Britt Balser Foundation For TTP Information on Research on TTP
by Dr. Spero Cataland:
The National Blood Foundation (NBF) Announces
Recipients of the 2007 NBF Scientific Research Grants
Bethesda, Md. - The National Blood Foundation (NBF) Board of Trustees recently announced the recipients of the 2007 NBF Scientific Research Grants. Each grant recipient will receive up to $65,000 to pursue either a one- or two-year research project in the field of blood banking, transfusion medicine or cellular and related biological therapies. To date, NBF has awarded more than $5 million in grants since 1985 to 145 early-career researchers. This year’s recipients are: Spero Cataland, MD; Peiman Hematti, MD; Cheryl Lobo, PhD; Louise McCormick, PhD; Michael Milsom, PhD; Lirong Qu, MD, PhD; Astrid Van Halteren, PhD; Saul Yedgar, PhD; and Gregory Barshetin, PhD.
“The NBF Grants Review Committee received 32 applications for innovative research proposals from professionals in the United States and four other countries,” said Connie Westhoff, PhD, chair of NBF's Grants Review Committee. “This year we saw a marked increase in applications on cellular and related biological therapies, compared to past years.”
Proposals for NBF grants are evaluated on the basis of their scientific merit; relevance to and impact on transfusion medicine and science. NBF scientific research grants are made possible by contributions from NBF's Council on Research and Development (CORD) members and its NBF Partners, along with gifts from individuals, institutions and foundations.
The following are synopses of the eight winning proposals:
Spero Cataland, MD, Ohio State University
Cyclosporine or Corticosteroids with Plasma Exchange in TTP
With an interest in the use of immune-based therapy of thrombotic thrombocytopenic purpura (TTP) and funding from the NBF grant, Cataland will begin a randomized study of the efficacy of cyclosporine or corticosteroids as an adjunct to plasma exchange for the treatment of TTP. Previous studies have indicated that the effectiveness of cyclosporine is related to the suppression of the antibody inhibitor of a disintegrin and metalloprotease with thrombospondin type-1 motif, member 13 (ADAMTS13) and improvement in ADAMTS13 activity and antigen. ADAMTS13 is reduced in TTP. Developing a practical immune-based therapy of TTP potentially could minimize a patient’s exposure to plasma and the complications of the plasma exchange procedure, while also conserving valuable blood bank resources.
Effect of Prophylactic Cyclosporine Therapy on ADAMTS13 Biomarkers in Patients with Idiopathic Thrombotic Thrombocytopenic Purpura
Spero R. Cataland,1 Ming Jin,2 Shili Lin,3 Eric H Kraut,1 James N. George,4 and Haifeng M. Wu2
1 Division of Hematology/Oncology, Department of Internal Medicine, Ohio State University, Columbus, OH 43210
2 Department of Pathology, Ohio State University, Columbus, OH 43210
3 Department of Statistics, Ohio State University, Columbus, OH 43210
4 Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73190
Corresponding Author: Spero R. Cataland, M.D., Department of Internal Medicine, Ohio State University College of Medicine and Public Health, 320 W. 10th Ave., 306B Starling Loving Hall, Columbus, OH 43210, Telephone: (614) 293-2887; Fax: (614) 293-7529, Email:
The publisher's final edited version of this article is available at Am J Hematol
Abstract
Several reports have been published regarding the use of cyclosporine (CSA) in the treatment of idiopathic thrombotic thrombocytopenic purpura (TTP). We hypothesized that prophylactic CSA therapy may prevent recurrences in patients with a history of multiple relapses of TTP. Nineteen patients with idiopathic TTP were enrolled on prospective studies at Ohio State University between September 2003 and May 2007. Patients achieving remission remained on CSA therapy for 6 months, allowing us to evaluate the efficacy of CSA as prophylactic therapy. CSA was administered orally at a dose of 2–3 mg/kg in a twice a day divided dose in all patients and continued for a total of 6 months. Long-term clinical follow-up with serial analysis of ADAMTS13 biomarkers during and after CSA therapy were performed to evaluate the efficacy of CSA as a prophylactic therapy. 17/19(89%) patients completed 6 months of CSA therapy in a continuous remission. Two patients relapsed during therapy with CSA and 7 patients relapsed after discontinuing CSA therapy. Ten patients have maintained a continuous remission a median of 21 months (range, 5 to 46) after discontinuing CSA. The ADAMTS13 data suggest that CSA resulted in a significant increase in the ADAMTS13 activity during therapy with CSA. 8/9(89%) relapsing patients had severely deficient ADAMTS13 activity (< 5%) suggesting this is a significant risk factor for relapse of TTP. These data support the hypothesis that prophylactic CSA improves the ADAMTS13 activity and may be effective at preventing relapses in patients at risk for recurrences of TTP.
Keywords: thrombotic thrombocytopenic purpura, ADAMTS13, cyclosporine, relapse, prophylactic therapy
Introduction
Our group has conducted several clinical studies to evaluate the efficacy of CSA, both as an adjunct to plasma exchange (PE) (1, 2) and alone in the treatment of idiopathic TTP(3). While these data suggest the efficacy of CSA in idiopathic TTP, questions regarding the mechanism of action and the risk of relapse after stopping CSA remain to be answered. Therapy with CSA continued after a patient has achieved a sustained (> 30 days) remission could be viewed as prophylactic, with a goal of preventing relapses (recurrence of TTP > 30 days after the last exchange) of TTP. This analysis is focused over the time period beginning 30 days after remission was achieved, allowing us to study the efficacy and potential mechanisms of action of prophylactic CSA in the prevention of relapses of TTP.
Results
Clinical Efficacy Data
Seventeen out of the 19(89%) patients completed the planned 6 months of CSA therapy in a continuous clinical remission (Figure 1). Two of 19 (11%) patients relapsed during the 6 month course of CSA after 3 and 4 months of CSA respectively, one of which relapsed 2 weeks after a 50% dose reduction of the CSA as mandated by the study for an increased serum creatinine. After discontinuing CSA, 7/17 (41%) patients relapsed a median of 2 months (range, 0.5 to 33) after stopping CSA therapy. An analysis of the risk of relapse both during and after discontinuing CSA therapy in terms of events per month at risk was completed. During therapy with CSA, 3 recurrences (2 patient relapsing as described above during the initial 6 month CSA course, and one additional patient during his extended course of CSA as described below in the section entitled: “Long-Term Prophylactic CSA Therapy) occurred over 61 total months of cumulative CSA therapy for all patients. After discontinuing CSA, 6 recurrences occurred over 263 months of cumulative follow-up for all patients. The difference in the recurrence rate per month at risk during therapy with CSA compared to after discontinuing CSA therapy was not statistically significant (4.9% v. 2.3%, p=0.49). Ten of 17 (59%) patients have maintained a continuous clinical remission a median of 21 months (range, 5 to 46) after discontinuing CSA therapy.
Patients
Nineteen patients with idiopathic TTP previously enrolled on prospective, therapeutic studies at our institution between September 2003 and May 2007 that achieved remission after CSA therapy alone or as an adjunct to PE were included in this analysis. Eligibility criteria for these studies included a clinical diagnosis of idiopathic TTP, defined as a microangiopathic hemolytic anemia and thrombocytopenia (<100·109/L) without an alternative etiology. ADAMTS13 activity and inhibitor status were not known at enrollment and were not eligibility criteria for these studies. The focus of this analysis was the efficacy of CSA at preventing future relapses of TTP, therefore only patients from these previous studies that achieved a sustained remission (clinical remission >30 days after the last exchange procedure) with CSA were included. Fifteen patients achieved remission after treatment with concurrent CSA and PE that are included have been reported previously(2). Four additional patients achieved remission with the use of CSA. Two patients were treated with CSA alone for early recurrences of TTP as reported previously(3), and 2 additional patients had CSA added to PE after their failure to be successfully tapered from PE. Both patients had PE discontinued on at least 2 occasions, only to develop a recurrent thrombocytopenia and rising lactate dehydrogenase levels within 48 hours necessitating the resumption of PE. After the last failed tapering from PE, CSA was started with the resumption of PE and continued for 6 months as with the other patients. These two patients have not been reported previously. Demographic details for all 19 patients are shown in Table I.
Treatment
In the patients that received CSA concurrent with PE to achieve remission, PE was performed and tapered using a uniform protocol that was consistent across all clinical trials as reported previously using cryoprecipitate-poor plasma as the replacement fluid(1, 2). CSA was started concurrently with the initiation of PE and administered orally at a dose of 2–3 mg/kg in a twice a day divided dose and continued for 6 months. Steroids were not administered except for intermittent intravenous doses of hydrocortisone as needed to treat reactions to the infused plasma. The 4 patients that started CSA at later time points (2 for early recurrences of TTP, 2 who failed tapering of PE) were treated with CSA at the same dose (2–3 mg/kg) and duration (6 months) of therapy. Based upon a history of multiple (>2) recurrences of TTP, 5 of the19 patients continued CSA beyond the planned 6 months as long-term prophylactic therapy. Patients were seen monthly during the six month course of CSA and then every 3 months in follow-up after discontinuing CSA therapy for clinical follow-up and to obtain samples to analyze the ADAMTS13 biomarkers.
Measurement of ADAMTS13 Biomarkers (ADAMTS13 Activity, Antigen, and ADAMTS13 Antibody (IgG) Concentration)
Plasma ADAMTS13 activity was determined using a method involving Surface Enhanced Laser Desorption/Ionization Time-of-flight Mass Spectrometry (SELDI-TOF-MS) that has been reported previously(14). SELDI-TOF-MS has the ability to provide rapid protein/peptide analysis. One distinguishing feature of SELDI-TOF-MS involves the surface chemistry of ProteinChips that allows for selective, rapid purification of protein/peptide candidates prior to analysis by mass spectrometry. Determination of the ADAMTS13 activity using the peak area of the peptide generated from the cleavage reaction rather than the peak height of the curve provides greater reproducibility and accuracy for all levels of ADAMTS13 activity, but especially at low levels of ADAMTS13 activity. The mass spectrometer-based assay directly measures the analyte in the sample and therefore is less affected by potential interfering factors such as hemolysis or bilirubin. ADAMTS13 autoantibody and ADAMTS13 antigen levels were determined using ELISA kits developed by American Diagnostica Inc. (Stamford, CT; USA)(® ADAMTS13 Autoantibody ELISA Imubind, IMUBIND® ADAMTS13 ELISA). The results from these tests are reported as micrograms of IgG antibody and nanograms of ADAMTS13 protein per milliliter of patient plasma respectively.
Statistical Methods
We fitted a regression model to compare the profiles (based on serial measurements) of the ADAMTS13 activity during the 6-month course of prophylactic CSA therapy between the group of patients maintaining a continuous remission versus the group who eventually relapsed after discontinuing CSA. Because the serial measurements of each patient are correlated, we included a random effect component in the model to account for such correlations. Analysis to compare the ADAMTS13 antibody inhibitor and antigen between these two groups was carried out similarly, but with the data being log-transformed first to achieve approximate normality. To gauge whether any of the three ADAMTS13 biomarkers could be used to predict whether a patient would benefit from using CSA as a prophylactic treatment therapy, we also compared the 2 patients who relapsed during CSA treatment with the patients that completed 6 months of therapy in a continuous remission. The same analysis strategy used for the first set of comparisons was applied to this comparison.
Acknowledgments
This study is supported in part by grants from National Institutes of Health K08HL03279, grant support from Ohio Biomedical Research and Technology Transfer Commission, and support from the Britt Balser Foundation for TTP.
References
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