Fungal Infections May Pose a Greater Risk for Future CAR-T Applications

Jessica S. Little, MD

Because allogeneic hematopoietic stem cell transplant (HSCT) for the treatment of acute myeloid leukemia (AML) and other hematologic malignancies often leaves patients immunocompromised, they are vulnerable to dangerous fungal infections like fusarium. Although this risk is lower for patients receiving FDA-approved chimeric antigen receptor T-cell (CAR-T) therapies for hematologic malignancies, fungal infections may pose a greater threat for patients receiving CAR-T in the future when allogeneic CAR-T therapies or other new CAR-T types become available.

Jessica S. Little, MD, a transplant infectious diseases physician at Dana-Farber Cancer Institute, spoke about a challenging case of fusarium infection in a patient who received allogeneic HSCT in a session entitled “Challenging cases in HCT and cellular therapy” at the 2024 Tandem Meetings |Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR, held in San Antonio, Texas, February 21-24, 2024. After her presentation, CGTLive® interviewed Little to learn more about the current and future research regarding fusarium infections for patients receiving HSCT or CAR-T.

CGTLive: Can you give some background context about your case study presentation?

Jessica S. Little, MD: This is the first year that we've had the Infectious Diseases (ID) Track at Tandem. I think it's really important because infectious diseases are a serious complication that our immunocompromised patients suffer from and as we come up with new and better ways to treat hematologic malignancies, we're seeing more and more complications of that with infections. The purpose of this session was to really think about these tough cases and how we would manage them.

What were the key points that you discussed?

My case was in a patient who had undergone a matched unrelated donor transplant with posttransplantation cyclophosphamide (PTCy), who had developed acute graft versus host disease after transplant, and then came into the hospital for treatment with high dose steroids and ruxolitinib and developed new fevers and skin lesions, which were ultimately found to be due to fusarium infection. Fusarium infection is a rare mold infection that we see in highly immunocompromised patients, most often either patients with acute myeloid leukemia, other acute leukemias, or those who have undergone transplant. This infection is important because there's an extremely high associated morbidity and mortality. I think this case was an interesting one to discuss because we're really lacking a lot of data around treatment and diagnosis of this infection. No clinical trials to date have shown any benefit of any of the treatment regimens that we use. The host status, the recovery of the patient's neutrophils and immune status, after whatever procedure treatments they've gone through is extremely important. That’s really the only thing that has been shown to have an impact on overall prognosis. That was where a lot of the discussion went.

What would you say is the big picture takeaway for doctors and the healthcare community?

For fusariosis, I think there's a couple of things to think about. We're seeing increased rates of rare mold infections in general in our immunocompromised patients. We don't know exactly why that is. It may be that patients are now living longer because we're treating them with more effective treatments for their malignancies. The other thought is that we've seen an increase in breakthrough infections with the use of oral azole prophylaxis. This patient had been on posaconazole and this is not covered by the spectrum of posaconazole in many cases and so it's a common breakthrough infection that we're seeing and something that should be considered. Then I think one other exciting and hopefully optimistic point is that we are seeing a lot of new antifungal agents in the pipeline, which haven't been approved yet. The most important for fusarium would be fosmanogepix, which has been used for a recent outbreak of fusarium meningitis in Mexico. I think we're all very hopeful that this will come to market soon and represent another option for patients with these very serious morbid infections.

Can you speak about areas of interest for further research in this field?

In general, we're seeing rising rates of mold infections and breakthrough infections in our transplant population. I think that's an important area to continue to investigate about. [We really need to be] making sure that we're choosing the right patients to prophylax and that we're not overdoing it with prophylaxis, while still using prophylaxis in ways that are going to prevent fungal infections. I think that antifungal stewardship is going to be a big area of future research, especially as we see more of these resistant-refractory fungal infections. I think another area of interest will be to think about fungal infections in our CAR T-cell recipients, which has been a big area of research for me. I think overall, the rates of fungal disease in our CAR T-cell recipients tend to be much lower than in our transplant patients. The risk is much lower for some of the patients we've seen for the approved indications. I think there's a huge question mark in terms of some of the new applications of CAR T-cell therapy, such as allogeneic CAR T-cells or CAR T-cells for AML. I expect [these] to be much higher risk for fungal disease. CAR-T for things like autoimmune disease may potentially be lower risk, but it's something that deserves more investigation.

Is there anything else you would like to share?

For these infections because it's so challenging in terms of the optimal treatment, it's important to always have your ID teams involved and involved as early as possible because the mortality of these diseases are so high. There's some interesting questions around whether things like Granix or other neutrophil enhancements for these patients may be helpful as part of the treatment regimen. That's another interesting area for the future.

This transcript has been edited for clarity.

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REFERENCES
1. Little JS. Challenging cases in HCT and cellular therapy. Presented at: 2024 Tandem Meetings, February 21-24, San Antonio, Texas.