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. Author manuscript; available in PMC: 2026 Jun 14.
Published in final edited form as: Leukemia. 2024 Dec 12;39(2):381–390. doi: 10.1038/s41375-024-02497-z

Relationship Between Donor Source, Pre-Transplant Measurable Residual Disease, and Outcome after Allografting for Adults with Acute Myeloid Leukemia

Corentin ORVAIN 1,2,3,4, Filippo MILANO 1,5, Eduardo RODRÍGUEZ-ARBOLÍ 1,6, Megan OTHUS 7, Effie W PETERSDORF 1,5, Brenda M SANDMAIER 1,5, Frederick R APPELBAUM 5,8, Roland B WALTER 1,5,9
PMCID: PMC13264263  NIHMSID: NIHMS2183182  PMID: 39668236

Abstract

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 1,265 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.

Keywords: Acute myeloid leukemia (AML), allogeneic hematopoietic cell transplantation (HCT), donor type, human leukocyte antigen (HLA) disparity, measurable residual disease (MRD)

INTRODUCTION

Allogeneic hematopoietic cell transplantation (HCT) is potentially curative for many adults with high-grade myeloid stem cell disorders such as acute myeloid leukemia (AML) or myelodysplastic neoplasm/AML (MDS/AML).1–9 A suitable human leukocyte antigen (HLA)-identical sibling donor (MSD) is still preferred as source of hematopoietic cells for allografting. However, an MSD or an HLA-matched unrelated donor (MUD) is often unavailable. Therefore, to broaden the reach of allogeneic HCT, alternative stem cell sources, i.e., HLA-mismatched unrelated donors (MMD), HLA-haploidentical donors, and umbilical cord blood (UCB) are increasingly considered.10,11 Complicating the decision making process, there is ongoing controversy as to which donor source might lead to best outcomes for patients if more than one is available.12–24 In two randomized trials, outcomes with HLA-haploidentical donors were better than with UCB, but both trials were closed early for slow accrual and were not limited to AML.20,22 Results from non-randomized studies have been mixed, with several reporting lower relapse rates and/or higher non-relapse mortality (NRM) with alternative donor grafts, suggesting differences in graft-versus-leukemia (GVL) effects and/or toxicities relative to conventional donor transplants.16,18,24 Adding to this uncertainty, some25,26 but not all studies27,28 have suggested relative differences in outcome between donor sources may depend on the pre-HCT leukemia cell burden, as assessed by measurable residual disease (MRD) testing, for individuals allografted in morphologic remission. Specifically, some studies indicated UCB may be a better option than MSD/MUD if residual disease is detectable.25,29 As a limitation, these studies included pediatric and non-AML patients receiving MAC, and it has remained unclear what the relative value of UCB HCT might be across different distinct subsets of AML patients. Here, we used a large cohort of consecutive patients with AML or MDS/AML receiving an allograft in first or second remission at a single institution who underwent uniform multiparameter flow cytometry (MFC)-based pre-HCT MRD testing to examine the relationship between donor type/HLA disparity, pre-HCT MRD status, conditioning intensity, and post-HCT outcomes.

PATIENTS AND METHODS

Study cohort

We identified all adults ≥18 years of age with MDS/AML or AML (2022 ICC criteria)30 who received a first allograft while in first or second morphologic remission (i.e. had <5% blasts in bone marrow, with or without peripheral blood count recovery) between 4/2006 and 3/2023 at Fred Hutchinson Cancer Center/University of Washington. Related or unrelated donors were selected by high resolution HLA-typing for HLA-A, -B, -C, -DRB1, and -DQB1 with unrelated donors matched for all 10 alleles defined as MUD. High-dose fractionated total body irradiation (TBI; ≥12 Gy) with or without cyclophosphamide (CY) or fludarabine (FLU), high-dose TBI/thiotepa/FLU, busulfan (4 days) with CY or FLU, treosulfan/FLU with or without low-dose TBI, or any regimen containing a radiolabeled antibody were considered myeloablative conditioning (MAC) regimens. Reduced intensity conditioning (RIC) and non-myeloablative conditioning (i.e., 2–3 Gy TBI with or without fludarabine) were grouped together as non-MAC regimens. Information on post-HCT outcomes was captured via the Long-Term Follow-Up Program through medical records from our outpatient clinic and local clinics that provided primary care for patients in addition to records obtained on patients in research studies. Data/outcome follow-up was current as of July 17, 2023.

Classification of disease risk and treatment response

Secondary AML was defined as disease following an antecedent hematologic disorder (AHD; i.e., MDS, myeloproliferative neoplasm [NPM], and MDS/MPN such as chronic myelomonocytic leukemia [CMML]) or treatment with systemic chemotherapy and/or radiotherapy for a different disorder. The European LeukemiaNet (ELN) 2022 criteria were used to assign cytogenetic risk at diagnosis.31 The karyotype analysis was based on 20 metaphases for most samples as a routine procedure; FISH studies were performed according to standard procedures at the time of diagnosis and pre-HCT assessment in a subset of patients. The presence of any clonal abnormality by either karyotyping or FISH was considered an abnormal cytogenetic result.32–34

The HCT-specific comorbidity index (HCT-CI) and the Treatment Related Mortality (TRM) score were calculated as described.35,36 Treatment responses were categorized as proposed by the ELN (2022 criteria) except that post-HCT relapse was defined as emergence of >5% blasts by morphology or MFC in blood or bone marrow, emergence of cytogenetic abnormalities seen previously, or presence/emergence of any level of disease if leading to a therapeutic intervention.31 Blood count recovery was defined as absolute neutrophil count ≥1,000/μL and platelets ≥100,000/μL. Ten-color flow cytometry was performed as a routine clinical test on bone marrow aspirates obtained before starting conditioning therapy. The methodology of the MFC MRD assay has remained essentially unchanged throughout the study period.34,37–42 Any measurable level of MRD was considered positive, consistent with prior analyses and the performance characteristics of the assay.33,34,37–41,43–47 Acute GVHD manifestations were scored using the Acute GVHD Activity Index reported previously.48 Chronic GVHD was diagnosed using the National Institutes of Health consensus criteria.49

Statistical analysis

Categorical variables are presented as numbers with proportions and were compared with the Chi2 test or, for small samples (expected values <5), the Fisher’s exact test. Continuous variables are presented as medians with interquartile range (IQR) and were compared with the Kruskal Wallis test. Unadjusted probabilities of relapse-free survival (RFS; events: relapse and death) and overall survival (OS; event: death) were estimated using the Kaplan-Meier method and compared with the Log-Rank test; associations with RFS and OS were assessed using Cox regression. Probabilities of relapse (with non-relapse mortality as a competing event) and non-relapse mortality (NRM; death without prior relapse with relapse as a competing risk) were summarized using cumulative incidence estimates; associations with cumulative incidence of relapse and NRM were assessed using cause-specific regression models. To study GVHD, death and relapse were considered competing events. All tests were two-sided with a level of P<0.05 considered significant. Statistical analyses were performed with R (R Foundation for Statistical Computing, Vienna, Austria; http://www.r-project.org).

RESULTS

Characteristics of study cohort

We included all 1,265 adults ≥18 years with MDS/AML or AML in our analyses who received a first allograft while in first or second morphologic remission at a single institution, underwent uniform pre-HCT MRD testing via MFC, and agreed to their data being used for research purposes. The characteristics of these patients are summarized in Table 1. Recipients of UCB grafts (n=157) were younger than patients undergoing MSD [n=287], MUD [n=633], MMD [n=137], or HLA-haploidentical [n=51] HCT (46 vs. 55 vs. 58 vs. 60 vs. 62 years, respectively, P<0.001), had lower TRM scores at transplant (median 1.05 vs. 1.50 vs. 1.70 vs. 1.78 vs. 1.79, P<0.001), and were more likely to have a higher body mass index (BMI) at HCT (median 27.7 vs. 25.6 vs. 26.5 vs. 27.4 vs. 25.6, P=0.003). On the other hand, the time between last remission achievement and allografting was shortest for patients receiving MSD grafts (79 days vs. 98 days [MUD] vs. 105 days [HLA-haploidentical] vs. 112 days [UCB and MMD], P<0.001). In line with this, patients receiving UCB transplants received more cycles of chemotherapy before HCT. Patients receiving transplants from MSD or UCB were more likely to receive MAC (71% and 66%) than patients receiving MUD, MMD, or HLA-haploidentical allografts (54%, 46%, and 49%, respectively, P<0.001). Except for patients who received HLA-haploidentical grafts who were transplanted more recently, the median HCT year was similar across other groups. Among non-UCB transplants, mobilized peripheral blood was used as stem cell source in a higher proportion of MSD, MUD, or MMD HCT (94%, 93%, and 91%, respectively) than HLA-haploidentical HCT (73%, P<0.001). There was no difference in donor source according to pre-HCT status (P=0.53), including for UCB (12% of patients, with and without pre-HCT MRD).

TABLE 1.

Pre-HCT demographic and clinical characteristics of study cohort (n=1,265), stratified by graft source (matched sibling donor [MSD] vs. matched unrelated donor [MUD] vs. mismatched unrelated donor [MMD] vs. HLA-haploidentical donor vs. umbilical cord blood [UCB]).

Characteristic All patients (n=1,265) MSD (n=287) MUD (n=633) MMD (n=137) Haploidentical (n=51) UCB (n=157) P
Age at HCT (IQR), years 57 (44–65) 55 (45–62) 58 (45–67) 60 (51–67) 62 (54–67) 46 (34–58) <0.001
Female gender, n (%) 587 (46%) 140 (49%) 289 (46%) 58 (42%) 17 (33%) 83 (53%) 0.10
BMI at HCT (IQR), kg/m2 26.5 (23.4–30.6) 25.6 (22.9–28.9) 26.5 (23.3–31.3) 27.4 (23.9–31.3) 25.6 (23.8–30.4) 27.7 (24.1–32.2) 0.003
WBC count at diagnosis (IQR), G/l 5 (2–31) 6 (2–34) 5 (2–27) 4 (2–32) 3 (1–20) 12 (3–51) <0.001
Disease type, n (%) 0.26
MDS/AML 151 (12%) 39 (14%) 76 (12%) 20 (15%) 4 (8%) 12 (8%)
AML 1,114 (88%) 248 (86%) 557 (88%) 117 (85%) 47 (92%) 145 (92%)
Secondary AML, n (%) 274 (22%) 67 (23%) 140 (22%) 28 (20%) 9 (18%) 30 (19%) 0.77
Adverse cytogenetic risk (ELN 2022), n (%) 334 (27%) 80 (30%) 166 (27%) 39 (30%) 14 (29%) 35 (23%) 0.56
HCT year (IQR) 2015 (2010–2019) 2013 (2009–2016) 2016 (2012–2019) 2014 (2009–2018) 2019 (2014–2021) 2014 (2010–2018) <0.001
Time from last remission to HCT (IQR), days 95 (66–141) 79 (54–115) 98 (71–141) 112 (67–167) 105 (61–134) 112 (80–165) <0.001
Number of chemotherapy cycles before HCT, n (%) 3 (2–5) 3 (2–4) 3 (2–4) 3 (2–5) 3 (2–5) 4 (2–5) <0.001
Disease status at HCT, n (%) 0.012
First remission 1,008 (80%) 232 (81%) 519 (82%) 110 (80%) 36 (71%) 111 (71%)
Second remission 257 (20%) 55 (19%) 114 (18%) 27 (20%) 15 (29%) 46 (29%)
MFC status before HCT, n (%) 0.53
MRD-negative 1,005 (79%) 237 (83%) 495 (78%) 110 (80%) 38 (75%) 125 (80%)
MRD-positive 260 (21%) 50 (17%) 138 (22%) 27 (20%) 13 (25%) 32 (20%)
Blood cell count recovery, n (%) 891 (70%) 206 (72%) 435 (69%) 95 (69%) 35 (69%) 120 (76%) 0.40
HCT-CI at HCT, n (%) 0.97
Low (0–1) 476 (38%) 100 (35%) 246 (39%) 45 (33%) 21 (41%) 64 (41%)
Intermediate (2–3) 419 (33%) 107 (37%) 202 (32%) 46 (34%) 15 (29%) 49 (31%)
High (≥4) 339 (27%) 76 (26%) 172 (27%) 37 (27%) 14 (27%) 40 (25%)
TRM score at HCT (IQR) 1.57 (0.75–3.15) 1.50 (0.68–3.11) 1.70 (0.78–3.31) 1.78 (0.94–3.26) 1.79 (0.76–4.32) 1.05 (0.60–2.25) 0.001
Stem cell source, n (%)
Bone marrow 87 (7%) 16 (6%) 45 (7%) 12 (9%) 14 (27%) _
Peripheral blood 1,021 (81%) 271 (94%) 588 (93%) 125 (91%) 37 (73%) _
Umbilical cord blood 157 (12%) _ _ _ _ 157 (100%)
Conditioning intensity, n (%) <0.001
MAC 735 (58%) 203 (71%) 340 (54%) 63 (46%) 25 (49%) 104 (66%)
Non-MAC 530 (42%) 84 (29%) 293 (46%) 74 (54%) 26 (51%) 53 (34%)
GVHD prophylaxis, n (%) <0.001
CNI + MTX ± other 457 (37%) 130 (48%) 265 (42%) 62 (45%) 0 0
CNI + MMF ± sirolimus 608 (49%) 116 (42%) 276 (44%) 58 (42%) 1 (2%) 157 (100%)
PTCy 184 (15%) 27 (10%) 91 (14%) 17 (12%) 49 (98%) 0
Post-HCT maintenance therapy, n (%) 74 (6%) 15 (5%) 46 (7%) 5 (4%) 2 (4%) 6 (4%) 0.40
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Abbreviations: AML, acute myeloid leukemia; BMI, body mass index; CNI, calcineurin inhibitor; GVHD, graft-versus-host disease; HCT, hematopoietic cell transplantation; HCT-CI, HCT comorbidity index; IQR, interquartile range; MAC, myeloablative conditioning; MDS, myelodysplastic neoplasm; MFC, multiparameter flow cytometry; MMD, mismatched unrelated donor; MMF, mycophenolate mofetil; MRD, measurable residual disease; MSD, matched sibling donor; MTX, methotrexate; MUD, matched unrelated donor; PTCy, post-transplantation cyclophosphamide, TRM, treatment-related mortality; UCB, umbilical cord blood; WBC, white blood cell.

Relationship between donor type, pre-HCT MRD by MFC, and post-HCT outcome

With a median follow-up of 5.11 years after HCT among survivors (IQR: 2.40–9.63), there were 259 NRM events, 385 relapses, and 591 deaths contributing to the probability estimates for NRM, relapse, RFS, and OS. As post-HCT outcomes were very similar between patients receiving either MSD or MUD grafts (Supplementary Figure 1), they were grouped together as MSD/MUD for all analyses. The cumulative risk of relapse at three years was statistically non-significantly higher in patients receiving HLA-haploidentical grafts (41%) and lower in patients receiving UCB grafts (22%) than other patients (30%, P=0.10) whereas the three-year cumulative risk of NRM was significantly higher in patients undergoing MMD HCT (29%) than those receiving HLA-haploidentical and UCB grafts (25% and 21%, respectively) or MSD/MUD grafts (14%, P<0.001). These differences translated into significantly lower three-year RFS in patients receiving MMD or HLA-haploidentical grafts (42 and 34%, respectively) relative to those receiving MSD/MUD (56%) or UCB grafts (57%, P<0.001). Three-year OS estimates were equally lower for patients with MMD (46%) or HLA-haploidentical grafts (46%) than those with MSD/MUD (62%) or UCB as stem cell source (59%, P<0.001; Table 2; Figure 1). Three-month grade 2–4 acute GVHD was significantly higher in patients receiving UCB grafts (75% vs. 58% vs. 66% vs. 51% in patients receiving MSD/MUD, MMD, or HLA-haploidentical grafts, P<0.001). In contrast, three-month grade 3–4 acute GVHD was significantly higher in patients receiving MMD (15%) or UCB grafts (18%) than patients with MSD/MUD (10%) or HLA-haploidentical grafts (8%, P=0.015). Three-year chronic GVHD was lower in those receiving HLA-haploidentical (19%) or UCB HCT (11%) than MDS/MUD (40%) and MMD HCT (38%, P<0.001; Table 2; Supplementary Figure 2).

TABLE 2.

Outcome probabilities (with 95% confidence interval) stratified by donor type/HLA disparity.

Outcomes All patients (n=1,265) MSD (n=287) MUD (n=633) MMD (n=137) Haplo (n=51) UCB (n=157)
Relapse
One year 24% (22–26%) 24% (19–29%) 24% (21–28%) 25% (17–32%) 28% (16–41%) 21% (14–27%)
Three years 29% (27–32%) 31% (26–36%) 29% (26–33%) 30% (22–38%) 41% (25–56%) 22% (15–29%)
Five years 31% (29–34%) 33% (27–38%) 32% (28–36%) 32% (24–40%) 41% (25–56%) 23% (16–30%)
RFS
Median 4.70 (3.66–6.48) 6.48 (2.95–12.43) 5.06 (3.93–8.10) 1.29 (0.71–3.98) 1.74 (0.59-NR) 10.59 (2.23-NR)
One year 64% (62–67%) 67% (62–73%) 67% (63–71%) 53% (45–62%) 55% (42–71%) 62% (55–70%)
Three years 54% (51–57%) 55% (50–62%) 56% (53–61%) 42% (34–51%) 34% (21–56%) 57% (50–66%)
Five years 49% (47–52%) 52% (47–59%) 50% (46–55%) 36% (28–45%) 34% (21–56%) 56% (49–65%)
OS
Median 7.21 (5.49–9.29) 11.49 (6.48-NR) 6.94 (5.39–13.62) 2.29 (1.44–4.94) 2.97 (0.70-NR) NR (7.96-NR)
One year 73% (71–76%) 77% (72–82%) 77% (73–80%) 62% (54–71%) 58% (45–74%) 68% (61–76%)
Three years 59% (56–62%) 61% (56–67%) 62% (58–66%) 46% (38–55%) 46% (32–65%) 59% (52–68%)
Five years 54% (51–57%) 58% (52–64%) 55% (51–60%) 40% (32–49%) 41% (28–62%) 59% (51–67%)
Non-relapse mortality
100 days 5% (3–6%) 3% (1–6%) 4% (2–5%) 8% (3–13%) 8% (0–15%) 8% (4–12%)
One year 12% (10–13%) 9% (6–12%) 9% (7–11%) 23% (15–30%) 17% (6–27%) 17% (11–23%)
Three years 17% (15–19%) 14% (10–18%) 15% (12–17%) 29% (21–36%) 25% (9–41%) 21% (14–27%)
Grade 2–4 aGVHD
100 days 60% (58–63%) 56% (50–62%) 59% (55–62%) 66% (59–74%) 51% (37–65%) 75% (68–81%)
Grade 3–4 aGVHD
100 days 11% (10–13%) 8% (5–11%) 11% (9–13%) 15% (9–21%) 8% (0–15%) 18% (12–24%)
cGVHD
One year 25% (23–28%) 28% (22–33%) 30% (26–33%) 26% (18–33%) 10% (0–19%) 10% (5–14%)
Three years 35% (32–38%) 37% (31–42%) 41% (37–46%) 38% (29–47%) 19% (5–32%) 11% (6–16%)
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Abbreviations: GVHD, graft-versus-host disease; MMD, mismatched unrelated donor; MSD, matched sibling donor; MUD, matched unrelated donor; NR, not reached; OS, overall survival; RFS, relapse-free survival; UCB, umbilical cord blood.

FIGURE 1.

FIGURE 1.

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Post-HCT outcomes for 1,265 adults with AML or MDS/AML undergoing allogeneic HCT while in first or second morphologic remission, stratified by donor type (matched sibling donor [MSD]/matched unrelated donor [MUD] vs. mismatched unrelated donor [MMD] vs. HLA-haploidentical donor vs. umbilical cord blood [UCB]). (A) Relapse, (B) relapse-free survival, (C) overall survival, and (D) non-relapse mortality.

In patients with pre-HCT MRD by MFC (n=260), donor source was not associated with relapse (P=0.62), NRM (P=0.30), or RFS (P=0.15), but three-year OS estimates were significantly lower in patients receiving an HLA-haploidentical allograft (8% vs. 40% vs. 17% vs. 34% with MSD/MUD, MMD, or UCB grafts, respectively, P=0.003; Supplementary Table 1 and Supplementary Figure 3). On the other hand, in patients without pre-HCT MRD (n=1,005), three-year risk of NRM was significantly higher in patients receiving MMD (29%) and, to a lesser extent, HLA-haploidentical (24%) and UCB grafts (20%), relative to MSD/MUD (14%, P<0.001). By comparison, three-year risks of relapse were similar across all five groups (P=0.21). These NRM differences translated into lower three-year RFS estimates for patients receiving MMD (48%) or HLA-haploidentical grafts (42%) than those receiving MSD/MUD (63%) or UCB grafts (64%, P<0.001). Three-year OS estimates were lower in patients receiving MMD grafts (53%) than those receiving MSD/MUD (67%), HLA-haploidentical (60%), or UCB grafts (66%, P<0.001; Supplementary Table 2 and Supplementary Figure 4).

Donor source as an independent prognostic factor for post-HCT outcome

To study the relationship between graft source and post-HCT outcomes in more detail, we evaluated univariable and multivariable regression models for the endpoints of relapse, RFS, OS, and NRM. In univariable analysis, UCB HCT was statistically non-significantly associated with a lower risk of relapse (hazard ratio [HR]=0.72 [95% confidence interval: 0.51–1.02]) relative to MSD/MUD transplants (P=0.067). Other graft sources were not associated with relapse risk in comparison to MSD/MUD (Supplementary Table 3). MMD HCT was, however, significantly associated with higher NRM (HR=2.29 [1.66–3.16], P<0.001). Relative to MSD/MUD transplants, RFS was significantly lower in patients receiving MMD HCT (HR=1.53 [1.22–1.91], P<0.001) whereas OS was significantly lower in patients receiving MMD or HLA-haploidentical HCT (HR=1.65 [1.31–2.08], P<0.001; and HR=1.59 [1.07–2.37], P=0.022). After multivariable analysis excluding graft source due to redundancy in patients receiving a UCB transplantation, UCB HCT was significantly associated with a lower risk of relapse (HR=0.68 [0.47–1.00], P=0.049) relative to MSD/MUD HCT, whereas MMD HCT was associated with higher NRM (HR=1.92 [1.35–2.73], P<0.001), lower RFS (HR=1.33 [1.05–1.70], P=0.020), and lower OS (HR=1.45 [1.13–1.87], P=0.004; Table 3). Including transplant periods did not modify results of the multivariable model. There was no significant interaction between pre-HCT MFC MRD and donor type for relapse, RFS, OS, and NRM (data not shown).

TABLE 3.

Multivariable regression models of study cohort.

Risk of relapse Risk of relapse/death Risk of death Risk of NRM
HR (95% CI) P HR (95% CI) P HR (95% CI) P HR (95% CI) P
Age at transplantation, years 1.00 (0.99–1.01) 0.7 1.00 (1.00–1.01) 0.2 1.01 (1.00–1.01) 0.2 1.02 (1.00–1.03) 0.009
Female gender 1.09 (0.88–1.36) 0.4 0.99 (0.83–1.17) >0.9 0.92 (0.77–1.10) 0.4 0.83 (0.63–1.09) 0.2
BMI at HCT, kg/m2 1.00 (0.98–1.02) >0.9 1.01 (1.00–1.02) 0.14 1.01 (1.00–1.02) 0.2 1.03 (1.01–1.05) 0.014
WBC count at diagnosis, G/l 1.00 (1.00–1.01) 0.004 1.00 (1.00–1.00) <0.001 1.00 (1.00–1.00) <0.001 1.00 (1.00–1.01) 0.054
Disease type
AML Ref. Ref. Ref. Ref.
MDS-AML 0.94 (0.66–1.35) 0.8 1.09 (0.83–1.44) 0.5 1.35 (1.01–1.79) 0.039 1.42 (0.92–2.19) 0.11
Secondary AML 0.80 (0.60–1.06) 0.12 0.83 (0.67–1.04) 0.11 0.84 (0.67–1.06) 0.14 0.90 (0.64–1.28) 0.6
Adverse cytogenetic risk (ELN 2022) 2.06 (1.63–2.61) <0.001 1.55 (1.29–1.87) <0.001 1.52 (1.25–1.85) <0.001 0.91 (0.65–1.28) 0.6
Time from last remission to HCT, days 1.00 (1.00–1.00) 0.3 1.00 (1.00–1.00) <0.7 1.00 (1.00–1.00) 0.7 1.00 (1.00–1.00) 0.8
HCT year 0.97 (0.95–1.00) 0.031 1.25 (1.01–1.55) 0.013 0.97 (0.95–1.00) 0.017 0.99 (0.95–1.02) 0.4
Disease status at HCT
First remission Ref. Ref. Ref. Ref.
Second remission 1.29 (0.97–1.71) 0.081 1.25 (1.01–1.55) 0.045 1.23 (0.98–1.54) 0.072 1.27 (0.90–1.78) 0.02
MFC status before HCT
MRD-negative Ref. Ref. Ref. Ref.
MRD-positive 3.45 (2.70–4.40) <0.001 2.49 (2.04–3.05) <0.001 2.00 (1.63–2.45) <0.001 1.28 (0.88–1.87) 0.2
Blood cell count recovery 1.17 (0.91–1.51) 0.2 1.12 (0.93–1.37) 0.2 1.09 (0.89–1.34) 0.4 1.07 (0.79–1.45) 0.7
HCT-CI 0.99 (0.93–1.04) 0.6 1.02 (0.98–1.07) 0.3 1.05 (1.01–1.09) 0.046 1.07 (1.01–1.15) 0.035
TRM score 1.06 (1.03–1.10) <0.001 1.07 (1.05–1.10) <0.001 1.09 (1.06–1.12) <0.001 1.09 (1.06–1.13) <0.001
HLA matching/donor type
MSD/MUD Ref. Ref. Ref. Ref.
MMD 0.96 (0.68–1.36) 0.8 1.33 (1.05–1.70) 0.020 1.45 (1.13–1.87) 0.004 1.92 (1.35–2.73) <0.001
HLA-haploidentical 1.34 (0.80–2.24) 0.3 1.40 (0.92–2.13) 0.12 1.59 (1.03–2.46) 0.035 1.50 (0.72–3.14) 0.3
UCB 0.68 (0.47–1.00) 0.049 0.87 (0.66–1.15) 0.3 1.01 (0.76–1.35) >0.9 1.28 (0.84–1.95) 0.2
Conditioning intensity
MAC Ref. Ref. Ref. Ref.
Non-MAC 1.59 (1.21–2.07) <0.001 1.57 (1.28–1.94) <0.001 1.47 (1.19–1.83) <0.001 1.49 (1.06–2.08) 0.021
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Abbreviations: AML, acute myeloid leukemia; HCT, hematopoietic cell transplantation; HCT-CI, HCT comorbidity index; HR, hazard ratio; MAC, myeloablative conditioning; MDS, myelodysplastic neoplasm; MFC, multiparameter flow cytometry; MMD, mismatched unrelated donor; MRD, measurable residual disease; MSD, matched sibling donor; MUD, matched unrelated donor; NRM, non-relapse mortality; OS, overall survival; RFS, relapse-free survival; TRM, treatment-related mortality; UCB, umbilical cord blood; WBC, white blood cell count.

Relationship between donor source, conditioning intensity, pre-HCT MRD, and post-HCT outcomes

To further explore the relationship between donor source and post-HCT outcomes, we performed subset analyses in which we separately studied patients who underwent HCT after MAC or non-MAC. These analyses were partly motivated by a significant interaction we found for UCB HCT between conditioning intensity (MAC vs. non-MAC) and NRM (P=0.016), RFS (P=0.018), and OS (P=0.045). The interaction models indicated the HRs for the association between UCB and post-HCT outcomes were different according to conditioning intensity (for NRM: HR=0.96 [0.52–1.1.78] after MAC vs. HR=2.34 [1.27–4.32] after non-MAC; for RFS: HR=0.73 [0.50–1.07] vs. HR=1.13 [0.74–1.72]; for OS: HR=0.87 [0.58–1.29] vs. HR=1.28 [0.83–1.98]; Supplementary Tables 4 and 5). Patient and disease characteristics according to conditioning intensity are described in Supplementary Table 6.

In patients who received MAC (n=735), results were like those in the whole cohort with a statistically non-significant higher relapse risk in patients receiving MMD and HLA-haploidentical HCT relative to MSD/MUD HCT, while this risk was non-significantly lower with UCB HCT (P=0.10). In contrast, NRM was higher in patients receiving MMD HCT (P=0.03) compared to MSD/MUD HCT. RFS (P=0.001) and OS (P=0.001) were lower in patients receiving MMD and HLA-haploidentical HCT (Figure 2). On the other hand, in patients who received non-MAC (n=530), the risk of relapse was similar across all donor type cohorts (P=0.46) while NRM was higher in patients receiving MMD, HLA-haploidentical, and UCB HCT (P<0.001). The latter differences translated into lower OS (P=0.015) in these patients (Figure 2).

FIGURE 2.

FIGURE 2.

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Post-HCT outcomes for 735 adults with AML or MDS/AML undergoing allogeneic HCT following myeloablative conditioning (MAC) and 530 patients following non-myeloablative conditioning (non-MAC) while in first or second morphologic remission, stratified by donor type (matched sibling donor [MSD]/matched unrelated donor [MUD] vs. mismatched unrelated donor [MMD] vs. HLA-haploidentical donor vs. umbilical cord blood [UCB]). (A) Relapse, (B) relapse-free survival, (C) overall survival, and (D) non-relapse mortality following MAC and (E) relapse, (F) relapse-free survival, (G) overall survival, and (H) non-relapse mortality following non-MAC.

Because of these differences in post-HCT outcomes according to conditioning intensity, especially for patients receiving UCB, we further analyzed post-HCT outcomes of patients according to pre-HCT MRD in the context of both conditioning intensity and donor type. Despite small numbers, in patients with pre-HCT MRD receiving MAC, relapse risk was lower and RFS was higher in those who underwent UCB HCT (Figure 3; Supplementary Figures 5, 6, and 7). Two-by-two comparisons showed that post-HCT outcomes were better for patients undergoing UCB relative to MDS/MUD for both relapse (P=0.038) and RFS (P=0.037). Similar results were observed when restricting the analysis to patients receiving high-dose TBI (data not shown). There were no differences for NRM and OS. On the other hand, post-HCT outcomes were worse for patients without pre-HCT MRD after MMD when receiving MAC. For patients with pre-HCT MRD who received non-MAC, the relapse risk was not different according to donor type but NRM (P=0.053), RFS (P=0.006), and OS (P=0.007) were better in those receiving MSD/MUD or MMD HCT relative to HLA-haploidentical and UCB HCT.

FIGURE 3.

FIGURE 3.

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Relapse-free survival of 1,265 patients with AML or MDS/AML undergoing allogeneic HCT while in first or second morphologic remission, stratified by donor type (matched sibling donor [MSD]/matched unrelated donor [MUD] vs. mismatched unrelated donor [MMD] vs. HLA-haploidentical donor vs. umbilical cord blood [UCB]), conditioning intensity (myeloablative conditioning [MAC] vs. non-MAC), and pre-HCT MRD. (A) MAC and pre-HCT MRD negativity, (B) MAC and pre-HCT MRD positivity, (C) non-MAC and pre-HCT MRD negativity, and (D) non-MAC and pre-HCT MRD positivity.

DISCUSSION

Previous studies comparing outcomes of transplants with different donor types for patients with AML have come to varying conclusions,12,14–18,21,50–53 but very few studies have specifically considered the context of pre-HCT MRD.25–28 In the retrospective analysis presented herein, we overall observed that patients receiving MMD or HLA-haploidentical transplants but not UCB HCT had worse post-HCT outcomes than those receiving MSD/MUD transplants due to increased NRM (MMD) or relapse (HLA-haploidentical transplants) risk. Relative to these overall findings, post-HCT outcomes were similar for patients with pre-HCT MFC MRD, except that OS estimates were lower for patients receiving an HLA-haploidentical graft. In contrast, in patients without pre-HCT MRD, NRM estimates were higher, and RFS and OS estimates were lower, for MMD HCT. Importantly, our analyses suggested a difference in the relative value of UCB transplant in different patient subsets, with a significant interaction between UCB and conditioning intensity with high NRM in those receiving UCB HCT after non-MAC, and a particular benefit in patients with pre-HCT MRD.

Relative to MSD and MUD transplant recipients, UCB HCT was associated with better outcomes overall in comparison to other alternative donor type, i.e., MMD and HLA-haploidentical HCT. While many retrospective studies did not find an association between alternative donor type and post-HCT outcomes in patients with AML,12,14,17,19,21,53 some have reported differences in specific subgroups of patients related to disease status at transplant,16,50 conditioning intensity,14 or GVHD prophylaxis (post-transplant cyclophosphamide or antithymocyte globulin).29,51,54,55 The improved outcomes observed with UCB transplantations in our analyses relative to previously reported patient series might be due to the significant experience with UCB HCT of our center,25,56 with conduct of prospective trials aiming specifically at improving this type of allografting.57

As the likelihood of relapse after allogeneic HCT is high in patients with pre-HCT MRD,33,34,37–41,43–46,58–61 different strategies have been proposed to mitigate this risk. Supporting the hypothesis that some donor sources might be associated with increased GVL effects relative to others, some but not all studies have reported improved outcomes with alternative donor source HCT such as UCB or HLA-haploidentical donors in patients with pre-HCT MRD.15,25–29,62,63 In our cohort as a whole, donor source was not associated with post-HCT outcomes in patients with pre-HCT MRD. However, when we restricted our analyses to patients with pre-HCT MRD who received MAC, we observed improved post-HCT outcomes in patients receiving UCB HCT, including in comparison to patients receiving MSD/MUD HCT, in line with a previous analysis from our institution that included pediatric patients and patients with malignancies other than AML25 and an analysis from patients treated elsewhere.29 It is interesting to speculate that this decrease in relapse risk may be due to higher GVL effects with UCB HCT, e.g., secondary to lower susceptibility to HLA loss as a mechanism of immune evasion.64

In our analyses, patients receiving MMD grafts had higher NRM, similar relapse risk, and lower RFS and OS after receiving MAC or non-MAC regimens. Interestingly, other alternative donor sources were not associated with post-HCT outcomes in the same fashion. Specifically, while HLA-haploidentical transplants were associated with an increased relapse risk only after MAC, UCB was associated with increased NRM only after non-MAC, as was previously observed in a retrospective analysis comparing MSD to UCB HCT.23 To our knowledge, only one study focused on AML patients explored the association between donor source and post-HCT outcomes after different conditioning intensity.16 In that study, NRM was higher after MAC but to the same degree with MMD, HLA-haploidentical, or UCB HCT, whereas the risk of relapse was lower in patients receiving HLA-haploidentical grafts regardless of conditioning intensity.16 In large retrospective studies not limited to AML patients, HLA-haploidentical HCT was differentially associated with outcome after RIC, with improved outcomes in comparison to other donor sources in one study,14 but increased NRM in another.13

Several limitations of our study must be acknowledged. First, this is a retrospective observational analysis of patients that received allografts largely as part of non-randomized trials or standard of care limiting our ability to draw definitive conclusions on the optimal donor source. At our Institution, MSD/MUD have priority over the other donor type; if MSD/MUD is not available, alternative donor type is selected based on donor ability and/or research protocol prioritization. For conditioning intensity, our general preference has been to use MAC whenever it was deemed safe based on patient age and comorbidities. Although disease characteristics at HCT were not considered for the choice of donor source or conditioning intensity, we cannot exclude that some patients with specific disease subtypes might have been more likely to receive transplant with a certain donor source over another. For example, because the time between CR and HCT was the longest UCB recipients, it is possible such patients were more likely to have disease characterized by relapses with slow kinetics. Second, the small number of patients receiving an HLA-haploidentical transplant, in a more recent period and thus with shorter follow-up, in our institution further limited this analysis. Third, methods of GVHD prophylaxis varied among the groups making it impossible to determine if differing outcomes were due to donor source, GVHD prophylaxis, or both. Fourth, mutational profiles at diagnosis and prior to HCT were available only for a small subset of patients and we could not therefore examine whether differences in molecular profiles could account for some of the observed differences in post-HCT. Because of limited molecular data, we were unable to examine the prognostic role of MRD in adverse risk disease defined by cytogenetic/molecular rather than cytogenetic markers. Fifth, HLA-associated relapse risks were not evaluated among the HLA-haploidentical transplants due to limited numbers.65 Sixth, account for the HCT year in our univariate and multivariable models may not have completely addressed potential practice changes during the wide inclusion period of our patients. Seventh, the more recent used of post-HCT maintenance therapy may also have modified post-HCT outcomes although only very few patients received such therapies in our cohort. Finally, the single center setting of this analysis may limit its generalizability as patient characteristics may differ in other institutions and/or different parts of the world.

In conclusion, our analyses highlight the outcomes with alternative donor HCT vary across different subsets of patients with AML or MDS/AML, with HLA-haploidentical grafts being associated with increased relapse after MAC and UCB grafts being associated with increased NRM after non-MAC; MMD grafts were associated with increased NRM with MAC and non-MAC transplants. For patients suitable for MAC, our findings indicate UCB HCT may be the preferred alternative donor source. Adding to the value of UCB HCT, in patients with pre-HCT MRD receiving MAC, our data suggest post-HCT outcomes with UCB may be better than with MSD/MUD. This observation would provide the rationale for further prospective evaluation of the relative merits of UCB vs. MSD/MUD in patients with pre-HCT MRD if suitable for MAC to minimize risk of relapse in these patients at very high risk of leukemia recurrence following conventional allografting.

Supplementary Material

Supplemental Data

ACKNOWLEDGMENTS

Research reported in this publication was supported by grants P01-CA078902, P01-CA018029, and P30-CA015704 from the National Cancer Institute/National Institutes of Health (NCI/NIH), Bethesda, MD, USA. The authors acknowledge the excellent care provided by the physicians and nurses of the HCT teams, the staff in the Long-Term Follow-up office at the Fred Hutchinson Cancer Center, the Hematopathology Laboratory at the University of Washington, and the patients for participating in our research protocols. R.B.W. acknowledges support from the José Carreras/E. Donnall Thomas Endowed Chair for Cancer Research.

Footnotes

DISCLOSURE OF CONFLICTS OF INTEREST

Employment or Leadership Position: none; Consultant or Advisory Role: none: Stock Ownership: none; Honoraria: none; Research Funding: none; Expert Testimony: none; Patents: none; Other Remuneration: none.

ETHICS APPROVAL

All patients were treated on Institutional Review Board (IRB)-approved research protocols (all registered with ClinicalTrials.gov) or standard treatment protocols. All analyses conducted herein were performed under a research protocol approved by the Fred Hutchinson Cancer Center’s IRB (#FH2562).

INFORMED CONSENT

All patients gave informed consent for study participation in accordance with the Declaration of Helsinki.

DATA AVAILABILITY STATEMENT

The dataset analyzed in this study is available from the corresponding author on reasonable request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplemental Data
NIHMS2183182-supplement-Supplemental_Data.docx (3MB, docx)

Data Availability Statement

The dataset analyzed in this study is available from the corresponding author on reasonable request.

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