Factors associated with long-term outcomes of CD19 CAR T-cell therapy for R/R CLL

While CD19-targeted chimeric antigen receptor (CAR)-modified T-cell therapy has shown high response rates in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL), there is limited research on the factors associated with duration of response (DOR).

The Lymphoma Hub has previously reported on a phase I/II clinical trial (NCT01865617) demonstrating high rates of durable responses with CD19 CAR T-cell therapy combined with ibrutinib. Below, we summarize a recent publication by Liang et al. published in Blood Advances that provides an update on this phase I/II clinical trial, including >6 years of median follow-up.

Study design¹

Patients with R/R CLL and/or Richter transformation were enrolled and received either JCAR014 without concurrent ibrutinib (n = 30) or with concurrent ibrutinib (n = 19).

Patients received sequential or concurrent LD chemotherapy with cyclophosphamide (Cy) and fludarabine (Flu), Cy alone, or Flu alone. Following LD chemotherapy, an infusion of 2 × 10⁵, 2 × 10⁶, or 2 × 10⁷ CD19 CAR T cells per kilogram of body mass was given. In the concurrent ibrutinib cohort, patients received ibrutinib (420 mg, daily) starting ≥2 weeks before leukapheresis up to ≥3 months after CAR T-cell infusion.

Results¹

Overall, 49 patients were enrolled with a median age of 61 years, and most patients had intolerance to, and/or progression on, ibrutinib (Table 1).

Table 1. Key baseline characteristics*

BM, bone marrow; CLL, chronic lymphocytic leukemia; CAR, chimeric antigen receptor; Cy, cyclophosphamide; ECOG PS, Eastern Cooperative Oncology Group Performance Status; Flu, fludarabine; IHC, immunohistochemistry; LD, lymphodepletion; MFC, multiparameter flow cytometry; WBC, white blood cell. *Data from Liang, et al.1 †Defined as 17p deletion and/or complex karyotype. ‡n=47. §n = 43. |Defined as largest lymph node ≥5 cm. ¶Cy 300 to 500 mg/m2 × 3 days + Flu 20 to 30 mg/m2 × 3 days. **Cy 30 to 60 mg/kg or 1 g/m2 × 1 day, then Flu 25 mg/m2 × 3 or 5 days. ††One patient with Richter transformation was treated on a dose-dense protocol, in which a second infusion of CAR T cells was administered on day +14 without interval LD. ‡‡Recommended phase 2 dose.
Characteristic, % (unless otherwise specified)	N = 49
Median age, years	61.0
Sex
Female	33.0
Male	67.0
ECOG PS score
0	49.0
1	51.0
Prior history of or current Richter transformation	18.0
Median number of prior therapies	5.0
Prior fludarabine	29.0
Prior bendamustine	51.0
Prior venetoclax	39.0
High-risk cytogenetics†	94.0
Intolerance to and/or progression on ibrutinib	96.0
Median absolute lymphocyte count, 109/L	1.8
Median absolute CD4+ T-cell count, cells per μL	547.3
Median absolute CD8+ T-cell count, cells per μL	350.4
Median CLL cell in the blood by MFC, % of WBCs‡	22.3
Marrow CLL burden
Median CLL cells in the BM by IHC§	60.0
Median CLL cells in BM by MFC	49.4
Bulky disease|	27.0
LD regimen
Concurrent Cy/Flu¶	55.0
Sequential Cy/Flu**	39.0
Cy 2 g/m2 × 1 day	2.0
Flu 25 mg/m2 × 3 days	4.0
CAR T-cell dose level
2 × 105 cells per kg	10.0
2 × 106 cells per kg††,‡‡	88.0
2 × 107 cells per kg	2.0

Long-term outcomes

Overall, 47 patients were evaluable for response (two patients died before response assessment due to Grade 5 cytokine release syndrome and neurotoxicity [n = 1] and presumed ibrutinib-related cardiac arrhythmia [n = 1]).

The median follow-up was 79.6 months, and the median DOR was 18.9 months; the 6-year DOR was 26.4%. The progression-free survival (PFS) and overall survival (OS) rates for all patients who received CAR T-cell therapy are shown in Figure 1.

OS, overall survival; PFS, progression-free survival.
*Data from Liang, et al.¹

 

One patient each with current Richter transformation experienced complete response (CR) and CR with incomplete hematologic recovery but relapsed 9.8 and 3.0 months after CAR T-cell infusion, respectively.

Predictors of PFS, DOR, and OS

Univariate Cox regression analyses were carried out to identify predictors of PFS, DOR, and OS (Figure 2).

CAR, chimeric antigen receptor; CR, complete response; DOR, duration of response; LD, lymphodepletion; MFC, multiparameter flow cytometry; MRD, measurable residual disease; NGS, next-generation sequencing; OS, overall survival; PET-CT, positron emission tomography-computed tomography; PFS, progression-free survival.
*Data from Liang, et al.¹

 

An association between higher pre-LD, Day +0, and peak serum levels of several cytokines with shorter PFS was observed during an exploratory analysis.

Factors associated with shorter OS included Eastern Cooperative Oncology Group Performance Status of 1, maximum standardized uptake values, and bulky disease.

Conclusion

This 6-year follow-up update demonstrated durable responses in patients with high-risk R/R CLL and MRD-negative response after CD19 CAR T-cell therapy. Predictors of long-term outcomes were also identified, including both pretreatment and posttreatment variables that were strongly associated with PFS. Day +28 CR by positron emission tomography-computed tomography, Day +28 MRD negativity by MFC, Day +28 MRD negativity by next-generation sequencing, higher peak CD8⁺ CAR T-cell expansion, higher peak CD4⁺ CAR T-cell expansion, and longer CAR T-cell persistence were associated with longer PFS.