The Main Cause of Non-Relapse Mortality after CAR T Cell Therapy is Not What You Think

A Q&A with MSK Visiting Investigator and Research Fellow Dr. Kai Rejeski

CAR T cell therapy against CD19 and B cell maturation antigen (BCMA) is a potent immunotherapy for treating advanced B cell malignancies. It comes with a unique toxicity profile that includes cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and hemophagocytic lymphohistiocytosis (HLH)-like syndromes.

However, a new systematic review and meta-analysis led by investigators at Memorial Sloan Kettering Cancer Center (MSK) has revealed that none of these prototypical immune-related side effects are the leading cause of nonrelapse mortality (NRM) – referring to all deaths not related to cancer progression or recurrence. Instead, they found infections are the main cause of NRM following CAR T cell therapy. Their study, published recently in Nature Medicine, ⁽¹⁾ included a comprehensive analysis of NRM after CAR T cell therapy in patients with lymphoma and multiple myeloma across multiple clinical trials and real-world studies.

“Our findings underscore the importance of infectious complications following CAR T cell therapy,” said senior author Kai Rejeski, MD, a visiting investigator and research fellow with the Adult Bone Marrow Transplantation Service at MSK. “We also found variations in NRM risk for the six CAR T cell products on the market today, which may help guide treatment decisions and toxicity management strategies to further improve patient outcomes.”

In this Q&A with Dr. Rejeski, we discuss the study’s key findings and implications and a new tool for assessing infection risk prior to CAR T cell therapy.

Your study analyzed outcomes for 7,604 patients across 18 clinical trials and 28 real-world studies, and is the largest on this topic to date. The results revealed infections caused a majority of nonrelapse deaths after CAR T cell therapy. How did infections stack up against other known mortality-related health issues from this immunotherapy?

Our meta-analysis revealed that infections caused just over one-half of nonrelapse deaths (50.9%), followed by secondary malignancies (7.8%), and cardiovascular/respiratory events (7.3%). On the other hand, CAR T cell-specific toxicities, which included CRS, ICANS, and HLH, were responsible for only a minority of nonrelapse deaths (11.5% collectively). 

Were you surprised by these findings?

There was good news and bad news. The good news is that efforts to identify and address CRS and ICANS as soon as possible have pushed them down on the list of complications leading to nonrelapse deaths, a welcome advance since CAR T cell therapies were first introduced. Based on observational reports of clinical experience, we had suspected infection played a more significant role than previously appreciated. Still, we did not expect to find that infections are such a prominent driver of nonrelapse mortality.

Did non-relapse mortality rates vary by indication? 

Our analysis found that NRM was highest in patients with mantle cell lymphoma (10.6%), followed by multiple myeloma (8.0%), large B cell lymphoma (6.1%), and indolent lymphoma (5.7%).

Did non-relapse mortality rates vary by CAR T cell therapy product and how may this inform treatment choice?

Yes. Among patients with large B cell lymphoma, we found a higher NRM rate of 7.4% in patients treated with axicabtagene ciloleucel compared with 4.1% for tisagenlecleucel and 3.8% for lisocabtagene maraleucel. NRM rates also varied by product among patients with multiple myeloma, with the highest rate of 15.2% for ciltacabtagene autoleucel compared with 6.3% for idecabtagene vicleucel. Importantly, these product-specific differences were confirmed in meta-regression analyses accounting for potential confounders.

These findings may inform treatment choice in settings where more than one product is approved for a particular indication. However, patient and disease characteristics will still be essential decision-making factors. For example, a higher risk of NRM from CAR T cell therapy may be acceptable for a young, otherwise healthy patient with large B cell lymphoma with relapse after multiple prior lines of treatment because their alternative is likely death from their disease. By contrast, NRM could be one factor in a more nuanced discussion with an older, transplantation-ineligible patient with disease that responded to salvage chemotherapy or immunotherapy. Oncologists may also consider non-CAR T cell therapies, like bispecific antibodies, for some indications such as indolent lymphoma or myeloma.

What factors increase a patient’s susceptibility to infectious complications after CAR T cell therapy?

Several factors predispose patients receiving CAR T-cells for severe infections. This includes the underlying malignancy and its associated immune dysregulation, as well as the many prior treatment lines that patients receive prior to CAR T-cell therapy which can negatively impact bone marrow reserve. In addition, patients often receive immunosuppressive agents for the management of immune-related side effects, particularly high-dose corticosteroids. Finally, the lymphodepleting chemotherapy that is applied to enable CAR T-cells to expand can deplete both T cells and neutrophil counts, and the CAR T-cells themselves not only target malignant B cells, but also the patient’s own B cell repertoire. So all in all, the underlying immune suppression is multifactorial and can be quite profound and protracted over a long period of time.

To put the high infection-related NRM into context, it is also important to note that many of the studies included in our meta-analysis occurred during the COVID-19 pandemic (2020-2023), which may have, in part, influenced the observed NRM rates. 

What are your thoughts on the recent class-wide boxed warning from the U.S. Food and Drug Administration about an increased risk of secondary malignancies associated with six CAR T cell therapies and advising life-long patient monitoring for this complication?

The FDA boxed warning and rise in media mentions of this issue have given the impression that secondary malignancies are one of the most relevant complications of CAR T-cell therapy. Yet, our present study found they only accounted for about 8% of non-relapse deaths.

Also, it’s difficult to conclude that CAR T cell therapy itself is the main driver of second primary cancers in an often elderly patient population with substantial cumulative exposure to previous chemotherapies. Nonetheless, in a recent pharmacovigilance study our group published in JAMA Oncology,  ⁽²⁾ we found higher than expected reporting of second primary malignant cancers and T cell malignancies after CAR T cell therapy versus other treatments in patients with hematologic cancers. Most secondary cancers were myeloid neoplasms or solid tumors, while the T cell malignant neoplasms that could in theory be attributed to CAR-related mutagenesis were exceedingly rare (< 0.1% of patients).

While we await long-term follow-up of patients, caution is warranted and monitoring is thus certainly reasonable. The results of our study highlight that the overall toxicity of CAR T cell therapy is not to be taken lightly. Close monitoring for all potential adverse events is essential, as one in 15 patients died of a treatment-related complication within one year of treatment.

What are the main takeaway messages from your findings for researchers and clinicians?

For clinical trials, we hope our findings encourage more structured and mandatory reporting of NRM, focusing on infections and secondary malignancies in addition to CRS and ICANS.

There is also a need for more attention to infection control procedures outside clinical studies, as we found infections were an even more predominant cause of nonrelapse deaths in real-world settings (64.6%) compared with clinical trial settings (59.1%). 

Are there any tools for preventing infections and managing their complications?

Yes. In previous work, we developed the CAR-HEMATOTOX score, a useful tool that is available free online. It assesses the risk of a patient developing hematologic toxicity, referring to prolonged and/or profound cytopenias, a frequent adverse event after CAR T cell therapy that can predispose for the severe infectious complications we outline in our meta-analysis. The score is determined before lymphodepleting chemotherapy, typically 5 days prior to CAR T cell infusion, and includes five markers of hematotoxicity such as the baseline platelet count and ferritin level.

Importantly, the score has been validated to predict infections in patients with large B cell lymphoma receiving commercial CD19 CAR T cell therapies. ⁽³⁾ It has also demonstrated utility in patients with relapsing/recurrent multiple myeloma ⁽⁴⁾ and mantle cell lymphoma, ⁽⁵⁾ and can be applied to guide toxicity management, including anti-infective prophylaxis, early granulocyte-colony stimulating factor (G-CSF), and potentially the use of hematopoietic stem cell boosts.

What is MSK’s approach to preventing and managing infections associated with CAR T cell therapy?

During the critical early phase of CAR T therapy, patients typically receive a variety of prophylactic anti-infective agents aimed to protect against different pathogens (antibacterial, antifungal, antiviral).

CAR T specialists at MSK may also administer growth factors like G-CSF that shorten the time period that patients have critically low blood counts. Overall, patients are monitored closely for infections during the first weeks and months and encouraged to practice measures of infection prevention such as avoiding crowded rooms or sick contacts. Finally, intravenous immunoglobulins can be applied in the outpatient setting to replete the low antibody titers that occur when the CAR T cells target the patient’s own B cells.

Do you have a final comment on this systematic review and meta-analysis?

Many thanks to my co-authors at MSK, bone marrow transplant specialist and cellular therapist Dr. Roni Shouval, MD, PhD, head of the Precision Cellular Therapy Lab, and Miguel-Angel Perales, MD, Chief of the Adult Bone Marrow Transplant Service.

I also extend thanks to our collaborators at the Dana-Farber Cancer Institute and Harvard Medical School, in Cambridge; the LMU University Hospital in Munich, Germany; and the Davidoff Cancer Center in Petah-Tikva and Tel Aviv University in Israel.