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).

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).