Significance of minimal residual disease before myeloablative allogeneic hematopoietic cell transplantation for AML in first and second complete remission

Abstract

• The negative impact of pre-HCT flow cytometrically determined MRD is similar for AML in CR1 and CR2.• Even minute levels of MRD (#0.1%) are associated with adverse outcome.Minimal residual disease (MRD) before myeloablative hematopoietic cell transplantation (HCT) is associated with adverse outcome in acute myeloid leukemia (AML) in first complete remission (CR1). To compare this association with that for patients in second complete remission (CR2) and to examine the quantitative impact of MRD, we studied 253 consecutive patients receiving myeloablative HCT for AML in CR1 (n 5 183) or CR2 (n 5 70) who had pre-HCT marrow aspirates analyzed by 10-color flow cytometry. Three-year estimates of overall survival were 73% (64%-79%) and 32% (17%-48%) for MRD neg and MRD pos CR1 patients, respectively, and 73% (57%-83%) and 44% (21%-65%) for MRD neg and MRD pos CR2 patients, respectively. Similar estimates of relapse were 21% (14%-28%) and 58% (41%-72%) for MRD neg and MRD pos CR1 patients, respectively, and 19% (9%-31%) and 68% (41%-85%) for MRD neg and MRD pos CR2 patients, respectively. Among the MRD pos patients, there was no statistically significant evidence that increasing levels of MRD were associated with increasing risks of relapse and death. After multivariable adjustment, risks of death and relapse were 2.61 times and 4.90 times higher for MRD pos patients (P < .001). Together, our findings indicate that the negative impact of pre-HCT MRD is similar for AML in CR1 and CR2 with even minute levels (£0.1%) as being associated with adverse outcome. (Blood. 2013;122(10):1813-1821

Cord-Blood Transplantation in Patients with Minimal Residual Disease

“…In the HLA-matched and HLA-mismatched unrelated-donor groups, the presence of minimal residual disease before transplantation was associated with a higher risk of death and disease relapse after transplantation than was the absence of minimal residual disease, a finding similar to results described in previous reports. 9,22 However, in contrast to these previous reports, in the cord-blood group, the overall mortality and rate of relapse were similar among patients with minimal residual disease and those without minimal residual disease. These observations are not entirely consistent with previous reports regarding transplants from cord-blood donors, [23][24][25] in which a higher risk of relapse and a lower rate of leukemia-free survival was seen among patients with minimal residual disease than among those without minimal residual disease.…”

Improved outcome of children transplanted for high-risk leukemia by using a new strategy of cyclosporine-based GVHD prophylaxis

“…This contrasts with previous studies where DFS was about two times lower in patients with pretransplant detectable MRD. 25,27,[55][56][57] However, MRD could not be measured in all patients in our study. Thus, for those patients for whom data were available, only a few had positive MRD.…”

“…This is consistent with studies reporting no effect of GvHD on survival, while using MMF or MTX with a negative impact on NK cells. 57 Further studies are mandatory to evaluate the possible link between CsA pharmacokinetics and NK cell production after HSCT.…”

Multi-color flow cytometric immunophenotyping for detection of minimal residual disease in AML: past, present and future

“…This approach requires robust daily quality control measures in order to ensure that normal cells show consistent expression levels for all tested antigens, so that a shift in antigen expression can be correctly identified as aberrant rather than due to technical artifact. 24 252 pediatric patients a Different from normal approach MRD measured post induction and post consolidation Multivariate analysis showed MRD amount ⩾ 0.5% at either time point increased risk of relapse and worsened OS Multivariate analysis showed MRD was most potent predictor of relapse, even when cytogenetic findings were included Venditti et al 27 56 adult patients a LAP-based approach MRD measured post induction and post consolidation MRD amount ⩾ 0.045% showed no effect on survival or relapse when measure post induction MRD amount ⩾ 0.035% was associated with higher rates of relapse when measured post consolidation 16 was the most important prognostic factor for EFS and an independent prognostic factor for OS Kern et al 30 Adult patients a LAP-based approach MRD measured post-induction (n = 58) and post consolidation (n = 62) or at both time points (n = 27) MRD amount expressed as log decrease between % LAP + cells at diagnosis and post induction or post consolidation (LD) 32 203 pediatric patients LAP-based approach MRD measured after induction 1 and induction 2 Patients with ⩾ 0.1% MRD after induction 1 or 2 had a worse EFS, mainly due to relapse MRD determination using microscopy, PCR and MFC showed poor overall correlation MRD measurement using MFC was best overall predictor of outcome Loken et al 25 249 pediatric patients Different from normal approach Double induction with GO in induction 1 Presence of any amount of detectable MRD (>0%) after induction 1 or 2 correlated with worse RFS and OS Prevalence of MRD correlated with cytogenetic risk group MRD was not detected in 26% of patients classified as having residual disease by morphology (5-20% blasts) Such patients showed better OS Walter et al 33 253 adult and pediatric patients undergoing HSCT for AML MRD measured pre-transplant during CR1 or CR2 Different from normal approach The presence of even low levels (o 0.1%) MRD at CR1 or CR2 correlated with higher relapse and worse OS post-HSCT Abbreviations: ADE = cytarabine, daunorubicin, etoposide; CR1 = first complete remission; CR2 = second complete remission; donor = matched sibling donor; EFS = event-free survival; GO = gemtuzumab ozogamicin (anti-CD33 monoclonal antibody); HSCT = hematopoietic stem cell transplant; LD 16 = log (%LAP-positive cells at diagnosis/%LAP-positive cells at day 16); LFS = leukemia-free survival; LAP = leukemia-associated immunophenotype; MRD = minimal residual disease; MRD amount = % of total cells analyzed; MFC = multi-color flow cytometric immunophenotyping; RFS = relapse-free survival. a Methods section states that patients with acute promyelocytic leukemia with t(15;17) were specifically excluded from analysis.…”