Ph-like acute lymphoblastic leukemia: a high-risk subtype in adults

Abstract

Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL) is a high-risk subtype of ALL in children. There are conflicting data on the incidence and prognosis of Ph-like ALL in adults. Patients with newly diagnosed B-cell ALL (B-ALL) who received frontline chemotherapy at MD Anderson Cancer Center underwent gene expression profiling of leukemic cells. Of 148 patients, 33.1% had Ph-like, 31.1% had Ph⁺, and 35.8% had other B-ALL subtypes (B-other). Within the Ph-like ALL cohort, 61% had cytokine receptor-like factor 2 (CRLF2) overexpression. Patients with Ph-like ALL had significantly worse overall survival (OS), and event-free survival compared with B-other with a 5-year survival of 23% (vs 59% for B-other, P = .006). Sixty-eight percent of patients with Ph-like ALL were of Hispanic ethnicity. The following were associated with inferior OS on multivariable analysis: age (hazard ratio [HR], 3.299; P < .001), white blood cell count (HR, 1.910; P = .017), platelet count (HR, 7.437; P = .005), and Ph-like ALL (HR, 1.818; P = .03). Next-generation sequencing of the CRLF2⁺ group identified mutations in the JAK-STAT and Ras pathway in 85% of patients, and 20% had a CRLF2 mutation. Within the CRLF2⁺ group, JAK2 mutation was associated with inferior outcomes. Our findings show high frequency of Ph-like ALL in adults, an increased frequency of Ph-like ALL in adults of Hispanic ethnicity, significantly inferior outcomes of adult patients with Ph-like ALL, and significantly worse outcomes in the CRLF2⁺ subset of Ph-like ALL. Novel strategies are needed to improve the outcome of these patients.

Figure 1.

Frequency of B-ALL subtypes in adults (N = 148).

Figure 2.

Clinical outcomes of patients with Ph-like ALL and B-other ALL. (A) OS, (B) EFS, and (C) remission duration of Ph-like ALL and B-other ALL.

Figure 3.

OS of Ph-like ALL and B-other ALL (hyper-CVAD–based treatment only).

Figure 4.

Clinical outcomes of patients with CRLF2⁺ Ph-like ALL, non-CRLF2 Ph-like ALL, Ph+ ALL, and B-other ALL. (A) OS, (B) EFS, and (C) remission duration of CRLF2⁺ Ph-like ALL, non-CRLF2 Ph-like ALL, Ph⁺ ALL, and B-other ALL. (A) For OS, P for comparison between Ph-like CRLF2⁺ vs B-other was .001; P for comparison between Ph-like CRLF2⁺ vs Ph-like non-CRLF2 was .01; all other comparisons were not significant. (B) For EFS, P for comparison between Ph-like CRLF2⁺ vs B-other was <.001; P for comparison between Ph-like CRLF2⁺ vs Ph-like non-CRLF2 was .01; P for comparison between Ph-like CRLF2⁺ vs Ph⁺ was .02; all other comparisons were not significant. (C) For remission duration, P for comparison between Ph-like CRLF2⁺ vs B-other was <.001; P for comparison between Ph-like CRLF2⁺ vs Ph⁺ was .001; P for comparison between Ph-like non-CRLF2 vs B-other was .03; all other comparisons were not significant.

Figure 5.

Mutational landscape in CRLF2⁺ Ph-like ALL (n = 40), categorized by JAK2 mutation status. *Patients with paired tumor and germ line samples. ^#Relapsed samples.