Daratumumab in relapse-refractory immune-mediated thrombotic thrombocytopenic purpura: additional evidence for its efficacy

Preemptive strategies have substantially reduced clinical relapses in immune-mediated thrombotic thrombocytopenic purpura (iTTP) and thereby the inherent risk of death and potential comorbidities in survivors [1]. Historically, 36% of patients experienced iTTP relapses after a 10-year follow-up [2]. Following stratification of patients according to ADAMTS-13 activity, ADAMTS-13 relapses during follow-up (ie, the recurrence of a severe ADAMTS-13 deficiency in patients otherwise in clinical response) were associated with a subsequent clinical relapse in up to 75% of cases after a median follow-up of 7 years, whereas a preemptive strategy based on B-cell depletion with rituximab allowed a decrease in the rate of clinical relapse to 15% in these patients, thanks to a rapid improvement in ADAMTS-13 activity occurring typically after only a 30-day period following rituximab administration [3]. The mechanisms at work accounting for this efficient response are still speculative, but these could involve at least in part short-lived plasmablasts producing anti–ADAMTS-13 antibodies [4] having poor renewal capacities when upstream CD20⁺ B-cells are depleted with rituximab (Figure). These impressive results led to a rapid change in practices, and therapeutic recommendations now support the systematic use of preemptive rituximab in iTTP [5].

Figure.

Antibody-secreting cells involved in the production of anti–ADAMTS-13 antibodies and their epitopes targeted by therapeutic monoclonal antibodies. By targeting upstream B-cells, rituximab may also deplete short-lived plasmablast cells producing antibodies against ADAMTS-13, thereby providing a rapid and efficient improvement in ADAMTS-13 activity. On the opposite, long-lived plasma cells are specifically targeted by daratumumab.

In 4% to 12% of cases, however, patients are unresponsive to rituximab; moreover, half of responders need retreatment with rituximab for repeated relapses [3,6]. Factors influencing the occurrence of relapses are still poorly defined, but African ancestry, an open ADAMTS-13 conformation, and the number of previous rituximab courses were associated with a shortened ADAMTS-13 relapse-free survival [[7], [8], [9]]. Despite the possible use of subcutaneous rituximab to alleviate the burden of care and improve patient satisfaction [10], alternative strategies are needed when relapses are frequent. These mostly include more intensive regimens with rituximab inspired from maintenance therapies used in patients with B-cell indolent malignancies, second-generation humanized anti-CD20 monoclonal antibodies like obinutuzumab [11,12], cyclosporine A [13], and, more rarely, azathioprine and mycophenolate mofetil [14]. In recent years, the plasma cell–depleting agent daratumumab, a human immunoglobulin G 1k monoclonal antibody binding to a unique CD38 epitope and formerly developed in plasma cell malignancies, provided efficacy in autoantibody-mediated diseases, including autoimmune hemolytic anemia and rare cases of refractory patients with iTTP [15]. To date, however, data regarding this emerging strategy are scarce, and despite encouraging preliminary results, further experience is needed to confirm daratumumab as a valuable salvage therapy in patients with multiresistant iTTP.

In the present work, Schimmer et al. [16] reported their experience in the use of daratumumab from 8 episodes in 5 patients with relapsed or refractory iTTP, based on the rationale that patients unresponsive to B-cell depletion strategies could have long-lived plasma cells involved in the autoimmune process against ADAMTS-13. In this retrospective multicentre study, daratumumab was administered as a compassionate-use therapy in patients with either persistent ADAMTS-13 deficiency and detectable inhibitor despite rituximab, or a frequently relapsing disease course. The standard daratumumab regimen usually consisted of intravenous infusions at a dose of 16 mg/kg body weight administered weekly over 6 weeks; 1 patient was treated with subcutaneous daratumumab at a fixed dose of 1800 mg weekly during induction, followed by monthly maintenance injections. Daratumumab was initiated after a median of 5 months following the last rituximab administration, ensuring that late responses to rituximab were excluded. The major finding of this study is an overall response rate of 87.5%, reflecting an improvement in ADAMTS-13 activity in 7 of 8 episodes considered. Moreover, ADAMTS-13 activity reached protective levels rapidly, as median times from daratumumab initiation to partial and complete ADAMTS-13 responses were only 13 and 26 days, respectively. Response to daratumumab was sustained, as after a median follow-up of 44 months, the median ADAMTS-13 relapse-free survival was 32 months, and at 12 months, 87.5% of patients remained in ADAMTS-13 remission with a median time to next treatment of 19 months. Of note, reexposure to daratumumab was successful in 2 of 3 retreatment episodes. Daratumumab was well tolerated, with no infectious complications recorded. These findings are in line with previous reports [15,17], and with the longest follow-up reported to date in this setting, they further support the use of daratumumab as a valuable strategy in patients unresponsive to B-cell–depleting agents, but also more generally the rationale to target long-lived plasma cells in iTTP [18] (Figure).

From a perspective point of view, the results provided by Schimmer et al. [16] involve a small group of patients (as in the majority of cases, patients with iTTP are responsive to B-cell–depleting agents) who have, otherwise, a rare disease; consequently, conclusions need to be further strengthened to reach higher levels of evidence. This aspect is a general issue in the field of rare diseases that requires the challenging approach of conducting concerted international programs through clinical trials and real-world evidence studies. However, it proved to be feasible for a rare disease like TTP [19,20]. Therefore, no doubt that in the near future, similar studies will ultimately better define the optimal sequence of therapy in patients with iTTP unresponsive or intolerant to rituximab [14], which is a key aspect in the field.