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. Author manuscript; available in PMC: 2018 Aug 1.
Published in final edited form as: Biol Blood Marrow Transplant. 2017 Apr 21;23(8):1350–1358. doi: 10.1016/j.bbmt.2017.04.015

Factors associated with long-term risk of relapse after unrelated cord blood transplantation for children with acute lymphoblastic leukemia in remission

Kristin M Page 1, Myriam Labopin 2, Annalisa Ruggeri 2,3, Gerard Michel 4, Cristina Diaz de Heredia 5, Tracey O’Brien 6, Alessandra Picardi 7, Mouhab Ayas 8, Henrique Bittencourt 9, Ajay J Vora 10, Jesse Troy 1, Carmen Bonfim 11, Fernanda Volt 3, Eliane Gluckman 3, Peter Bader 12, Joanne Kurtzberg 1, Vanderson Rocha 3,13,14, on behalf of Duke University, Cord blood Committee-Cellular Therapy and Immunobiology Working Party (CBC-CTIWP) and Paediatric Disease Working Party (PDWP) of EBMT and Eurocord
PMCID: PMC5569913  NIHMSID: NIHMS887061  PMID: 28438676

Abstract

For pediatric patients with acute lymphoblastic leukemia (ALL), relapse is an important cause of treatment failure after unrelated cord blood transplant (UCBT). Compared to other donor sources, relapse is similar or even reduced after UCBT despite less graft-versus-host disease (GvHD). We performed a retrospective analysis to identify risk factors associated with the 5-year cumulative incidence (CI) of relapse after UCBT. In this retrospective, registry-based study, we examined the outcomes of 640 children (<18 years) with ALL in first (n = 257, 40%) or second complete remission (CR; n = 383, 60%) who received myeloablative conditioning followed by a single-unit UCBT from 2000–2012. Most received anti-thymocyte globulin (88%) or total body irradiation (TBI; 69%) and cord blood grafts were primarily mismatched at 1 (50%) or 2+ (34%) HLA loci. Considering CR1 patients, the 5-year OS, leukemia-free survival (LFS), and relapse were 59%, 52%, and 23%, respectively. In multivariate analysis (MVA), acute GvHD (grade II–IV) and TBI protected against relapse. In CR2 patients, 5-year OS, LFS and the CI of relapse were 46%, 44%, and 28%, respectively. In MVA, longer duration from diagnosis to UCBT (≥30 months) and TBI were associated with decreased relapse risk. Importantly, receiving a fully HLA matched graft was a strong risk factor for increased relapse in MVA. An exploratory analysis of all 640 patients supported the important association between the presence of acute GvHD and less relapse, but also demonstrated an increased risk of NRM. In conclusion, the impact of GvHD as a GvL marker is evident in pediatric ALL after UCBT. Strategies that promote GvL while harnessing GvHD should be further investigated.

Keywords: cord blood, pediatric, acute lymphoblastic leukemia, relapse, transplantation

Introduction

Modern risk-based chemotherapy regimens are curative for many children and adolescents with de novo acute lymphoblastic leukemia (ALL)1. An additional subset of patients can achieve long-term remission with allogeneic hematopoietic stem cell transplantation (HSCT), but outcomes are poor for those who relapse after HSCT. Current practice is to offer HSCT to patients with high-risk disease in first complete remission (CR1) or relapsed disease once a second remission (CR2) is achieved. The curative effect of HSCT is due to the use of high-dose chemotherapy with or without total body irradiation (TBI) along with the potential for graft-versus-leukemia (GvL) effect. It is well established that the GvL effect, likely due to immune surveillance provided by donor NK- and T-cells, is important in eradicating leukemia after allogeneic HSCT 2–5, although the GvL effect in ALL may be weaker than in other malignancies 6–8. Select clinical reports have demonstrated lower rates of relapse in pediatric patients with ALL who experience graft-versus-host disease (GvHD) after HSCT, providing indirect evidence of GvL actions in this disease9–11.

For children and adolescents with ALL in need of HSCT, the use of unrelated donor cord blood (UCB) offers several benefits including rapid procurement, more lenient human leukocyte antigen (HLA)-matching, and lower rates of GvHD12. Clinical reports have also demonstrated lower rates of relapse after UCB transplantation (UCBT) as compared to other donor sources13–19. The benefits of UCBT have historically been offset by higher non-relapse mortality (NRM). Recently, outcomes are similar to those seen with other donor sources13, 20, 21. Outcomes after UCBT for pediatric ALL have been described as part of larger prospective 9, 16, 22, 23 and retrospective 18, 24–26 studies, but a focused examination of factors influencing relapse in pediatric ALL recipients after UCBT is needed. In this report, we describe the long-term outcomes of a collaborative effort between Eurocord, European Society of Blood and Marrow Transplantation (EBMT) and Duke University Pediatric Blood and Marrow Transplant Program (PBMT) to define risk factors associated with relapse and other outcomes after UCBT for pediatric ALL.

Study design

Eligible patients were <18 years old with a diagnosis of de novo ALL in morphologic CR1 or CR2. All patients received myeloablative conditioning followed by transplantation with a single, non-manipulated unrelated donor cord blood unit as their first graft. All UCBTs were performed from 2000 through 2012 to allow for long-term outcomes to be considered. Patients with diagnoses of biphenotypic leukemia, secondary or treatment-related leukemia or with history of prior HSCT were excluded. Data on patient and graft characteristics, as well as on outcomes were collected from the Eurocord or Duke PBMT Clinical databases. All participating EBMT transplant centers received the synopsis of the study and gave their approval. The Institutional Review Boards (IRB) of the Eurocord-Netcord scientific committee and Duke University approved this study. All patients gave informed consent for treatment and for data entry and use for analysis in accordance with the Declaration of Helsinki.

Definitions and Endpoints

The primary endpoint for this analysis was the cumulative incidence (CI) of relapse, defined as morphologic recurrence of leukemia at any site. Secondary endpoints included leukemia-free survival (LFS) defined as survival while in continuous CR, overall survival (OS) and non-relapse mortality (NRM) defined as death occurring while in remission. Neutrophil recovery was defined as achieving an absolute neutrophil count ≥ 0.5×109/L for 3 consecutive days. Platelet recovery was defined as achieving a platelet count ≥ 20×109/L without transfusion support. Full donor chimerism was defined as ≥ 95% cells of donor origin and mixed chimera was between ≥5% and <95% donor cells, as measured using techniques according to the individual transplant center. The diagnosis and grading of acute (aGVHD) and chronic GvHD (cGvHD) was assigned by the transplant center using standard criteria27, 28. Myeloablative conditioning (MAC) was defined as containing either TBI with a dose >8 Gy, a total dose of busulfan (Bu) >8 mg/kg orally or intravenous equivalent. Human leukocyte antigen (HLA) matching was assigned at the antigen level for Class I –A and –B loci, and at the allelic level for Class II – DRB1. Cytogenetic findings were considered: high risk if any of the following was present: BCR/ABL [t(9.22)], t(1, 19), MLL rearrangements [t(4, 11)], hypodiploid, or complex (>3 abnormalities); intermediate if abnormalities not considered high risk were present, normal if no abnormalities were detected or missing if not available. Presence or absence of minimal residual disease prior to UCBT was available for a subset of the cohort (n = 215), but was not considered in the analysis.

Statistical Approach

Separate analyses were performed for CR1 and CR2 patients to account for the fact that disease status is a well-established predictor of outcomes after HSCT23, 29. An exploratory analysis was also performed that included all patients in the study cohort. The probabilities of relapse, NRM, acute and chronic GvHD were estimated using the cumulative incidence (CI) function method in a competing risk setting treating death and relapse as competing events30. Differences between subgroups were compared using the Gray K-Sample test31. Probabilities of OS and LFS were calculated with the use of the Kaplan-Meier estimator and differences between groups were compared using the log-rank statistics32. Cox proportional-hazards regression was used to create prognostic multivariate models33. Factors known as potential prognostic factors, and all factors associated with a p value <0.10 in univariate analysis were included in the final models. The presence of acute (aGvHD) or chronic GvHD (cGVHD) were considered as time-dependent variables. Statistical analyses were performed with the SPSS 22 (SPSS Inc./IBM, Armonk, NY, USA) and R 3.2.3 (R Development Core Team, Vienna, Austria) software packages.

Results

Patient, donor and transplantation characteristics

Patient, donor and transplantation characteristics are presented in Table 1. From 2000 to 2012, 640 children or adolescents (median age: 6.3 years) with ALL in either morphological CR1 (n = 257; 40.2%) or CR2 (n = 383; 59.8%) underwent UCBT at an EBMT and Eurocord participating center (n = 99 centers) or Duke University. Most patients were transplanted for B-cell lineage ALL (79.2%). Patients and grafts were HLA matched (15.6%) or mismatched at 1 (50.1%) or ≥2 (34.3%) loci. The majority of patients (68.8%) received TBI-containing regimens, most commonly TBI + Cyclophosphamide (Cy; 23.9%). Most TBI-containing regimens delivered total fractionated doses of 1200–1350 cGy (86%; range 800–1500 cGy). The use of TBI-containing regimens was generally limited to children ≥3 years (94.5%), whereas 51.3% of patients who received chemotherapy-only regimens were younger than 3 years old. No infants (<12 months of age) received TBI. The most common chemotherapy based regimen was Bu + Cy (15.8%) with the majority of patients receiving a total Busulfan dose of 16 mg/kg (data regarding Busulfan pharmacokinetics not available). Most patients (88.0%) received anti-thymocyte globulin (ATG) prior to UCBT. The median total nucleated cell dose was 5.0×107/kg (0.3–35.4). GvHD prophylaxis was primarily cyclosporine-based with corticosteroids (72.3%) or mycophenolate mofetil (MMF; 21.3%). The median follow up was 50.1 months (range, 2–172.3) for the overall cohort.

Table 1.

Patient and transplant characteristics based on disease status at time of transplant.

Characteristics All (n = 640) CR1 (n = 257) CR2 (n = 383)
% (n)
Patient
 Age in years at UCBT (median, range) 6.4 (0.5–17.9) 5.3 (0.5–17.9) 6.9 (0.7–17.9)
 Gender (male) 58.1 (370) 54.5 (139) 60.5 (231)
 Cytomegalovirus serology (positive) 44.8 (287) 44.4 (114) 45.2 (173)
Disease
 Immunophenotype
  B-cell lineage 79.2 (507) 75.1 (193) 82.0 (314)
  T-cell lineage 17.5 (112) 21.4 (55) 14.9 (57)
 Cytogenetic risk
  High 36.3 (149) 48.5 (83) 27.5 (66)
  Intermediate 36.7 (151) 32.7 (56) 39.6 (95)
  Normal 27.0 (111) 18.8 (32) 32.9 (79)
Donor
 Number of HLA mismatches
  0 15.6 (95) 18.1 (45) 13.9 (50)
  1 50.1 (305) 51.6 (128) 49.0 (177)
  ≥2 34.3 (209) 30.2 (75) 37.1 (134)
 TNC (×107/kg) infused (median, range) 5.0 (0.3–35.4) 5.5 (0.3–29.9) 4.7 (0.5–35.4)
Transplantation
 Year of transplantation
  <2007 51.2 (328) 47.9 (123) 53.5 (205)
  ≥2007 48.8 (312) 52.1 (134) 46.5 (178)
 Time in months from diagnosis to UCBT (median, range) 16.4 (1.8–154.7) 6.7 (1.8–32.7) 30.7 (2.3–154.5)
 TBI-containing regimen
  Yes 68.8 (439) 55.1 (141) 78.0 (298)
  No 31.2 (201) 44.9 (116) 22.0 (85)
 TBI-containing regimens
  TBI + Cyclophosphamide + Fludarabine 9.9 (63) 8.2 (21) 11.0 (42)
  TBI + Other chemotherapy 58.8 (376) 46.7 (120) 66.8 (256)
 Chemotherapy-based regimens
  Busulfan +Cyclophosphamide 16.1 (103) 23.7 (61) 11.0 (42)
  Thiotepa + Busulfan + Fludarabine 8.3 (53) 11.3 (29) 6.3 (24)
  Other chemotherapy 7.1 (45) 10.1 (26) 5.0 (19)
 Received Serotherapy 88.0 (500) 86.2 (194) 89.2 (306)
 Follow up in months (median, range) 50.1 (1.7–172.4) 46.5 (2.4–172.4) 54.5 (1.7–172.2)
 GvHD prophylaxis
  Cyclosporine + Steroids 72.3 (438) 70.6 (168) 73.4 (270)
  Cyclosporine + Mycophenolate Mofietil 21.3 (129) 21.0 (50) 21.5 (79)
  Other 6.4 (39) 8.4 (20) 5.2 (19)
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CR1, first complete remission; CR2, second complete remission; UCBT, umbilical cord blood transplantation; HLA, human leukocyte antigen; TNC, total nucleated cell dose; TBI, total body irradiation; GvHD, graft versus host disease

GvHD

The CI of acute (grade II–IV) and chronic GvHD at 5-years post-transplant was 40.4% (95%CI: 36.5–44.2) and 17% (95%CI: 14.1–20.2), respectively, for the overall cohort. Acute GvHD grades II–IV was experienced by 248 patients (grade II n = 163; grades III–IV n = 85) in a median of 18 days (range 4–99) after UCBT. Chronic GvHD was observed in 105 patients (CR1 n = 41; CR2 n = 64); 45 presented with extensive disease (CR1 n = 21; CR2 n = 24). Similar rates of acute and chronic GvHD were observed in CR1 and CR2 patients.

Relapse

Considering the patients transplanted while in CR1, the CI of relapse at 5-years was 23.4% (18.0–29.0; Figure 1A) with a median time from UCBT to identification of relapse of 7.5 months (range, 1–65). In multivariate analysis, two factors were independently associated with less relapse in CR1 patients: the presence of acute GvHD (grade II–IV) as a time-dependent variable (HR 0.32, 95%CI 0.14–0.70, p = 0.004) and receiving TBI-containing regimens (HR 0.53, 95%CI 0.29–0.99, p = 0.04; Table 2; Figure 2A). While the median age of CR1 patients who received TBI was older (8.1 vs. 4.3 years), age at transplant was not a significant predictor of relapse. The risk of relapse was also not influenced by the degree of HLA matching, the GvHD prophylaxis used, or the presence of cGvHD in these patients.

Figure 1.

Figure 1

Figure 1

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A. The estimated 5-year cumulative incidence of relapse in children with ALL in first or second complete remission at time of UCBT. The cumulative incidence of relapse at 5-years was 23.4% (18.0–29.0) and 27.8% (23.2–32.6) for children who in first (CR1) and second complete remission (CR2), respectively. B. The 5-year probability of leukemia-free survival (LFS) in children with ALL in first or second complete remission at time of UCBT. The LFS was 52.4% (49.0–55.8) and 43.9% (41.2–46.6) for children in first and second complete remission, respectively.

Table 2.

Significant predictors in multivariate analyses of patients transplanted in either first or second complete remission.

Outcome Variable* CR1 patients CR2 patients
HR (95% CI) P value HR (95% CI) P value
Relapse Acute GvHD (time dependent variable) 0.32 (0.14–0.70) 0.004
TBI-containing regimen 0.53 (0.29–0.99) 0.04 0.56 (0.34–0.93) 0.03
HLA mismatched graft 0.53 (0.30–0.94) 0.03
Longer duration from diagnosis to UCBT (≥30 months)+ 0.41 (0.25–0.67) <0.001
LFS Age at UCBT (in years) 1.05 (1.01–1.09) 0.02 1.05 (1.01–1.09) 0.04
TBI-containing regimen 0.53 (0.35–0.82) 0.004
Longer duration from diagnosis to UCBT (≥30 months)+ 0.62 (0.45–0.88) 0.006
OS Age at UCBT (in years) 1.05 (1.01–1.09) 0.03 1.05 (1.01–1.10) 0.03
TBI-containing regimen 0.51 (0.32–0.79) 0.003
Longer duration from diagnosis to UCBT (≥30 months)+ 0.61 (0.43–0.86) 0.005
Use of serotherapy+ 1.84 (1.01–3.36) 0.04
NRM Acute GvHD (time dependent variable) 1.67 (1.05–2.66) 0.03
Age at UCBT (in years) 1.06 (1.01–1.12) 0.03 1.07 (1.01–1.14) 0.03
HLA mismatched graft 3.79 (1.17–12.35) 0.03 0.81 (0.39–1.71)
T-cell ALL+ 1.78 (1.03–3.09) 0.04
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*

Models including CR1 or CR2 patients adjusted for the following variables: presence of acute GvHD (II–IV) as a time dependent variable, presence of chronic GvHD as a time dependent variable, age at UCBT (in years), TBI-containing regimen (yes/no), HLA matching (<6 of 6 loci vs. 6 of 6), year of transplant.

+

These additional variables were included in the CR2 multivariate model: longer duration from diagnosis to UCBT (≥30 months), T-cell ALL (vs. B-cell), use of serotherapy (yes/no). CR1, first complete remission; CR2, second complete remission; GvHD, graft versus host disease; TBI, total body irradiation; HLA, human leukocyte antigen; UCBT, umbilical cord blood transplantation; LFS, leukemia-free survival; OS, overall survival; NRM, non-relapse mortality;

Figure 2.

Figure 2

Figure 2

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A. The estimated 5-year cumulative incidence of relapse in children with ALL in first complete remission at time of UCBT based on conditioning regimen. The cumulative incidence of relapse was 17.4% and 30.5% for children who received TBI and chemotherapy-based regimens, respectively (p = 0.03). B. The 5-year probability of leukemia-free survival (LFS) in children with ALL in first complete remission at time of UCBT based on conditioning regimen. The 5-year probability of LFS for children who received total body irradiation (TBI)-containing or chemotherapy-containing regimens was 40.9% and 60.2%, respectively (p = 0.01).

The CI of relapse in patients transplanted while in CR2 was 27.8% (23.2–32.6; Figure 1A) with a median time to relapse of 5.9 months (range, 1–65) after UCBT. In multivariate analysis, three factors were associated with a lower risk of relapse (Table 2): HLA mismatched cord blood grafts (HR 0.53, 95%CI 0.30–0.94, p = 0.03), the use of TBI-containing regimens (HR 0.56, 95%CI 0.34–0.93, p = 0.03), and an interval of ≥30 months from original diagnosis to UCBT (HR 0.41, 95%CI 0.25–0.67, p <0.0001).

Leukemia-free Survival

The 5-year probabilities of LFS for children transplanted in CR1 and CR2 were 52.4% (49.0–55.8) and 43.9% (41.2–46.6), respectively (Figure 1B). For CR1 patients, the benefit of TBI-containing regimens extended to improved LFS (60.2% vs. 42.9%, p = 0.01, Figure 2B). Two factors were predictive of LFS in multivariate analysis of CR1 patients: regimens containing TBI (HR 0.53, 95% CI 0.35–0.82, p = 0.004) and increasing age (in years, HR 1.05, 95%CI 1.01–1.09, p = 0.02; Table 2).

CR2 patients experienced improved LFS when the interval from initial diagnosis to UCBT was ≥30 months (50.9% vs. 36.8%, p = 0.001). Recipients of HLA-mismatched grafts experienced improved LFS but this was not statistically significant (45.6% vs. 32.4%, p = 0.09). In multivariate modeling, longer interval from diagnosis to UCBT (HR 0.62, 95%CI 0.45–0.88, p = 0.006) and increasing age (in years, HR 1.05, 95% CI 1.01–1.09, p = 0.04) were both predictive of LFS after adjusting for other variables (Table 2).

Overall Survival, Non-relapse Mortality (NRM) and Causes of Death

The probability of OS at 5-years was 58.8% (55.4–62.2) for CR1 patients. Patients who received TBI-conditioning regimens (HR 0.51, 95% CI 0.32–0.79, p = 0.003) had a lower risk of death at 5-years (Table 2), whereas increasing age (in years) negatively impacted OS (HR 1.05, 95% CI 1.01–1.09, p = 0.03). Of the 257 CR1 patients, a total of 99 patients died due to relapse (n = 38), NRM (n = 57) or unknown causes (n = 3). Causes of NRM included infection (n = 28), organ toxicity (n = 11), GvHD (n = 9), hemorrhage (n = 6), rejection (n = 1), EBV-associated lymphoproliferative disease (EBV-LPD; n = 1) or other (n = 1). Risk factors associated with NRM in multivariate analysis included receiving a mismatched cord blood graft (HR 3.79, 95% CI 1.17–12.35, p = 0.03) and increasing age (in years; HR 1.06, 95% CI 1.01–1.12, p = 0.03; Table 2). There was also a trend towards improved NRM in patients who received TBI (HR 0.58, 95% CI 0.32–1.02, p = 0.06).

The 5-year probability of OS was 46.3% (43.5–49.1) in CR2 patients. In multivariate analysis, three factors were associated with OS: longer duration from diagnosis to UCBT (>30 months; HR 0.61, 95% CI 0.43–0.86, p = 0.005; Table 2), increasing age (in years, HR 1.05, 95% CI 1.01–1.10, p = 0.03; Table 2) and the use of serotherapy (HR 1.84, 95% CI 1.01–3.36, p = 0.04). Of the 383 total CR2 patients, 191 patients died due to relapse (n = 79), NRM (n = 110) or unknown causes (n = 2). Causes of NRM included infection (n = 46), organ toxicity (n = 21), GvHD (n = 19), rejection (n = 9), hemorrhage (n = 6), EBV-LPD (n = 4) or other causes (n = 5). The risk of NRM was higher in patients with acute GvHD (II–IV)(HR 1.67, 95% CI 1.05–2.66, p = 0.03), or with a diagnosis of T-cell ALL (HR 1.78, 95% CI 1.03–3.09, p = 0.04), and increased with age (in years; HR 1.07, 95% CI 1.01–1.14, p = 0.03; Table 2).

Overall cohort

Based on the above results and driven by inspection of the data, we then performed an exploratory analysis of the entire cohort. Considering all 640 patients, the 5-year CIs of relapse, LFS and OS were 26% (22.4–29.7), 47.4% (45.3–49.5) and 51.3% (49.2–53.4), respectively. The median time to diagnosis of relapse was 6 months (1.1–65 months) after UCBT. While no differences were noted between CR1 and CR2 patients with respect to rates of aGvHD, cGvHD, NRM or relapse in univariate analysis, patients transplanted in CR1 experienced improved LFS (52.4% vs. 44%, p = 0.03) and OS (58.8% vs. 46.4%, p = 0.009) as compared to those transplanted while in CR2.

In the overall cohort, the risk of relapse after UCBT was lower in patients who experienced any GvHD (aGvHD grade II–IV or cGvHD; HR 0.51, 95% CI 0.34–0.76, p = 0.0008). Further analysis revealed that acute grade II (HR 0.59, 95% CI 0.38–0.94, p = 0.025; Table 3) was associated with less relapse, but did not impact NRM, LFS and OS. While not associated with relapse, grade III–IV aGvHD increased the risk of NRM (HR 3.19, 95% CI 1.93–5.27, p <0.0001) leading to decreased LFS (HR 1.51, 95% CI 1.02–2.24, p = 0.04) and OS (HR 1.94, 95% CI 1.28–2.94, p = 0.002). Multivariate models did not demonstrate an association between cGvHD with relapse, NRM or LFS, but cGvHD was associated with improved overall survival (HR 0.57, 95% CI 0.35–0.93, p = 0.03). The impact of disease status on outcomes was also demonstrated in multivariate analysis. Patients transplanted in CR2 were more likely to experience relapse (HR 1.63, 95% CI 1.10–2.40, p = 0.01) leading to worse LFS (HR 1.35 95% CI 1.02–1.79, p = 0.04) and OS (HR 1.51 95% CI 1.11–2.06, p = 0.008).

Table 3.

Graft-versus-host disease and other significant predictors of outcomes in multivariate analyses of all patients.

Outcome Variable (Reference) HR (95% CI) P value
Relapse Acute GvHD Grade II as a timedependent variable 0.59 (0.39–0.94) 0.03
Second complete remission 1.63 (1.10–2.40) 0.01
LFS Acute GvHD Grade III–IV as a timedependent variable 1.51 (1.02–2.24) 0.04
Conditioning regimen (TBI+Fludarabine +Cyclophosphamide)
 TBI + Other 2.32 (0.99–5.46) 0.05
 Chemotherapy-only 2.89 (1.20–6.94) 0.02
Second complete remission 1.35 (1.02–1.79) 0.04
OS Acute GvHD Grade III–IV as a time dependent variable 1.94 (1.28–2.94) 0.002
Chronic GvHD as a time dependent variable 0.57 (0.35–0.93) 0.03
Conditioning regimen (TBI+Fludarabine +Cyclophosphamide)
 TBI+Other 2.84 (1.09–7.41) 0.03
 Chemotherapy-only 3.08 (1.15–8.23) 0.03
First complete remission 0.67 (0.49–0.90) 0.009
NRM Acute GvHD III–IV as a time dependent variable 3.19 (1.93–5.27) <0.0001
Age at transplant in years 1.07 (1.02–1.14) 0.01
Conditioning regimen (TBI+Fludarabine +Cyclophosphamide)
 TBI+Other 6.42 (1.33–30.94) 0.02
 Chemotherapy-only 4.88 (0.96–24.68) 0.05
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All models included the following variables: acute grade II GvHD as a timedependent variable, acute grade III–IV as a time-dependent variable, chronic GvHD as a time-dependent variable, disease state (first or second complete remission), leukemia phenotype (B-cell vs. T-cell ALL), history of central nervous system leukemia (yes or no), age at time of transplantation (in years), year of transplantation, total nucleated cell dose adjusted for patient weight, conditioning regimen (TBI + Fludarabine + Cyclophosphamide vs. other TBI regimens vs. chemotherapy-only regimen, GvHD prophylaxis (cyclosporine + steroids or MMF or other regimen) and treatment center. GvHD, graft versus host disease; TBI, total body irradiation; LFS, leukemia-free survival; OS, overall survival; NRM, non-relapse mortality;

A subgroup analysis performed in the separate cohorts demonstrated improved outcomes in patients who received TBI + Fludarabine (Flu) + Cy conditioning. We further explored this finding in the overall cohort. While the conditioning regimen was not predictive of relapse, the use of TBI + Flu + Cy was associated with a lower risk of NRM, improved OS and a trend to improved LFS as compared to other TBI-containing regimens (Table 3; NRM: HR 6.42 95% CI 1.33–30.94, p = 0.02; OS: HR 2.84 95% CI 1.09–7.41, p = 0.03; LFS: HR 2.32, 95% CI 0.99–5.46, p = 0.05). Overall and leukemia-free survival was also improved for those who received TBI + Flu + Cy as compared to chemotherapy-only regimens (OS: HR 3.08 95% CI 1.15–8.26, p = 0.03; LFS: HR 2.89 95% CI 1.20–6.94, p = 0.02).

Discussion

The aim of this retrospective registry-based study was to identify the impact of clinical factors on long-term outcomes including relapse after UCBT in a cohort of children and adolescents with ALL. These results provide insight into outcomes of pediatric recipients of UCBT beyond the clinical endpoints typically reported in the literature. To our knowledge, this study is the largest analysis to date focused solely on recipients of UCBT for pediatric ALL with a long-term follow-up.

The impact of GvHD and, by extension, GvL on relapse after UCBT for pediatric ALL was an important finding of this study. A select number of studies have shown an impact of acute 10, 34, 35 or cGvHD11, 36 on relapse after related or unrelated bone marrow HSCT for pediatric acute leukemia. Pulsipher et al observed that aGvHD and pre-transplant MRD, independently and in combination, influenced the risk of relapse after HSCT for pediatric ALL after controlling for graft source and other variables9. Our results, focused on single cord pediatric recipients with ALL, are consistent with the recent findings of Chen et al after UCBT (single and double) in patients with ALL or AML26. They also observed a strong association between ATG use with relapse and NRM, which our results did not support.

Our results also demonstrated the delicate balance between GvL and GVHD. While the presence of aGvHD grade II decreased relapse, patients who experienced grade III–IV were at higher risk of NRM without the benefit of less relapse. Therefore, efforts to harness GvHD with the goal of enhancing GvL are not without risk. Despite this, it is common practice to rapidly withdraw immunosuppression once relapse has occurred. Others have used also this approach to prevent relapse after HSCT in the setting of increasing host chimerism with tolerable rates of GvHD and some clinical effect 37–39. It remains unclear if this approach could be extended to patients without signs of impending relapse. Our results suggest that high-risk patients, especially those transplanted in CR1 as compared to CR2 patients, could benefit from more rapid tapers of immunosuppression. Given that most patients relapse beyond the first 100 days post-UCBT, it would be very reasonable to consider weaning immunosuppression in patients without active GvHD at that point. However, further studies are needed to define the optimal timing and the efficacy of this approach. The potential risk of such an approach would be increased risk of GvHD-associated NRM, although patients more commonly died of infectious causes not GvHD in this current study. Improvements in supportive care could help to offset potential increases in NRM especially in older children and adolescents. Promising early phase results using ex vivo cord blood graft expansion technologies may allow for more rapid immune recovery also leading to improved NRM40–43.

One approach that has been suggested is to use cord blood grafts intentionally mismatched to the recipient in an effort to enhance the GVL effect. Our results indicate that the use of HLA mismatched grafts decreased the risk of relapse by nearly half in CR2 patients, without any associated increase in NRM. Outcomes of CR2 patients were nearly identical whether a 4/6 or 5/6 HLA-matched graft was used with respect to relapse, LFS, OS and NRM. While there was a trend towards higher cGVHD in recipients of 4/6 HLA-matched grafts, there was no increase in aGVHD (data not shown). Our study supports the earlier finding of Eapen et al who noted lower relapse in pediatric leukemia patients who received 4/6 conventionally HLA-matched grafts18. More recently, Eapen et al demonstrated the importance of allelic high-resolution matching, including HLA-C loci, on NRM after UCBT, but they did not observe any impact on relapse or OS 44. Interestingly, HLA-matching was not a significant predictor of relapse for CR1 patients or in the overall cohort whereas aGvHD was associated with less relapse in both settings. It is possible that HLA matching is serving as a surrogate for aGvHD in the CR2 cohort but that is only speculative. Therefore, the use of intentionally mismatched cord blood graft, especially in CR2 patients, is intriguing and warrants further investigation.

Total body irradiation has been a mainstay of conditioning regimens used in patients with ALL45–47. Concerns regarding the considerable late effects associated with TBI48, including neurocognitive effects 49–51, have led to the practice of using chemotherapy-based regimens in young children. Older children and adolescents routinely receive TBI as part of conditioning, although TBI-sparing strategies in this population continue to be explored 52–54. Our results, after adjusting for age and other clinical factors, support the use of TBI as a critical component of treatment. Less relapse was observed in CR1 and CR2 patients receiving TBI-containing regimens without any increase in NRM. TBI-containing regimens were also associated with improved LFS and OS in CR1 patients. Recently, Eapen et al showed an advantage after UCBT for pediatric patients who received TBI + Flu + Cy conditioning55. This led us to perform an exploratory analysis in the overall cohort. In multivariate analysis of the larger cohort, the use of the TBI + Flu + Cy regimen did not improve the risk of relapse but was associated with lower NRM leading to improved 5-year LFS and OS. Two prospective UCBT trials in pediatric leukemia have recently reported low overall rates of relapse associated with this regimen16, 22, making this an intriguing conditioning regimen in pediatric ALL. Our results do not necessarily suggest that the use of TBI should be extended to young children who may be subject to significant neurocognitive deficits after TBI56–58. Young children are also at risk for certain late effects related to myeloablative conditioning59. Therefore, the decision to use TBI in younger children should balance disease-related factors with these known potential late effects. It is also important to acknowledge that clinicians may have selected non-TBI regimens based on patient specific co-morbidities including age. Importantly, we also investigated in a subgroup analysis whether very young patients (< 2 years old) and those with t(4, 11) influenced the outcomes in patients receiving chemotherapy-based regimens. Our results (data not shown) indicated that there were no significant differences in outcomes between recipients of chemotherapy-only regimens (< 2 years vs. older children). In summary, our results support the use of TBI as currently practiced for children and adolescents, especially in CR1 patients, in reducing relapse without additional NRM.

Limitations to this study include the retrospective nature and the use of registry-based data. While pre-transplant MRD status was available for a portion of the patients, we elected not to include this data in the analysis due to the amount of missing data and acknowledge that it is a limitation of the study. Pre-transplant MRD status has been shown in pediatric ALL to be a strong independent predictor of outcomes after HSCT9,29,60,61 and, while techniques have been significantly refined over the years, the optimal timing and clinical application of post-HSCT MRD testing continues to be explored. Continued advances in cellular and immunotherapy may also provide more effective approaches to management of MRD and relapse post-HSCT.

In summary, our results support the presence of a GvL effect in pediatric ALL after UCBT. We observed that patients who experienced acute GvHD, especially those transplanted while in CR1, were less likely to relapse. Strategies to enhance the GvL effect after UCBT should be further explored. On the basis of this study, the use of TBI in conditioning regimens should be strongly considered for patients given the lower CI of relapse observed in all patients and a survival advantage in CR1 patients. All together, optimizing these clinical factors could lead to improved outcomes in pediatric patients receiving a UCBT transplant for acute lymphoblastic leukemia.

Highlights.

  • Acute GvHD was protective of relapse after UCBT for children with ALL in first or second remission.

  • TBI-containing regimens improved outcomes after UCBT for pediatric ALL.

  • Risk of relapse after UCBT in second remission was lower using mismatched grafts.

Acknowledgments

The authors would like thank Drs. Mitchell Horwitz and Andrzej Kosinski for their critical review of the manuscript. The authors would like to acknowledge the following participating centers: Argentina ITMO, La Plata; Australia The Children’s Hospital at Westmead, Sydney; Randwick Sydney Children’s Hospital, Sydney; Belgium Children’s University Hospital BMT Unit, Brussels; Cliniques Universitaires St. Luc, Brussels; Universitair Ziekenhuis, Brussels; University Hospital, Gent; University Hospital Gasthuisberg Dept. of Hematology, Leuven; University of Liege, Liege; Brazil University Est. de Campinas, Campinas; Hospital Amaral Carvalho, Jau Sao Paulo; Canada Ste-Justine Hospital, Montréal; Czech Republic Institute of Hematology and Blood Transfusion, Prague; University Hospital Motol, Prague; Denmark Rigshospitalet, Copenhagen; Finland Hospital for Children & Adolescents University of Helsinki, Helsinki; Turku University Central Hospital, Turku; France Saint Jacques, Besançon; CHU Bordeaux Groupe Hospitalier Pellegrin-Enfants, Bordeaux; Haut-Lévêque, Bordeaux; Hotel Dieu CHU/Jean Perrin, Clermont-Ferrand; Tronche CHU/Albert Michallon, Grenoble; Claude Huriez, Lille; Hôpital Jeane de Flandre, Lille; Debrousse (pédiatrie), Lyon; La Timone (pédiatrie), Marseille; Centre Hospitalier Universitaire La Conception, Marseille Bouches du Rhone; Lapeyronie- adulte, Montpellier; Brabois, Nancy; Hotel Dieu, Nantes; Archet, Nice; Robert Debré, Paris; Saint-Antoine, Paris; Saint-Louis, Paris; Jean Bernard, Poitiers; Pontchaillou, Rennes; Charles Nicolle- pédiatrie, Rouen; Hautepierre (adulte), Strasbourg; Germany Universitaetsklinikum Dresden, Dresden; Universitaetsklinikum, Düsseldorf; Martin-Luther-Univ. Halle-Wittenberg, Halle; Greece St. Sophia Childrens Hospital, Athens; Hungary St. László Hospital, Budapest; Postgraduate Medical School, Miskolc; Israel Rambam Medical Center, Haifa; Schneider Childrens Medical Center of Israel, Petach-Tikva; Edmond & Lily Safra Children’s Hospital, Chaim Sheba Med Center, Tel-Hashomer; Italy Azienda Ospedaliero-Universitaria di Bologna, Bologna; Azienda Ospedaliero Universitaria Meyer – Ospedale di Careggi, Firenze; Institute G. Gaslini, Genova; Monza Ospedale San Gerardo Clinica Pediatrica dell Universita di Milano Bicocca; Clinica di Oncoematologia Pediatrica, Padova; Ospedale dei Bambini, Palermo; Fondazione IRCCS Policlinico San Matteo, Pavia; Università di Perugia, Perugia; Pesaro Hospital, Pesaro; Ospedale Civile Department of Hematology, Pescara; Azienda Ospedaliera Universitaria Pisa, Pisa; Ospedale S. Camillo, Roma; Rome Transplant Network, Roma; Univ.La Sapienza, Roma; Ospedale Infantile Regina Margherita Onco-Ematologia Pediatrica, Torino; Istituto per l’Infanzia Burlo Garofolo, Trieste; Hospital Pausilipon, Napoli; Jordan King Hussein Cancer Centre, Amman; Poland Wroclaw Medical University, Wroclaw; Portugal Inst. Portugues Oncologia, Lisboa; Inst. Portugues de Oncologia do Porto, Porto Saudi Arabia King Faisal Specialist Hospital & Research Centre, Riyadh; Spain Hospital Santa Creu i Sant Pau, Barcelona; Hospital Universitari Germans Trias i Pujol, Barcelona; Hospital Vall d Hebron, Barcelona, Hosp. Reina Sofia, Córdoba; Hospital Universitario La Paz, Madrid; Niño Jesus Children’s Hospital, Madrid; Hospital Universitario Virgen de la Arrixaca, Murcia; University Hospital of Asturias, Oviedo; Hospital Clínico, Salamanca; Hospital U. Marqués de Valdecilla, Santander; Hospital Universitario Virgen del Rocío, Sevilla; Hospital Universitario La Fe, Valencia; Hospital Infantil La Fe, Valencia; Sweden Sahlgrenska University Hospital, Goeteborg; University Hospital, Lund; Karolinska University Hospital Children’s Hospital, Stockholm; University Hospital, Uppsala; Switzerland University Hospital, Basel; Hopitaux Universitaires de Geneve, Geneva; University Children s Hospital, Zürich; The Netherlands University Hospital, Leiden; University Medical Centre, Utrecht; Turkey Akdeniz University Medical School, Antalya; United Kingdom Royal Hospital for Sick Children, Glasgow; Birmingham Childrens Hospital, Birmingham; Royal Hospital for Children, Bristol; Great Ormond Street Hospital, London; Royal Marsden Hospital, London Surrey; Royal Hallamshire Hospital, Sheffield;

This project was supported by Grant Number K23HL104575 from the National Heart, Lung, and Blood Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, And Blood Institute or the National Institutes of Health.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Authorship statement: K.P., V.R., E.G. and A.R. designed the study. K.P., M.L., A.R. and F.V. prepared and analyzed data. K.P. and F.V. wrote the manuscript. V.R., C.B. and J.T. participated in the writing of the manuscript. All other authors provided data for the study, edited and approved the manuscript.

Financial disclosures: The authors had no conflicts of interest to disclose.

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