JAK inhibitor that suppresses pro-inflammatory cytokines and growth factor receptors that use JAK1 and JAK2 for signaling and was first agent approved for treatment of MF 54 . Ruxolitinib is not selective for only JAK2 mutated disease and can be used in both JAK2 positive and JAK2 negative MF including secondary MF 55 . Regulatory approval in Canada was based on the results of two pivotal randomized phase III trials: Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment (COMFORT)-I and COMFORT II. Both trials included patients with Intermediate -2 or high-risk MF and compared ruxolitinib to placebo (COMFORT I) or to best available therapy (COMFORT II). In both COMFORT-I and -II, treatment with ruxolitinib led to significant reduction in spleen size, with primary end point of > 35% reduction in spleen size, by imaging techniques (MRI), at 24 and 48 weeks, respectively. Patients had significant improvement in MFrelated symptoms and quality of life. There was no significant difference in response among patients with or without the JAK2 V617F mutation or those with PMF compared to secondary MF 56,57 .
The final 5 year updates on the COMFORT trials have been published. Long-term comparisons in both trials is limited by crossover design with patients transitioned to comparator arms at either 6 months (COMFORT 1) or 12 months (COMFORT II). The rates of best response improve over time and median duration of spleen response is 3 years 58,59 . Long term findings from the COMFORT II trial showed that 28% of patients achieved a >35% reduction in spleen size at week 48 compared to no patients on BAT (P <0.001). Median survival was not reached in the ruxolitinib arm compared to 4.1 years in BAT arm with 33% reduced risk (crossover corrected HR 0.44) of death among patients on ruxolitinib compared to BAT 59 . Pooled data from both COMFORT studies (n=528) found a 30% risk reduction in death among patients with ruxolitinib compared to control arms with median survival of 5.3 years versus 3.8 years, respectively. Based on subgroup analysis, OS was improved with ruxolitinib regardless of age, sex, IPSS risk, spleen size, primary or secondary MF, anemia or thrombocytopenia and JAK mutational status 58 .
Overall, ruxolitinib is well tolerated, with the main toxicity being hematological. In COMFORT I, Grade 3-4 hematological effects occurring more frequently with ruxolitinib included anemia (45.2% vs. 19.2%), thrombocytopenia (12.9% vs. 1.3%), and neutropenia (7.1% vs. 2.0%). However, the platelet count and hemoglobin levels tend to stabilize and improve over time and do not affect response to ruxolitinib treatment 56 . Sudden withdrawal of ruxolitinib can lead to a shock-like syndrome due to reemergence of suppressed cytokines therefore, tapering of the drug is strongly suggested and current recommendations are to taper by 5 mg weekly 60 . Lastly, occasional reactivation of tuberculosis and opportunistic infections have been reported and linked to chronic suppression of T lymphocytes  . Currently, no specific prophylaxis is provided for patients. Appropriate screening for TB is suggested in high risk populations.
The recommended starting dose of ruxolitinib is based on platelet count. For a platelet count >200 x 10 9 /L, the recommended starting dose is 20 mg BID and for a platelet count 100-200 x 10 9 /L, the recommended dose is 15 mg twice daily (BID). A dose of 15 mg BID may also be considered in transfusion independent patients, who may have difficulty tolerating a drop-in hemoglobin of 20 g/L.
Ruxolitinib can be used in moderate thrombocytopenia (50-100 x 10 9 /L) and it is feasible to start at lower dose such as 5 mg BID and escalate accordingly without causing severe thrombocytopenia 64 . Dose reduction should be considered for patients receiving ruxolitinib 15 or 20 mg BID if the platelet count declines below 100 x 10 9 /L. Complete blood and platelet counts must be performed before initiating therapy, every 2 to 4 weeks until doses are stabilized, and then as clinically indicated, typically on a 4-week basis. Dose increases in increments of 5 mg BID can be considered on a monthly basis to a maximum dose of 25 mg BID in patients with inadequate response if no significant hematological toxicity occurs 37,65 . If no clinically meaningful response is achieved in 6 months, consider an alternative treatment. No specific criteria define ruxolitinib failure but if spleen response is less than 25% from baseline or constitutional symptoms persists it is suggested to consider alternative treatment 36 . 

# Ruxolitinib failure:
There is currently no consensus on the definition of Ruxolitinib failure. The Canadian MPN Group recently published practical recommendations for management of patients on ruxolitinib with suboptimal or loss of response and/or intolerance. 102 Studies of second-line JAK inhibitor therapy in patients including fedratinib, momelotinib and pacratinib are briefly described below. Limited data exists for ruxolitinib usage second line. There are reports of the effectiveness of ruxolitinib rechallenge via a case series of 13 patients with MF who were retreated with ruxolitinib after loss of an initial response or inadequate response to a median initial ruxolitinib duration of 62 weeks. Among all 13 patients, ruxolitinib rechallenge was associated with a significant spleen size reduction in 9 patients and symptom improvement in 12 patients. Four patients received a second rechallenge and all 4 experienced some improvement in spleen length and constitutional symptoms. 103 high-risk primary MF, post-polycythemia vera (PV) MF, or post-essential thrombocythemia (ET) MF, including patients who have been previously exposed to ruxolitinib. Recommended dose of fedratinib is 400 mg taken orally once daily for patients with a baseline platelet count of 50 x 10 9 /L Approval was on the basis of two JAKARTA trials. The path to approval included a period of FDA clinical hold (2013-2017). Recent approval includes a "black box warning" regarding the risk of serious and fatal encephalopathy, particularly, Wernicke encephalopathy (WE), which, ultimately was determined not to be resulting from fedratinib, following investigations during the clinical hold.
Fedratinib is selective for JAK2 relative to other kinases which could be advantageous because JAK1, JAK3, and TYK2, the other members of the Janus family of kinases, are critical for proper immune function. Therefore, activity against JAK1, JAK3, or TYK2, promotes immune suppression which may pose increased risk of infections. 104 The JAKARTA study was a phase 3 randomized MF study for intermediate 2 and high-risk disease including patients with platelets 50 x 10 9 /L included 3 equal arms (400 mg daily, 500 mg daily, or placebo for 24 weeks with crossover from placebo after that time. The primary end point was reduction in spleen volume (SVR) by at least 35%, with confirmation 4 weeks later by diagnostic imaging. The secondary end point was 50% reduction in total symptom burden by the Myelofibrosis Symptom Assessment Form (MFSAF). Between 2011 and 2012, prior to hold, 289 patients were enrolled (96 at 400 mg of fedratinib, 97 at 500 mg of fedratinib, and 96 placebo). The SVR (all confirmed 4 weeks later) observed at week 24 was 36% in the 400mg group, 40% in the 500mg group versus 1% in the placebo group. The MFSAF symptom response (durable until week 24) was 36% for 400 mg, 34% for 500 mg, and 7% for placebo. Anemia was the most common hematological toxicity (~45%) with an initial nadir, as seen with ruxolitinib, but usually followed by improvement. GI toxicities (~50%) of nausea and diarrhea were the most common nonhematological side effects requiring supportive management. 105 JAKARTA-2 72 was a single-arm, open-label, nonrandomized, phase 2, multicenter study conducted to evaluate the utility of fedratinib in intermediate-1, intermediate-2, or high-risk primary or secondary MF who had previously been treated with ruxolitinib, which was performed in parallel with the JAKARTA study and also included patients evaluated with platelet count of 50 x 10 9 /L or higher. Patients received initial oral fedratinib doses of 400 mg once daily in repeated 28-day treatment cycles. The primary endpoint was SVR of  35% reduction from baseline spleen volume at the end of cycle 6 (EOC6), and a key secondary endpoint was symptom response rate of  50% reduction in total symptom score (TSS) on MFSAF. This study was also halted early due to the clinical hold placed by the FDA concerning Wernicke's Encephalopathy (WE) and once resumed ruxolitinib failure was redefined. Patients initially were deemed resistant or intolerant to rollatini according to the individual investigator initially. Following removal of the clinical hold, a more stringent criteria for resistance/intolerance: relapse/refractory was defined for prior ruxolitinib therapy . In all, 97 patients were enrolled and treated in JAKARTA2 and comprised the intention-to-treat (ITT) population. For the entire intention-to-treat cohort, with a median age of 67 years, SVR of 35% after 6 cycles was met by 31% (95% confidence interval, 22, 41). Of the 79 patients (81% who met more stringent criteria for ruxolitinib resistance or intolerance) 30% (95% confidence interval, 21, 42) achieved at least 35% SVR following 6 cycles of treatment with no significant difference in responses between either category. TSS reduction of 50% were observed in 27% of both the intention-to-treat group and stringent criteria groups. Most common grade 3-4 hematological adverse events were anemia (46%) and thrombocytopenia (24%). Non-hematological adverse events were mainly GI in ~50% in both JAKARTA studies. /L. Practical issues for choosing first line JAKi might include their side effect profiles, thiamine requirements as well as dosing of therapy (once daily vs twice daily). Certainly, JAKARTA 2 72 provides data supporting fedratinib's effectiveness post ruxolitinib so it is reasonable to consider this as a second line option. Whether there is a benefit to the lack of JAK1 inhibition with fedratinib, or it has a wider kinome effects such as FLT3 and bromodomain targets remains uncertain. In terms of safely for transition from ruxolitinib to fedratinib, most patients can switch directly from one drug to another without "washing out" the first drug and ruxolitinib tapering is always advised. No tapering of fedratinib is required due to its long half-life (~41 hrs vs ~3 hrs for ruxolitinib).
Additional JAK inhibitors have been tested in MF and reviewed in detail elsewhere with most having been discontinued due to toxicity or poor response in comparison to ruxolitinib 71 . Momelotinib (MMB) is a JAK1/JAK inhibitor, which in murine models of anemia in chronic disease, inhibited bone morphogenic protein receptor kinase activin A receptor type I (ACVR1)-mediated hepcidin expression, which resulted in erythropoiesis. 109 In a phase I/II study of momelotinib in myelofibrosis (MF) the rates of spleen and anemia response, per International Working Group criteria, were 48% and 59%, respectively 110 SIMPLIFY-1 74 and SIMPLFY-2 75 phase III studies compared momelotinib(MMB) to ruxolitinib in MF without prior Jak inhibitor therapies and momelotinib vs BAT in MF with prior JAK inhibitor exposure, respectively. SIMPLIFY I (n=432) found MMB to be non-inferior to ruxolitinib with 35% spleen response of 26.5% vs. 29.0% (p=0.011) although it had a better anemia response at Week 24. Secondary endpoints of TSS reduction was seen in 28.4% and 42.2% of patients in MMB cohort and ruxolitinib cohort with no statistical difference (p = 0.98). The incidence of grade 3 AEs in MMB and ruxolitinib group were 35.5% and 43.5%, respectively. The most common hematological toxicities in both groups were thrombocytopenia and anemia, but the incidence of grade 3 or 4 anemia in ruxolitinib group was significantly higher than that in MMB (23.1% and 5.6%). A main side effect was neuropathy with 10% vs 5% peripheral neuropathy (grade 10%) grade 3 or 4 were thrombocytopenia and anemia. Overall in patients with platelet counts < 50 x 10 9 /L, there was no evidence of increasing thrombocytopenia in the pacritinib or BAT arms during treatment. However, there were concerns of high-grade cardiac and hemorrhagic events in the PERSIST studies which led to clinical hold. The follow-up PAC203 trial 112 a dose-finding study of pacritinib in patients with ruxolitinib failure, evaluated the efficacy of the 200 mg BID dose compared to lower pacritinib doses (100 mg QD and 100 mg BID). This incorporated more stringent eligibility/exclusion criteria, monitoring, and further dose modifications were implemented to mitigate risk of cardiac and hemorrhagic events. Patients had strict ruxolitinib failure criteria (similar to JAKARTA-2. 72) The endpoints were 35% SVR and 50% reduction in TSS at week 24. Of 161 patients, 73% were intolerant of and 76% had ruxolitinib resistance with a total of 50% meeting criteria for both. Severe thrombocytopenia (platelet count <50 x 10 9 /L) was present in 44% of patients enrolled. SVR rates were highest with 200 mg twice per day (100 mg once per day, 0%; 100 mg twice per day, 1.8%; 200 mg twice per day, 9.3%). The TSS response rate was not statististically different between doses (100 mg once per day, 7.7%; 100 mg twice per day, 7.3%; 200 mg twice per day, 7.4%). Overall the greatest SVR and TSS reduction were seen at 200 mg twice per day compared with lower doses. Pacritinib 200 mg twice per day demonstrated clinical activity and an acceptable safety profile without an excess of hemorrhagic or cardiac events at 200 mg twice per day therefore this is recommended dose for a following phase three studies and use. 112 Several ongoing trials are investigating novel therapies that target different pathways used alone or in combination with ruxolitinib 77,78 .
Cytoreductive therapies: Hydroxyurea has been longstanding treatment prior to the development of JAK inhibitors and can be initiated at a dose of 500-1000 mg oral daily. The overall response is 40% with median duration of 13.2 months. Hydroxyurea does provide symptom control for constitutional symptoms and is suggested to be used second line to ruxolitinib. Alternatively, it can be used first line for low risk MF patients who would not be eligible for ruxolitinib. Other drugs such as busulfan are rarely used and its use is limited to elderly patients with shortened life survival due to concerns of leukemic potential 36 .
Interferon: Myelofibrosis can be very symptomatic resulting from elevated cytokines with a large inflammatory component that may benefit from immune modulation through interferon. Silver et al. performed a prospective single centre study on the use of recombinant interferon- (rIFN-) in "early" primary myelofibrosis in settings of grade 1 and 2 myelofibrosis with residual hematopoiesis. Seventeen patients received either rIFN-2b 500,000 to 3 million units three times weekly or pegylated rIFN--2 45 to 90g weekly. Based on IWG prognostic and response criteria, 11 patients were low risk with 6 were intermediate-1 risk with complete remission (CR) and partial remission (PR) achieved in 2 and 7 patients, respectively. Overall, 58.8% patients derived clinical benefit with 23.5% achieving disease stability. The median time to any documented response was 1.0 years (0.4-7.4 years) with median duration of response of 2.0 years (0.1-14.0 years). Based on bone marrow followup in 15 patients, performed in a median of 3.2 years (0.9 -7.6 years) after therapy initiation, marrow morphology remained unchanged in 11 patients with 4 remissions achieved (2 CR and 2 PR). In the 4 with marrow improvement, sustained reduction in splenomegaly was also achieved. Quantitative JAK2 allele burden was assessed in 17 patients with 12 patients having mutated JAK status and 16 undergoing serial analysis whereby 14 had no molecular response and 2 had partial response. There was no correlation between molecular response and spleen response. Overall, rIFN- was tolerated with 80 % of patients having some clinical benefit or stability in early phase PMF 79 . Overall, 13 small clinical studies have evaluated the use of interferon with PMF but unfortunately, are variable on disease definition and treatment response criteria. Overall response rates ranged from 0-79% with spleen reductions 0-26%. Three studies have included pegylated IFN-2 or IFN2b with overall response rates of 9-85% and spleen reductions of 0-76% with Silver et al. showing the most clinical benefit of 80% among patients, specifically among early PMF 79,80 . The largest study of 62 patients from French and Belgium centres retrospectively reviewed use of PEG-IFN-2 therapy in myelofibrosis including 29 PMF, 19 PPV-MF, and 14 PET-MF of all risk categories. Treatment was initiated at median of 19.1 months from time of diagnosis with median age of 66 years at time of initiation of therapy. At mean follow up of 26 months, 64% of anemic patients achieved a complete response (time to achieve best response was 7.1 months) with 38.5% becoming transfusion independent. For patients in proliferative stages of their disease, complete resolution of leukocytosis and thrombocytosis occurred in 68.8% and 82.8% of patients, respectively. Eighty-two percent had resolution of constitutional symptoms and 46.5% had resolution of splenomegaly. Treatment was stopped in 45% patients after mean time of 11.7 months but was relatively well tolerated with majority of adverse events being grade 1-2 toxicities relating to cytopenias. Routine bone marrow assessments were not performed to assess morphological response. Spleen enlargement greater than 6 cm below costal margin was negatively associated with treatment response 81 . In a long-term follow up of these patients, at 58 months after PEG-IFN-2 initiation and 69.6 months after MF diagnosis, 30 patients (48.4%) of patients were still alive and had treatment duration of 39 months. The median overall survival (OS) of the cohort was 7.4 years with leukemia free survival (LFS) not reached. Median OS was 30 months among patients treated with PEG-IFN-2 for less than 2 years compared to 70 months if treated >2 years (p95% reduction however, no difference in OS or LFS was observed based on allele burden reduction. All seven patients that proceeded to alloSCT died within median time of 10 months associated with mainly graft versus host disease (GHVD) in 5/7 patients. Overall, PEG-IFN-2 is a treatment option in MF and is currently being considered moreso, in low risk MF. Its impact on molecular allele burden does not clearly correlate with survival rates and also requires further understanding 82 .
Splenectomy: Traditionally, splenectomy has been used to manage burdensome symptoms associated with splenomegaly, but the procedure involves substantial risk with 31% and 9% morbidity and mortality, respectively 83 . The main complications are bleeding, infections, and thrombosis (primarily in the splanchnic veins) 84 . Subsequent extramedullary hematopoiesis resulting in massive hepatomegaly develops in 16-24% of patients and can result in liver failure 85 . Splenectomy may be considered in immune related hemolysis unresponsive to steroids or in refractory transfusiondependent anemia or those with refractory splenomegaly. Durable responses in transfusiondependent anemia occur in 23% of patients 84 .
Splenic irradiation: Splenic irradiation has been used in selected patients for palliative purposes when splenomegaly is resistant to medication and a splenectomy is contraindicated. The doses used range from 30-365 Gy in 5-10 fractions. The benefit is transient but the risk of severe and prolonged cytopenias occurs in 1/3 of patients and an increase in transfusion requirements occurs in 40% of cases 37,86 .  90 . These findings identify MF patients who may likely benefit from earlier alloSCT given their anticipated poorer response to medical treatment and expected shorter survival. We therefore recommend that MF patients who are ineligible for JAK inhibitor treatment or lack of response to JAK inhibitor therapy, display pretreatment transfusion dependence, have high risk DIPSS score, are "triple negative" or have the presence of ASXL1 or EZH2 be referred and considered early for alloSCT. In retrospective comparative analysis of patients treated with drugs or alloSCT, the latter was superior in DIPSS int-2 and high risk patients with expected median survival of 4.5 year and 2 years, respectively 88 . Recently, integrated clinical, genetic and molecular prognostic models with (MIPSS70-plus) or without (MIPSS-70) cytogenetics have been developed to better stratify transplant eligible patients who are  70 years old and are best suited for transplant 44 . Risk factors for OS included: hemoglobin 25 x 10 9 /L, platelets <100 x 10 9 /L, circulating blasts  2%, bone marrow fibrosis grade  2, constitutional symptoms and absence of CALR type -1 mutation, and presence of high molecular risk mutations (HMR) (ASXL1, EZH2, SRSF2, IDH1/2) and presence of 2 or more HMR specifically. Three risk categories were delineated for MIPSS70 (see Table 4) with a median OS of 2.3 years among high risk patients and a risk of death of 81% at 5 years without disease intervention, suggesting upfront use of alloSCT. Similarly, based on the MIPSS70-plus model with four categories (Table 4), the 5-year OS among patients with high risk and very high risk was 42% and 7%, respectively with median OS of 3.9 years and 1.7 years, respectively 44 . In both cases, alloSCT should be strongly considered in MIPSS-70 high risk disease and/or high or very high risk MIPSS70-Plus MF patients.
Recently, a personalized MPN prediction model was developed which incorporates genomic and clinical data in order to provide a more personalized risk stratification and prognosis. A total of 2035 patients (63 genomic and clinical variables) were included in the analysis and outcomes correlated with an independent external cohort. The calculator can be found at:  and may assist physicians in providing a more personalized treatment approach for MF; in particular provide a better understanding for an optimal timeline for consideration of alloSCT 91 . Despite advances in our understanding of molecular markers, and the development of novel prognostic tools, the complete understanding of their relevance for alloSCT remains to be studied prospectively. There are no definite guidelines on integration of these newer scores in clinical practice. Ultimately, many factors need to be considered when proceeding to alloSCT including the Hematopoietic stem cell transplant comorbidity index (HCT-CI) and donor status 92 .
It has been demonstrated that pretreatment with JAK1/2 inhibitors has no adverse impact on the outcomes of subsequent alloSCT but rather improves clinical status and symptom burden, particularly reduction of splenomegaly pre-alloSCT. Furthermore, serious adverse events during drug discontinuation appear to be less frequent when JAK inhibitors are continued until close to the conditioning regimen. Patients undergoing alloSCT while responding to JAK inhibitors appear to have better outcomes compared to those with progressive disease 93,94 . It is important to consider timing of alloSCT and recognizing that 50% discontinue at 2-3 years and it is best to proceed with alloSCT before loss of ruxolitinib response 36 . We suggest ruxolitinib use pre-transplant and that it be discontinued at the start of conditioning for alloSCT.
Transplant: Recommendations 1. Allogeneic stem cell transplant (alloSCT) is the only curative treatment in MF and should be considered in fit patients with DIPSS Intermediate -2 or higher risk disease. Ultimately fit patients (<75yrs) with expected overall survival less than 5 years are suggested for referral to alloSCT. Younger patients with Intermediate -1 risk disease should be assessed for additional prognostic factors (see below) with consideration for alloSCT as future therapy. 2. Newer scores such as MIPSS70 and MIPSS70-Plus also identify patients with "high" or "very high" risk as being appropriate candidates for alloSCT. Personalized MPN genomic and clinical calculators are also available.
Additional factors for early alloSCT consideration include: ineligibility for JAK inhibitor treatment or lack of response to JAK inhibitor therapy, pretreatment transfusion dependence, or presence of HMR mutations.

# Emerging Treatments
Anemia is a significant problem among MF patients. A novel class of drugs termed activing receptor type II ligand traps consist of fusion proteins that sequester ligands belonging to the transforming growth factor B (TGFRB) superfamily and therefore inhibit their suppressive effects on terminal erythropoiesis 95 . Sotatercept is the first molecule in its class studied which has had response rates of 40% 78 . In a phase 2 trial in MF patients, 6 of 17 patients (35%) and 1 of 8 patients (12.5%) treated with sotatercept alone and combined with ruxolitinib, respectively, achieved erythroid response, with good tolerance. 113 Likewise, phase 2 study of MF patients (n=74) with anemia were randomized to luspatercept with or without ruxolitinib. Among those patients on ruxoilitinib and transfusion dependant (n=19) , 53% had a  50% reduction in RBC transfusion burden with 32% achieving transfusion independence  12 weeks, Among those on ruxolitinib with anemia that were nontransfusion dependant 57% achieved a mean increase of Hgb level of 15 g/L. 114 

# Additional Concerns
Blast phase myelofibrosis: Blast phase MF (MPN-BP) is synonymous with acute myeloid leukemia (AML) and is defined by the presence of 20% blasts in the blood or bone marrow 96 . The risk of leukemic transformation depends on the MPN variant and is highest in PMF, with an incidence of 10-20% during the first decade 42 . The prognosis is poor with median survival of approximately 3 months which has not improved in 15 years 97,98 . In a recent retrospective study, intensive chemotherapy resulted in complete remission (CR) or CR with incomplete count recovery (CRi) rates of 35% and 24%, respectively. Treatment-specified 3-and 5-year survival rates were 32% and 10% for patients receiving alloSCT (n = 24), compared to 19% and 13% for patients achieving CR/CRi but were not transplanted (n = 24), and 1% vs 1% in the absence of both alloSCT and CR/CRi (n = 200) (p < 0.01). Less intensive strategies, such as Azacitidine fail to achieve CR rates however at a dose of 75 mg/m 2 x 7 days on 28-day cycle overall response rate (ORR) of 38% including in 4/7 cases of transformed MF resulted in median survival of 8 months 99 . AlloSCT remains the only curative option in transformed MF but can only be offered to a select few patients. Overall 3-year survival is dismal at 6-11% 98 . Refer to current AML guidelines for further treatment options.

# Appendix A: Assessment Tools
Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) MPN-SAF TSS, also known as MPN10, includes 10 items: fatigue, concentration, early satiety, inactivity, night sweats, itching, bone pain, abdominal discomfort, weight loss, and fever. The tool has been validated in a prospective study of over 1400 patients and results correlated with other measures of disease burden. It can be used to: quantitatively assess the burden of symptoms of patients with MPNs, track disease progression and response to treatment 100 . MPN Symptom Assessment Form Total Symptom Score: Reassess thiamine monthly for first 3 months

# Reassess thiamine every 3 months thereafter or as clinically indicated
Do not start fedratinib treatment unless thiamine levels are within normal range

# Development and Revision History
This guideline was reviewed and endorsed by the Alberta Hematology Tumour Team. Members include surgical oncologists, radiation oncologists, medical oncologists, hematologists, nurses, pathologists, and pharmacists. Evidence was selected and reviewed by a working group comprised of members from the Alberta Tumour Teams, external participants identified by the Working Group Lead, and a knowledge management specialist from the Guideline Resource Unit. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.
This guideline was originally developed in 2020 and revised in 2021.

# Maintenance
A formal review of the guideline will be conducted in 2022. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly.