An ASTCT, CIBMTR, EBMT, and APBMT Consensus Statement Defining Response Criteria for Hematopoietic Cell Transplantation Associated Thrombotic Microangiopathy (TA-TMA) Directed Therapy
Transplantation and Cellular Therapy, vol. 31, pp. 610–623
Abstract
BACKGROUND: Transplant associated thrombotic microangiopathy (TA-TMA) confers significant morbidity and mortality in hematopoietic cell transplant recipients. The safety and efficacy of multiple TA-TMA directed therapeutic agents are being tested in ongoing clinical trials. In the absence of approved drugs, several treatments are used off-label. Response definitions to TA-TMA directed therapy from retrospective studies and ongoing interventional clinical trials vary widely, limiting cross study comparisons. An expert panel from multiple international blood and marrow transplant societies (ASTCT, CIBMTR, EBMT, APBMT) who initially convened to harmonize diagnostic and risk stratification criteria for TA-TMA extended its mandate to review response criteria. OBJECTIVE: Our objective was to propose clinically meaningful response criteria for TA-TMA directed therapy to enhance consistent evaluation of therapeutic agents in clinical practice, interventional trials, and registry studies. METHODS: After a relevant literature review, the Delphi method was used to achieve consensus on proposed response criteria. RESULTS: The panel focused on the 3 key concepts. First, due to ongoing concurrent co-morbidities and severity of illness, the complete resolution of TA-TMA manifestations may be difficult to achieve immediately after initiating treatment, making the definition of clinically meaningful partial responses essential to assess early efficacy of TA-TMA-directed therapies. Second, because hematologic manifestations may resolve faster than organ damage, we suggest assessing hematologic/biochemical and organ manifestations independently, in addition to having an overall response assessment. Finally, using the previously established diagnostic criteria as a framework, we propose objective response definitions for each TA-TMA criterion and organ manifestation. While consensus was achieved on response definitions, due to the lack of evidence, there was no agreement on standardized time points for assessing response or when to consider alternative therapies for patients unresponsive to initial treatments. Hematologic and biochemical response assessments include anemia and thrombocytopenia, with criteria accounting for transfusion dependence or independence at the time of treatment, schistocytes, lactate dehydrogenase, and soluble C5b-9. Patients with other established etiologies of cytopenias (i.e. poor graft function or relapsed hematologic malignancy) should be considered unevaluable for hematologic response. Responses for involved organ manifestations were also proposed. In an overall assessment, the best overall response is limited by the lowest hematologic/biochemical or organ response. NR of either hematologic/biochemical or organ is considered an overall NR. CONCLUSION: The consensus response criteria proposed by this expert panel are a step towards standardizing the assessment of treatment responses of TA-TMA directed agents for future studies and interventional clinical trials. Adoption of these criteria will enhance consistency of response assessment and facilitate the comparison of TA-TMA treatments. Since achieving an early overall CR may be challenging/protracted in patients with organ injury; establishment of criteria for clinically meaningful PR is important and may be a more useful early endpoint in studies. Given the complexity of these patients and assessment of response, these definitions may need be revised in the future after application in large cohorts diverse in age, HCT approaches, and interventional agents.
Authors 19
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Emory University · Children's Healthcare of Atlanta
Affiliation as printed
Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University, Atlanta, Georgia
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G. Papanikolaou General Hospital
Affiliation as printed
Hematology Department, G Papanikoloaou Hospital, Thessaloniki, Greece
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Hospital Universitario Puerta de Hierro Majadahonda
Affiliation as printed
Department of Hematology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
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Affiliation as printed
Department of Internal Medicine, Catholic Blood and Marrow Transplantation Center, Seoul, Korea
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Cincinnati Children's Hospital Medical Center
Affiliation as printed
Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
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Affiliation as printed
Department of Medical Oncology, Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts
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Cincinnati Children's Hospital Medical Center
Affiliation as printed
Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
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Affiliation as printed
RM Gorbacheva Research Institute, Pavlov University, Saint-Petersburg, Russian Federation
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Isabel Sánchez‐Ortega Aachen
European Society for Blood and Marrow Transplantation · European Society for Blood and Marrow Transplantation
Affiliation as printed
European Society for Blood and Marrow Transplantation (EBMT) Executive Office, Barcelona, Spain
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Christian Medical College, Vellore
Affiliation as printed
Department of Haematology, Christian Medical College, Vellore, India
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The Japanese Data Center for Hematopoietic Cell Transplantation
Affiliation as printed
Japanese Data Center for Hematopoietic Cell Transplantation, Nagoya, Japan
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Affiliation as printed
Department of Medical Oncology, Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts
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Affiliation as printed
Division of Hematology, Ohio State University, Columbus, Ohio
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Karolinska University Hospital
Affiliation as printed
Department of Cellular Therapy and Allogeneic Stem Cell Transplantation, Karolinska University Hospital Huddinge, Stockholm, Sweden
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The University of Texas MD Anderson Cancer Center
Affiliation as printed
Department of Stem Cell Transplantation & Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas
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Affiliation as printed
Center for International Blood and Marrow Transplant Research, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin
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Affiliation as printed
Clinical Hematology Department, Institut Català d'Oncologia-Hospitalet, Barcelona, Spain
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Affiliation as printed
Department of Medical Oncology, Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts
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Sumithira Vasu corresponding
Affiliation as printed
Division of Hematology, Ohio State University, Columbus, Ohio. Electronic address: Sumithira.Vasu@osumc.edu
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