Pre-emptive Rituximab Prevents Long-Term Relapses in Immune-Mediated TTP

Patients with immune-mediated thrombotic thrombocytopenic purpura (iTTP) who have persistent, severe ADAMTS13 deficiency have a high likelihood of relapse, but pre-emptive treatment with rituximab reduced the long-term relapse risk by maintaining normal ADAMTS13 activity, according to research published in Blood, led by Mathieu Jestin, MD, from the Hôpital Saint-Antoine in Paris, reported.

“We established that the number of patients needed to treat to prevent a clinical relapse is only two, suggesting that our pre-emptive strategy using this B-cell depleting therapy is an attractive strategy to prevent most clinical relapses of iTTP,” study coauthor Paul Coppo, MD, PhD, also from the Hôpital Saint-Antoine, told ASH Clinical News. “This treatment strategy should profoundly modify the epidemiology of this disease.”

The study included 92 patients with iTTP in clinical remission who were prospectively enrolled in the French Reference Center for Thrombotic Microangiopathies network. Evaluable patients also had severe immunemediated ADAMTS13 deficiency (<10%).

To determine the effects of the preemptive treatment strategy, the researchers compared the median number of iTTP episodes and the median cumulative incidence of annual relapses in the 54 months (range = 45-82 months) preceding and the 35.8 months (range = 23.3-68) following pre-emptive rituximab.

Pre-emptive rituximab was administered at the following doses: 500 mg/m2 per infusion (n=13) or 375 mg/m2 per infusion (n=79).

In the period before pre-emptive rituximab was initiated, 37 patients had more than one iTTP episode (median = 3; range not reported), for a median cumulative relapse incidence of 0.33 episodes per year (range = 0.23-0.66).

After initiating the pre-emptive rituximab therapy, this incidence decreased to 0 episodes per year (range = 0-1.32; p<0.001).

The investigators also monitored ADAMTS13 activity starting 30 days after the first rituximab infusion and then systematically measured levels every three months until 24 months of follow-up. Patients were deemed unresponsive to therapy if they continued to demonstrate persistent severe ADAMTS13 deficiency for at least six months after the first rituximab infusion.

Thirty-four patients (37%) achieved sustained ADAMTS13 activity recovery during a median follow-up of 31.5 months (range = 18-65 months) after pre-emptive rituximab. “These patients required no further courses of rituximab and were therefore considered as long-term responders,” the authors reported.

Thirteen patients (14%) had undetectable ADAMTS13 activity after the first course of rituximab, and 19 patients (20.7%) experienced mild adverse effects (including pruritus, rhinitis, dyspnea, nausea and vomiting, hypotension, and arrhythmia). Ten received repeated rituximab administration; of these, four experienced persistent ADAMTS13 deficiency and six had recovery of ADAMTS13 activity.

Levels were eventually normalized with cyclosporine A in two of the three patients with severe ADAMTS13 activity after the first course of rituximab but remained undetectable in the remaining patient.

“In these patients, further studies [are needed] to define the best approach, particularly in regard to whether clinicians should intensify immunosuppression or use a tight watch-and-wait approach,” Dr. Coppo explained. “In this specific small group of patients, the risk-benefit balance of a more intensive immunosuppressive treatment needs additional evaluation.”

“An important message is that patients may need additional infusions of rituximab during follow-up, because anti-ADAMTS13 antibodies may reoccur along with peripheral B-cell recovery, leading to further decreases of ADAMTS13 activity,” Dr. Coppo said. “Therefore, iTTP should now be considered a chronic disease, and patients with a history of iTTP should be offered long-term follow-up with regular ADAMTS13 activity assessment.”

The investigators compared study participants’ ADAMTS13 activity with that of 23 historical controls who had persistent, severe ADAMTS13 deficiency and no history of pre-emptive rituximab. During a median follow-up of seven years (range = 5-11 years), their rate of clinical relapse was 74 percent, corresponding to a median cumulative incidence of relapse of 0.26 episodes per year (range = 0.19- 0.46). Again, these data suggest that pre-emptive rituximab reduced the risk of relapse, compared with no preemptive rituximab (p<0.001).

“Our hope is that this strategy will become widespread among the other groups involved in the management of iTTP and that it will lead to a substantial decrease of relapse of this debilitating disease worldwide,” Dr. Coppo said.

The researchers noted that participants were treated at different times in the course of their disease, which could potentially limit the study’s findings. “This raises the possibility that other changes in iTTP management could have affected the results,” they wrote. The small sample size also may limit the generalizability of the findings.

The authors report financial relationships with Alexion, Ablynx, Shire, and Octapharma.

Reference

Jestin M, Benhamou Y, Schelpe AS, et al. Preemptive rituximab prevents long-term relapses in immune-mediated thrombotic thrombocytopenic purpura. Blood. 2018 September 10. [Epub ahead of print]

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