Refractory postallogeneic stem cell transplant pure red cell aplasia in remission after treatment with daratumumab
Authors: Srilakshmi Bathini, Noa G. Holtzman, Rima Koka, Zeba Singh, Emily Wilding, Ying Zou, Kathleen Ruehle, Mehmet H. Kocoglu, Ashraf Badros, Nancy Hardy, Jean Yared, Aaron P. Rapoport, Magali Fontaine, Ashkan Emadi, Firas El Chaer, Saurabh Dahiya
Journal: American Journal of Hematology (2019)

Pure red cell aplasia (PRCA) is a normocytic normochromic anemia with severe reticulocytopenia and marked reduction or absence of erythroid precursors in the bone marrow. Acquired PRCA can be secondary to autoimmune disorders, lymphoproliferative disorders, infections, or hematopoietic stem cell transplantation (HSCT) between ABO incompatible donors and recipients.1 Although most cases of PRCA spontaneously resolve, up to 30% to 40% of post-HSCT PRCA require treatment.2 Most cases improve with reduction or discontinuation of immunosuppression, however, those that persist can be associated with high morbidity from complications of frequent packed red blood cell (PRBC) transfusions, such as iron overload and alloimmunization. Daratumumab, an anti-CD38 monoclonal antibody targeting plasma cells, is approved for multiple myeloma (MM) treatment. Herein, we report the successful use of daratumumab to treat refractory post-HSCT PRCA (Figure 1). This report highlights the efficacy and safety of daratumumab for treating PRCA to decrease the morbidity associated with conventional immunosuppression and PRBC transfusion-dependency, if used earlier in the treatment course. A 60-year-old man with history of treated hepatitis C infection presented with persistent bleeding postdental extractions. White blood cell (WBC) count was 9.5 K/mcL with 12% peripheral myeloid blasts, hemoglobin 7.4 g/dL, and platelet count 51 K/mcL. Bone marrow aspirate and biopsy (BMBx) was hypercellular for age with dysgranulopoiesis, dyserythropoiesis, and dysplastic megakaryocytes establishing the diagnosis of myelodysplastic syndrome with refractory anemia with excess blasts 2 (MDS-RAEB-2) (Figure 2A,B). Cytogenetic analysis showed a 46, XY karyotype and molecular analysis identified ASXL1, TET2, and RUNX1 mutations. The patient was started on subcutaneous azacitidine 75 mg/m2/day for seven consecutive days every 4 weeks, throughout which he continued to require weekly platelet and monthly PRBC transfusions. The patient was referred for HSCT and a matched, unrelated male donor was identified, but with a major ABO incompatibility (recipient blood group O, donor blood group A). He underwent allogeneic HSCT with reduced intensity conditioning—fludarabine 30 mg/m2/day from D-7 to D-2 (ie, from 7 days to 2 days prior to HSCT), busulfan 3.2 mg/kg/day on D-5 and D-4 and two doses of 200 cGy of total body irradiation on D-1. For graft-vs-host-disease (GVHD) prophylaxis he received tacrolimus, rabbit antithymocyte globulin (ATG), and methotrexate. The patient received peripheral blood HSCT at a dose of 6 × 106 CD34+ cells per kg. WBC engrafted on D+11 and his platelet count recovered on D+18, however, he continued to require PRBC transfusions. D+30 peripheral blood chimerism showed 100% donor-derived cells. D+60 BMBx was variably cellular with rare maturing granulopoiesis and megakaryopoiesis, and markedly decreased erythropoiesis with <1% blasts. On immunohistochemistry, no erythroid precursors were identified by E-cadherin (Figure 2C,D). Immunostain for Parvovirus B19 was negative. Cytogenetic analysis showed normal male karyotype and clearance of the myeloid mutations. Further workup of his persistent anemia revealed normal erythropoietin level, no splenomegaly, negative hemolysis markers, absent reticulocytosis, and blood viral quantitative polymerase chain reactions were negative for cytomegalovirus, human herpes virus-6, Epstein-Barr virus and adenovirus. ABO RBC typing confirmed O type with anti-A reactivity: anti-A IgM (titer 1:16), anti-A IgG (titer 1:32). On D+201, the anti-A IgG titers peaked at 1:256. The patient was diagnosed with postallogeneic-HSCT PRCA due to major ABO incompatibility. Tacrolimus dose-reduction was started on D+68, however, without improvement in his anemia. High-dose corticosteroids were started and tapered without abatement in transfusion-dependence. Therefore, on D+103, he received weekly rituximab 375 mg/m2 for four doses, again without improvement of his anemia. Next, on D+152, he received subcutaneous bortezomib 1.3 mg/m2 weekly for 6 weeks after which his transfusion requirements decreased slightly. On D+309, tacrolimus was discontinued, however, isohemagglutinin titers remained detectable with persistent transfusion-dependent anemia and undetectable reticulocytosis. Thereafter, on D+411, the patient was started on short course of intravenous daratumumab at 16 mg/kg weekly for 4 weeks. He was noted to have brisk recovery of reticulocytosis after just one dose of daratumumab. Following the final daratumumab infusion, the patient became PRBC transfusion-independent. Currently, he is 4 months postdaratumumab therapy. Now, his blood type forward types as A with decreased anti-A IgM titers to 1:2 and anti-A IgG titers to 1:8. He continues to do well with a normal hemoglobin at 14.3 g/dL. A repeat BMBx performed 3 months after daratumumab therapy showed normal erythroid precursors without evidence of MDS (Figure 2E,F). As human leukocyte antigen and blood group systems (ABO) are on different chromosomes, they are inherited separately. As such, up to 50% of HSCT can occur across ABO blood groups.3 The resultant major ABO incompatibility can lead to immediate and delayed hemolysis, delayed engraftment with graft failure, higher incidence of GVHD and/or relapse, increased nonrelapse mortality and decreased overall survival. The rare disorder of PRCA, caused by inhibition of engraftment of donor erythroid precursors by residual host isohemagglutinins, can occur in up to 29% of patients with ABO mismatched donors.3 PRCA is a diagnosis of exclusion and other more common causes of anemia, such as hemolysis, GVHD, blood loss, parvovirus B19 infection, and recurrent malignancy must be ruled out. Most cases of PRCA do spontaneously remit. However, the disease can be associated with significant morbidity secondary to high PRBC transfusion requirements that could lead to transfusion reactions, alloimmunization, and iron overload. When PRCA persists beyond 60 days after HSCT, spontaneous resolution becomes uncommon and treatment is advised. Currently, there is no approved standard of care for PRCA management. Treatment approach includes tapering immunosuppression, if feasible. Other treatment modalities including donor lymphocyte infusions, corticosteroids, rituximab, plasma exchange, ATG, and bortezomib have been used with limited benefits. Daratumumab, an IgG1k anti-CD38 monoclonal antibody currently approved for the treatment of MM, results in complement-mediated, antibody-dependent cell cytotoxicity, and cellular apoptosis.4 As CD38 is overexpressed on the surface of plasma cells, it is a therapeutic target that can selectively eliminate the plasma cell clone responsible for the delayed erythroid engraftment post ABO-mismatched HSCT. In a single previous case report, daratumumab was successfully used to treat post-HSCT PRCA without adverse events.5 In the current report, despite higher anti-A IgG titers than IgM titers, our patient still had a rapid response to daratumumab probably due to the decrease in the plasma cell burden and serologic response could have lagged behind the clinical recovery due to the longer half-life of IgG antibodies. Due to its safety profile in MM and its efficacy in the treatment of PRCA, daratumumab proves to be a promising treatment option. Further studies exploring the role of daratumumab therapy for refractory PRCA or in the upfront setting are warranted. The authors have no relevant conflict of interest to report. S.D. identified the described case. S.B. wrote the manuscript with assistance from FEC, NGH, and SD. Z.S. and R.K. provided interpretation and delivery of the images. All authors provided critical feedback and helped shape the manuscript.