Core Binding Factor Acute Myeloid Leukemia In Pediatric Patients Enrolled In The AIEOP AML 2002/01 Trial: The Impact Of Minimal Residual Disease On Patient Outcome

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3884-3884
Author(s):  
Martina Pigazzi ◽  
Valzerda Beqiri ◽  
Elena Manara ◽  
Roberto Rondelli ◽  
Riccardo Masetti ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Minimal Residual Disease ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Prognostic Impact ◽  
Rt Pcr ◽  
The Impact ◽  
Minimal Residual ◽  
Acute Myeloid

Abstract Introduction Acute Myeloid Leukemia (AML) accounts for 15% of pediatric leukemia. Improvements of prognosis achieved in the last twenty years are also due to a better stratification of patients into risk groups that allowed to deliver tailored treatment. The AIEOP LAM 2002/01 protocol classified patients with t(8;21)(q22,q22)AML1-ETO and inv(16)(p13;q22)CBFB-MYH11, who responded to induction therapy as belonging to the Standard-Risk (SR) group. These patients were considered at good prognosis; unfortunately, although they all reached morphological complete remission (CR) after the first induction course, they showed a high incidence of relapse (24%) (Pession A. et al., Blood 2013). At present, little is known about the kinetics of relapse or the development of resistance mechanisms; moreover, in many studies post-remission therapy in AML does not take into account the level of residual leukemia. Here, we evaluate the prognostic impact of molecular minimal residual disease (MRD) levels in terms of onset of relapse. Methods We studied bone marrow of 49 and 30 patients carrying either t(8;21) or inv(16) abnormalities, respectively, at time of diagnosis, and at the end of first and second course of induction therapy (ICE: Idarubicine, Citarabine and Etoposide). MRD was evaluated as number of fusion transcripts by quantitative RT-PCR using absolute quantification, and calculated as logarithmic (Log) disease reduction after the first and second ICE course as compared to diagnosis. Fusion transcripts were normalized to 10(5) ABL copies. The prognostic impact was assessed by the calculation of Overall Survival (OS) and cumulative incidence of relapse (CIR) according to the different MRD levels. Results After I ICE, t(8;21)-rearranged patients distributed equally in the four classes of MRD reduction. In particular, 10 patients reduced MRD levels of less than 1 Log, 11 patients reduced 1-2 Log, 17 patients reduced 2-3 Log and 11 patients reduced MRD levels of more than 3 Log as compared to diagnosis. After II ICE, the majority of patients increased the reduction of MRD levels (> 3 Log). We focused on the 10 patients who did not respond to the I ICE course and we found that 7 out of 10 reduced MRD levels of more than 1 Log after the II ICE, confirming a slow clearance of blasts for this subgroup of patients. We found that a reduction of MRD lower than 1 Log conferred a worst outcome to t(8;21)-rearranged patients (OS being 53.3% vs 85.2%, p=0.073 after I ICE; 33.3% vs 82.4 p= 0.062 after II ICE), and higher CIR after I and II ICE (52% vs 12.3%, p=0.0049, and 66.7 %, vs 17.2, p=0.024, at 6 years respectively). The group of inv(16)-rearranged achieved more than 1 Log reduction of MRD since I ICE course. After II ICE course, the majority of of patients reduced MRD of more than 3 Log, and 20% of them were completely negative. Inv(16) rearranged patients were all alive at last follow-up, and CIR never showed statistically significant differences for MRD levels in inv(16)-rearranged patients after the induction therapy. The impact of copy numbers (i.e. transcript levels) at diagnosis and after induction courses on relapse risk never showed significant results in both subgroups of CBF-rearranged patients. Conclusions Our data indicate that MRD evaluation using quantitative RT-PCR is an important diagnostic tool that permits the assessment of response to CT and the identification of patients at greater risk of relapse after induction therapy for AML1-ETO rearranged patients. We propose that at the end of induction therapy the cut-off of MRD< 1 Log be used to guide therapeutic decisions for this subgroup of SR patients. On the contrary, MRD levels of CBFB-MYH11 rearranged patients do not have prognostic value on CIR after induction therapy, this suggesting that novel molecular features should be investigated for this subgroup of AML. Disclosures: No relevant conflicts of interest to declare.

Allogeneic Hematopoietic Stem Cell Transplantation Overcomes the Adverse Prognostic Impact of Minimal Residual Disease in Acute Myeloid Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2027-2027
Author(s):  
Betul Oran ◽  
Timothy Singleton ◽  
Pablo A. Ramirez ◽  
Ryan Shanley ◽  
Claudio Brunstein ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Minimal Residual Disease ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Prognostic Impact ◽  
Hematopoietic Stem ◽  
Disease Outcomes ◽  
The Impact ◽  
Minimal Residual ◽  
Acute Myeloid

Abstract Abstract 2027 BACKGROUND: The identification of minimal residual disease (MRD) can predict impending relapse in acute myeloid leukemia (AML) patients. Little data exists evaluating the prognostic impact of MRD, as determined by multiparametric flow cytometry (MFC), at the time of allogeneic (allo-HCT). Although disease outcomes may be worse for MRD positive (MRD+) patients, MRD is often associated with other adverse risk factors leaving it unclear whether MRD is an independent risk factor for relapse or a surrogate marker for underlying poor risk disease features. METHODS: We retrospectively analyzed 97 consecutive AML patients in complete morphological remission (CR) who underwent allo-HCT with a matched related donor (MRD, n=30, 31%), matched unrelated donor (MUD, n=4, 4%) or umbilical cord blood (UCB, n=63, 65%) at the University of Minnesota between January 2005 and June 2009. Presence of MRD at allo-HCT was determined by MFC. Analyses were done separately for myeloablative (MAC) and reduced intensity conditioning (RIC) patients, testing the impact of MRD along with conditioning intensity, age, donor type and disease status on allo-HCT outcomes. RESULTS: Of 97 patients, 41 (42%) had MAC; 57 (58%) had RIC. Sixty-six were in first CR (CR1) with the rest in CR2 or later remission (CR2+). MRD at allo-HCT was detected in 7 patients after MAC (17%) and 7 after RIC (12.5%); and this frequency was similar in patients in CR1 and CR2+ (13% vs. 16%, p=0.7). MRD+ and MRD- patients had similar median age (40 vs. 44 yrs), gender, donor source (MSD or MUD vs. UCB), CMV serostatus and diagnostic cytogenetic risk group. Six of 40 (15%) intermediate and 5 of 39 (13%) high risk cytogenetics patients had MRD+ (p=0.8). Only 3 of 53 patients with a cytogenetic abnormality at diagnosis had it detected prior allo-HCT and 1 of 3 had MRD. The median follow-up of survivors was 25 months. Two-year probabilities for MAC and RIC patients were similar: Overall survival (OS), 48% and 47 % and leukemia free survival (LFS) 43% and 41% respectively. When disease outcomes were analyzed separately by MRD status (table), OS and LFS were markedly worse in MRD+ patients receiving RIC, but this difference was not statistically significant. In multivariate analysis, MRD+ was not an independent prognostic factor for OS and LFS. Although we identified no adverse prognostic factors for MAC patients, patient with RIC in CR2+ had worse OS and LFS vs. CR1 (HR 2.6, p=0.04 and HR 2.7, p=0.04 respectively). CONCLUSION: The negative prognostic impact of MRD was overcome by allo-HCT with MAC, but outcomes with MRD+ were suggestively inferior after RIC. However due to limited sample size, MRD in patients with RIC should be further investigated. Disclosures: Weisdorf: Genzyme: Consultancy, Research Funding.

Relation of Clinical Response and Minimal Residual Disease and Their Prognostic Impact on Outcome in Acute Myeloid Leukemia

2015 ◽  
Vol 33 (11) ◽  
pp. 1258-1264 ◽  
Author(s):  
Xueyan Chen ◽  
Hu Xie ◽  
Brent L. Wood ◽  
Roland B. Walter ◽  
John M. Pagel ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Minimal Residual Disease ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
Blood Count ◽  
Residual Disease ◽  
Prognostic Impact ◽  
Minimal Residual ◽  
Acute Myeloid ◽  
Count Recovery

Purpose Both presence of minimal residual disease (MRD) and achievement of complete remission (CR) with incomplete platelet recovery (CRp) rather than CR after induction therapy predict relapse in acute myeloid leukemia (AML). These results suggest a correlation between response (peripheral count recovery) and MRD at the time of morphologic remission. Here we examine this hypothesis and whether MRD and response provide independent prognostic information after accounting for other relevant covariates. Patients and Methods We retrospectively analyzed data from 245 adults with AML who achieved CR, CRp, or CR with incomplete blood count recovery (CRi) after induction therapy. Bone marrow samples were collected on or closest to the first date of blood count recovery, and MRD was determined by 10-color multiparameter flow cytometry. Results The 71.0% of patients who achieved CR had MRD less frequently and had lower levels of MRD than the 19.6% of patients achieving CRp and 9.4% achieving CRi. Although pretreatment covariates such as cytogenetics, monosomal karyotype, relapsed or refractory rather than newly diagnosed AML, and FLT3 internal tandem duplication were associated with relapse, their prognostic effect was much lower once MRD and response were taken into account, the univariable statistical effect of which was not materially affected by inclusion of pretreatment covariates. Conclusion Our data indicate that post-therapy parameters including MRD status and response are important independent prognostic factors for outcome in patients with AML achieving remission. MRD status and type of response (CR v CRp or CRi) should play important, and perhaps dominant, roles in planning postinduction therapy.

scholarly journals Prognostic Impact of Minimal Residual Disease Assessment in Elderly Patients with Secondary Acute Myeloid Leukemia. a Comparison between CPX-351 and Intensified Fludarabine-Based Regimens

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3442-3442
Author(s):  
Fabio Guolo ◽  
Paola Minetto ◽  
Marino Clavio ◽  
Maurizio Miglino ◽  
Riccardo Marcolin ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Minimal Residual Disease ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
Prognostic Value ◽  
Residual Disease ◽  
Rt Pcr ◽  
Younger Patients ◽  
Minimal Residual ◽  
Acute Myeloid

Abstract Background: Minimal residual disease (MRD) assessment retains high prognostic value in Acute Myeloid Leukemia patients (AML) undergoing intensive induction therapy. Widely available MRD techniques include multicolour flow cytometry (MFC), RT-PCR for recurrent genetic lesion and, for patients lacking specific markers, RT-PCR for the pan- leukemic marker WT1. However, most of the data on the prognostic value of MRD come from trials including younger patients treated with conventional 3+7 regimen. AML arising from a previous myelodisplastic syndrome (s-AML) and therapy-related AML (t-AML) are usually under-represented in trial involving younger patients and are unlikely to respond to conventional induction. Few data are therefore available on the kinetics and the prognostic value of MRD in elderly s- AML and t-AML patients, particularly in the context of alternative induction regimens. Aims: We evaluated MRD in a cohort of elderly s-AML or t-AML patients receiving induction therapy either with a fludarabine-containing regimen or CPX-351, in order to compare the probability of achieving MRD negativity, to disclose the prognostic value of MRD in this setting and to define the best time-points for MRD assessments. Methods: A total of 136 elderly (&gt;60 year, median age 67, range 60-75) patients were analyzed in this study. Patients were treated between January 2005 and January 2020 in our Center, either with CPX-351 (n=35) or fludarabine- high dose cytarabine-idarubicin (FLAI), with (n=72) or without (n =29) gemtuzumab-ozogamicin (GO). MRD was retrospectively analyzed in all patients achieving hematological complete remission (CR) with both MFC and WT1 expression levels.All patients were affected by s-AML or t-AML, defined according to the WHO 2016 criteria. Results: After induction, CR was achieved in 83 patients (61%). CR rate was 28/35 in patients treated with CPX-351 (80%), significantly higher when compared to patients receiving FLAI (55/101, 54.5%, p&lt;0.05). The addition of GO to FLAI did not increase CR rate. Among CR patients, a total of 41 (49.4%) and 44 patients (53%) achieved MRD negativity, with MFC or WT1-based methods, respectively. MFC MRD negativity probability was higher among patients receiving CPX-351 as induction therapy (MFC MRD negativity rate of 16/28, 57% and 25/55, 45% in CR patients who received CPX-351 or FLAI, respectively, p&lt;0.05). Adding GO to FLAI did not improve MRD negativity probability. Moreover, MRD showed significant prognostic value in terms of Overall Survival in all treatment group (2-year OS of 74 and 36% in patients with or without residual MFC MRD after induction, respectively, p&lt;0.05). WT1-based MRD lead to similar results. Conclusion: In conclusion MRD assessment retains a strong prognostic value and may help to identify patients with suboptimal response to treatment. The higher rate of MRD negativity observed with CPX-351 may be related with a more efficient anti-leukemic activity of the drug in this particular setting. The evaluation of MRD with both MFC and WT1-based assessment lead to superimposable conclusions and allowed us to obtain MRD data from virtually all AML patients treated in the selected time period. Disclosures No relevant conflicts of interest to declare.

Prognostic Impact of Pretransplantation Minimal Residual Disease Detection for Flow Cytometric, on Outcome of Allogeneic Hematopoietic Cell Transplantation for Acute Myeloid Leukemia. a Single Center Experience in Colombia over 14 Years

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5411-5411
Author(s):  
Andres Armando Borda Molina ◽  
Iris Cordoba ◽  
Virginia Abello ◽  
Carmen Rosales ◽  
Rosales Manuel ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Minimal Residual Disease ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Prognostic Impact ◽  
Allogeneic Bone ◽  
Flow Cytometric ◽  
Minimal Residual ◽  
Acute Myeloid

Abstract Background: The accumulated evidence from studies of multiparameter flow cytometric MRD (MFC-MRD) assessment in AML leaves little doubt that this method of MRD detection can be used to risk stratify both younger and older patients at treatment time points. Persistence of disease or high levels of pretransplantation minimal residual disease (MRD) have been reported to predict disease relapse after Allogeneic bone marrow transplantation (BMT). The prognostic impact of MFC-MRD is strong enough to have emerged despite study differences in the MFC assays and the limitations of now outdated restricted antibody panels. Aims: To determine the value of Minimal Residual Disease (MRD) assessed by Multi-parameter Flow Cytometry (MFC) pretransplantation Allogeneic BMT, in predicting outcome in patients with acute myeloid leukemia (AML). Methods: We performed a retrospective analysis the predictive value of MRD assessment by MFC pre trasnplantation alogeneic in 119 patients (diagnosed AML treated between january 2010 and october 2014 submitted at our institution who had available MRD assessment). MRD by MFC on bone marrow specimens obtained approximately 30 days before transplantation. MRD was identified as a cell population showing deviation from normal antigen expression patters compared with normal or regenerating marrow. The detection threshold for defining pre transplantation positive MRD was >0.3%. Results - Of the 119 patients, 80 (67%) were in complete remission (CR1) , 31 (26%) CR2 and > CR2 8 (6%). Their median age was 38 years (Range, 10-64). Hyperleucocytosis in 39 (32%) and Cytogenetics was favorable risk in 32 (26%), intermediate risk in 39 (32.%), adverse risk in 35 (29%) and unknown in 13 (14%). There were a total of 44 deaths and 17 relapses; these contributed to the probability estimates for overall survival (OS) and disease free survival (DFS), stratified by MRD status and shown in figure 1. The median follow-up after BMT among survivors was 8.3 years (range, 6.9 to 9,6 years). The 7.5-years estimates of OS for MRD-positive and MRD-negative patients were 43.1% (range, 23,2% to 58,6%) and 68% (range 56% to 78.3%), respectively, and the 7,5 year estimates for DFS for MRD-positive and MRD-negative patients were 40.5% (range 21.4% to 52.6%) and 56% (range 42.5% to 65.8%). After adjustment for various covariates, age, cytogenetics risk, hyperleucocytosis, secundary AML, the hazard ratios of MRD positive versus MRD negative were 2.06 (range 1.52 to 6.24; P=0,003) for overall mortality, 3.45 ( range 2.14 to 7.32; p=0.014) for DFS. Conclusion: That detection of MRD pre transplantation define a population of patients with AML who are at higher risk for adverse outcome, even after adjusting for other factors that influence post-BMT outcome. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

Early immunophenotypical evaluation of minimal residual disease in acute myeloid leukemia identifies different patient risk groups and may contribute to postinduction treatment stratification

Blood ◽  
2001 ◽  
Vol 98 (6) ◽  
pp. 1746-1751 ◽  
Author(s):  
Jesús F. San Miguel ◽  
Marı́a B. Vidriales ◽  
Consuelo López-Berges ◽  
Joaquı́n Dı́az-Mediavilla ◽  
Norma Gutiérrez ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Minimal Residual Disease ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Response To Therapy ◽  
Low Risk ◽  
Prognostic Impact ◽  
Minimal Residual ◽  
Acute Myeloid

Abstract Early response to therapy is one of the most important prognostic factors in acute leukemia. It is hypothesized that early immunophenotypical evaluation may help identify patients at high risk for relapse from those who may remain in complete remission (CR). Using multiparametric flow cytometry, the level of minimal residual disease (MRD) was evaluated in the first bone marrow (BM) in morphologic CR obtained after induction treatment from 126 patients with acute myeloid leukemia (AML) who displayed aberrant phenotypes at diagnosis. Based on MRD level, 4 different risk categories were identified: 8 patients were at very low risk (fewer than 10−4 cells), and none have relapsed thus far; 37 were at low risk (10−4 to 10−3 cells); and 64 were at intermediate risk (fewer than 10−3 to 10−2 cells), with 3-year cumulative relapse rates of 14% and 50%, respectively. The remaining 17 patients were in the high-risk group (more than 10−2 residual aberrant cells) and had a 3-year relapse rate of 84% (P = .0001). MRD level not only influences relapse-free survival but also overall survival (P = .003). The adverse prognostic impact was also observed when M3 and non-M3 patients with AML were separately analyzed, and was associated with adverse cytogenetic subtypes, 2 or more cycles to achieve CR, and high white blood cell counts. Multivariate analysis showed that MRD level was the most powerful independent prognostic factor, followed by cytogenetics and number of cycles to achieve CR. In conclusion, immunophenotypical investigation of MRD in the first BM in mCR obtained after AML induction therapy provides important information for risk assessment in patients with AML.

Prognostic Impact of Minimal Residual Disease inCBFB-MYH11–Positive Acute Myeloid Leukemia

2010 ◽  
Vol 28 (23) ◽  
pp. 3724-3729 ◽  
Author(s):  
Andrea Corbacioglu ◽  
Claudia Scholl ◽  
Richard F. Schlenk ◽  
Karina Eiwen ◽  
Juan Du ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Minimal Residual Disease ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Prognostic Impact ◽  
Consolidation Therapy ◽  
Old Patients ◽  
Minimal Residual ◽  
Acute Myeloid

PurposeTo evaluate the prognostic impact of minimal residual disease (MRD) in patients with acute myeloid leukemia (AML) expressing the CBFB-MYH11 fusion transcript.Patients and MethodsQuantitative reverse transcriptase polymerase chain reaction (PCR) was performed on 684 bone marrow (BM; n = 331) and/or peripheral blood (PB; n = 353) samples (median, 13 samples per patient) from 53 younger adult (16 to 60 years old) patients with AML treated in prospective German-Austrian AML Study Group treatment trials. Samples were obtained at diagnosis (BM, n = 45; PB, n = 48), during treatment course (BM, n = 153; PB, n = 122), and at follow-up (BM, n = 133; PB, n = 183). To evaluate the applicability of PB for MRD detection, 198 paired BM and PB samples obtained at identical time points were analyzed.ResultsThe following three clinically relevant checkpoints were identified during consolidation and early follow-up that predicted relapse: achievement of PCR negativity in at least one BM sample during consolidation therapy (2-year relapse-free survival [RFS], 79% v 54% for PCR positivity; P = .035); achievement of PCR negativity in at least two BM or PB samples during consolidation therapy and early follow-up (≤ 3 months; 2-year RFS, P = .001; overall survival, P = .01); and conversion from PCR negativity to PCR positivity with copy ratios of more than 10 after consolidation therapy. Analysis of paired BM and PB samples revealed BM samples to be more sensitive during the course of therapy, whereas for follow-up, PB samples were equally informative.ConclusionWe defined clinically relevant MRD checkpoints that allow for the identification of patients with CBFB-MYH11–positive AML who are at high risk of relapse. Monitoring of CBFB-MYH11 transcript levels should be incorporated into future clinical trials to guide therapeutic decisions.

Minimal Residual Disease in Patients with Acute Myeloid Leukemia Quantified by Multiparameter Flow Cytomety and Quantitative RT-PCR Is an Independent Prognostic Parameter.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 319-319 ◽  
Author(s):  
Wolfgang Kern ◽  
Claudia Schoch ◽  
Torsten Haferlach ◽  
Daniela Voskova ◽  
Wolfgang Hiddemann ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Minimal Residual Disease ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Prognostic Impact ◽  
Cox Regression Analysis ◽  
Minimal Residual ◽  
Acute Myeloid

Quantification of minimal residual disease (MRD) is becoming increasingly important to guide therapy in patients with acute myeloid leukemia (AML). While MFC can be applied to more patients with AML than QPCR, the latter has the advantage of a higher sensitivity in many cases. We compared data obtained by both methods in parallel in bone marrow samples in 160 patients at diagnosis and at 469 follow-up checkpoints. MFC was applied at diagnosis with a comprehensive panel of antibodies to identify leukemia-associated aberrant immunophenotypes (LAIP) useful for MRD monitoring. QPCR targeted on the leukemia-specific fusion transcripts AML1-ETO, AML1-EVI1, CBFB-MYH11, MLL-AF10, MLL-AF6, MLL-AF9, MLL-ELL, MLL-ENL, and PML-RARA as well as overexpression of EVI1, length mutations of FLT3, and partial tandem duplications of MLL. In order to adjust for differences in the percentages of bone marrow cells covered by the respective LAIP by MFC at diagnosis and for the heterogeneity of transcript levels detected by QPCR at diagnosis, the logarithmic difference (LD) was calculated for each follow-up sample in comparison to the diagnostic sample. There was a significant correlation between MFC and QPCR with regard to the LD from diagnosis to follow-up checkpoint (r=0.645, p=0.000001). Concordant results with regard to negativity between QPCR (no signal) and MFC (<0.01% positive cells) was found in 301/469 (64.2%) samples (both methods positive, 270 (57.6%); both methods negative, 31 (6.6%)). In 44 samples (9.4%) QPCR detected positivity and MFC negativity while in 124 samples (26.4%) MFC detected positivity and QPCR negativity (sensitivity of QPCR was lower than 1:100,000 in some cases). In 133 patients clinical follow-up data was available allowing the analysis of the prognostic impact of MRD levels. Cytogenetics were favorable, intermediate, and unfavorable in 86, 30, and 17 cases, respectively. Median age was 46 years (range, 17–83). Median event-free survival (EFS) was 22.1 months, overall survival (OS) at three years was 77%. The median LDs for MFC and QPCR at the checkpoint 1 (up to day 21), 2 (day 22–60), 3 (day 61–120), 4 (day 121–365), and 5 (after day 365) were 2.40 and 0.62, 2.05 and 1.55, 2.51 and 3.34, 2.71 and 3.70, and 2.60 and 3.45, respectively. Separating patients according to these median LDs resulted in a better EFS and OS for cases with higher LDs at all five checkpoints for each method. Significant differences in EFS were observed at checkpoints 2 (MFC, 22.1 vs. 12.6 months, p=0.0379; QPCR, median not reached vs. 9.9, p=0.0081), 3 (QPCR, 30.9 vs. 14.1 months, p=0.0011), 4 (MFC, median not reached vs. 16.9 months, p=0.0007; QPCR, median not reached vs. 15.1 months, p=0.0102), and 5 (QPCR, median not reached vs. 17.2, p=0.0008). Cox regression analysis taking into consideration cytogenetics, age, WBC count, and bone marrow blast count at diagnosis identified the LD at checkpoint 4 determined by MFC and the LD at checkpoints 2 and 5 determined by QPCR as independent prognostic factors. The results of our analyses confirm that both MFC and QPCR are highly sensitive methods capable of quantifying MRD in AML. While data are concordant for both methods in many cases, either of the two has advantages in distinct cases depending on the individual MRD marker. Clinical trials should consider MRD monitoring by both methods in order to prove their respective roles in risk prediction and treatment stratification.

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