Myelofibrosis

 Initial assessment

1. Age: less than 70 yr or > 70 yr
2. Disease specific symptoms and comorbidities: night sweats, fever, wt loss, itching, fatigue, Early satiety
3. Disease associated comorbidities: pulm HTN, portal HTN, portal vein thrombosis, VTE, thrombocytopenia, anemia
4. Transfusion needs
5. Iron overload yes or no
6. Other unrelated comorbidities: Cardiac, 
7. Spleen size: 
8. Driver mutations: CALR/MPL are good in transplant eligible. ASXL1 and related high risk mutations(IDH1/2, EZH2, SRSF2) as a whole have no impact on HSCT. ASXL1 and TP53 multihit status are negative predictors. HSCT can overcome the negative effect of poor-risk cytogenetics so cytogenetics not included in the risk stratification. Patients carrying MPL mutation showed excellent 5-year survival of >80%
9. MIPSS- R

Current consensus recommends HSCT for patients with MF with a DIPSS intermediate-2 and high-risk score and age <70 years.

Circulating blasts and anemia are not predictors of HSCT outcomes unless anemia is associated with iron overload. Spleen size can predict graft failure and delayed engraftment. Fibrosis can be reversed with HSCT in 90% cases by 6 months after HSCT.

We currently do not use any blast reduction therapy before HSCT for chronic-phase MF (<10% blasts), whereas investigational blast reduction can be considered in accelerated-phase MF to reduce risk for relapse.

Blast-phase transformation before HSCT represents the most feared complication in MF and its estimated incidence after 20 years is <10%. HSCT is the only option for significantly improved outcomes, showing a 3-year survival of ∼30%, whereas only 1% survived in the absence of HSCT.

Patients with high iron overload determined by high serum ferritin at time of HSCT, need deferasirox during conditioning to suppress the appearance of labile plasma iron in order to decrease free radicals, which may decrease the incidence of infection and organ toxicity Importantly, therapeutic drug monitoring is the key to facilitate a safe coadministration with busulfan, because deferasirox leads to a considerable increase in busulfan area under the curve.

Reference: ASH

Non transplant candidates with MF

Treatment decisions in MF are guided by the manifestations of the disease and the type/degree of cytopenias ; patients with symptoms or splenomegaly are candidates for JAKi.

proliferative MF--> Jakafi, fedratinib

Cytopenic MF- pacritinib, momelotinib

1. Symptomatic, and with plt > 50K:

- Ruxolitinib was the first JAK1/2 inhibitor approved for intermediate or high-risk MF. It is effective in controlling splenomegaly and constitutional symptoms, and has been shown to improve overall survival. The typical starting dose is based on platelet count: 20 mg twice daily for platelet counts >200 x 10^9/L, 15 mg twice daily for counts between 100-200 x 10^9/L, and 5 mg twice daily for counts between 50-100 x 10^9/L.

-spleen responses are dose dependent so use max dose as tolerated per plt

-main se: grade ≥3 (Gr 3/4) anemia and thrombocytopenia occurred in 42-45% and 8-13% of the patients in the COMFORT studies

-prediction tool for prognosis after 6 months on Jakafi www.rr6.eu

-Abrupt ruxolitinib discontinuation without administering another JAKi should be avoided to prevent a cytokine storm, particularly when spleen length is ≥10 cm.

 Gradual dose-tapering or symptom management with steroids is advisable if further JAKi therapy is not planned

-Fedratinib ( first line or second line) is another JAK2-selective inhibitor, approved for patients with intermediate-2 or high-risk MF, particularly those who are resistant or intolerant to ruxolitinib. It is administered at 400 mg once daily, with dose adjustments for adverse reactions and in patients with severe renal impairment. Prophylaxis with thiamine is required to prevent Wernicke's encephalopathy

-frontline MF patients with moderate thrombocytopenia (platelets 50-100x109 /L) can be treated with fedratinib without dose modifications. Furthermore, fedratinib may be considered in the frontline in patients with adequate blood counts and a history of skin cancer or widespread skin cancer prior to initiation of JAKi treatment.

-can start fedratinib 2nd line without washout when changing from ruxolitinib

- causes more GI side effects due to FLT3 inhibition ( rx with loperamide and ondansetron)

-60% GI se, 40% anemia, 20% low plt

2. Symptomatic plt less than 50K: 

Pacritinib is preferred for patients with severe thrombocytopenia (platelet counts <50 x 10^9/L) due to its less myelosuppressive profile. It is also effective in reducing splenomegaly and alleviating symptoms. Monitor for prolonged QTc, MACE, thrombosis, bleeding, GI toxicity, second malignancy

3. Role of momelotinib: if the main cytopenia is anemia, and plt are at least above 25K

4. When to use other agents:

- ven+aza: blast phase of MF

- danazol with or without prednisone: may improve anemia

-hydroxyurea: to reduce high counts.

-revlimid: MF with chromosome 5q del

-splenic radiation: for symptom control to sites of extra medullary hematopoiesis

Pearls in MF treatment

1. Splenectomy is not associated with improved outcomes and should be only done in refractory cytopenias. Surgical mortality is 10% and pts may develop compensatory liver enlargement and liver failure.

2. Avoid ESA in patients with significant splenomegaly as it can worsen splenomegaly.

3. Ruxolitinib 5 mg BID has lower efficacy when plt are low

4.  momelotinib as a second-line treatment after pacritinib of severe tpenia but consider it a frontline option for patients with platelets ≥25x109 /L and moderate/severe anemia, especially when anemia is the predominant cytopenia. 

5. In cases with co-existing thrombocytopenia and anemia, which occurs frequently, the choice depends on the most dominant cytopenia and the patient’s clinical manifestations.   

A/P

age-year-old male/female presented with ongoing constitutional symptoms  for *** months, weight loss (25 lb), decreased appetite, and early satiety. Physical exam showed splenomegaly (measurement) and hepatomegaly (*** cm) on palpation. Blood work revealed white blood cells (WBC)*** hemoglobin (Hb) ***, platelets ***, lactate dehydrogenase (LDH)*** and peripheral blasts*** Diagnosis of primary MF was confirmed by BM biopsy; reticulin fibrosis was grade MF-2 /MF3 with occasional collagen fibers. Karyotype was diploid. Next generation sequencing detected JAK2 V617F with variant allele frequency (VAF)***. The Dynamic International Prognostic Score (DIPSS)20 was intermediate1/ intermediate-2/high, and the risk was *** based on the Mutation-Enhanced International Prognostic Score System 70-plus version 2 (MIPSS70-plus v.2)

• Patient with symptomatic MF and proliferative blood counts: Ruxolitinib or fedratinib ( often 2L)
• Patient with platelet counts 50-100x109 /L and Hb ≈10 g/dL: Rux, fedratinib or momelotinib
• patients with platelets 25-50 x109 /L and higher Hb levels or patients requiring occasional RBC transfusions:pacritinib 
• patients with platelets 25-50 x109 /L and moderate/severe anemia requiring frequent RBC transfusions, or patients who have poor tolerance to RBC transfusions, or other comorbidities (e.g., heart failure and difficulty in tolerating extra fluid volume):momelotinib