Measurable residual disease evaluated by flow cytometry using leukemia associated immune phenotypes following allogeneic stem cell transplantation is associated with high relapse rates in patients with acute myeloid leukemia

2019 ◽  
Vol 61 (3) ◽  
pp. 745-748
Author(s):  
Yoshimitsu Shimomura ◽  
Masahiko Hara ◽  
Hayato Maruoka ◽  
Tomohiro Yabushita ◽  
Takayuki Ishikawa
Keyword(s):  
Flow Cytometry ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Immune Phenotypes ◽  
Relapse Rates ◽  
Measurable Residual Disease ◽  
Acute Myeloid

Optimal Post-Remission Therapy for Flow-Cytometry Minimal Residual Disease Positive Patients with Acute Myeloid Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 610-610
Author(s):  
Francesco Buccisano ◽  
Luca Maurillo ◽  
Valter Gattei ◽  
Giovanni Del Poeta ◽  
Maria Ilaria Del Principe ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Minimal Residual Disease ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Consolidation Therapy ◽  
Minimal Residual ◽  
Acute Myeloid

Abstract Autologous (AuSCT) and allogeneic stem cell transplantation (SCT) are well established post-remissional strategies for patients with Acute Myeloid Leukemia (AML). However, there is still a debate ongoing about the relative merit of each of these options in first CR. Minimal residual disease (MRD) may be a useful tool to stratify AML patients into categories of risk which can benefit from differentiated post-remissional approaches. To address this issue, we analysed retrospectively, a series of 123 patients affected with AML in whom flow-cytometry serial determinations of MRD were available, at established time-points (post-induction, post-consolidation, post-stem cell transplantation). All were entered into the EORTC/GIMEMA protocols AML10/AML12 (age <61 yrs) or AML13 (age>61 yrs), all consisting in intensive induction and consolidation cycles, and, for patients aged <61 years, AuSCT or SCT. Median age was 52 years (range 18–78), no APL cases were included in the study. The “Maximally Selected Rank Statistic” analysis was used to select the MRD level and the time-point of analysis achieving the best prognostic significance in terms of overall survival (OS) and relapse free survival (RFS). This test was specifically developed to find out the optimal cut-off for a given biological variable correlating with clinical parameters of interest. This approach confirmed the threshold of 3.5x10−4 residual leukemic cells after consolidation therapy, as a discriminator between MRD− and MRD+ cases with different 5-years OS (64% vs. 14%, P<.001) and RFS (68% vs. 13%, P<.001). Therefore, among these 123 patients, we enucleated 2 groups of patients which underwent stem cell transplant procedure, 53 AuSCT and 11 SCT. The two subgroups were balanced in terms of FAB categories, WBC count, karyotype and expression of MDR-1 phenotype; 34/64 (53%) were MRD+ (9 SCT, 25 AuSCT) and 30/64 (47%) were MRD− (1 SCT, 28 AuSCT). Among the 53 patients submitted to AuSCT, MRD− had a significant better outcome than those MRD+, both in terms of 5-years OS (68% vs. 24%, P=0.003) and RFS (68% vs. 11%, P<.001). In the SCT group the low numbers hampered any firm conclusion; however, when the category of post-consolidation MRD+ patients was separately analysed, the use of SCT was associated with a better RFS (49% vs. 11%, P=NS); we assume that the lack of statistical significance was merely due to the few cases in the SCT group. In conclusion, the threshold of 3.5x10−4 at post-consolidation check-point is critical to predict disease outcome; MRD− patients have an excellent outcome regardless of the post-consolidation therapy; in the MRD+ group, AuSCT seems not to improve the prognosis whereas the use of SCT is associated with a superior outcome, although a larger number of patients is required to confirm this assumption. Figure Figure

scholarly journals Differential Prognostic Relevance of Measurable Residual Disease in Acute Myeloid Leukemia Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation in First Versus Second Morphologic Remission

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 416-416
Author(s):  
Madlen Jentzsch ◽  
Johannes Küpper ◽  
Dominic Brauer ◽  
Donata Backhaus ◽  
Julia Schulz ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Complete Remission ◽  
Stem Cell Transplantation ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Secondary Aml ◽  
Allogeneic Hsct ◽  
Measurable Residual Disease ◽  
Acute Myeloid

Abstract Introduction: Allogeneic stem cell transplantation (HSCT) offers still the best chance for relapse-free long-term survival for most patients (pts) with acute myeloid leukemia (AML). Allogeneic HSCT may be performed as first line consolidation or following first relapse. Evaluation of measurable residual disease (MRD) at the time of HSCT allows for risk stratification apart from genetic risk at diagnosis. Outcomes of pts transplanted in first vs. second complete remission (CR) or CR with incomplete recovery (CRi) have not been assessed in the context of MRD status at HSCT. Methods: We analyzed 580 AML pts consolidated by allogeneic peripheral blood HSCT at a median age of 60 (range 16-77) years in either first (79%) or second (21%) complete remission (CR) or CR with incomplete peripheral recovery (CRi). Conditioning regimens were non-myeloablative (66%), reduced-intensity (6%) or myeloablative (28%) according to EBMT guidelines. At diagnosis, cytogenetics, and the mutation status of CEBPA, NPM1 and presence of FLT3-ITD were assessed. Using a next-generation targeted amplicon sequencing approach we analyzed a panel comprising 54 recurrently mutated genes in myeloid malignancies on the MiSeq platform (Illumina). In pts with adequate material available (n=300), MRD status at HSCT based on NPM1 mutations , BAALC, MN1, and WT1 expression were evaluated and interpreted as published previously (Lange 2010, Jentzsch 2017 & 2019, Bill 2018). MRD pos pts were defined by being positive for any of the analyzed markers. Median follow up after HSCT was 3.9years. Results: Compared to pts transplanted in first CR/CRi, pts in second CR/CRi were less likely to have a secondary AML (P=.002). They less frequently had a monosomal (P<.002) or complex (P<.001) karyotype, but were more likely to have a normal karyotype (P<.001), to be NPM1 mutated (P=.001), to be biallelic CEBPA mutated by trend (P=.09), and to harbor a FLT3-ITD (P=.04). Pts in second CR/CRi received significantly less chemotherapy prior to HSCT (relapse to HSCT, 71%, 26%, and 3% of pts received 1, 2, or 3 or more cycles, respectively) than pts in first CR/CRi (diagnosis to HSCT, 16%, 61%, and 23% of pts received 1, 2, or 3 or more cycles, respectively, P<.001). Pts transplanted in second CR/CRi tended to more often be MRD pos (P=.10) and had a significantly higher cumulative incidence of relapse (CIR, P<.001, Figure 1A) and significantly shorter event-free survival (EFS, P=.002, Figure 1B) than pts transplanted in first CR/CRi. The MRD status at HSCT was an important prognostic factor in both pts transplanted in first (CIR, P<.001 and EFS, P=.002) and second CR/CRi (CIR, P<.001 and EFS, P=.04, Figure 1C,D). Similar results were obtained when we analyzed the four MRD markers separately. Noteworthy, MRD pos pts transplanted in first CR/CRi and MRD neg pts transplanted in second CR/CRi had similar CIR (P=.42) and EFS (P=.70), which again reflects the worse outcomes of AML pts transplanted in second compared to first CR/CRi as well as the prognostic significance of MRD assessment irrespective of the adapted markers. In the clinically highly relevant group of ELN intermediate risk AML pts where the optimal consolidation (chemotherapy vs. allogeneic HSCT) remains a matter of debate, both MRD neg pts transplanted in in first or second CR/CRi had favorable outcomes (at three years, CIR 15% and 13%, respectively, and EFS, 64% and 63%, respectively), while outcomes were intermediate in MRD pos pts transplanted in first CR/CRi (at 3 years, CIR 38%, and EFS 46%) and very dismal in MRD pos pts transplanted in second CR/CRi (at 3 years, CIR 86%, and EFS 14%). Conclusion: Despite pts transplanted in second CR/CRi had better disease risk at diagnosis, including a lower incidence of monosomal or complex karyotypes, secondary AML and a higher incidence of NPM1 mutations, they had a higher CIR and shorter OS than pts transplanted in first CR/CRi. While the MRD status at HSCT remained an important risk factor independently of the number of remission, MRD pos pts transplanted in first CR/CRi had comparable outcomes as MRD neg pts transplanted in second CR/CRi. The adverse outcomes of MRD pos patients and pts transplanted in second CR/CRi should be taken into account when planning consolidation treatment in AML pts. Benefit of additional therapies prior to HSCT should be evaluated to improve outcomes of eligible MRD pos AML pts, especially when transplanted in second CR/CRi. Figure 1 Figure 1. Disclosures Jentzsch: Astellas: Honoraria; Jazz Pharmaceuticals: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Backhaus: Bayer: Other: Current Employment of Family Member. Franke: Novartis: Honoraria; MSD: Honoraria; Jazz Pharmaceuticals: Honoraria, Other: Travel Sponsoring; Gilead: Honoraria, Other: Travel Sponsoring; BMS: Honoraria; Pfizer: Honoraria. Vucinic: Novartis: Honoraria; Janssen: Honoraria, Other: Travel Sponsoring; Abbvie: Honoraria, Other: Travel Sponsoring; Gilead: Honoraria, Other: Travel Sponsoring; MSD: Honoraria. Platzbecker: Geron: Honoraria; Novartis: Honoraria; Takeda: Honoraria; AbbVie: Honoraria; Janssen: Honoraria; Celgene/BMS: Honoraria. Schwind: Novartis: Honoraria, Research Funding; Pfizer: Honoraria.

scholarly journals Measurable Residual Disease Detected by Multiparameter Flow Cytometry and Sequencing Improves Prediction of Relapse and Survival in Acute Myeloid Leukemia

2021 ◽  
Vol 11 ◽  
Author(s):  
Fu-Jia Liu ◽  
Wen-Yan Cheng ◽  
Xiao-Jing Lin ◽  
Shi-Yang Wang ◽  
Tian-Yi Jiang ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Prognostic Significance ◽  
Multiparameter Flow Cytometry ◽  
Net Reclassification Improvement ◽  
Measurable Residual Disease ◽  
Acute Myeloid ◽  
Time Point

The clinically ideal time point and optimal approach for the assessment of measurable residual disease (MRD) in patients with acute myeloid leukemia (AML) are still inconclusive. We investigated the clinical value of multiparameter flow cytometry-based MRD (MFC MRD) after induction (n = 492) and two cycles of consolidation (n = 421). The latter time point was proved as a superior indicator with independent prognostic significance for both relapse-free survival (RFS, HR = 3.635, 95% CI: 2.433–5.431, P <0.001) and overall survival (OS: HR = 3.511, 95% CI: 2.191–5.626, P <0.001). Furthermore, several representative molecular MRD markers were compared with the MFC MRD. Both approaches can establish prognostic value in patients with NPM1 mutations, and FLT3, C-KIT, or N-RAS mutations involved in kinase-related signaling pathways, while the combination of both techniques further refined the risk stratification. The detection of RUNX1–RUNX1T1 fusion transcripts achieved a considerable net reclassification improvement in predicting the prognosis. Conversely, for patients with biallelic CEBPA or DNMT3A mutations, only the MFC method was recommended due to the poor prognostic discriminability in tracking mutant transcripts. In conclusion, this study demonstrated that the MFC MRD after two consolidation cycles independently predicted clinical outcomes, and the integration of MFC and molecular MRD should depend on different types of AML-related genetic lesions.

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<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.

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