Immuno-Oncology Resource Center
Immuno-Oncology Resource Center
Issue: February 2020
Source/Disclosures
Disclosures: Jain reports a consultant role with Takeda Oncology. Perales reports honoraria from AbbVie, Bellicum Pharmaceuticals, Bristol-Myers Squibb, Incyte, Merck, Novartis, Nektar Therapeutics, Omeros and Takeda Oncology. Goy reports no relevant financial disclosures.
February 24, 2020
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Expert Panel Document Guides CAR-T Use for Advanced B-Cell Lymphoma

Issue: February 2020
Source/Disclosures
Disclosures: Jain reports a consultant role with Takeda Oncology. Perales reports honoraria from AbbVie, Bellicum Pharmaceuticals, Bristol-Myers Squibb, Incyte, Merck, Novartis, Nektar Therapeutics, Omeros and Takeda Oncology. Goy reports no relevant financial disclosures.
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The American Society for Transplantation and Cellular Therapy published an expert panel opinion document on the use of chimeric antigen receptor T-cell therapies for patients with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma.

The document, published in Biology of Blood and Marrow Transplantation, provides guidance for the use of both CD19-directed CAR T-cell therapies — axicabtagene ciloleucel (Yescarta; Kite Pharma, Gilead) and tisagenlecleucel (Kymriah; Novartis) — that are FDA-approved for this patient population.

“Given the relatively recent introduction of CAR T-cell therapy to standard-of-care practice, concerns have been raised about important factors involved in safe and appropriate use of this novel treatment approach and the recognition and treatment of side effects,” Tania Jain, MBBS, assistant professor of oncology at Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, and colleagues wrote.

Cell Therapy Next spoke with Jain, lead author of the expert panel document, and others in the field about the significance of this document and how it can be applied to clinical practice.

In the Absence of Guidelines

Tania Jain

Given the lack of comprehensive treatment guidelines on CAR T-cell therapy for B-cell non-Hodgkin lymphoma, the American Society for Transplantation and Cellular Therapy (ASTCT) expert panel convened to provide answers to practical clinical questions about the use of this relatively new treatment.

“Our group thought about the various practical questions that come about with the utilization of CAR-T, both from a referring physician standpoint and also from the [standpoint of a] treating physician at a tertiary center,” Jain told Cell Therapy Next. “At our first meeting, we talked about what questions we could address in this paper. ... We formulated responses, based on the data available, and provided our recommendations to help with those questions in clinical practice.”

This type of document typically precedes more technical, comprehensive, evidence-based guidelines at a time when the evidence for a particular treatment is still accumulating and best practices are being formulated, Jain said.

Andre Goy

The panel comprised experts in stem cell transplantation, cell therapy and lymphoma. It also included investigators involved in the pivotal trials of approved CAR T-cell products, as well as key members of ASTCT.

“We addressed some of the questions that we have encountered in our practice as we start our experience with CAR-Ts,” Jain said. “We put our heads together to come up with practice suggestions in certain situations.”

Patients have been receiving CAR T-cell therapies at participating trial sites for several years, and the treatment’s proliferation beyond those sites makes an expert opinion document useful in the absence of guidelines, according to Andre Goy, MD, chief of the division of lymphoma and chairman and director of John Theurer Cancer Center at Hackensack University Medical Center, as well as a member of the Cell Therapy Next peer perspective board.

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“This expert panel document highlights some of the important points that are relevant to clinical practice,” Goy told Cell Therapy Next. “Some of the issues raised in this document are crucial because CAR T-cell therapy is not something that has been used in every center.”

Answering Your Most Important Questions

The document identified 10 key clinical questions (see box) about the use of CAR T-cell therapy for patients with advanced B-cell non-Hodgkin lymphoma. A summary of the evidence for each situation is provided, along with brief recommendations.

Here are some of the highlighted sections from the document:

Referring patients for CAR T-cell therapy: Eligibility criteria for the two pivotal trials of axicabtagene ciloleucel and tisagenlecleucel are provided as a table in the document. This section discusses which patients may be eligible for treatment with either product and for which indication. Key referral considerations include use of previous therapies, disease-specific considerations, comorbidities, and when and where to refer patients. This section also contains a schema for the recommended treatment of patients with relapsed or refractory diffuse large B-cell lymphoma.

Lymphodepletion or bridging therapy:The use of bridging therapy will depend on which product is chosen to treat a patient. The pivotal trial for axicabtagene ciloleucel, ZUMA-1, did not permit bridging therapy, whereas more than 90% of patients in the pivotal trial for tisagenlecleucel, JULIET, received bridging therapy. Because the two products contain different CAR T-cell constructs, the expert panel advised against direct comparison of the two trials. The panel concluded that more data with longer follow-up are needed to determine the impact of bridging therapy on clinical response to CAR T-cell therapy. This section also contains a table with package label recommendations for lymphodepletion chemotherapy regimen options and timing for each CAR T-cell product.

Lymphoma/CAR-T-specific toxicity considerations: The two most significant treatment-related toxicities to monitor for are cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The document recommends using the ASTCT Toxicity Consensus Grading system across all CAR T-cell products and indications to enable consistent reporting and comparison between products. Previously published reports have used a mix of grading systems. The document also details specific requirements for administering CAR T-cell therapies through the FDA’s restricted Risk Evaluation and Mitigation program and advises monitoring for signs of treatment-related toxicities for at least 4 weeks after infusion. Specific toxicity management strategies for CRS and ICANS also are discussed.

Monitoring response to therapy and long-term effects: This section provides an overview of how to monitor for disease progression after administration of CAR T-cell therapy, including the methods and time intervals. Also included are recommendations on laboratory monitoring, treatment options for patients who achieve disease remission, and treatment options for patients who have disease progression after CAR T-cell therapy. A separate section discusses current follow-up data up to 4 years after treatment and FDA/European Medicines Agency reporting requirements for regulatory approval.

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Key Takeaways

One of the key takeaways from the consensus document is the need for uniform guidelines on treatment-related toxicity assessments, such as those created by the ASTCT, according to Miguel-Angel Perales, MD, deputy chief of the adult bone marrow transplant service at Memorial Sloan Kettering Cancer Center and one of the co-authors of the expert panel document.

Many centers and trial sites are adopting the ASTCT Toxicity Consensus Grading system, which he said has received the support of the FDA.

Perales told Cell Therapy Next that ASTCT is working on guidelines for the consensus governance and management of CAR T-cell therapy-related toxicities, and they hope to have that document ready for publication early this year. In the absence of a more evidence-based guideline, however, the expert opinion document provides guidance on the management of toxicity for both the referring physician and the physician administering the therapy, Perales said.

Jain agreed with Perales’ assessment regarding the need for a uniform toxicity grading system.

“It’s imperative to harmonize how we rate toxicity across institutions and across trials so that we can make more sense out of that information, as various products are currently being studied or getting ready to do so,” she told Cell Therapy Next. “It becomes difficult to compare those toxicities if they have been graded using different criteria,” she added.

Jain highlighted two other points of emphasis in the expert consensus document: the importance of early referral to CAR T-cell therapy for eligible patients and long-term follow-up of patients who receive CAR T-cell therapy.

“Long-term data are lacking for patients treated with CAR-T,” she said. “We must continue to follow these patients and collect that data, and determine if there are any adverse events that we’re missing because of a lack of long-term analysis.”

Perales agreed about the importance of collecting long-term data on patients who receive CAR T-cell therapy.

“The data are actually required to be collected because of the way these drugs were approved by the FDA,” he said. “These data are currently being reported by centers to the Cellular Immunotherapy Data Resource (CIDR) of the Center for International Blood and Marrow Transplant Research (CIBMTR). As of the end of 2019, more than 1,500 patients had been reported.”

As for the expert panel document’s clinical relevance, Perales said its format and content make it both easy to use and clinically useful.

“The document is in a very practical FAQ format, and it is intended to provide answers to clinically useful and relevant questions,” he said.

Jain said she would recommend physicians who treat patients eligible for CAR T-cell therapy keep a copy of it handy.

“I’m hopeful that people will find this expert panel document useful because it covers various practical questions that come up in clinical practice,” Jain said. “I think it would be valuable as the use of CAR T-cell therapy grows for relapsed or refractory B-cell lymphoma.” by Drew Amorosi

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Disclosures: Jain reports a consultant role with Takeda Oncology. Perales reports honoraria from AbbVie, Bellicum Pharmaceuticals, Bristol-Myers Squibb, Incyte, Merck, Novartis, Nektar Therapeutics, Omeros and Takeda Oncology. Goy reports no relevant financial disclosures.