Genetic correlates in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia treated with Hyper-CVAD plus dasatinib or ponatinib

Abstract

Recurring genetic abnormalities have been identified in Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). Among them, IKZF1 deletion was associated with poor prognosis in patients treated with imatinib-based or dasatinib-based regimens. However, the molecular determinants for clinical outcomes in ponatinib-treated patients remain unknown. We systematically analyzed genetic alterations in adults with Ph-positive ALL uniformly treated in clinical trials with dasatinib-based regimens or a ponatinib-based regimen and investigated the molecular determinants for treatment outcomes using pretreatment specimens collected from adults with Ph-positive ALL treated with Hyper-CVAD plus dasatinib or ponatinib. DNA sequencing and SNP microarray were performed and recurrent genetic abnormalities were found in 84% of the patients, among whom IKZF1 deletion was most frequently detected (60%). IKZF1 deletion frequently co-occurred with other copy-number abnormalities (IKZF1^plus, 46%) and was significantly associated with unfavorable overall survival (OS) (false discovery rate < 0.1) and increased cumulative incidence of relapse (p = 0.01). In a multivariate analysis, dasatinib therapy, lack of achievement of 3-month complete molecular response, and the presence of IKZF1^plus status were significantly associated with poor OS. The differential impact of IKZF1^plus was largely restricted to patients given Hyper-CVAD plus ponatinib; dasatinib-based regimens had unfavorable outcomes regardless of the molecular abnormalities.

Figure 1.

CONSORT diagram of the current retrospective study. Total 100 patients were analyzed using the diagnostic samples in Hyper-CVAD plus dasatinib (N = 39), Hyper-CMAD plus dasatinib (N = 11), or Hyper-CVAD plus ponatinib (N = 50). Note*: Of 31 patients participated in NCT01319981, 21 patients were Ph-positive ALL; 19 patients were treated with HCMAD plus dasatinib and 2 patients were treated with HCMAD plus imatinib. Abbreviations: NCT, The National Clinical Trial; HCMAD; Hyper-CMAD; ALL, acute lymphoblastic leukemia.

Figure 2.

(A) Landscape of 100 patients with Ph-positive ALL. IKZF1 deletion was most frequently detected and detailed information about IKZF1 deletion. (B) Types of IKZF1 deletion. Dominant-negative type and haploinsufficiency type were frequently detected subtype of IKZF1 deletion. (C) Co-occurrence and exclusiveness of each genetic alteration. (D) Correlation between clinical characteristics and genetic alterations. Abbreviations: Ph, Philadelphia chromosome; del, deletion; mut, mutation; CNS, central nervous system; AYA, adolescent and young adult; TKI, tyrosine kinase inhibitor.

Figure 2.

(A) Landscape of 100 patients with Ph-positive ALL. IKZF1 deletion was most frequently detected and detailed information about IKZF1 deletion. (B) Types of IKZF1 deletion. Dominant-negative type and haploinsufficiency type were frequently detected subtype of IKZF1 deletion. (C) Co-occurrence and exclusiveness of each genetic alteration. (D) Correlation between clinical characteristics and genetic alterations. Abbreviations: Ph, Philadelphia chromosome; del, deletion; mut, mutation; CNS, central nervous system; AYA, adolescent and young adult; TKI, tyrosine kinase inhibitor.

Figure 3.

OS by TKI in the current study (N = 100; Hyper-CVAD (CMAD) plus dasatinib [N = 50] and Hyper-CVAD plus ponatinib [N = 50]). Abbreviations: OS, overall survival; TKI, tyrosine kinase inhibitor; CI, confidence interval.

Figure 4.

(A) Impact of clinical features and genetic alterations on OS. (B) Impact of IKZF1 deletion status on OS in the entire cohort. (C) Impact of IKZF1 deletion status on CIR in the entire cohort. Note*: poor-risk ACA, +der(22)t(9;22) or −9/9p in the absence of high hyperdiploidy. Note**: *CMR 1 mo at and/or 3 mos was evaluated for patients who survived more than 3 months and whose bone marrow samples at 3 months were available. Abbreviations: OS, overall survival; mo, month; CIR, cumulative incidence of relapse; AYA, adolescent and young adult; CNS, central nervous system; cyto, cytogenetics; Ph, Philadelphia chromosome; ACA, additional chromosomal abnormality; TKI, tyrosine kinase inhibitor; CMR, complete molecular response; del, deletion; mut, mutation; CI, confidence interval; FDR, false discovery rate; HR, hazard ratio.

Figure 4.

(A) Impact of clinical features and genetic alterations on OS. (B) Impact of IKZF1 deletion status on OS in the entire cohort. (C) Impact of IKZF1 deletion status on CIR in the entire cohort. Note*: poor-risk ACA, +der(22)t(9;22) or −9/9p in the absence of high hyperdiploidy. Note**: *CMR 1 mo at and/or 3 mos was evaluated for patients who survived more than 3 months and whose bone marrow samples at 3 months were available. Abbreviations: OS, overall survival; mo, month; CIR, cumulative incidence of relapse; AYA, adolescent and young adult; CNS, central nervous system; cyto, cytogenetics; Ph, Philadelphia chromosome; ACA, additional chromosomal abnormality; TKI, tyrosine kinase inhibitor; CMR, complete molecular response; del, deletion; mut, mutation; CI, confidence interval; FDR, false discovery rate; HR, hazard ratio.

Figure 5.

(A) Impact of IKZF1^plus status on OS and CIR in Hyper-CVAD plus ponatinib cohort. (B) Impact of IKZF1^plus status on OS and CIR in Hyper-CVAD plus dasatinib cohort. Abbreviations: OS, overall survival; CIR, cumulative incidence of relapse; TKI, tyrosine kinase inhibitor; CI, confidence interval; NA, not applicable.