Stanford Study Finds Low Risk of Secondary Blood Cancers After CAR-T
Of 724 patients treated at the center, the cumulative incidence of secondary hematologic malignancy at 3 years posttreatment was 6.5%.
Ash Alizadeh, MD, PhD
Credit: Stanford Medicine
A study from Stanford Medicine has found that the risk of secondary
malignancies after chimeric antigen receptor (CAR) T-cell therapy is low in patients treated for hematological malignancies.1
“We wanted to understand this one rare case, so we analyzed all the patients treated with CAR-T cell therapy at Stanford with wide breadth and studied this single case extraordinary depth,” Ash Alizadeh, MD, PhD, professor of medicine and member, Stanford Cancer Institute, said in a statement.2 “We compared protein levels, RNA sequences and DNA from single cells across multiple tissues and time points to determine that the therapy didn’t introduce the lymphoma into this patient; instead it was already brewing in their body at very low levels.”
The review is timely and adds valuable information to the field, as the FDA recently added a requirement for boxed warnings for T-cell malignancies after treatment with CAR T-cell therapies to all such approved therapies: Bristol Myers Squibb (BMS) and 2seventybio’s idecabtagene vicleucel (ide-cel; marketed as Abecma); BMS’s lisocabtagene maraleucel (liso-cel; marketed as Breyanzi); Janssen and Legend Biotech’s ciltacabtagene autoleucel (cilta-cel; marketed as Carvykti); Novartis’s tisagenlecleucel (tisa-cel; marketed as Kymriah); Kite Pharma’s brexucabtagene autoleucel (brexu-cel; marketed as Tecartus); and Kite Pharma’s axicabtagene ciloleucel (axi-cel; marketed as Yescarta).3
The added warnings came after the FDA investigated the 12 instances of T-cell lymphoma in patients treated with approved CAR T-cell therapies. These cases have been seen in patients treated with Kymriah (n = 7), Yescarta (n = 3), Carvykti (n = 1), and Breyanzi (n = 1).3
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The investigators reviewed Stanford’s experience with CAR T-cell therapy and the incidence of secondary malignancies. This included 724 patients who had received T-cell therapies.1
One patient who had received axi-cel therapy for diffuse large B-cell lymphoma developed lethal secondary T-cell lymphoma, and the investigators used a broad array of molecular, genetic, and cellular techniques to interrogate the tumor, the CAR T cells, and the normal hematopoietic cells in the patient. They found no evidence of oncogenic retroviral integration.1
“These results may help researchers focus on the immune suppression that can precede and often follows CAR-T cell therapy,” senior author David Miklos, MD, PhD, professor of medicine and chief of bone marrow transplantation and cellular therapy said.2 “Understanding how it contributes to cancer risk is particularly important as the CAR-T cell field pivots from treating high-risk, refractory blood cancers to lower risk, but clinically important, disorders including autoimmune diseases.”
All in all, the investigators identified 25 secondary tumors, excluding nonmelanoma skin cancers, after a median follow-up of 15 months. Of 14 hematologic second tumors, 13 were associated with myelodysplastic syndrome or acute myeloid leukemia and 1 was a T-cell lymphoma. There were 11 cases of solid tumors (4 melanomas, 2 prostate carcinomas, 2 breast ductal carcinomas, 1 endometrial adenocarcinoma, 1 lung adenocarcinoma, and 1 metastatic mesothelioma). The cumulative incidence of a hematologic second tumor at 3 years was 6.5%.
“This study could serve as a blueprint for how to capture and characterize the outcomes of CAR-T therapies so we can develop a very clear understanding of their risks and benefits,” Alizadeh added.2 “These are lifesaving therapies that come with a very low risk of secondary cancers. The challenge lies in how to predict which patients are at higher risk, and why.”
