A Multicenter, Case-Control Study Evaluating the Characteristics and Outcome of ITP Patients Refractory to, Rituximab, Splenectomy and Both TPO Receptor Agonists

Introduction: Before the emergence of new treatments, refractory immune thrombocytopenia (ITP) was defined as the failure to achieve a minimum response to splenectomy and the requirement of long-term treatments to reduce risk of significant bleeding events. These patients experience a significant morbidity and mortality rate (1). The first aim of this study was to describe the characteristics of patients with multirefractory ITP (multi-ref ITP) according to an updated definition, i.e., patients who failed to respond to splenectomy, monoclonal anti-CD20 antibodies (rituximab, RTX) and both thrombopoietin-receptor agonists (TPO-RAs), as well as to identify associated factors with this phenotype. The second aim was to examine the long-term outcome of these patients.

Patients and Methods: We carried out a multicenter retrospective study in France. Inclusion criteria of patients with multi-ref ITP were failure to splenectomy, rituximab and the two marketed TPO-RAs, or presentation of an absolute contraindication to these treatments. Failure to treatment was defined according to standardized international criteria and bleeding score as described by Khellaf et al. Physicians were interviewed and patients' medical charts collected using the standardized form of the Referral Center for Adult ITP. In order to assess the variables associated with multirefractory occurrences, patients with multi-ref ITP were compared with non-multirefractory patients: for each case, 5 controls were randomly selected from the ITP clinical research database at Henri-Mondor Hospital, matched on the year of diagnosis. This database includes all ITP patients followed in the French national center for autoimmune cytopenias. Univariate and multivariate conditional logistic regression models were performed (backward procedure, α=5%).

Results: Thirty-seven patients (12 men/25 women) with multi-ref ITP and 183 controls were included in the study. Patients with multi-ref ITP have presented more initial bleeding symptoms than controls (75.6% vs 52.75%, p=.012)), had more frequently secondary ITP (35% vs 8.74%, p<.001), presented more clinical/biological auto-immune abnormalities (59.46% vs 28.42%, p=0008) and had more frequently a monoclonal gammopathy of undetermined significance than controls (19% vs 2.89%, p<.001). Only 24 patients with multi-ref ITP (68.57%) achieved initial transient response to steroid therapy (CR: n=10, R: n=12), compared to 91.61% responders in controls (p<.0001). In multivariate analysis, 4 factors were found to be associated with multi-ref ITP occurrence: (1) secondary ITP (OR: 4.81, 95%CI [1.31-17.86], p=.018), (2) presence of monoclonal gammopathy (OR: 5.93, 95%CI [1.08-32.48], p<.04), (3) bleeding symptoms at diagnosis (OR: 3.54 95%CI [1.11-11.22], p=.032) and (4) no response to steroid therapy (OR: 0.38 95%CI [0.20-0.72], p= .003). After a median follow-up of 84 months (range: 12-455), patients with multi-ref ITP have received a median of 10.5 lines of treatments (range: 6-15) including splenectomy, TPO-RAs and RTX, 5 patients (14%) died (intracranial hemorrhage, n=2; sepsis, n=1; breast cancer, n=1; unknown, n=1). Throughout the course of ITP, all patients required hospitalization; 22 (60%) received platelet transfusion, and 6 red-blood cells transfusion, 9 (24%) were admitted to intensive care units, 15 (40%) presented at least one bacterial infection, and 9 experienced at least one thrombosis (arterial, n=3; venous, n=6). At the end of follow-up, 20 patients (54%) were still non responders. Nine patients achieved a complete response: one after autologous hematopoietic stem cell transplantation, 2 after chemotherapy for hematological malignancy, and 5 after a combination of immunosuppressive therapy and TPO-RA.

Conclusion: Our study demonstrated that multirefractory ITP is an extremely serious condition, associated with a high morbidity and mortality. Factors significantly associated with this phenotype were secondary ITP, association with autoimmune disorders, monoclonal gammopathy and no response to steroids. Most of these patients remained non-responsive to alternative lines of rescue treatment, but some successes has been obtained with the combination of immunosuppressive therapy and TPO-RA.

(1) McMillan R, Durette C. Long-term outcomes in adults with chronic ITP after splenectomy failure. Blood 2004;104(4):956-60