Impact of Minimal Residual Disease Detected By Multiparameter Flow Cytometry on Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia Patients in First Complete Remission

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4562-4562
Author(s):  
Zoya V. Konova ◽  
Elena N. Parovichnikova ◽  
Irina V. Galtseva ◽  
Nikolay M. Kapranov ◽  
Julia O. Davydova ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Multiparameter Flow Cytometry ◽  
Hematopoietic Stem ◽  
A Cell ◽  
The Impact ◽  
Minimal Residual ◽  
Risk Of Relapse ◽  
Acute Myeloid

Introduction. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) could be curative for acute myeloid leukemia (AML) patients. However, the disease relapse after allo-HSCT lead to poor outcomes almost in all cases. Minimal residual disease (MRD) is a strong prognostic marker of increased risk of relapse and reflects overall (OS) and relapse-free survival (RFS) in patients with AML. Immunophenotypic evaluation using multiparameter flow cytometry (MFC) is an important strategy for detecting MRD, because of its simplicity and wide availability. Aim. Determine the impact of MRD detected by MFC before allo-HSCT on clinical outcomes. Patients and methods. To assess the impact of MRD status before transplantation we include 56 AML patients who underwent allo-HSCT in National Research Center for Hematology between July 2016 and June 2019. Patient's characteristics are shown in table 1. All these patients were in first compete morphologic remission at the time of allo-HSCT. MRD was evaluated by MFC. Bone marrow samples were obtained before allo-HSCT and were analyzed by 6-color MFC (BD FACS Canto II, USA). Positive MRD was identified as a cell population deviating from the normal patterns of antigen expression on specific cell lineages at specific stages of maturation for all patients. In addition, for patients with LAIP at diagnosis, positive MRD was also defined as a cell population carrying LAIP markers at diagnosis. The probabilities of OS and RFS were estimated using the Kaplan-Meier method. Results. Among 56 AML patients before allo-HSCT (all were in CR at the time of MRD analysis). Median of follow-up was 9.3 months.11 patients (19,6%) were identified as MRD+ (0,011%-5,08%, mean 1%). And 5 of them relapsed (45,5%). Out of 45 MRD negative patients before HSCT relapse was registered in one (relapse rate 2,2%). Statistical analysis revealed significant differences between MRD- and MRD+ patients: MRD+ had much worse OS (22,9% vs. 85.5%, p=0.0047, Fig.1A) and RFS (26% vs. 97.4%, p<0,0001, Fig.1B). Conclusions. Despite the presence of morphological CR before allo-HSCT, MRD persistence can lead to worse probabilities of OS and RFS, which is comparable to patients who were transplanted in relapse. Because of the association between MRD and relapse risk, it can be assumed, that testing for MRD before allo-HSCT may help to identify a subgroup of patients at high risk of relapse who might benefit from preemptive posttransplantation treatment. Disclosures No relevant conflicts of interest to declare.

scholarly journals Prognostic Value of Minimal Residual Disease before Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Acute Myeloid Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5733-5733
Author(s):  
Olga Pérez-López ◽  
Teresa Caballero-Velázquez ◽  
Enrique Colado ◽  
Sara Alonso ◽  
José González-Campos ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Prognostic Value ◽  
Residual Disease ◽  
Hematopoietic Stem ◽  
Multiparametric Flow Cytometry ◽  
Minimal Residual ◽  
Acute Myeloid

Abstract Introduction Several studies have shown that the minimal residual disease (MRD) in acute myeloid leukemia (AML) patients has a prognostic value after induction and consolidation therapy. Nevertheless the relapse is the most important cause of treatment failure in these patients, although they achieved a negative MRD, and even after an allogeneic hematopoietic stem cell transplantation (allo-HSCT). Nowadays, the value of the MRD before allogeneic BMT is still controversial. Method Multicentric study where we have studied correlative AML patients who went under an allo-HSCT in a situation of complete response, between 2012 and April'18. The MRD was analyzed by 8-coloured multiparametric flow cytometry, at least with 2 tubes per patient and 1,000,000 events per tube. We evaluated the prognostic value of the MRD before allo-HSCT. Results Between January'12 and April'18 we have gathered 90 allogeneic BMT in AML patients who were in CR, with a median age of 45 years old (17 - 66). The pre-HSCT situation was 1st complete remission (CR) in 75 patients and 2nd CR in 15. In 45 patients the conditioning regimen was myeoablative. In the group of patients (67) where we could know the risk group at diagnosis, the distribution was: low risk 18%, intermediate risk 59.7% and high risk 22.4%. The 46.7% of the donors were not related. In the last follow-up after allo-HSCT 24 patients have suffered a relapse (26.7%) and 41 (45.5%) have died (17 cases of mortality related to the transplant and 24 not related). In the global analysis the median follow-up of the overall survival (OS) was 37.5 months. Among the 90 patients, MRD was valuable in 86. Ten of 59 patients (16.9%) with negative MRD relapsed vs 12/27 (44.4%) with positive MRD, p= 0.016. If we consider only patients in 1st CR, 9/50 (18%) patients with negative MRD relapsed vs 10/22 (45.5%) with positive MRD, p= 0.02. This statistically significant difference does not exist if we consider only patients in 2nd CR. The median follow-up of OS and event free survival (EFS) was not reached in the negative MRD group and 571 days and 299 days in the positive MRD group. OS and EFS at 2 years after transplantation were 65% and 64% in the negative MRD group and 42% and 37% in the positive MRD group, p= 0.03 and p= 0.008 respectively (figure 1). Conclusions The detected MRD by 8-colour multiparametric flow cytometry previous an allo-HSCT in patients with AML in 1st CR is a prognostic factor in terms of relapse. Patients with a positive MRD before the allo-HSCT have a poorer OS and EFS than the patients with a negative MRD. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Impact of Minimal Residual Disease and Chimerism Monitoring at Different Timepoints after Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 7-7
Author(s):  
Reyes María Martín-Rojas ◽  
Gillen Oarbeascoa ◽  
Rebeca Bailén ◽  
Ignacio Gómez-Centurión ◽  
Luis Miguel Juarez ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Cumulative Incidence ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Minimal Residual ◽  
Risk Of Relapse ◽  
Acute Myeloid

¶ Martin-Rojas RM and Oarbeascoa G contributed equally to this work. INTRODUCTION Relapse is the main cause of treatment failure after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acute myeloid leukemia (AML). The evaluation of minimal residual disease (MRD) could provide a more accurate assessment of the depth of response, and therefore identify patients with higher risk of relapse. AIMS The aim of our study was to analyze the impact of pre-HSCT flow cytometry (FCM) and molecular MRD together with chimerism and MRD in the early post-HSCT period in patients with AML. METHODS We conducted a retrospective study in patients with complete remission AML who underwent a HSCT between 2008 and 2019 in our center. MRD was analyzed by flow cytometry in bone marrow aspirates and by quantitative RT-PCR (NMP1, RUNX1-RUNX1T1, CBFB-MYH11, KMT2A-MLLT3, WT1) in bone marrow aspirates and/or peripheral blood. MRD was determined within the 30 days preceding the HSCT and at day +30 and +90 post-HSCT. Bone marrow and selected CD34+ lineage chimerism was analyzed by STR (AmpFISTR SGM Plus, Thermo Fisher) at days +30 and +90 post-HSCT. This study was approved by our Institutional Ethics Committee. Data were analyzed using IBM SPSS Statistics version 24 and R version 3.5.1. RESULTS A total of 115 patients were analyzed. Pre-HSCT MRD was negative in 58 patients (50.4%) and positive in 57 patients (49.6%). We found no statistically significant differences in the characteristics between the two groups (Table 1). Median follow up was 39 months (IQR 10.4-55.8). 3-year overall survival (OS) for patients with pre-HSCT negative MRD was 72.5% versus 70.3% in patients with positive MRD (p=0.41), with an event free survival (EFS) of 66.9% versus 66.1 (p=0.48) respectively (Figure 1). Median time to the beginning of immunosuppression withdrawal was 82.5 days (IQR 59-93) for patients with negative MRD and 68 days (IQR 55.3-85.3) for patients with positive MRD (p&lt;0.001). The cumulative incidence of grade II-IV acute graft versus host disease (aGVHD) and moderate-severe chronic GVHD did not show statistically significant differences based on the MRD status. Similarly, the cumulative incidence of relapse and the 2-year mortality was not significantly different between the two groups. Patients with negative MRD at day +30 showed a 2-year OS of 83.5% versus 58.1% in patients with positive MRD (p=0.03) and a EFS of 79.9% versus 48.6% (Figure 2). The cumulative incidence of relapse was more elevated in patients with positive MRD (29.8% versus 13.6%) at day +30. Patients with mixed chimerism (MC) at day +30 showed a significantly lower 3-year OS and EFS than patients with complete chimerism (CC). Likewise, the cumulative incidence of relapse was significantly higher in patients with MC, both if detected in bone marrow aspirate and in CD34+ cells. The multivariate analysis revealed that MRD status at day +30 post-HSCT was an independent prognostic factor for EFS (HR 3.74; 95% CI 1.38-10.1; p=0.009). CONCLUSIONS Patients with AML presenting a positive MRD in the early post-HSCT period and those who show a MC at day +30 post-HSCT have lower EFS, with positive MRD at day +30 being an independent prognostic factor for EFS. The evaluation of MRD and chimerism in the early post-HSCT period is useful to identify patients with higher risk of relapse, who may take advantage of preemptive measures. Disclosures Kwon: Gilead, Novartis, Pfizer, Jazz: Consultancy, Honoraria.

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.

The Detection of Minimal Residual Disease By Multiparameter Flow Cytometry Predicts a Higher Risk of Relapse in Patients with ELN Intermediate Risk Acute Myeloid Leukemia Where Molecular Markers Are Not Available

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2882-2882
Author(s):  
Erika Borlenghi ◽  
Mirko Farina ◽  
Marco Chiarini ◽  
Viviana Giustini ◽  
Cinzia Lamorgese ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Risk Group ◽  
Risk Groups ◽  
Multiparameter Flow Cytometry ◽  
Intermediate Risk ◽  
Rt Pcr ◽  
Minimal Residual ◽  
Acute Myeloid

Abstract INTRODUCTION: Over the last years multiparameter flow cytometry (MFC) has proven an effective method for the detection of minimal residual disease (MRD) not only in Acute Lymphoblastic Leukemia but also in Acute Myeloid Leukemia (AML) (Inaba, JCO 2012) providing powerful independent prognostic information (Loken, Blood 2012; Freeman, JCO 2013) in addition to molecularly-based approaches. It is unclear if it should be useful in all AML patients (pts) with a detectable leukemia associated immune-phenotype (LAIP) or just in pts without a molecular marker. Herein we report the results obtained in a consecutive series of pts followed at our institution. METHODS: Between July 2010 and March 2016, we analyzed MRD by MFC in 144 AML pts treated according to NILG AML study (Bassan, Blood 2003) at diagnosis and at the following subsequent time points (TP): achievement of complete remission (CR) after 1 or 2 courses of induction therapy (TP1), after the first consolidation course (TP2) and at the end of the treatment program (TP3). Bone marrow samples were analyzed by eight/six-colours MFC, the cut-off value used for MRD was 0.1% and 0.035% at TP1 (Al-Mawali, 2009) and 0.035% at TP2 and TP3 (Buccisano, Blood 2010). Molecularly based real-time quantitative PCR (RT-PCR) methods were used to monitor CBF in 10 pts and NPM1 in 25 pts (Gorello, Leukemia 2006). The pts median age was 56 years (19-73y), the F/M 59/85; de-novo AML 125/144 (86.8%) and secondary AML (s-AML) were 19/144 (13.2%). Most pts belonged to the intermediate (int) cytogenetic risk group (MRC favorable n=12, 8.3%, int n=105, 73%, adverse n=27, 18.7%), while the distribution according to ELN risk group was 51 favorable (35.4%), 47 int-I (32.6%), 19 int-II (13.2%) and 27 adverse (18.8%), respectively. RESULTS: At diagnosis 120/144 pts (83.3%) had a LAIP. There were no differences in clinical or biologic characteristics between pts with or without a LAIP, except that in the no-LAIP group the s-AML and adverse risk ELN were more represented (25% vs 10.7% and 25% vs 16.6%, respectively). In pts with LAIP, after a median follow-up of 23 months (ms), the CR rate was 88.3%, median relapse free survival (RFS) was 49%+/-7 ES, at 5y and median overall survival (OS) was 57.9 ms, with no differences compared to no-LAIP pts. Distribution among cytogenetic and molecular risk groups was as follows: for MRC favorable n=10 (8.3%), int n=90 (75%), adverse n=20 (16.7%); according to ELN risk: 43 favorable (35.8%), 40 int-I (33.3%), 17 int-II (14.2%), and 20 adverse (16.7%). The ELN risk classification stratified both for OS (p=0.004) and for RFS (p=0.0095), while MRC classification did not (p=0.33 and p=0.36, respectively). In the LAIP group we serially analyzed marrow cells at the different TP: 106/120 at TP1 (10 pts did not reach CR, 4 inadequate sample), 99 at TP2, while 66 were evaluable at TP3. MRD negativity was achieved at TP1 in 52/106 (49%) and in 21/106 (19.8%) pts with a threshold of 0.1% and 0.035%, respectively; at TP2 in 35/99 (35.4%) and at TP3 in 19/66 (24.2%). According to risk classification, at TP1 MRD positivity by MFC predicted relapse in int-I and int-II ELN risk groups, both with a threshold of 0.035% (p=0.018), and of 0.1% (p=0.0013) (Figure 1). The median of time to relapse was 11.9 ms in MRD positivity and 14.4 ms in MRD negativity pts. In the other ELN risk group there was no difference in relapse rate according to MRD negativity (p=0.19 and p=0.9 in favorable and p=0.16 and p=0.7 in adverse, respectively, according to 2 threshold). In the favorable ELN group the comparison of MRD results obtained by MFC with those obtained by RT-PCR was possible in 25 pts with NPM-mutated AML who achieved CR in 100% and relapsed in 20% of cases. MRD by MFC resulted detectable in 2 pts (8%) at TP1, in 7 pts at TP2 (28%), and in 13 of 25 pts (53%) at TP3, with no correlation with relapse risk. MRD positivity by RT-PCR predicted the relapse at TP2 (p=0.07) and at TP3 (p=0.0058) (Figure 2). CONCLUSION: Methods for determining MRD in AML may differ in their accuracy. Our study confirms that while in pts with favorable ELN risk AML, molecular methods may be considered the gold standard, in pts without a molecularly evaluable marker, the use of MFC may be useful for predicting relapse. Promising results of MFC MRD determination were achieved in the subset of AML at ELN intermediate risk where it is clinically most helpful in supporting the difficult choice among different postremission treatment strategy. Disclosures No relevant conflicts of interest to declare.

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