Background
We observed high efficacy in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) treated on a phase I/II clinical trial with a defined-composition (1:1 ratio of CD8+:CD4+) CD19 CAR T-cell product (NCT01865617). We now report comprehensive analyses of factors associated with duration of response (DOR) with over 6 years of median follow-up.
Methods
We included 49 patients with R/R CLL and/or Richter’s transformation (n = 9) (Table 1). Response was defined as complete (CR) or partial response (PR) by investigator-assessed 2018 iwCLL criteria at day+28. Measurable residual disease (MRD) in bone marrow (BM) was evaluated by multiparameter flow cytometry (MFC) and IGH next-generation sequencing (NGS; clonoSEQ assay).
Table 1.Patient and disease characteristics.
| Characteristic |
N = 49 |
| Age |
|
| Median (IQR) |
61.0 (55.0, 67.0) |
| Range |
40.0 - 73.0 |
| Sex |
|
| Female |
16 (33%) |
| Male |
33 (67%) |
| ECOG score |
|
| 0 |
24 (49%) |
| 1 |
25 (51%) |
| Prior history of or current Richter transformation |
9 (18%) |
| Prior history of Richter transformation |
7 (14%) |
| Current Richter transformation |
2 (4%) |
| Number of prior therapies |
|
| Median (IQR) |
5.0 (4.0, 7.0) |
| Range |
1.0 - 10.0 |
| Prior fludarabine |
14 (29%) |
| Prior bendamustine |
25 (51%) |
| Prior venetoclax |
19 (39%) |
| High-risk cytogenetics1 |
46 (94%) |
| Complex karyotype2 (n = 48) |
36 (75%) |
| 17p deletion |
33 (67%) |
| Intolerance to and/or progression on ibrutinib |
47 (96%) |
| Intolerance to ibrutinib |
5 (10%) |
| Progression on ibrutinib |
43 (88%) |
| Prior allogeneic HCT |
7 (14%) |
| Bridging chemotherapy |
8 (16%) |
| Absolute lymphocyte count (109/L) |
|
| Median (IQR) |
1.8 (1.0, 7.1) |
| Range |
0.2 - 58.9 |
| Percentage of CLL cell count in blood by MFC (% of WBC) (n = 47) |
|
| Median (IQR) |
22.3 (4.0, 60.0) |
| Range |
0.0 - 92.0 |
| Marrow CLL burden |
|
Percentage of CLL cells in bone marrow by IHC (%)
(n = 43) |
|
| Median (IQR) |
60.0 (12.5, 70.0) |
| Range |
0.0 - 90.0 |
| Percentage of CLL cells in bone marrow by MFC (%) |
|
| Median (IQR) |
49.4 (14.1, 73.5) |
| Range |
0.0 - 96.0 |
| Serum LDH concentration (U/L) |
|
| Median (IQR) |
200.0 (153.0, 308.0) |
| Range |
94.0 - 1,872.0 |
| Tumor cross-sectional area3 (mm2) |
|
| Median (IQR) |
3,092.9 (1,489.7, 4,436.4) |
| Range |
0.1 - 20,406.2 |
| Maximum SUV (n = 37) |
|
| Median (IQR) |
5.1 (3.7, 7.5) |
| Range |
0.0 - 27.5 |
| Bulky disease4 |
13 (27%) |
Unless otherwise noted, data are n (%).
All variables were assessed prior to lymphodepletion chemotherapy, unless specified.
Abbreviations: IQR, interquartile range; ECOG, Eastern Cooperative Oncology Group; HCT, hematopoietic cell transplantation; CLL, chronic lymphocytic leukemia; IHC, immunohistochemistry; MFC, multiparameter flow cytometry; WBC, white blood cells; LDH, lactate dehydrogenase; SUV, standardized uptake value
1 Defined as 17p deletion and/or complex karyotype
2 Defined as ≥3 chromosomal abnormalities
3 In patients with evaluable nodal disease (n = 45); sum of the product of the diameters of up to 6 of the largest lymph nodes or masses evaluated on the pre-lymphodepletion CT scan
4 Defined as largest lymph node ≥ 5 cm
Results
In the response-evaluable cohort (n = 47), median follow-up was 79.6 months. Median DOR was 18.9 months (95% CI, 9.66-55.6) (Figure 1A). In NGS MRD-negative responders, the median DOR was 53.4 months (95% CI, 27.1-not reached) (Figure 1B). In all infused patients (n = 49), the 6-year PFS and OS were 17.8% and 31.2%, respectively (Figure 1C-D).
Figure 1.A) Duration of response (DOR) in patients who were in complete or partial response by iwCLL criteria at day +28. B) DOR in day +28 IGH next-generation sequencing (NGS) measurable residual disease (MRD)-negative responders. C) Progression-free survival and D) overall survival in all infused patients.
In univariate Cox regression, day +28 CR by PET-CT scan, day +28 MRD negativity by MFC, day +28 MRD negativity by NGS, higher peak CD8+ CAR T-cell expansion, higher peak CD4+ CAR T-cell expansion, and longer CAR T-cell persistence were associated with longer DOR (Table 2). These factors were also associated with longer PFS and OS in univariate Cox regression. In the 7 patients who were progression-free at 5 years, 7 had day +28 MRD negativity by MFC, and 5 (1 missing) had day +28 MRD negativity by NGS.
Table 2.Factors associated with duration of response by univariate Cox regression.
| Characteristic |
N |
Event N |
HR |
95% CI |
p-value |
| Day +28 nodal response by PET-CT scan |
19 |
13 |
|
|
|
| PR |
|
|
— |
— |
|
| CR |
|
|
0.17 |
0.05, 0.64 |
0.008 |
| Day +28 bone marrow MRD by MFC |
33 |
24 |
|
|
|
| Positive |
|
|
— |
— |
|
| Negative |
|
|
0.03 |
0.01, 0.15 |
<0.001 |
| Day +28 bone marrow MRD by IGH NGS |
25 |
17 |
|
|
|
| Positive |
|
|
— |
— |
|
| Negative |
|
|
0.25 |
0.09, 0.68 |
0.006 |
| Peak CD4+ CAR T-cell expansion (log10 cells/µL) |
33 |
24 |
0.49 |
0.28, 0.85 |
0.011 |
| Peak CD8+ CAR T-cell expansion (log10 cells/µL) |
33 |
24 |
0.53 |
0.33, 0.85 |
0.009 |
CAR T-cell persistence
(CAR transgene copies/µg genomic DNA)4 |
— |
— |
0.56 |
0.39, 0.81 |
0.002 |
Abbreviations: HR, hazard ratio; CI, confidence interval; PET-CT, positron emission tomography-computed tomography; MRD, measurable residual disease; MFC, multiparameter flow cytometry; NGS, next-generation sequencing; CAR, chimeric antigen receptor; DNA, deoxyribonucleic acid
1 Defined as ≥3 chromosomal abnormalities
2 By Lee 2014 CRS criteria
3 By Common Terminology Criteria for Adverse Events v4.03 criteria
4 Modeled as a time-dependent continuous covariate (limit of quantitation: 10 copies/µg genomic DNA)
Summary/Conclusions
In patients with R/R CLL receiving CD19 CAR T-cell therapy, day +28 CR by PET CT, day +28 MRD negativity, higher in vivo peak CAR T-cell expansion, and longer CAR T-cell persistence were associated with long-term outcomes, including DOR.
