Pretransplant Measurable Residual Disease Research Articles

Relationship between donor source, pre-transplant measurable residual disease, and outcome after allografting for adults with acute myeloid leukemia.

Lack of HLA-matched related/unrelated donor remains a barrier to allogeneic hematopoietic cell transplantation (HCT) for adult acute myeloid leukemia (AML), with ongoing uncertainty about optimal donor type if more than one alternative donor is available. To assess the relationship between donor type, pre-HCT measurable residual disease (MRD), and post-HCT outcomes, we retrospectively analyzed 1265 myelodysplastic neoplasm (MDS)/AML and AML patients allografted in first or second remission with an HLA-matched sibling (MSD) or unrelated donor (MUD), HLA-mismatched unrelated donor (MMD), an HLA-haploidentical donor, or umbilical cord blood (UCB) at a single institution. Relapse risk was non-significantly higher after HLA-haploidentical and lower after UCB HCT. Non-relapse mortality (NRM) was significantly higher in patients undergoing MMD HCT, HLA-haploidentical HCT, and UCB, translating into significantly lower relapse-free survival (RFS) and overall survival for MMD and HLA-haploidentical HCT. There was a significant interaction between conditioning intensity and post-HCT outcomes for UCB HCT with better RFS for UCB HCT after MAC but higher NRM after non-MAC. In patients with pre-HCT MRD receiving MAC, relapse risk was significantly lower and RFS higher in those who underwent UCB HCT in comparison to MSD/MUD. Together, UCB HCT is a valuable alternative for MAC HCT, particularly in patients with pre-HCT MRD.

Measurable residual disease assessment prior to allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia and myelodysplastic syndromes: a 20-year monocentric study.

Patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) who undergo allogeneic hematopoietic stem-cell transplantation (alloHSCT) can have divergent survival outcomes while all in morphological complete remission (CR). Techniques of measurable residual disease (MRD) have allowed us to refine their prognosis in two categories: MRD-positive and MRD-negative patients. We conducted a monocentric retrospective study (01/2000-12/2020) to assess the prognosis of pretransplant MRD status measured by multiparametric flow cytometry (MFC) and molecular biology assessed by PCR. 192 patients were included. The median follow-up period was 77months. Among patients undergoing alloHSCT in CR, overall survival (median-OS: 130.6 vs. 16.0months, P < 0.001), disease-free survival (median-DFS: 109.6 vs. 7.1months, P < 0.001) and cumulative incidence of relapse (12-month CIR: 7.3% vs. 33.7%, P < 0.0001) were significantly different between MRD-negative and MRD-positive patients. Patients with discordant intermethod results had intermediate DFS. MRD-negative patients according to molecular PCR-based techniques, WT1 overexpression and MFC had longer median-DFS, compared to MRD-positive patients (P = 0.001, P < 0.001, P < 0.001, respectively). Looking into subgroups, MRD-positive patients among the ELN2017 adverse-category (P < 0.0001), myeloablative and reduced-intensity conditioning regimens (P < 0.0001, P = 0.005), < 60-year patients (P < 0.001) and AML patients (P < 0.001) were associated with lower DFS. This difference was not found in ≥ 60-year patients (P = 0.27) and MDS patients (P = 0.70). MRD-positive patients within the favorable/intermediate ELN2017 category trended toward lower DFS (P = 0.05). We confirmed that MRD status prior to alloHSCT is a strong prognostic factor for OS, DFS and CIR. Combining MFC and molecular-PCR techniques to assess MRD seems primordial as inter-method discordance can be consequential.

A Pilot Study of UM171-Expanded Cord Blood Grafts for Tandem Auto/Allogeneic Hematopoietic Cell Transplant in High and Ultra-High-Risk Myeloma Patients

Multiple myeloma (MM) remains associated with a poor outcome, particularly in patients with advanced disease and high-risk (HR) cytogenetics. To date, the only curative treatment is allogeneic (allo) hematopoietic cell transplantation (HCT), but high incidences of graft versus host disease (GVHD), non-relapse mortality (NRM) and disease progression remain important obstacles. Cord blood (CB) transplantation has been associated with low rates of relapse and chronic (c) GVHD, but its use has declined because of high incidences of infections, severe acute GVHD and high NRM. In other hematologic malignancies, UM171-expanded CB transplants have led to improved outcomes, allowing for the selection of smaller, better HLA-matched units. We aimed to investigate the safety and feasibility of single UM171-expanded single CB unit transplantation in frontline tandem auto/allo HCT for HR/ultra-HR MM patients. Newly diagnosed MM patients ≤ 65 years with an ISS stage II/III and del17p, t4,14, t14,16, t14,20, del1p or +1q, R-ISS 3, ≥ 2 cytogenetic abnormalities, or plasma cell leukemia without a sibling donor and availability of a 5-7/8 matched CB graft with ≥ 0.5 x 105 CD34+/kg and ≥ 1.5 x 107 TNCs/kg were eligible to this phase I/II prospective study (ClinicalTrials.gov NCT03441958). After induction and autologous HCT, patients received a reduced intensity conditioning regimen and were infused with 7-day UM171-expanded CD34+ cells, along with the lymphocytes contained in the CD34-negative fraction. The primary endpoints were feasibility of UM171 expansion, safety, kinetics of engraftment, incidences and maximum grades of acute and cGVHD at 1 and 2 years, assessment of measurable residual disease (MRD) and quality of life (QoL). Between 05/2018 and 11/2021, 20 patients were enrolled. One patient had an unsuccessful CB expansion with UM171, leaving 19 patients with a median age of 56 years. Median CD34+ cell dose infused after expansion was 4.62 x 106/kg (range: 0.79-5.76). Median times to achieve absolute neutrophil counts of 0.1 and 0.5 x 109/L were D+6 and D+10.5; median time to reach ≥ 20 x 109/L platelets was D+36. Full donor chimerism was achieved in all cell lineages by D+120 in recipients of reduced intensity conditioning. Cumulative incidences of grade II-IV, grade III-IV acute GVHD and moderate/severe cGVHD at 12 months were 68.4% (95% CI: 46-90), 5.3% (95% CI: 0-16%), and 10.5% (95% CI: 0-25%), respectively. With a median follow-up of 2.9 years (range: 0.46-5.3), cumulative incidences of relapse, PFS, OS and NRM at 3 years were 36.8% (95% CI: 14-59), 47.4% (95% CI: 29-76), 68.4% (95% CI: 50-93) and 15.8% (95%CI: 0-33), respectively. Median time to complete immunosuppression discontinuation was D+238. No unexpected adverse events were observed. Only one of 7 patients alive at 2 years with negative MRD at transplant has relapsed. Non-relapsing patients had a QoL after transplant similar to the general population. UM171-expanded CB transplant in HR/ultra-HR myeloma patients is feasible and allows the use of single CB units with a low risk of cGVHD. Patients with negative pre-transplant MRD might benefit most from a UM171-expanded CB transplant.

Relationship between morphologic remission with or without hematologic recovery and outcome after allogeneic hematopoietic cell transplantation in adult acute myeloid leukemia.

Outcomes of adults with AML after allografting vary widely. While numerous covariates have been associated with relapse, non-relapse mortality (NRM), and/or shorter survival, the impact of incomplete blood count recovery before transplantation has remained unclear. To address this uncertainty, we examined all adults with AML or MDS/AML who received an allograft in first or second remission between 2006 and 2023 at a single institution. Of 1264 patients, 891 (70%) met criteria for CR, whereas 291 (23%), 24 (2%), and 58 (5%) were classified as CRh, CRi, and morphologic leukemia-free state (MLFS), respectively. CR, CRh, CRi, and MLFS patients differed significantly regarding demographics, disease biology, pre-transplant measurable residual disease, and types of transplants. After multivariable adjustment, outcomes for CRh and CRi patients were not significantly different from each other or from those of CR patients. In contrast, outcomes of MLFS patients were substantially worse than those of CR and CRh patients, with significantly higher risk of NRM and relapse, and significantly shorter relapse-free and overall survival. Similar results were obtained in several distinct subsets. Together, our analysis provides empiric evidence for the importance of distinguishing MLFS from CR and CRh patients for optimized risk assessment and, possibly, individualized treatment decision making.

Prognostic impact of number of induction courses to attain complete remission in patients with acute myeloid leukemia transplanted with either a matched sibling or human leucocyte antigen 10/10 or 9/10 unrelated donor: An Acute Leukemia Working Party European Society for Blood and Marrow Transplantation study.

For the majority of patients with acute myeloid leukemia (AML) an allogeneic stem cell transplant (SCT) in first complete remission (CR) is preferred. However, whether the number of courses required to achieve CR has a prognostic impact is unclear. It is unknown which factors remain important in patients requiring more than one course of induction to attain remission. This Acute Leukaemia Working Party study from the European Society for Blood and Marrow Transplantation identified adults who received an allograft in first CR from either a fully matched sibling or 10/10 or 9/10 human leucocyte antigen (HLA)-matched unrelated donor (HLA-A, HLA-B, HLA-C, HLA-DR, or HLA-DQ). Univariate and multivariate analyses were undertaken to identify the prognostic impact of one or two courses of induction to attain CR. A total of 4995 patients were included with 3839 (77%) patients attaining a CR following one course of induction chemotherapy (IND1), and 1116 patients requiring two courses (IND2) to attain CR. IND2 as compared to IND1 was a poor prognostic factor in a univariate analysis and remained so in a multivariate Cox model, resulting in an increased hazard ratio of relapse (1.38; 95% confidence interval [CI], 1.16-1.64; p=.0003) and of death (1.27; 95% CI, 1.09-1.47; p=.002). Adverse prognostic factors in a multivariate analysis of the outcomes of patients requiring IND2 included age, FLT3-ITD, adverse cytogenetics, and performance status. Pretransplant measurable residual disease retained a prognostic impact regardless of IND1 or IND2. Initial response to chemotherapy as determined by number of courses to attain CR, retained prognostic relevance even following SCT in CR.

Evaluation of the Impact of the Disease Risk Index and Pre-Transplant Measurable Residual Disease By Flow Cytometry As Prognostic Factors in Allogeneic Hematopoietic Cell Transplantation in Patients with Acute Myeloid Leukemia

Introduction: Allogeneic hematopoietic cell transplantation (HCT) is the therapy with the best curative potential for patients with intermediate/high-risk acute myeloid leukemia (AML). Although many factors may influence the outcomes of allogeneic HSCT, risk stratification and disease status at the time of transplant are two of the strongest prognostic factors of post-transplant survival². In this context, the Disease Risk Index (DRI) was developed and validated in a cohort of more than 13.000 patients and stratifies patients into 4 groups with different overall survivals (OS)². Measurable residual disease (MRD) is also an important and consolidated biomarker for the prognosis, monitoring, and treatment effectiveness evaluation³. Objective: To compare the impact of the pre-transplant DRI and MRD in patients with AML in OS and leukemia-free survival of patients treated with allogeneic HSCT in a private institution in Brazil from January 2017 to May 2023. Methods: This is a retrospective, unicentric study. MRD was evaluated immediately before transplantation by 10-color flow cytometry and was considered positive if ≥0.1%. DRI was grouped into two groups: low/intermediate risk and high/very high risk. Statistical analyzes were performed using the Cox regression model. Results: With a median follow-up of 18 months, a total of 57 patients were included, 34 of whom had negative MRD and 23, positive. The mean ages in these groups were 55 and 60 years, respectively. HCT-CI was 0-2 in 91% of the patients in the MRD-negative group, and in 78% of the MRD-positive group. The type of donors was similar in both group (MRD positive or negative): 20-30% of related donors, 25-40% of haploidentical and 40-45% unrelated donors. The reduced-intensity conditioning regimen (RIC) was the used in 70% of the patients. In the MDR + group, peripheral stem cell source was more used than in the MDR negative group. In univariate analysis, DRI had an impact on overall survival (OS) with an HR=3.52 (95%CI 1.46 - 8.5) and p=0.075 for low/intermediate risk compared with high/very high risk, while in the multivariate analysis this impact was not maintained with HR=2.31 (95%CI 0.92 - 5.82) and p=0.075. A pre-transplant positive MRD was a risk factor for death in univariate analysis, with an HR=5.99 (95%CI 2.93- 26.82) and p&amp;lt;0.001. The impact of MRD HR 8.87 (2.93 - 26.83) and p &amp;lt; 0.001, age HR 1.09 (1.04 - 1.15) with p = 0.001 and bone marrow source HR 0.29 (0.08 - 1.06) are prognostic factors even when controlled for age, cell source and type of transplant. One-year overall survival in the MRD-negative group was 90% (79-100%), and 53% (36-80%) in the MRD-positive group. Additionally, one-year leukemia-free survival in the MRD-negative group was 70% (55-89%) and 45% (28-72%) in MRD-positive. Conclusion: Our results show that both DRI and pre-transplant MRD may have an impact on OS and LFS, although pre-transplant MRD seemed to perform better than DRI in multivariable analysis in patients with acute myeloid leukemia undergoing hematopoietic cell transplantation.

Impact of Pre-Transplant Molecular and Cytogenetic Remission on Outcomes of Allogeneic Stem Cell Transplant in Patients with Myelodysplastic Syndrome

Background: Allogeneic stem cell transplant (allo-SCT) carries a high relapse rate (~35% within 2 years) in patients (pts) with myelodysplastic syndrome (MDS). Pre-transplant measurable residual disease (MRD) increases the risk of relapse and death in acute myeloid leukemia (Thol et al, Blood 2018). However, the impact of pre-transplant MRD on post-transplant outcomes is less clear in MDS. Prior studies have compared outcomes between myeloablative (MAC) and reduced intensity conditioning (RIC) in pts with pre-transplant MRD persistence based on either cytogenetic remission alone or ultra-deep genomic sequencing with a limited 10-gene panel, suggesting reduced risk of relapse in pts receiving MAC (Festuccia et al, Biol Blood Marrow Transplant 2016; Dillon et al, JCO PO 2021). However, pre-transplant MRD assessment using a commercial next-generation sequencing (NGS) panel in addition to cytogenetic testing to assess post-transplant outcomes has not been evaluated in MDS. Methods: We conducted a multicenter retrospective review of MDS pts who underwent allo-SCT from 2015-2022. Pts with FISH/cytogenetic (FC) and/or molecular abnormalities at diagnosis and MRD assessment by commercial myeloid-panel NGS (with a variant-allele frequency detection limit up to 5%) and FC performed on peripheral blood (PB) or bone marrow (BM) aspirate within 3 months prior to transplant were included for analysis. The Kaplan-Meier method and log-rank tests were used to estimate overall survival (OS). Gray's test/cumulative incidence functions were used to estimate relapse-free survival (RFS) with non-relapse mortality (NRM) as competing risk. Results: Table 1 includes baseline pt characteristics. Of 81 pts, 69 pts (85.2%) had residual FC and/or molecular abnormalities (MRD+) at pre-transplant PB/BM assessment. Twelve (14.8%) pts were in both FC and molecular remission (MRD-) prior to transplant. With a median follow-up of 13.9 months [IQR 6.8 - 38.9], 43 (53%) died and 24 (30%) pts experienced a relapse. Twenty-three of 69 (33%) MRD+ pts had relapsed disease with a 38% cumulative incidence of relapse (CIR) at 2 years. In contrast, only 1/12 (8.3%) MRD- pts experienced a relapse after 7 years, with chromosomal loss of TP53 not present at initial diagnosis. CIR at 2 years was 33% and 41% (p=0.207) for MRD+ pts who received MAC vs RIC, respectively with NRM of 34.5% associated with MAC vs 28.2% for RIC (p=0.61). TP53 mutations were most frequently associated with relapse in 8/24 (33%) pts with a median OS of 9.8 months [8.2 - NR]. Besides the previously defined 10-gene panel (Dillon et al, JCO PO 2021), relapses were also driven by SRSF2, U2AF1, KRAS, SETBP1 and NF1 mutations present in the original clone. Six pts had DNMT3A, TET2 and/or ASXL1 (DTA) mutations only on pre-transplant NGS, with 2/6 pts relapsing without the re-emergence of DTA mutations. Median OS was not reached for MRD- pts and was 14.1 months [11.35-NR] for MRD+ pts, p = 0.061 [Fig.1]. OS probability at 2 years was 35% for MRD+ pts vs 75% for MRD- pts. Type of conditioning regimen, RIC vs MAC, did not impact OS (p= 0.6). An equal number of deaths, 35% each, were attributable to GvHD and relapse, respectively. Thirteen (30%) pts died from other causes, primarily infections and bleeding complications. NRM was 25% and 36% for MRD- and MRD+ cohorts, respectively. Pts received a median of 6 cycles [range, 2-36] of hypomethylating agent (HMA) +/- venetoclax prior to transplant with no association between the number of cycles and MRD status (p=0.80). The incidence of grade 3-4 acute GvHD and chronic GvHD requiring systemic therapy did not significantly differ, at 25% and 18.8% (p= 0.696) and 33.3% and 31.8% (p= 1.00) in MRD+ and MRD- pts, respectively. Conclusions: MRD assessment using commercially available NGS panels and cytogenetic testing that are routinely performed in MDS pts in real-world practice can predict risk of relapse. Pre-transplant MRD is associated with worse OS irrespective of the intensity of conditioning regimen. Although limited in statistical power due to a small sample size of MRD- pts in our cohort, further studies with a larger cohort are underway to better clarify the role of MRD on transplant outcomes in MDS. Our data also highlights that only a small minority of MDS pts (&amp;lt;15%) achieve complete molecular and cytogenetic remission at the time of transplant; strategies to eliminate the pre-transplant MDS clone are urgently needed.

Pre-Transplant Measurable Residual Disease (MRD) Detection of KMT2A-rearranged Acute Myeloid Leukemia Is Strongly Associated with Inferior Post-Transplant Outcome

Introduction KMT2A-rearranged ( KMT2Ar ) acute myeloid leukemia (AML) is associated with inferior survival and allogeneic hematopoietic cell transplant (HCT) in first remission (CR1) is an important post-remission objective (Issa et al, Blood Cancer Journal 2021). Despite HCT, however, the relapse risk is ~50% (Menghrajani et al, Blood Adv. 2022). Several small cohort studies have described the prognostic utility of pre-HCT MRD assessment using real-time reverse transcription quantitative polymerase chain reaction (RT-qPCR), but currently, this is not standard practice (Scholl et al, Haematologica 2005; Huang et al, Med Sci Monitor 2016; Liu et al, Biol Blood Marrow Transplant 2014; Heuser et al, Blood 2021). A significant barrier to widespread implementation of KMT2A::X MRD monitoring is the presence of diverse fusion-partner genes and varied breakpoint regions. The potential to detect and pre-emptively target pre-HCT KMT2A::X MRD has relevance with the development of menin inhibitors, which have been shown to be active in the clinic (Issa et al, Nature 2023). In the current work, we report the prognostic impact of pre-HCT KMT2A::X MRD detection by RT-qPCR and the relationship with post-HCT outcome in adults with KMT2Ar AML. We also describe a novel 3 common primer/probe KMT2A::X reverse transcription digital PCR (RT-dPCR) MRD assay as a simplified dPCR alternative to MRD monitoring. Methods Archived pre-HCT cDNA were available from 54 patients treated in the UK (including UK NCRI AML17 and AML19) and Australia. Samples were analyzed by RT-qPCR using previously described methods in 45 patients (Abildgaard et al, Eur J Haematol. 2013), and RT-dPCR in 9 patients (Ivey, unpublished 2023). The RT-dPCR method, which uses a common 3 primer/probe set to capture breakpoints within KMT2A obviating the need for fusion-gene specific plasmid standards, showed high concordance with RT-qPCR across 20 samples (R 2=0.9915) . Copy numbers were expressed per 100 ABL copies. Assay sensitivity was ~0.001%. Survival outcomes were estimated using the Kaplan-Meier method for relapse-free survival (RFS, date of HCT to relapse or death from any cause) and overall survival (OS, date of HCT to death or last follow-up). Cox proportional hazards was used to assess variables impacting RFS and OS. Categorical variables were calculated using Fisher exact test and continuous variables using Mann-Whitney-U test. The study was approved by human research ethics committees (AUS 21/26; UK 14/WA/1056, NC10.13). Results A total of 54 patients with KMT2Ar AML underwent HCT between 2010-2022. Median age was 43 years (range, 17-70), 63% were female, 94% had de novo AML, all had received prior intensive chemotherapy and 76% were transplanted in CR1, 50% with myeloablative conditioning. KMT2A::X subtypes included t(9;11)/ KMT2A::MLLT3 in 35%, t(6;11)/ KMT2A::AFDN in 26%, t(11;19)/ KMT2A::ELL in 13% and KMT2A::MLLT1 in 5%, t(10;11)/ KMT2A::MLLT10 in 17% and other rare KMT2A::X variants in 4%. Pre-HCT MRD was detected (MRD-pos) in 46% of patients (25 of 54) at a median level of 0.3 copies/100ABL (range, 0.006-35.0394). The frequency of post-HCT relapse was significantly higher in patients with RT-qPCR/RT-dPCR levels ≥0.01% pre-HCT (68% relapsed vs 24% if MRD-neg, p=0.002) (Figure 1). Median time to relapse was 4.7 months (range, 0.8-22.5), with 100% of patients (22 of 22 with available molecular status at relapse) retaining the KMT2A::X variant at relapse. With median follow-up time of 37 months, pre-HCT KMT2A::X MRD-pos was associated with significantly inferior 2-year RFS (19% vs. 63%, p=0.0013) (Figure 2) and 2-year OS (47% vs. 69%, p=0.031). On univariate analysis, variables associated with inferior RFS were pre-HCT MRD-pos status (hazard ratio (HR) 3.2 [95% confidence interval (CI) 1.5-6.9], p=0.002) and transplant in second remission vs. CR1 (HR 2.6 [95% CI 1.2-5.5], p=0.01), however, pre-HCT MRD-pos status was the only variable associated with inferior RFS on multivariate analysis (HR 2.8 [95% CI 1.3-6.1], p=0.01). Conclusions Pre-HCT KMT2A::X MRD detection by RT-qPCR and RT-dPCR is a robust prognostic indicator of post-transplant relapse and inferior survival outcome. Targeting patients with KMT2A::X MRD positive disease pre-HCT using novel menin inhibitors is currently the subject of an enrolling clinical trial (AMLM26 INTERCEPT) (ACTRN12621000439842).

Posttransplant MRD and T-cell chimerism status predict outcomes in patients who received allografts for AML/MDS.

Allogeneic stem-cell transplant allows for the delivery of curative graft-versus-leukemia (GVL) in patients with acute myeloid leukemia/myelodysplasia (AML/MDS). Surveillance of T-cell chimerism, measurable residual disease (MRD) and blast HLA-DR expression may inform whether GVL effectiveness is reduced. We report here the prognostic impact of these biomarkers in patients allografted for AML/MDS. One hundred eighty-seven patients from FIGARO, a randomized trial of reduced-intensity conditioning regimens in AML/MDS, were alive and relapse-free at the first MRD time-point and provided monitoring samples for flow cytometric MRD and T-cell chimerism, requested to month+12. Twenty-nine (15.5%) patients had at least 1 MRD-positive result posttransplant. MRD-positivity was associated with reduced overall survival (OS) (hazard ratio [HR], 2.18; P= .0028) as a time-varying Cox variable and remained significant irrespective of pretransplant MRD status in multivariate analyses (P< .001). Ninety-four patients had sequential MRD with T-cell chimerism results at months+3/+6. Patients with full donor T-cell chimerism (FDTC) had an improved OS as compared with patients with mixed donor T-cell chimerism (MDTC) (adjusted HR=0.4; P=.0019). In patients with MDTC (month+3 or +6), MRD-positivity was associated with a decreased 2-year OS (34.3%) vs MRD-negativity (71.4%) (P= .001). In contrast, in the group with FDTC, MRD was infrequent and did not affect the outcome. Among patients with posttransplant MRD-positivity, decreased HLA-DR expression on blasts significantly reduced OS, supporting this as a mechanism for GVL escape. In conclusion, posttransplant MRD is an important predictor of the outcome in patients allografted for AML/MDS and is most informative when combined with T-cell chimerism results, underlining the importance of a GVL effect in AML/MDS.

Application of prophylactic or pre-emptive therapy after allogeneic transplantation for high-risk patients with t(8;21) acute myeloid leukemia

ABSTRACTObjectivesTo determine the impact of pretransplant measurable residual disease (pre-MRD) and the efficacy of maintenance therapy in t(8;21) acute myeloid leukemia (AML) patients after allogeneic hematopoietic cell transplantation (allo-HCT).MethodsWe retrospectively analyzed 100 t(8;21) AML patients who underwent allo-HCT between 2013 and 2022. 40 patients received pre-emptive therapy including immunosuppressant adjustment, azacitidine, and donor lymphocyte infusion (DLI) combined with chemotherapy. 23 patients received prophylactic therapy, including azacitidine or chidamide.ResultsPatients with a positive pre-MRD (pre-MRDpos) had a higher 3-year cumulative incidence of relapse (CIR) (25.90% [95% CI, 13.87%–39.70%] vs 5.00% [95% CI, 0.88%–15.01%]; P = 0.008). Pre-MRDpos patients were less likely to have a superior 3-year disease-free survival (DFS) (40.83% [95% CI, 20.80%–80.16%]) if their MRD was still positive at 28 days after transplantation (post-MRD28pos). The 3-year DFS and CIR were 53.17% (95% CI, 38.31% – 73.80%) and 34.87% (95% CI, 18.84% – 51.44%), respectively, for patients receiving pre-emptive interventions after molecular relapse. The 3-year DFS and CIR were 90.00% (95%CI, 77.77% – 100%) and 5.00% (95%CI, 0.31% – 21.10%), respectively, for high-risk patients receiving prophylactic therapy. In most patients, epigenetic-drug-induced adverse events were reversible with dose adjustment or temporary discontinuation.ConclusionPatients with pre-MRDpos and post-MRD28pos were more likely to have higher rates of relapse and inferior DFS, even after receiving pre-emptive interventions. Prophylactic therapy may be a better option for high-risk t(8;21) AML patients; however, this warrants further investigation.

Impact of measurable residual disease on outcomes of unrelated donor haematopoietic cell transplantation with post-transplant cyclophosphamide in AML in first complete remission.

Pre-transplant measurable residual disease (MRD) predicts relapse and outcome of allogeneic haematopoietic cell transplantation (allo-HCT). The impact of MRD on the outcomes of post-transplant cyclophosphamide (PTCy)-based allo-HCT from a matched unrelated donor (UD) is unknown. This study assessed the impact of MRD in acute myeloid leukaemia (AML) in the first complete remission (CR1). A total of 272 patients (MRD negative [MRD-], n= 165; MRD positive [MRD+], n= 107) with a median follow-up of 19 (range: 16-24) months were studied. The incidence of grades II-IV and grades III-IV acute GVHD at day 180 was 25.2% and 25% (p= 0.99), and 10.6% and 6.8% (p= 0.29), respectively, and 2-year chronic GVHD was 35% and 30.4% (p= 0.96) in MRD+ and MRD- cohorts, respectively. In multivariate analysis, MRD+ status was associated with a higher incidence of relapse (RI) (hazard ratio [HR]=2.56, 95% CI: 1.39-4.72), lower leukaemia-free survival (LFS) (HR=2.04, 95% CI: 1.23-3.39), overall survival (OS) (HR=1.83, 95% CI: 1.04-3.25) and GVHD-free, relapse-free survival (GRFS) (HR=1.69, 95% CI: 1.10-2.58). MRD status did not have a significant impact on non-relapse mortality (NRM), or acute or chronic GVHD risk. Among patients with AML undergoing UD allo-HCT with PTCy, pre-transplant MRD+ status predicted a higher relapse rate, lower LFS, OS and GRFS.

128 - Pre-Transplant Measurable Residual Disease By Next-Generation Sequencing Is a Better Predictor of Relapse Compared to BCR-ABL PCR in Adult Patients with Ph+ Acute Lymphoblastic Leukemia

128 - Pre-Transplant Measurable Residual Disease By Next-Generation Sequencing Is a Better Predictor of Relapse Compared to BCR-ABL PCR in Adult Patients with Ph+ Acute Lymphoblastic Leukemia

Transplant in AML with measurable residual disease: proceed or defer?

Allogeneic stem cell transplantation plays a central role in the management of fit adults with high-risk acute myeloid leukemia (AML) in first complete morphologic remission (CR1). Advances in both donor selection and transplant technology have both dramatically increased accessibility of transplant and led to significant reductions in transplant-related mortality over the past 2 decades. There has, however, been no concomitant reduction in the risk of disease relapse, which remains the major cause of transplant failure. Pivotal to the design of innovative strategies with the potential to reduce relapse risk is accurate identification of patients at the highest risk of disease recurrence. Multiple retrospective studies have identified an increased risk of disease relapse in patients allografted for AML in CR1 with evidence of pretransplant measurable residual disease (MRD). The prognostic significance of pretransplant MRD has been confirmed recently in prospective analyses. The optimal management of patients with evidence of pretransplant MRD remains a matter of conjecture with regard to 2 key issues. First, should the presence of pretransplant MRD delay a decision to proceed to transplant, allowing time for delivery of additional MRD-directed therapy prior to transplant? Second, to what extent can the intensity of the conditioning regimen or the magnitude of the graft-vs-leukemia effect be manipulated to improve the outcome of such patients?

The Impact of Maintenance Therapy Post Allogeneic Hematopoietic Cell Transplantation on Survival Outcomes in Patients Diagnosed with Acute Myeloid Leukemia and Persistent Measurable Residual Disease: A Retrospective Cohort

Background: Despite achieving complete remission with standard chemotherapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT), patients with acute myeloid leukemia (AML) are still at high risk of transplant failure due to disease relapse. Maintenance therapy post allo-HSCT including hypomethylating agents or FLT3 inhibitors is implemented in our institutional guidelines to mitigate this risk. Moreover, measurable residual disease (MRD) status of patients is considered an important independent marker of disease prognosis, in which a detectable MRD status pre-transplant is associated with poorer long-term outcomes. Objective: The aim of this research is to evaluate the impact of maintenance therapy post allo-HSCT on the survival outcomes of transplanted patients based on their pre-transplant MRD status. Methods: We performed a retrospective chart review for a total of 108 adult patients diagnosed with AML and who had undergone allo-HSCT at our center between 2015 and 2021. We estimated both overall survival (OS) and relapsed free survival (RFS) using Kaplan Meier curves from the time of transplant among patients who received maintenance treatment based on their MRD status pre-transplant. MRD status was determined using either multiparametric flow cytometry, next-generation sequencing, and/or RT-PCR. Results: The median age at transplant was 47 years, 60% (n=65) of the patients were males. 66.7% of the patients had an intermediate disease risk index score. 25.2%, 61.8% and 13% of the patients had favorable, intermediate and adverse ELN risk respectively. Among the 108 patients, 77 received maintenance therapy post-transplant, of which 36 patients had a detectable pre-transplant MRD and 41 patients did not. Maintenance therapy consisted mainly of low dose hypomethylating agent (HMA) azacitidine in 68.8% (n=53) of the patients, followed by tyrosine kinase inhibitors (TKI) in 18.2% (n=14) of the patients, and a combination of HMA with TKI, and/ or a BCL2 inhibitor in 13% (n=10). Median duration of maintenance was 20.7 months (range: 0.1-84.2 months). Among patients who received maintenance therapy (n=77), there were no statistically significant difference in both OS and RFS based on MRD status pre-transplant, (4-year OS: 76% versus 63%, p=0.6; 4-year RFS: 63% versus 57%, p=0.53). Conclusions: Our analysis showed no significant difference in survival outcomes of patients receiving maintenance therapy post allo-HSCT based on their pre-transplant MRD. Maintenance treatment could overcome the negative predictive value of detectable MRD to be confirmed by larger prospective studies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

TBI-Based Myeloablative Conditioning Prior to Haploidentical Versus Matched Donor Transplantation for Acute Lymphoblastic Leukemia

Data from the CIMBTR has previously demonstrated the non-inferiority of transplantation from a haploidentical donor (HAPLO) using post-transplant cyclophosphamide (PTCy) vs. matched related (MRD) or unrelated donors (MUD) for acute lymphoblastic leukemia (ALL) (Wieduwilt et al. Blood Advances 2022). However, total body irradiation (TBI)-containing myeloablative conditioning (MAC) was used in less than 60% of MRD/MUD patients and in approximately 40% of HAPLO patients. We aimed to better define the role of donor type (HAPLO vs. MRD/MUD) following TBI-MAC-based allogenic transplant for ALL. To this end, we analyzed 105 consecutive ALL patients receiving a first allogeneic transplant at our institution following TBI-MAC from an MRD [30], MUD [24] or HAPLO [51] donor between Jan 2011 to Sept 2021. HAPLO patients received a preparative regimen of fludarabine (90mg/m2) and TBI 1200 cGy, followed by post-transplant cyclophosphamide (PTCy), tacrolimus and mycophenolate mofetil. MRD/MUD patients received TBI 1200 cGy with either Cy (120mg/kg, n= 33) or etoposide (60mg/kg, n=21), followed by tacrolimus and methotrexate for GVHD prophylaxis. Baseline characteristics include a median age of 40 (range, 29-51) years, HCT-CI ≥3 in 53%, poor risk cytogenetics in 60% (Ph+ [37%], Ph-like [11%], complex karyotype [7%] and 11q23 translocation [5%]). PBSC was the graft source in 94%. Pre-transplant status was CR1, CR2/3, or PIF/relapse in 75%, 12% and 13% respectively. Pre-transplant measurable residual disease (MRD) was seen in 28%). Baseline demographics of HAPLO and MRD/MUD recipients were similar with the exception of race/ethnicity, where HAPLO recipients (vs. MRD/MUD) were significantly less likely to be non-Hispanic White (29% vs. 67%). Comparison of baseline disease characteristics revealed more T-cell lineage disease (27% vs. 4%) and less poor risk cytogenetics (47% vs. 72%) in HAPLO vs. MRD/MUD recipients, respectively. After a median follow-up of 70 months (range, 8-134), 5-yr overall survival (OS), disease-free survival (DFS), cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) for the whole cohort was 62%, 54%, 29% and 18% respectively, with no significant differences between HAPLO and MRD/MUD transplants (see figure). In multivariable analysis, controlling for other significant covariates (race, pre-transplant disease status and pre-transplant MRD), donor type (HAPLO vs. MRD/MUD) did not have a significant impact on OS (HR 1.04, p=0.91)) or DFS (HR 0.99, p=0.97)). TBI-MAC-based HAPLO represents a favorable alternative donor source with comparable long-term DFS and OS. This is of particular importance to patients of racial/ethnic minorities, whereby rapid and practically universal access to a HAPLO donor allows for curative-intent therapy in the vast majority of high-risk ALL patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Prognostic Significance of Measurable Residual Disease for Patients with Acute Lymphoblastic Leukemia Undergoing Allogeneic Stem Cell Transplant in Second Complete Remission and Beyond

Introduction: For patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (HCT) in first complete remission (CR1), measurable residual disease (MRD) prior to HCT is strongly associated with post-HCT relapse rates and overall survival (OS). However, for a growing number of patients with ALL, HCT is deferred until the second remission (CR2) or beyond. It is unclear whether pre-transplant MRD assessment is also prognostic in the setting of HCT beyond CR1. Methods: We performed a single center retrospective study to test the hypothesis that pre-transplant MRD positivity is associated with outcomes in patients receiving HCT in CR2 or beyond for ALL. MRD was measured by 6-color flow cytometry with a sensitivity of 0.01%. Consecutive pediatric and adult patients who underwent first allogeneic HCT between the years 2004-2021 for ALL in CR2 or beyond were included. Results: We identified 162 patients (Table 1), 123 (76%) with B-ALL and the remainder with T-ALL. The majority (80%, n=129) of patients were in CR2 at the time of HCT, the remainder in third CR or beyond (CR3+). One hundred and five (65%) patients were male and median age at transplant was 31 (range 4-69) years. Graft source was either matched unrelated donor (MUD) (43%, n=69), matched sibling donor (MSD) (24%, n=39), haploidentical (18%, n=29) or cord blood transplantation (CBT) (15%, n=25). Pre-HCT MRD status was determined for 150 (93%) of patients and of those was positive in 43 (26%). Subsequent analyses were limited to the subset of patients with known MRD status. There was no statistical difference in characteristics according to MRD status except for higher proportion of CR3+ patients (33% vs. 16%, p=0.02) and comorbidity index >2 (70% vs. 40%, p=0.001) in MRD positive vs. negative patients. The median follow-up in surviving patients was 62 (range 20-104) and 47 (range: 2-171) months in MRD positive and negative patients, respectively. In multivariate analysis (MVA) evaluating transplantation outcomes at 3 years, pre-HCT MRD positivity was associated with a higher rate of disease relapse (HR 1.9, 95% CI 1.1-3.6; p=0.02); but it had no impact on non-relapse mortality (NRM) (HR 0.8, 95% CI 0.4-1.8; p=0.6). Subset analyses showed that these trends were consistent for patients receiving HCT in CR2 or CR3+; however the impact on disease relapse was more pronounced for patients in CR2 at HCT. MRD positivity was also associated with less favorable overall (HR 1.96, 95% CI 1.2-3.3; p=0.01) and progression-free survival (PFS) (HR 2.5, 95% CI 1.5-4.2; p<0.001) for patients receiving HCT in CR2. MRD was not associated with OS (HR 0.9, 95% CI 0.4-2, p=0.8) or PFS (HR 0.8, 95% CI 0.3-1.7, p=0.5) for patients receiving HCT in CR3+. As shown in Figure 1 A-B, OS and PFS were significantly superior for MRD negative patients receiving HCT in CR2. OS and PFS for MRD positive patients in CR2 were comparable to patients receiving HCT in CR3+. Conclusions: Pre-transplant MRD positivity is predictive of disease relapse in patients undergoing HCT for ALL in CR2 or beyond; however, the survival advantage associated with MRD negativity maybe limited to patients undergoing HCT in CR2. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Maintenance Therapy with Venetoclax/Azacitidine Can be Safely Given after Venetoclax/FluBu2 RIC Allogeneic Transplantation for the Treatment of High Risk MDS/AML: Results of a Phase 1 Study

Background: Relapse is the main cause of transplant failure. We previously reported safety and durable remissions with venetoclax (Ven) added to fludarabine/busulfan (FluBu2) reduced intensity conditioning allogeneic hematopoietic cell transplantation (HCT) without planned maintenance therapy in patients (pts) with high risk myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML) (Garcia, Blood Advances, 2021). Detectable measurable residual disease (MRD) at day +100 frequently resulted in relapse after transplant. To address relapse risk after VenFluBu2 transplant in this high risk population, we assessed the safety and activity of Ven/Azacitidine (VenAza) maintenance therapy. Methods: In a Phase 1 trial (NCT03613532), pts with an 8/8 HLA-matched donor and diagnosis of AML with <5% blasts (ELN adverse, secondary, or flow MRD positive) or MDS/MPN or MDS with ≥10% blasts (secondary, IPSS higher risk, or TP53mut or RAS pathway mutations) received VenFluBu2 (Ven 400 mg on D-8 to D-2; fludarabine 30 mg/m2/d on D-5 to D-2; IV busulfan 0.8 mg/kg bid on D-5 to D-2), followed by PBSC infusion (D0) and tacrolimus/methotrexate GVHD prophylaxis. Between D42-D90, VenAza maintenance therapy (Ven 400 mg on D1-D14 and Aza 36 mg/m2 IV on D1-D5) was initiated in pts who engrafted and had no evidence of morphologic relapse or uncontrolled GVHD in 42-day (dose level 1) or 28-day (dose level 2) cycles for up to 1 year. DLT was defined as Gr 4 neutropenia/thrombocytopenia >2 wks. Clinical NGS (sensitivity 1-3%) was performed before and after HCT (+28, +100). BH3 profiling analysis was performed on 11 paired blood samples before/after cycle 1 of VenAza. Results: As of 6/2022, 27 pts were enrolled and had the following disease status at time of HCT: 10 AML pts (8 CR, 2 CRi); 16 MDS pts (1 CR, 5 marrow CR (mCR) with hematologic improvement (HI), 5 mCR without HI, 1 HI-erythroid alone, and 4 active disease (5-10% blasts)); and 1 MDS/MPN pt in CR. Pts had a median age of 67y (range 47,78), co-morbidities (52% HCT-CI≥4), 44% were flow MRD negative, and 56% had Ven exposure prior to HCT. Baseline TP53mut was present in 59% (16/27). After VenFluBu2 RIC HCT, 22 of 27 pts received VenAza maintenance therapy (n=11 per dose level); remaining 5 of 27 pts did not (3 relapsed early, 2 withdrew). No DLTs were observed. The most common grade 3-4 treatment emergent adverse events (AE) during maintenance were anemia (45%), neutropenia (95%) and thrombocytopenia (91%), which were mainly transient. Cycle 1 nadir occurred on D29 for ANC (median 1.2 K/µL, range 0,3.7) and on D15 for platelet (median 119 K/µL, range 70,169). Infection during maintenance was reported in only 1 pt (n=1 BK viruria). Serious AEs were reported in 2 (1 rash; 1 BK case). Median of 4 VenAza cycles were received in DL1 (range 1,8); DL2 on-going. Cumulative incidence of grade ≥2 acute GVHD at 6 mo was 22% (95% CI: 9,39) and chronic GVHD at 1y was 23% (95% CI: 8,42). With a median 12 mo follow up (range 4-21), regardless of maintenance status, 1y OS, PFS, NRM and relapse were 70% (95% CI: 46,85), 57% (95% CI: 36,74), 0% and 43% (95% CI: 28,57), respectively. To date, 12 of 27 pts have relapsed (4 before, 7 during, and 1 after maintenance on D523). Ven use prior to HCT did not impact outcome. Pre-transplant flow MRD negativity was associated with improved 1y OS (88% vs 50%, p=0.03) and 1y PFS (81% vs 39%, p=0.08). Flow MRD was positive in 17% (4/24) at D28 and in 44% (11/25) at D100. At time of HCT, NGS was positive in 89% (24/27), but this reduced to 42% (10/24) at D28 and 58% (14/24) at D100 (Figure 1). PFS was similar for those with or without TP53mut at HCT (p=0.14). Among 22 pts that received VenAza maintenance therapy, 1y PFS and 1y OS were 65% (95% CI: 40,82) and 79% (95% CI: 52,92), respectively. BH3 profiling did not reveal any significant changes in baseline apoptotic priming in CD3+, CD3+CD4+, CD3+CD8+ T cells, and CD3+CD4+CD127-CD25+ Treg cells, suggesting VenAza was not cytotoxic to T cells. Flow cytometry to assess for immune recovery is in process. Conclusions: VenAza maintenance therapy after VenFluBu2 RIC alloHCT appears to be safe with low infection rate and no excessive GVHD. This Ven-based peri-transplant strategy for high risk MDS/AML pts has encouraging activity though relapses still occurred. A cohort assessing all oral maintenance (Ven plus decitabine/cedazuridine) is enrolling. A randomized trial will be required to evaluate the benefit of Ven with conditioning chemotherapy or with maintenance therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Presence of Measurable Residual Disease in NPM1 Positive AML in Remission Pre-Transplant Does Not Impact on Survival after Allogeneic Hematopoietic Stem Cell Transplantation

Due to their biological and clinical features, acute myeloid leukemia (AML) with Nucleophosmin-1 (NPM1) gene mutations represents a distinct entity within the WHO classification 2022. As per ELN classification, they are mainly categorized either as favorable or intermediate-risk disease, and as such patients are referred for allogeneic hematopoietic stem cell transplantation (allo-HSCT) at disease relapse, during CR1 or, less frequently, due to primary refractoriness. However, even when transplanted, relapse remains the most common cause of treatment failure. Besides conditioning intensity, presence of measurable residual disease (MRD) at time of allo-HSCT has recently been shown to be associated with an increased risk of relapse post-transplant. Yet, the reported effect might vary according to genetic and immunophenotypic diversity of the disease, transplant setting and MRD technology used. Here, we aim to determine the impact of NPM1 presence assessed via qPCR on post allo-HSCT outcomes. This retrospective study included adult AML patients harboring an NPM1 mutation (NPM1mut) who received a first allo-HSCT between January 2011 and January 2022 at four German transplant centers. NPM1 mutation status was assessed at diagnosis, and monitored throughout the treatment course by qPCR. NPM1 MRD monitoring was performed as previously described (Papadaki et al., 2009, sensitivity of 10−6). MRD status pre-transplant was correlated with outcome. There were no restrictions regarding donor type or conditioning intensity We identified 161 adult AML patients with available pre-transplant MRD status. Median age of the entire cohort was 55 years (21-75). The majority of patients (86%) had cytogenetically normal AML and presented in hematologic remission (CR1, CR2) (69%) at time of allo-HSCT. Whereas NPM1mut was measurable in all patients with active disease, 85/111 (77%) patients in remission had either NPM1mut persistence after antecedent induction/consolidation therapy (n=68) or molecular relapse (n=17). Conditioning intensity used was RIC in 57, MAC in 12, sequential-RIC in 88 and sequential-MAC in 4 patients. Most patients (n=90) were transplanted from matched unrelated donor (matched related: n=37, haploidentical: n=34), using preferentially PBSCs as graft source (n=146). At a median follow-up of 28 months (3-127), the estimated probability of OS and LFS at 2 years was 63% and 55%, respectively. When patients are stratified into groups with active disease, vs NPM1+CR vs NPM1- CR, 2-year OS and LFS show a significant difference (45% vs. 73% vs. 71%; p=0.002 and 55% vs. 62% vs. 67% p=0.005, respectively). Yet, if considering only patients in remission, no survival difference according to NPM1-MRD status at transplantation was detected (OS, p=0.49 and LFS, p=0.33). Likewise, cumulative incidence of relapse at 2 years was 44%, 15% and 17% (p=0.001); however among remission patients there was no significant difference between MRD+ and MRD- patients before allo-HSCT (p=0.96). CI of NRM at 1-year was 14%, 18% and 8% for non-CR, NPM1+ CR and NPM1- CR patients (p=0.9). Intriguingly, MRD positivity as assessed per qPCR at time of transplant did not impact on post-transplant outcome in our cohort of NPM1 positive AML. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Effects of CD34+ cell dose on haematopoietic recovery in acute lymphoblastic leukaemia patients with positive pretransplant measurable residual disease.

A higher CD34+ cell dose in allografts is associated with faster haematopoietic recovery after allogeneic haematopoietic stem cell transplantation (allo-HSCT). Leukaemia stem cells impair normal bone marrow (BM) niches and induce BM failure during leukemogenesis. However, whether measurable residual disease (MRD), known as the persistence of low-level leukaemic cells, could influence the effects of CD34+ cell dose on haematopoietic recovery after transplantation in acute lymphoblastic leukaemia (ALL) patients is unknown. A total of 975 ALL patients were enrolled and classified into pre-HSCT MRD-positive and MRD-negative subgroups. Cox proportional hazard regression models were built for time-to-event outcomes. Multivariate analysis was performed to determine independent influencing factors from the univariate analysis. An appropriate CD34+ cell dose was positively associated with faster haematopoietic recovery in the total ALL population. More importantly, in pre-HSCT MRD-positive ALL patients, a higher CD34+ cell dose (≥2.76 × 106 /kg) was related to faster neutrophil (HR 1.330, 95% CI 1.045-1.692, p=0.021) and platelet engraftment (HR 1.808, 95% CI 1.412-2.316, p < 0.001) in multivariate analysis. CD34+ cell dose was a crucial factor associated with either engraftment or transplant outcomes, although we did not demonstrate direct correlations of CD34+ cell dose with relapse, TRM, LFS or OS after allo-HSCT. Our results indicated that no additional CD34+ stem and progenitor cell harvests were needed to ensure successful haematopoietic recovery in pre-HSCT MRD-positive patients compared to pre-HSCT MRD-negative patients.

Clinical Impact of Measurable Residual Disease in Acute Myeloid Leukemia.

Simple SummaryAdvances in immunophenotyping and molecular techniques have allowed for the development of more sensitive diagnostic tests in acute leukemia. These techniques can identify low levels of leukemic cells (quantified as 10−4 to 10−6 ratio to white blood cells) in patient samples. The presence of such low levels of leukemic cells, termed “measurable/minimal residual disease” (MRD), has been shown to be a marker of disease burden and patient outcomes. In acute lymphoblastic leukemia, new agents are highly effective at eliminating MRD for patients whose leukemia progressed despite first line therapies. By comparison, the role of MRD in acute myeloid leukemia is less clear. This commentary reviews select data and remaining questions about the clinical application of MRD to the treatment of patients with acute myeloid leukemia.Measurable residual disease (MRD) has emerged as a primary marker of risk severity and prognosis in acute myeloid leukemia (AML). There is, however, ongoing debate about MRD-based surveillance and treatment. A literature review was performed using the PubMed database with the keywords MRD or residual disease in recently published journals. Identified articles describe the prognostic value of pre-transplant MRD and suggest optimal timing and techniques to quantify MRD. Several studies address the implications of MRD on treatment selection and hematopoietic stem cell transplant, including patient candidacy, conditioning regimen, and transplant type. More prospective, randomized studies are needed to guide the application of MRD in the treatment of AML, particularly in transplant.