Patient With Polycythemia Vera Who Develops Progressive Anemia

Presentation

Mr. B is a pleasant 71-year-old male with past medical history significant for deep vein thrombosis (DVT), pulmonary embolism (PE), coronary bypass grafting, and polycythemia vera (PV). He was diagnosed with PV in 2013 after presenting with hyperproliferation of all three cell lines (white blood cells, red blood cells, and platelets) and a bone marrow biopsy confirmed JAK2+ PV. Mr. B was initially treated with phlebotomy alone. Hydroxyurea was added in 2015 due to rising white blood cell count and development of a left lower extremity DVT and subsequent PE. In addition to cytoreductive therapy, he was started on anticoagulation with apixaban at the time of the thrombotic events.   

Mr. B continued hydroxyurea until mid-2020, when he started requiring increasing doses of hydroxyurea to control his blood counts. In April 2020, he was taking 1,500 mg of hydroxyurea daily and hematocrit (Hct) was ~55%. Given his poorly controlled disease with persistent leukocytosis, the need for frequent phlebotomies on 1,500 mg of hydroxyurea/day, and newly palpable splenomegaly, he was transitioned to second-line therapy with ruxolitinib.

Laboratory studies at time of transition from hydroxyurea to ruxolitinib showed the following:

Ruxolitinib Initiation

 Mr. B was started on ruxolitinib 20 mg twice daily. After 2 months on this therapy he achieved a complete hematologic remission (CHR) without the need for phlebotomy; CBC at that time revealed: WBC 9.0 x 10⁹/L, Hct 43.1%, and platelets 145 x 10⁹/L. He proceeded with every-3-month monitoring, blood counts remained stable, and there were no phlebotomy requirements for nearly 2 years.

Development of Anemia

During a routine follow-up visit, Mr. B reported fatigue and shortness of breath that had been progressive over the past month. For these concerns, he had been following up with his primary care provider and cardiologist who did note an elevated BNP and a diuretic was started. He did not have lower extremity or central edema, and a repeat echocardiogram reveled adequate ejection fraction. He was unable to complete a stress test due to severe dyspnea walking at an incline.

A CBC performed at the clinic visit was consistent with the development of anemia, Hgb had dropped from 13.2 g/dL (Hct 39%) to 9.2 g/dL (Hct 27%). WBC and platelets remained stable and within goal. Due to concerns of ruxolitinib-induced anemia, the dose was decreased by 50% to 10 mg twice daily (the standard dosing for PV). This dose adjustment did result in minor improvement, yet Mr. B continued to feel low energy and therefore the dose was reduced again to 5 mg twice daily.

Additional Workup

Collaboration with cardiology and primary care were critical to ruling out alternative etiologies for the development of anemia, elevated BNP, and related side effects. From a hematologic perspective, a repeat bone marrow biopsy was performed and did not indicate evidence of progression to post-PV myelofibrosis:

• Persistent myeloproliferative neoplasm. Normal cellularity (35%) with trilineage hematopoiesis; increased atypical megakaryocytes. Minimal reticulin fibrosis (grade MF 0-1).
• Next-generation sequencing + JAK2 V617F, no additional mutations identified
• Cytogenetics are diploid

Additionally, abdominal ultrasound with Doppler was ordered to rule out progressive splenomegaly and portal hypertension; results were negative for evidence of either. 

 The pathology report was consistent with minimal reticulin fibrosis (MF 0-1), which was unchanged from prior bone marrow. The APP reviewed with Mr. B that the presence of low-grade fibrosis alone does not indicate disease progression; additionally, he had not acquired new molecular mutations or cytogenetic abnormalities. Notably, there were no increased blasts and no dysplasia. 

Mr. B continued to have slow count recovery and in parallel an improvement in his symptoms on a low dose of ruxolitinib 5 mg twice daily. After 4 months of very close lab monitoring and diagnostic testing his Hgb/Hct were back within goal range. He continues on low-dose ruxolitinib 5 mg twice daily. His most recent labs were consistent with a complete hematologic remission: (WBC 10.0 x 10⁹/L, Hct 44.1%, platelets 233 x 10⁹/L) and he was feeling back to baseline, which was a significant improvement for him.  

Discussion

Patients with PV are at risk for disease progression¹, and any unexpected changes in laboratory values should be careful examined. In this case, the development of anemia in a patient with PV prompted thorough investigation into potential etiologies. It is imperative to consider dose reduction/holding cytoreductive therapy to allow for recovery. Repeating a bone marrow biopsy to evaluate for evidence of progression is recommended, and secondary causes for anemia should not be overlooked.

Reference

1. Tefferi A, et al. Polycythemia vera: Historical oversights, diagnostic details, and therapeutic views. Leukemia. 2021;35:3339-3351.