Genomic CDKN2A/2B deletions in adult Ph+ ALL are adverse despite allogeneic stem cell transplantation

Abstract

We investigated the role of copy number alterations to refine risk stratification in adult Philadelphia chromosome positive (Ph) acute lymphoblastic leukemia (ALL) treated with tyrosine kinase inhibitors (TKIs) and allogeneic stem cell transplantation (aSCT). Ninety-seven Ph ALL patients (median age 41 years; range 18-64 years) within the prospective multicenter German Multicenter ALL Study Group studies 06/99 (n = 8) and 07/2003 (n = 89) were analyzed. All patients received TKI and aSCT in first complete remission (CR1). Copy number analysis was performed with single nucleotide polymorphism arrays and validated by multiplex ligation-dependent probe amplification. The frequencies of recurrently deleted genes were: IKZF1, 76%; CDKN2A/2B, 45%; PAX5, 43%; BTG1, 18%; EBF1, 13%; ETV6, 5%; RB, 14%. In univariate analyses, the presence of CDKN2A/2B deletions had a negative impact on all endpoints: overall survival ( = .023), disease-free survival ( = .012), and remission duration ( = .036). The negative predictive value of CDKN2A/2B deletions was retained in multivariable analysis along with other factors such as timing of TKI therapy, intensity of conditioning, achieving remission after induction phase 1 and BTG1 deletions. We therefore conclude that acquired genomic CDKN2A/2B deletions identify a subgroup of Ph ALL patients, who have an inferior prognosis despite aSCT in CR1. Their poor outcome was attributable primarily to a high relapse rate after aSCT.

Molecular profiling refines minimal residual disease‐based prognostic assessment in adults with Philadelphia chromosome‐negative B‐cell precursor acute lymphoblastic leukemia

“…More concretely, CDKN2A/B deletions may represent adverse prognostic markers independent from MRD at the end of induction, indicating that testing for CDKN2A/B deletions can identify adult patients with Ph-neg BCP ALL with poor outcome, not assessable by MRD.The prognostic role of CDKN2A/B deletions has been evaluated at all ages with controversial results in BCP ALL. The impact of these deletions may be more pronounced in adults, particularly in Phpositive ALL,7 although some studies have also reported unfavorable prognosis in Ph-neg BCP-ALL 5,8. To the best of our knowledge, this is the first study reporting a prognostic significance for CDKN2A/B independent of MRD in adolescents and adults with Ph-neg BCP-ALL.…”

Integrated clinicomolecular characterization identifies RAS activation and CDKN2A deletion as independent adverse prognostic factors in cancer of unknown primary

“…Deletion of CDKN2A and KRAS mutations were reported as adverse prognostic markers throughout a plethora of diverse malignancies . Thus, poor prognosis associated with CDKN2A deletion and KRAS activation appears as a recurrent feature of a broad spectrum of malignancies.…”

“…12 Deletion of CDKN2A and KRAS mutations were reported as adverse prognostic markers throughout a plethora of diverse malignancies. [21][22][23][24][25][26][27][28][29] Thus, poor prognosis associated with CDKN2A deletion and KRAS activation appears as a recurrent feature of a broad spectrum of malignancies. As CUP may arise from any organ site, it is plausible that these negative prognostic effects observed in other cancer entities are also reflected in CUP.…”

How I treat Philadelphia chromosome–positive acute lymphoblastic leukemia

“…26 Other studies have also reported on the negative prognostic impact of a number of genomic abnormalities in addition to IKZF1 deletions, including deletions of CKND2A/2B and PAX5 genes with some maintaining this adverse impact despite allo-HCT. [27][28][29] These genomic aberrations, as well as other reported prognostic factors such as high presentation WBC or presence of additional cytogenetic abnormalities, are not yet routinely considered when deciding on allo-HCT. 15,30 Reported pediatric studies have raised questions about the necessity of allo-HCT in first CR.…”