A 60-year-old man with a history of coronary artery disease and JAK2 V617F–positive polycythemia vera presented to our bone marrow transplantation clinic with progressive fatigue, splenomegaly, and cytopenias. He had been in good health up until 14 years prior, when he was found to have polycythemia on routine blood work. He was treated with low-dose aspirin and serial phlebotomies for many years without complications. However, he eventually developed worsening thrombocytosis that required treatment with hydroxyurea and anagrelide. A bone marrow biopsy was performed; this demonstrated post–polycythemia vera myelofibrosis, World Health Organization grade 3/3, with 80% cellularity and 2% blasts. Cytogenetics revealed deletion of chromosome 20q. JAK2 V617F mutation testing was performed, and the patient was found to harbor this mutation. Treatment with ruxolitinib was initiated, which within 2 months resulted in resolution of his splenomegaly and improvement in his anemia. However, 1 year later, he developed progressive fatigue, splenomegaly, and worsening anemia, and he was referred for evaluation for hematopoietic stem cell transplantation.
On presentation to our clinic, he complained of significant fatigue and abdominal fullness. Laboratory analysis revealed a white blood cell count of 9,100/μL, a hemoglobin level of 9.6 g/dL, and a platelet count of 271,000/μL. His spleen measured 22 cm longitudinally on cross-sectional CT imaging. Human leukocyte antigen (HLA) typing was performed on the patient and his siblings, but this did not identify any matched related donors. A search was initiated with the National Marrow Donor Program, but no matched unrelated donors were identified. His two daughters then underwent HLA typing, and both were found to be haploidentical.
He subsequently underwent a haploidentical hematopoietic transplantation with fludarabine/cyclophosphamide/total body irradiation conditioning, followed by posttransplantation cyclophosphamide. His posttransplant course was complicated by polyarticular inflammatory arthritis. Unfortunately, 30 days after transplantation, autologous hematopoietic stem cell recovery was identified through testing for chimerism. Sixty days after his first transplant, he underwent a second haploidentical transplantation utilizing his other daughter’s stem cells. He first received conditioning with fludarabine and alemtuzumab and again received posttransplantation cyclophosphamide. His posttransplant course was complicated by BK virus–associated cystitis and mild grade 1 cutaneous graft-vs-host disease (GVHD), treated with topical corticosteroids. He continued to have cytopenias, and a bone marrow biopsy (Figure 1) performed 90 days after his second transplant showed persistent myelofibrosis, with deletion 20q on cytogenetics in 3 of 20 metaphase cells. Despite tapering of immunosuppression, he developed progressive loss of donor myeloid chimerism. However, he retained donor T-cell chimerism (> 90%).
Due to progressive disease, he was offered enrollment in a clinical trial utilizing the cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) checkpoint inhibitor ipilimumab for patients with relapsed hematologic malignancies following allogeneic stem cell transplantation (ClinicalTrials.gov identifier: NCT01822509). On day 395 after his second transplant, he began treatment with ipilimumab at 5 mg/kg. He tolerated the first infusion well, without toxicity. His hemoglobin level was 9.5 g/dL. Twenty-one days later he was given his second dose of ipilimumab; his hemoglobin level was 8.6 g/dL. Fifteen days after his second dose of ipilimumab, his hemoglobin level dropped to 7.7 g/dL and his reticulocyte count increased to 10.1%; his white blood cell and platelet counts remained stable. His lactate dehydrogenase (LDH), total bilirubin, and indirect bilirubin levels rose to 449 U/L, 2.33 mg/dL, and 2.13 mg/dL, respectively. Two days later, his hemoglobin dropped further—to 7.0 g/dL.
Which diagnostic test should be performed next?
A. Bone marrow biopsy
B. Peripheral blood flow cytometry for CD55 and CD59
C. Direct Coombs test
D. Further donor chimerism studies
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