Guideline sources The following summarized guidelines for the evaluation and management of primary myelofibrosis (PMF) are prepared by our editorial team based on guidelines from the European Leukemia Net (ELN 2018), the European Society of Medical Oncology (ESMO 2015), and the British Committee for Standards In Haematology (BCSH 2014; 2012). 1 2 3 4 Calculator Calculator Calculat Dynamic International Prognosti Eastern Cooperative Oncology G Karnof Guidelines https://web.pathway.md/diseases/recEfgEDPqhFNZnP0 1/7 6/29/23, 11:29 PM Primary myelofibrosis Pathway 1. Screening and diagnosis Diagnostic criteria: As per ELN 2018 guidelines, use the 2016 revised WHO criteria for diagnosis of PMF. E As per ESMO 2015 guidelines, ensure accurate differentiation among the three unique myeloproliferative neoplasm subtypes as well as the exclusion of reactive conditions (in mutation-negative patients only) and disorders, such as myelodysplasia and chronic myeloid leukemia, for appropriate prognosis and treatment decision-making. Do not use the generic diagnostic label 'myeloproliferative neoplasm' alone. A 2. Classification and risk stratification Risk assessment: As per ELN 2018 guidelines, use the International Prognostic Scoring System prognostic score (based on hematological and clinical variables) in all patients at diagnosis of myelofibrosis. E Show 4 more As per ESMO 2015 guidelines, categorize patients with newly diagnosed myeloproliferative neoplasm at baseline according to the risks associated with the disease. B As per BCSH 2012 guidelines: Use the DIPSS-plus prognostic score to make therapeutic decisions, especially regarding the use of allo-SCT, in patients with PMF. E Consider using the International Prognostic Scoring System, DIPSS, and DIPSS-plus prognostic scores in patients with post-polycythemia vera or post-essential thrombocythemia myelofibrosis. C 3. Diagnostic investigations Genetic testing: As per ELN 2018 guidelines, obtain mutational analysis for JAK2V617F, CALR, and MPL on peripheral blood or bone marrow samples in patients with suspected PMF. E Show 2 more As per ESMO 2015 guidelines, obtain testing for 3 driver mutations in all patients with suspected myeloproliferative neoplasms. B As per BCSH 2012 guidelines, obtain JAK2V617F mutation testing routinely in patients with PMF. E Show 2 more 4. Diagnostic procedures Bone marrow biopsy: perform bone marrow biopsy in all patients with suspected Philadelphia chromosome-negative myeloproliferative neoplasms, except for patients with polycythemia vera with Hgb > 18.5 g/dL in males and > 16.5 g/dL in females. E https://web.pathway.md/diseases/recEfgEDPqhFNZnP0 2/7 6/29/23, 11:29 PM Primary myelofibrosis Pathway 5. Medical management Cytoreductive therapy: As per ELN 2018 guidelines: Offer observation alone in patients with International Prognostic Scoring System/DIPSS/DIPSS-plus low- or intermediate-1 risk myelofibrosis without significant symptoms, significant anemia (Hgb < 10 g/dL), splenomegaly (palpable spleen size > 10 cm), leukocytosis (leukocyte count > 25 10 /L), or marked thrombocytosis (platelet count > 1, 000 10 /L). E Administer hydroxyurea as the first-line agent of choice if cytoreductive treatment for the reduction of leukocytosis or thrombocytosis is indicated. E As per BCSH 2014 guidelines, initiate ruxolitinib as first-line therapy for symptomatic splenomegaly A , myelofibrosis-related constitutional symptoms affecting the quality of life B , and/or hepatomegaly and portal hypertension due to myelofibrosis, regardless of JAK2V617F mutation status. B Show 3 more As per BCSH 2012 guidelines, be cautious when using anagrelide in patients with established myelofibrosis. B Show 2 more Management of anemia: As per ELN 2018 guidelines, decide on the choice of a specific drug for myelofibrosis- associated anemia based on the overall toxicity profile and its expected risk in the individual patient. E Show 5 more As per ESMO 2015 guidelines, decide on treatment initiation based on individual variations depending upon age and comorbidities, usually with a Hgb level of < 10 g/dL. Initiate ESAs as one of the first options recognizing that response is often restricted to patients with inadequate EPO levels (< 125 mU/mL), and less frequently when there is significant splenomegaly or transfusion dependence. Discontinue treatment if no response is obtained at 3 months. B Show 3 more As per BCSH 2012 guidelines, consider administering a trial of EPO-stimulating agents for the management of anemia in patients with PMF with inappropriately low EPO levels (< 125 U/L). C Show 7 more Management of splenomegaly: As per ELN 2018 guidelines, administer ruxolitinib as first-line therapy for myelofibrosis- associated splenomegaly in patients with intermediate-2 or high-risk disease. E Show 2 more As per ESMO 2015 guidelines, administer ruxolitinib as first-line therapy for reducing spleen volume in patients with PMF. A 6. Therapeutic procedures https://web.pathway.md/diseases/recEfgEDPqhFNZnP0 3/7 6/29/23, 11:29 PM Primary myelofibrosis Pathway Allogeneic stem cell transplantation: As per ELN 2018 guidelines: Consider offering allo-SCT in all transplant-eligible patients with International Prognostic Scoring System/DIPSS/DIPSS-plus high or intermediate-2 risk disease. E Consider offering allo-SCT in transplant-eligible patients with International Prognostic Scoring System/DIPSS/DIPSS-plus intermediate-1 risk disease presenting with either refractory, transfusion-dependent anemia, a percentage of blasts in peripheral blood > 2% in at least 2 repeated manual measurements, adverse cytogenetics, or high-risk mutations. E As per ESMO 2015 guidelines, offer allo-SCT in eligible patients with myelofibrosis with an expected survival of < 5 years, including patients with International Prognostic Scoring System intermediate-2 and high-risk disease. B Show 2 more As per BCSH 2012 guidelines, use the DIPSS-plus prognostic score to make therapeutic decisions, especially regarding the use of allo-SCT, in patients with PMF. E Show 6 more Radiotherapy: As per ESMO 2015 guidelines: Consider offering splenic irradiation in patients not tolerating JAK inhibitors and being poor candidates for surgery. C Offer low-dose radiation for symptomatic extramedullary hematopoiesis in places other than the spleen and liver, as well as for myelofibrosis-associated pulmonary hypertension, due to extramedullary hematopoiesis. B As per BCSH 2012 guidelines: Offer radiotherapy in patients with symptomatic splenomegaly with an adequate platelet count (> 50 10 /L) unsuitable for surgical intervention. Consider administering platelet transfusions post-treatment. Offer radiotherapy in patients with extramedullary hematopoiesis involving vital organs or with severe bone pain. B 7. Perioperative care Perioperative management: consider controlling blood counts preoperatively to standard targets in high-risk patients undergoing surgery, when bleeding is a risk or thromboprophylaxis would normally be prescribed. C 8. Surgical interventions Indications for splenectomy: As per ELN 2018 guidelines, offer splenectomy as a palliative treatment option for drug- refractory symptomatic splenomegaly, and consider offering when drug-induced anemia hampers the effective use of hydroxyurea or ruxolitinib. E As per ESMO 2015 guidelines: https://web.pathway.md/diseases/recEfgEDPqhFNZnP0 4/7 6/29/23, 11:29 PM Primary myelofibrosis Pathway Offer splenectomy in patients with large and painful splenomegaly if JAK inhibitors are not available or prove ineffective. B Consider offering splenectomy in patients with transfusion-dependent anemia refractory to drug therapy, C taking the complication rates into careful consideration. As per BCSH 2012 guidelines, offer splenectomy in patients with PMF in any of the following situations: drug-refractory symptomatic splenomegaly drug-refractory anemia symptomatic portal hypertension (such as ascites, bleeding varices) severe catabolic symptoms (including cachexia). B Show 4 more 9. Specific circumstances Pediatric patients: offer a conservative approach in most pediatric patients. Consider offering a trial of corticosteroids once acute megakaryoblastic leukemia and vitamin D deficiency have been excluded. B Breastfeeding patients: recognize that breastfeeding is contraindicated with cytoreductive therapy. Decide about breastfeeding while taking interferon on an individual basis after discussion regarding possible risks and benefits. B Patients on hormonal therapy: Obtain an individualized risk-benefit assessment to decide on hormonal therapy. B Advise using progesterone-only preparations for oral contraception and avoid combined oral contraceptives. B Patients with leukemic transformation: As per ESMO 2015 guidelines, consider administering acute leukemia-like regimens in patients with leukemic transformation deemed potential candidates for allo-SCT. Consider offering azacitidine. C As per BCSH 2012 guidelines, provide supportive care in patients with blast phase PMF because of the poor prognosis. B Show 2 more 10. Follow-up and surveillance Assessment of treatment response: consider using the Myeloproliferative Neoplasm Symptom Assessment Form for objective monitoring of symptoms. B Show 2 more Clinical findings Patient demographics Symptoms https://web.pathway.md/diseases/recEfgEDPqhFNZnP0 5/7 6/29/23, 11:29 PM Primary myelofibrosis Pathway Elderly Abdominal discomfort Bone pain Past medical history Early satiety Fatigue Acquired vWD Fever Acute coronary syndrome Generalized pruritus Budd-chiari syndrome Night sweats Cerebral venous thrombosis Shortness of breath DVT Weight loss PE Portal hypertension Abdominal exam Stroke TIA Ascites Vitamin B12 deficiency Hepatomegaly Splenomegaly Lab findings Hematological findings Iron deficiency serum LDH Anemia WBC count Genetic testing blood platelet count blood leukocyte count Jak2 gene mutation blood platelet count reticulocyte count Studies 2020 TRIST In patients with hematologic malignancies requiring hematopoietic cell transplantation, restrictive strategy was noninferior to liberal strategy with respect to a health-related quality of life measured by Functional Assessment of Cancer Therapy-BMT score at day 100. Jason Tay et al. J Clin Oncol. 2020 May 1. References 1. John T Reilly, Mary Frances McMullin, Philip A Beer et al. Guideline for the diagnosis and management of myelofibrosis. Br J Haematol. 2012 Aug;158 4 453 71. Open 2. Tiziano Barbui, Ayalew Tefferi, Alessandro M Vannucchi et al. Philadelphia chromosome-negative classical myeloproliferative neoplasms: revised management recommendations from European LeukemiaNet. Leukemia. 2018 May;32 5 1057 1069. Open 3. A M Vannucchi, T Barbui, F Cervantes et al. Philadelphia chromosome-negative chronic myeloproliferative neoplasms: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015 Sep;26 Suppl 5:v85 99. Open 4. John T Reilly, Mary Frances McMullin, Philip A Beer et al. Use of JAK inhibitors in the management of myelofibrosis: a revision of the British Committee for Standards in Haematology Guidelines for https://web.pathway.md/diseases/recEfgEDPqhFNZnP0 6/7 6/29/23, 11:29 PM Primary myelofibrosis Pathway Investigation and Management of Myelofibrosis 2012. Br J Haematol. 2014 Nov;167 3 418 20. Open 5. Tefferi A. Primary myelofibrosis: 2019 update on diagnosis, risk-stratification and management. Am J Hematol. 2018 Dec;93 12 1551 1560. Open https://web.pathway.md/diseases/recEfgEDPqhFNZnP0 7/7