Combination immunosuppressant therapy for patients with chronic refractory immune thrombocytopenic purpura

Abstract

Treatment options for patients with chronic refractory immune thrombocytopenic purpura (ITP) are limited. Because combination immunosuppressant therapy appeared to be effective in ITP and other disorders, we used this approach in patients with particularly severe and refractory ITP. In this retrospective, observational study, we determined the response (platelet count above 30 ؋ 10 9 /L and doubling of baseline) among 19 refractory ITP patients. Treatment consisted of azathioprine, mycophenolate mofetil, and cyclosporine. The patients had failed a median of 6 prior treatments, including splenectomy (in all except 1 IntroductionImmune thrombocytopenic purpura (ITP) is an acquired bleeding disorder characterized by autoantibody-mediated platelet destruction and impaired platelet production. Patients with chronic refractory ITP have the highest risk of death and disease-related or therapy-related complications. 1,2 Treatment options include aggressive immunosuppressant therapy, and most recently thrombopoietin (TPO) receptor agonists. 3,4 Single-agent immunosuppressant drugs such as azathioprine and cyclosporine have been used to treat refractory patients with moderate success 5 ; however dose escalation can cause morbidity, and other options are needed.Over the past several decades, physicians have noted that greater efficacy can be achieved using a combination of unrelated but synergistic medications. 6,7 In this report, we describe our experience using a combination of azathioprine, mycophenolate mofetil, and cyclosporine to treat patients with particularly severe and refractory ITP. MethodsPatients in this report had a platelet count less than 20 ϫ 10 9 /L that persisted for at least 12 months with an inadequate or transient response to multiple therapies. The senior author (J.G.K.) offered the option of a combination of immunosuppressant therapy. Patients with comorbidities such as liver failure or uncontrolled hypertension were not offered this treatment. Institutional Review Board approval from McMaster University was obtained to retrospectively review the medical charts of all patients with ITP treated in our clinic; this report describes only those patients treated with combination immunosuppressant therapy. Institutional Review Board approval was not required for the administration of the combination of immunosuppressant agents (each on its own an accepted therapy for ITP 8 ), which was given per clinical need.Medical records of each patient were reviewed by 3 independent assessors and data were abstracted in triplicate and verified for consistency. Platelet count measurements and follow-up visits were done as per routine care and mean monthly platelet counts were calculated. Target doses of immunosuppressant medications were azathioprine 2 mg/kg per day; mycophenolate mofetil 1 to 2 g/d; and cyclosporine 2 mg/kg per day. Low-dose cyclosporine was chosen to minimize toxicity and avoid the need for drug level monitoring.We defined overall response as a platelet count level of 30 ϫ 10 9 /L or higher and do...

Blind men and the refractory ITP elephant

“…In contrast, patients with underlying autoimmune disorders and/or hematologic malignancies demonstrate a loss of central tolerance and differentiation blocks 6 ; these patients have poor and short-lived responses to immune-directed therapy because additional cell types are involved in disease pathogenesis and the implicated lymphocyte repertoire is largely autoreactive and able to reconstitute rapidly after therapy (see figure). As demonstrated by this and other reports, 7,8 combination therapy directed at multiple arms of the immune response, along with TRAs, improves response rates. This is an important observation, though treatment of refractory ITP nevertheless remains reminiscent of the story of the "blind men and the elephant," in which a group of blind men touch different parts of an elephant, and when they compare notes find they are in complete disagreement.…”

Characteristics, outcome, and response to therapy of multirefractory chronic immune thrombocytopenia

“…Our findings contrast with several reports or clinical studies showing prolonged response with such therapies, but patients showed less refractory disease than our patients. [13][14][15][16][17][18][19] Despite the efficacy of HSCT, the high risk of mortality associated with this procedure (1 death in our cohort) argues for its proposal for patients with no alternative therapeutic option only. However, the combination of Tpo-RAs with immunosuppressant drugs was effective with an overall response rate (R 1 CR) of 70% in the 10 patients who received this treatment.…”

Rituximab and three dexamethasone cycles provide responses similar to splenectomy in women and those with immune thrombocytopenia of less than two years duration

“…Sixtyseven patients is larger than almost all other single-arm studies in ITP 14,[32][33][34] and it was thus possible to reach hypothesis-generating conclusions about base-line characteristics associated with response. In this analysis, only 80% of patients received the intended dosing regimen ( Figure 1); however, there was no difference in response between the 53 patients receiving R+3Dex and the 14 whose treatment regimen was slightly modified.…”