Minimizing Toxicity, Predicting Efficacy With CD19 CAR T-Cell Therapy in B-Cell ALL

Treatment with CD19-directed chimeric antigen receptor (CAR) T cells has induced high rates of complete response in adults with relapsed/refractory B-cell acute lymphocytic leukemia (ALL), ranging from 70-80 percent, but the toxicity associated with the treatment – including severe neurotoxicity and cytokine release syndrome (CRS) – are serious concerns.

At the 2017 ASCO Annual Meeting, Jae Hong Park, MD, from Memorial Sloan Kettering Cancer Center in New York, and colleagues attempted to answer two critical questions about optimizing the use of CAR T-cell therapy in these patients: how to identify those who would benefit most from the treatment, and how to mitigate the severe neurotoxicity associated with CAR T-cell infusion.

“The toxicities associated with this therapy are not insignificant. We [should concentrate on] identifying patient populations [who experience] less toxicity but more clinical benefit.” Dr. Park told ASH Clinical News.

In analyses of a phase I trial of CD19-specific CAR T-cell therapy in patients with relapsed/refractory CD19-positive B-cell ALL, patients with a low disease burden at the time of T-cell infusion had longer remissions and lower risk of severe neurotoxicity, suggesting that CAR T-cell therapy should be incorporated earlier in treatment, before morphologic relapse.

In one report from the trial, the authors evaluated whether certain baseline characteristics at the time of T-cell infusion were associated with durable remission.1 The trial included 53 patients (median age = 44 years; range = 23-74 years). Patients were excluded if they had active central nervous system disease or active graft-versus-host disease requiring immunosuppressants.

Researchers assessed disease burden (via bone marrow biopsy) immediately prior to infusion and classified patients as having minimal residual disease (MRD; defined as <5% blasts; n=21) or morphologic disease (defined as ≥5% blasts; n=27). The remaining five patients had blasts <5 percent with extramedullary disease.

CAR T cells were infused at doses of 1×106/kg in patients with MRD and 3×106/kg in those with morphologic evidence of disease; patients also received conditioning with fludarabine and cyclophosphamide.

After a median follow-up of 18 months (range = 0.2-57.3 months), the complete remission rate (CRR; defined as a neutrophil count of >1,000×106/L, a platelet count of >100,000×106/L, and hemoglobin >10 g/dL) was 84.6 percent (n=44 of 52 evaluable patients).

CRRs were comparable between the MRD (95.2%) and morphologic disease (77%) cohorts. Response rates also were similar across several patient subgroups, including number of prior therapies, age, and conditioning regimen.

Overall, median event-free survival (EFS) and overall survival (OS) were 6.1 months
(range = 5-11.5 months) and 12.9 months (range = 8.7-23.4 months), respectively. Both EFS and OS were longer in the MRD cohort than in the morphologic disease cohort:

  • EFS: not reached (range = 4.2 to not reached) vs. 6.3 months (range = 4.8-9 months; p=0.008)
  • OS: not reached (range = 15.3 to not reached) vs. 17 months (range = 8.5-36.2 months; p=0.018)

Patients in the MRD cohort developed substantially less CRS and neurotoxicity, (p=0.033 and p<0.001, respectively).

In a second report from the study, authors evaluated whether certain baseline and post-treatment clinical and laboratory factors (including demographics, treatment regimens, and hematologic parameters) were associated with the development of CRS or severe (grade ≥3) neurotoxicity.2

“Severe neurotoxicity is one of the two most common toxicities associated with CAR T cells, but it remains an enigma,” Dr. Park explained. “The mechanism of action is unclear. We wanted to know if there are particular clinical characteristics associated with [developing this complication].”

Thirty-one patients experienced neurotoxicity (grade 1, n=8; grade 2, n=2; grade 3, n=18; grade 4, n=3).

Disease burden (defined as ≥50% blasts) at the time of T-cell infusion (p=0.0045) and post-treatment grade ≥3 CRS (p=0.0010) were significantly associated with serious neurotoxicity, as were the following factors (p<0.01 for all):

  • fever
  • low platelet count
  • high ferritin and mean corpuscular hemoglobin concentration
  • elevated granulocyte macrophage colony-stimulating factor, interferon gamma, interleukin (IL)-15, IL-5, IL-10, and IL-2 at day 3 of T-cell infusion
  • in vivo peak CAR T-cell expansion at day 7

“[If a patient] has a higher degree of T-cell expansion, this will generally indicate higher degree of immune activation, translating to severe neurotoxicity,” Dr. Park explained. The authors found no association between serious neurotoxicity and patient age, weight, T-cell dose, choice of conditioning chemotherapy, or number of prior lines of treatment.

“Patients with higher disease burden tended to have a higher neurotoxicity, though it is not a clear dichotomy as we see with CRS,” Dr. Park said. “Low disease burden patients still get severe neurotoxicity, although less frequently.”

These results should help clinicians identify patients who are at risk for developing severe neurotoxicity and require intervention, and “patients who might completely recover and revert back to grade 1 or 2 neurotoxicity,” Dr. Park noted. “Non-specific immunosuppression with a steroid is the most common [intervention], but as we learn more, maybe we could come up with a better, targeted way to manage this neurotoxicity.”

Both reports are limited by small patient populations, lack of a comparator arm, and their retrospective design.

Dr. Park reports research funding from Juno Therapeutics.


References

  1. Park JH, Riviere I, Wang X, et al. Durable long-term survival of adult patients with relapsed B-ALL after CD19 CAR (19-28z) T-cell therapy. Abstract #7008. Presented at the 2017 ASCO Annual Meeting, June 5, 2017; Chicago, Illinois.
  2. Park JH, Santomasso B, Riviere I, et al. Baseline and early post-treatment clinical and laboratory factors associated with severe neurotoxicity following 19-28z CAR T cells in adult patients with relapsed B-ALL. Abstract #7024. Presented at the 2017 ASCO Annual Meeting, June 5, 2017; Chicago, Illinois.

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