A literature review of the use of daratumumab in non-neoplastic immunologic disorders

Introduction

Non-neoplastic immune disorders span multiple disciplines—from hematology to neurology to rheumatology and beyond. Despite heterogeneity in presentation, these conditions share the feature of being caused by humoral immune activity. Autoimmune conditions result from failure of self-tolerance, where self-antigens become the target of immune responses (1). Diagnosis of these conditions often requires identification of causative antibodies. For example, the presence of anti-double stranded DNA aides in the diagnosis of systemic lupus erythematosus (SLE), and antibodies against the acetylcholine receptor signal a diagnosis of myasthenia gravis (2,3). Unlike autoimmune disorders, some antibody-mediated conditions, such as red blood cell (RBC) alloimmunization and antibody-mediated organ transplant rejection, arise from appropriate immune identification of and response to non-self-antigens but are no less unwanted (4,5).

Options to manage non-neoplastic immune disorders target all known aspects of the humoral immune response. There are no known methods to prevent initial self-antigen recognition in autoimmune disorders, and the only definitive method to prevent alloimmunization in transplant and transfusion recipients is to avoid exposure to non-identical or compatible antigens, which is not always feasible. Following onset of an antibody-mediated condition, traditional management approaches have focused on minimizing the impact of these antibodies via mechanical removal with plasmapheresis, antibody cleavage, and antibody effector activity blockade (e.g., with Fc receptor inhibition) (6-10). Efforts are also made to reduce antibody production through lymphocyte depletion. Although antibody-secreting plasma cells arise from B-cells, B- and T-cells are often the target for these therapies because helper T-cell co-stimulation can assist B-cell affinity maturation in lymphoid tissues (11,12). Therapies such as systemic corticosteroids, calcineurin inhibitors, mTOR inhibitors, antimetabolites, anti-thymocyte globulin, and traditional chemotherapies have been used to facilitate lymphocyte depletion (2,6,10,13,14). Disadvantages to all these approaches include their non-specific effects which can cause generalized immunosuppression and increased susceptibility to infections, non-infectious adverse drug effects, and, for some therapies, high ancillary resource requirements. For example, plasmapheresis requires specialized equipment and trained personnel which may not be universally available (15).

Monoclonal antibody (MoAb) therapies have seen increasing use in the treatment of non-neoplastic immune disorders because they (I) exhibit specific activity to immune receptors or proteins; (II) are easy to administer; and (III) have a favorable safety profile (16-18). Rituximab, an anti-CD20 MoAb therapy, revolutionized the treatment landscape of several antibody-mediated autoimmune and alloimmune disorders. In combination with other immunosuppressive agents, rituximab effectively removes CD20⁺ B-cells ideally before they have had the opportunity to mature into antibody-secreting plasma cells (19). However, mechanisms of resistance to rituximab have been described, and some patients exhibit persistent antibody-mediated pathology despite receiving rituximab (20). It has been theorized that antibodies produced by long-lived CD38⁺ plasma cells (LLPCs) play a prominent role in antibody-mediated disorders that are refractory to rituximab and other traditional immunosuppressive therapies (21-23). LLPCs do not express CD20 and are not susceptible to anti-CD20 therapy. Further bone marrow LLPCs exist in niches that promote long-term survival and durability (24).

Daratumumab, a novel anti-CD38 monoclonal IgG1 kappa therapy, has emerged as a promising therapy for refractory antibody-mediated disorders, where traditional immunosuppression and anti-CD20 therapies have been ineffective and persistent antibody production is thought due to CD38⁺ plasma cells (25). Daratumumab received accelerated Food and Drug Administration (FDA) approval in 2015 for the treatment of multiple myeloma (26). However, it has been increasingly applied “off-label” to treat refractory, non-neoplastic conditions. Clinical trials demonstrating the efficacy of daratumumab in these conditions have not been performed in large part because many are rare, rendering trials infeasible. Several case reports and case series have been published detailing the use of daratumumab in non-neoplastic conditions, though few current reviews have summarized these studies. Our objective was to highlight disease states with the most evidence supporting daratumumab use and to identify areas where daratumumab may be efficacious but require additional investigation. We present this article in accordance with the Narrative Review reporting checklist (available at https://aob.amegroups.com/article/view/10.21037/aob-24-23/rc).

Methods (see Table 1)

A literature search was conducted in PubMed utilizing the following MESH terms: (Daratumumab) AND (immune) with added restrictions of humans, English language, and date range January 1, 2015 to November 1, 2023. Articles were first screened by title and abstract. Preclinical animal studies, in vitro experiments, reviews, or reports with non-immunologic use intention were excluded. Instances of uncertainty were resolved through full manuscript review and discussion between authors. During full-text review of retained articles, additional reports were identified (i.e., bibliographic search). Extracted datapoints included indication, therapeutic agents used prior to daratumumab (referred to as “prior lines of therapy”), days to initiation of daratumumab, its dose and route, and response to daratumumab. Studies without these core datapoints were excluded. Responses to daratumumab were graded as complete response (CR), partial response (PR), or no response (NR) based on treatment response criteria for each condition as described by national societies, consensus guidelines, or foundational clinical trials (Table S1). Patient demographics (sex and age) and infusion reactions to daratumumab were recorded if available. Extracted data were analyzed according to diagnostic group (wherever 3 or more individuals had the same daratumumab use indication) and utilizing descriptive statistics. Nonparametric data are presented as medians with interquartile ranges.

Results

The initial search returned 192 reports of which 36 reports comprising 95 cases met initial inclusion criteria. Adjudication between authors led to exclusion of one report entailing 14 cases of pediatric nephrotic syndrome (27) leaving 35 reports comprising 81 cases. Of these cases, 2 reports with 3 duplicate cases (28,29) were identified and removed leaving 33 reports and 78 cases. Through bibliographic search, 17 additional reports comprising 21 cases were found for a total of 50 reports and 99 cases (Figure 1). Sex was reported for 83/99 (84%) and age for 95/99 (96%); 43/83 (52%) were female and the mean age was 36 years (range, 0.8–82 years).

Figure 1 Flowchart of article selection.

Published experience with daratumumab spanned several antibody-mediated conditions. Of included cases, 92/99 (93%) cases fell into 12 diagnostic groups containing 3 or more patients (Table 2): autoimmune hemolytic anemia (AIHA) (30-39), autoimmune cytopenias (AIC) (36,37,40,41), acquired hemophilia A (Acq Hem A) (11), myositis/myopathy/myasthenia (M/M/M) (42-44), immune thrombocytopenia (ITP) (37,45-47), cold agglutinin disease (CAD) (48-51), SLE (52,53), antibody mediated rejection (ABMR) (54-56), thrombotic thrombocytopenic purpura (TTP) (57-59), hemophilia A with inhibitors (60), pure red cell aplasia (PRCA) (61-70), and encephalitis (29,44,71). Seven of 99 cases fell into 5 diagnostic groups that contained 2 patients or less: RBC alloimmunization (72), human leukocyte antigen (HLA) alloimmunization (55,72), post-transplant hepatitis (73), antiphospholipid syndrome (74), and acquired von Willebrand disease (75) (Table 2).

Patients within the 12 diagnostic groups containing 3 or more patients received a median of 4 lines [interquartile range (IQR), 2 to 5 lines] of therapy prior to daratumumab. Prior lines of therapy were loosely grouped according to mechanism of action (Table 3). There were 370 total therapeutic use instances recorded (excluding daratumumab); 253 (68.4%) antibody/B-cell/plasma-cell directed therapeutics (Ab/B/PC), 45 (12.2%) immunosuppressants/anti-rejection agents (IS/AR), 28 (7.6%) disease specific and supportive therapies (Dz Spec), 22 (5.9%) antineoplastic/antimetabolites (AN/AM), 9 (2.4%) other MoAbs, 8 (2.2%) other agents, 5 (1.4%) kinase inhibitors (KI) (Table 4). Within the 12 diagnostic groups, the broadest array of therapeutic categories attempted were in treatment of AIHA, AIC, Acq Hem A, and M/M/M at 6/7; followed by ITP and CAD at 5/7, SLE at 4/7, ABMR and TTP at 3/7, and hemophilia A with inhibitors, post transplant PRCA, and encephalitis at 2/7 each (Table 4).

Most reported cases showed a positive response to daratumumab. The overall CR, PR, and NR response rates were 57/99 (58%), 31/99 (31%), and 11/99 (11%), respectively (Table 2). Any response therefore occurred in 88/99 (89%). Time to response could be assessed in 77/88 (88%) of responders and occurred at a median timepoint in days of 32 (IQR, 14 to 60). Durability of response was assessable in 81/88 (92%) of responders. Median duration of response was 270 days (IQR, 153 to 365 days). Presence or absence of disease recurrence could be assessed in 86/99 (87%) patients. Absence of disease recurrence during follow up was noted in 73/86 (85%), with recurrences in 12/86 (14%). Presence or absence of daratumumab-related acute infusion reactions could be assessed in 96/99 (97%) patients, of whom 11/96 (12%) experienced infusion reactions, which were generally mild. The delayed complication of hypogammaglobulinemia was specifically attributed to daratumumab in 12/99 (12%) patients (Table 5).

Response metrics for the 12 diagnostic groups mirrored that of the overall cohort (Table 6). Complete and partial responses were reported in 53/92 (58%) and 28/92 (30%) of cases, respectively, for a total response rate of 81/92 (88%). Median time to response with daratumumab was 28 days (IQR, 14 to 61 days), and responses were durable (median 270 days; IQR, 123 to 365 days). Mild infusion reactions occurred in 11 cases (11%) (Table 5). No severe allergic reactions or deaths due to daratumumab were reported.

Novel use of daratumumab as frontline therapy was reported in one series. Xie et al. described 5 patients with TTP who received daratumumab, corticosteroids, and TPE. Four out of 5 also received rituximab (59). Four of 5 patients experienced an initial clinical response with normalization of their platelet count prior to hospital discharge. Three patients achieved clinical remission. One patient relapsed, and one patient experienced an exacerbation. However, the latter two patients developed clinical remission after additional daratumumab, corticosteroids, and TPE. Of note, these patients were not part of a clinical trial and were treated in a non-US healthcare system.

Conclusions

We conducted a literature review of published cases describing off-label use of daratumumab for the treatment of antibody-mediated, non-neoplastic immune disorders. Most patients received daratumumab after they were deemed refractory to conventional therapy and had received 4 prior lines of therapy. Addition of daratumumab was associated with a significant overall response rate of 89% (58% CR and 31% PR). Overall, time to response was rapid—median 32 days, and durability of response prolonged—median of 270 days. Response durability was likely longer in most cases but limited by duration of follow up. Recurrence rates and immediate infusion reaction rates were low at 14% and 12%, respectively. Infusion reactions were mild, and, in most cases, subsequent doses were administered uneventfully.

CD38⁺ plasma cells may play a significant role in refractory antibody-mediated disorders. Specifically, LLPCs may be the dominant antibody-producing cells in patients who have been treated with anti-CD20 agents. Mahévas et al. [2013] demonstrated that LLPCs populated splenic tissues in 10 individuals with refractory ITP who had received anti-CD20 therapy. Notably, splenic tissue from 5 individuals who had not received anti-CD20 therapy but who experienced ITP for a similar duration showed mostly short-lived CD19⁺ plasmablasts (76). Analogous splenic studies performed in individuals with refractory warm AIHA despite anti-CD20 agents also demonstrated increased LLPCs (77). Taken together these studies suggest that administration of anti-CD20 therapy may provide selective pressure to shift the splenic antibody-producing cell milieu towards LLPCs. In these settings, daratumumab may be a reasonable second line therapy.

However, autoreactive plasma cells may persist in locations outside of the spleen which are difficult to access with traditional immunosuppression (78,79). Immature plasma cells (plasmablasts and short-lived plasma cells) which develop in peripheral germinal centers can migrate to the bone marrow, where they are thought to compete with pre-existing LLPCs for survival niches (80), although these processes are poorly understood (23). LLPCs in the bone marrow, which may exhibit greater longevity than LLPCs that develop in the spleen or other inflamed tissues, may contribute to refractoriness in autoimmune disorders (21-23). As immature plasma cells evolve to LLPCs, intermediate forms express CD38 and would likely be susceptible to daratumumab. Daratumumab-mediated plasma cell clearance occurs successfully in the bone marrow as demonstrated by clinical trial of its use in multiple myeloma (81). As noted in this work, most individuals with refractory autoimmune disorders responded to daratumumab, which suggests that these processes are driven CD38⁺ plasma cells and that daratumumab mediates plasma cell clearance in all niches.

Interestingly, daratumumab also demonstrated efficacy in conditions driven by alloimmunization, which is not a pathologic process per se but an expected immune response following exposure to foreign antigens. The effect of daratumumab on normal plasma cells is unclear and is difficult to evaluate in human subjects, who have received daratumumab for neoplastic processes. Frerichs et al. [2020] demonstrated a significant reduction in normal (non-clonal) plasma cell quantity from baseline to 3 months after initiation of daratumumab and at time of progression in bone marrow biopsy samples from 17 patients with relapsed/refractory multiple myeloma (RRMM) (82). The reduction in normal plasma cells corresponded to reductions in polyclonal IgA, IgM, and IgE levels, but not IgG. The authors speculate that the preserved IgG levels may be the result of a subset of normal plasma cells with reduced CD38 and CD19 expression following daratumumab treatment. Further, daratumumab-treated and naïve patients with RRMM showed similar, suboptimal responses to vaccination, which suggests that despite the inherent immune dysregulation in multiple myeloma, daratumumab does not further degrade the ability to produce normal IgG-producing plasma cells. These observations seem at odds with the findings in this study that daratumumab may be helpful in patients experiencing HLA alloimmunization. We propose several explanations for these observations. HLA antibody producing plasma cells may express CD38 more prominently than other LLPCs in the bone marrow niche and therefore may be more susceptible to daratumumab. Alternatively, HLA antibody-producing plasma cells may make up a smaller proportion of total bone marrow plasma cells. Thus, any loss in this population may result in significant decrement in HLA antibody production. Lastly, HLA antibody-producing plasma cells may be more often located in extramedullary locations with survival niches that are less robust than the bone marrow and therefore are more susceptible to clearance efforts.

Despite the lack of mechanistic understanding of daratumumab activity against normal plasma cells, experience with off-label use of daratumumab is expanding in the transplant community. Antibody-mediated phenomena can impede several steps of the transplant process for hematopoietic stem cell (HSC) and solid organ transplant: (I) ABO isohemagglutinins may cause delayed red cell engraftment in HSC; and solid organ rejection in ABO incompatible transplants; (II) HLA sensitization can narrow the potential donor pool, cause platelet refractoriness, and result in HSC or solid organ transplant rejection; and (III) minor red cell antigen alloimmunization may limit red cell availability for transfusion support. Many of these indications were the subject of published cases included in this review. In post-HSC transplant AICs, post-ABO incompatible HSC transplant PRCA, and HLA antibody-mediated solid organ transplant rejection, daratumumab administration resulted in an overall reported response rate of 92%. We may be able to rationalize these findings in the context of the discussion above. ABO isohemagglutinins are predominantly of IgM isotype, and as described above, IgM isotype normal plasma cells may be uniquely sensitive to daratumumab. In contrast, HLA antibodies are often of IgG isotype and would be predicted to be more difficult to eradicate. However, post-transplant HLA sensitization requires evolution of B cells to immature plasma cells and eventually to antigen-specific LLPCs. There may be many opportunities along this continuum for B- and plasma cell removal prior to establishment of the plasma cell in a durable survival niche. In these patients, daratumumab may be an effective addition to a multimodal anti-humoral rejection strategy.

Fewer cases described use of daratumumab in the pre-transplant setting. Desensitization may be difficult to achieve pre-transplant if HLA or RBC alloantibody production arises from LLPCs in durable survival niches, even with daratumumab use. Only one report detailed success with this approach. Pereda et al. described a case of HLA-immune platelet refractoriness in a patient with aplastic anemia who, after receiving daratumumab, could be supported with platelet transfusions and became eligible for haploidentical transplant (72). The same series described successful daratumumab use to reduce red cell alloimmunization in patients with sickle cell disease prior to allogenic HSC transplant (72). Notably, clinical trials in the United States are recruiting for pre-transplant use of daratumumab in HLA-sensitized renal transplant candidates (NCT04827979) and in sickle cell patients with red cell alloimmunization prior to stem cell transplant (NCT06358638). Data from these clinical trials, continued outcomes reporting, and pre-clinical animal models and in vitro studies will enhance our understanding of the effect of daratumumab on IgG isotype LLPCs and the utility of daratumumab in desensitization regimens.

Our review also identified several cases where daratumumab administration did not improve the underlying antibody-mediated condition or the underlying condition recurred despite initial response. In most of these cases, providers employed traditional B-cell depletion with rituximab prior to administration of daratumumab. Interval CD20⁺ B-cell quantitation to confirm depletion is not routinely reported; therefore, it is possible that initial “resistance” to daratumumab was due to incomplete CD20⁺ B-cell depletion or B-cell resistance to anti-CD20 therapy (20). Mechanisms of true resistance to daratumumab, where daratumumab fails to reduce antibody production from plasma cells or when initial response to daratumumab is followed by failure to respond on disease recurrence, in non-malignant conditions are unknown. In patients with multiple myeloma, downregulation of CD38 expression, upregulation of complement inhibitor proteins, and Fcγ receptor mutations play a role in daratumumab resistance (83-86). It is possible that these mechanisms, especially downregulation of CD38 expression, are occurring in normal, healthy or pathologic, autoreactive plasma cells that are exposed to daratumumab. Additional investigation of patients who are initially or subsequently refractory to daratumumab with flow cytometry from bone marrow samples (if available), plasma-drug concentration levels, and drug antibody studies may clarify mechanisms of daratumumab resistance. Understanding these mechanisms may better inform selection of patients who may most benefit from daratumumab and timing of daratumumab administration in the disease course.

Our study had several weaknesses. These include low sample size—particularly for individual disease groups—and the risk of publication bias. Generalization of these results to future cases should occur cautiously. Another weakness is adjudication of response. Autoimmune disorders may have resulted in significant end-organ damage by the time daratumumab was initiated. It therefore becomes difficult to assess clinical response. For example, recovery in the autoimmune myositis/myopathy cases were judged by improvement in strength as measured by an objective scale but were necessarily impacted by severe baseline impairment. Response criteria characterized by antibody detection only, may not capture clinically meaningful responses. In one instance of anti-NMDA-R mediated encephalitis—the clinical response persisted despite gradual re-emergence of antibodies (71). Additionally, standardized response definitions were not always available at the time of publication of each case. The authors sought to standardize response reporting through application of society recommended criteria or consensus definitions where available. For conditions without these the authors applied commonly used response criteria for clinical trials or best judgement to adjudicate responses. For cases which did not present all details included in the response criteria, the authors adjudicated responses with the information available. These adjudications would be expected to have the greatest impact on disease categories with the fewest included cases or where most cases came from the same publication. Lastly, not all included studies occurred in the United States, where insurers can dictate which patients are eligible for off-label therapies. Again, this could impact generalizability of these results to American providers.

In this literature review, we found that daratumumab is a promising therapy for the management of a wide variety of antibody mediated, non-neoplastic immune disorders. Daratumumab mediates removal of antibody-producing plasma cells, which may be responsible for pathologic antibody production in refractory immune conditions. Several case reports and series have been published demonstrating successful use of daratumumab for autoimmune and alloimmune disorders after multiple lines of conventional immunosuppression and anti-CD20 monoclonal therapy and with minimal infusion related-adverse effects. However, publication bias remains a concern. Building the evidence base for daratumumab use in these conditions will be essential to expand the labelled indications for this therapy and ultimately increase its availability for patients with persistent disease despite usual treatment. We encourage high-quality prospective study of daratumumab use in these settings. Baring these, we recommend continued reporting on daratumumab use, performance, and safety as these factors will inform its integration into treatment algorithms and guidelines for antibody-mediated, non-neoplastic immune disorders.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://aob.amegroups.com/article/view/10.21037/aob-24-23/rc

Peer Review File: Available at https://aob.amegroups.com/article/view/10.21037/aob-24-23/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://aob.amegroups.com/article/view/10.21037/aob-24-23/coif). M.H.T. serves as an unpaid editorial board member of Annals of Blood from May 2024 to April 2026. M.H.T. also received speaking and consulting fees from Sanofi for speaking engagements. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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