Post-Polycythemia Vera Myelofibrosis with Progressive Anemia—Secondary Cytopenias on Cytoreductive Therapy

Clinical Pearl: Patients with polycythemia vera (PV) or essential thrombocythemia (ET) who develop progressive cytopenias, including anemia, should be evaluated for secondary myelofibrosis (MF).

Ms. R is an 84-year-old woman diagnosed with polycythemia vera (PV) in 2010 at age 72. At the time, she had a hematocrit level of 58%, a white blood cell count of 18.8 K/mm³, and a platelet count of 554 K/mm³. She was managed with periodic phlebotomies with normalization of her hemoglobin and hematocrit levels, but no improvement was shown in her leukocytosis or thrombocytosis.

A bone marrow biopsy confirmed a diagnosis of post-PV myelofibrosis (MF). Ms. R was started on hydroxyurea. She developed mouth sores, severe thrombocytopenia and progressive anemia despite dose reductions and dose interruptions of the hydroxyurea. She was hospitalized for nose bleeds, progressive fatigue, and shortness of breath. Her platelet count was 9 K/mm³, and her hemoglobin level was 6.8 g/dL. She received both platelet and packed red blood cell transfusions. A lower dose of hydroxyurea was tried but did not adequately control all three cell lines, and the patient continued to develop anemia requiring transfusions.

A repeat bone marrow biopsy was performed with samples sent for next-generation sequencing (NGS) showing mutations of JAK2, TP53, and BCOR indicating high-risk disease.¹ Ms. R is not a candidate for allogeneic stem cell transplant based on her age (78). The patient started on ruxolitinib. Dose reduction and interruptions were required due to progressive anemia requiring transfusion, thrombocytopenia, and general intolerance.

The patient was initiated on momelotinib based on data from the phase 3 MOMENTUM trial, which demonstrated clinically significant improvements in MF-associated symptoms, anemia measures, and spleen response as compared to danazol.² One week after beginning therapy, Ms. R reported new onset diarrhea, with 3 loose stools per day. Given that her symptoms were Grade 1, she was continued on therapy and the diarrhea was managed with Imodium and a low-residue diet. The diarrhea improved with only intermittent mild episodes after a month on therapy. After 3 months of therapy her platelet count remains above 90,000 and her hemoglobin has remained above 8.9 g/dL.

References

1. Garrote M, López-Guerra M, Arellano-Rodrigo E, et al. Clinical characteristics and outcomes of patients with primary and secondary myelofibrosis according to the genomic classification using targeted next-generation sequencing. Cancers (Basel). 2023;15:3904.
2. 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;401:269-280.

Primary Myelofibrosis with Progressive Anemia Requiring Transfusion of Red Blood Cells

Clinical Pearl: Progressive anemia and transfusion-dependent anemia are inevitable in most patients with myelofibrosis (MF). Transfusion of red blood cells carries significant risks, both acute and chronic, with repeated transfusions. Monitoring for this risk is essential in patients that are transfusion dependent.

Mr. W is a 42-year-old man diagnosed with primary myelofibrosis (MF) in 2022. He presented to the ED with progressive fatigue, abdominal bloating and pain, shortness of breath, and chest pain.

CT of the chest, abdomen, and pelvis noted massive hepatosplenomegaly (spleen measuring 28 cm). Labs obtained in the ED revealed a white blood cell count of 26 K/mm³, a hemoglobin (Hgb) level of 6.8 g/dL, a platelet count of 100 K/mm³, and an elevated lactate dehydrogenase level of 375; ULN 240). The patient was admitted for further evaluation including a bone marrow biopsy and aspirate. A diagnosis of very high-risk primary MF was confirmed, with a mutation-enhanced MIPSS70 v 2 score of 13.^{1, 2}

Mr. W received a transfusion of one unit of packed red blood cells. Upon completing the transfusion, he developed shaking chills, chest pain, shortness of breath, severe back pain, hypoxia (O₂ sat 82% on room air), and a fever of 39°C. He was transferred to the ICU for evaluation of transfusion-associated circulatory overload (TACO). Chest x-ray showed pulmonary edema; electrocardiogram showed sinus tachycardia. He was given emergency medications for a suspected transfusion reaction, and his symptoms improved gradually with aggressive diuresis. The post transfusion Hgb was 7.9 g/dL. Mr. W was discharged on Day 4 of his hospital stay and was referred to a hematologist for follow-up of his new diagnosis of primary MF.

During his initial consultation, the diagnosis of primary MF was explained as an incurable myeloid malignancy for which an allogeneic stem cell transplant provides the only potential cure. Mr. W does not want to proceed with an allogenic stem cell transplant at this time due to limited financial resources and concerns about loss of employment. For this patient, using the algorithm for anemia with splenomegaly and symptoms, the recommended treatment in lieu of or as a bridge to allogeneic stem cell transplant, would be momelotinib. This recommendation is based on the culmination of three phase III randomized trials, comprising 725 patients with either primary or secondary MF. Based on the most recent MOMENTUM trial,¹ momelotinib is considered the recommended JAK inhibitor for anemic patients with MF who are also disabled by symptomatic splenomegaly and constitutional symptoms.

Mr. W was started on momelotinib 200 mg orally once daily. He tolerated therapy well, and his symptoms of abdominal pain and bloating improved as his spleen size decreased. He developed a grade 1 elevation in AST/ALT, which was monitored without intervention or change in dose. After 24 weeks on therapy, his Hgb increased to 8.2g/dL. Mr. W presented to clinic for a regular follow-up visit noting a new non-painful swelling in his right lower extremity. The AP ordered a right leg ultrasound, which was positive for a partially occlusive thrombus in the right popliteal vein. CT of the chest did not show pulmonary emboli. Mr. W was started on a direct oral anticoagulant (DOAC) with resolution of the swelling and pain. His treatment with momelotinib continued.

Reference

1. 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;401:269-280.