Efficacy and Safety of Obinutuzumab in Immune-Mediated Thrombotic Thrombocytopenic Purpura

Abstract

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare form of thrombotic microangiopathy (TMA) caused by an autoantibody-mediated deficiency of the von Willebrand factor (vWF) cleaving protease ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin-1 motifs, 13th Member) [1]. Without treatment, the disease is almost always fatal. In the last decades, the combination of therapeutic plasma exchange (TPE), corticosteroids, the chimeric anti-CD20 B-cell depleting monoclonal antibody rituximab and the anti-vWF nanobody caplacizumab, resulted in an improvement of survival rate, now exceeding 90% in the acute phase [2, 3]. However, relapses may occur during follow-up, exposing patients to death and treatment-related complications while increasing the burden of care. To circumvent these issues, a regular monitoring of ADAMTS13 activity during follow up, and the use of preemptive rituximab treatment in patients experiencing a severe ADAMTS13 deficiency (ADAMTS13 relapse) became a standard of care [3-5]. However, up to 15% of patients fail to improve ADAMTS13 activity following rituximab treatment; moreover, patients can develop adverse events, including immediate infusion intolerance or later serum sickness. In this context, alternative therapeutic options are needed, while evidence-based experience or direct comparisons of possible agents are scarce.

Obinutuzumab (Gazyvaro, Roche) is a type 2 humanized anti-CD20 monoclonal antibody, glyco-engineered to potently induce direct death of CD20-positive cells. Obinutuzumab proved to be efficient in various B-cell malignancies even following previous rituximab treatments, as well as in autoimmune diseases, where rituximab was contraindicated due to either resistance or intolerance. In iTTP, case reports and small series of patients suggested an efficacy for obinutuzumab in patients with intolerance or refractoriness to rituximab [6]. Here, we report from a large series of patients more definitive evidence that obinutuzumab is efficient and safe in preventing relapses in iTTP patients experiencing refractoriness or intolerance to rituximab.

Data on patients with a diagnosis of iTTP treated with obinutuzumab in the registry of the French Thrombotic Microangiopathies Reference Center (www.cnr-mat.fr) have been collected according to a predefined computerized dataset. Treatment of iTTP in the acute phase was based on current national and international guidelines [2-5]. Obinutuzumab was used as a compassionate off-label therapy; it was considered in patients with a persistent severe ADAMTS13 deficiency despite the use of rituximab, combined or not with other immunomodulators, or in patients with an ADAMTS13 relapse and intolerance to rituximab. Persistent severe ADAMTS13 deficiency was defined by an ADAMTS13 activity < 20% on at least two consecutive time points, on patients usually assessed for ADAMTS13 activity every month when ADAMTS13 activity is < 20%. All indications of obinutuzumab were extensively discussed through a national monthly advisory board, on which national experts of the French reference center for thrombotic microangiopathies (CNR-MAT) provide recourse advices for the most challenging patients. Obinutuzumab was administered as an intravenous infusion of 1000 mg; the first dose was administered in 2 days: 100 mg on the first day and 900 mg on the second day intravenously (the 1st and 2nd day was counted as one infusion in the description of treatment); subsequent doses were administered as single 1000 mg infusions, typically at Day-8, Day-15, Day-28 and eventually day-56. Premedication before obinutuzumab consisted in paracetamol, antihistamine and corticosteroid. To evaluate the efficacy of obinutuzumab, we determined both the clinical and ADAMTS13 relapse-free survival (RFS) as the time from first obinutuzumab administration to clinical relapse, or to ADAMTS13 relapse (ADAMTS13 activity < 20% in patients otherwise in clinical remission), respectively. Partial or complete ADAMTS13 response was defined by an improvement of ADAMTS13 activity ≥ 20% or ≥ 50%, respectively. ADAMTS13 activity and anti-ADAMTS13 antibodies were assessed before treatment and during follow-up, usually weekly for 1 month after the course of treatment with B-cell depleting agents, then monthly until ADAMTS13 activity normalization, and subsequently every 3 months [5]. The compassionate, off-label use of obinutuzumab including its expected benefits and disadvantages was extensively discussed with patients, and their informed consent was systematically obtained before treatment was initiated.

From January 2020 (date of the first patients with iTTP treated with obinutuzumab in France) until June 2024, 60 iTTP patients were treated with obinutuzumab in France and recruited in the CNR-MAT registry (44 female, 16 male). Baseline characteristics, previous therapeutic lines, details of obinutuzumab administration and outcome after obinutuzumab therapy are reported in Table 1. One pediatric patient (3 years old) and two adolescents (16 and 17 years old) with proven iTTP were included in the analysis. Significant comorbidities were reported in 42 patients (Table S1). Patients received a median of three previous treatments (IQR, 2–5), which included rituximab in all cases (Table S2). Obinutuzumab was administered for refractoriness to rituximab (N = 32), intolerance (N = 25), or both refractoriness and intolerance to rituximab (N = 3). Intolerance to rituximab included serum sickness (25 cases) and allergic reaction to rituximab (3 cases). Obinutuzumab was administered pre-emptively in 49 patients and in the acute phase of the disease in 11.

TABLE 1. Baseline characteristics and outcome after therapy.

Patients, n	60
Episodes, n	64
Sex, male/female, n	16/44
Ethnicity
Caucasian, n	47
African, n	7
Other, n	6
Age, years, median (IQR)	44 (33–57)
Previous treatment lines, n, median (IQR)	3 (2–5)
Indication of obinutuzumab initiation
Refractoriness to RTX ± other therapies, n (%)	35 (56%)*
Intolerance to RTX ± other therapies, n (%)	28 (44%)*
Time of initiation during management
Acute phase, n (%)	11 (18%)
Preemptively, n (%)	49 (82%)
Infusions per patient, n, median (IQR)	3 (1–4)
Associated immunosuppressive therapies, n	9
During the acute phase
Corticosteroids, n	4
During the preemptive setting
Cyclosporine A, n	5
ADAMTS13 response
≥ 20%, n (%)	51 (85%)
≥ 50%, n (%)	43 (72%)
No response, n (%)	9 (15%)
Time to ADAMTS13 ≥ 20%, days, median (IQR)	36 (17–80)
Time to ADAMTS13 ≥ 50%, days, median (IQR)	76 (33–234)
Relapse after obinutuzumab
Clinical relapse, n	1
ADAMTS13 relapse, n	2
Combined relapse-free survival, months, median	Not reached
2-year combines relapse-free survival	86%
Follow up, months, median (IQR)	11 (4–19)
Death, n	2

• Abbreviations: ADAMTS13, a disintegrin and metalloproteinase with thrombospondin-1 motifs, 13th member; IQR, interquartile range; RTX, rituximab; TPE, therapeutic plasma exchange.
• * Three patients had both refractoriness and intolerance; these patients were added to both groups.

Patients received a median of 3 (IQR, 1–4) obinutuzumab infusions. Nine patients received obinutuzumab in combination with another immunosuppressive therapy. Following obinutuzumab treatment, 51 (85%) patients improved ADAMTS13 activity ≥ 20%, including 43 patients (72% among all) who normalized ADAMTS13 activity (activity ≥ 50%). The nine others (15%) were unresponsive to obinutuzumab as they maintained a persistently undetectable ADAMTS13 activity (activity < 20%) for a median time of 11 weeks (IQR, 9–30) following obinutuzumab initiation, which included at least 2 consecutive measurements 1 month apart showing an undetectable ADAMTS13 activity. The median time to ADAMTS13 activity ≥ 20% and ≥ 50% was 36 days (IQR, 17–80 days) and 76 days (IQR, 33–234 days), respectively (Table 1). By comparing responsive and unresponsive patients, no significant risk factors for refractoriness were identified among age, sex, ethnicity, number of previous treatment lines, time from diagnosis to obinutuzumab, and number of obinutuzumab infusions. However, patients formerly unresponsive to rituximab improved ADAMTS13 activity post-obinutuzumab less frequently than patients intolerant to rituximab (27/35 [77%] vs. 27/28 [96%], respectively, p < 0.05; OR = 0.13; 95% CI 0.003–1.07); among patients refractory to obinutuzumab, most were also formerly unresponsive to rituximab (N = 8; 89% of patients unresponsive to obinutuzumab) (Table S3, Figure S1). Of note, a patient previously refractory to daratumumab responded to obinutuzumab therapy.

B-cell depletion following obinutuzumab treatment was available in 34 cases; in all, a total B-cell depletion (peripheral CD19⁺ B-cell lymphocytes < 1%) was observed within 2 months following obinutuzumab initiation.

After an initial response to obinutuzumab, 3 patients experienced an ADAMTS13 relapse (N = 2) or a clinical relapse (N = 1) (Table 1). By considering the whole population, median combined RFS was not reached after a median follow up of 11 months (IQR, 4–19 months) (Table 1, Figure S2). Two-year and five-year combined RFS was 86% and 61%, respectively. After excluding three patients who were both refractory and intolerant to previous rituximab treatment, the comparison of patients refractory to rituximab to those intolerant to rituximab found similar combined RFS (p = 0.72, HR = 3.22, 95% CI 0.81–13) (Figure S3). For both groups, median combined RFS was not reached; 1-year and 2-year combined RFS was 96% and 84% in patients intolerant to rituximab, respectively, and 68% at both time points for patients refractory to rituximab (Figure S3).

Two patients died during follow-up, one intracranial hemorrhage during a clinical relapse of iTTP in a pediatric patient and one cardiac arrest due to a history of severe valvular heart disease. None of these events were considered adverse events related to obinutuzumab.

Treatment-related adverse events occurred in 11 patients (Table S4). The most prevalent toxicity was infusion-related reaction, described in 6 patients. No severe treatment-related adverse events were described.

From this large series of patients, we provide more definitive evidence that obinutuzumab allows achieving high response rates in iTTP patients unresponsive or intolerant to rituximab and other immunosuppressants. Even in heavily pre-treated patients, we observed a response rate of 85% on ADAMTS13 activity, with acceptable adverse events.

One of the main reasons of obinutuzumab initiation in our study was serum sickness following rituximab. In this context, obinutuzumab represents an attractive alternative strategy for B-cell depletion for these patients. Although serum sickness following obinutuzumab has been described, it seems rare; in this regard, no serum sickness was documented in our cohort following obinutuzumab administration.

Obinutuzumab was also effective in patients with previous refractoriness to rituximab, with impressive response rates of 77%. The exact mechanism by which obinutuzumab circumvents rituximab refractoriness is not completely understood. In autoimmune diseases studies emphasize the superior B-cell depleting capacity of obinutuzumab as a background for efficiency.

The limitations of our study include the retrospective data collection; although the general diagnostic and treatment guidelines of TTP are well standardized in France, time points for the first ADAMTS13 measurement after initiating a new preemptive therapy remained variable between centers.

The optimal management of iTTP patients unresponsive or intolerant to rituximab is still in debate, while multiple immunosuppressive strategies are available. Cyclosporine A and lymphoablation with cyclophosphamide were reported as valuable options, but their tolerability might limit their use. Data are limited for plasma cell-directed therapies with bortezomib and daratumumab, which use might probably be devoted to patients who are unresponsive to intensive B-cell depletion. Consequently, and based on our results, obinutuzumab could represent the first option for patients with iTTP who experience intolerance or refractoriness to rituximab. Efforts from international, prospective trials should more definitely demonstrate the role of obinutuzumab as a valuable salvage immunosuppressive therapy in iTTP.