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Refining Use of CAR-T in ALL

Chimeric antigen receptor T-cells (CAR-T) have saved lives in some patients with acute lymphoblastic leukemia (ALL) who had run out of other treatment options. This type of immunotherapy is making inroads in other hematologic malignancies as well, but it is still being studied in very sick patients.

The downside of CAR-T is cytokine release syndrome (CRS), which can result in death if not recognized and treated promptly. As researchers gain experience with CAR-T, they are learning more about dosing and how to minimize the chances of CRS occurring while retaining efficacy.

Two abstracts presented at the 2016 ASCO Annual Meeting further refine understanding of optimal dosing of CAR-T in patients with ALL. The first focused on how a split or fractionated dosing scheme can lessen the incidence of CRS. The second presentation focused on adjusting the dose according to burden of disease.

Split or Fractionated Dosing

Treatment with CAR-T starts with apheresis to collect the patient’s own T cells, which are genetically engineered, expanded, and activated ex vivo. After lymphodepleting chemotherapy and expansion, patients receive an infusion of the genetically engineered CAR-T.

Protocols vary, with different centers using different vehicles and different types of T-cell antigens. Noelle Frey, MD, Abramson Cancer Center at the University of Pennsylvania, Philadelphia, discussed use of CAR-T that bind to CD19 on the surface of normal and malignant B cells.

“Unprecedented remission rates from 67% to 90% have been achieved for various investigational CAR-T therapies, including CD19-directed CTL019. Unfortunately, the immune activation that is critical for these high responses unleashes CRS, which is associated with treatment-related death,” she said.

Disease burden of ALL at baseline correlates with CRS severity. Fever and malaise are the first signs, and patients should receive supportive care and tocilizumab.

Dr Frey discussed 2 NCI clinical trials that are attempting to find the optimal dose of CAR-T. These included a total of 30 adults with CD19-positive relapsed or refractory ALL.

The investigators found that a high dose of CTL019 (5 × 108 T cells) achieved a response rate of 100% but also a CRS rate of 100%. When they split the dose over 3 days, they achieved an 86% response rate and a 66% CRS rate. A single low-dose infusion (5 × 107 T cells) reduced both efficacy (33%) and CRS (66%).

Three of 6 patients treated with a single high dose of CTL019 developed CRS and died days to weeks after treatment. These patients all had infections, including sepsis, which are thought to have contributed to their deaths.

Dr Frey said, “Clinicians should conduct aggressive infectious disease monitoring and treat patients preemptively with antimicrobials before getting an infusion of CTL019.”

There was no dose relationship between adverse neurologic events in these 2 trials.

“Using a split or fractionated dose, patients can be monitored after each dose and adjustments made if toxicity occurs,” she said.

Alternatives to fractionated dosing are also being studied.

Dose Modifications and Disease Burden

The second presenter explored modifying the dose of CAR-T according to disease burden at baseline. Jae H. Park, MD, Memorial Sloan Kettering Cancer Center, New York City, presented data from a phase 1 clinical trial that included 51 adults with relapsed/refractory ALL using a CAR called CD19-28z. This product is similar to CTL019, and it also contained an intracellular CD28 domain that should improve the expansion and persistence of CAR-T in patients.

First, Dr Park and colleagues determined each patient’s disease burden and categorized them as morphologic disease (≥5% blasts) or minimal disease (<5% blasts). Patients with morphologic disease received a lower dose of CAR-T (1 × 106) per kg whereas those with minimal disease received 3 × 106 CAR-T per kg. The last 9 patients in the trial received conditioning chemotherapy 2 days prior to CAR-T infusion.

High rates of remission were observed regardless of disease burden at baseline. For morphologic disease, 77% achieved complete remission (CR) by day 20 following treatment, and 90% of the CR patients were minimal residual disease–negative (MRD−). For minimal disease, the CR was 90% by day 25 after treatment and 78% were MRD−. In patients who still had MRD, 45% relapsed after treatment.

Thirty-nine percent went on to allogeneic transplant. There was no effect of transplant on survival in patients who were MRD−.

“This is the largest data set with relapsed/refractory B-ALL treated with CAR-T,” he said. “Durable responses and survival are observed in a subset of patients with no subsequent allogeneic transplant in both morphological and minimal disease cohorts. The benefit of allogeneic transplant after CAR-T remains unclear,” he said.

Dr Park suggested that CAR-T could be studied earlier in the disease to achieve even better results.

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