The Clinical Outcome of Patients with Refractory/Relapsed Lymphoid Blastic Phase of Chronic Myeloid Leukemia Treated with CAR T-Cells Therapy
Authors: Liu Yujie , Tu Yuqing , Xiao Jinyan , Shen Yifan , Zhou Biqi , Yang Qiannan , Liu Tianhui , Qi Lijuan , Chen Jia , Yu Lei , Wu Depei , Yang Xu 
Published: December 2023

Introduction : Chimeric antigen receptor T (CAR T) is an effective therapy for refractory/relapsed (R/R) philadelphia chromosome positive acute lymphoblastic leukemia (ph+ ALL) patients in TKIs era. Patients with lymphoid blastic phase of chronic myeloid leukemia (CML-LBC) also have BCR-ABL fusion oncogenes, and usually shows an aggressive clinical course with a poor prognosis. However, outcomes of CAR T therapy for patients with R/R CML-LBC is still uncertain. This study was designed to compare the efficacy and safety of CAR T-cells therapy in patients with R/R CML-LBC and ph+ ALL.
Patients and Methods : Clinical data from 13 patients with R/R CML-LBC and 121 R/R ph+ ALL patients who received CAR T treatments at our center from February 2017 to March 2023 were retrospectively collected and analyzed. Before CAR T-cells treatment, fifty patients (11.2%) had primary refractory disease, 106 patients (79.1%) were experiencing the first relapse, and 13 patients (9.7%) were experiencing the second or more relapse. All patients received lymphodepletion with fludarabine (30 mg/m2 /d) and cyclophosphamide (300 mg/m2 /d) -based conditioning regimens on day −5 to −3. CAR T-cells were then infused at day 0. Among them, 8 patients with CML-LBC and 92 ph+ ALL patients received single CD19 CAR T therapy, others received tandem CD19/CD22 CAR T.
Results:The baseline characteristics of all patients were shown in Table 1. Patients with CML-LBC carried a higher proportion of mutations in the ABL kinase region ( P=0.036).The clinical timeline of CML-LBC patients as shown in Figure 1A,and ABL kinase region mutations and gene mutations of patients are shown in Figure 1B. Patients with CML-LBC (58.3%) had significantly lower CR rates than ph+ ALL (97.2%) patients at +2 month after CAR-T therapy (P&lt;0.001) ( Fig. 1B). ABL kinase region mutation (odds ratio, 0.091; 95% CI, 0.015-0.571) and CML-LBC (odds ratio, 0.063; 95% CI, 0.010-0.376) remained risk factors in multivariate logistic regression analysis of CR rate in all patients. Furthermore, minimal residual disease (MRD)-negative CR rates were 58.3% and 95.3% at +2 month after CAR T-cells therapy, respectively (P&lt;0.001) ( Fig. 1B). There was no significant difference in the incidence of adverse events among the two groups. Severe cytokine release syndrome (CRS, Grade ≥ 3) occurred in 7.7% of patients with CML-LBC and 8.3% in ph+ ALL patients (P=1.000). Moreover, patients with CML-LBC showed poorer 2-year prognoses than the ph+ ALL patients (overall survival: P=0.0068; leukemia-free survival: P&lt;0.0001; cumulative incidence of relapse: P&lt;0.001) ( Fig. 1C-1E). Univariate and multivariate Cox regression analyses showed that a poorer LFS was related to ABL kinase region mutation (hazard ratio, 3.257; 95% CI, 1.404-7.553) and CML-LB (hazard ratio, 3.803; 95% CI, 1.507-9.596).
Conclusions: Worser sustained antitumor efficacy and long-term survival with CAR T-cells therapy in patients with CML-LBC compared to ph+ ALL patients, and ABL kinase region mutation is an independent risk factor for CR and LFS.