Fludarabine shortage requires flexibility, alternative approaches for CAR-T and HSCT
Click Here to Manage Email Alerts
For the second time in the last 2 years, a drug related to the administration of cellular therapy — fludarabine — has been placed on the FDA’s drug shortage list.
The FDA first noted the fludarabine shortage in May, with four of its manufacturers reporting either backordered or limited supplies available as of October.
The FDA Drug Shortages website lists four manufacturers for the drug. Areva and Accord Healthcare provide no reason for the supply shortage, whereas Fresenius Kabi USA noted increased demand. Teva and Areva claim to have available supplies of fludarabine as of October.
Fresenius, meanwhile, estimated January of next year for resupply.
Fludarabine is a cytotoxic chemotherapy that, when used in combination with cyclophosphamide, acts as a preconditioning treatment that suppresses the immune system to allow for the engraftment and expansion of cellular therapies within the host patient’s body.
Its integral role in the preconditioning regimen provided before most chimeric antigen receptor T-cell and hematopoietic stem cell transplant procedures means that shortages have required providers to be flexible to continue these services, according to Nirav N. Shah, MD, MSHP, associate professor of hematology and medical oncology at Medical College of Wisconsin and member of the Healio | Cell Therapy Next Peer Perspective Board.
“It’s a big problem,” he told Healio. “It's unfortunate, but drug shortages are becoming a common issue — for all sorts of drugs and across different medical disciplines.”
The shortage has affected individual institutions on different timelines, based on the amount of fludarabine they had stockpiled before supply issues became apparent, Shah added. Initially, his intuition was not affected by the shortage, but as summer turned to autumn and additional supply remained unavailable, it has forced Shah’s clinic to explore alternatives — where possible — to keep their treatment pipeline moving.
“We managed during the beginning of the shortage and were not dramatically affected,” he said. “But as time has gone by the situation has not relented.”
The biggest challenge he faces is having enough fludarabine available for his center’s clinical trial enrollees in studies evaluating HSTC or CAR-T. The regimens from clinical trials are locked in and there is no flexibility relative to substitutions, he added.
“This makes it difficult for patients to enroll in clinical trials if we're not able to acquire the fludarabine that is needed for them to get the regimen as prescribed on the clinical trial protocol,” Shah said.
Exploring the alternatives
Shah recently coauthored an editorial in Transplantation and Cellular Therapy highlighting the ongoing fludarabine shortage and recommending steps cell therapy clinics should take to address the issue.
Given the lack of a resupply timeline from manufacturers and reports that one supplier plans to drastically increase cost of the drug, Shah and colleagues called upon the American Society for Transplantation and Cellular Therapy to endorse a policy of fludarabine rationing to ensure proper conduct of clinical trials and maximize benefits of the available supply.
“It is our opinion that to maintain clinical trial standards and data validity, our immune effector community must remain committed to strict adherence to the protocol-defined lymphodepletion in ongoing clinical trials, unless the FDA allows for substitutions to corporate sponsors,” Shah and colleagues wrote. “In the event that the fludarabine shortage is persistent ... it becomes necessary for centers to establish algorithms for management now.”
Alternative regimens for allogeneic HSCT are in need, where fludarabine serves as the backbone of the preconditioning regimen, Shah said.
“We are now looking at alternatives for a lot of our standard-of-care regimens,” he told Healio, including the use of clofarabine or pentostatin instead of fludarabine.
“We've also now developed a protocol for bendamustine to be given in lieu of fludarabine,” Shah added.
The track record for fludarabine alternatives is somewhat more established in CAR T-cell therapy, as the use of bendamustine for preconditioning therapy is part of the regimen for administration of tisagenlecleucel (Kymriah, Novartis), Shah explained.
“We have extrapolated the data that was generated with the Kymriah product, and we are starting to use bendamustine as an alternative for lymphodepletion with other CAR-T products,” he said.
Be prepared
With drug shortages becoming a more frequent occurrence, Shah said cell therapy clinics should take a few steps to stay ahead of the issue to make it more manageable once scarcity sets in.
“Every institution needs to have a good understanding of its supply chain, monitor what it has in storage, and evaluate commitments that were previously made, especially to clinical trial participants,” he said. “Then you have to come up with your own triage on how to prioritize the use of fludarabine.”
Shah said the process begins by meeting with members of the pharmacy team and anyone involved with drug acquisition, followed by assessing the current and future need for the drug vis-à-vis the available supply.
After clinical trial participants, Shah said HSTC recipients would be the highest priority.
“What I have learned from this process is that you need to be flexible,” Shah said. “It’s important to get to know all of your team members at a large institution so that you can have the flexibility to handle these shortages.”
Part of that flexibility means continuing to employ alternatives, but Shah is hopeful that supply chain issues affecting fludarabine will resolve because evidence shows it is the standard of care that patients should be receiving.
“Are we all coming up with alternatives? Absolutely. But have they been studied as extensively? The answer is no, so that always makes me nervous,” Shah said. “But we can't necessarily stop care just because we have a shortage of a single drug.”
References:
Maziarz RT, et al. Transplant Cell Ther. 2022;doi:10.1016/j.jtct.2022.08.002.
US FDA. Current and resolved drug shortages and discontinuations reported to FDA. Available at: www.accessdata.fda.gov/scripts/drugshortages/. Accessed Nov. 22, 2022.
For more information:
Nirav N. Shah, MD, MSHP, can be reached at Blood and Marrow Transplant and Cellular Therapy Program, Division of Hematology and Oncology, Medical College of Wisconsin, 9200 W. Wisconsin Ave., Milwaukee, WI 53226; email: nishah@mcw.edu.
Collapse
Healio Interviews
Click Here to Manage Email Alerts