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Outcomes for Plasma Exchange to Treat TTP
Abstract & Commentary
By Andrew S. Artz, MD, Division of Hematology/Oncology, University of Chicago. Dr. Artz reports no financial relationships relevant to this field of study.
Synopsis: The risk of relapse after effective therapy with plasma exchange for thrombotic thrombocytopenic purpura (TTP) has not been well-characterized. Among 376 patients with an initial episode of TTP treated with plasma exchange, overall survival was around 68%, with a survival of 78% among the subset with idiopathic TTP. Survival did not differ on those having a low (< 10%) ADAMTS13 level. Relapse was greater for those with a low ADAMTS13 level at the time of presentation.
Source: Hovinger J, et al. Survival and relapse in patients with thrombotic thrombocytopenic purpura. Blood. 2010;115:1500-1511.
The classic pentad of anemia, thrombocytopenia, neurologic abnormalities, renal abnormalities, and fever historically defined thrombotic thrombocytopenic purpura (TTP). TTP may be divided into idiopathic where no apparent underlying cause exists and secondary TTP related to a variety of disorders such as hematopoietic transplant, pregnancy, infection, drug, autoimmune or cancer. The realization of very low ADAMST13 levels in a substantial number of patients further clarified pathophysiology.
Plasma exchange has dramatically improved survival from around 10% to 70%–80%.1 With an available treatment, the diagnostic criteria were loosened to require only microangiopathic hemolytic anemia and thrombocytopenia, leading to better recognition. More effective treatment has also presented the problem of relapse. In this paper, the authors report on the experience of the Oklahoma TTP registry to better characterize outcomes related to TTP.
The registry enrolled 398 consecutive patients with a diagnosis of TTP or HUS for whom plasma exchange (PEX) was requested in a 58 county region covering 2.3 million people. ADAMTS13 activity was measured by both quantitative immunoblotting and a fluorogenic assay. Of these, 376 met eligibility criteria. ADAMTS13 was available in 261 subjects. The median follow-up was 4.7 years. Of these, 148 of 361(41%) had idiopathic TTP. Among the 59% with secondary TTP, the most common causes in decreasing frequency were: drug, autoimmune, infection, bloody diarrhea, pregnancy, and stem cell transplant. The ADAMTS13 level was < 10% in 60 (23%) and > 10% in 201 (77%) patients. Of patients with low levels, most were in the idiopathic TTP group.
Overall survival was 69%. Survival was 80% for idiopathic TTP. Secondary TTP related to pregnancy/post-partum TTP fared extremely well, realizing survival of 93%. In contrast, less than 30% of patients after stem-cell transplant and infection-related TTP survived. Interestingly, survival did not change over the 20-year time period using plasma exchange. Relapse was significantly more common for patients with an ADAMTS13 < 10% among those surviving (and, thus, available for follow-up). The five patients who relapsed with baseline ADAMTS13 activity < 10% had unique characteristics. One was re-exposed to drug, leading to relapse, two patients had lupus with features overlapping with TTP, one patient had a low ADAMTS 13 that evolved over time, and another had a low level on one of the two assays.
Among the 47 surviving patients who had ADAMTS13 < 10%, only male sex predicted for relapse. Relapses in those with low ADAMTS13 activity occurred in the first year (63%), with a cumulative incidence of relapse at 7.5 years of 41%. In recent years, ADAMTS13 activity was periodically during remission for those with low activity at the time of presentation. Since December 2003, 13 patients with ADAMTS 13 activity < 10% received rituximab, generally for refractory or recurrent disease.
Oncologists are often asked to assist in the diagnosis and management of patients who have thrombotic thrombocytopenic purpura (TTP). The substantial improvement in mortality from plasma exchange demands early diagnosis and treatment and prompt initiation of treatment for TTP. Diagnosis only requires microangiopathic hemolytic anemia and thrombocytopenia. Data on outcomes from plasma exchange and relapse rates in responders have been limited. In this study, the authors were able to perform a population-based study derived from patients in a large area in Oklahoma, serviced by a single provider of plasma exchange. Over 20 years, 376 consecutive patients were studied who received TTP for an initial episode of TTP. Idiopathic TTP occurred in 41% whereas secondary TTP, related to a defined condition, accounted for the majority. The survival rate of patients with idiopathic TTP was 80% similar to prior reports.1 ADAMTS13 levels were available from more recent patients. Around half (47%) of the patients with idiopathic TTP had levels < 10% at presentation, although some patients with secondary TTP also had low levels. Thus, low ADAMTS13 is neither sufficient nor necessary for diagnosing idiopathic TTP. However, low ADAMTS13 level at presentation had a much higher risk of relapse compared to those with higher levels at presentation. Among those with low ADAMTS13 at presentation, 34% relapsed with a cumulative incidence of relapse at 7.5 years of 41%. Relapses were clustered within one year of initial diagnosis, indicating the need for close monitoring after remission, particularly during the first year. Interestingly, six patients received rituximab maintenance to avoid relapse, and none have relapsed. For those with ADAMTS13 levels > 10% at presentation, relapses rarely occurred; only 4% of 136 surviving patients relapsed, all within two years.
This large study of a large cohort of TTP patients treated with plasma exchange reveals that secondary TTP may be more common than idiopathic TTP. Reassuringly, plasma exchange enables reasonable survival of 80% for those presenting with idiopathic TTP. This study defies the common notion that low ADAMTS13 are pathognomonic for idiopathic TTP; some patients with low levels had secondary TTP and many patients classified as idiopathic TTP had levels > 10%. Lower levels of ADAMTS13 at presentation may predict for relapse once in remission. However, the exact monitoring strategy and intervention for this subset (e.g., rituximab) remain undefined.
1. Rock GA, et al. Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. Canadian Apheresis Study Group. N Engl J Med. 1991;325:393-397.