Pre-transplant Minimal Residual Disease Research Articles

Survival after allogeneic transplantation according to pretransplant minimal residual disease and conditioning intensity in patients with acute myeloid leukemia.

The measurement of minimal residual disease (MRD) by multiparametric flow cytometry (MFC) before hematopoietic stem cell transplantation (HSCT) in patients with acute myeloid leukemia (AML) is a powerful prognostic factor. The interaction of pretransplant MRD and the conditioning intensity has not yet been clarified. The aim of this study is to analyze the transplant outcomes of patients with AML who underwent HSCT in complete remission (CR), comparing patients with positive MRD (MRD+) and negative MRD (MRD-) before HSCT, and the interaction between conditioning intensity and pre-HSCT MRD. We retrospectively analyzed the transplant outcomes of 118 patients with AML who underwent HSCT in CR in a single institution, comparing patients with MRD+ and MRD- before HSCT using a cutoff of 0.1% on MFC, and the interaction between conditioning intensity and pre-HSCT MRD. Patients with MRD+ before HSCT had a significantly worse 2-year (2y) event-free survival (EFS) (56.5% vs. 32.0%, p = 0.018) than MRD- patients, due to a higher cumulative incidence of relapse (CIR) at 2 years (49.0% vs. 18.0%, p = 0.002), with no differences in transplant-related mortality (TRM) (2y-TRM, 19.0% and 25.0%, respectively, p = 0.588). In the analysis stratified by conditioning intensity, in patients who received MAC, those with MRD- before HSCT had better EFS (p = 0.009) and overall survival (OS) (p = 0.070) due to lower CIR (p = 0.004) than MRD+ patients. On the other hand, the survival was similar in reduced intensity conditioning (RIC) patients regardless of the MRD status. Patients with MRD+ before HSCT have worse outcomes than MRD- patients. In patients who received MAC, MRD- patients have better EFS and OS due to lower CIR than MRD+ patients, probably because they represent a more chemo-sensitive group. However, among RIC patients, results were similar regardless of the MRD status.

Effects of Pre-Transplant CONUT and Post-Transplant MRD on Prognosis of Patients with Multiple Myeloma after Auto-HSCT

To explore the effects of pre-transplant controlling nutritional status (CONUT) and post-transplant minimal residual disease (MRD) on prognosis of patients with multiple myeloma (MM) after autologous hematopoietic stem cell transplantation (auto-HSCT). The clinical data of 79 patients who received auto-HSCT from 2011 to 2020 in The First Affiliated Hospital of Chongqing Medical University were retrospectively analyzed. The patients were divided into Low-CONUT group (n=62) and High-CONUT group (n=17) according to whether the CONUT score was less than 5. The differences in clinical features, hematopoietic reconstruction, adverse reactions, efficacy and survival between the two groups were compared. In addition, the prognostic risk factors were analyzed and verified by time-dependent ROC curve. The proportions of male patients and bone marrow plasma cells>30% at initial diagnosis in High-CONUT group were both higher than those in Low-CONUT group (both P <0.05). While, there were no significant differences in hematopoietic reconstruction and adverse reactions (>grade 2) between the two groups. The complete response (CR) rate and CR+very good partial response (VGPR) rate before transplantation in Low-CONUT group were both significantly higher than those in High-CONUT group (both P <0.05). After 3 months of transplantation, the CR+VGPR rate still remained an advantage in Low-CONUT group compared with High-CONUT group (P <0.01), but CR rate did not(P >0.05). The overall survival (OS) and progression-free survival (PFS) in Low-CONUT group were both superior to those in High-CONUT group (both P <0.05). Low CONUT score (0-4) before transplantation and negative MRD at 6 months after transplantation were favorable factors affecting OS and PFS (both P <0.05), while the International Myeloma Working Group (IMWG) high-risk at initial diagnosis and lactate dehydrogenase (LDH) level>250 U/L before transplantation were only risk factors for PFS (both P <0.05). Time-dependent ROC curve analysis showed that pre-transplant CONUT score and MRD status at 6 months after transplantation could independently or jointly predict 1- and 2-year OS and PFS, and the combined prediction was more effective. The combination of pre-transplant CONUT and post-transplant MRD can better predict the prognosis of MM patients.

Intensified conditioning regimens with total marrow irradiation/etoposide/cyclophosphamide and busulfan/etoposide/cyclophosphamide overcome the impact of pre-transplant minimal residual disease on outcomes in high-risk acute lymphoblastic leukemia patients in complete remission.

Among high-risk acute lymphoblastic leukemia (ALL) patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT), those with positive minimal residual disease (MRD) are susceptible to poor outcomes. Therefore, it is necessary to determine the most suitable preparatory regimen for these patients. Data were analyzed from 141 patients who received allo-HSCT and were diagnosed with high-risk ALL. These patients underwent intensified conditioning regimens, including either total marrow and lymphoid irradiation (TMLI)-etoposide (VP16)-cyclophosphamide (CY) or busulfan (BU)-VP16-CY between October 2016 and November 2022. A total of 141 individuals were in complete remission (CR) before transplantation and, among all patients, 90 individuals exhibited a negative MRD status and 51 patients had a positive MRD status. In patients who tested negative for MRD, the incidence of relapse within a 2-year timeframe was 25.0% (24.8%-25.5%), compared with 32.2% (31.2%-33.2%) in MRD-positive patients; however, this difference was not statistically significant. There were no significant differences in the 2-year disease-free survival (DFS) and 2-year overall survival (OS) rates between the MRD-negative and MRD-positive groups (DFS: 67.2% (57.9%-78.1%) vs. 55.5% (42.6%-72.3%); OS: 69.0% (61.9%-88.2%) vs. 66.7% (53.9%-82.5%)). Furthermore, no notable variations were observed in the occurrence of transplant-related mortality (TRM) and graft-versus-host disease (GVHD) across the two groups. This study reveals the benefits of TMLI-VP16-CY and BU-VP16-CY conditioning regimens in high-risk ALL patients with CR and MRD-positive status. A large-scale prospective clinical trial is warranted in the future.

Impact of pretransplant minimal residual disease in patients with multiple myeloma and a very good partial response or better receiving autologous hematopoietic stem cell transplantation.

The prognostic significance of minimal residual disease (MRD) status before autologous hematopoietic stem cell transplantation (autoHCT) in patients with multiple myeloma (MM) has not been clearly elucidated. Retrospective single-center study of adult MM patients who achieved ≥very good partial response (VGPR) after induction therapy from 2015 to 2021 received upfront autoHCT and had available pretransplant MRD status by next-generation flow cytometry. The cohort was divided into pretransplant MRD-negative (MRDneg) and MRD-positive (MRDpos) groups. A total of 733 patients were included in our analysis; 425 were MRDneg and 308 MRDpos at autoHCT. In the MRDpos group, more patients had high-risk cytogenetic abnormalities (48% vs. 38%, respectively; p=.025), whereas fewer patients achieved ≥CR before autoHCT (14% vs. 40%; p<.001). At day 100 after autoHCT, 37% of the MRDpos versus 71% of the MRDneg achieved ≥CR, and at best posttransplant response 65% versus 88% achieved ≥CR, respectively. After a median follow-up of 27.6months (range, 0.7-82.3), the median PFS was significantly shorter for patients in the MRDpos group compared to the MRDneg group: 48.2months (95% confidence interval [CI], 0.3-80.5) versus 80.1months (95% CI, 0.5-80.1), respectively (p<.001). There was no significant difference in overall survival between the two groups (p=.41). Pretransplant MRDpos status was predictive of shorter PFS in multivariate analysis (hazard ratio, 1.80; 95% CI, 1.31-2.46; p<.001). The impact of pretransplant MRD status was retained in most of the examined subgroups. In patients achieving ≥VGPR to induction, pretransplant MRDpos status was associated with a lower CR rate after autoHCT and a shorter PFS.

B-Cell Acute Lymphoblastic Leukemia: Donor Matters in Allogeneic Stem Cell Transplant Outcomes of Hispanic Patients

Introduction: Hematopoietic stem cell transplantation (HSCT) improves long term overall survival (OS) and disease-free survival (DFS) in those with intermediate or high-risk B- cell ALL. Historically, matched related donors were the ideal choice, but with improved GVHD prophylactic regimens and supportive care, haploidentical donors are being increasingly used. Due to their increased graft-versus-leukemia (GVL) effect, they may be an option for Hispanic patients, for whom matched donation may be more challenging. Methods: This is a retrospective chart review of B- cell ALL patients that received allogeneic HSCT at Norris Comprehensive Cancer Center (NCCC) from 2012 to 2023. Mismatch-unrelated donors were excluded. For OS, DFS, and cumulative incidence of relapse (CIR), match sibling donors (MSD) and match unrelated donors (MUD) were grouped. However, for GVHD outcomes including graft-versus-host disease (GVHD)-free relapse-free survival (GRFS), incidence of grade 3-4 acute GVHD (aGVHD), and incidence of severe chronic GVHD (cGVHD) requiring immunosuppression MSD and MUD were separated. Incidence outcomes were evaluated using competing risk regression (Fine-Gray method), with death as a competing outcome, while survival outcomes were analyzed using Cox proportional hazards model. Results: One hundred eighteen B- cell ALL patients were included with a median age at transplant of 43 years (range: 21-69). Donor types included 46 (40.0%) MSD, 45 (38.1%) haploidentical, and 27 (22.9%) MUD. Most were Hispanic (N= 92, 78.0%) and our median follow-up time was 23.6 months. The majority of patients achieved CR1 (N=79, 66.9%) and MRD negativity by flow (N=106, 89.8%), pre-transplant. The 3-year OS and DFS for the cohort were 82.1% (95% CI 73.8-91.3%) and 66.2% (95% CI 57.2-76.6%), respectively, while the CR1 subgroup was 90.5% (95% CI 83.3-98.3%) and 77.1% (95% CI 67.8-87.7%) respectively. When compared to haploidentical HSCT, patients who received matched donors had significantly worse CIR (HR = 2.42; 95% CI 1.06-5.51; P = 0.036) and DFS (HR = 2.14; 95% CI 1.03-4.44; P = 0.041), along with a non-significant trend towards worse OS (HR = 2.54; 95% CI 0.83-7.80; P=0.10). Additionally, pretransplant minimal residual disease (MRD) positivity demonstrated worse OS (HR = 5.01; 95% CI 1.73-14.5; P = 0.003), DFS (HR = 3.25; 95% CI 1.48-7.16; P = 0.003), and CIR (HR = 2.05; 95% CI 0.78-5.39; P = 0.15). The 1-year GRFS, 1-year incidence of severe cGVHD, and 100-day incidence of grade 3-4 aGVHD was 52.6% (95% CI 43.5-63.6%), 29.5% (95% CI 20.9-38.6%), and 7.74% (95% CI 3.79-13.5%), respectively. Compared to haploidentical donors, GRFS was worse in the MUD (HR = 2.07; 95% CI 1.08-3.96; P = 0.028) but similar in MSD. This is likely driven by differences in survival and relapse, and there were no differences in the incidence of severe cGVHD or aGVHD between donor types. Multivariate analysis, which included age, MRD status pretransplant, and stage prior to transplant, demonstrated the improved predictive effect of haploidentical donors. Matched donors exhibited worse DFS (HR = 2.25; 95% CI 1.04-4.90; P = 0.04) and CIR (HR = 2.47; 95% CI 1.09-5.60; P = 0.03), with a trend towards worse OS (HR = 2.84; 95% CI 0.92-8.79; P = 0.07). Given the heterogeneity in donor-type outcomes, we conducted a subgroup analysis of the 45 haploidentical HSCT patients on the GRFS and DFS composite outcomes. After controlling for patient age, older donor age analyzed as a continuous variable was a significant predictor of worse GRFS (HR = 1.05; 95% CI 1.00-1.11; P = 0.039) but did not affect DFS. Conclusion: In a predominantly Hispanic population of ALL patients, haploidentical donors demonstrate improved OS and CIR. In those haploidentical patients, younger donor age confers improved GRFS.

Impact of Pre-Transplant Minimal Residual Disease in Patients with Multiple Myeloma with ≥ Very Good Partial Response Receiving Autologous Hematopoietic Stem Cell Transplantation

Background: Minimal residual disease (MRD) has emerged as one of the most important prognostic markers in patients with multiple myeloma (MM). However, the prognostic significance of MRD status prior to autologous hematopoietic stem cell transplantation (autoHCT) has not been clearly elucidated. Methods: In this retrospective single-center study we included adult MM patients who achieved ≥VGPR after induction therapy between 2015-2021, received an upfront autoHCT and had available data for pre-transplant MRD status by next-generation flow cytometry (NGF). The sensitivity of our assay is 1/10 -5 cells (0.001%) based on acquisition and analysis of at least 2 million events. We divided the cohort into pre-transplant MRD negative (MRDneg) and MRD positive (MRDpos) groups. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Results: A total of 734 patients were included in our analysis, 425 were MRDneg and 309 were MRDpos at autoHCT. Median age of the entire cohort was 60 (range 25-82) years and 436 (59%) were male. In the MRDpos group, more patients had high-risk cytogenetic abnormalities (48% vs. 38%, respectively; p=0.025), while fewer patients had achieved &amp;gt;CR prior to autoHCT (14% vs. 40%; p&amp;lt;0.001) (Table 1). At day 100 after autoHCT, 37% of the MRDpos achieved &amp;gt;CR vs. 71% of the MRDneg group, and at best post-transplant response 65% vs. 88% achieved &amp;gt;CR, respectively. At day 100, 16% of the patients in the MRDpos group achieved MRD negative ≥VGPR vs. 27% in the MRDneg group, and at best post-transplant response 33% vs. 37% achieved MRD negative ≥VGPR, respectively. After a median follow up of 27.6 months (0.7-82.3), the median PFS of the entire cohort was 63.4 months (95% CI 0.3-8.5), and median OS was 80.0 months (95% CI 0.3-82.3). Median PFS was significantly shorter for patients in the MRDpos group compared to MRDneg: 48.2 months (95% CI 0.3-80.5) vs. 80.1 months (95% CI 0.5-80.1), respectively; p&amp;lt;0.001 (Figure 1). There was no significant difference in OS between the two groups (p=0.41). Pre-transplant MRDpos status (HR 1.80, 95% CI 1.31-2.46; p&amp;lt;0.001) and high-risk cytogenetics (HR 1.86, 95% CI 1.32-2.61; p&amp;lt;0.001) were predictive of shorter PFS in MVA. Use of post-transplant maintenance was predictive of longer PFS (HR 0.49, 95% CI 0.34-0.69; p&amp;lt;0.001) and OS (HR 0.19, 95% CI 0.11-0.32; p&amp;lt;0.001) in MVA. In a subset analysis, pre-transplant MRD status remained highly predictive of PFS in patients with high-risk cytogenetics (HR 1.48; 95% CI 1.03-2.11; p=0.033) as well as non-high-risk cytogenetics (HR 1.75; 95% CI 1.13-2.70; p=0.012) and in patients with a response of VGPR prior to transplant (HR 1.79; 95% CI 1.33-2.42; p&amp;lt;0.001). Similarly, in patients with R-ISS stage I and II MM, pre-transplant MRD status was highly predictive of PFS [(HR 2.28; 95% CI 1.21-4.29; p=0.011) and (HR 1.73; 95% CI 1.17-2.56; p=0.006), respectively]. However, for patients with R-ISS III disease (HR 2.00; p=0.079), for patients with a response of ≥CR prior to transplant (HR=0.85; p=0.67) and for patients ≥65 years (HR=1.46; p=0.062) the pre-transplant MRD status was not significantly predictive of PFS. Conclusions: In patients achieving &amp;gt;VGPR to induction, pre-transplant MRDpos status was associated with a lower CR rate after autoHCT and a shorter PFS.

High Progression-Free Survival with Low Relapse Rates after Double-Unit Cord Blood Transplantation in Patients with High-Risk AML

Background : Double-unit cord blood transplantation (dCBT) is standard therapy for patients with acute myelogenous leukemia (AML) who do not have suitable adult donors. We &amp; others have reported low relapse rates &amp; high progression free survival (PFS) in dCBT recipients suggesting robust CB-derived graft-versus-leukemia effects. However, the efficacy of dCBT in high-risk AML as determined by ELN genetic risk &amp; pre-transplant minimal residual disease (MRD) status has not been performed to date. Methods : All consecutive adult patients with AML who received first dCBT with intermediate intensity conditioning (Cy50/ Flu150/ Thio10/ TBI400) between 2014-2022 were analyzed. GVHD prophylaxis was with either Cyclosporine-A (CSA)/ Mycophenolate Mofetil (MMF) or CSA/MMF/Tocilizumab on an institutional protocol. Results : 63 patients (pts) (median age 49 years, range 23-63) were eligible for analysis (Table); 42 (67%) were CMV seropositive, 31 (49%) had non-European ancestry, &amp; median HCT-CI was 2 (range 0-6). Most (n = 55, 87%) were in CR1, 5 (8%) in CR2, &amp; 3 were relapsed or primary refractory at transplant (5-9% blasts). By ELN2022 genetic risk criteria, 8 pts had favorable, 29 intermediate, &amp; 20 adverse risk AML (6 were missing ELN status). Of the 60 pts in CR, 36 were MRD- &amp; 18 MRD+ by multicolor flow cytometry (6 had unknown/ indeterminate MRD status). Sixty-one of 63 pts engrafted for a 60-day cumulative incidence of 98% (95%CI:81-100). The median follow-up of survivors was 58 months (range 8-104 months). The 1- &amp; 3-yr incidences of transplant-related mortality (TRM) were 13% (95%CI: 5.9-22) &amp; 18% (95%CI: 9.6-29), respectively. The 1- &amp; 3-year relapse incidences were 3.2% (95%CI: 0.6-9.9) &amp; 8.6% (95%CI: 3.1-18), respectively. The 1- &amp; 3-year OS were 87% (95%CI: 79-96) &amp; 82% (95%CI:72-92) respectively, whereas the 1- &amp; 3-year PFS were 84% (95%CI: 76-94) &amp; 73% (95%CI: 63-85), respectively. When stratified by ELN2022 genetic risk, the 3-year relapse incidence was 0% in favorable, 10% (95%CI: 2.5-25) in intermediate &amp; 13% (95%CI: 2-36%) in adverse risk AML patients. Pts with favorable risk AML had a 3-year PFS of 88% (95%CI: 67-100); the 3-year PFS was similar in patients with intermediate [68% (95%CI: 53-88)] or adverse [67% (95%CI: 48-93)] risk AML (Figure 1A). When stratified by MRD status, the 3-year relapse incidence was 8.4% (95%CI:2.1-20) in MRD- &amp; 13% (95%CI: 1.9-34) in MRD+ patients. The 3-year PFS was similar in patients with AML in CR who were MRD- 80% (95%CI: 68-94) or MRD+ 76% (95%CI: 57-100), whereas all 3 relapsed/ refractory patients died of TRM (Figure 1B). Of 4 TP53-mutated AML patients, one relapsed, one died of TRM, &amp; two are alive in remission. Conclusions: While retrospective, our findings highlight the low relapse rates &amp; promising PFS in adult AML patients, including those with high risk features such as adverse-risk ELN genetic risk &amp;/ or MRD positivity supporting robust CB-derived graft-versus-leukemia (GVL) effects. This observation, together with the mitigation of TRM in recent years due to the optimized transplant practices in adult dCBT (see Politikos et al, ASH 2023), makes intermediate intensity dCBT an attractive strategy for AML patients with a suitable dCB graft &amp; high-risk disease. Our findings warrant prospective multi-center investigation with correlative studies to elucidate the biology of CB-derived GVL.

Association of CDKN2A/2B deletion with relapse after hematopoietic stem cell transplantation for acute lymphoblastic leukemia.

The most important prognostic factor for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) is minimal residual disease (MRD). Previous studies have reported copy number variants of genes such as IKZF1, CDKN2A/2B, and PAX5. These gene mutations can be analyzed using multiplex ligation-dependent probe amplification (MLPA), which is less costly and easier to perform than large-scale gene mutation analyses. In this study, we performed copy number variant analysis of leukemia cells at the first onset of Ph+ALL in a case series of allogeneic hematopoietic stem cell transplantation (allo-HSCT) using the MLPA method. We analyzed how it influenced allo-HSCT prognosis together with MRD information. CDKN2A/2B copy number variations significantly increased the rate of post-transplant recurrence (P=0.025) and significantly reduced disease-free survival (P=0.015). Additionally, patients with IKZF1 deletions had a significantly higher post-transplant recurrence rate (P=0.042). Although they were positive for pre-transplant MRD, no relapse was observed in patients with wild-type copy number variations in IKZF1 or CDKN2A/2B. CDKN2A/2B copy number variation is a crucial factor that can be confirmed at initial onset as a post-transplant prognostic factor of Ph+ALL.

Individualized busulfan dosing improves outcomes compared to fixed-dose administration in pre-transplant minimal residual disease-positive acute myeloid leukemia patients with intermediate-risk undergoing allogeneic stem cell transplantation in CR.

Pre-transplant minimal residual disease (MRD) impacts negatively on post-transplant relapse risk in acute myeloid leukemia (AML). Therapeutic drug monitoring by calculating area under the curve (AUC) was developed to optimize busulfan (Bu) exposure. Here, we compared post-transplant outcomes after individualized versus fixed busulfan dosage in intermediate-risk AML who achieved CR prior to allograft focusing on pre-transplant flow-MRD. Eighty-seven patients (median, 56 years) with intermediate-risk AML and pre-transplant flow-MRD ("different from normal") were included. Thirty-two patients received individualized busulfan; 54 fixed dosages. Individualized dosage was adjusted in 25/32 patients: increased, n= 18/25 (72%); decreased: n= 7/25 (28%). After median follow-up of 27 months, we observed lower 3-year relapses (6%, 2%-19% vs. 35%, 23%-49% p= 0.02), improved 3-year leukemia-free survival (LFS) (78%, 54%-91% vs. 55%, 40%-70% p= 0.009) and - overall survival (OS) (82%, 60%-93% vs. 69%, 54%-81% p= 0.05) after individualized compared to fixed Bu. Non-relapsed mortality (NRM) and acute graft versus host disease (GvHD) were not different. In multivariate analysis, fixed Bu showed unfavorable impact on OS (hazard ratio [HR] 4.6, p= 0.044), LFS (HR 3.6, p= 0.018) and relapses (HR 3.6, p= 0.033). Fixed Bu also had unfavorable impact on LFS (3.6, 1.1-12.6, p= 0.041) in pre-transplant MRD-positive patients. Individualized, AUC-based, busulfan is associated with lower relapses in intermediate-risk AML patients allografted in CR and may overcome pre-transplant MRD-positivity.

ALL-228 Unfavorable Influence of Minimal Residual Disease on the Outcome of Allogeneic Hematopoietic Cell Transplantation in Acute Lymphoblastic Leukemia in the First Remission

Persistence of minimal residual disease (MRD) is the most important adverse prognostic factor for patients with acute lymphoblastic leukemia (ALL), irrespective of classical risk factors identified at onset. Detection of MRD in the post-induction phase of ALL treatment is the only generally accepted risk factor that is considered a direct indication for inclusion in the treatment of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Several studies in recent years have shown that MRD determined before transplantation may increase the risk of disease relapse in ALL patients. To assess the impact of pre-transplant MRD status determined by multiparameter flow cytometry (MFC) on the long-term results of allo-HSCT in ALL patients. The study involved 98 patients with ALL in the 1st CR (n=58) and 2nd or 3rd CR (n=40) who underwent allo-HSCT in our center from November 2015 to July 2021. The median follow-up was 11.7 (1-65.5) months. To determine MRD, 12-color MFC was performed on bone marrow samples obtained before allo-HSCT. The probabilities of OS and DFS and the probability of relapse (PR) were estimated using the Kaplan-Meier method. The Cox proportional hazards model was used to assess the influence of various independent factors (donor type, conditioning regimen, graft source, GVHD prophylaxis, pre-transplant MRD status, age) on PR. Ten patients in 1st CR and 14 patients in 2nd or 3rd CR were identified as MRD+ before allo-HSCT. OS of MRD+ patients in 1st CR did not significantly differ from MRD- patients, although it was worse (28% vs. 78%, P=0.09). Significant differences were found in the DFS of MRD+ and MRD- patients (20% vs. 56%, P=0.0317); PR was also significantly higher in MRD+ patients (73% vs. 22%, P=0.0079). OS, DFS, and PR in MRD+ and MRD-patients were comparable. In our study, the presence of MRD before allo-HSCT (HR=3.858) was an independent factor influencing the probability of relapse. MRD determined by MFC is an independent predictor of the risk of relapse after allo-HSCT in ALL patients. Detection of MRD in patients with ALL in 1st CR before allo-HSCT is necessary to stratify the risk and identify patients who need post-transplant therapy.

Impact on Outcome of Minimal Residual Disease after Hematopoietic Stem Cell Transplantation with Fludarabine, Amsacrine, and Cytosine Arabinoside-Busulfan Conditioning: A Retrospective Monocentric Study

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) after conditioning with a sequential association of fludarabine, amsacrine, and cytosine arabinoside (FLAMSA) followed by a reduced-intensity conditioning regimen has emerged for patients with high-risk acute myeloid leukemia (AML), especially in refractory or relapsing patients. Here we aimed to address retrospectively the impact of pretransplantation minimal residual disease (MRD) by flow cytometry on the outcomes of high-risk AML patients who underwent allo-HSCT after sequential FLAMSA-busulfan (FLAMSA-Bu)-based conditioning regimens. We included 165 high-risk AML patients who underwent transplantation after FLAMSA-BU in this retrospective single-center "real life" study. All patients received in vivo T cell depletion with antithymocyte globulin (5 mg/kg). MRD detection was based on a leukemia-associated immunophenotype using the European LeukemiaNet recommendations, with a threshold of .1%. Univariate and multivariate analyses were performed using R version 4.1.1 (R Foundation for Statistical Computing, Vienna, Austria). With a median follow-up of 4.0 years post-transplantation, the median overall survival (OS) was 54.9 months. Overall, 41 patients (24.8%) relapsed post-transplantation, with a resulting cumulative incidence of relapse (CIR) of 26.7% at 2 years and 34.0% at 5 years. Detectable MRD preceding allo-HSCT and refractory status were associated with worse median OS and CIR rates compared with patients without detectable MRD; however, OS was not significantly different between pre-HSCT MRD-positive and refractory patients (median, .7 year versus 2.0 years; P=.3). Conversely, pre-HSCT MRD negativity was associated with a reduced 2-year CIR. Neither European LeukemiaNet risk stratification nor age had a significant influence on OS. In the multivariate analysis, only pre-HSCT MRD positivity and lower conditioning regimen intensity were significantly associated with a poorer OS. The cumulative incidence of extensive chronic graft-versus-host disease at 2 years was 26.15%. The estimated nonrelapse mortality (NRM) of the entire cohort at 2 years was 23.1%, with age and unrelated donor identified as risk factors for higher NRM. Our data ahow that FLAMSA-Bu conditioning did not reverse the pejorative effect of detectable pre-HSCT MRD, suggesting that such patients should be offered alternative strategies before HSCT to reach deeper remission.

Pretransplantation minimal residual disease monitoring by multiparameter flow cytometry predicts outcomes of AML patients receiving allogeneic hematopoietic stem cell transplantation

Background and purposeIs minimal residual disease (MRD) monitoring by multiparameter flow cytometry (MFC) prognostic for acute myeloid leukemia (AML) patients before allogeneic hemopoietic stem cell transplantation (allo-HSCT)? And if so, what level of MRD eradication can be used to help guide the timing of HSCT? Can haplo-HSCT improve the prognosis of AML patients with MRD positive? To figure out these questions, we initiated this retrospective study. Methods96 AML patients were included retrospectively and divided into 5 groups, according to pre-transplantation MRD levels (from 5 × 10−2 to <1 × 10−4), to analyze the overall survival (OS), disease-free survival (DFS) and cumulative incidence of relapse (CIR). Secondly, we compared the prognosis of MRD-negative (MRDneg) and MRD-positive (MRDpos) AML patients (cutoff value = 1 × 10−3) who underwent allo-HSCT, and further analyzed the prognosis of MRDpos patients after received different transplantation modalities. ResultsIt is found that the 2-year OS and DFS of MRD negative group were better than the MRD positive group, and that the deeper the eradication of MRD before transplantation, the better the prognosis of patients. The CIR in patients received HLA-identical transplantation, was higher in the MRDpos than in the MRDneg. Haploid transplantation reduced the CIR disparity between MRDpos and MRDneg group. Subsequently, in AML patients who remain MRD positive before HSCT, we show that haplo-HSCT offered a better prognosis than HLA-identical transplantation (MSDT and MUDT). ConclusionIt is suggested that achieving MFC-MRD <10−3 (10−4 or even better) before allo-HSCT could reduce the relapse of AML and improve OS and DFS significantly, while haplo-HSCT may be preferred for patients not achieving MRD negativity.

A retrospective comparative study of haplotype hematopoietic stem cell transplantation and human leukocyte antigen-matched sibling donor hematopoietic stem cell transplantation in the treatment of acute B-lymphocyte leukemia

目的探讨单倍型造血干细胞移植（haplo-HSCT）治疗移植前微小残留病（Pre-MRD）阳性急性B淋巴细胞白血病（B-ALL）是否较全相合同胞造血干细胞移植（MSDT）具有生存优势，以及该作用是否受Pre-MRD的影响。方法对2009年6月至2018年6月在北京大学血液病研究所接受异基因造血干细胞移植（allo-HSCT）的998例移植前处于完全缓解（CR）的B-ALL患者进行回顾性分析，其中haplo-HSCT组788例、MSDT组210例，移植前用多参数流式细胞术（MFC）检测MRD水平。结果①全部998例B-ALL患者中，997例获得持续的完全供者嵌合状态，移植后100 d中性粒细胞、血小板植入率分别为99.9％（997/998）、95.3％（951/998），Ⅱ～Ⅳ度急性移植物抗宿主病（GVHD）发生率为26.6％（95％CI 23.8％～29.4％），3年慢性GVHD累积发生率为49.1％（95％CI 45.7％～52.4％），移植后3年白血病累积复发率（CIR）为17.3％（95％CI 15.0％～19.7％），非复发死亡率（NRM）为13.8％（95％ CI 11.6％～16.0％），移植后3年无白血病生存（LFS）率、总生存（OS）率分别为69.1％（95％CI 66.1％～72.1％）、73.0％（95％CI 70.2％～75.8％）。②Pre-MRD阳性组（282例）患者移植后3年CIR高于Pre-MRD阴性组（716例）［31.6％（95％CI 25.8％～37.5％）对14.3％（95％CI 11.4％～17.2％），P<0.001］。③在Pre-MRD阳性组中，haplo-HSCT患者（219例）移植后3年CIR低于MSDT患者（63例）［27.2％（95％CI 21.0％～33.4％）对47.0％（95％CI 33.8％～60.2％），P＝0.002］。④全部998例患者按照Pre-MRD结果分为阴性组（716例）、<0.01％组（46例）、0.01％～<0.1％组（117组）、0.1％～<1％组（87例）、≥1％组（32例）；5组患者中，<0.01％组haplo-HSCT患者（40例）移植后3年CIR低于MSDT患者（6例）［10.0％（95％CI 0.4％～19.6％）对32.3％（95％CI 0％～69.9％），P＝0.017］，0.01％～<0.1％组haplo-HSCT患者（81例）移植后3年CIR也低于MSDT患者（36例）［20.4％（95％CI 10.4％～30.4％）对47.0％（95％CI 29.2％～64.8％），P＝0.004］；其他三组中，haplo-HSCT和MSDT患者移植后3年CIR差异无统计学意义。⑤在Pre-MRD<0.1％组（163例）中，haplo-HSCT患者（121例）移植后3年CIR低于MSDT患者（42例）［16.0％（95％CI 9.4％～22.7％）对40.5％（95％ CI 25.2％～55.8％），P<0.001］，3年LFS率、OS率均高于MSDT组［78.2％（95％CI 70.6％～85.8％）对47.6％（95％CI 32.2％～63.0％），P<0.001；80.5％（95％CI 73.1％～87.9％）对54.6％（95％CI 39.2％～70.0％），P<0.001］，两组3年NRM差异无统计学意义［5.8％（95％CI 1.6％～10.0％）对11.9％（95％CI 2.0％～21.8％），P＝0.188］。多因素分析显示，haplo-HSCT是Pre-MRD<0.1％组移植后低CIR（HR＝0.248，95％CI 0.131～0.472，P<0.001）、高LFS率（HR＝0.275，95％CI 0.157～0.483，P<0.001）和高OS率（HR＝0.286，95％CI 0.159～0.513，P<0.001）的独立影响因素。结论haplo-HSCT治疗Pre-MRD<0.1％的B-ALL患者较MSDT具有生存优势。

Prognostic value of minimal residual disease before allogeneic hematopoietic stem cell transplantation in patients with acute leukemia

Introduction. One of the main causes of treatment failure after allogeneic hematopoietic stem cells transplantation (alloHSCT) for acute leukemia (AL) is disease relapse. In recent years, multiparameter fl ow cytometry (MPC) has been widely used to detect minimal residual disease (MRD) because of its capacity to identify patients with a high risk of relapse due to availability and the ability to obtain results in a timely manner.Aim — to evaluate the prognostic value of MRD status before allo-HSCT and the effect of donor type and conditioning intensity on long-term results of allo-HSCT of MOB-positive patients.Patients and methods. The analysis included 107 patients with acute myeloid leukemia (AML) and 63 patients with acute lymphoblastic leukemia (ALL) who underwent allo-HSCT between September 2015 and June 2020. All patients were in complete morphological remission before allo-HSCT. At the time of allo-HSCT 91 patients with AML and 37 patients with ALL were in the first complete remission (CR), in their second and more than two CRs were 16 and 26 patients, respectively. The median follow-up was 18 (1.5–48) months for AML and 14 (1.8–60.1) months for ALL. Immunophenotypic study was performed before allo-HSCT. MRD was detected using a combination of the “different from normal” method and the search for cells with a leukemia-associated immunophenotype.Results. The disease status at the time of transplantation and the presence of MRD before allo-HSCT were independent factors infl uencing the probability of relapse (disease status: HR = 2.911, 95% CI: 1.328–6.379; MRD before allo-HSCT: HR = 7.667, 95% CI: 3.606–16.304) and post-transplant mortality (disease status: HR = 2.911, 95% CI: 1.328–6.379; MRD before allo-HSCT: HR = 7.667, 95% CI: 3.606–16.304). In univariate analysis, the relapse-free survival of MRD+ patients with AL in the first CR was significantly worse than in MRD– (AML: 23 % versus 57 %, p &lt; 0.0001, ALL: 34 % versus 61.7 %, p = 0.0484), and the probability of relapse in MRD+ patients was significantly higher (AML: 75 % versus 12 %, p &lt; 0.0001, ALL: 57 % versus 7 %, p = 0.0072). Pre-transplant MRD status was not prognostically significant for AL-patients in the second and third remission. The development of chronic GVHD reduces post-transplant mortality if it does not require systemic therapy with glucocorticosteroids (HR = 0.006, 95% CI: 0.008–0.446).Conclusion. Testing for MRD of patients with AL in the first CR before allo-HSCT is necessary for risk stratification and identification of patients who will need preventive post-transplant therapy in order to prevent disease relapse.

Combination of NCCN Risk Stratification System and Pre-Transplant Minimal Residual Disease Levels for the Prognosis of Acute Myeloid Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation

BackgroundNumerous studies have confirmed that National Comprehensive Cancer Network (NCCN) risk stratification or pre-transplant minimal residual disease (MRD) levels can predict the risk of recurrence and survival after transplantation. But it is unclear whether combining these two parameters can more accurately predict prognosis.MethodsWe retrospectively analyzed 85 patients with acute myeloid leukemia (AML) who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) and constructed a new risk stratification tool combining NCCN risk stratification and pre-MRD levels. All patients were grouped by NCCN risk stratification (favorable/intermediate prognosis and poor prognosis group), pre-MRD levels (MRD (-) group (<0.1%) and MRD (+) group (≥0.1%)) and a combination of the above (low, intermediate and high risk groups), and graft-versus-host disease (GVHD) and prognosis were compared between groups.ResultsRelative to the favorable/intermediate prognosis group, OS and RFS were poorer in the poor prognosis group (71% vs 82%, P= .156; 60% vs 74%, P= .101) and CIR (29% vs 20%, P= .229) and NRM (23% vs 14%, P= .200) were better. The incidence of aGVHD and cGVHD was slightly lower in the favorable/intermediate prognosis group than in the poor prognosis group (38% vs 46%, P= .415; 10% vs 11%, P=. 572). Relative to the MRD (+) group, the MRD (-) group had significantly better OS and RFS (89% vs 59%, P= .002; 79% vs 50%, P= .003), lower CIR and NRM (15.1% vs 37.5%, P= .011; 11.3% vs 28%, P= .040), and a lower incidence of cGVHD (6% vs 19%, P= .022). The new risk stratification tool stratified patients into low, intermediate and high risk groups. Patients in the high-risk group had the highest incidence of aGVHD and cGVHD (42% vs 35% vs 53%, P= .606; 6% vs 11% vs 20%, P= .157). The difference in cGVHD between the low- and high-risk groups was significant (P= .038). Three-year OS was 93.9%, 70% and 60% (P= .011) and RFS was 85%, 62% and 46.7% (P= .009) for low-, intermediate- and high-risk patients, respectively. The differences in OS and RFS between the low- and intermediate-risk groups were statistically significant (P= .010; P= .025), as were the differences in OS and RFS between the low- and high-risk groups (P= .001; P= .001). Patients in the high-risk group had the highest CIR and NRM relative to those in the low- and intermediate-risk groups (9% vs 32% vs 33.3%, P= .027; 6% vs 24.3% vs 26.7%; P= .059). The differences in CIR (P= .012) and NRM (P= .028) were statistically significant in both the low-risk and intermediate-risk groups, as well as in the low- and high-risk groups (CIR: P= .028; NRM: P= .021). Multivariate analysis indicated that time to ANC recovery, time from diagnosis to transplantation, and novel risk stratification were independent prognostic factors.ConclusionsBoth pre-MRD levels and NCCN risk stratification predict AML prognosis after allo-HSCT, and combining the two can more accurately predict post-transplant prognosis. DisclosuresNo relevant conflicts of interest to declare.

The Importance of Disease Burden after Induction and Prior to Transplantation in Patients with Acute Myeloid Leukaemia Receiving Allogeneic Transplantation

Introduction: Response to chemotherapy treatment both by cytology and by more sensitive techniques such as cytometry is one of the most influential parameters in the survival of patients with Acute Myeloid Leukaemia (AML). Patients with detectable minimal residual disease (MRD) or those with active disease (AD) after induction or prior to allogeneic transplantation (HCST) represent a high-risk group.Objectives: to analyse the impact of disease burden before HSCT in terms of Overall Survival (OS) and Event Free Survival (EFS) in a group of patients who received HSCT in a single institution. We also analysed the influence of disease burden at the end of induction (considering best response after 1 or 2 cycles) and its impact on those patients in Cytological Remission (CR) with MRD <0.1% prior to transplantation.Methods: We analysed 103 patients who received HSCT in one centre between 2008 and 2020 in whom we knew disease status after induction and before HSCT. We divided the cohort into three groups according to preHSCT disease: Group 1) Patients in CR with MRD <0.1% by cytometry, Group 2) CR with MRD ≥0.1% and Group 3) patients with AD (≥5% blasts by cytology). We analysed post-transplant EFS and OS using the Kaplan Meier method and the Cumulative Incidence of Relapse (CIR) using Gray's test.Results: The baseline characteristics of the population are reflected in table 1. Median follow-up was 13 months (0-140). One-year EFS (1y-EFS) was 49%. One-year OS (1y-OS) was 57.5%, with a 1y-IAR of 27%. We first analysed the impact on post-transplant survival according to the different groups. Group 1 had significantly better EFS than Group 2 (p=0.04) and Group 3 (p<0.001) (Figure 1A). Regarding OS there was no difference between Group 1 and Group 2 (p=0.2) although it was significantly better than Group 3 (p<0.001) (Image 1B). IAR-1 was 14% vs 48% vs 50% (p<0.001) respectively. We subsequently analysed the impact on post-transplant survival according to the response to induction. Post-transplant EFS and OS were better in those in CR MRD- after induction compared to patients in CR with MRD+ (p=0.05 and p=0.002) as well as in patients with AD at the end of induction (p=0.002 and p=0.008). We stratified Group 1 according to the best response to induction (MRD- or MRD+/EA) and we performed an analysis according to the following groups: A) Patients with MRD- after induction and also before HSCT, B) Patients with MRD+/EA after induction achieving MRD- before HSCT. Comparing both groups there were no differences in either EFS (1y-EFS Group A 69% vs Group B 54%, p=0.5) or OS ( Group A 69% vs Group B 61%, p=0.8).Conclusions: Patients with pre-transplant AD or MRD+ are a high-risk group due to a high incidence of post-HSCT relapse. Although patients with AD or CR with MRD+ after induction have a worse prognosis, those who achieve MRD- before HSCT have a similar survival to the MRD- group from the start of chemotherapy. [Display omitted] DisclosuresGarcia-Gutiérrez: Pfizer: Research Funding; Bristol-Myers Squibb: Consultancy; Incyte: Consultancy; Novartis: Consultancy.

Minimal Residual Disease Prior to and After Haematopoietic Stem Cell Transplantation in Children and Adolescents With Acute Lymphoblastic Leukaemia: What Level of Negativity Is Relevant?

Minimal residual disease (MRD) assessment plays a central role in risk stratification and treatment guidance in paediatric patients with acute lymphoblastic leukaemia (ALL). As such, MRD prior to haematopoietic stem cell transplantation (HSCT) is a major factor that is independently correlated with outcome. High burden of MRD is negatively correlated with post-transplant survival, as both the risk of leukaemia recurrence and non-relapse mortality increase with greater levels of MRD. Despite growing evidence supporting these findings, controversies still exist. In particular, it is still not clear whether multiparameter flow cytometry and real-time quantitative polymerase chain reaction, which is used to recognise immunoglobulin and T-cell receptor gene rearrangements, can be employed interchangeably. Moreover, the higher sensitivity in MRD quantification offered by next-generation sequencing techniques may further refine the ability to stratify transplant-associated risks. While MRD quantification from bone marrow prior to HSCT remains the state of the art, heavily pre-treated patients may benefit from additional staging, such as using 18F-fluorodeoxyglucose positron emission tomography/computed tomography to detect focal residues of disease. Additionally, the timing of MRD detection (i.e., immediately before administration of the conditioning regimen or weeks before) is a matter of debate. Pre-transplant MRD negativity has previously been associated with superior outcomes; however, in the recent For Omitting Radiation Under Majority age (FORUM) study, pre-HSCT MRD positivity was associated with neither relapse risk nor survival. In this review, we discuss the level of MRD that may require pre-transplant therapy intensification, risking time delay and complications (as well as losing the window for HSCT if disease progression occurs), as opposed to an adapted post-transplant strategy to achieve long-term remission. Indeed, MRD monitoring may be a valuable tool to guide individualised treatment decisions, including tapering of immunosuppression, cellular therapies (such as donor lymphocyte infusions) or additional immunotherapy (such as bispecific T-cell engagers or chimeric antigen receptor T-cell therapy).

Dasatinib-based 2-step induction for adults with Philadelphia chromosome–positive acute lymphoblastic leukemia

AbstractThe standard treatment for adults with Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL) in Japan is imatinib-based chemotherapy followed by allogeneic hematopoietic stem cell transplantation (HSCT). However, ∼40% of patients cannot undergo HSCT in their first complete remission (CR1) because of chemotherapy-related toxicities or relapse before HSCT or older age. In this study, we evaluated dasatinib-based 2-step induction with the primary end point of 3-year event-free survival (EFS). The first induction (IND1) was dasatinib plus prednisolone to achieve CR, and IND2 was dasatinib plus intensive chemotherapy to achieve minimal residual disease (MRD) negativity. For patients who achieved CR and had an appropriate donor, HSCT during a consolidation phase later than the first consolidation, which included high-dose methotrexate, was recommended. Patients with pretransplantation MRD positivity were assigned to receive prophylactic dasatinib after HSCT. All 78 eligible patients achieved CR or incomplete CR after IND1, and 52.6% achieved MRD negativity after IND2. Nonrelapse mortality (NRM) was not reported. T315I mutation was detected in all 4 hematological relapses before HSCT. Fifty-eight patients (74.4%) underwent HSCT in CR1, and 44 (75.9%) had negative pretransplantation MRD. At a median follow-up of 4.0 years, 3-year EFS and overall survival were 66.2% (95% confidence interval [CI], 54.4-75.5) and 80.5% (95% CI, 69.7-87.7), respectively. The cumulative incidence of relapse and NRM at 3 years from enrollment were 26.1% and 7.8%, respectively. Dasatinib-based 2-step induction was demonstrated to improve 3-year EFS in Ph+ ALL. This study was registered in the UMIN Clinical Trial Registry as #UMIN000012173.

Pre-transplant minimal residual disease assessment and transplant-related factors predict the outcome of acute myeloid leukemia patients undergoing allogeneic stem cell transplantation.

We studied pretransplant minimal residual disease (MRD) in 224 patients (median age 44years; range 17-65) with acute myeloid leukemia (AML) undergoing allogeneic stem cell transplant (HSCT) in complete remission. MRD was evaluated on marrow samples using multicolor flow cytometry and assessment of WT1 gene expression. Both methods showed a strong prognostic value and their combination allowed the identification of three groups of patients with different risk of relapse. In multivariate analysis, combined MRD was the only predictor of cumulative incidence of relapse, regardless of donor type, conditioning regimen, first or second CR at HSCT, HSCT year, and ELN risk group. Multivariate regression model showed that only negative combined MRD status (P<.001) and myeloablative conditioning (P=.004) were independently associated with better OS. Among MRD-positive patients, a reduced incidence of relapse was observed in patients receiving haplo transplant (P<.05) and in patients who showed grade II-IV aGVHD (P<.03). In patients with negative combined MRD, the intensity of conditioning regimen did not affect the overall favorable outcome. We suggest that pretransplant MRD evaluation combined with transplant-related factors can identify AML patients at higher risk for relapse and might help in defining the overall transplant strategy.

Prognostic Significance of Minimal Residual Disease in Patients with Secondary Acute Myeloid Leukemia

BACKGROUNDSecondary acute myeloid leukemia (AML) is defined as AML that develops from a prior myelodysplastic or myeloproliferative disorder, or from exposure to chemotherapy, radiation, or environmental toxins. Patients with secondary AML have inferior prognosis compared to those with de novo AML,1 and are more likely to be elderly with increased comorbidities and worse performance status.2 The detection of minimal residual disease (MRD) also has independent prognostic value in patients with AML.3-6 In elderly AML patients, MRD predicts worse outcomes independent of the poor treatment risk factors associated with increased age.7Due to the similar disease pathogenesis between elderly AML and secondary AML patients, it is likely that MRD testing will have similar implications. However, there is limited data on the prognostic role of MRD testing in secondary AML. METHODSWe retrospectively analyzed de novo and secondary AML patients at Washington University Medical Center who received post-induction, post-consolidation, pre-transplant, or post-transplant MRD testing during their treatment. MRD testing was performed with multiparameter flow cytometry testing using the “different from normal” method at one reference laboratory,8,9 with positive MRD defined as detection of an abnormal myeloblast population above 0.1%. A total of 180 patients were included. Any patient with at least one positive MRD was considered “MRD positive.” Baseline pretreatment characteristics were compared between groups with Mann-Whitney, Chi-square, or Fisher's exact test, when appropriate. We evaluated overall survival (OS) and relapse rates in de novo and secondary AML patients stratified by MRD status using Kaplan-Meier curves and the log rank test, or cumulative incidence function, as appropriate. Multivariate Cox proportional hazards model was also fitted to determine if MRD testing has similar prognostic value across de novo and secondary AML patients. RESULTSOur analysis included 133 patients with de novo and 47 patients with secondary AML. Secondary AML patients were significantly older at age of diagnosis (mean age 59.85 versus 51.17, p<0.001), however had similar rates of MRD positivity (28% versus 29%, p=0.830). There was a trend toward poorer cytogenetic risk profiles and worse Karnofsky Performance Status in secondary AML (Table 1). In all patients, we confirmed that MRD positivity confers significantly worse OS (45.5% versus 70.8%, p=0.020) and relapse rates at 2 years (53% versus 25.5%, p=0.029) (Figure 1). In de novo AML patients, MRD positivity continued to demonstrate significantly worse 2-year OS (44.1% versus 76.3%, p=0.006) and relapse rates (57.6% versus 20.7%, p=0.008). However, in secondary AML patients, there were no differences in OS (p=0.69) or relapse rates (p=0.98) between MRD positive and negative patients. Multivariate analysis demonstrated significant interaction (p=0.042) between MRD status and AML subtypes. MRD positivity emerged as an independent prognostic indicator of worse OS in de novo patients (HR 2.8, 95% CI 1.524-5.405) but not in secondary patients (HR 1.5, 95% CI 0.188-2.336). DISCUSSIONWe confirm that MRD status is a poor prognostic indicator in all AML patients, and this also holds true in patients with de novo AML. However, we found that MRD status has less prognostic value in secondary AML patients. This may be due to the overall poor prognosis seen in secondary AML patients, suggesting that MRD monitoring in this group of patients may be less useful for risk stratification. However, our study is limited by the small sample size, particularly in the number of secondary AML patients who displayed MRD positivity (N=13). In addition, we defined MRD positivity across all time points of testing, which may decrease patient homogeneity. A larger study with increased follow-up is necessary to confirm our findings, as these results have important implications in risk-stratification and treatment of patients with secondary AML. [Display omitted] DisclosuresDiPersio:BMS, Asterias, Amphivena, Bluebird: Other: Travel, Accomodations, Expenses; Hemedicus, DAVA Oncology: Speakers Bureau; Celgene, Bioline, Vasculox, Cellworks, Rivervest: Consultancy; Magenta Therapeutics: Equity Ownership.