Abstract
Background:
Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a key treatment for acute myeloid leukemia (AML). Measurable residual disease (MRD) predicts post-transplant outcomes. This study evaluates the impact of pre-transplant MRD status on outcomes in AML patients undergoing allo-HCT.
Methods:
We retrospectively analyzed AML patients who underwent allo-HCT from matched related or unrelated donors (2013–2018) using the CIBMTR P-5646 dataset. Patients were stratified by pre-transplant MRD status. Outcomes included overall survival (OS), disease-free survival (DFS), relapse, non-relapse mortality (NRM), acute graft-versus-host disease (aGVHD), GVHD-free relapse-free survival (GRFS), and engraftment. Hazard ratios (HR) with 95% confidence intervals (CI) were calculated using multivariate Cox regression, adjusted for significant univariate variables (p<0.05).
Results:
Of 2404 AML patients (354 MRD-positive, 2050 MRD-negative), MRD-positive patients had lower Karnofsky performance status (≥90%: 46.1% vs. 55.1%, p=0.004) and more myeloablative conditioning (66.6% vs. 52.7%, p<0.001). MRD positivity predicted worse OS (HR 1.91, 95% CI 1.62–2.23, p<0.001), DFS (HR 2.05, 95% CI 1.77–2.36, p<0.001), relapse (HR 2.25, 95% CI 1.91–2.64, p<0.001), aGVHD grade II–IV (HR 1.24, 95% CI 1.03–1.50, p=0.024), GRFS (HR 1.59, 95% CI 1.41–1.81, p<0.001), and slower platelet engraftment (HR 0.71, 95% CI 0.63–0.81, p<0.001). NRM (p=0.387) and neutrophil engraftment (p=0.159) were similar.
Conclusion:
Pre-transplant MRD status is predictive of post-allo-HCT outcomes, with MRD positivity correlating with decreased overall and disease-free survival and a higher incidence of relapse regardless of conditioning regimen intensity. Strategies to eradicate MRD before allo-HCT may improve outcomes in AML patients undergoing allogeneic transplantation.
Keywords: Allogeneic Hematopoietic Cell Transplantation, Acute Myeloid Leukemia, Outcomes, Minimal Residual Disease
INTRODUCTION
Allogeneic hematopoietic stem cell transplantation (allo-HCT) has become a cornerstone in the treatment of acute myeloid leukemia (AML), with a steadily increasing number of patients undergoing this life-saving procedure [1]. Despite significant advancements in AML therapy, relapse remains a major concern, particularly among high-risk groups [2]. It also remains the primary cause of treatment failure and mortality among allo-HCT recipients for AML, highlighting the need for vigilant monitoring of minimal or measurable residual disease (MRD) status post-transplant to detect early signs of relapse [16]. Pre-transplant MRD is associated with an elevated risk of post-transplant relapse, regardless of the patient’s early MRD status after the transplant. In addition, the assessment of MRD status in AML patients post-transplant has proven to be a critical predictor of relapse and carries significant prognostic implications for survival [3, 4]. A study by Zhou et al. found that patients with pre-transplant MRD-positivity had a significantly lower three-year overall survival rate (OS) of approximately 25%, compared to around 60% for MRD-negative patients. The study also found that MRD-positive patients could achieve MRD negativity within 28 days with intensive conditioning regimens; however, despite this temporary clearance, their overall long-term outcomes remained poor [5]. The two most common methods for measuring MRD are quantitative polymerase chain reaction (qPCR) and multiparameter flow cytometry (MFC) [6]. Furthermore, next-generation sequencing (NGS) and digital PCR may enhance current MRD detection capabilities [7, 8]. While qPCR is highly sensitive, it only applies to about 50% of AML patients with specific molecular markers [9]. In contrast, MFC is more widely applicable, covering up to 90% of cases. MFC can detect subclinical levels of leukemic cells before relapse, allowing for timely interventions to improve patient survival [10, 11].
We investigated the impact of pre-transplant MRD status on post-transplant outcomes in AML patients undergoing allo-HCT, including OS, relapse, disease-free survival (DFS), graft-versus-host disease (GVHD) and non-relapse mortality (NRM), utilizing a large cohort from the CIBMTR database.
METHODS
Study Design and Settings:
This retrospective multicenter study analyzed data collected by the Center for International Blood and Marrow Transplant (CIBMTR) using the publicly available P-5646 dataset by Ramathan et al. The analysis included patients diagnosed with AML who underwent allo-HCT from matched related or matched unrelated donors between 2013 and 2018, utilizing any conditioning regimen, graft source, or GVHD prophylaxis regimen.
Data Collection:
Data were collected for baseline demographic and clinical characteristics and stratified based on pre-transplant MRD status. Baseline demographic and clinical characteristics included age, year of transplant, gender, ethnicity, race, cytogenetics, graft type, human leukocyte antigen (HLA) match, Karnofsky Performance Status (KPS), cytomegalovirus (CMV) status, hematopoietic cell transplantation comorbidity index (HCT-CI), conditioning regimen i.e., myeloablative conditioning (MAC) or reduced-intensity/non-myeloablative conditioning (RIC/NMAC), and GVHD prophylaxis approach. The CIBMTR dataset did not specify the MRD assessment methods (e.g., MFC, NGS, qPCR), the sample source (bone marrow vs. peripheral blood), or the sensitivity levels.
Outcomes:
The study assessed post-transplant outcomes, including OS, DFS, NRM, infection-related mortality (IRM), acute and chronic GVHD, GVHD-free relapse-free survival (GRFS), and neutrophil and platelet engraftment. NRM was defined as death from causes other than disease relapse or progression. IRM was defined as mortality attributable to infections post-transplant. Acute GVHD was graded according to the Mount Sinai Acute GVHD International Consortium (MAGIC) criteria, while chronic GVHD was graded using the 2014 National Institute of Health (NIH) criteria [21, 22].
Statistical Analysis:
Baseline demographics for the two MRD groups were evaluated using descriptive analysis. The chi-square test was used to compare categorical variables, while a t-test was used to compare continuous variables. Univariate Cox regression analysis was conducted to estimate significant factors for OS, DFS, relapse, NRM, IRM, aGVHD, cGVHD, GRFS, neutrophil engraftment, and platelet engraftment. Multivariable Cox regression was utilized to calculate hazard ratios (HR) with 95% confidence intervals (CI) for OS, DFS, NRM, IRM, aGVHD, cGVHD, GRFS, platelet, and neutrophil engraftment, comparing the MRD negative versus positive groups, adjusting for significant variables identified in the univariate analyses. The Kaplan-Meier curve was obtained for overall and disease-free survival stratified by MRD status. Data were analyzed using R version 4.16. Statistical significance was considered at p<0.05.
RESULTS
The study included a total of 2404 AML patients, comprising 354 (14.7%) MRD-positive and 2050 (85.3%) MRD-negative patients who underwent allo-HCT. The median age was 57.85 years (range, 18.05–81.54), with 54.1% of the patients being male. Most patients were Caucasian (84.3%). The primary graft source was peripheral blood stem cells (83.8%) and bone marrow (16.1%). Karnofsky’s performance status of 90% or higher was observed in 53.9% of the patients. HCT-CI score of 3 or more was noted in 52.1% of patients. Over half (54.7%) of patients received myeloablative conditioning. GVHD prophylaxis regimens included ex-vivo CD34 selection (3.1%), post-transplant cyclophosphamide-based (13.9%), calcineurin inhibitor-based (82%), and others (0.8%). The MRD-positive cohort was more likely to have poor-risk cytogenetics (p < 0.001), poor performance status (p = 0.004), and myeloablative conditioning (p < 0.001). All other baseline characteristics were balanced between the groups. [Table 1]
Table 1:
Demographic and clinical characteristics of allogeneic HCT recipients with AML stratified by MRD status
| Characteristics | Total= 2404 | MRD+= 354 | MRD−= 2050 | p-value |
|---|---|---|---|---|
| Age (median) | 57.85 (18.05–81.54) | 58.48 (19.82–81.54) | 57.62 (18.05–79.83) | 0.309 |
| Age | ||||
| 18–39 | 410(17.1) | 57(16.1) | 353 (17.2) | 0.637 |
| 40–64 | 1395(58) | 202(57) | 1193(58.1) | |
| >/ 65 | 599(24.9) | 95(26.8) | 504(24.5) | |
| Year of transplant | ||||
| 2013 | 205(8.5) | 21(5.9) | 184(8.9) | 0.163 |
| 2014 | 635(26.4) | 107(30.2) | 528(25.7) | |
| 2015 | 562(23.3) | 83(23.4) | 479(23.3) | |
| 2016 | 477(19.8) | 63(17.7) | 414(20.1) | |
| 2017 | 311(12.9) | 52(14.6) | 259(12.4) | |
| 2018 | 214(8.9) | 28(7.9) | 186(9.0) | |
| Gender | ||||
| Male | 1302(54.1) | 202(57.1) | 1100(53.6) | 0.259 |
| Female | 1102(45.8) | 152(42.9) | 950(46.3) | |
| Ethnicity | ||||
| Hispanic | 2229 (92.7) | 327(92.3) | 1902(92.7) | 0.907 |
| Non-Hispanic | 116(4.8) | 18(5.1) | 98(4.7) | |
| Race | ||||
| Caucasian | 2028(84.3) | 295(83.3) | 1733(84.5) | 0.494 |
| African American | 151(6.2) | 20(5.6) | 131(6.3) | |
| Asian | 149(6.1) | 28(7.9) | 121(5.9) | |
| Others | 17(0.7) | 2(0.6) | 15(0.7) | |
| BMI | ||||
| <18.5 | 298(12.39) | 37(10.4) | 261(12.7) | 0.173 |
| 18.5–24.5 | 697(28.9) | 118(33.3) | 579(28.2) | |
| 25–29 | 726(30.1) | 112(31.6) | 614(29.9) | |
| 29–33 | 328(13.6) | 48(13.5) | 334(16.2) | |
| >33 | 300(12.47) | 39(11.0) | 261(12.7) | |
| Cytogenetics | ||||
| Favorable | 116(4.8) | 9(2.5) | 107(5.2) | <0.001 |
| Intermediate | 1423(59.1) | 176(49.7) | 1247(60.8) | |
| Poor | 756(31.4) | 149(42.1) | 607(29.6) | |
| Graft type | ||||
| Bone marrow | 389(16.1) | 61(17.2) | 328(17.4) | 0.615 |
| Peripheral Blood | 2015(83.8) | 293(82.7) | 1722(84.0) | |
| HLA match | ||||
| Match related/twins | 1026(42.6) | 144(40.6) | 882(43.0) | 0.444 |
| 8/8 unrelated | 1378(57.3) | 210(59.3) | 1168(56.9) | |
| KPS | ||||
| <80 | 405(16.8) | 66(18.6) | 339(16.5) | 0.004 |
| 80–90 | 686(28.5) | 123(34.7) | 563(27.4) | |
| >=90 | 1296(53.9) | 163(46.1) | 1133(55.2) | |
| Gender match | ||||
| Male-Male | 867(36.1) | 133(37.5) | 734(35.8) | 0.603 |
| Male-Female | 680(28.2) | 90(25.4) | 590(28.7) | |
| Female-Male | 431(17.9) | 68(19.2) | 363(17.7) | |
| Female-Female | 419(17.4) | 61(17.2) | 358(17.4) | |
| CMV match | ||||
| +/+ | 779(32.4) | 107(30.2) | 672(32.7) | 0.601 |
| +/− | 237(9.8) | 39(11.0) | 198(9.6) | |
| −/+ | 768(31.9) | 119(33.6) | 649(31.6) | |
| −/− | 535(22.2) | 74(20.9) | 461(22.4) | |
| HCTCI | ||||
| 0 | 388(16.1) | 53(14.9) | 335(16.3) | 0.761 |
| 1–2 | 762(31.6) | 108(30.5) | 654(31.9) | |
| 3–4 | 758(31.5) | 114(32.2) | 644(31.4) | |
| 5+ | 496(20.6) | 79(22.3) | 417(20.3) | |
| Conditioning | ||||
| Myeloablative | 1317(54.7) | 236(66.6) | 1081(52.7) | <0.001 |
| RIC/NMA | 1087(45.2) | 118(33.3) | 969(47.2) | |
| ATG/CAMPATH | ||||
| ATG alone or Alemtuzumab alone | 527(21.9) | 81(22.8) | 446(21.7) | 0.700 |
| No ATG or Alemtuzumab | 1873(77.9) | 273(77.1) | 1600(78.0) | |
| GVHD prophylaxis | ||||
| Ex-vivo CD34 selection | 76(3.1) | 9(2.5) | 67(3.2) | 0.233 |
| PT-Cy based | 336(13.9) | 59(16.6) | 277(13.5) | |
| CNI based | 1972(82.1) | 285(80.1) | 1687(82.2) | |
| Others | 20(0.8) | 1(0.2) | 19(0.9) |
Abbreviations -
MRD: measurable residual disease, HCT: Hematopoietic Cell Transplantation, AML: Acute Myeloid Leukemia, BMI: Body Mass Index, HLA: Human Leukocyte Antigen, CMV: Cytomegalovirus, HCT-CI: HCT-specific Comorbidity Index, KPS: Karnofsky Performance Status, RIC/NMA: Reduced-Intensity Conditioning/Non-Myeloablative Conditioning, ATG: Anti-Thymocyte Globulin, GVHD: Graft-Versus-Host Disease, PT-Cy: Post-Transplant Cyclophosphamide, CNI: calcineurin inhibitor (Tacrolimus, Cyclosporine A)
The median follow-up (95% CI) was 14.2 months (95% CI 1.4–69.7). Median OS was 11.5 months (95% CI 9.3–15.9) in the MRD-positive group compared to 44.8 months (95% CI 41.2–52.2) in the MRD-negative group (p<0.001). [Figure 1] Median DFS was 4.8 months (95% CI 3.7–6.0) in the MRD-positive group and 24.4 months (95% CI 20.1–29.1) in the MRD-negative group (p<0.001). [Figure 2] Median GRFS was 9.4 months (95% CI 7.4–11.8) in the MRD-positive group and 23.5 months (95% CI 21.1–24.0) in the MRD-negative group (p<0.001). The one-year OS, DFS, and GRFS rates were significantly higher in the MRD-negative group, with 71% for OS, 57% for DFS, and 19.6% for GRFS, compared to 49%, 34%, and 9.5%, respectively, in the MRD-positive group (all p<0.001). The relapse rate was significantly higher in the MRD-positive compared to the MRD-negative group (60% vs. 37%, p<0.001). Median platelet engraftment occurred at 19 days in the MRD-positive group and 17 days in the MRD-negative group (p=0.045). Acute GVHD rate was slightly higher, although not statistically significant, in the MRD-positive compared to the MRD-negative group (42% vs. 37%, p=0.063). The chronic GVHD rate was lower in the MRD-positive group compared to the MRD-negative group (37.0% vs. 45%, p = 0.006). IRM was higher in the MRD-positive compared to the MRD-negative group (4% vs. 2%, p=0.041). There was no difference in NRM (14% vs. 15%, p=0.794) or neutrophil engraftment (15 vs. 14 days, p=0.570). [Table 2]
Figure 1: Impact of measurable residual disease on overall survival after allogeneic hematopoietic cell transplantation in acute myeloid leukemia patients.
Figure 2: Impact of measurable residual disease on disease-free survival after allogeneic hematopoietic cell transplantation in acute myeloid leukemia patients.
Table 2:
Outcomes of allogeneic HCT recipients with AML stratified by MRD status
| Outcome | Total | MRD + | MRD − | p-value |
|---|---|---|---|---|
| Median follow-up (95% CI) | 14.2 (1.35,69.70) | 9.31 (0.87,49.09) | 16.48 (1.45,59.92) | <0.001 |
| Overall survival (OS) | ||||
| n (%) | 1334(55.4) | 134(37.8) | 1200(58.5) | <0.001 |
| Median (95% CI) | 38.5 (35.10,43.62) | 11.48 (9.27,15.92) | 44.80 (41.18,52.20) | <0.001 |
| 1-year OS, n (%) | 1628(67.7) | 173 (49) | 1454 (70.9) | <0.001 |
| Disease free survival (DFS) | ||||
| n (%) | 1056(43.9) | 89(25.1) | 967(47.1) | <0.001 |
| Median (95% CI) | 17.24 (3.45,30.68) | 4.79 (3.71,5.98) | 24.4 (20.1–29.1) | <0.001 |
| 1-year DFS, n (%) | 1322 (55) | 122 (34.4) | 1201 (58.6) | <0.001 |
| GVHD-free Relapse-free Survival (GRFS) | ||||
| n (%) | 339(14.1) | 19(5.3) | 320(15.6) | <0.001 |
| Median (95% CI) | 19.9 (16.3,22.8) | 9.41 (7.43,11.84) | 23.49 (21.1,24.01) | <0.001 |
| 1-year GRFS, n (%) | 435 (18.1) | 34 (9.5) | 402 (19.6) | <0.001 |
| Relapse, n (%) | 975(40.5) | 213(60.1) | 762(37.1) | <0.001 |
| Non-relapse mortality (NRM), n (%) | 361(15.0) | 51(14) | 310(15.1) | 0.794 |
| Acute GVHD grade II-IV, n (%) | 905(37.6) | 148(41.8) | 757(36.9) | 0.063 |
| Chronic GVHD, n (%) | 1055(43.8) | 131(37.0) | 924(45.1) | 0.006 |
| Neutrophil engraftment | ||||
| n (%) | 2364(98.3) | 347(98.0) | 2017(98.3) | 0.866 |
| Median (95% CI) | 14 (1,25) | 15 (9,27) | 14 (1,27) | 0.57 |
| Platelet engraftment | ||||
| n (%) | 2281(94.8) | 317(89.5) | 1964(95.8) | <0.001 |
| Median (95% CI) | 18 (1,82) | 19 (1,130) | 17 (1,75) | 0.045 |
| Infection-related mortality (IRM), n (%) | 61(2.5) | 15(4.2) | 46(2.2) | 0.041 |
Abbreviations - MRD: measurable residual disease, HCT: hematopoietic cell transplantation, AML: acute myeloid leukemia, GVHD: acute graft versus host disease
In multivariable analysis after adjusting for significant variables identified in the univariate analyses, MRD-positive, compared to MRD-negative status, independently predicted OS (HR 1.91, 95% CI 1.62–2.235, p<0.001), DFS (HR 2.05, 95% CI 1.77–2.36, p<0.001), GRFS (HR 1.59, 95% CI 1.41–1.81, p<0.001), and relapse (HR 2.25, 95% CI 1.91–2.64, p<0.001). Higher rates of IRM (HR 2.76, 95% CI 1.51–5.06, p=0.001), acute GVHD grade II-IV (HR 1.24, 95% CI 1.03–1.50, p=0.024) and slower platelet engraftment (HR 0.71, 95% CI 0.63–0.81, p<0.001) were noted in the MRD-positive compared to MRD-negative group. Neutrophil engraftment (HR 0.92, 95% CI 0.81–1.03, p=0.159), NRM (HR 1.15, 95% CI 0.84–1.57, p=0.387), and chronic GVHD (HR 1.20, 95% CI 0.99–1.45, p=0.067) did not significantly differ between MRD-positive compared to MRD-negative groups. [Table 3]
Table 3:
Multivariable regression analyses for outcomes of allogeneic HCT recipients with AML stratified by MRD status
| Outcome | HR, 95% CI | p-value |
|---|---|---|
| OS*A | 1.91 (1.62–2.235) | <0.001 |
| DFS*B | 2.05 (1.77–2.36) | <0.001 |
| GRFS*C | 1.59 (1.405–1.805) | <0.001 |
| Relapse*D | 2.25 (1.91–2.64) | <0.001 |
| NRM*E | 1.15 (0.839–1.57) | 0.387 |
| IRM*F | 2.76 (1.51–5.06) | <0.001 |
| Acute GVHD grade II-IV*G | 1.24 (1.03–1.5) | 0.024 |
| Chronic GVHD*H | 1.20 (0.99–1.45) | 0.067 |
| Neutrophil engraftment*I | 0.92 (0.814–1.03) | 0.159 |
| Platelet engraftment*J | 0.71 (0.629–0.81) | <0.001 |
Abbreviations - OS: overall survival, DFS: disease-free survival, NRM: non-relapse mortality, IRM: infection related mortality, GVHD: graft versus host disease
adjusted for age, ethnicity, cytogenetics, KPS, CMV match, HCTCI, conditioning
adjusted for age, cytogenetics, KPS, HCTCI, conditioning
adjusted for age, cytogenetics, graft type, HLA match, KPS, HCTCI, conditioning, ATG, GVHD prophylaxis
adjusted for cytogenetics, KPS, HCTCI, conditioning
adjusted for age, gender, ethnicity, cytogenetics, HLA match, KPS, gender match, HCTCI, conditioning
adjusted for age, cytogenetics, HLA match, gender match, HCTCI, conditioning,
adjusted for ethnicity, BMI, cytogenetics, HLA match, CMV match, HCTCI, conditioning, ATG, GVHD prophylaxis
adjusted for age, cytogenetics, graft type, gender match, conditioning, ATG, GVHD prophylaxis
adjusted for BMI, cytogenetics, graft type, HLA match, KPS, conditioning, ATG, GVHD prophylaxis
adjusted for age, cytogenetics, graft type, KPS, conditioning, ATG, GVHD prophylaxis
adjusted for age, cytogenetics, graft type, HLA match, KPS, HCTCI, conditioning, ATG, GVHD prophylaxis
We also investigated the impact of conditioning intensity on post-transplant outcomes. In adjusted multivariable analysis including all patients (n=2404), MAC independently predicted lower relapse (HR 0.87, 95% CI 0.76–0.99, p=0.045), higher grade II-IV acute GVHD (HR 1.31, 95% CI 1.13–1.51, p<0.001) and faster neutrophil engraftment (HR 1.87, 95% CI 1.27–1.51, p<0.001) compared to RIC. OS (HR 0.99, 95% CI 0.86–1.14, p=0.906), DFS (HR 0.89, 95% CI 0.78–1.01, p=0.070), NRM (HR 1.03, 95% CI 0.81–1.32, p=0.815), IRM (HR 1.04, 95% CI 0.58–1.87, p=0.900), chronic GVHD (HR 1.13, 95% CI 0.98–1.31, p=0.107), platelet engraftment (HR 0.92, 95% CI 0.84–1.02, p=0.104) and GRFS (HR 1.05, 95% CI 0.95–1.72, p=0.314) did not significantly between the groups. In adjusted multivariable analysis including only MRD-positive patients (n=354), MAC did not impact any of the post-transplant outcomes, including OS (HR 0.94, 95% CI 0.71–1.25, p=0.660), DFS (HR 0.66, 95% CI 0.40–1.08, p=0.100), Relapse (HR 0.94, 95% CI 0.70–1.27, p=0.704), NRM (HR 0.71, 95% CI 0.38–1.34, p=0.294), IRM (HR 0.57, 95% CI 0.21–1.57, p=0.273), acute GVHD grade II-IV (HR 0.90, 95% CI 0.64–1.26, p=0.532), chronic GVHD (HR 0.83, 95% CI 0.57–1.12, p=0.311), neutrophil engraftment (HR 1.205, 95% CI 0.96–1.15, p=0.109), platelet engraftment (HR 1.14, 95% CI 0.90–1.44, p=0.276) and GRFS (HR 0.829, 95% CI 0.65–1.05, p=0.117). In adjusted multivariable analysis including only MRD-negative patients (n=2050), MAC independently predicted lower relapse (HR 0.84, 95% CI 0.73–0.97, p=0.021), higher acute grade II-IV GVHD (HR 1.37, 95% CI 1.18–1.59, p< 0.001), higher chronic GVHD (HR 1.20, 95% CI 1.03–1.40, p=0.017), faster neutrophil engraftment (HR 1.39, 95% CI 1.27–1.52, p<0.001), and inferior GRFS (HR 1.12, 95% CI 1.01–1.26, p=0.041). Other post-transplant outcomes including OS (HR 0.987, 95% CI 0.838–1.16, p=0.879), DFS (HR 0.903, 95% CI 0.78–1.04, p=0.159), NRM (HR 1.15, 95% CI 0.88–1.50, p=0.296), IRM (HR 1.46, 95% CI 0.76–2.80, p = 0.258) and platelet engraftment (HR 0.927, 95% CI 0.83–1.03, p=0.164) did not differ between the two groups.
DISCUSSION
This study builds on previous findings in the literature to examine the impact of minimal residual disease status on post-transplant outcomes. Our analysis demonstrated a significant effect of MRD status on relapse rates, as well as overall and disease-free survival. Several studies have consistently shown that MRD positivity is associated with decreased overall survival, reduced disease-free survival, and increased relapse rates. For example, a comprehensive meta-analysis by Buckley et al. confirmed these findings across various cohorts, concluding that MRD-positive patients had substantially poorer outcomes than MRD-negative patients [12]. One of the most striking results was the significantly higher relapse rate observed in the MRD-positive group. In our cohort, the relapse rate for MRD-positive patients was 57%, compared to 37% for MRD-negative patients. This finding is consistent with previous research demonstrating that pre-transplant MRD positivity is a strong predictor of post-transplant relapse, further underscoring the importance of MRD as a key prognostic marker.
Interestingly, despite the known benefits of myeloablative conditioning regimens, our study found that the MRD-positive group had a higher proportion of patients receiving these intense regimens than the MRD-negative group. However, this increased intensity did not overcome the negative impact of MRD positivity, suggesting that even aggressive treatment strategies may be insufficient to mitigate the poor outcomes associated with pre-transplant MRD positivity. Even with a higher proportion of MRD-positive patients receiving MAC in this study, their outcomes remained poor, which further emphasizes the limitations of intensified regimens alone for this high-risk group [13, 14].
Our study also revealed a higher incidence of both acute and chronic GVHD in MRD-positive patients. Grade 2–4 acute GVHD was more common in the MRD-positive group, and chronic GVHD was also slightly more prevalent. Although the literature on the relationship between MRD status and GVHD is limited, our results suggest a potential link that warrants further investigation. Our multivariate analysis adjusted for variables such as ethnicity, HLA match, CMV status, HCT-CI, graft type, and conditioning regimen. This adjustment aligns with prior studies indicating that these factors can independently impact GVHD incidence and overall survival [17,18]. By controlling for these variables, we aimed to isolate the impact of MRD status on GVHD, further demonstrating the association we observed between MRD positivity and increased GVHD risk.
Infectious-related mortality was another outcome on which MRD positivity appeared to have a significant impact. Our findings indicated that infection-related mortality post-transplant was more prevalent in the MRD-positive group, with a notably shorter time from transplant to death due to infection (5.03 months) compared to the MRD-negative group (12.2 months). This finding suggests that MRD positivity may predispose patients to a higher risk of post-transplant infections, potentially due to the weakened immune response associated with residual leukemia cells [17, 18].
Collectively, these outcomes—including a prolonged time to relapse, improved DFS, and reduced infection-related mortality—contributed to the superior survival observed in the MRD-negative group. Although quality of life was not directly assessed, the improved DFS and fewer cases of acute and chronic GVHD in the MRD-negative group suggest a correlation with better quality-of-life outcomes. This study’s findings are consistent with previous research showing the prognostic importance of pre-transplant MRD status in AML patients undergoing allo-HCT. For example, Buckley et al. conducted a meta-analysis that also found a strong connection between pre-transplant MRD positivity and higher relapse risk, poorer overall survival, and reduced disease-free survival [12]. Similarly, Klyuchnikov et al. noted a significant effect of pre-transplant MRD levels on transplant outcomes in AML patients.
Since MRD-positive patients are more likely to develop both acute and chronic GVHD, the remaining leukemia cells in their bodies may create a pro-inflammatory environment, which could raise the risk of GVHD. Moreover, this inflammation, along with the immunosuppressive effects of the transplant process, probably weakened immune function, making these patients more prone to infections. This highlights the critical role of MRD status in managing complications after a transplant and underscores the need for personalized treatment strategy to reduce both GVHD and infection risks in MRD-positive patients.
Several studies have highlighted the role of immune dysregulation in MRD-positive patients. For example, a study by Klyuchnikov et al. demonstrated that residual leukemia cells in MRD+-positive patients after transplant could impair the normal immune reconstitution process, leading to a higher risk of infections and other complications such as GVHD [19]. The persistence of leukemic cells may disrupt the normal function of T-cells, dendritic cells, and other antigen-presenting cells (APCs), making it more difficult for the immune system to effectively respond against foreign pathogens or malignant cells [20]. This immune dysfunction is a critical factor in the high relapse rates and poor long-term outcomes observed in MRD-positive patients.
This study is subject to the limitations inherent in retrospective registry analyses. Data were collected from multiple transplant centers, which varied in MRD detection methods, timing, and sensitivity, potentially affecting the consistency of MRD classification. Additionally, some potentially relevant clinical or molecular variables, such as mutational status or serial MRD monitoring, were not uniformly captured. Selection bias may also be present, as patients with missing MRD data were excluded from the analysis. Despite multivariable adjustment, residual confounding by unmeasured factors cannot be entirely ruled out.
CONCLUSION
This study provides further evidence for the prognostic significance of pre-transplant MRD status in AML patients undergoing allo-HCT, with MRD-positive status independently predicting worse overall survival, disease-free survival, and higher relapse rates. The findings underscore the significance of MRD assessment in risk stratification and emphasize the necessity for personalized treatment strategies for patients with MRD-positive disease. Future research should focus on developing targeted therapies that can effectively eliminate residual leukemia cells and improve outcomes for these patients.
Funding:
This paper did not receive any financial support. This dataset was collected by the Center for International Blood and Marrow Transplant Research (CIBMTR) which is supported primarily by the Public Health Service U24CA076518 from the National Cancer Institute; the National Heart, Lung, and Blood Institute; the National Institute of Allergy and Infectious Diseases; 75R60222C00011 from the Health Resources and Services Administration; N00014–23-1–2057 and N00014–24-1–2057 from the Office of Naval Research; NMDP; and the Medical College of Wisconsin.
Footnotes
DECLARATIONS
Competing interests:
No relevant conflicts of interest. MH has consultancy roles in Incyte Corporation, ADC Therapeutics, Pharmacyclics, Omeros, Genmab, Morphosys, Kadmon, Kite, Novartis, Abbvie, Legend, Gamida Cell, SeaGen, Autolus, Byondis, and Forte Biosciences Inc., and is on the speaker’s bureau for Sanofi Genzyme, AstraZeneca, BeiGene, and ADC Therapeutics. JPM has consulting and advisory roles in Bristol Myers Squibb, Kite, Novartis, AlloVir, Envision, Autolus, Nektar Therapeutics, CRISPR therapeutics, Caribou Bio, Sana Technologies, Legend Biotech, and Cargo Therapeutics. MUM has research funding from Iovance Biotherapeutics. The remaining authors declare no other commercial or financial relationships that could be construed as a potential conflict of interest.
Disclosure of Prior Presentation/Publication: This manuscript has not been previously published and has not been submitted for publication elsewhere while under consideration.
Availability of data and materials:
The dataset is publicly available and can be accessed at: https://cibmtr.org/CIBMTR/Resources/Publicly-Available-Datasets.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The dataset is publicly available and can be accessed at: https://cibmtr.org/CIBMTR/Resources/Publicly-Available-Datasets.