Distinct outcomes, ABL1 mutation profile, and transcriptome features between p190 and p210 transcripts in adult Philadelphia-positive acute lymphoblastic leukemia in the TKI era

Ting Shi; Mixue Xie; Li Chen; Wei Yuan; Yungui Wang; Xin Huang; Wanzhuo Xie; Haitao Meng; Yinjun Lou; Wenjuan Yu; Hongyan Tong; Xiujin Ye; Jinyan Huang; Jie Jin; Honghu Zhu

doi:10.1186/s40164-022-00265-2

Distinct outcomes, ABL1 mutation profile, and transcriptome features between p190 and p210 transcripts in adult Philadelphia-positive acute lymphoblastic leukemia in the TKI era

Exp Hematol Oncol. 2022 Mar 11;11(1):13. doi: 10.1186/s40164-022-00265-2.

Authors

Ting Shi^#^{1

2

3}, Mixue Xie^{1

2}, Li Chen^#^{4

5}, Wei Yuan⁶, Yungui Wang^{1

2}, Xin Huang^{1

2}, Wanzhuo Xie^{1

2}, Haitao Meng^{1

2}, Yinjun Lou^{1

2}, Wenjuan Yu^{1

2}, Hongyan Tong^{1

2}, Xiujin Ye^{7

8}, Jinyan Huang^{9

10

11}, Jie Jin^{1

2}, Honghu Zhu^{12

13

14

15}

Affiliations

¹ Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, #79 Qingchun Road, Hangzhou, 310003, Zhejiang Province, China.
² Zhejiang Province Key Laboratory of Hematology Oncology Diagnosis and Treatment, Hangzhou, China.
³ Program in Clinical Medicine, School of Medicine of Zhejiang University, Hangzhou, Zhejiang, China.
⁴ Bio-Med Big Data Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
⁵ Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
⁶ Department of Physiology, Medical College of Three Gorges University, Yichang, Hubei, China.
⁷ Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, #79 Qingchun Road, Hangzhou, 310003, Zhejiang Province, China. yxjsunny@zju.edu.cn.
⁸ Zhejiang Province Key Laboratory of Hematology Oncology Diagnosis and Treatment, Hangzhou, China. yxjsunny@zju.edu.cn.
⁹ Zhejiang University Cancer Center, Zhejiang University, Hangzhou, China. huangjinyan@zju.edu.cn.
¹⁰ Bio-Med Big Data Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. huangjinyan@zju.edu.cn.
¹¹ Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. huangjinyan@zju.edu.cn.
¹² Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, #79 Qingchun Road, Hangzhou, 310003, Zhejiang Province, China. zhuhhdoc@zju.edu.cn.
¹³ Zhejiang Province Key Laboratory of Hematology Oncology Diagnosis and Treatment, Hangzhou, China. zhuhhdoc@zju.edu.cn.
¹⁴ Zhejiang University Cancer Center, Zhejiang University, Hangzhou, China. zhuhhdoc@zju.edu.cn.
¹⁵ Zhejiang Laboratory for Systems & Precision Medicine, Zhejiang University Medical Center, Hangzhou, China. zhuhhdoc@zju.edu.cn.

^# Contributed equally.

Abstract

Background: The differential signaling and outcome of patients with p190 or p210 transcripts of BCR-ABL1 have been systematically investigated in chronic myeloid leukemia rather than in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph⁺ ALL).

Methods: We analyzed the outcomes and ABL1 mutation profiles in 305 consecutive adult patients with Ph⁺ ALL treated with chemotherapy plus tyrosine kinase inhibitors. We also studied transcriptome features in two newly diagnosed patients with p190 and p210 using single-cell RNA sequencing (scRNA-seq).

Results: P190 and p210 were found in 199 (65%) and 106 (35%) patients, respectively. Compared to patients with p190, a higher white blood cell count (p = 0.05), platelet count (p = 0.047), BCR-ABL1 transcript level (p < 0.001), and lower bone marrow blasts (p = 0.003) were found in patients with p210. Patients with p210 had fewer types of ABL1 mutations (4 vs. 16) and a higher prevalence of T315I and E225K/V mutations (91.3% vs. 68.6%; p = 0.031). Patients with p210 had a similar complete remission rate (91.0% vs. 90.1%; p = 0.805) but a lower complete molecular remission rate at 1 month (9.9% vs. 22.0%; p = 0.031) compared with p190. Patients with p210 had lower 3-year overall survival (OS) and disease-free survival (DFS) rates than those with p190 (3-year DFS: 10.4% vs. 9.2%, p = 0.069, 3-year OS: 44.3% vs. 38.2%, p = 0.018, respectively). Multivariate analysis revealed that p210 was independently associated with worse OS [HR 1.692 (95% CI 1.009-2.838), p = 0.046]. Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) was associated with a better prognosis in patients with p210 (p < 0.0001). In addition, scRNA-seq data showed distinct molecular and cellular heterogeneity between bone marrow cells of the two transcripts.

Conclusions: Ph⁺ ALL patients with p190 and p210 had different clinical characteristics, outcomes, ABL1 mutation profiles, and transcriptome features. Allo-HSCT could improve the outcomes of patients with p210.

Keywords: BCR-ABL1; Ph+ ALL; TKIs; p190; p210; scRNA-seq.