Optimizing Chimeric Antigen Receptor T-Cell Therapy for Adults With Acute Lymphoblastic Leukemia

Noelle V. Frey, MD; Pamela A. Shaw, PhD; Elizabeth O. Hexner, MD; Edward Pequignot, MS; Saar Gill, MD, PhD; Selina M. Luger, MD; James K. Mangan, MD, PhD; Alison W. Loren, MD; Alexander E. Perl, MD; Shannon L. Maude, MD, PhD; Stephan A. Grupp, MD, PhD; Nirav N. Shah, MD; Joan Gilmore, BS; Simon F. Lacey, PhD; Jos J. Melenhorst, PhD; Bruce L. Levine, PhD; Carl H. June, MD; David L. Porter, MD

Disclosures

J Clin Oncol. 2020;38(5):415-422. 

In This Article

Results

Patient Characteristics

A total of 49 patients were enrolled (7 in the first-in-human study and 42 in the follow-up study). Fourteen patients did not receive study treatment for the following reasons (Figure 1): manufacturing failure (n = 1), patients sought alternative treatment (n = 3), died (n = 5), or were medically unfit to receive treatment because of rapid disease progression or comorbid illness (n = 5). Thirty-five patients with r/r ALL (median age, 34 years; range, 21–70 years) received CTL019 through 3 dosing cohorts and were included in the study analysis (Table 2). Thirteen patients (37%) had experienced relapse after prior HSCT, and 11 (31%) had received prior blinatumomab. The median number of prior therapies was 3 (range, 1–7 therapies), and 11 patients (31%) had primary refractory disease. For patients with bone marrow biopsies available between lymphodepleting chemotherapy and CTL019 infusion (n = 29), the majority (93%) had > 5% bone marrow involvement.

Lymphodepleting chemotherapy was administered to 33 of 35 patients 1–2 weeks before CTL019 infusion. The majority of patients (n = 25) received single-agent cyclophosphamide (300 mg/m2 every 12 hours × 6), and 5 patients received cyclophosphamide (500 mg/m2 × 2 days) with fludarabine (30 mg/m2 × 4 days). One patient received clofarabine and one patient received methotrexate, and cytarabine and cyclophosphamide, vincristine, and doxorubicin. Two patients did not receive lymphodepletion at physician discretion because of leukopenia (WBC ≤60/μL [below the level of quantification] and WBC = 200/μL).

Response Rates and Survival

The overall CR rate by D28 for patients in all treatment cohorts was 69% (95% CI, 51% to 83%). Response rates, treatment-related toxicity, and survival varied significantly by dosing cohort (Table 3). In the HDS cohort (n = 6), 3 patients died before disease response assessment as a result of complications of CRS and infections; the surviving 3 patients achieved CR. In the LD cohort (n = 9), patients had manageable CRS, but only 33% achieved CR. In the HDF cohort (n = 20), toxicity was manageable, and the CR rate was 90%. All patients who achieved CR and had concurrent bone marrow assessment for MRD by flow cytometry (n = 19) were MRD negative.

Long-term Survival

At a median follow-up of 13 months (range, 0.2–52.7 months), the median OS for the entire cohort was 19.1 months (95% CI, 6.2 months to not estimable), and the median EFS was 5.6 months. OS and EFS were significantly improved in the HDF cohort (n = 20) compared with the HDS and LD cohorts. In the HDF cohort, median OS was not reached, with a 2-year survival rate of 73% (95% CI, 46% to 88%); median EFS was 19.4 months, and the 2-year EFS rate was 49.5%. For HDS, the 2-year OS and EFS rates were both 17% (95% CI, 0.8% to 52%). For LDS, the 2-year OS and EFS rates were 22% (95% CI, 3% to 51%) and 0% (95% CI, 0% to 33%), respectively (Figure 2; Table 3).

Figure 2.

Kaplan-Meier graphs of overall survival (OS) and event-free survival (EFS). (A) OS by cohort. (B) EFS by cohort. (C) OS for complete responders. (D) EFS for complete responders. (E) Landmark analysis for OS by subsequent allogeneic hematopoietic stem-cell transplantation (HSCT). (F) Landmark analysis for EFS by subsequent allogeneic HSCT. HDF, high-dose fractionated; HDS, high-dose single infusion; LD, low dose.

We evaluated the effect of age on survival. OS and EFS curves were similar between patients age ≥ 35 years (n = 17) versus younger patients (n = 18; log-rank P = .56 and 1.00, respectively). Cox regression was used to examine the effect of age as a continuous covariate, and no significant effect of age was found; a 10-year increase in age was associated with 1.03-fold increase in the hazard of death (95% CI, 0.76 to 1.41) and a 1.15-fold increase in the hazard of an event (95% CI, 0.86 to 1.53).

For patients who achieved CR (n = 24), the median OS was not reached, with a 2-year survival rate of 64% (95% CI, 38% to 82%), and the median EFS was 19.4 months (95% CI, 5.6 months to not estimable; Figures 2C and 2D). Nine of the 24 patients who achieved CR received a consolidative allogeneic HSCT in CR, and 15 received no therapy after CTL019 unless relapse occurred. The median time to subsequent HSCT was 2.6 months (range, 1.7–5.2 months). For patients bridged and not bridged to HSCT, median ages were 38.7 years (range, 24.4–50.5 years) and 35.5 years (range, 27.2–63.0 years), respectively. To estimate the impact of HSCT in responding patients, we did a landmark analysis for OS and EFS by subsequent HSCT and found a nonsignificant improvement in OS and a significant improvement in EFS in patients who received HSCT (Figures 2E and 2F).

Toxicity

Treatment-related neurocognitive toxicity of any grade affected 14 patients (40%). Grade 1–2 toxicity occurred in 13 patients (37%) and grade 3 in 2 (6%), and no patient had grade 4 neurotoxicity. One patient in the LD cohort died as a result of intracranial hemorrhage D17 after CART infusion in the setting of persistent disease and thrombocytopenia. The most prevalent treatment-related adverse event was CRS, which was graded with the Penn grading scale[11] (Appendix Table A1). CRS of any grade occurred in 33 patients (94%). Grade 1–2 CRS occurred in 8 patients (23%), grade 3 in 19 (54%), grade 4 in 3 (9%), and grade 5 in 3 (9%). The frequency of grade 4/5 CRS varied by treatment cohort (Fisher's exact P = .017; Table 3). The 3 patients with grade 5 CRS were all in the HDS cohort, and all had concurrent infections. All 3 patients (ages 32, 56, and 63 years) died as a result of refractory hypotension, having developed pulmonary edema that required mechanical ventilation. All 3 patients received at least 2 doses of tocilizumab and systemic corticosteroids, and all had concern for concurrent sepsis at the time of death (1 with influenza B, 1 with Stenotrophomonas pneumonia, and 1 with Pseudomonas pneumonia). Only 1 grade 4 CRS and no grade 5 CRS were observed in the 20 patients treated in the HDF cohort.

Fractionated Dosing

The 20 patients in the HDF cohort had planned infusions of CTL019 over 3 days, with 10% delivered on D1, 30% on D2, and 60% on D3. D2 and D3 were withheld for early signs of clinical CRS, such as fever, that occurred after the first or second dose. Nine patients received 1 dose, 4 received 2 doses, and 7 received all 3 doses. Only 2 of the 20 patients in the HDF cohort did not achieve CR; both received 2 doses of cells.

Given that baseline disease burden in ALL is a predictor for severe CRS, we analyzed whether baseline disease burden (available for 15 of 20 patients in the HDF cohort) correlated with the number of fractions given. Both evaluable patients with<5% bone marrow blasts received all 3 doses of CTL019. Of note, of the 9 patients in the HDF cohort with high disease burden (> 50%), 3 received D1 only, 3 received D1 and D2 only, and 3 received all 3 doses of cells. The Spearman's rank correlation coefficient was 0.12 (95% CI, −0.42 to 0.6; P = .66).

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