Administration of Daratumumab in the Case of Severe Pure Red Cell Aplasia after Allogeneic Transplantation

Abstract

Pure red cell aplasia is a well-known complication of AB0 major mismatched allogeneic hematopoietic stem cell transplantation. This side effect can be selflimiting, but is occasionally persistent and treated using modalities such as steroids, anti-thymocyte globulin, erythropoietin, donor lymphocyte infusions, rituximab, or plasmapheresis. In some cases, these standard treatments have no effect. We describe a patient with pure red cell aplasia, who received an AB0 major mismatched allogeneic hematopoietic stem cell transplantation. He underwent various treatment for the pure red cell aplasia, but no reticulocytes were present. Daratumumab was started on day 60 and 69 after transplantation, and after two doses of daratumumab, reticulocytosis and the hematocrit increased. Our case clearly represents an additional successful administration of daratumumab, resulting in full recovery of the patient with pure red cell aplasia.

Keywords: Allogeneic transplant, pure red cell aplasia, daratumumab, AB0 mismatch

Abbreviations

PRCA: Pure Red Cell Aplasia

Case Presentation

Pure red cell aplasia is a syndrome characterized by a severe normocytic and normochromic anaemia, reticulocytopenia, and absence of erythroblasts from an otherwise normal bone marrow [1,2]. It can be congenital, but mostly associated with other diseases, such as malignancies, autoimmune disorders, parvovirus B19 infections, drugs or toxic agents [3,4]. Pure red cell aplasia is a well-known complication after major AB0 mismatched allogeneic hematopoietic stem cell transplantation. It is more common in group 0 recipients with group A donors, and based on the presence of residual recipient B lymphocytes or plasma cells, which can produce isohemagglutinins against donor red blood cells. The laboratory findings are the following: The absolute reticulocyte count is always less than 10 000/millilitre (reticulocyte percentage, 1%), and in many cases is much lower. In most of the cases white blood cell and platelet counts are normal. The diagnosis of PRCA requires the detection of the antibodies in the sera of patients upon the abovementioned anaemia and low reticulocyte count [5]. The occurrence of PRCA after a major mismatch allogenic transplantation severely impacts the patients quality of life, as transfusion support may be needed up to 6 months [6].

The treatment of PRCA is usually based on immunosuppression, there are many different agents such as steroids, antithymocyte globulin, erythropoietin, donor lymphocyte infusions, rituximab, or plasmapheresis. But in some cases, these standard treatments have no effect, and the time to recovery is relatively slow [7]. As the pathogenetic base of the condition is residual plasma cells, it is logical to target these to stop production of the antibodies. CD38 as expressed on activated B cells and plasma cells, posing a very rational target for therapy. It is also expressed on activated T cells, helping the B cell antibody production [8]. Daratumumab is a humanized anti- CD38 monoclonal antibody developed for the treatment of myeloma multiplex. It is a rational approach to utilize daratumumab to target, and eliminate the resting plasma cells from the donor in case of developed PRCA. This treatment has been recently published as case reports [9,10]. Here we describe a case of post allogenic transplant PRCA, where a short course of daratumumab therapy yielded fast and complete resolution of PRCA without any side effects.

A 66-year-old man with acute myeloid leukemia presented for evaluation. Given the refracter disease, allogeneic stem cell transplantation was planned. During the donor search, he received two cycles of FLAG-IDA (fludarabine, cytarabine, idarubicin and granulocyte colony stimulating factor), and two cycles of high-dose cytarabine. From day -9 to day -1 patient received a reduced intensity conditioning regimen consisting of fludarabin (200 milligrams), busulfan (540 milligrams), thymoglobulin (400 milligrams). An 11/12 DP mismatched, unrelated donor was identified with a major ABO incompatibility. His pretransplant blood type was 0 positive, and he was transplanted from an A positive bone marrow donor. For prophylaxis against graft versus host disease, the standard cyclosporin, methotrexate and mycophenolate mofetil was given.

On the day of transplantation, our patient received a stem cell transplant with a dose of 5.31x106 CD34+ stem cells per body weight kilogram. Engraftment of white blood cells developed on day 24, and platelet count started to increase on day 19, but the patient continued to have anaemia, and required red blood cell transfusions. With short tandem repeat analysis on day 30 after transplant, the donor was responsible for 93% of haematopoiesis. Red blood cells with A blood group were not present. After six weeks of stem cell transplantation, a control bone marrow biopsy was done, and showed no blasts, and no sing of acute myeloid leukemia, but a serious red cell aplasia with 3-4 % of erythroid elements, and normoblasts were missing. Anti-A antibody titer was 1:64 on day 28, day 44 and day 54 too. To treat PRCA, he received 100mg of rituximab on day 37 and 47, but it had no effect on the hematocrit level. Alfa-epoetin was administered three times, on day 27, 37, and 47, but the hematocrit and reticulocyte count did not increase. Patient received 400 milligrams of daratumumab intravenously on day 60, 69, 78 and 96 after stem cell transplantation. After this treatment the hemoglobin level stabilized, and we could detect an increase in the reticulocyte count (Figure 1). This was followed by a decrease of the anti-A titer. He did not require any red blood cell transfusion from day 75.

    

    

    Figure 1: The absolute reticulocyte count and hemoglobin levels are
presented during the timeline. Hemoglobin is presented as grams per liter
value and reticulocyte as giga per liter. The administration of Rituximab,
erythropoetin alpha and daratumumab is indicated by arrows on the stated
days after transplantation. Rituximab and erythropoetin alpha were not
benificial. Patient received 400 milligrams of daratumumab intravenously four
times on day 60, 69, 78 and 96 after stem cell transplantation. Thereafter
hemoglobin level stabilized, and the reticulocyte count is increased.