Poor Prognostic Combination of Additional Chromosomal Abnormalities in Ph + ALL : JALSG Ph+ALL TKI- SCT Study

Background: Additional chromosomal abnormalities (ACAs) are frequently observed in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). The types of ACAs are diverse, and their relationship with the prognosis had not been established. The aim of this study is to identify prognostic factors in Ph+ALL, including ACAs with poor prognosis.

Methods: The JALSG Ph+ALL TKI-SCT study analyzed data of 206 de novo adult Ph+ALL ALL patients age15 to 64 who were treated with the combination of chemotherapy and a tyrosine kinase inhibitor in three prospective clinical studies conducted by the JALSG. In the Ph+ALL202 study and the Ph+ALL208 study, imatinib was used as a tyrosine kinase inhibitor (TKI), whereas dasatinib was used in the Ph+ALL213 study. Relapse was defined as the recurrence of hematological leukemia. For analyses of overall survival (OS), failure was defined as death from any cause, and surviving patients were censored at the date of the last contact. Leukemia-free survival (LFS) was measured from the time of achievement of CR until relapse or death from any cause. The BCR-ABL1 transcript levels below the threshold for quantification, which corresponded to a minimal sensitivity of 10^-5, were defined as molecular CR. For the multivariate analyses, potential covariates were included in the final multivariate model regardless of their statistical significances in univariate models: Covariates in the multivariate analyses included karyotype, patient age, white blood cell count at diagnosis, and TKI. A significance level of P < 0.05 was used for all analyses.

Results: Five-year OS and LFS was 58.8% and 51.0%. ACA was identified in 63.6% of patients, and the most common structural chromosomal abnormality was +der(22)t(9;22) (32.8% of patients with ACA). Complex karyotype was observed in 48.1% of patients with ACA. In multivariate analysis, +der(22)t(9;22), and complex karyotype were marginal risk factors for OS, and +der(22)t(9;22) was a significant and complex karyotype was a marginal risk factor for LFS. However, when ACA+ was analyzed together as one variable, ACA was not a significant prognostic factor for both OS and LFS. Among 43 patients with +der(22)t(9;22), 67.4 % (29 patients) also had complex karyotype. In multivariate analysis, co-existence of +der(22)t(9;22) and complex karyotype was a significant risk factor for both OS (Hazard ratio (HR) 2.33, 95%CI 1.26-4.30, P=0.007, no ACA as reference) and LFS (HR 2.43, 95%CI 1.38-4.28, P=0.002), whereas +der(22)t(9;22) alone, complex karyotype alone or other ACAs was not a significant risk factor (Fig). The survival of patients with co-existence of +der(22)t(9;22) and complex karyotype (high-risk) was significantly inferior to the others (standard-risk) (5-year OS: 33.4% vs. 62.7%, P=0.0003; 5-year LFS: 23.3% vs. 55.3%, P<0.0001). There was no significant difference in baseline characteristics between standard and high-risk patients. CR1 achievement rate was not significantly different between standard and high-risk patients (95.1% vs. 100%, P=0.22). In addition, molecular CR rate at 3 months was not significantly different between standard and high-risk patients (79.8% vs. 78.2%, P=0.86). However, among patients who achieved CR1, the CR duration was significantly shorter in high-risk patients compared with standard-risk patients (0.68 years vs. 1.1 years, P=0.046).

Conclusion: Co-existence of +der(22)t(9;22) and complex karyotype was identified as a high-risk combination of ACAs and a significant prognostic factor in Ph+ALL.

Fujisawa:Chugai Pharma: Research Funding; Kyowa Hakko Kirin: Research Funding; Shionogi: Research Funding; AbbVie Inc: Honoraria; Meiji Seika Pharma: Honoraria; CSL Behring K.K: Honoraria; AstraZeneca: Honoraria; Kyowa Hakko Kirin: Honoraria; SymBio Pharma: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; MSD K.K.: Honoraria; Novartis KK: Honoraria; Pfizer Japan Inc: Honoraria; Otsuka: Honoraria; Astellas, Nipppon Shinyaku: Honoraria; Bristol-Myers-Squibb: Honoraria; Otsuka: Research Funding; Asahi-Kasei Pharma: Research Funding. Hatta:Kyowa Kirin Co: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Honoraria; Novartis Pharma: Honoraria. Ueda:Sanofi Otsuka Pharmaceutical: Honoraria. Dobashi:Astellas Pharma Inc: Research Funding; Chugai Pharmaceutical Co., Ltd..: Research Funding; Daiichi Sankyo Co.., Ltd.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Other: Paid expert testimony, Research Funding; AbbVie GK: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding; Ono Pharmaceutical Co. Ltd.: Research Funding; Bristol Myers Squibb K.K.: Research Funding; Pfizer Inc.: Research Funding. Maeda:Otsuka Pharmaceutical Co., Ltd.: Honoraria; Novartis Pharmaceuticals: Honoraria; TOPPAN INC: Honoraria; Nippon Shinyaku Co., Ltd.: Honoraria; Sumitomo Pharma Co., Ltd.: Research Funding; Pfizer Inc.: Honoraria; Amgen K.K.: Honoraria; Nippon Becton Dickinson Company, Ltd.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding. Atsuta:Astellas Pharma Inc.: Honoraria; Novartis Pharma KK: Honoraria; AbbVie GK: Honoraria; Mochida Pharmaceutical Co., Ltd.: Honoraria; Kyowa Kirin Co., Ltd: Honoraria; Meiji Seika Pharma Co, Ltd.: Honoraria. Kiyoi:Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Kyowa Kirin Co., Ltd.: Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; Sumitomo Pharma Co., Ltd.: Research Funding; Eisai Co., Ltd.: Honoraria, Research Funding; Daiichi Sankyo Co., Ltd: Honoraria, Research Funding; otsuka Pharmaceutical Co.,Ltd.: Research Funding; Perseus Proteomics Inc.: Research Funding; CURED Co., Ltd: Research Funding; Astellas Pharma Inc.: Honoraria, Research Funding; Asahi Kasei Corporation: Research Funding; AbbVie Inc.: Honoraria, Research Funding; Nippon Shinyaku Co.,Ltd.: Honoraria, Research Funding; JCR Pharmaceuticals Co.,Ltd.: Research Funding; Takeda Pharmaceutical Company Limited: Research Funding; AstraZeneca pic: Honoraria; Novartis Pharma K.K.: Honoraria; SymBio Pharmaceuticals Limited: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen inc.: Honoraria; Meiji Seika Pharma Co., Ltd.: Honoraria; Pfizer Inc.: Honoraria; Nippon Kayaku Co.,Ltd.: Honoraria; Towa Pharmaceutical Co., Ltd.: Honoraria. Matsumura:Otsuka Pharmaceutical Co., Ltd.: Consultancy, Research Funding, Speakers Bureau; Chugai Pharmaceutical Co., Ltd.: Research Funding; Kyowa Kirin Co., Ltd: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Shionogi & Co., Ltd: Research Funding; Asahi Kasei Pharma Corp.: Research Funding; Eisai Co., Ltd: Research Funding; Taiho Pharmaceutical Co., Ltd.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Ono Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Sanofi K.K.: Research Funding; Mitsubishi Tanabe Pharma Corp.: Research Funding; Novartis Pharma KK: Research Funding, Speakers Bureau; Astellas Pharma Inc.: Research Funding, Speakers Bureau; Janssen Pharmaceutical K.K: Research Funding, Speakers Bureau; AbbVie G.K.: Research Funding, Speakers Bureau; SymBio Pharmaceuticals Ltd.: Speakers Bureau; Pfizer Japan Inc.: Research Funding, Speakers Bureau; Alexion Pharmaceuticals, Inc.: Research Funding; Bristol-Myers Squibb K.K.: Speakers Bureau; Daiichi Sankyo Co., Ltd.: Speakers Bureau. Miyazaki:Chugai: Honoraria; SyinBio: Honoraria; Astellas: Honoraria; Dainippon-Sumitomo Pharma: Honoraria, Research Funding; Bristol-Myers: Honoraria; Kyowa-Kirin: Honoraria; Pfizer: Honoraria; Otsuka Pharmaceutical: Honoraria; Takeda: Honoraria; Daiichi-Sankyo: Honoraria; Abbvie: Honoraria; Novartis: Honoraria; Nippon Shinyaku: Honoraria; Janssen Pharmaceutical: Honoraria; Celgene: Honoraria.