Obinutuzumab in two patients suffering from immune‐mediated thrombotic thrombocytopenic purpura intolerant to rituximab
Authors: Judith Robertz, Martin Andres, Behrouz Mansouri Taleghani, Irene Koneth, Isabelle Binet, Johanna A. Kremer Hovinga
Journal: American Journal of Hematology (2019)

Acute episodes of immune-mediated thrombotic thrombocytopenic purpura (iTTP) are life threatening and characterized by thrombocytopenia, microangiopathic hemolytic anemia with schistocytes on the blood smear and variable degrees of ischemic end-organ damage. The underlying pathophysiology is a severe ADAMTS13 deficiency (ADAMTS13 activity <10% of the normal), due to circulating ADAMTS13 autoantibodies.1 Current treatment of iTTP is based on two pillars: daily therapeutic plasma-exchange (TPE) with replacement of plasma, and immunosuppression to block autoantibody formation. Besides corticosteroids, rituximab, a type I anti-CD20 antibody, licensed to treat B-cell neoplasia, is used to treat refractory or relapsed iTTP. It is more and more used also in first-line, or preemptively during follow-up of patients when ADAMTS13 autoantibodies and ADAMTS13 deficiency reappear before overt iTTP is present.2 Rituximab treatment of iTTP is more frequently associated with normalization of ADAMTS13 activity, and with fewer and delayed relapses, that occur in at least 40% of survivors of a first acute episode not treated with rituximab.1 Infusion-related reactions to rituximab are frequent and reported in >80% of patients in randomized trials. The reaction severity is usually mild to moderate (grade 1 and 2 according to Common Terminology Criteria for Adverse Events [CTCAE]), and their frequency decreases with subsequent infusions.3 Here, we report on two iTTP patients, who became intolerant to rituximab because of infusion related reactions of CTCAE grade 2-3, and serum-sickness, respectively. Both patients were subsequently successfully treated with second-generation anti-CD20 antibodies. The first patient, a 54-year-old male known for rheumatic heart disease with mitral and aortic valve replacement, and long-term anticoagulation with a vitamin K antagonist, presented with upper abdominal pain. Laboratory work-up and imaging were compatible with an acute cholecystitis, and laparoscopic cholecystectomy was performed. Abdominal bleeding, progressive deterioration of consciousness, and eventually seizures complicated the postoperative period and prompted intubation and referral to our ICU, where a diagnosis of iTTP was established (ADAMTS13 activity <10%, functional ADAMTS13 inhibitor ≫2 BU/ml). We started daily TPE and immunosuppressive therapy with corticosteroids. Following an initial good response to TPE, the patient had a sudden decrease of his platelet count on day 9, TPE was continued and immunosuppression intensified by the addition of rituximab in four weekly doses of 375 mg/m2 (Figure 1). Altogether, 26 TPE sessions were required to achieve remission. During follow-up in remission, ADAMTS13 activity dropped to <10% in September, 2016 (Figure 1). Preemptive rituximab treatment was complicated by allergic reactions during the third and fourth administration that had to be interrupted. Overall, he received 2530 mg (79%) of the planned 3200 mg of rituximab. ADAMTS13 activity, however, failed to normalize and dropped to <10% four months later. Because of the cardiac situation, splenectomy was not considered and a watch-and-wait attitude with regular follow-up visits was adopted. Given that individual platelet counts are remarkably stable,4 we established a biological passport, as used by professional athletes, with an individualized platelet profile based on the patient's historical and remission platelet counts. While severe ADAMTS13 deficiency persisted, the patient's blood count remained stable for the ensuing six months, when the platelet count dropped (minimal 125 × 109/L, Figure 1), and new neurological signs (headache, blurred vision) occurred. We decided to treat the patient with an alternative, second-generation anti-CD20 antibody, and chose the type II anti-CD20 antibody, obinutuzumab because of its distinct mode of action in comparison with type I anti-CD20 antibodies (i.e. rituximab, that had failed to normalize ADAMTS13 activity; or ofatumumab).5 After written informed consent, the patient received three doses of 1000 mg of obinutuzumab every two weeks, with the first dose split into 100 mg, and 900 mg given on two consecutive days after premedication with corticosteroids. Within one month of completion of obinutuzumab, ADAMTS13 activity had normalized and the patient has remained in complete clinical and serological remission over the past 1.5 years. Given this experience, we treated a second iTTP patient with the same regimen. This female patient presented at 20 years of age during her first pregnancy with a first acute iTTP episode (ADAMTS13 activity 7%) that resulted in intra-uterine fetal death at 22 weeks of gestation. During the following 4 years, the patient had four iTTP relapses. Treatment in her native Hungary consisted of TPE, corticosteroids and low-dose rituximab (100 mg per application, three and four applications for the first and fourth relapse, respectively). In October, 2015, now living in Switzerland, the patient presented with her 6th acute iTTP episode, ADAMTS13 activity was <10% in the presence of a functional ADAMTS13 inhibitor of 2BU/ml. Treatment consisted of TPE and corticosteroids. Rituximab was initiated, however, stopped after the first administration because of severe serum-sickness, which manifested as an itching rash and whole-body pain. During follow-up in clinical remission, ADAMTS13 activity increased to 49%, but in March, 2016, ADAMTS13 activity dropped again to <10%. Preemptive treatment with corticosteroids and the type I anti-CD20 antibody, ofatumumab (two doses of 700 mg each) was well tolerated and successful, documented by the normalization of ADAMTS13 activity 1 month later. However, within 1 year, the seventh episode occurred. Besides daily TPE and corticosteroids, splenectomy was performed, resulting in clinical remission that lasted for 13 months despite persistence of severe ADAMTS13 deficiency. The eighth and to date last acute iTTP episode occurred in 2018. Standard treatment was complemented with three weekly doses of obinutuzumab 1000 mg, with the first dose split into two administrations. The patient has been in remission with normal ADAMTS13 activity for the past 12 months. Although infusion-related adverse events are more common with obinutuzumab than with rituximab3, 5 both patients tolerated obinutuzumab after intravenous premedication with corticosteroids and antihistamines well, no allergic symptoms, no infections or other adverse events occurred in either patient. In conclusion, iTTP patients intolerant to rituximab may tolerate and benefit from second-generation anti-CD20 antibody therapy, recently demonstrated for the type I anti-CD20 antibody, ofatumumab6 and here, for the type II anti-CD20 antibody, obinutuzumab. Given the high risk of mortality (still 10%-20%) and morbidity of acute iTTP episodes, their prevention by an alternative, yet off-label anti-CD20 treatment is feasible and likely of clinical benefit. The patients' biological passport containing a platelet profile was helpful in guiding follow-up and treatment decisions. The patients gave written informed consent for publication. JAKH serves on the advisory boards of Ablynx/Sanofi for the development of caplacizumab, and Shire for the development of recombinant ADAMTS13. The hereditary TTP registry (www.ttpregistry.net, ClinicalTrials.gov NCT01257269) is supported by an investigator-initiated research grant of Shire. In addition, she receives research funding from the Swiss National Science Foundation (grant 310 030-160 269), the ISTH 2007 Presidential Fund, the GTH congress presidential fund and the Answering T.T.P. Foundation (project number 1009). The other authors have nothing to declare. All authors were involved in the treatment and follow-up of the patients. MA, BMT, IK, IB, and JAKH were responsible for the treatment concept. JR and JAKH wrote the manuscript; its final version was reviewed and approved by all authors.