Telltale signs of progress in the management of thrombotic thrombocytopenic purpura

We have learned much about the etiology and pathophysiology of thrombotic thrombocytopenic purpura (TTP) since publication of the pivotal randomized clinical trial demonstrating the effectiveness of plasma exchange (PEX) more than 20 years ago.1 Clarification of the molecular defects and the recognition of autoantibody-mediated deficiency of ADAMTS13 activity provide the central pathophysiologic basis for the current paradigm, which has begun to change our clinical approach to this devastating disease.2, 3 Our desire to capture the impact of new classification and treatment strategies has spawned international registries in the United Kingdom, France, Japan, and Australia over the past few years.3-6 Together with the well-established Oklahoma Registry, they seek to answer key questions regarding management such as the benefit of using potent immunosuppressive drugs that suppress autoantibody production.7, 8 Two studies in this issue of TRANSFUSION provide insight that targeting autoimmunity may be an effective approach. The study by Som and colleagues9 extends the previous work of the Oklahoma group in cataloging the complications of PEX in the management of TTP. They describe the incidence of major complications of PEX observed in the most recent 3-year cohort (2008-2011) compared to sequential 3-year cohorts extending back to 1996 (a total of five periods spanning 15 years). As before, they found that a majority of complications arise from use of a central venous catheter. Their analysis of the most recent cohort indicates a significant reduction in major morbidity of PEX in ADAMTS13 severely deficient patients but not in the nonseverely deficient (≥10%) patients, which correlated with a reduction in the number of procedures required to treat the ADAMTS13 severely deficient patients. They go on to show significant differences in the manner of treatment, with more patients in the contemporary group being treated with corticosteroids and rituximab. They hypothesize that the reduction in the procedures per patient is due to the increasing use of immunosuppression in recent years, as clinicians altered their practice by using corticosteroids in all patients and rituximab in up to 40% of severely ADAMTS13-deficient patients. Although the study has “street cred” because it is based on prospectively collected registry data without the referral and selection bias inherent in many single-center studies, it still represents only an indirect demonstration of efficacy and does not differentiate which of the two immunosuppressive agents is responsible for the apparent benefit. A few other questions are also raised by their study, such as the optimal timing of rituximab use. The investigators did not use a prescribed protocol for deciding when to administer rituximab, relying instead on the clinical judgment of different physicians in 12 hospitals to initiate the drug “when patients had a prolonged clinical course, such as the occurrence of new neurologic abnormalities or recurrence of thrombocytopenia. …” Should the autoantibody-producing B cells be targeted early as an adjuvant strategy or later? Corticosteroids are generally used as early adjuvant therapy in the management of TTP, whereas rituximab is typically used (as it was in this study) for salvage treatment of patients who are refractory to therapy (relapsed patients who received rituximab soon after they relapsed were not included). Although the timing of first dose was not provided in the Oklahoma series, in 2009 the NHLBI Transfusion Medicine Hemostasis Clinical Trials Network conducted a survey among 10 of its sites (including Oklahoma) to address the current clinical use of rituximab. Based on the survey data, of the 40 patients considered to have “idiopathic” TTP, 11 (27.5%) were given rituximab. The time to starting rituximab averaged 12.7 (range, 1-58) days from the first PEX procedure. So, it appears that clinicians decide to use rituximab about 2 weeks or so after starting PEX. The relatively high rate of salvage therapy in this survey and in the Oklahoma Registry, given after current therapy utilizing PEX and corticosteroids, raises the question of whether rituximab should be used earlier in management. Another key question, not addressed in the Oklahoma report, concerns the effect of rituximab on the high rate of relapse in TTP, estimated at 30% to 50%.2, 10, 11 Two recent Phase II prospective studies have evaluated early rituximab use in comparison to historical controls (a third trial is under way in Canada).12 Scully and colleagues13 in the United Kingdom reported in 40 patients that giving very early rituximab (within 3 days of initial exchange) along with high-dose corticosteroids resulted in a shorter period of thrombocytopenia but not in PEX number (18 vs. 16.5) and shorter hospital stay (approx. 7 days less but only in a subgroup of non-ICU patients). They also reported a significantly lower relapse rate compared to historical control patients treated with corticosteroids and PEX: only 10% of trial patients relapsed (median, 27 months remission) versus 57% of controls (median, 18 months). In a related study Froissart and colleagues14 reported on the use of rituximab as a salvage therapy compared to historical controls. The mean time to initiation of rituximab was 8.4 ± 3.3 days after first PEX, based on patients having a “suboptimal response,” which they defined as a platelet (PLT) level less than two times initial count after 4 days of PEX/corticosteroids or clinical and/or PLT exacerbation (decline to <100 × 109/L at least 2 days) before achieving durable remission. As above, the French investigators also found that the time to PLT recovery was shorter: by Day 35 all 21 rituximab-treated survivors (one death) attained durable remission compared to 41 (78%) of 53 controls (p < 0.02). Although relapse was low in the first year, in contrast to the experience of Scully and colleagues, the incidence of long-term relapse (>1 year) was not significantly different in the two groups. George15 has also reported the Oklahoma results, with no early relapses occurring in the first 2 years but 3 of 21 (14%) rituximab-treated patients having relapsed at 30, 32, and 34 months after treatment (p = NS). This observation is significant in that a high proportion of relapses in severe ADAMTS13-deficient patients not treated with rituximab occur within the first year and suppressed autoantibody-producing B-lymphocyte levels begin to recover 9 to 12 months after a course of therapy.10, 14 Thus, consistent with its measured B-cell–depleting effect, it appears that rituximab protects against early but not later relapse. On this score, additional follow-up data and/or clinical trials will be required for its full impact to be known. At the present time nonrandomized studies of rituximab in addition to corticosteroids in acute TTP, with variable criteria for initiating rituximab therapy, suggest benefit in reducing the duration of thrombocytopenia and a reduction in subsequent relapse. The main effect in terms of duration of thrombocytopenia appears to be reducing exacerbation of TTP after PEX is discontinued.15 This observation has led the Oklahoma group to discontinue the time-honored practice of “tapering” PEX treatments over several weeks to assure attainment of remission, resulting in a net reduction in procedures. Interestingly, the number of PEX procedures needed to achieve remission in the Oklahoma and UK experience varied quite a bit: a mean of 8 days in the latest cohort from Oklahoma and twice that number, or 16.5, in the UK series despite earlier use of rituximab! Although it is difficult to compare studies using varied methods, differences in steroid use (both groups used pulse methylprednisolone 1 g daily for 3 days, but corticosteroids were not used thereafter in the United Kingdom whereas daily oral prednisone was used in the Oklahoma series) and/or racial attributes of the patient populations studied could account for some of this variation: in the United Kingdom the median number of procedures needed to induce remission for Afro-Caribbean patients was 24 while only 11.5 procedures were needed in the white patients. In addition to the increasing use of rituximab in the management of acute TTP, several reports on the use of rituximab to maintain remission have appeared.16-18 Not surprisingly, the approaches to maintenance therapy are quite varied in terms of dose and frequency of drug administration and clinical or laboratory factors used to guide therapy. Illustrative of these observations is the case report by Bhagirath and coworkers19 reported in this issue of TRANSFUSION. The authors describe a 45-year-old woman with relapsing (every 2 years for 20 years) idiopathic TTP characterized by absent ADAMTS13 activity and the presence of ADAMTS13 inhibitor during acute presentations who responded to a standard-dose regimen of rituximab (375 mg/m2 × 4 doses) given as salvage therapy after failing multiple therapeutic interventions. The patient relapsed 19 months later and again failed standard therapy. However, she then experienced a dramatic response after receiving a single dose of rituximab with her PLT count reaching normal levels within 48 hours as ADAMTS13 activity levels increased. Due to development of serum sickness, the investigators employed an alternative dose regimen whereby three subsequent doses of rituximab (375 mg/m2) were administered over a period of 1 year (at 4-month intervals) without consideration of circulating levels of ADAMTS13 activity or inhibitor; the patient remains in remission at 3.5+ years. The authors suggest the success of this approach may be derived from persistent suppression of autoreactive plasma cells as a consequence of maintenance immunosuppressive therapy as has been described by reports on rituximab's mechanism of action in autoimmune disease.20 Other approaches to remission maintenance have been described based on rituximab treatment “tailored” to monitoring ADAMTS13 activity levels.17, 18 Clearly, clinicians are utilizing the potent immunomodulating effects of rituximab in many different ways. What is the downside? Fortunately, reports of serious adverse events are infrequent. Acute infusion-related hypotensive reactions witnessed in lymphoma patients with a high lymphocyte burden are quite rare in patients with TTP who have normal or even low B-cell counts. Also rare are serious infectious complications reported in patients with TTP, which include reactivated cytomegalovirus and varicella zoster myelitis.21, 22 Additional serious infectious complications reported in other patient populations receiving rituximab include progressive multifocal leukoencephalopathy, reactivated hepatitis B, and serious infections related to prolonged hypogammaglobulinemia (>11 months’ duration).23 Overall, the risk profile for rituximab appears to be favorable and the morbidity of TTP outweighs the risk. However, monitoring for long-term toxicity remains critically important. In the absence of randomized controlled trial evidence or protocol guidance, the decision to use rituximab should be individualized. Relapsed TTP and early refractory TTP (within 1-2 weeks of the start of PEX) are reasonable candidates. Since slightly more than half of newly diagnosed patients do not experience relapse, it is difficult to justify early adjuvant treatment with rituximab in all patients. Serial monitoring of ADAMTS13 activity and inhibitors during remission may be useful in identifying those headed for a relapse.24 There is only anecdotal data to support maintenance therapy at the present time. In light of the difficulties of conducting large-scale randomized trials in TTP, the Oklahoma, UK, and French registries whose results are highlighted here are to be congratulated for their efforts in documenting how clinicians manage patients with TTP and pursuing standard data collection protocols with carefully monitored clinical outcomes. Through their efforts we are indeed getting closer to understanding the powerful role of immunomodulatory therapies that will continue to translate into improved care for patients with this challenging disorder. None.

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