Lack of fludarabine requires flexibility, alternative strategies for CAR-T and HSCT

November 23, 2022

4 thousand trains


Source/information

Source:

Healio interviews


Disclosures: Shah reports no relevant financial information.


We could not process your request. Please try again later. If you continue to have this problem, please contact customerservice@slackinc.com.

For the second time in the last 2 years, a drug related to the administration of chemotherapy – 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 backorders or limited supplies available in October.



stem cells_136697242
Pretreatment therapy suppresses the immune system to allow the implantation and expansion of cell therapies in the host patient’s body. Source: Adobe Stock.

The FDA Drug Shortages website lists four manufacturers for the drug. Areva and Accord Healthcare did not give a reason for the supply shortage, but Fresenius Kabi USA pointed to increased demand. Teva and Areva say they have available supplies of fludarabine as of October.

Fresenius, meanwhile, estimated January next year for restocking.

Fludarabine is a cytotoxic cancer drug that, when used in combination with cyclophosphamide, acts as a pretreatment that suppresses the immune system to allow cell therapies to be implanted and expanded in the host patient’s body.

Shah_Nirav_80x106

Nirav N. Shah

Its integral part in the pretreatment program provided for most chimeric antigen receptor T-cell and hematopoietic stem cell transplant procedures means that shortages have required providers to be flexible in order to continue this service, according to Nirav N. Shah, MD, MSHP, associate professor of hematology and oncology at the Medical College of Wisconsin and a member of 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 kinds of drugs and in different fields of medicine.

The shortages have affected individual agencies on different timelines, based on the amount of fludarabine they had stockpiled before supply issues became apparent, Shah added. Initially, his intuition wasn’t affected by the shortage, but as summer turned to fall and additional supplies were unavailable, it forced Shah’s clinic to explore other options—where possible—to keep their treatment pipelines running.

“We were successful at the beginning of the shortage and weren’t really affected,” he said. “But as time has passed, the situation has not relented.

The biggest challenge he faces is having enough fludarabine available for those participating in clinical trials at his center in studies evaluating HSTC or CAR-T. The plans from the clinical trials are locked and there is no flexibility in terms of switching, he added.

“This makes it difficult for patients to enroll in clinical trials if we cannot obtain the fludarabine needed to receive the treatment as prescribed in the clinical trials,” Shah said.

Exploring the options

Shah recently co-wrote an editorial in the Transplantation and cell therapy highlight the ongoing fludarabine shortage and recommend steps that cell therapy clinics should take to address the issue.

Due to the lack of a timeline for restocking by manufacturers and reports that one supplier plans to significantly increase the cost of the drug, Shah and colleagues called on the American Society for Transplantation and Cellular Therapy to adopt a policy on fludarabine dosing to ensure proper conduct of clinical trials and maximize benefits. available supply.

“It is our opinion that, in order to maintain clinical trial standards and data validity, our immunology community will remain committed to strict adherence to protocol-defined lymphadenopathy in ongoing clinical trials, unless the FDA permits a change of corporate sponsor,” Shah and colleagues. wrote. “If the fludarabine shortage persists … it will be necessary for centers to establish management algorithms now.”

Alternative therapies for allogeneic HSCT are needed, with fludarabine serving as the backbone of the pretreatment regimen, Shah said.

“We are now looking at alternatives to many of our standard regimens,” he told Healio, including using clofarabine or pentostatin instead of fludarabine.

“We have now also developed a protocol for bendamustine to be given instead of fludarabine,” Shah added.

The track record for fludarabine selection is even better established in CAR T-cell therapy, where the use of pretreatment bendamustine is part of the regimen for the administration of tisagenlecleucel (Kymriah, Novartis), Shah explained.

“We’ve extrapolated the data that was generated with the Kymriah product and we’re starting to use bendamustine as an alternative to lymphadenectomy with other CAR-T products,” he said.

Be prepared

With drug shortages becoming more frequent, Shah said cell therapy clinics should take steps to stay ahead of the issue to make it more manageable when shortages begin.

“Every organization needs to have a good understanding of their supply chain, track what they have in storage and evaluate commitments made in the past, especially with clinical trial participants,” he said. “Then you have to come up with your own puzzle about how to prioritize the use of fludarabine.”

Shah said the process begins with meeting with members of the pharmacy team and everyone involved in drug procurement, followed by assessing the current and future need for the drug against the available supply.

After clinical trial participants, Shah said HSTC recipients would be given the highest priority.

“What I’ve learned from this process is that you have to be flexible,” Shah said. “It’s important to get to know all your team members at a large organization so you can have the flexibility to deal with this shortage.”

Part of that flexibility means continuing to use alternatives, but Shah is hopeful that supply chain issues affecting fludarabine will be resolved because evidence shows it’s the standard of care patients should receive.

“Are we all coming up with alternatives?” Absolutely. But have they been studied as much? The answer is no, so that always makes me nervous,” said Shah. “But we can’t necessarily stop care just because we’re missing one drug.”

Sources:

Maziarz RT, et al. Graft cell Th. 2022; doi:10.1016/j.jtct.2022.08.002.
US FDA. Current and resolved drug shortages and drug practices reported to FDA. Available at: www.accessdata.fda.gov/scripts/drugshortages/. Viewed Nov. 22, 2022.

For more information:

Nirav N. Shah, MD, MSHP, can be reached at the Blood and Marrow Transplant and Cellular Therapy Program, Department of Hematology and Oncology, Medical College of Wisconsin, 9200 W. Wisconsin Ave., Milwaukee, WI 53226; email: nishah@mcw.edu.

Leave a Comment

Your email address will not be published. Required fields are marked *