Acute Myeloid Leukemia Patients with an Undefined Genetic Profile at Diagnosis: Clinical and Prognostic Aspects

Conventional cytogenetics and molecular analyses allow to stratify acute myeloid leukemia (AML) patients into subgroups with different clinical and prognostic relevance. AMLs with unsuccessful cytogenetics and no known recurrent mutations are a subgroup of cases for which information on possible underlying genetic lesions of the leukemic cells is lacking and with a poorly defined outcome. Previous studies have quantified the rate of unsuccessful karyotyping in approximately 10% of the analyzed AML samples and it is conceivable that if cases with molecular rearrangements were to be included this figure could be lower. With the aim of investigating the prevalence and impact of cases with an undefined genetic profile (UGP), we studied 437 AML patients - 228 males and 209 females, with a median age of 50 years (range 1-81) - treated on successive intensive chemotherapy protocols at our Institution. Conventional cytogenetic and molecular analyses - RUNX1-RUNX1T1, CBFB-MY11, DEK-NUP214, FLT3-ITD, NPM1, BCR-ABL, MLL-PTD - were performed at diagnosis. According to the genetic alterations, patients were comprehensively stratified into three subgroups: a favorable risk group - t(8;21) RUNX1-RUNX1T1, inv(16) CBFB-MY11, normal karyotype with mutated NPM1 without FLT3-ITD - with a 5-year overall survival (OS) of 65%, an intermediate risk group - normal karyotype with mutated or wild type NPM1 and FLT3 ITD or wild-type NPM1 without FLT3-ITD, t(9;11)(p22;q23), cytogenetic abnormalities not classified as favorable or adverse - with a 5-year OS of 27% and an unfavorable risk group - inv(3)(q21q26) or t(3;3)(q21;q26), t(6;9)(p23;q34), DEK-NUP214, t(v;11)(v;q23), -5 or del(5q), -7, complex karyotype - with a 5-year OS of 11%. Thirty-three patients (7.5%) were identified as having an UGP and their baseline characteristics, as well as clinical outcome, were compared to those of patients with defined molecular and cytogenetic features. Patients with an UGP were older at the onset of the disease than those with a delineated genetic profile (median 55 vs 49 years). In addition, the proportion of UGP cases increased with age, being 3% in patients <20 years, 6% in patients between 20 and 50, and 9.5% in patients >50 years. The complete remission (CR) rate for UGP patients (69.6%) was similar to that of intermediate risk patients (71.1%), but inferior to that of patients with a favorable risk profile (90.5%) (p=0.0046) and better than that of unfavorable genetic risk patients (63.7%). After adjusting for age, gender, WBC and platelet count, Hb, marrow blast percentage at diagnosis and treatment, UGP remained an independent factor for lower CR rate with respect to patients with a favorable genetic risk profile. The frequency of relapse was significantly higher in patients with UGP compared to the favorable risk group (60.8% vs 32%) (p=0.011). In multivariate analysis, the 5-year OS of patients with UGP was significantly worse than that of patients with a favorable genetic risk profile (p<0001) and similar to that of the intermediate genetic risk subgroup.

Our study documents that, despite progress in the detection of genetic lesions, patients with an UGP - having a failed karyotype and without known molecular markers - still represent an important subgroup in AML. An UGP occurs more frequently with increasing age and is associated with a worse outcome compared to patients with a favorable genetic risk profile and with a prognostic likelihood similar to that of intermediate risk AML patients.