Daratumumab for immune-mediated thrombotic thrombocytopenic purpura (iTTP): Results from the international, multicenter darttp study

Abstract

Abstract Background and Methods: approximately 15% of patients with iTTP fail to achieve a sustained ADAMTS13 remission with rituximab or other immunosuppressants (IST), which are often burdened by relevant toxicity. Targeting CD38-positive, CD20-negative long-lived plasma cells with daratumumab appears to be a promising strategy in this scenario. However, evidence stems only from very limited case series. Here we present the preliminary results of an international, multicentric, retrospective study on the use of daratumumab in iTTP patients who are refractory/intolerant to other IST. We included adult iTTP patients receiving daratumumab in the acute or remission phase with a post-treatment follow-up >6 months. The primary endpoint was the proportion of responders (i.e., patients with ADAMTS13 activity >20% of normal after daratumumab treatment without additional IST). Secondary endpoints were the proportion of sustained responders (i.e., response lasting >6 months), median time to ADAMTS13 remission and median duration of ADAMTS13 remission, and number and type of daratumumab-related adverse events. Data were collected in a dedicated electronic CRF on the REDCap platform. Results: 20 iTTP patients [median age 51.6 years, interquartile range (IQR) 20; 75% females; 85% white ethnicity] followed at 7 European Centers were enrolled. Among comorbidities at enrollment, 40% of patients had cardiovascular risk factors, and 3 had experienced an arterial thrombotic event. Daratumumab was administered at a median of 9.7 years (IQR 11.6) from iTTP diagnosis, after a median of 4 (IQR 4) acute episodes and 1 (IQR 3) ADAMTS13 relapse. Patients had received a median of 3 (IQR 2) previous IST, including rituximab (100%), bortezomib and mycophenolate (25% each), cyclosporine and cyclophosphamide (20% each), azathioprine (15%), vincristine (10%), obinutuzumab, ofatumumab, and splenectomy (5% each). Seventeen patients received daratumumab in the remission phase (i.e., for ADAMTS13 relapse or intolerance to other IST), while 3 during an acute episode (plasma-based therapy and caplacizumab ongoing in 3 and 2 patients, respectively). The reason to start daratumumab was refractory disease (N=11), short-lasting response to rituximab (N=5), or toxicity to previous IST (N=4). A median of 4 (IQR 4) doses of daratumumab was administered (N=11 16 mg/kg intravenous, N=9 1,800 mg subcutaneous). Fifteen of 20 patients achieved response (75%), including 11 ADAMTS13 complete and 4 ADAMTS13 partial remissions. Response was reached after a median of 26 days (IQR 27) from the first infusion, and was sustained in 10/15 responders (one patient on monthly maintenance infusions). All 4 patients treated for previous toxicities responded (100%), while response occurred in 8/11 refractory patients (73%) and 3/5 patients with a short-lasting response to rituximab (60%), among whom only 1/3 had a sustained response. Disease duration, previous IST used, daratumumab schedule, or demographics did not correlate with response or its duration. During a median follow-up of 17.6 months (IQR 16.2) no deaths occurred. ADAMTS13 remission lasted for a median of 11 months (IQR 10.7, median ADAMTS13-relapse free survival not reached), and 5 ADAMTS13 relapses were reported: daratumumab was effective in 1 of 2 re-treated patients. In the whole cohort, 2 clinical relapses occurred: 1 in a daratumumab responder and 1 in a non-responder. Regarding safety, 8 patients experienced daratumumab-related immediate infusion reactions (N=6 grade 1, N=1 grade 2, N=1 grade 3), independently from the use of premedication but more common in intravenous (63%) than subcutaneous (10%) administration (p=0.02). Antimicrobial prophylaxis was employed in 6 patients (N=6 antiviral, with anti-Pneumocystis in 3/6). A patient not receiving acyclovir had a grade 2 zoster skin infection 3 months after her last daratumumab infusion.Conclusions: in this study, daratumumab warranted rapid ADAMTS13 remission in 75% of iTTP patients refractory or intolerant to rituximab and other conventional IST. Sustained remission was observed in two-thirds of responders, although less frequently in patients with an already short-lasting response to rituximab. The safety profile was manageable, with mild infusion reactions more common with intravenous than subcutaneous administration. These findings support the use of CD38-directed monoclonal antibodies in challenging iTTP cases, warranting prospective evaluation in clinical trials.