FLT3-internal tandem duplication and age are the major prognostic factors in patients with relapsed acute myeloid leukemia with normal karyotype

Abstract

Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Carl-Neuberg Str. 1, 30625 Hannover, Germany. Phone: international +49.511.5323691. Fax: international +49.511.5323611. E-mail: wagner.katharina@mh-hannover.de Background Several genetic aberrations with prognostic impact in first-line therapy have been described in patients with acute myeloid leukemia and normal karyotype. However, little is known about the influence of these aberrations on outcome after relapse. This study aimed to identify clinical and molecular risk factors for patients with relapsed acute myeloid leukemia with normal karyotype. Design and MethodsWe analyzed 94 patients with acute myeloid leukemia and normal karyotype after first relapse for clinical and molecular risk factors for survival. All patients had received first-line treatment and follow-up within two prospective, multicenter trials. Leukemic blasts were analyzed at diagnosis for genetic aberrations in the FLT3, NPM1, CEBPA, WT1, IDH1 and IDH2 genes by polymerase chain reaction and/or direct sequencing. ResultsA second complete remission was achieved in 52% of patients who received re-induction therapy. The presence of an FLT3-internal tandem duplication, duration of first complete remission less than 6 months and age above the median of 47 years were associated with a significantly lower rate of second complete remission. The median survival after relapse was 11 months and the 6-year survival rate was 28%. In multivariate analysis, FLT3-internal tandem duplication and age above the median were the only independent negative prognostic factors for survival. The 6-year survival rate of patients with none of these factors was 56%, whereas it was significantly inferior in patients with one or both of these factors (15% and 6%, respectively). This was also true for patients who underwent allogeneic stem cell transplantation after relapse. ConclusionsFLT3-internal tandem duplication and age are the major prognostic factors in patients with relapsed acute myeloid leukemia with a normal karyotype. Patients with at least one of these risk factors have a dismal outcome and might be considered for investigational treatment approaches after relapse. (ClinicalTrials.gov Identifier: NCT00209833) Key words: prognostic factors, FLT3-ITD, CN-AML, second complete remission.Citation: Wagner K, Damm F, Thol F, Göhring G, Görlich K, Heuser M, Schäfer I, Schlegelberger B, Heil G, Ganser A, and

Influence of molecular subgroups on outcome of acute myeloid leukemia with normal karyotype in 141 patients undergoing salvage allogeneic stem cell transplantation in primary induction failure or beyond first relapse

“…In patients transplanted beyond CR1, the prognostic significance of molecular subgroups, originally developed to estimate the individual prognosis at time of diagnosis, 4 was confirmed, as shown both by the different patients' characteristics at relapse and transplantation, and by the differences in outcome among patients with various genotypes. Similar data have been reported in a smaller cohort of patients with FLT3-ITD, 9 but so far not in patients with double negative (NPM1 wt /FLT3 wt ) CN-AML. Considering the intrinsic limitations of a retrospective analysis, several steps have been taken to assure data quality: i) the uniform use of FLAMSA-RIC as standard regimen for all consecutive patients with advanced AML in the participating centers excluded a frequent bias of retrospective studies in HSCT, in which non-myeloablative, RIC, and standard regimen are often mixed; ii) a strict definition for PIF according to published guidelines 2,13,18 was applied, assuring a homogeneous cohort that had failed double induction and/or HiDAC-based chemotherapy; iii) median follow up was three years from HSCT in all subgroups, covering the vast majority of expected events, which in advanced AML are usually seen within two years; 25 iv) repeated questionnaires were completed, personal visits were made to centers, and direct contact with the treating physicians was maintained.…”

“…Patients with PIF had a promising outcome. In relapsed CN-AML, results after alloHSCT compared favorably to published data, 8,9,25,[38][39][40] although the prognostic significance of NPM1 mut and FLT3-ITD was carried through. Confirmation of these findings in a larger cohort, and integration with other genetic aberrations and leukemogenic mechanisms are warranted for a more precise estimation of individual prognosis.…”

“…4 Recently, the favorable genotype was shown to maintain a good prognosis in relapsed and refractory AML after gemtuzumab-ozogamicin based therapy, 8 whereas FLT3-ITD retained its negative prognostic value in two series of relapsed patients which both included a limited number of patients receiving salvage alloHSCT. 9,10 Here, we present the results of a large cohort of patients who had all received the FLAMSA-RIC regimen before alloHSCT for CN-AML, either in PIF or beyond CR1. The study aimed to further evaluate the role of the most common molecular aberrations in this setting, and to determine the efficacy of FLAMSA-RIC based alloHSCT in clinically and molecularly defined patient subgroups.…”

Prognostic implication of molecular aberrations in cytogenetically normal acute myeloid leukemia patients receiving allogeneic hematopoietic stem cell transplantation

“…In patients beyond first remission, the impact of molecular aberrations on allo-HSCT is unclear. In one study, FLT3-ITD and age were independently negative prognostic factors for survival in relapsed CN-AML patients, including patients who underwent allo-HSCT after relapse (Wagner et al, 2011). The NPM1 and CEBPA mutation status had no impact on survival after relapse, but the impact on allo-HSCT was not reported.…”

Impact of molecular prognostic factors in cytogenetically normal acute myeloid leukemia at diagnosis and relapse

“…In a study published in this issue of the Journal, Wagner et al sought to determine whether molecular factors present at diagnosis maintain their prognostic impact at the time of relapse. 34 This is important as not only is little known about the prognostic value of these markers at this time point, but also, the information could guide therapeutic decisions for patients with relapsed disease based on a more accurate assessment of the likelihood of achieving remission. The authors retrospectively analyzed patients with CN-AML who achieved a first complete remission following double induction and consolidation chemotherapy, which also included allogeneic or autologous hematopoietic stem cell transplantation according to the original study, but then subsequently relapsed.…”