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

Abstract

P hiladelphia-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 Phlike 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.

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

“…7,[9][10][11] There are conflicting data regarding the incidence and prognosis of Ph-like ALL in adults. [12][13][14][15] In a preliminary report of 692 patients with B-ALL, Ph-like ALL comprised 26% of patients between 21 and 39 years of age and 20% of patients age $40 years. 7,12 These patients were treated on varying pediatric and adult ALL treatment regimens.…”

Treatment of older patients with acute lymphoblastic leukemia

“…4 In a cohort of 95 patients with B-precursor ALL, negative for BCR-ABL1 and mixed lineage leukemia (MLL) rearrangements, and a median age of 42 years, the incidence of Ph-like ALL was 27%. 5 There was no linear increase of incidence with increasing age. 6 In another cohort of 132 adult precursor B-cell ALL patients (excluding BCR-ABL1, MLL-AF4, and E2A-PBX1) with a median age of 54 years, the overall incidence of Ph-like ALL was 10% and the incidence in patients .40 years was 8%.…”

Cytogenetics, Molecular Genetics and Epigenetics and Their Impact on The Management of Acute Lymphoblastic Leukemia

“…Nevertheless, novel therapies are needed to improve the outcome of patients with Ph-like ALL as this this subtype of ALL represents a disease where precision medicine testing, and treatment approach should be implemented [90,94,99]. Newly discovered genetic alterations that drive HR Ph-like ALL can now be targeted with TKIs and JAK inhibitors leading to clinical trials for this particular HR subset [100].…”

“…It has characteristic and distinct genetic mutations and rearrangements that are activated by a diverse array of cytokine receptor and tyrosine kinase signaling [87,89,[92][93][94]96]. The genetic lesions in adults with Ph-like ALL resembles that in children with Ph-like ALL but differs from the profile in the remaining patients with pre-B ALL [99]. Deletion mutations involving IKZF1 gene, that codes for the transcription factor IKAROS, underlie many cases as a key factor inducing aggressive phenotype and poor responses to treatment [19].…”

“…Ph-like ALL is associated: with resistance to cytotoxic chemotherapy, very high risk of disease relapse and poor OS [88,90,92,93,95,96,98,99]. The identification of a wide range of genetic alterations that activate certain signaling pathways makes such gene alterations amenable to inhibition by a variety of TKIs [97].…”