The following article features coverage from the American Society of Hematology 2019 meeting. Click here to read more of Cancer Therapy Advisor‘s conference coverage.

According to results of a study presented at the 61st American Hematology Society (ASH) Annual Meeting and Exposition in Orlando, Florida, predictors of improved progression-free survival (PFS) in patients with relapsed/refractory B-cell hematologic malignancies receiving a second round of autologous CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy include the use of high-intensity lymphodepletion chemotherapy prior to the initial administration of CD19-directed CAR-T, as well as a higher second-round CAR-T cell dose relative to the first round of CAR-T cell therapy.1 

Although the results of clinical trials involving a single infusion of CD19-directed CAR-T cell therapy have shown good results in patients with relapsed/refractory CD19-positive B-cell malignancies, very little is known about the potential benefits of additional CAR-T infusions. Furthermore, factors associated with response and PFS in this setting have not been previously studied.

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In this open-label, phase 1/2 clinical trial of 44 patients with chronic lymphocytic leukemia (CLL) or Richter transformation (11 individuals), non-Hodgkin lymphoma (NHL; 19 individuals), or acute lymphoblastic leukemia (ALL; 14 individuals) (ClinicalTrials.gov Identifier: NCT01865617), a first infusion of 3 different doses of CD19-directed CAR-T therapy (which the researchers dubbed CART1) was administered to different patient subgroups after either high-dose, low-dose, or no lymphodepletion therapy, followed by a second infusion of 1 of 2 different doses of the same CD19-directed CAR-T therapy (CART2) with or without lymphodepleting therapy. Antitumor activity, PFS, and the peak intensity of CD8-positive CAR-T1 and CAR-T2 cells were assessed.

In this heavily pretreated patient population (the median number of prior therapies was 5 or 7, depending on type of cancer), 15 patients did not respond to CART1, 22 patients relapsed following a response to CART1, and 7 patients had an ongoing partial response to CART1. The median time between CART1 and CART2 infusions was 50 to 102 days, depending on cancer type.

Interestingly, some patients with progressive disease or a partial response to CART1 were able to achieve a complete response (CR) following CART2 therapy. Specifically, approximately 1 month after  administration of CART2, the CR rate was 21% in patients with ALL, 27% in those with CLL, and 16% in patients with NHL.

Results of multivariable analyses showed that predictors of response to CART2 were receipt of high-dose cyclophosphamide/fluradabine lymphodepletion therapy vs none priortoCART1 (hazard ratio [HR], 13.07; 95% CI, 1.19-1802.32; P =.03), and a higher peak of in vivo CD8-positive CAR-T cell expansion after CART2 (HR, 2.09; 95% CI, 1.08-4.66; P =.03).

Regarding the former finding, Evandro Bezzera, MD, now of the Mayo Clinic, Rochester, Minnesota, who presented the results of this study, suggested that high-dose lymphodepletion therapy prior to CART1 therapy may “decrease the risk of building an immunogenic response to CART2.”

Furthermore, a higher peak of in vivo CD8-positive CAR-T cell expansion after CART2 (HR, 0.46; 95% CI, 0.31-0.67; P <.001), and a CART2 cell dose greater than the previously administered CART1 cell dose (HR, 0.36; 95% CI, 0.15-0.84; P =.02) were found to be significant predictors of longer PFS on multivariable analyses.

Notably, rates of cytokine release syndrome and neurotoxicity were not increased following CAR-T2 compared with CAR-T1.

In summarizing these results, the study authors noted that these “findings suggest outcomes after second infusions of CD19 CAR-T cells might be improved with high-intensity lymphodepletion prior to CART1 and by increasing the CAR-T cell dose at the time of CART2.”

Dr Bezerra also referred to an ongoing phase 1 study (ClinicalTrials.gov Identifier: NCT03103971) of JCAR021 (which is called huJCAR014 in the clinical trial documents for that trial number), an investigational product featuring fully human scFv CD19 CAR-T cells. This trial is investigating approaches to improve clinical outcomes of patients treated with repeat infusions of CD19-directed CAR-T therapy in patients with relapsed/refractory B-cell NHL or ALL.

“Although the results of the second infusion are not as good as the first infusion, some response can be achieved in a population without other therapy options,” Dr Bezerra said in a Fred Hutch news release.2

Read more of Cancer Therapy Advisor‘s coverage of ASH’s annual meeting by visiting the conference page.

References

  1. Bezerra, ED, Gauthier J, Hirayama AV, et al. Factors associated with response, CAR-T cell in vivo expansion, and progression-free survival after repeat infusions of CD19 CAR-T cells. Presented at: 61st American Society of Hematology (ASH) Annual Meeting and Exposition. Orlando, FL. December 7-10, 2019. Abstract 201.
  2. Keown, S. Try, try again: Can a 2nd dose of CAR T cells succeed when the first fails? Fred Hutch. Published December 7, 2019. Accessed December 8, 2019.