Title: Intensive rituximab regimen in immune‐mediated thrombotic thrombocytopenic purpura can circumvent unresponsiveness to standard rituximab treatment
Abstract: The identification of a role for anti-ADAMTS13 antibodies in the pathogenesis of immune-mediated thrombotic thrombocytopenic purpura (iTTP)1 led to the use of B-cell depletion for this diagnosis. The chimaeric monoclonal anti-CD20 antibody rituximab is now proposed as frontline therapy in association with standard treatment,2 and as a pre-emptive treatment in asymptomatic patients with persistent severe (activity <10%) immune-mediated ADAMTS13 deficiency.3, 4 Nevertheless, pre-emptive rituximab fails to improve ADAMTS13 activity in ~15% of cases.3 In these situations, few data regarding management of the risk of relapse are available.5, 6 Our group proposed an intensive rituximab regimen inspired by the maintenance treatment of B-cell-indolent lymphoid malignancies.7 We report here our experience with this strategy in iTTP patients who are unresponsive to standard pre-emptive rituximab treatment. We focused on iTTP patients in clinical remission who failed to display improved ADAMTS13 activity following a standard treatment with rituximab.3 Patients were enrolled prospectively in our registry from January 2012 to July 2018 through the French Reference Center for Thrombotic Microangiopathies network (www.cnr-mat.fr). Acute phase was managed according to international guidelines.2 ADAMTS13 activity was systematically assessed following the acute phase, then every three months. iTTP patients in clinical remission who failed to demonstrate improved ADAMTS13 activity (i.e. activity persistently <10%) at least one month following a standard treatment with rituximab (375 mg/m2; 1–4 infusions during the acute phase or follow-up) were considered unresponsive. Clinicians were then encouraged to perform an intensive rituximab regimen consisting in repeated infusions of rituximab (Mabthera®, Roche, Paris, France) 375 mg/m2 until ADAMTS13 improvement and for at least one year. Clinical relapse was defined as any recorded thrombocytopenia <100 × 109/l, with or without clinical features of iTTP. ADAMTS13 relapse was defined as ADAMTS13 activity <10% following improvement. Toxicity and side effects were recorded. Measures of ADAMTS13 activity and anti-ADAMTS13 antibodies were performed as previously described.3 Informed consent was obtained from all patients. This study was approved by our institutional review board in accordance with the Declaration of Helsinki. From February 2010 to July 2018, 104 patients received a standard pre-emptive treatment. Among them, six received an intensive treatment with rituximab because of a persistent immune-mediated severe ADAMTS13 deficiency for at least one month following the standard infusion of pre-emptive rituximab. Two others received an alternative treatment (cyclosporine A).3 Seven additional patients whose ADAMTS13 activity remained undetectable following the acute phase of the disease despite a standard rituximab regimen associated with therapeutic plasma exchange (TPE) and corticosteroids, subsequently received an intensive rituximab regimen. Patient's clinical data in the acute phase are consistent with previous reports8 (Table SI). Median age was 33 years (range, 19–56); six patients were females. Most patients had a French score of 2.8 Eight patients (61%) had cerebral involvement. Median anti-ADAMTS13 antibody concentration was 60·5 U/ml (range, 22–200). The median number of acute iTTP episodes before the intensive rituximab regimen was two (range, 1–5). Five patients had received immunosuppressive therapies without improvement in ADAMTS13 activity, and three of them were splenectomized. The median time between the end of last iTTP episode and intensive rituximab regimen initiation was seven months (range, 10 days–5·75 years). The median duration of the intensive rituximab regimen was two years (range, 1–6 years). Patients received 5 to 13 infusions of rituximab (median, 8). Rituximab was administered every 2–3 months (eight patients) or twice a year (five patients) (Table I). In 10 patients (77%), ADAMTS13 improved with a median time from the initiation of intensive treatment to the first detectable ADAMTS13 activity of 56 days (range, 10 days–2 years). The three others (patients 9, 10 and 11) remained with a persistent severe ADAMTS13 deficiency at the end of treatment (Table I), despite at least three years of intensive regimen. Of note, all three received a twice-a-year rituximab regimen. Twenty-two (range, 9–34) months following the end of intensive treatment, four responders again received pre-emptive infusions of rituximab after a severe drop in ADAMTS13 activity. A fifth patient received four ofatumumab infusions weekly (300 mg–1000 mg/week × 3) when he started to drop ADAMTS13 activity, as he was considered no longer responsive to rituximab. In all five cases, ADAMTS13 activity recovered (Table II). Only patient 10 experienced a clinical relapse of favourable outcome in the context of pregnancy, 18 months after the end of the intensive rituximab regimen. In this patient, ADAMTS13 activity was persistently undetectable following the intensive regimen and no subsequent pre-emptive treatment had been considered (Table II). The median follow-up is five years (range, 1·75–8·16 years). One patient fainted during rituximab infusion and two experienced mild allergic manifestations; another patient presented symptoms suggestive of serum sickness. Other minor events are recorded in Table II. No severe or repeated infectious event occurred during follow-up. iTTP is a debilitating disease and the prevention of relapses is crucial; this can usually be achieved with the addition of rituximab at the acute phase, and with pre-emptive infusions in case of an ulterior severe drop in ADAMTS13 activity.3, 9 However, no consensual attitude exists for patients unresponsive to this strategy. We report that an intensive rituximab regimen inspired by maintenance regimens of low-grade B-cell lymphomas allows improving ADAMTS13 activity in most cases (>75% of formerly unresponsive patients), with an acceptable safety profile. Notably, we observed an improvement in ADAMTS13 activity in patients who had a persistently undetectable activity for more than three years with standard rituximab regimens. So far, only single cases previously supported the relevance of this strategy.10-12 Of interest, all three patients who did not respond to intensive therapy received a regimen consisting in a twice-a-year infusion of rituximab instead of the two- to three-month infusion regimen typically offered to the other patients. Therefore, it is likely that iTTP patients unresponsive to the standard regimen should be managed with the more intensive two- to three-month infusion-based regimen. We successfully treated one patient with the second-generation anti-CD20 monoclonal antibody ofatumumab following a drop in ADAMTS13 activity after the intensive rituximab regimen.13 Further studies are therefore needed to address the possible role of other immunomodulators as well as splenectomy as alternative strategies in iTTP patients unresponsive to rituximab.14, 15 In conclusion, an intensive rituximab regimen could circumvent unresponsiveness to standard rituximab treatment in iTTP, with an acceptable tolerance. Our results need confirmation from larger studies. MP and CB performed the research and analysed the data. MP, CB and PC wrote the paper. SM, LG, PC and DR provided essential data and substantial corrections to the paper. P. Coppo is a member of the Clinical Advisory Board for Alexion, Sanofi, Takeda and Octapharma. Agnès Veyradier is a member of the Clinical Advisory Board for Sanofi. The members of the Reference Center for Thrombotic Microangiopathies (CNR-MAT) are: Augusto Jean-François (Service de Néphrologie, dialyse et transplantation; CHU Larrey, Angers); Azoulay Elie (Service de Réanimation Médicale, Hôpital Saint-Louis, Paris); Barbay Virginie (Laboratoire d’Hématologie, CHU Charles Nicolle, Rouen); Benhamou Ygal (Service de Médecine Interne, CHU Charles Nicolle, Rouen); Bordessoule Dominique (Service d’Hématologie, Hôpital Dupuytren, Limoges); Charasse Christophe (Service de Néphrologie, Centre Hospitalier de Saint-Brieuc); Charvet-Rumpler Anne (Service d’Hématologie, CHU de Dijon); Chauveau Dominique (Service de Néphrologie et Immunologie Clinique, CHU Rangueil, Toulouse); Choukroun Gabriel (Service de Néphrologie, Hôpital Sud, Amiens); Coindre Jean-Philippe (Service de Néphrologie, CH Le Mans); Coppo Paul (Service d’Hématologie, Hôpital Saint-Antoine, Paris); Corre Elise (Service d’Hématologie, Hôpital Saint-Antoine, Paris); Delmas Yahsou (Service de Néphrologie, CHU de Bordeaux, Bordeaux); Deschenes Georges (Service de Néphrologie Pédiatrique, Hôpital Robert Debré, Paris); Devidas Alain (Service d’Hématologie, Hôpital Sud-Francilien, Corbeil-Essonnes); Dossier Antoine (Service de Néphrologie, Hôpital Bichat, Paris); Fain Olivier (Service de Médecine Interne, Hôpital Saint-Antoine, Paris); Fakhouri Fadi (Service de Néphrologie, CHU Hôtel-Dieu, Nantes); Frémeaux-Bacchi Véronique (Laboratoire d’Immunologie, Hôpital Européen Georges Pompidou, Paris); Galicier Lionel (Service d’Immunopathologie, Hôpital Saint-Louis, Paris); Grangé Steven (Service de Réanimation Médicale, CHU Charles Nicolle, Rouen); Guidet Bertrand (Service de Réanimation Médicale, Hôpital Saint-Antoine, Paris); Halimi Jean-Michel (Service de Néphrologie Pédiatrique, Hôpital Bretonneau, Tours); Hamidou Mohamed (Service de Médecine Interne, Hôtel-Dieu, Nantes); Herbrecht Raoul (Service d’Oncologie et d’Hématologie, Hôpital de Hautepierre, Strasbourg); Hié Miguel (Service de Médecine Interne, Groupe Hospitalier Pitié-Salpétrière, Paris); Jacobs Frédéric (Service de Réanimation Médicale, Hôpital Antoine Béclère, Clamart); Joly Bérangère (Service d’Hématologie Biologique, Hôpital Lariboisière, Paris); Kanouni Tarik (Unité d’Hémaphrèse, Service d’Hématologie, CHU de Montpellier); Kaplanski Gilles (Service de Médecine Interne, Hôpital la Conception, Marseille); Lautrette Alexandre (Hôpital Gabriel Montpied, Service de Réanimation médicale, Clermont-Ferrand); Le Guern Véronique (Unité d’Hémaphérèse, Service de Médecine Interne, Hôpital Cochin, Paris); Moulin Bruno (Service de Néphrologie, Hôpital Civil, Strasbourg); Mousson Christiane (Service de Néphrologie, CHU de Dijon); Ojeda Uribe Mario (Service d’Hématologie, Hôpital Emile Muller, Mulhouse); Ouchenir Abdelkader (Service de Réanimation, Hôpital Louis Pasteur, Le Coudray); Parquet Nathalie (Unité de Clinique Transfusionnelle, Hôpital Cochin, Paris); Pène Frédéric (Service de Réanimation Médicale, Hôpital Cochin, Paris); Perez Pierre (Service de Réanimation polyvalente, CHU de Nancy); Poullin Pascale (Service d’Hémaphérèse et d’Autotransfusion, Hôpital la Conception, Marseille); Pouteil-Noble Claire (Service de Néphrologie, CHU Lyon-Sud, Lyon); Presne Claire (Service de Néphrologie, Hôpital Nord, Amiens); Provôt François (Service de Néphrologie, Hôpital Albert Calmette, Lille); Rondeau Eric (Urgences Néphrologiques et Transplantation Rénale, Hôpital Tenon, Paris); Saheb Samir (Unité d’Hémaphérèse, Hôpital la Pitié-Salpétrière, Paris); Seguin Amélie (Service de Réanimation Médicale, CHU de Nantes); Servais Aude (Service de Néphrologie, CHU Necker-Enfants Malades); Stépanian Alain (Laboratoire d’Hématologie, Hôpital Lariboisière, Paris); Veyradier Agnès (Service d’Hématologie Biologique, Hôpital Lariboisière, Paris); Vigneau Cécile (Service de Néphrologie, Hôpital Pontchaillou, Rennes); Wynckel Alain (Service de Néphrologie, Hôpital Maison Blanche, Reims); Zunic Patricia (Service d’Hématologie, Groupe Hospitalier Sud-Réunion, la Réunion). 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