Adults with Philadelphia chromosome-like acute lymphoblastic leukemia frequently have IGH-CRLF2 and JAK2 mutations, persistence of minimal residual disease and poor prognosis

Abstract

Philadelphia-like B-cell precursor acute lymphoblastic leukemia (Ph-like ALL) is characterized by distinct genetic alterations and inferior prognosis in children and younger adults. The purpose of this study was a genetic and clinical characterization of Ph-like ALL in adults. Twenty-six (13%) of 207 adult patients (median age: 42 years) with B-cell precursor ALL (BCP-ALL) were classified as having Ph-like ALL using gene expression profiling. The frequency of Ph-like ALL was 27% among 95 BCP-ALL patients negative for BCR-ABL1 and KMT2A-rearrangements. IGH-CRLF2 rearrangements (6/16; P=0.002) and mutations in JAK2 (7/16; P<0.001) were found exclusively in the Ph-like ALL subgroup. Clinical and outcome analyses were restricted to patients treated in German Multicenter Study Group for Adult ALL (GMALL) trials 06/99 and 07/03 (n=107). The complete remission rate was 100% among both Ph-like ALL patients (n=19) and the "remaining BCP-ALL" cases (n=40), i.e. patients negative for BCR-ABL1 and KMT2A-rearrangements and the Ph-like subtype. Significantly fewer Ph-like ALL patients reached molecular complete remission (33% versus 79%; P=0.02) and had a lower probability of continuous complete remission (26% versus 60%; P=0.03) and overall survival (22% versus 64%; P=0.006) at 5 years compared to the remaining BCP-ALL patients. The profile of genetic lesions in adults with Ph-like ALL, including older adults, resembles that of pediatric Ph-like ALL and differs from the profile in the remaining BCP-ALL. Our study is the first to demonstrate that Ph-like ALL is associated with inferior outcomes in intensively treated older adult patients. Ph-like adult ALL should be recognized as a distinct, high-risk entity and further research on improved diagnostic and therapeutic approaches is needed. (NCT00199056, NCT00198991).

Copyright© Ferrata Storti Foundation.

Figures

Figure 1.

Study design. Flow chart showing the study design and distribution of patients.

Figure 2.

Distribution of genetic alterations in Ph-like and remaining BCP-ALL. (A) Panel A shows the distribution of common mutations, deletions and fusions and CRLF2 expression in Ph-like and remaining BCP-ALL (Ph-negative, MLL-t negative, non-Ph-like) patients. The definition of kinase and B-cell pathway reported by Roberts et al. was used. Patients represented by light gray boxes for Relapse and Death were not treated in GMALL trials 06/99 and 07/03 and no clinical data were available for them. Patients marked with “*” had either ETV6-RUNX1 or TCF3-PBX1 fusions or ALL with high hyperdiploidy. (B) Panel B shows the correlation of common mutations, deletions and fusions and CRLF2 expression in Ph-like and remaining BCP-ALL (Ph-negative, MLL-t negative, non-Ph-like).

Figure 3.

Disease-free survival, remission duration and overall survival of patients with Ph-like or remaining BCP-ALL. (A) Disease-free survival, (C) remission duration and (C) overall survival in ALL patients treated in GMALL trials 06/99 and 07/03, comparing the Ph-like ALL subgroup with remaining BCP-ALL patients (Ph-negative, MLL-t negative, non-Ph-like).