Recent Decrease in Acute Graft-versus-Host Disease in Children with Leukemia Receiving Unrelated Donor Bone Marrow Transplants

Recent Decrease in Acute Graft-versus-Host Disease in Children with Leukemia Receiving Unrelated Donor Bone Marrow Transplants Stella M. Davies,1 Dan Wang,2 Tao Wang,3 Muhkta Arora,2 Olle Ringden,4 Claudio Anasetti,5 Steven Pavletic,6 James Casper,7 Margaret L. MacMillan,8 Jean Sanders,9 Donna Wall,10 Nancy A. Kernan11 Unrelated donor (URD) bone marrow transplantation (BMT) is an effective treatment for leukemia in children, but its success is threatened by graft-versus-host disease (GVHD) and relapse. In this report, we describe the incidence of and risk factors for GVHD over time in children receiving URD BMT. We analyzed outcomes of 638 myeloablative URD BMTs performed between 1990 and 2003 to treat acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia, or myelodysplastic syndrome MDS, using the Center for International Blood and Marrow Transplant Research (CIBMTR) database. All recipients were under age 18 years and had available high-resolution HLA typing for HLA-A, -B, -C, and -DRB1. Overall, 27% of the recipients developed acute GVHD (aGVHD) grade III-IV; the risk was significantly higher in children receiving T cell–replete grafts compared with those receiving T cell–depleted grafts (odds ratio [OR] 5 3.12; 95% confidence interval [CI] 5 2.02 to 4.83; P \ .0001). Acute GVHD significantly reduced the risk of relapse in children with ALL (OR 5 0.34; 95% CI 5 0.13 to 0.86; P 5 .0052), but not in those with AML (OR 5 0.58; 95% CI 5 0.22 to 2.98; P 5 .26). The risk of aGVHD was higher in children undergoing transplantation in 1990-1998 (n 5 365) compared with those doing so in 1999-2003 (OR 5 1.93; 95% CI 5 1.27 to 2.91; P 5 .002). We conclude that outcomes have changed significantly over time, with a reduced risk of aGVHD associated with the more recent transplantations. Biol Blood Marrow Transplant 15: 360-366 (2009) Ó 2009 American Society for Blood and Marrow Transplantation

KEY WORDS: GVHD, Unrelated donor transplantation, Children, Leukemia INTRODUCTION For more than 30 years, bone marrow transplantation (BMT) has been used as a curative therapy to treat From the 1Dept. of Pediatrics, Cincinnati Children’s Hospital and Medical Center, Cincinnati, Ohio; 2Center for International Blood and Marrow Transplant Research, Minneapolis, Minnesota; 3Center for International Blood and Marrow Transplant Research, Milwaukee, Wisconsin; 4Dept. of Laboratory Medicine, Karolinska University Hospital, Huddinge, Sweden; 5Blood and Marrow Transplant, H. Lee Moffit Cancer Center and Research Institute, Tampa, Florida; 6Experimental Transplant and Immunology Branch, National Institutes of Health, Bethesda, Maryland; 7Dept. of Pediatrics, Children’s Hospital and Medical College of Wisconsin, Milwaukee, Wisconsin; 8Dept. of Pediatrics, University of Minnesota, Minneapolis, Minnesota; 9Dept. of Pediatrics, Fred Hutchinson Cancer Research Center, Seattle, Washington; 10Texas Transplant Institute, San Antonio, Texas; and 11Dept. of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York. Financial disclosure: See Acknowledgments on page 366. Correspondence and reprint requests: Stella M. Davies, ML 7015, Cincinnati Children’s Hospital and Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45230 (e-mail: [email protected]). Received September 25, 2008; accepted December 13, 2008. 1083-8791/09/153-0001$36.00/0 doi:10.1016/j.bbmt.2008.12.495

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malignant and nonmalignant diseases in children [1-3]. The early success of BMT in pediatric populations allowed extension of the treatment to adult populations, and today, the majority of BMTs are performed in adults. The distribution of diagnoses, comorbid conditions, and the impact of previous treatments differ significantly between pediatric and adult populations. Most studies have found superior outcomes in younger patient populations [4-8]; however, patient numbers are generally too low to enable a detailed analysis of the impact of younger age on specific outcomes. The occurrence of graft-versus-host disease (GVHD) significantly threatens the success of unrelated donor (URD) BMT and is a frequent cause of morbidity and mortality. In this study, we used a large Center for International Blood and Marrow Transplant Research (CIBMTR) database of myeloablative URD BMT to perform a detailed analysis of risk factors for and clinical impacts of acute GVHD (aGVHD) and chronic GVHD (cGVHD) in a pediatric population. Our data indicate some significant temporal changes in the outcomes of URD BMT for children with leukemia. In particular, the risk of aGVHD was higher in children who underwent transplantation in 1990-1998

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compared with those who did so in 1999-2003, but the risk of relapse was lower in the former group. PATIENTS AND METHODS The CIBMTR The CIBMTR, a research affiliation of the International Bone Marrow Transplant Registry (IBMTR), Autologous Blood and Marrow Transplant Registry (ABMTR), and the National Marrow Donor Program (NMDP), is a voluntary working group comprising more than 450 transplantation centers worldwide. These centers contribute detailed data on consecutive allogeneic and autologous hematopoietic stem cell transplantations to a Statistical Center at the Health Policy Institute of the Medical College of Wisconsin in Milwaukee or the NMDP Coordinating Center in Minneapolis. Participating centers are required to report all transplantations consecutively; compliance is monitored by onsite audits. Patients are followed longitudinally, with yearly follow-up. Computerized checks for errors, physicians’ review of submitted data, and onsite audits of participating centers ensure data quality. The CIBMTR collects data at 2 levels: registration and research. Registration data include disease type, age, sex, pretransplantation disease stage and chemotherapy responsiveness, date of diagnosis, graft type (bone marrow– and/or blood-derived stem cells), conditioning regimen, posttransplantation disease progression and survival, development of a new malignancy, and cause of death. Requests for data on progression or death for registered patients are made at 6-month intervals. All CIBMTR teams contribute registration data. Research data, including detailed disease, pretransplantation, and posttransplantation clinical information, are collected on subsets of registered patients selected using a weighted randomization scheme. Patients and Transplantation Procedure The analysis was restricted to BMT recipients under age 18 years with available results of highresolution typing reported by the transplantation center or performed retrospectively by the NMDP [9,10]. All patients received URD bone marrow as the primary stem cell source. Patients receiving peripheral blood stem cell or cord blood grafts were excluded, because the natural history of GVHD may differ in these cases. Study Population The NMDP retrospectively obtained consent for data submission and study participation from surviving patients or parents/legal guardians for transplantations that it facilitated in the United States before 2002. Thereafter, informed consent was obtained prospectively. The NMDP’s Institutional Review Board waived

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consent for patients who had died before consent was solicited (transplantations facilitated before 2002), and any nonconsenting surviving patients were excluded. To overcome the bias associated with the inclusion of a proportion of surviving patients (those consenting) but all deceased recipients, and hence their overrepresentation, a sample of deceased patients was selected using a weighted randomized scheme that adjusted for overrepresentation of deceased patients in the consented cohort [11]. This weighted randomized scheme was developed based on all survivors included in the NMDP database. A logistic regression model was fit to identify the factors that predicted whether or not a patient had consented to the use of data collected by the NMDP. This analysis found that the following factors were associated with the likelihood of a patient consenting: age, disease type, race, sex, cytomegalovirus serostatus, and country of transplantation (United States vs non-United States). Using estimated consenting probabilities from this model based on the characteristics of dead patients, the biased coin method of randomization was performed to determine which of the dead patients likely would have consented to participate had they been alive. Thus, this procedure includes the dead patients at the same probability as the surviving patients who consented to participate. The NMDP facilitated a total of 2013 pediatric BMTs between 1990 and 2003 in patients with acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), or myelodysplastic syndrome (MDS) as their first transplantation, with bone marrow as the stem cell source. High-resolution HLA typing was available for 1043 of these patients. Approximately 12% of dead patients (n 5 123) were deleted by the weighted randomized method. Patients who had more than 1 antigen mismatch (n 5 208) or who received a nonmyeloablative preparative regimen (n 5 28) were excluded. An additional 46 patients were subsequently excluded because of the presence of more than 1 allele mismatch (n 5 30) or missing information on aGVHD or cGVHD (n 5 16). The final study population comprised 638 children. Patient characteristics are summarized in Table 1. The most common diagnosis was ALL, and the median patient age was 10 years (range, \ 1 year to 17.9 years). Median donor age was 36 years (range, 19 to 60 years). The patients received a variety of preparative regimens, as determined by the individual transplantation centers. Most of the recipients (90%) received total body irradiation (TBI; 550 to 1500 cGy); 10% received chemotherapy alone. Chemotherapic drugs administered as part of the preparative regimen included cyclophosphamide, busulfan, cytosine arabinoside, etoposide, and thiotepa. GVHD prophylaxis varied among transplantation centers. The graft was depleted of T cells ex vivo (TCD) in 37% of cases; these children

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Table 1. Characteristics of Patients Age < 18 Years Who Underwent URD BMT after a Myeloblative Conditioning Regimen Reported to the CIBMTR between 1990 and 2003 Characteristic Number of patients Age at transplantation, years, median (range) Age at transplantation, years, n (%) <5 6 to 10 11 to15 >15 Male sex, n (%) Performance score, n (%) < 90 90 to 100 Unknown Disease, n (%) AML ALL CML MDS Disease status at transplantation, n (%)* Early Intermediate Advanced Other† Donor age, years, median (range) Donor age, years, n (%) 18 to 30 31 to 40 41 to 60 Donor–-recipient sex match, n (%) Male / Male Male / Female Female / Male Female / Female Donor–recipient CMV match, n (%) D(2)/R(2) D(2)/R(+) D(+)/R(2) D(+)/R(+) Unknown Donor pregnancy status, n (%) Male donor Female, no pregnancy One or more pregnancies Unknown Conditioning regimen, n (%) Cy + TBI ± other TBI + other Bu + Cy ± other Bu ± other GVHD prophylaxis, n (%) T cell depletion CSA + MTX ± other CSA ± other FK506 ± other MTX ± other Missing HLA match, n (%) Matched Single allele mismatch Single antigen mismatch Follow-up of survivors, months, median (range)

638 10 (<1 to 17.9) 151 (24) 183 (29) 167 (26) 137 (21) 365 (57) 111 (17) 513 (80) 14 (2) 168 (26) 329 (52) 75 (12) 66 (10) 175 (27) 310 (49) 128 (20) 25 (4) 36 (19 to 60) 169 (26) 240 (38) 229 (36) 230 (36) 132 (21) 135 (21) 141 (22) 277 (43) 136 (21) 125 (20) 88 (14) 12 (2) 362 (57) 117 (18) 153 (24) 6 (1) 543 (85) 29 (5) 57 (9) 9 (1) 234 (37) 338 (53) 18 (3) 46 (7) 1 (<1) 1 (<1) 296 (46) 84 (13) 258 (40) 87 (3 to 195)

Cy indicates cyclophosphamide; Bu, busulfan; CSA, cyclosporin A; MTX, methotrexate. *Risk groups are defined as early, including AML or ALL in CR1, CML in CP1, or MDS with RA or RARS; intermediate, including AML or ALL in $ CR2, CML in accelerated phase or $CP2; or advanced, including AML or ALL in relapse or PIF, CML in blast phase, and MDS with RAEB-Tor IPSS-4. †Other (n 5 25) includes ALL, disease status before transplantation missing (n 5 1); MDS, not otherwise specified (n 5 3); chronic myelomonocytic leukemia (n 5 3); and paroxysmal nocturnal hemoglobinuria (n 5 1).

may or may not have received treatment with a calcineurin inhibitor, based on the degree of T cell depletion; 67% received a non–T cell–depleted graft along with GVHD prophylaxis with cyclosporine A or tacrolimus. Risk groups were defined as follows: early, including AML or ALL in first complete remission (CR1), CML in first chronic phase (CP1), and MDS with refractory anemia (RA) or RA with ringed sideroblasts (RARS); intermediate, including AML or ALL in $ CR2 and CML in accelerated phase or $ CP2; and advanced, including AML or ALL in relapse or primary induction failure (PIF), CML in blast phase, and MDS with RA with excess blasts in transformation (RAEB-t) or international prognostic scoring system (IPSS-4). Donor Selection and Bone Marrow Processing Donor characteristics are summarized in Table 1. High-resolution typing at HLA-A, -B, -C, and -DRB1 was performed for all donor–recipient pairs [12]. Of the recipients, 46% were matched with their recipient at all 8 loci, 13% had a single allele mismatch, and 40% had a single antigen mismatch. Statistical Analysis Univariate analysis of survival was calculated using the Kaplan-Meier method, and comparisons were made using log-rank statistics [13,14]. Rates of aGVHD, cGVHD, and relapse were calculated using cumulative incidence, with death serving as the competing risk [15]. Cumulative incidences for aGVHD, cGVHD, and relapse were compared using Taylor series linear approximation to estimate the variance [16]. The proportional hazards model was used for the multivariate analysis of survival [17]. Cumulative incidence estimates of aCVHD, cGVHD, relapse, and treatment-related mortality (TRM) were estimated using the pseudovalue approach of Klein [18]. Additional models were constructed for relapse and TRM, treating aGVHD as a time-dependent variable. Variables considered in the analyses included recipient age, sex, performance score, diagnosis, and disease stage at transplantation. Transplantation- related variables included donor age, donor–recipient sex match, donor– recipient cytomegalovirus serology, donor parity, preparative therapy (radiation-containing vs non–radiation-containing), GVHD prophylaxis (T cell depletion vs no T cell depletion), HLA matching (8 allele match vs 7/8 match, including single allele mismatch but antigen match and single antigen mismatch), and year of transplantation (1990-1998 vs 1999-2003). RESULTS Acute GVHD The cumulative incidence of grade II-IV aGVHD was 45% (95% confidence interval [CI] 5 42% to 49%), and that of grade III-IV aGVHD was 27%,

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indicating that most cases of aGVHD were severe. Multivariate analysis found similar risk factors for grade II-IV and grade III-IV aGVHD. As expected, T cell–replete grafts were associated with a significantly increased risk of aGVHD compared with T cell–depleted grafts (odds ratio [OR] 5 3.12; 95% CI 5 2.02 to 4.83; P \ .0001). In addition, transplantation in 1990-1998 was associated with significantly increased risk of aGVHD compared with transplantation in 1999-2003 (OR 5 1.93; 95% CI 5 1.27 to 2.91; P 5 .002). Notably, HLA mismatch at a single locus did not increase risk of GVHD (OR 5 1.00; 95% CI 5 0.68 to 1.46; P 5 .98), and age and diagnosis also did not significantly modify the risk. Chronic GVHD The cumulative incidence of cGVHD was 35% (95% CI 5 31% to 38%) 3 years after BMT. Multivariate analysis of risk factors for cGVHD revealed only a modest, non–statistically significant increase in the risk of cGVHD associated with a parous female donor (OR 5 1.45; 95% CI 5 0.92 to 2.29; P 5 .11), and no effect on risk associated with HLA mismatch (OR 5 1.19; 95% CI 5 0.78 to 1.79; P 5 .41) or T cell depletion. Relapse The cumulative incidence of relapse was 26% (95% CI 5 22% to 29%) at 3 years. Multivariate analysis of risk factors for relapse was conducted for the entire group and separately for those children with AML and with ALL, because we hypothesized that risk factors might differ in these 2 categories. The risk of relapse was significantly lower in children with MDS compared with those with acute leukemias, with markedly increased risk in those children with the most advanced disease (OR 5 15.37, 95% CI 5 6.1 to 38.7; P\.0001). The risk of relapse declined markedly with increasing recipient age (OR 5 0.23 for recipients age 16 to 18 years compared with a reference group of children under age 5 years; 95% CI 5 0.10 to 0.54; P 5 .0004). The risk of relapse was reduced in recipients of marrow from parous female donors (OR 5 0.43; 95% CI 5 0.23 to 0.83; P 5 .01), perhaps reflecting the modest increase in cGVHD in these children, and was not increased in recipients of T cell–depleted marrow. A perhaps surprising observation was a decreased risk of relapse in children who underwent transplantation in 1990-1998 compared with those who did so in 1999-2003 (OR 5 0.47, 95% CI 5 0.28 to 0.78; P 5 .004). Multivariate analysis of risk factors for relapse restricted to children with AML (n 5 156) demonstrated a nonsignificant reduction in incidence of relapse (OR 5 0.58 comparing relapse incidence in children with GVHD grade III-IV with those without GVHD; 95% CI 5 0.22 to 1.58; P 5 .26) (Table 2).

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Table 2. Multivariate Analysis for Relapse in Children Diagnosed with AML Who Underwent URD BMT (n 5 156) Variable HLA matching Matched 7/8 matched Other significant covariates Grade III-IV aGVHD No Yes Disease stage Early Intermediate Advanced Recipient age category < 5 years 6 to 10 years 11 to 15 years 16 to 17.9 years Transplantation era 1999-2003 1990-1998

n

OR (95% CI)

P value

69 87

1.00* 0.63 (0.26 to 1.55)

89 67

1.00* 0.58 (0.22 to 1.58)

33 69 54

1.00* 0.90 (0.23 to 3.54) 12.59 (3.09 to 51.32)

46 32 47 31

1.00* 0.40 (0.13 to 1.28) 0.12 (0.04 to 0.39) 0.12 (0.02 to 0.65)

.12 .0005 .014

64 92

1.00* 0.14 (0.13 to 0.73)

.0075

.36

.26 <.0001 .88 .0004 .0059

AGVHD III-IV is treated as a time-dependent variable. *Reference group.

But the risk of relapse was significantly higher in children who underwent BMT in 1999-2003, in children under age 5 years, and in children with advanced disease, as was seen in the group overall. In contrast, the occurrence of aGVHD significantly reduced the risk of relapse in children with ALL (OR 5 0.34 comparing relapse incidence in children with aGVHD grade II-IV with those without aGVHD; 95% CI 5 0.13 to 0.86; P 5 .0052) (Table 3). Similar to the findings in children with AML, children over age 5 years with ALL and less advanced disease had a reduced risk of relapse. Although the risk of relapse was increased in children who underwent BMT in 19992003, this increase was of only marginal statistical significance in the children with ALL.

Table 3. Multivariate Analysis for Relapse in Children Diagnosed with ALL Who Underwent URD BMT (n 5 311) Variable HLA matching Matched 7/8 matched Grade III-IV aGVHD No Yes Disease stage Early Intermediate Advanced Recipient age category < 5 years 6 to 10 years 11 to 15 years 16 to 17.9 years Transplantation era 1999-2003 1990-1998

*Reference group.

n

OR (95% CI)

P Value

147 164

1.00* 0.72 (0.37 to 1.43)

168 143

1.00* 0.34 (0.13 to 0.86)

62 214 35

1.00* 1.96 (0.74 to 5.17) 12.77 (3.83 to 42.55)

67 114 75 55

1.00* 0.38 (0.17 to 0.89) 0.22 (0.07 to 0.66) 0.31 (0.11 to 0.87)

.025 .0069 .025

113 198

1.00* 0.51 (0.26 to 1.01)

.054

.45

.0052 .0012 .17 < .0001 .05

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Survival and TRM Fifty six percent (95% CI 5 52% to 59%) of children were surviving at 1 year after BMT, and 43% (95% CI 5 39% to 47%) were surviving at 5 years. The occurrence of aGVHD had a significant effect on survival (Figure 1). Survival was notably reduced in children with grade III-IV GVHD, but not in those with grade II GVHD. In a multivariate model of risk factors for mortality, the occurrence of aGVHD was associated with an almost doubled risk of death (relative risk 5 1.96; 95% CI 51.46 to 2.29; P \ .0001); however, survival was not improved by T cell depletion, despite a significant reduction in GVHD. Mortality was increased in older children, as a consequence of increased TRM (OR 5 1.72 in children age 16 to 18 years compared with those age \ 5 years; 95% CI 5 1.11 to 2.67; P 5 .016). Children receiving marrow mismatched at a single locus had significantly reduced survival, despite the absence of a significant effect on GVHD (OR 1.42; 95% CI 5 1.05 to 1.92; P 5 .02). TRM was significantly increased in children with grade III-IV GVHD, but not in children with grade II GVHD (Figure 2). TRM was higher in the children who underwent BMT in 1990-1998 compared with those who did so in 1999-2003 (OR 5 1.61; 95% CI 5 1.03 to 2.51; P 5 .027). Figure 3 illustrates the overall effect of transplantation era and GVHD. Survival was reduced in the children who developed GVHD, regardless of transplantation era. The increased risk of relapse in the children who underwent BMT in 1999-2003 led to slightly lower disease-free survival in these children whether or not they developed GVHD, but the difference is not statistically significant (P 5 .81).

DISCUSSION Children constitute an important subset of patients receiving BMT. Despite differences in diagnoses, organ function, and immune reconstitution capability, 1.0 0.9 0.8

Survival

0.7 Grade 0-I Acute GVHD (n=345)

0.6 0.5 0.4

Grade II Acute GVHD (n=117)

0.3

Grade III-IV Acute GVHD (n=176)

0.2 0.1 0.0

Log-rank p-value < 0.0001 0

12

24

36

48

60

Months after transplant Figure 1. Probability of overall survival by aGVHD grade in children with leukemia undergoing URD BMT.

Cumulative Incidence of TRM

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Pointwise p-value @ 5-year < 0.0001 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0

Grade III-IV Acute GVHD (n=176)

Grade II Acute GVHD (n=117) Grade 0-I Acute GVHD (n=345)

0

12

24

36

48

60

Months after transplant Figure 2. TRM according to aGVHD grade in children with leukemia undergoing URD BMT.

children and adults often are considered together in studies of GVHD, and reports of the effect of age on the incidence of GVHD have been inconsistent [4,5,7,8,19-25], with a lower risk of GVHD in younger patients described in some reports but not in others. The small number of children undergoing BMT relative to adults has limited studies focused specifically on children. We examined a large database to examine the incidence, risk factors, and outcome of GVHD in children to determine whether children with GVHD have similar risk factors and outcomes as adults, and to examine temporal trends in outcome of URD transplantation in children. Our analysis found that T cell depletion for GVHD prophylaxis significantly reduced the risk of GVHD, as might have been expected. In addition, year of transplantation was a significant risk factor, with a lower risk of GVHD seen in the more recent transplantations. Perhaps unexpectedly, the risk of GVHD was not increased by an allele or antigen mismatch at a single HLA locus, in contrast to findings in adult studies [20,21,23,24]. This may indicate a greater tolerance of modest degrees of HLA disparity in pediatric transplant recipients compared with adults, or greater success of GVHD prophylaxis in controlling alloreactivity. It should be noted, however, that survival was reduced in recipients of allele- or antigen-mismatched bone marrow, perhaps indicating inferior immune reconstitution in this circumstance, despite the lack of a measurable excess of GVHD. Our analysis of risk factors for cGVHD failed to identify any important risk factors besides a marginal increase in risk with multiparous female donors, as described by others [26-33]. Of note, HLA mismatch did not increase the risk of cGVHD, in agreement with our findings in aGVHD, and the risk was not decreased by T cell depletion of the graft. It should be noted that the overall incidence of cGVHD was significant, with approximately 1/3 of children affected, including even the youngest children; thus, efforts should be made to provide effective treatment for cGVHD in all age groups.

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Figure 3. Disease-free survival in 1990-1998 and 1999-2003, adjusted for the occurrence of GVHD (P 5 .81).

Our study found a marked reduction in relapse in children with ALL who developed grade III-IV aGVHD. This finding is perhaps surprising, because the clinical experience of quite limited responses to donor lymphocyte infusions in ALL suggest that any graft-versus-leukemia (GVL) effect in ALL might be modest reviewed in [34]. But data from previous nonpediatric registry studies of sibling and URD BMT support the finding of a reduced relapse rate in patients with ALL who develop GVHD [35,36]. Horowitz et al. [35] analyzed 2254 sibling donor transplantations performed in children and adults with early-stage leukemia (ALL or AML in CR1 and CML in CP1) reported to the IBMTR. This study, which included 439 cases of ALL, found an almost 3-fold reduced risk of relapse associated with aGVHD, but no effect in cGVHD. Similarly, a low relapse rate, attributed to GVL, was reported in a study of 127 adults receiving URD BMT for high-risk ALL, facilitated by the NMDP [36]. It is perhaps equally surprising that reduced relapse was not seen in the children with AML; the reason for this is not clear. It is possible that competing mortality from severe GVHD obscured any benefit from GVHD, or that the small sample size rendered a biologically meaningful effect statistically insignificant. Future studies will readdress this question as additional transplantation data are accrued. Our data demonstrate a significant effect of grade IIIIV aGVHD on mortality, with an almost doubled risk of death in children with aGVHD, demonstrating the inadequacy of current treatments for aGVHD. In contrast, grade II GVHD had only a minor effect on survival. Performance of randomized controlled trials to optimize the treatment of aGVHD is an essential step toward improving survival in children receiving URD BMT. Our analysis identified some striking temporal changes in the outcome of URD BMT in children with leukemia. The risk of aGVHD was reduced in transplantations performed in 1999-2003 compared

with those performed before 1999, even with inclusion of T cell depletion and HLA matching in the multivariate model. These data may indicate greater recent success in optimizing the use of calcineurin inhibitors and/or methotrexate as GVHD prophylaxis. In contrast to this improvement in outcome, the risk of relapse was increased in the children undergoing transplantation in 1999-2003, with this increase most notable in children with AML. This may reflect the use of increasingly intense chemotherapy in the primary treatment of children with AML. Of note, 35% of the children with AML underwent transplantation with advanced disease, compared with 11% of the children with ALL. In addition, criteria for selecting children with leukemia for transplantation change frequently, based on, for example, improved identification of genetic characteristics that affect the risk of relapse and increased effectiveness of chemotherapy. Notably, the era of transplantation was not a significant risk factor for overall survival, perhaps indicating that recent reductions in GVHD are counterbalanced by the increase in relapse, illustrating the dynamic nature of leukemia patient populations as chemotherapy outcomes continue to evolve. The present study is a registry analysis and so is limited by the heterogeneity of treatment regimens and clinical practices at different institutions. A strength of the study is the size of the population, allowing analyses of subsets that could not be examined in single institution studies. In summary, this study is the largest single analysis of GVHD in URD BMT in children reported to date. We have identified important temporal changes in clinical outcomes that will merit continued observation as chemotherapy and transplantation strategies continue to improve. In addition, we have shown a significant effect of GVHD in reducing relapse in children with ALL, but not in those with AML. But overall, aGVHD had a significant negative effect on survival, demonstrating the need for further improvements in both GVHD prophylaxis and aGVHD treatment.

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