Pretransplant minimal residual disease level predicts clinical outcome in patients with acute myeloid leukemia receiving high-dose chemotherapy and autologous stem cell transplantation

Abstract

A total of 31 adult patients with AML entered in the EORTC/ GIMEMA AML-10 trial, who received autologous stem cell transplantation (ASCT) after induction and consolidation chemotherapy, were prospectively evaluated for minimal residual disease (MRD) by multidimensional flow cytometry (MFC). Using a cutoff level of 3.5 Â 10 À4 leukemic cells pre-ASCT, 12 patients (39%) were stratified to MRD high-risk group and 19 (61%) into MRD low-risk group. During follow-up, all patients who were in the high-risk group relapsed at a median time of 7 months; in the low-risk group, five patients relapsed at a median time of 11 months and 14 remained in remission for 56 (range 7-80) months (P ¼ 0.00004). Longitudinal MFC determinations post-ASCT showed increased MRD levels in three of the five patients who underwent subsequent relapse, while disease recurrence was unpredicted in the remaining two cases. The pre-ASCT MRD status was the factor most strongly associated with relapse risk in the multivariate analysis (P ¼ 0.0014). We conclude that: (1) pre-ASCT MRD status predicts successful outcome in patients receiving ASCT; (2) high-dose chemotherapy conditioning regimen followed by ASCT has no impact on the unfavorable prognostic value of high pre-ASCT MRD level; and (3) sequential MRD monitoring post-ASCT may allow the prediction of impending relapse.

Prognostic and therapeutic implications of minimal residual disease at the time of transplantation in acute leukemia

“…50,51 In contrast, the prognostic role of pre-HCT MRD in non-APL AML is primarily studied via MFC-based assays to detect and quantify MRD. 46,47,[52][53][54][55][56][57][58][59][60][61] Nevertheless, as summarized in Table 4, more recent series show that both pediatric and adult patients with non-APL AML who are MRD À by current sensitive methods have excellent outcomes following myeloablative AlloHCT, with 2-5 year OS estimates around 75-80%. 47,58,61 For such patients, even AutoHCT may result in good disease control, with some studies showing 5-year OS estimates in the 60-70% range.…”

“…57,59 On the other hand, MRD þ patients fair significantly worse with either type of HCT, with particularly high rates of relapse following AutoHCT. 46,47,[53][54][55][57][58][59][60][61] Not surprisingly, MRD is associated with other adverse risk factors, such as older age, poor-risk cytogenetics, leukemia arising from an antecedent hematologic disorder or after chemo-/ D is e a s e p e r s is t e n c e V e r y e a r ly r e la p s e E a r ly r e la p s e L a t e r e la p s e V e r y la t e r e la p s e radiotherapy and a multidrug resistance phenotype. 53,57,61,62 However, MRD appears to bear significance as an independent prognostic marker, as suggested by multivariate regression modeling in many of the studies.…”

Minimal residual disease as biomarker for optimal biologic dosing of ARA‐C in patients with acute myeloid leukemia

“…As previously demonstrated [17,19,21,23], achieving MRD-negative status post-consolidation, regardless of ARA-C schedule, translates into significant RFS and OS prolongations, especially in SDACtreated patients who are MRD negative. The lack of a clear advantage for MRD-negative HDAC recipients is likely due to the small sample size (nine patients) and unusually high TRM, with 30% mortality during stem cell transplantation.…”

“…One plausible explanation for conflicting evidence is that the efficacy of a given regimen, as reflected by survival estimates, may be influenced by the nature of post-consolidation strategies. In addition, evaluation of BM morphology, although still accepted as the standard index of therapeutic response, may fail to detect clinically relevant amounts of persistent leukemia [16][17][18][19]21]. In this regard, MRD assessment promises to be a valid alternative.…”

“…At diagnosis, bone marrow (BM) samples were collected for immunophenotypic, chromosomal, and genetic studies, as detailed elsewhere [16,17,19,21]. Genetic/cytogenetic abnormalities were classified according to the European LeukemiaNet criteria [22].…”