CDKN2 Gene Deletion Impair Prognosis in Adult Ph+ Acute Lymphoblastic Leukemia Even in Tyrosine Kinase Inhibitors Era

Background:Philadelphia chromosome-positive (BCR-ABL1+) ALLs benefit from the addition of a specific tyrosine kinase inhibitors(TKIs) to chemotherapy, However, treatment failures and relapses are common and new markers are needed to identify patients with poor prognosis in prospective trials. The 9p21 locus, encoding important tumor suppressors (CDKN2A/B), is a major target of inactivation in the pathogenesis of many human tumors, but only few report investigated this deletion effect on clinical prognosis in Ph+ ALL.

Purpose:Many studies found that deletion of CDKN2 was associated with poor prognosis in ALL,and CDKN2 deletion also as a frequent cytogenetic aberration in Ph+ ALL patients. Here we study about the prognostic significance of the CDKN2 in Ph+ ALL in TKIs era.

Patients and Methods: To explore the frequency and size of alterations affecting this locus in adult BCR-ABL1–positive ALL and to investigate their prognostic value, 135 patients (98 denovo and 37 relapsed cases) were analyzed by Paired diagnosis–relapse samples were interphase fluorescence in situ hybridization(I-FISH).

Results:The prevalence of CDKN2 deletions in all study population was 27.4%(37/135). There is no difference between patients with CDKN2 deletion and wild-type patients in sex, age, white blood cells(WBC) count, BM blast percentage,and induction complete remission(CR) rate. Compared with patients with wild-type CDKN2, the patients with CDKN2 deletion had higher rates of hepatosplenomegaly, CD20 expression  (p<0.05). Deletions of CDKN2 were significantly associated with poor outcomes including decreased overall survival (OS) (P<0.001), lower disease free-survival (DFS) (P<0.001), and increased cumulative incidence of relapse (P=0.003). In case of 37 patients with CDKN2 deletion,20 patients treated with chemotherapy and Dasatinib  followed  by allogeneic hematopoietic stem cell transplantation(Allo-HSCT),and another 13 patients treated with chemotherapy and Imatinb followed  by Allo-HSCT,there were no difference associated with OS(P=0.813) and DFS(p=0.513) between the above groups.

Conclusions:Deletion of CDKN2 by I-FISH is a frequent event in Ph–positive ALL, and frequently acquired during leukemia progression and are a poor prognostic marker of long-term outcomes even though treated by adding dasatinib. We also found CDKN2 deletion  patients had higher CD20 expression, this group patients may be benefit from rituximab.