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Graft Source

GvHD after umbilical cord blood transplantation for acute leukemia: an analysis of risk factors and effect on outcomes

Abstract

Using the Center for International Blood and Marrow Transplant Research (CIBMTR) registry, we analyzed 1404 umbilical cord blood transplantation (UCBT) patients (single (<18 years)=810, double (18 years)=594) with acute leukemia to define the incidence of acute GvHD (aGvHD) and chronic GvHD (cGvHD), analyze clinical risk factors and investigate outcomes. After single UCBT, 100-day incidence of grade II–IV aGvHD was 39% (95% confidence interval (CI), 36–43%), grade III–IV aGvHD was 18% (95% CI, 15–20%) and 1-year cGvHD was 27% (95% CI, 24–30%). After double UCBT, 100-day incidence of grade II–IV aGvHD was 45% (95% CI, 41–49%), grade III–IV aGvHD was 22% (95% CI, 19–26%) and 1-year cGvHD was 26% (95% CI, 22–29%). For single UCBT, multivariate analysis showed that absence of antithymocyte globulin (ATG) was associated with aGvHD, whereas prior aGvHD was associated with cGvHD. For double UCBT, absence of ATG and myeloablative conditioning were associated with aGvHD, whereas prior aGvHD predicted for cGvHD. Grade III–IV aGvHD led to worse survival, whereas cGvHD had no significant effect on disease-free or overall survival. GvHD is prevalent after UCBT with severe aGvHD leading to higher mortality. Future research in UCBT should prioritize prevention of GvHD.

Introduction

Acute GvHD (aGvHD) and chronic GvHD (cGvHD) are significant complications after allogeneic hematopoietic stem cell transplantation. Many recent changes in practice have led to changing patterns of GvHD. These include the introduction of alternative donor sources, reduced intensity conditioning and novel prophylaxis for GvHD. Risk factors for and effects on outcomes from GvHD have been described for conventional adult donor hematopoietic stem cell transplantation.1

Umbilical cord blood (UCB) has emerged as an alternative donor source with the development of new protocols that have significantly improved outcomes.2 It is unclear whether aGvHD and cGvHD after umbilical cord blood transplantation (UCBT) has similar risk factors and effects on outcomes compared with conventional donor sources. In this study, we proposed to establish the incidence of clinically significant aGvHD and cGvHD after UCBT, analyze the risk factors that are associated with its development and investigate the influence of aGvHD and cGvHD on patient outcomes after UCBT.

Materials and methods

Data source

The Center for International Blood and Marrow Transplant Research (CIBMTR) registry includes a voluntary working group of more than 450 centers worldwide that contribute detailed data on consecutive allogeneic and autologous hematopoietic cell transplantations to a statistical center at the Medical College of Wisconsin in Milwaukee and the National Marrow Donor Program (NMDP) Coordinating Center in Minneapolis. Participating centers are required to report all transplants consecutively; patients are followed longitudinally and compliance is monitored by on-site audits. Computerized checks for discrepancies, physicians’ review of submitted data and on-site audits of participating centers ensure data quality. Observational studies conducted by the CIBMTR are performed in compliance with all applicable federal regulations pertaining to the protection of human research participants. Protected Health Information used in the performance of such research is collected and maintained in the capacity of CIBMTR as a Public Health Authority under the HIPAA (Health Insurance Portability and Accountability Act of 1996) Privacy Rule.3

Patient selection

All patients who underwent UCBT for AML and ALL between 2003 and 2012 and were reported to CIBMTR were included initially (n=2663). Cases were then excluded for several reasons including: related UCB units (n=51), ex vivo expanded units (n=84), ex vivo T-cell depletion (n=7), lack of research consent (n=24), lack of conditioning (n=4), lack of GvHD prophylaxis (n=49), use of nonmyeloablative conditioning (n=4), use of 3/6 HLA-matched UCB units (n=40), lack of calcineurin inhibitor (n=68), missing HLA-matching data (n=18) and use of alemtuzumab (n=8). Based on numbers of cases and standard practice, only recipients of double UCBT 18 years old (excluded 206 recipients <18 years of age) who received myeloablative or reduced intensity conditioning, and only recipients of single UCBT <18 years old (excluded 247 recipients 18 years of age) who received myeloablative conditioning were included. HLA-match status was based on intermediate resolution for HLA-A and B and high resolution for HLA-DRB1. In the context of double UCBT, data on specific cord unit dominance were not available. For purposes of analysis of double UCBT, HLA matching (relative to the recipient) was analyzed using the following categories of double cord blood combinations: (1) 4/6+4/6, (2) 4/6+5/6 and (3) 5/6+5/6. Disease status at transplant was defined as early (first CR), intermediate (second, or greater, CR) and advanced (presence of active disease).

Study end points

The diagnoses of aGvHD and cGvHD were reported by the treating center. Acute GvHD was diagnosed and graded per previously published consensus guidelines.4 Chronic GVHD was diagnosed according to Seattle criteria5 as the National Institutes of Health (NIH) consensus criteria6 had not yet been implemented on CIBMTR forms during this time period. Overall survival (OS) considered death from any cause as the event, and surviving patients were censored at the date of last contact. Disease-free survival (DFS) was defined as survival without relapse or death from any cause, with patients who were alive and in CR censored at the time of last follow-up. Non-relapse mortality (NRM) was defined as death during a continuous CR. Relapse was defined as recurrence of the primary disease.

Statistical analysis

The χ2 or Fisher’s exact tests were used to compare frequencies for categorical variables, and analysis of variance was used to compare means for continuous variables in different subsets. Univariate probabilities for OS were calculated using the Kaplan–Meier estimator.7 Comparison of survival curves was made by the log-rank test. The cumulative incidences of aGvHD and cGvHD were calculated by treating death as a competing risk.8 Multivariate analysis was performed using Cox proportional hazards models for OS, PFS, relapse, NRM, aGvHD and cGvHD. All the clinical variables were first tested for affirmation of the proportional hazards assumption. Factors that violate the proportional hazards assumption were adjusted through stratification. Then, a stepwise model building procedure was used to develop models for each outcome with a threshold of 0.05 for both entry and retention in the model. We also assessed the effects of aGvHD II–IV, aGvHD III–IV and cGvHD on OS, PFS, relapse and NRM by forcing aGvHD II–IV, aGvHD III–IV or cGvHD into the multivariable models as a time-dependent variable. Center effect was also adjusted in all of the multivariable models. SAS version 9.3 (SAS Institute, Cary, NC, USA) was used for all the analyses.

Results

Clinical characteristics

A total of 810 recipients of single UCBT and 594 recipients of double UCBT were included. Patient and clinical characteristics are summarized in Table 1a. For the 810 recipients of single UCBT, median age was 6 years (range, <1–18). In all, 44% of patients had AML, 56% had ALL and all received myeloablative conditioning. In addition, 21% of patients received a 6/6 HLA-matched UCBT, 47% received a 5/6 HLA-matched UCBT and 32% received a 4/6 HLA-matched UCBT. All patients received calcineurin inhibitor-based GvHD prophylaxis. Antithymocyte globulin (ATG) was used in 64% of patients. Table 1a shows differences between patients who received ATG compared with those who did not.

Table 1a Clinical characteristics of patients undergoing single UCBT

For the 594 recipients of double UCBT, median age was 42 years (range, 18–79). 72% of recipients had AML and 28% had ALL. In all, 59% of patients received myeloablative conditioning, whereas 41% received reduced intensity conditioning. 26% received a 5/6+5/6-matched combination, 21% received a 5/6+4/6 combination, In addition, 42% of recipients received a 4/6+4/6 combination, and 10% received combinations including a 6/6 UCB unit. All patients received calcineurin inhibitor-based GvHD prophylaxis. ATG was employed in 21% of patients. Table 1b shows differences between patients who received ATG compared with those who did not.

Table 1b Clinical characteristics of patients undergoing double UCBT

Single UCBT: GvHD

After single UCBT, the cumulative incidence of grade II–IV and grade III–IV aGvHD at 100 days was 39% (95% confidence interval (CI), 36–43%) and 18% (95% CI, 15–20%), respectively (Table 2). Median time to aGvHD was 25 days (range, 3–211). Multivariate analysis showed that absence of ATG was the only significant factor associated with grades II–IV (hazard ratio (HR), 1.56; 95% CI, 1.21–2.01; P=0.0006; Figure 1). No significant factors were associated with grade III–IV aGvHD. Notably, the following were not associated with aGvHD: age, race, gender, CMV serostatus, HLA matching, total nucleated cell dose, year of transplant, underlying disease, use of TBI and GvHD prophylaxis regimen. Given the clinical differences between those who received ATG and those who did not, we also performed this analysis in patients who did not receive ATG. In this subset, no factors were significantly associated with the development of aGvHD.

Table 2 Cumulative incidences of acute and chronic GvHD
Figure 1
figure1

Cumulative incidence of grade 2–4 aGvHD in recipients of single UCBT who received ATG (n=521) and those who did not (n=289).

After single UCBT, the cumulative incidence of cGvHD was 27% (95% CI, 24–30%) at 1 year and median time to cGvHD was 5.3 months. Multivariate analysis showed that prior aGvHD (HR, 2.02; 95% CI, 1.51–2.70; P<0.0001) was the only significant factor associated with cGvHD. Notably, absence of ATG was not significantly associated with the development of cGvHD (HR, 1.05; 95% CI, 0.76–1.44; P=0.78).

Double UCBT: GvHD

For recipients of double UCBT, the cumulative incidence at day 100 of grade II–IV and grade III–IV aGvHD was 45% and 22%, respectively. Median onset to aGvHD was 26 days (range 6–380). Multivariate analysis demonstrated that absence of ATG was associated with grade II–IV aGvHD (HR, 2.33; 95% CI, 1.54–3.52; P=0.0001; Figure 2), but not with grade III–IV aGvHD (HR, 1.28; 95% CI, 0.89–1.84; P=0.17). In addition, reduced intensity conditioning protected from both II–IV (HR, 0.73; 95% CI, 0.56–0.95; P=0.019) and III–IV (HR, 0.63; 95% CI, 0.44–0.92; P=0.016) aGvHD. Notably, the following factors were not associated with aGvHD: age, gender, CMV serostatus, HLA matching, total nucleated cell dose, underlying disease, use of TBI, year of transplant and GvHD prophylaxis regimen. In patients who did not receive ATG, no factors were shown to be significantly associated with aGvHD.

Figure 2
figure2

Cumulative incidence of grades 2–4 aGvHD in recipients of double UCBT who received ATG (n=122) and those who did not (n=472).

For all recipients of double UCBT, the cumulative incidence of cGvHD was 26% (95% CI, 22–29%) at 1 year. Median time to cGvHD was 5.3 months. Multivariate analysis showed that prior aGvHD (HR, 2.12; 95% CI, 1.52–2.95; P<0.0001) was associated with cGvHD, whereas ATG had no significant effect.

Single UCBT: effect of GvHD on NRM, Relapse, DFS and OS

For all recipients of single UCBT, the development of grade II–IV aGvHD (HR, 2.06; 95% CI, 1.47–2.88; P<0.0001) and grade III–IV aGvHD (HR, 2.75; 95% CI, 1.92–3.93; P<0.0001) was associated with increased NRM. For disease relapse, grade II–IV aGvHD was protective (HR, 0.69; 95% CI, 0.51–0.93; P=0.014) whereas grade III–IV disease had no significant effect (HR, 0.78; 95% CI, 0.53–1.15; P=0.22). For DFS, the development of grade II–IV aGvHD has no effect (HR, 1.06; 95% CI, 0.86–1.32; P=0.58), whereas grade III–IV disease was associated with shorter DFS (HR, 1.38; 95% CI, 1.07–1.79; P=0.014). Similarly, for OS, grade II–IV aGvHD had no effect (HR, 1.08; 95% CI, 0.87–1.34; P=0.50), whereas grade III–IV disease was associated with shorter survival (HR, 1.51; 95% CI, 1.17–1.95; P=0.0017; see Table 3a). When analyzed independently, grade II aGvHD did not have a significant effect on DFS or OS compared with those without aGvHD (HR, 0.74; 95% CI, 0.55–0.99; P=0.045 for OS; HR, 0.77; 95% CI, 0.57–1.03; P=0.08 for DFS). Compared with patients with grade III–IV aGvHD, patients with grade II disease had similar rates of relapse, but less NRM and improved DFS and OS (data not shown). After single UCBT, cGvHD led to a higher risk of NRM (HR, 1.53; 95% CI, 0.97–1.90; P=0.022) but no effect on relapse (HR, 1.10; 95% CI, 0.74–1.63; P=0.63), DFS (HR, 1.23; 95% CI, 0.91–1.65; P=0.18) and OS (HR, 0.96; 95% CI, 0.72–1.29; P=0.82; see Table 3a). Table 3b shows full results of the multivariate modeling.

Table 3a Effect of acute and cGvHD on outcomes after single and double UCBT
Table 3b Hazard ratios for clinically significant predictors of major outcomes after single and double UCBT

Double UCBT: effect of GvHD on NRM, Relapse, PFS and OS

For all recipients of double UCBT, the development of grade II–IV aGvHD (HR, 1.41; 95% CI, 1.05–1.90; P=0.022) and grade III–IV aGvHD (HR, 2.24; 95% CI, 1.66–3.04; P<0.0001) was associated with increased NRM. In terms of disease relapse, neither grade II–IV aGvHD (HR, 0.87; 95% CI, 0.63–1.20; P=0.39) nor grade III–IV disease (HR, 0.68; 95% CI, 0.44–1.06; P=0.084) had any significant impact. Concerning DFS, the development of grade II–IV aGvHD had no effect (HR, 1.11; 95% CI, 0.90–1.37; P=0.34), whereas grade III–IV disease was associated with shorter DFS (HR, 1.41; 95% CI, 1.11–1.79; P=0.005). Similarly, for OS, grade II–IV aGvHD had no effect (HR, 1.05; 95% CI, 0.86–1.30; P=0.60), whereas grade III–IV disease was associated with shorter survival (HR, 1.48; 95% CI, 1.17–1.86; P=0.001; see Table 3a). When analyzed independently, grade II aGvHD did not have a significant effect on DFS (HR, 0.80; 95% CI, 0.60–1.06; P=0.12) but did lead to improved OS (HR, 0.69; 95% CI, 0.52–091; P=0.0084) when compared with those without aGvHD. Compared with patients with grade III–IV disease, patients with grade II aGvHD had similar rates of relapse, but had significantly less NRM and improved DFS and OS (data not shown). For all recipients of double UCBT, cGvHD showed a borderline significant association with a higher risk of NRM (HR, 1.49; 95% CI, 0.98–2.29; P=0.065) and a significantly lower risk of relapse (HR, 0.59; 95% CI, 0.36–0.96; P=0.033), but had no significant effect on DFS (HR, 0.98; 95% CI, 0.71–1.33; P=0.87) or OS (HR, 0.95; 95% CI, 0.71–1.27; P=0.70; see Table 3a). Table 3b shows full results of the multivariate modeling.

Discussion

We performed a large registry analysis using the CIBMTR database to define the incidence of aGvHD and cGvHD, the clinical factors associated with their development and the effect of GvHD on outcomes after pediatric single and adult double UCBT. Our results confirm that the incidence of aGvHD after UCBT is comparable to that observed with conventional donor sources,7 but the incidence of cGvHD appears to be less, as has been reported previously.8, 9

In our study, for pediatric recipients of single UCBT, the absence of ATG was significantly associated with the development of grade II–IV aGvHD. Prior aGvHD was associated with cGvHD. In the setting of adult double UCBT, the absence of ATG and myeloablative conditioning were associated with grade II–IV aGvHD, whereas prior aGvHD was associated with cGvHD. As expected, severe aGvHD resulted in increased NRM and decreased DFS and OS after both single and double UCBT. After single UCBT, the development of cGvHD appeared to increase NRM, whereas after double UCBT, cGvHD was associated with less disease relapse. Yet, cGvHD clearly had no significant effect on DFS and OS.

Several retrospective analyses have previously attempted to define risk factors for aGvHD and cGvHD after UCBT and these are summarized in Tables 4a and b, respectively. Similar to our analysis, lack of ATG and myeloablative conditioning have been associated with aGvHD in other studies,10, 11, 12 yet unlike our study, degree of HLA matching has also been shown to be influential.10, 12, 13 For cGvHD, as observed in our analysis, prior aGvHD has been shown to be the most important factor,10, 11, 12, 14 and several groups have also reported the association of higher HLA mismatch with cGvHD.10, 12, 14

Table 4a Summary of studies analyzing risk factors for acute GvHD after UCBT
Table 4b Summary of studies analyzing risk factors for chronic GvHD after UCBT

Our study represents the largest study of UCBT patients investigating risk factors for aGvHD and cGvHD, as well as the effect that aGvHD and cGvHD has on long-term outcomes. The use of ATG appeared to be the most significant factor associated with aGvHD after both single UCBT and double UCBT. It is important to note that our analysis did not distinguish different types of ATG, incorporate information on the dose or schedule employed as well as accompanying systemic corticosteroids given or report the rationale behind why treating physicians chose to use ATG. It is interesting that use of ATG was not significantly associated with cGvHD after single or double UCBT and this may reflect a significant difference between UCBT and other donor sources. After multivariate analysis, ATG had no significant effect on PFS or OS after single or double UCBT. Although the overall effect of ATG was not a primary objective of this study, we do believe that future analyses are warranted with a focus on other important endpoints not collected here such as graft failure, specific infections and post-transplant lymphoproliferative disease. The use of ATG in UCBT is controversial as recent studies have suggested a benefit in terms of protection from GvHD,15, 16 whereas other studies have shown that ATG is associated with an increase in overall mortality.17, 18, 19

Interestingly, the degree of HLA mismatch was not a significant factor in our multivariate analysis for single UCBT, and we could not analyze this factor accurately in double UCBT because of missing information on specific cord unit dominance. Other limitations of our analysis include those inherent to any large registry analysis including heterogeneity of practice. Specifically, for studies involving GvHD, the diagnosis does not undergo rigorous central review. This point is emphasized by a recent analysis describing characteristics of cGvHD in 87 patients undergoing UCBT at a single center. After review of medical records for the 54 patients who were reported to have cGvHD, only 7 had classic cGvHD.20 In our analysis, the severity of cGvHD could not be analyzed as the modern NIH classification and grading system for cGvHD was developed in the midst of the era of transplantation for this group.6 We also did not review or analyze any information on treatment for GvHD or response, but this should certainly be studied, especially as GvHD after UCBT may respond differently compared with GvHD after transplantation from other donor sources.21

In conclusion, aGvHD and cGvHD remain significant complications after UCBT with severe aGvHD, clearly affecting long-term survival. Rates of aGvHD appear comparable to that observed with conventional matched donor sources, yet the incidence of cGvHD appears to be significantly less. In our study, omission of ATG was the most important risk factor associated with the development of aGvHD, and prior aGvHD was the most significant risk factor for the development of cGvHD. Preventing aGvHD for patients after UCBT should be a priority and possible avenues include formally defining the role of ATG, enhanced or novel GvHD prophylaxis regimens22, 23 and improving methods of UCB expansion or activation to use better HLA-matched units.24 Although cGvHD appears to be less prevalent after UCBT, a future analysis should be performed when a large number of patients have been classified according to a standard grading scheme where severity of disease can be taken into account to truly assess its impact.

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Acknowledgements

The CIBMTR is supported by Public Health Service Grant/Cooperative Agreement 5U24-CA076518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID); a Grant/Cooperative Agreement 5U10HL069294 from NHLBI and NCI; a contract HHSH250201200016C with Health Resources and Services Administration (HRSA/DHHS); two Grants N00014-13-1-0039 and N00014-14-1-0028 from the Office of Naval Research; and grants from Alexion; *Amgen, Inc.; Anonymous donation to the Medical College of Wisconsin; Be the Match Foundation; *Bristol Myers Squibb Oncology; *Celgene Corporation; *Chimerix, Inc.; Fred Hutchinson Cancer Research Center; Gamida Cell Ltd; Genentech, Inc.; Genzyme Corporation; *Gilead Sciences, Inc.; Health Research, Inc. Roswell Park Cancer Institute; HistoGenetics, Inc.; Incyte Corporation; *Jazz Pharmaceuticals, Inc.; Jeff Gordon Children’s Foundation; The Leukemia & Lymphoma Society; The Medical College of Wisconsin; Merck & Co, Inc.; Mesoblast; *Millennium: The Takeda Oncology Co.; *Miltenyi Biotec, Inc.; National Marrow Donor Program; Neovii Biotech NA, Inc.; Novartis Pharmaceuticals Corporation; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc.; Otsuka America Pharmaceutical, Inc.; Otsuka Pharmaceutical Co, Ltd– Japan; Oxford Immunotec; Perkin Elmer, Inc.; Pharmacyclics; *Sanofi US; Seattle Genetics; Sigma-Tau Pharmaceuticals; *Spectrum Pharmaceuticals, Inc.; St Baldrick’s Foundation; *Sunesis Pharmaceuticals, Inc.; Swedish Orphan Biovitrum, Inc.; Telomere Diagnostics, Inc.; TerumoBCT; Therakos, Inc.; University of Minnesota; and *Wellpoint, Inc. The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense, Health Resources and Services Administration (HRSA) or any other agency of the US Government. The symbol ‘*’ indicates Corporate Members.

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YC, CSC, TW, SRS and MA drafted the research plan; YC, CSC, TW, SRS, MA, MTH, DRC, AA, JP, AU, SWC, TN, TT, YI, BW, DIM, HA, LL, LY, MB, MSC, MQ, RS, RPG, RM, SJ, AB, BS, HF, IDL, JS, MA, MAK, MA, OR, RR, RFO, SH, SS, TRS, MLM and AL critically revised research plan; TW and MTH performed statistics; YC, CSC, TW, SRS and MA analyzed and interpreted data; YC, CSC, TW, SRS and MA drafted the paper; YC, CSC, TW, SRS, MA, MTH, DRC, AA, JP, AU, SWC, TN, TT, YI, BW, DIM, HA, LL, LY, MB, MSC, MQ, RS, RPG, RM, SJ, AB, BS, HF, IDL, JS, MA, MAK, MA, OR, RR, RFO, SH, SS, TRS, MLM and AL critically revised the paper.

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Correspondence to Y-B Chen.

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Chen, YB., Wang, T., Hemmer, M. et al. GvHD after umbilical cord blood transplantation for acute leukemia: an analysis of risk factors and effect on outcomes. Bone Marrow Transplant 52, 400–408 (2017). https://doi.org/10.1038/bmt.2016.265

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