Daratumumab in rituximab‐refractory autoimmune haemolytic anaemia

Abstract

Autoimmune haemolytic anaemia (AIHA) is an autoantibody-mediated autoimmune disorder characterized by red blood cell (RBC) destruction by the host’s immune system. In warm-type AIHA, immunoglobulin type G (IgG), or rarely A (IgA), directed to surface antigens on RBC leads to haemolysis, often with a panreactive, mostly anti-Rhesus, antigen specificity. If platelets are affected additionally, it is called Evans syndrome.1 AIHA may manifest as a primary or secondary disease, such as a complication of various inflammatory or neoplastic conditions or after allogeneic stem cell transplantation (ASCT).2, 3 Traditional treatment options for AIHA as well as other autoimmune diseases include steroids, immunoglobulins, cyclophosphamide or surgical splenectomy.2, 3 However, they do not specifically target autoantibody production, but rather induce broad immunosuppression and are frequently associated with significant side effects themselves.4 In this retrospective analysis, we report four patients with refractory, warm-type AIHA, successfully treated with the anti-CD38-antibody daratumumab after insufficient response to the anti-CD20-antibody rituximab. In the early stages of autoimmunity, autoreactive B-cells (CD20+, CD38−) are thought to expand and quickly give rise to autoantibody production, boosting inflammatory activity.5 Rituximab targets the CD20+ B-cell-compartment and is broadly used in the treatment of autoantibody-mediated autoimmune diseases, such as AIHA.6 However, a significant proportion of patients still relapses and/or shows insufficient response. This might be due to autoantibody-producing plasma cells without CD20-Expression (CD20−, CD38+) which arise from B-cells, especially in the later stages of autoimmunity, and then maintain antibody production.5 The plasma cell compartment is only insufficiently targeted by rituximab or conventional immunosuppression.7 Consequently, the use of daratumumab seems reasonable and has been shown to be effective in single case reports of AIHA and other autoantibody-mediated autoimmune diseases.8-11 Patient characteristics are shown in Table I. All four patients presented with warm-type AIHA, defined as progressive anaemia with a positive direct antiglobulin test (DAT) and laboratory signs of haemolysis: high serum levels of lactate dehydrogenase (LDH), bilirubin, reticulocyte count and suppressed haptoglobin.2, 3 All patients had a positive DAT with anti-IgG (additionally with anti-C3d in patient 1, anti-C3d and anti-IgA in patient 4). In patient 3, AIHA co-occurred with severe immune thrombocytopenia (ITP; platelet count <20 g/l). All patients received multiple transfusions from diagnosis to the first dose of daratumumab (median 40, range 4–71). Before daratumumab was administered, an underlying active lymphoproliferative disorder was excluded by means of physical examination, laboratory evaluation, computed tomography and bone marrow examinations. Patients 1 and 2 had undergone ASCT in the past, patient 1 with ABO minor blood group incompatibility. While patient 1 had insufficiently controlled graft-versus-host disease, patient 2 had a relapse of chronic myelomonocytic leukaemia associated with the occurrence of AIHA. In patients 3 and 4, no underlying disease was detected despite an extensive search. All patients were heavily pretreated with multiple treatment approaches following existing evidence,2, 3 all including rituximab (Table I). A median of 43 months after diagnosis (range 20·5–73·3 months), all patients were treated with daratumumab at a dose of 16 mg/kg. Ongoing AIHA-directed co-medication at this point is listed in Table I. Daratumumab was repeated approximately every week for a maximum of six doses. One patient’s therapy was stopped after three administrations because of a very good response.3 In two patients, therapy was temporarily interrupted after two doses for the same reason and later completed because of imminent relapse.3 Patient 3 later received another six doses of daratumumab as maintenance at an external hospital (Figure S2). Access to daratumumab was provided via a compassionate use programme, which covered a maximum of six doses. Response to treatment was assessed by an increase in the haemoglobin level, reduction in laboratory signs of haemolysis (LDH, bilirubin) and transfusion need, as recommended by international consensus guidelines.3 The ITP response in patient 3 was assessed via an increase in platelet count.12 Furthermore, time to next treatment line was documented. All patients gave informed consent to participation, according to the local institution's practice. The local ethics committee provided approval for the study (BASEC number 2020-03062). After the first dose of daratumumab, the number of transfusions required decreased from a median of 40 (range 4–71, from AIHA-diagnosis to first daratumumab) to a median of 1 unit (range 0–3, from the first daratumumab dose to the end of follow-up). Two of those transfusions were administered soon after the start of therapy (Fig 1). After the last dose, only patient 1 needed another RBC transfusion. To varying degrees ,the highest levels of LDH and bilirubin decreased (Fig 1) in all four patients, while levels of haemoglobin (Fig 1) and thrombocytes increased (Figure S1). During follow-up, no major side effects of daratumumab or infections were observed. Patients 1 and 2 both received repeated immunoglobulin substitutions before and after daratumumab because of secondary hypogammaglobinaemia after ASCT. The other two patients showed normal total immunoglobulin G levels throughout follow-up. The intensity of DAT decreased in three of the four patients; no disease-specific antibody levels were measured. Median follow-up after the last dose of daratumumab was 360 days (range 87–492 days). During follow-up, patients 2 and 3 had sustained disease control (patient 3 with daratumumab “maintenance”). Patients 1 and 4 showed a clinically significant relapse2 and required an alternative treatment 58 and 163 days respectively after the last daratumumab-administration (Table I and Figure S2). This retrospective analysis demonstrates a fast benefit of daratumumab in four patients with rituximab-refractory, warm-type AIHA, irrespective of previous therapies. The data support results from previously published single case reports8, 9 and is one of the first to also include AIHA-patients without a history of ASCT. Daratumumab was well tolerated and no major side effects were observed. The immediate benefit of daratumumab in this heavily pretreated cohort might best be explained by the targeted depletion of long-living autoantibody-producing plasma-cells5, 7 (CD20−CD38+) that did not respond sufficiently to previous immunosuppression and anti-CD20-directed therapy. Daratumumab leads to a fast reduction of autoantibody production and, thus, may reduce autoimmune activity.7, 13, 14 Nevertheless, two patients relapsed during follow-up and required additional therapy, which could be explained by the re-expansion of memory B-cells (CD20+CD38−) that then differentiate into new plasma cells and lead to a new increase of autoantibody production. Consequently, a combined anti-CD20/CD38 approach would possibly be of even greater benefit in the treatment of chronic autoimmunity. In addition, because of the only transient reduction of antibody levels, the effect of daratumumab might have been more durable if therapy had been continued longer, as established in the treatment of plasma cell myeloma.15 SMS was supported by the Jacques and Gloria Gossweiler Foundation. MJR and SMS designed the research project, collected and analyzed the data and wrote the manuscript. SL, TB, MB, CW, RS, GN, AM, IH, MGM and US revised the paper critically and participated in the final data analysis. All authors read and approved the final manuscript. All authors report no competing financial interests. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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