The Hematologist

March-April 2019, Volume 16, Issue 2

Real World Data on CAR T-Cell Recipients: Are We There Yet?

Marcelo C. Pasquini, MD, MS Associate Professor of Medicine; Sr. Scientific Director for CIBMTR
Medical College of Wisconsin, Milwaukee, WI
Miguel-Angel Perales, MD Deputy Chief, Adult Bone Marrow Transplantation Service; Director, Adult Stem Cell Transplantation Fellowship
Memorial Sloan Kettering Cancer Center, New York, NY

Published on: February 13, 2019

These are unprecedent times for cancer treatment. Only the most prescient among us might have predicted that in 2019 routine clinical practice could include the genetic modification of a patient’s own cells being used against acute leukemia, lymphoma, and soon, many other cancers. And yet, that time is here. The rapid availability of these living drugs, which includes T cells expressing chimeric antigen receptors (CAR T-cells), is a result of their significant potential to control malignancies in patients who have failed other therapies. The U.S. Food and Drug Administration (FDA) has approved these drugs given a high efficacy signal but raised concerns related to their safety. The approval of tisagenlecleucel for treatment of pediatric acute lymphocytic leukemia (ALL), and tisagenlecleucel and axicabtagene ciloleucel for treatment of non-Hodgkin lymphoma (NHL), came with significant strings attached. Like any genetically engineered product using viral vectors, the FDA required that recipients of commercial CAR T-cells be observed for 15 years.1 Additionally, the FDA has implemented product-specific Risk Evaluation and Mitigation Strategy (REMS) programs to maximize safety.2,3 These requirements are unprecedented for any drug approval to date and give our community the opportunity to develop paradigms for measuring safety and efficacy over time in an rigorous and collaborative manner.

With this mission in mind, the Center for International Blood and Marrow Transplant Research (CIBMTR), a decades-old outcomes database for hematopoietic cell transplantation (HCT), has expanded its infrastructure to capture data on cellular immunotherapies. The aim is comprehensive data collection through a standardized approach that can be used for both regulatory requirements and research. The recent implementation of the National Cancer Institute–funded and Moonshot Initiative program called Cellular Immunotherapy Data Resource, awarded to the CIBMTR, will further assist in capturing real-world data on recipients of these cellular therapies.

The CIBMTR is a research collaboration between Medical College of Wisconsin and the National Marrow Donor Program/Be the Match that operates an outcomes database on HCT and now, cellular therapies. The operations of this nonprofit organization are funded primarily by federal grants. The CIBMTR also holds a contract with the Health Resource and Service Administration to operate the Stem Cell Therapeutics Outcomes Database (SCTOD) of the C.W. Bill Young Cell Transplantation Program. Through the SCTOD, according to the requirements of this contract, the CIBMTR functions as a public health authority to capture all allogeneic HCT performed in the United States, along with analyzing data to assess patient survival and center performance. The CIBMTR is a resource to the community, used for research in clinical outcomes, immunobiology, health services research, bioinformatics, statistical methodology, and clinical trials. This resource has resulted in more than 350 publications authored by 1,600 authors from 450 institutions in the past 10 years, highlighting both the productivity of the CIBMTR and its collaborative nature.

In the past three years, the CIBMTR has expanded its infrastructure to capture data on indications and outcomes of cellular therapies. The objective is to capture any cellular therapy infusion and to provide a mechanism for long-term follow-up. The long-term follow-up approach of the cellular therapy registry intentionally aligns with FDA regulatory requirements that patients receiving genetically modified cellular therapy products must be followed up on for at least 15 years to assess the risk of development of subsequent neoplasms and other potential late adverse effects. This also aligns with practices in the HCT field facilitated by the CIBMTR throughout the past 40 years, where data collection is part of the culture and sheds light on real-world outcomes of patients who received transplantation.

Since the release of the cellular therapy outcomes database in July 2016, the CIBMTR has engaged the community to implement data collection practices and to test data collection forms at participating centers. The FDA approvals for both CAR T-cell products carry a requirement that manufacturers establish a mechanism for long-term follow up of these patients. The CIBMTR is currently contracted with both Novartis and Kite/Gilead to use its cellular therapy registry to capture data on safety and efficacy in order to fulfill these regulatory requirements. Notably, after these data are collected and reported to the relevant regulatory agencies, they will be available for research purposes, following the pattern established with HCT data and the SCTOD. Additionally, in October 2018, the CIBMTR was awarded the Cellular Immunotherapy Data Resource program, whose main objective is to build and maintain an infrastructure for data collection from recipients of cellular therapies for cancer and implement data sharing practices to maximize the use of this data for research. The CIBMTR Cellular Therapy Registry is fully functional, with more than 80 centers in the U.S. currently reporting data.

Participation in the CIBMTR database is open to any program and requires establishing an agreement governing the terms and expectations of data and sample sharing, data completeness and quality, Institutional Review Board and Privacy Rule oversight, and use of the electronic data collection system. Data quality is a very high priority. CIBMTR performs regular data audits of centers to evaluate data quality. Audit reports are shared with the Foundation of Accreditation of Cell Therapies for inclusion in the center accreditation process.

The CIBMTR convened the fourth annual Cellular Therapy Registry Forum on October 26, 2018, in Washington, DC. The objectives of this meeting were to engage the broader community of cellular therapy stakeholders and to discuss relevant topics related to the development and implementation of the cellular therapy registry.

One theme that became apparent at the meeting was a desire by treatment centers to have alignment of data collection and toxicity reporting from recipients of commercial CAR T-cells. In addition to the mandate for long-term data reporting of recipients of these products, the FDA mandates the institution of a REMS program. The REMS program is intended to capture serious toxicities to understand whether risks are appropriately mitigated. Each REMS program is specific to a CAR T-cell product, but the toxicities are generally common to the treatment class and are intentionally captured by the CIBMTR Cellular Therapy Registry. After robust discussion, a recommendation was made to develop a plan to capture REMS-compliant toxicities systematically through the CIBMTR Cellular Therapy Registry and subsequently share reports with each pharmaceutical company for submission to the FDA for review. This could be appropriately done for expected CAR T-cell–associated toxicities that are already included in the forms. If successful, this approach will serve as another important point of synergy and utilization of this registry and facilitate standardized capture of toxicities related to these therapies.

Another challenge in the field has been capturing toxicity in a uniform way with several different grading systems being issued by different investigators and industry. In parallel to the efforts of the CIBMTR to standardize data collection, the American Society of Blood and Marrow Transplantation (ASBMT) focused on developing a common toxicity grading system and convened a group of experts on June 20, 2018, in Washington, DC. They recently published a consensus grading system that covers both cytokine release syndrome and neurotoxicity.4 Components from this new consensus grading criteria were incorporated in the CIBMTR cellular therapy report forms.

While new therapies can usher in feelings of hope, they come with a steep learning curve. Capturing real-world data on patient outcomes is an important exercise which will catapult this field forward. Fortunately, many lessons learned from the HCT field are readily applicable in this case and propel us closer to our destination.


  1. U.S. Department of Health and Human Services. Long term follow-up after administration of human gene therapy products. July 2018.
  2. U.S. Food and Drug Administration. Approved risk evaluation and mitigation strategies (REMS). Kymriah (tisagenlecleucel). 2018.
  3. U.S. Food and Drug Administration. Approved risk evaluation and mitigation strategies (REMS). Yescarta (axicabtagene ciloleucel). 2018.
  4. Lee DW, Santomasso BD, Locke FL, et al. ASBMT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant. 2018; doi: 10.1016/j.bbmt.2018.12.758. [Epub ahead of print].

Conflict of Interests

Dr. Pasquini indicated no relevant conflicts of interest. Dr. Perales reported honoraria from Abbvie, Bellicum, Bristol-Myers Squibb, Incyte, Merck, Novartis, Nektar Therapeutics, and Takeda. He serves on data and safety monitoring boards for Servier and Medigene and on the scientific advisory boards of MolMed and NexImmune. He has received research support for clinical trials from Incyte and Miltenyi Biotec. He serves in a volunteer capacity as a member of the Board of Directors of the American Society of Blood and Marrow Transplantation and Be the Match (National Marrow Donor Program), as well as on the CIBMTR Advisory Committee and Cellular Immunotherapy Data Resource Oversight Committee. back to top