Chimeric antigen receptor (CAR) T-cells 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-cell therapy is cytokine release syndrome, which can result in death if not recognized and treated promptly. As researchers gain experience with CAR T-cells, they are learning more about dosing and how to minimize the chances of cytokine release syndrome occurring while retaining efficacy of this type of therapy.
Two abstracts presented at ASCO 2016 further refine the understanding of the optimal dosing of CAR T-cells in patients with ALL. The first presentation focused on how a split or fractionated dosing scheme can lessen the incidence of cytokine release syndrome. The second presentation focused on adjusting the dose according to the burden of disease.
Split or Fractionated Dosing
Treatment with CAR T-cells starts with apheresis to collect the patient’s own T-cells, which are genetically engineered and are expanded and activated ex vivo. After lymphodepleting chemotherapy and expansion, patients receive an infusion of the genetically engineered CAR T-cells.
Protocols vary at centers, using various vehicles and different types of T-cell antigens. Noelle V. Frey, MD, MSCE, of the Abramson Cancer Center of the University of Pennsylvania, Philadelphia, discussed the use of CAR T-cells that bind to CD19 on the surface of normal and malignant B-cells.
Unprecedented Remission Rates
“Unprecedented remission rates from 67% to 90% have been achieved for various investigational CAR T-cell therapies, including CD19-directed CTL019,” she said. “Unfortunately, the immune activation that is critical for these high responses unleashes cytokine release syndrome, which is associated with treatment-related death.”
The disease burden of ALL at baseline correlates with cytokine release syndrome severity. Fever and malaise are the first signs, and patients should receive supportive care and tocilizumab.
Dr Frey discussed 2 National Cancer Institute clinical trials that are attempting to find the optimal dose of CAR T-cells. The trials included 30 adults with CD19-positive relapsed or refractory ALL.
A high dose of CTL019 (5 × 108 T-cells) achieved a response rate of 100% and a cytokine release syndrome rate of 100%. When the investigators split the dose over 3 days, the result was an 86% response rate and a 66% cytokine release syndrome rate. A single low-dose infusion of CTL019 (5 × 107 T-cells) reduced the efficacy (33%) as well as the cytokine release syndrome (66%).
Of 6 patients who received a single high dose of CTL019, 3 had cytokine release syndrome and died within days to weeks after treatment. These patients all had infections, including sepsis, which are thought to have contributed to their deaths.
Monitor for Infectious Diseases
“Clinicians should conduct aggressive infectious disease monitoring and treat patients preemptively with antimicrobials before getting an infusion of CTL019,” Dr Frey said.
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 can be made if toxicity occurs,” Dr Frey said.
Alternatives to fractionated dosing of CAR T-cells are also being studied.
Dose Modifications and Disease Burden
The second presenter explored modifying the dose of CAR T-cells according to disease burden at baseline. Jae H. Park, MD, Hematologic Oncologist at Memorial Sloan Kettering Cancer Center, New York City, presented data from a phase 1 clinical trial that included 51 adults with relapsed or refractory ALL using a CAR T-cells therapy called CD19-28z.
This drug is similar to CTL019 and contains an intracellular CD28 domain that should improve the expansion and persistence of CAR T-cell therapy.
Dr Park and colleagues first determined each patient’s disease burden and then clarified them as having morphologic disease (>5% blasts) or minimal disease (<5% blasts). The patients with morphologic disease received a lower dose of CAR T-cells (1 × 106) per kilogram, and those with minimal disease received a higher dose (3 × 106) of CAR T-cells per kilogram.
The last 9 patients who received treatment in the trial received conditioning chemotherapy 2 days before CAR T-cell infusion.
High rates of remission were observed regardless of disease burden at baseline. Of the patients with morphologic disease, 77% achieved complete remission by day 20 after treatment, 90% of whom were minimal residual disease (MRD)-negative.
For patients with minimal disease, the complete response rate was 90% by day 25 after treatment, and 78% were MRD-negative. Among the patients who still had MRD, 45% relapsed after treatment.
A total of 39% of the patients continued to allogeneic transplant. The transplant had no effect on survival in patients who were MRD-negative.
“This is the largest data set with relapsed or refractory B-cell ALL treated with CAR T-cells,” Dr Park said. “Durable responses and survival are observed in a subset of patients with no subsequent allogeneic transplant in both morphologic and minimal disease cohorts. The benefit of allogeneic transplant after CAR T-cells remains unclear.”
Dr Park suggested that CAR T-cells could be studied earlier in the disease to achieve even better results.