ISSN 1866-8836
Клеточная терапия и трансплантация

Daratumumab in post-transplantation pure red cell aplasia in adults

Ksenia S. Tsvirko, Yuriy N. Kuznetsov, Irina K. Golubovskaya, Anna G. Smirnova, Elena E. Lepik, Zarema K. Abdulkhalikova, Nikolay Y. Tsvetkov, Olga V. Pirogova, Ivan S. Moiseev, Alexander D. Kulagin

RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia


Correspondence:
Dr. Ksenia S. Tsvirko, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, L. Tolstoy St. 6-8, 197022, St. Petersburg, Russia
Phone: +7 (923) 575-70-56
E-mail: Ksenia_Kud_@mail.ru


Citation: Tsvirko KS, Kuznetsov YN, Golubovskaya IK, et al. Daratumumab in post-transplantation pure red cell aplasia in adults. Cell Ther Transplant 2024; 13(1): 28-33.

doi 10.18620/ctt-1866-8836-2024-13-1-28-33
Submitted 10 January 2024
Accepted 01 March 2024

Summary

Post-transplant pure red cell aplasia (PRCA) is a rare complication that occurs after allogeneic hematopoietic stem cell transplantation (allo-HSCT) with ABO incompatibility. In most cases, this condition resolves without any treatment. However, in some patients, PRCA can persist for a long time, worsening the quality of life and somatic status. There is currently no consensus on the treatment of PRCA: previously used therapeutic options have limited application in the post-transplant period and low pathogenetic validity. In this article, we present a series of clinical cases of PRCA treatment with daratumumab, a monoclonal IgG1k anti-CD38 antibody.

Keywords

Hematopoietic stem cell transplantation, allogeneic, pure red cell aplasia, post-transplant, daratumumab.


Introduction

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment for a wide range of malignant and non-malignant diseases [1]. The selection of a donor of hematopoietic stem cells is based on compatibility of the major histocompatibility complex (HLA) class I and II genes [2], ABO compatibility is usually a minor factor when selecting a donor. As shown in a number of studies, ABO incompatibility does not significantly affect overall and disease-free survival in allo-HSCT [3-7]. However, it can cause a number of serious complications, such as post-transplant pure red cell aplasia (PRCA), leading to a significant deterioration in the patient’s somatic status and quality of life [3].

Three types of ABO incompatibility are discerned, i.e., minor, when the recipient is transfused with graft containing anti-A and anti-B antibodies; major, when the recipient’s plasma contains anti-A and anti-B antibodies, and combined incompatibility, with presence of anti-A and anti-B antibodies both in donor graft and recipient’s plasma [6]. According to the literature, ABO – incompatible allo-HSCT accounts for 25-50% of all transplantations [6-8], with 7-30% of these patients developing PRCA [7, 9-11].

PRCA is characterized by persistent normochromic anemia, severe reticulocytopenia and deep suppression of erythroid lineage in the bone marrow [9, 12]. The pathophysiology of PRCA involves inhibition of donor erythroid progenitors by persistent recipient-derived antibodies that may be produced by residual long-lived plasma cells. [9, 13]. The average duration of this condition without specific treatment is 60-90 days, however, in some cases PRCA may continue for a longer time period [14]. It should be noted that the patients are transfusion-dependent over the entire period of PRCA thus increasing the duration of hospitalization and leading to iron overload with development of organ hemochromatosis. Currently, there is no consensus for the PRCA treatment, mainly, due to variability of proposed therapeutic options (glucocorticoids, plasmapheresis, monoclonal antibodies (anti-CD20) rituximab, infusion of donor lymphocytes, bortezomib) and their limitations for use in the post-transplant period [15-18]. The time frame for initiating specific treatment has been not yet determined. A number of studies recommend to decide on the initiation of therapy on the basis of changes in the levels of anti-A and anti-B antibodies [13, 14]. Taking into account the source of antibody production, the most reasonable principle for PRCA treatment is the depletion of long-lived plasma cells in the recipient. This hypothesis is confirmed by published clinical cases of successful use of the anti-CD38 monoclonal antibody daratumumab in PRCA [19-24].

The aim of the present article was to describe our clinical experience with usage of daratumumab in the patients with long-term persistence of PRCA.

Patients and methods

The study was performed at RM Gorbacheva Research Institute, Pavlov University, St. Petersburg, Russia over 2021 to 2022. A retrospective single-center study included 5 patients. The inclusion criteria were as follows: past allo-HSCT, major ABO incompatibility, documented clinical PRCA pattern, therapy with daratumumab.

The male to female ratio was 3:2, the median age was 35 (range, 25-48) years, the median follow-up period since the PRCA development was 921 (range, 381-1515) days. Detailed characteristics of the patients are presented in Table 1. PRCA was established when myeloid, lymphoid and megakaryocyte lineages were determined in absence of erythropoietic precursors (erythroblasts) in the bone marrow aspirate combined with reticulocytopenia (<10 000/ μL) in peripheral blood, upon the exclusion of other causes, e.g., infections, hemolysis, disease relapse and drug toxicity. The complete hematological response was defined by normal hemoglobin levels without transfusions and the reticulocyte level of >30 000/μL, and erythroid lineage cells of >14.5% at bone marrow cytology examination. Partial hematological response was registered at hemoglobin level of ≥100 g/L, or its increase by, at least, 20 g/L compared to the pre-treatment level in the absence of blood transfusions, at reticulocyte levels of 10 000 to 30 000/μL, erythroid lineage cells of more than 1%, but <14.5% at the cytology examination. Non-responders are those who do not meet the criteria for complete or partial response. Early reticulocyte response was determined at reticulocyte level of more than 30 000/μL during the first week after starting therapy; delayed response was defined as reaching the reticulocyte levels of >30 000/μL after 21 days of treatment.

Table 1. Clinical characteristics of patients

Tsvirko-tab01.jpg

Abbreviations: PRCA, post-transplant pure red cell aplasia; AML, acute myeloid leukemia; NHL, Non-Hodgkin Lymphoma; AA, aplastic anemia; R, recipient; D, donor; F, female; M, male; TPE, therapeutic plasma exchange; IVIG, intravenous immunoglobulin; RTX, rituximab; MSD, matched sibling donor; MUD, matched unrelated donor; CML, chronic myeloid leukemia; MAC, myeloablative conditioning; RIC, reduced intensity conditioning; Cy, cyclophosphamide; MMF, mycophenolate mofetil; Tac, tacrolimus; CsA, cyclosporine A; MTX, methotrexate; ATG anti-thymocyte globulin; CS, corticosteroids; BORT, Bortezomib; Dara, Daratumumab; CR, complete remission

Clinical case 1

A 31-year-old woman with aplastic anemia and paroxysmal nocturnal hemoglobinuria (AA/PNH) received allo-HSCT from an HLA-identical related donor. Due to active hemolytic PNH eculizumab was used (D-8, D-1 before allo-HSCT).

Recovery of granulocyte counts was recorded on D+18 and the megakaryocytic lineage has restored on D+19 after allo-HSCT. In the early period, reactivation of herpes virus type 6 was detected, for which therapy with valganciclovir was carried out. In the control bone marrow aspirate at D+47, there were no detectable erythroid lineage cells, along with single megakaryocytes, and mixed donor chimerism (80-89%). Over time, a progression in neutropenia and thrombocytopenia was noted, thus requiring administration of granulocyte colony-stimulating factor (G-CSF) and a thrombopoietin receptor agonist. Clinical effect showed up in partial restoration of the two lineages, but deep hyporegenerative anemia with high transfusion dependence still remained. Based on clinical and laboratory data, PRCA was diagnosed. Intravenous immunoglobulins were used as first-line therapy with no response. Usage of other therapeutic options was limited by the persistence of herpesvirus infection. The patient’s status did not change following resolution of viral infection: the blood counts at D+180 from allo-HSCT presented with severe anemia, grade 2-3 thrombocytopenia, grade 2-3 neutropenia, scarce erythroid lineage cells in bone marrow aspirate (<1%), mixed donor chimerism. With respect to persistent cytopenia, a course of therapy with rituximab was carried out, but without clinical effect. Subsequent lines of therapy (pulse therapy with dexamethasone, bortezomib) were also not effective. Due to the refractory course of PRCA, a decision was made to use daratumumab, an anti-CD38 monoclonal antibody. In order to achieve faster response in PRCA, 2 plasma exchange sessions were performed at weekly intervals (D+490, 498), followed by 2 injections of daratumumab at a dose of 16 mg/kg (D+501, 508).

During the first administration, the development of an infusion reaction in the form of skin itching and accommodative dysfunction was noted which resolved after adjustment of drug infusion rate, with full dose administered. At the 2nd administration, no adverse reactions were registered. Increased reticulocyte counts were recorded 3 days after the start of daratumumab therapy with achievement of blood transfusion independence since D+502. Erythroid lineage was restored in the control marrow aspirate 2 months later, and full donor chimerism was achieved. A complete response was recorded at D+670 from allo-HSCT. Remarkably, the granulocyte and platelet counts also restored to normal values after the treatment. At the time of the last contact with the patient (D+1500), the response was maintained; no significant infectious complications were noted.

Clinical case 2

A 48-year-old patient with acute myeloid leukemia underwent peripheral blood stem cell transplantation from an HLA-matched unrelated donor with major ABO incompatibility. The leukocyte engraftment was recorded at D+18; platelet recovery was observed at D+20, and complete donor chimerism was achieved at D+30 after allo-HSCT. The early post-transplant period was complicated by reactivation of cytomegalovirus (CMV) infection with a complete response to valganciclovir therapy. According to the bone marrow cytology at D+22, D+60, D+100, erythroid lineage was reduced to 1%, and the blood counts showed severe anemia. PRCA was diagnosed since other possible causes of anemia were excluded. Therapy with rituximab was initiated (D+464) without effect. By D+570, the erythroid lineage was restricted to <1%, with persistence of deep hyporegenerative anemia requiring RBC transfusions (one dose every 2-3 weeks). A resistant course of PRCA was established, and therapy with daratumumab was decided. As in case 1, two plasma exchange sessions were performed immediately before the drug administration (D+575, 581), followed by two infusions of daratumamab 16 mg/kg (D+586, +593) without any adverse events. A reticulocyte response was recorded a 1 week after the first administration of the drug, complete hematological response developed at D+634. During the follow-up examination at D+1515 after allo-HSCT, the blood counts were within normal ranges, and no significant infectious complications were observed.

Clinical case 3

A 35-year-old man diagnosed with acute myeloid leukemia underwent an allogeneic transplant from an HLA-identical unrelated donor. The early post-transplant period (D+15 after allo-HSCT) was complicated by the reactivation of CMV infection, and therapy with ganciclovir was initiated. On D+19 after allo-HSCT, recovery of leukocytes was recorded; on D+21 there was a significant reduction of erythroid lineage to 0.6%, along with complete donor chimerism in the control bone marrow aspirates, and no manifestations of the underlying disease. On D+41, a complete response to CMV was obtained, but severe anemia with high dependence on transfusions, reticulocytopenia, and grade 3-4 thrombocytopenia still persisted at D+100 after allo-HSCT. Thus, PRCA was diagnosed on the basis of clinical and laboratory data. In view of expected spontaneous resolution of this condition and potential undesirable complications of specific therapy, it was decided to continue monitoring the patient. However, dependence on RBC transfusions (once every 2 weeks) and thrombocytopenia remained by D+200 after allo-HSCT. As part of first-line therapy, 2 injections of daratumumab were performed at a dose of 16 mg/kg on D+205, 212 after allo-HSCT. At the first administration, an infusion reaction with transient accommodative dysfunction developed, which resolved after adjustment of the infusion rate. The reticulocyte response was recorded at D+21. According to the results of a bone marrow cytology, the erythroid lineage was 50.2% on D+226. A complete response was achieved at D+234 and remained to the last follow-up (D+921). Restoration of platelet levels to normal values was also achieved.

Clinical case 4

A 39-year-old man diagnosed with chronic myeloid leukemia (CML) underwent an allogeneic transplant from an HLA-identical unrelated donor. The patient had refractory CML in accelerated phase before allo-HSCT. On D+20 after allo-HSCT, recovery of leukocytes was recorded, bone marrow examination on D+21 after allo-HSCT showed complete donor chimerism with negative minimal residual disease (Bcr-abl transcript) status and no erythroid lineage cells.

At D+54 severe anemia remained with dependence on RBC transfusions (1-2 doses per week), grade 3-4 thrombocytopenia, reticulocytopenia, erythroid lineage of 0.4%, Upon exclusion of other possible causes of anemia, PRCA was diagnosed. Due to persistent anemia, reticulocytopenia, blood transfusion dependence (1-2 times a week), 2 injections of daratumumab were performed as a part of first-line therapy, at a dose of 13 mg/kg on D+113 and D+120 after allo-HSCT; both injections were tolerated well.

On D+163 blood transfusion independence was achieved. The reticulocyte response was recorded at D+167 after allo-HSCT. According to results of the bone marrow cytology, the erythroid lineage comprised 21.8%. However, a complete response of PRCA was not achieved; the maximum value of hemoglobin level of 109 g/L was recorded on D+201.

At D+131 after allo-HSCT, the patient developed severe chronic skin GvHD, which required modification of immunosuppressive therapy. On D+190 severe chronic lung GvHD was diagnosed, which required further 2nd line immunosuppression. Since D+223 the patient had multiple infectious episodes (reactivation of CMV, herpes virus type 6, pneumonia, development of probable pulmonary aspergillosis) and died on D+381 after allo-HSCT.

Clinical case 5

A 25-year-old man with non-Hodgkin lymphoma underwent an allogeneic transplant from an HLA-identical unrelated donor. On D+26 recovery of leukocytes was recorded, a control bone marrow aspiration showed no erythroid lineage cells; complete donor chimerism was established. Therefore, based on clinical and laboratory data, PRCA was diagnosed. On D+31 acute skin GvHD developed with complete resolution on topical steroids. On D+68, a relapse of the underlying disease without bone marrow involvement was detected; therapy with ceritinib and crizotinib induced a complete metabolic response on D+120. Due to persisting PRCA, the patient received first-line therapy with 2 injections of daratumumab at a dose of 12 mg/kg (D+110 and D+117) which were well tolerated without immediate adverse reactions. The reticulocyte response was recorded at D+135; bone marrow cytology showed 16% of erythroid lineage. RBC transfusion independence was registered at D+148 after allo-HSCT. A complete response according to PRCA was achieved at D+271 and persisted at the last follow-up (D+549).

Discussion

Fig. 1 summarizes the clinical course and outcomes in all 5 patients with post-transplant PRCA treated with daratumumab. An early reticulocyte response after the first dose was observed in three cases. Two patients experienced a delayed reticulocyte response and achieved transfusion independence 1-1.5 months after the second administration of daratumumab. The rapid achievement of response supports the hypothesis that removal of residual long-lived host plasma cells results in curation of PRCA. Selective elimination of plasma cells with a monoclonal anti-CD38 antibody proved to be superior to previously used therapeutic options. One should also note a low toxicity profile of daratumumab known from clinical experience with multiple myeloma patients. However, there is a high risk of developing infectious complications [25-27]. Currently, there is insufficient data on the use of daratumumab after allo-HSCT and assessing its effect on GvHD [28, 29]. Among our patients, severe GvHD and significant infectious complications developed in one case, thus requiring further study of the effectiveness and safety, possible immunomodulatory effects of daratumumab. Also, two out of five patients developed a complication in the form of transient accommodative dysfunction. Meanwhile, PRCA may resolve spontaneously and no rapid response was observed in two cases, with therapeutic options administered between D+100 and D+200 after allo-HSCT. Therefore, it is difficult to assess whether the resolution of PRCA is related to the therapy or a spontaneous remission occurred.

Tsvirko-fig01.jpg

Figure 1. Clinical course and outcomes in the patients with post-transplant PRCA treated with daratumumab

Abbreviations: PRCA, posttransplantation pure red cell aplasia; RetResp, Reticulocyte response; CR, complete response; PR, partial response; TPE, therapeutic plasma exchange; IVIG, intravenous immunoglobulin; RTX, rituximab; CS, corticosteroids; BORT, Bortezomib; Dara, Daratumumab.

Conclusion

To assess the efficiency and safety of daratumumab in PRCA therapy and to determine the minimally effective dose, one should further accumulate clinical data with inclusion of a large number of transplant centers, due to low incidence of this post-transplant complication.

One should note that the concept of depletion of long-lived plasma cells is also promising in treatment of other hematological diseases associated with allo- and autoantibody mechanisms, such as autoimmune hemolytic anemia and immune thrombocytopenic purpura, as demonstrated by a number of clinical cases [22, 30], and a positive effect in systemic autoimmune conditions cannot be ruled out [31].

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Volume 13, Number 1
03/31/2024

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doi 10.18620/ctt-1866-8836-2024-13-1-28-33
Submitted 10 January 2024
Accepted 01 March 2024

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