Allogeneic stem cell transplantation in second rather than first complete remission in selected patients with good-risk acute myeloid leukemia

Abstract

Summary:Through two consecutive trials, a policy that considered allogeneic stem cell transplantation (SCT) from a sibling donor in second rather than first complete remission (CR) in selected younger patients with acute myeloid leukemia (AML) with t(8;21)/inv(16) (core binding factor (CBF) group) or a normal karyotype (NN group) was followed by Acute Leukemia French Association (ALFA) centers. The outcome of 92 of these patients in first relapse (32 CBF, 60 NN) was reviewed with the aim of validating this strategy. The presence of an FLT3 internal tandem duplication (ITD) was retrospectively assessed in 50 patients. A total of 61 patients (66%) reached a second CR. Donor availability was an independent prognostic factor for survival in the whole patient population as well as in the CBF subset, but not in NN patients, further supporting this strategy for CBF-AMLs. In NN patients, FLT3-ITD was the main bad-prognosis factor for second CR achievement and survival, leading to consider SCT earlier, at least in FLT3-ITD patients with a donor. Allogeneic hematopoietic stem cell transplantation (SCT) from an HLA-matched sibling has been considered for years as the best treatment option to prevent relapse in younger adults with acute myeloid leukemia (AML) in first complete remission (CR). Following SCT, the risk of further relapse is generally less than 30% and lower than after conventional chemotherapy. [1][2][3][4] This benefit is, however, partially offset by the toxicity associated with the transplant procedure with treatment-related mortality (TRM) rates of 15-20%. Owing to increasing TRM with advanced age, conventional myeloablative SCT is usually restricted to patients under 50 years of age.To avoid statistical bias, recent studies evaluating the role of SCT in first CR have been based on donor vs no-donor comparisons according to the results of HLA typing as a random allocation. [5][6][7][8][9] Patients in first CR with suitable sibling donors have been compared with those without sibling donors. The use of more intensive regimens of chemotherapy has improved the outcome in the no-donor group enough so that no significant benefit in overall survival may be observed for the donor group. The importance of diagnostic cytogenetics as prognostic factor for outcome in patients with AML led investigators to compare SCT and chemotherapy within each cytogenetic subgroup. Results show that SCT in first CR does not appear to benefit to relatively good-risk AML patients, as those with t(8,21), inv(16/t(16;16) or a normal karyotype (NN group). 8,9 The French AML Intergroup has recently reported the results of two large retrospective studies conducted in patients with t(8;21) and inv(16) AML, which both confirm this observation in patients with core binding factor (CBF) AML. 10,11 No controlled study has, however, formally compared SCT in second vs first CR in selected AML patients. There is consequently no consensus on the appropriate group of patients in whom SCT might be safely delayed in second CR.As a common multicenter ...

Prevalence, clinical profile, and prognosis of NPM mutations in AML with normal karyotype

“…6,7 A normal karyotype was defined as more than 20 normal metaphases. Samples were obtained from blood and bone marrow aspirates (median leukemic blast percentage, 78%) at diagnosis.…”

Interactive diagnostics in the indication to allogeneic SCT in AML

“…51 Only a comprehensive diagnostic approach combining morphology, immunophenotyping, and diverse cytogenetic and molecular genetic techniques is able to provide the basis for this differentiated risk stratification. One recent major contribution was the definition of a molecular data set composed by the NPM1, FLT3-ITD and -TKD, MLL-PTD and CEBPA mutations, which is able to predict whether patients with a normal karyotype might benefit from an early allo-SCT.…”

“…In the 'favorable group' with the recurrent reciprocal translocations t(15;17)/ PML-RARA, t(8;21)/RUNX1-RUNX1T1 and inv(16)/ CBFB-MYH11, allo-SCT was removed from the first-line strategies in first CR but still remains an option in case of relapse. [51][52][53] The coincidence of an FLT3-ITD and a PML-RARA might confer an inferior prognostic impact, 14 but this observation is so far based on few studies only. Also, it was suggested that the t(8;21) and the inv(16) core binding factor leukemias have an inferior prognosis when being combined with a loss of Y in males.…”

“…19 In FLT3-ITD, standard chemotherapy is followed by high relapse rates of 480%. 51 In previous studies, allo-SCT improved survival from 20-25 to 45-50%. 107 Schlenk et al 58 demonstrated the beneficial effects of allo-SCT in first remission for FLT3-ITD and FLT3-TKD.…”

Importance of c-kit mutation detection method sensitivity in prognostic analyses of t(8;21)(q22;q22) acute myeloid leukemia

“…In fact, reports suggest that the prognosis of t(8;21) AML following first relapse is just as poor as other relapsed AMLs even when stem cell transplantation (SCT) is performed. [12][13][14][15] Stratifying prognoses for t(8;21) AML become critical when determining, for example, SCT indications during the initial remission period. The white blood cell (WBC) count at initial examination, 12 WBC index, 16,17 additional chromosomal aberrations such as del (9) 18 and loss of sex chromosomes and CD56 positivity 19 have been reported as adverse prognostic factors of t(8;21) AML.…”