LAUSR

TO THE EDITOR: Allogeneic hematopoietic stem cell transplant (allo-HCT) is a potentially curative treatment for several malignant and nonmalignant hematological disorders. The basis of allo-HCT is the matching of human leukocyte antigen (HLA), which is encoded by major histocompatibility complex located on the short arm of chromosome 6 (6p21). ABO blood group results from glycosyltransferases encoded by a gene located on the long arm of chromosome 9 (9q34). The inheritance of ABO type is entirely independent of that of HLA. Unlike solid organ transplants, ABO blood group matching between the donor and the recipient is not a prerequisite for HCT. It is estimated that ~30–50% of all HCTs involve some form of ABO incompatibility between the donor and the recipient [1, 2]. Segregation of different types of ABO mismatch between the donor and the recipient is guided by the immune system [2]. If the recipient has an antibody, iso-agglutinin, against the donor’s red cell antigen, this type of mismatch is classified as a major ABO mismatch which occurs in about 20–25% of all HCTs [2]. The presence of high titer iso-agglutinins in the recipient can have post-transplant complications ranging from acute hemolysis, delayed red cell engraftment, and pure red cell aplasia (PRCA). Pure red cell aplasia (PRCA) is defined as the absence of erythroid progenitors in the bone marrow associated with reticulocytopenia in the peripheral blood in the absence of drug toxicity, infection, and relapse of primary malignancy after the transplant with persistent need of red cell transfusion after 30–90 days of HCT [3–6]. The risk of PRCA is in the range of 29% post-allo-HCT with major ABO mismatch [2, 7, 8] and according to some studies, in the range of 7.5–15% [5, 9–11]. Major risk factor for developing PRCA is pre-HCT isoagglutinin titer of >1:64 [6, 9]. Other risk factors include reduced-intensity conditioning (RIC) [8], and patients whose donors are of blood group A due to higher antigenicity of A-antigen as compared to B-antigen [4]. Some preventive measures reported to decrease the risk of PRCA include higher intensity of conditioning, and plasma exchange in the recipient where iso-agglutinin titers are very high (1:256 or more) pre-infusion of HPCs or pre-emptively upon an increase in titers after HCT, and donor type red cell infusion. ABO incompatible PRCA does not affect overall survival but morbidity of PRCA comes from frequent transfusions resulting in iron overload with secondary complications like liver cirrhosis, diabetes mellitus, pancreatic islet cell damage, hypogonadism, and hypothyroidism, etc. Treatment of PRCA is mostly based on targeting the recipient’s and donor’s immune system. The first line of treatment for PRCA in patients with no evidence of GVHD, usually, is a reduction in immunosuppression that can lead to decreased production of iso-agglutinin which could cause GvHD to flare [8]. Erythropoietin replacement therapy has been used with modest and transient success. Other approaches include the use of highdose corticosteroids that are toxic to lymphocytes, and donor lymphocyte infusions (DLIs), with a very high risk of precipitation of GVHD with morbidity and mortality from GVHD. Therapies targeting the recipient’s lymphocytes and plasma cells have been tried with some success. One such agent used is rituximab with some efficacy [12–14]. There have been a couple of reports of using bortezomib with success, but it has associated toxicity [14– 16]. Daratumumab seems to be the best therapy available for PRCA. There have been nine reports on the use of daratumumab in a total of ten patients with PRCA after allo-HCT with major ABO mismatch [17–25]. These reports suggest that 2–4 doses of daratumumab can help achieve long term remission of PRCA. This is well tolerated, and common side effect is moderate to severe reduction of IgG, IgM, IgA levels [21]. Ibrutinib is a small molecule, Bruton’s tyrosine kinase (BTK) inhibitor, developed to treat B-cell malignancies [26, 27]. This agent is approved for the treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma, mantle cell lymphoma, marginal zone lymphoma, Waldenstrom’s macroglobulinemia, and chronic graft-versus-host disease (cGVHD) [28, 29]. Ibrutinib inhibits the proliferation and survival of B-cells by inhibiting BTK pathway. BTK is also overexpressed in multiple myeloma stem cells and use of ibrutinib in relapsed/refractory multiple myeloma has some some efficacy [30]. As therapies for PRCA have been directed against B-cells or plasma cells, ibrutinib would be an attractive oral single agent for treatment that has shown efficacy in inhibiting both B-cells and plasma cells. Herein, we report five cases of refractory PRCA successfully treated ibrutinib at COH. This retrospective study was approved by institutional IRB. Table 1 summarizes patient and donor characteristics; conditioning therapies; GVHD prophylaxis; isoagglutinin titer pre-HCT, at the time of PRCA diagnosis, before and after therapy with ibrutinib; therapy for PRCA, number of PRBC units transfused before starting ibrutinib and response to ibrutinib. The median age of the cohort is 46 years (range; 39–67), and there were three males and two female recipients. There were three patients with a diagnosis of AML, and one each with a diagnosis of CML and secondary myelofibrosis. Two patients received myeloablative conditioning (MAC), and three patients received RIC therapy. Donors included one fully matched (10/10) sibling (MSD), and four matched (10/10) unrelated donors (MUD),