CAR T-Cell Dose Refinement May Reduce Cytokine-Release Syndrome in Patients With Advanced Acute Lymphoblastic Leukemia

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Chimeric antigen receptor (CAR) T-cell therapy has been effective in adults and children with advanced acute lymphoblastic leukemia (ALL), but along with efficacy, the treatment can stimulate cytokine-­release syndrome, which can be deadly if it goes unrecognized and untreated. Adjusting the dose of CAR T-cell therapy to find the balance between effectiveness and the potential for cytokine-release syndrome appears to be an approach that is gaining ground, according to two presentations at the 2016 ASCO Annual Meeting.1,2 The first presentation described experience with split-dosing or fractionation of CAR T cells, and the second explored adjusting the dose based on baseline burden of disease.

The split high dose had high efficacy and less toxicity. It seems to be safe and effective compared with high-dose single infusion.
— Noelle Frey, MD

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“Relapsed refractory ALL has a very poor prognosis. Whether by age, gender, or time of relapse, outcomes are universally dismal. This has driven the pursuit of novel therapies,” said Noelle Frey, MD, of the Abramson Cancer Center at the University of Pennsylvania, Philadelphia.

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

Several centers are studying CAR T-cell therapy, including the University of Pennsylvania, the Fred Hutchinson Cancer Center, Memorial Sloan Kettering Cancer Center, and the National Cancer Institute (NCI). Protocols and components of CAR T-cell therapy differ among these centers, but the approach is similar.

“Disease burden of ALL at baseline correlates with cytokine-release syndrome severity,” Dr. Frey noted. “Fever and malaise are the first signs of cytokine-release syndrome, and patients should receive supportive care and may require intervention with anticytokine directed therapy such as tocilizumab [Actemra],” she told listeners.

Split Dosing

Dr. Frey discussed two University of Pennsylvania clinical trials that are exploring dosing regimens for CAR T-cell therapy. She reported on experience in a total of 30 adults with CD19-positive relapsed or refractory ALL.1 There were four cohorts: high-dose split, high-dose single, low-dose split, and low-dose single.

The overall response rate was 72%. A high dose of CTL019 (5 × 108 T cells) achieved a response rate of 100% and a severe cytokine-release syndrome rate of 100%. When the dose was split over 3 days, the response rate was 86% and the incidence of grade 3 or 4 cytokine-release syndrome rate was 66%. With a split dosing approach, CAR T-cell therapy was held on days 2 and/or 3 for emerging signs of low-grade cytokine-release syndrome. A single low-dose infusion (5 × 107 T cells) reduced both efficacy (33%) and the severity of cytokine-release syndrome.

“The split high dose had high efficacy and less toxicity. It seems to be safe and effective compared with high-dose single infusion. At the low dose, response rates are lower,” revealed Dr. Frey.

Three of six patients treated with a single high dose of CTL019 developed cytokine-release syndrome and died days to weeks after treatment. These patients all had cultures that tested positive for sepsis. To combat this threat, Dr. Frey suggested, “Clinicians should conduct aggressive infectious disease monitoring and consider treating patients prophylactically with antimicrobials before getting an infusion of CTL019.”

“Using a split or fractionated dose, patients can be monitored after each dose and adjustments made if toxicity occurs,” she added. Alternatives to fractionated dosing are also being studied.

Modifications Based on Disease Burden

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-cell therapy remains unclear.
— Jae H. Park, MD

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The second presenter explored dose modifications and outcomes according to baseline disease burden in patients with B-cell ALL. Jae H. Park, MD, of Memorial Sloan Kettering Cancer Center, New York, presented data from a phase I clinical trial that included 51 adults with relapsed/refractory B-cell ALL.2 “This is the largest data set of adult patients with relapsed/refractory ALL treated with CAR T-cell therapy,” Dr. Park told listeners.

Patients were treated with a CAR T-cell therapy called 19-28z, a product that is similar to CTL019 but contains an intracellular CD28 costimulatory domain.

Patients underwent leukapheresis, T-cell production, bone marrow biopsy to document disease burden, conditioning chemotherapy, and CAR T cells at two different dose levels. Patients with active central nervous system disease were excluded.

Patients were categorized according to their baseline disease burden as follows: morphologic disease (≥ 5% blasts) or minimal disease (< 5% blasts). Patients with morphologic disease received a lower dose of CAR T cells/kg (1× 106), whereas those with minimal disease received 3 × 106 CAR T cells/kg. The last nine patients in the trial received conditioning chemotherapy with fludarabine/cyclophosphamide 2 days prior to CAR T-cell infusion while the first 42 patients received cyclophosphamide conditioning.

CAR T-Cell Therapy: Balancing Efficacy and Toxicity

  • CAR T-cell immunotherapy has achieved dramatic responses in patients with advanced ALL, although with the potential for cytokine-release syndrome, which can be fatal if untreated.
  • Researchers are exploring better ways to administer CAR T-cell therapy so as to balance efficacy and toxicity.
  • A split dose appears to be effective, with less potential for cytokine-release syndrome.
  • Dosing can be adjusted according to disease burden at baseline in an attempt to improve outcomes.

At a median follow-up of 8.5 months, high rates of remission were observed regardless of disease burden at baseline. Patients with morphologic disease had a higher number of prior therapies than did those with minimal disease.

For those with morphologic disease, 77% achieved complete remission by day 20 following treatment, and 90% of the complete responders were minimal residual disease–negative. For those with minimal disease, the complete remission rate was 90% by day 25 after treatment, and 78% were minimal residual disease–negative. In patients who still had minimal residual disease, 45% relapsed after treatment.

Cytokine-release syndrome occurred in almost all patients with morphologic disease. It was treated with tocilizumab and/or steroids and appeared to have no impact on survival.

Thirty-nine percent of patients went on to allogeneic transplant. There appeared to be no effect of transplant on survival in patients who were minimal residual disease–negative. “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-cell therapy remains unclear,” Dr. Park concluded. ■

Disclosure: The first two clinical trials were sponsored by Novartis, and the last study was sponsored by Juno Therapeutics. Dr. Frey has consulted for Amgen and received research funding from Novartis. Dr. Park has consulted for Amgen and Juno Therapeutics as well as received institutional research funding from Genentech/Roche and Juno Therapeutics.


1. Frey NV, Shaw PA, Hexner EO, et al: Optimizing chimeric antigen receptor (CAR) T cell therapy for adult patients with relapsed or refractory acute lymphoblastic leukemia. 2016 ASCO Annual Meeting. Abstract 7002. Presented June 4, 2016.

2. Park JH, Riviere I, Wang X, et al: Impact of disease burden on long-term outcome of 19-28z CAR modified T cells in adult patients with relapsed B-ALL. 2016 ASCO Annual Meeting. Abstract 7003. Presented June 4, 2016.

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— Steven M. Devine, MD

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