Abstract
Introduction: Polycythemia vera is a myeloproliferative neoplasm (MPN) characterized by increased red blood cell mass. The natural evolution of this MPN is to progress to an anemic/cytopenic phase also known as “spent” phase prior to transformation into an accelerated and/or an overt leukemic phase.
Case Report: Herein, we describe a case of a patient with polycythemia vera transitioning though a “spent” phase to an MPN in accelerated phase (MPN-AP). The patient had genetic nurturance anemia, thrombocytopenia, neutrophilia and increased blasts in the bone marrow.
Management and outcome: Upon treatment with four cycles of 5-azacitidine, the patient’s polycythemia vera reversed Doxorubicin back to the proliferative phase. Serial phlebotomies were again required.
Discussion: Reversal of a “spent” phase by 5-azacitidine back to a proliferative polycythemia vera phase requiring phlebotomies has not been previously reported in the scientific literature. We might witness similar cases in the literature in the future years, which could lead to yet another therapeutic indication of this important pharmacologic agent.
Keywords
5-azacytidine, myelodysplastic syndrome, polycythemia vera, proliferative phase, ruxolitinib
Introduction
Polycythemia vera (PV) usually progresses to a “spent” phase prior to transformation into amyeloproliferative neoplasm in accelerated phase (MPN-AP) or blastic phase (MPN-BP).1 We describe herein a patient with PV transitioning to a “spent” phase, followed by MPN-AP. This case is unique as PV reverted back to the proliferative phase after therapy with 5-azacitidine.
Case report
In January 2018, an 84-year-old woman presented with an acute compression fracture at the level of the T12 vertebral body. She had a history of chronic atrial fibrillation, hypertension, hyperlipidemia, coronary artery disease, hypothyroidism, gout, chronic kidney disease, diverticulosis, and osteoarthritis. Aside from the T12 vertebral body fracture, magnetic resonance imaging (MRI) showed a diffuse abnormal bone marrow signal. Computed tomography (CT) scan of the abdomen showed splenomegaly measuring 15cm, increased from 9.3cm on the imaging performed in 2013. Blood work showed leukocytosis, erythrocytosis, and microcytosis. The manual differential showed moderate neutrophilia with a left shift, the presence of nucleated red blood cells(RBCs) and monocytosis. White blood cell (WBC) count was 12.9K/μL (normal values, 3.8–10.8K/μL), hemoglobin 16.5g/dL (normal values, 12.0–16.0 g/dL), hematocrit 49.6% (normal values, 36.0–48.0%), mean corpuscular volume (MCV) 71 fL (normal values, 80.0–99.0fL), and platelet count 187 K/μL (normal values 150–450K/μL). JAK2 kinase mutation V617F in the peripheral Eisenhower Medical Center, Rancho Mirage, CA, USA blood was positive. Bcr-abl transcript was negative. Erythropoietin level was low. A bone marrow aspiration and biopsy showed 70% panmyelosis with atypical megakaryocytes consistent with PV. Myeloblasts were not increased, and iron stores were depleted.
Management and outcome
As the patient was taking apixaban for stroke prophylaxis due to atrial fibrillation, aspirin was not prescribed to manage her polycythemia. The patient started serial phlebotomies to maintain a hematocrit of less than 42%.
Due to increasing leukocytosis with neutrophilia and erythrocytosis, she started ruxolitinib 10mg PO twice daily in September 2018. Hemoglobin stabilized at 11.8g/dL, and WBC count improved. In November 2018, the patient developed generalized weakness, night sweats and weight loss. In the next two weeks, the platelet count dropped to 20K/μL; WBC increased to 89.6/μL; and hemoglobin dropped to 6.9g/dL (Figures 1 to 3). At that time, ruxolitinib was stopped, and the patient was hospitalized. She was supported with irradiated packed RBC transfusions. A repeat bone marrow aspiration and biopsy showed 6% blasts and morphologic changes consistent with myelodysplastic syndrome (MDS). She received one cycle of 5-azacitidine 75mg/m2 IV daily 7/28days. The patient improved clinically and was discharged to home. Subsequent 5-azacitidine cycles were given subcutaneously as an outpatient with the same dosing and schedule at 75mg/m2 7/28days. She completed a total of four cycles of this therapy. The treatment lead to normalization of all blood cell lines, with corresponding decreases in WBC count and increases in hemoglobin and platelet counts (Figures 1 to 3). In March 2019, a repeat bone marrow aspiration and biopsy showed secondary myelofibrosis (MF) and myelodysplastic changes, but no increased number of myeloblasts. In May 2019, hemoglobin increased to 17.3g/dL, and she had normal WBC and platelet counts (Figures 1 to 3). The decision was made to restart ruxolitinib 10mg PO twice daily and phlebotomies as needed. As of today, she remains in good health, and continues to have regularly scheduled phlebotomies.
Discussion
PV is currently being regarded as a progressive disease characterized by a prodromal prepolycythemic phase with borderline erythrocytosis, followed by a prolonged proliferative (polycythemic) phase that, in some patients, evolves into a “spent” (anemic) phase. The “spent” (also known as “burnt out”) phase oftentimes transforms into MDS and secondary MF characterized by cytopenias and intramedullary fibrosis, and might further progress to secondary acute myeloblastic leukemia (AML).2 Once advanced to the “spent” phase (with associated MF or MDS), it is vanishingly rare for the disease to reverse back to the proliferative phase. Secondary AML (also known as MPN-BP) is usually preceded by MPN-AP which is defined by 10– 19% blasts in the bone marrow.1 This specific categorization based on bone marrow biopsy findings during the transition process aids in choosing the optimal therapy once traditional treatments for PV such as phlebotomy, hydroxyurea or ruxolitinib are no longer effective.3,4
In PV, JAK2 V617F mutation leads to overactivation of JAK-STAT signaling which increases production of certain cell lines.5 Research has shown that PV is not a homogenous entity as once thought, and displays different rates of progression in different individuals, sometimes more indolent while other times rapidly progressing to MPN-BP.1,2 Allogeneic bone marrow transplant is the only known curative modality for MPN-BP.1 As the patient was 84years old, this modality was felt suboptimal and was not considered.
Our patient’s initial bone marrow biopsy showed panmyelosis without increased number of blasts, MDS or secondary MF. The WBC count was only moderately increased. In addition to phlebotomy, empiric treatment with ruxolitinib was started, with WBC count normalization and decreased need for phlebotomy. Over the next six months, the patient became progressively anemic and eventually transfusion-dependent. Ruxolitinib had to be stopped due to severe thrombocytopenia. A repeat bone marrow biopsy showed MDS with increased number of blasts and secondary MF. That meant the patient was likely to soon enter MPN-AP, and was at high risk of transformation into AML. Therefore, the patient commenced treatment with 5-azacitidine. Within weeks, both platelets and hemoglobin improved. Eventually, platelet count normalized and hemoglobin increased until she became polycythemic again. Both phlebotomy and ruxolitinib had to be resumed.
This case highlights a unique transformation of polycythemia vera from the anemic “spent” phase back to the proliferative phase with an associated elevation of the RBC mass. Return of the PV to the proliferative phase was likely due to the treatment with 5-azacitidine.
5-azacitidine is a nucleoside analog of cytidine, a component of ribonucleic acid (RNA). It inhibits DNA methyltransferase, leading to DNA hypomethylation and resulting in cell death.6 It also incorporates itself into RNA and DNA, causing a direct cytotoxic effect upon abnormal bone marrow hematopoietic cells.7 As expected, its most common side-effects are anemia, thrombocytopenia, and neutropenia. Notwithstanding, our patient went from being anemic back to being polycythemic after treatment with 5-azacitidine.
Reversal of a “spent” phase by 5-azacitidine back translation-targeting antibiotics to a proliferative PV phase requiring phlebotomies has not been previously reported in the literature. If our observation is accurate, we believe that similar cases will surface in the literature in the future years. In turn, this may lead to yet another therapeutic indication of this important pharmacologic agent.
