In a multicenter, retrospective, cohort study, Matthieu Mahévas, MD, PhD, of the National Reference Center for Adult Auto-Immune Cytopenias at Hôpital Henri Mondor, in Créteil, France, and authors defined a new set of patients with “multirefractory” immune thrombocytopenia (ITP) who, compared with control patients with ITP, were at a greater risk for developing secondary ITP and monoclonal gammopathy of undetermined significance (MGUS).
“Refractory ITP was previously defined as lack of a minimum response to splenectomy and the requirement for long-term treatment to reduce the significant bleeding events,” Dr. Mahévas and colleagues wrote. However, in the current study, “the characteristics and outcome of [multirefractory ITP] clearly differed from those of controls with ‘typical’ ITP.”
The trial compared 37 patients with multirefractory ITP with 183 matched controls enrolled at tertiary-care university hospitals specializing in adult ITP between 1990 and 2014 to determine the characteristics and outcomes of multirefractory, defined as severe chronic ITP that does not respond to rituximab (used off-label for ITP), splenectomy (or if splenectomy was contraindicated), and the two thrombopoietin-receptor agonists (Tp-RAs) approved in France (romiplostim and eltrombopag). Patients could have achieved a transient response to corticosteroids and/or intravenous immunoglobulin (IVIg), as these are considered first-line and/or rescue therapies.
To analyze baseline data, researchers gathered clinical data from medical charts for each patient; to gather information about outcomes, they conducted telephone interviews with patients and physicians using a standardized questionnaire.
Among the 37 patients with multirefractory ITP, most were women (n=25; 67.5%), with a median age at ITP diagnosis of 47.2 years (range = 12-79 years). Many patients (n=28; 75.7%) presented with some bleeding symptoms at the time of ITP diagnosis – 30 percent of whom (n=11) had severe bleeding.
One-third of patients (n=13; 35%) presented with secondary ITP:
- 5 patients had definite autoimmune disease (including, antiphospholipid syndrome [n=1], lupus erythematosus [n=1], and Evans syndrome [n=3])
- 7 had an associated malignant hematologic disorder
- 1 had a primary immunodeficiency
Most patients achieved a transient initial response to first-line steroid therapy (n=24; 68.6%) and IVIg (n=22; 68.6%), before becoming refractory to treatment.
Median follow-up for patients with multirefractory ITP was 84 months (range = 12-455 months) and 48 months (range = 12-369 months) for ITP controls. In the control population, the researchers found that the following characteristics were associated with a higher risk of developing multirefractory ITP during follow-up:
- Bleeding symptoms at ITP onset (odds ratio [OR] = 3.54; 95% CI 1.12-11.22; p=0.032)
- No response to steroid therapy (OR=0.38; 95% CI 0.20-0.72; p=0.003)
Patients with multirefractory ITP were more likely to have secondary ITP (OR=4.84; 95% CI 1.31-17.86; p=0.018) and MGUS (OR=5.94; 95% CI 1.08-32.48; p=0.04). “This overrepresentation, and poor response to steroid therapy, suggest that the immunologic mechanism resulting in platelet destruction in these cases differs from the common form of ITP,” the authors wrote.
The median duration of ITP prior to multirefractory transition was 78 months (range = 6-450 months), and patients had received a median of 10.5 treatments for ITP (range = 6-15 treatments). Almost all of the multirefractory ITP patients (n=34; 91.8%) did not achieve a prolonged response to rituximab, splenectomy, and the two Tpo-RAs at the maximum tolerated dose.
At the end of follow-up for the multirefractory population, only 30 percent (n=11) had achieved a sustained response.
Seven patients had a malignant hematologic disorder – three of whom achieved a sustained response with chemotherapy, one with smoldering myeloma who received lenalidomide then Tpo-RAs with no efficacy, and three who received no specific treatment other than rituximab.
Among the 30 patients with no hematologic malignant disorder, 14 received at least one immunosuppressant or cytotoxic agent, but only one patient achieved a response. Ten patients received an immunosuppressant along with Tpo-RA; seven of these patients achieved a sustained response during a median follow-up of 15 months (range = 6-32 months).
“ITP can precede the diagnosis of a malignant hematologic disorder, which suggests that, with multirefractory ITP, the diagnosis of primary ITP should be reconsidered to carefully exclude hematologic disorders,” the authors wrote. Based on their findings, they suggest that multirefractory ITP can be divided into three categories:
- Primary ITP
- ITP associated with other malignant hematologic disorders
- ITP associated with other autoimmune disorders
Five patients (14%) in the study died due to intracranial hemorrhage (n=2), sepsis (n=1), breast cancer (n=1), and unknown reasons (n=1). All patients required several hospitalizations (median = 15; range = 6-100). Forty percent (n=15) presented with at least one bacterial infection and 24 percent (n=9) experienced thrombosis.
“Uncontrolled bleeding and therapy-related complications were the two most challenging problems: 60 percent of patients needed platelet transfusion during follow-up, and 40 percent had at least one severe infection,” the authors added.
“In the era of new ITP therapies, a minority of ITP patients still does not show response after several treatment lines and likely have severe disease, with high morbidity and risk of death,” Dr. Mahévas and colleagues concluded. “In the absence of guidelines, an individual approach with a combination of agents taking into account the risk/benefit balance of these treatments appears the best way to improve the outcome of patients with multirefractory ITP.”
The study is limited by its retrospective design, as well as the wide variety of previous therapies that patients had received since this variance may have affected the interpretation of study outcomes.
Mahévas M, Gerfaud-Valentin M, Moulis G, et al. Characteristics, outcome and response to therapy of multirefractory chronic immune thrombocytopenia. Blood. 2016 June 27. [Epub ahead of print]