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Biol Blood Marrow Transplant. Author manuscript; available in PMC 2012 August 1.
Published in final edited form as:
PMCID: PMC3113644
NIHMSID: NIHMS273773

The outcomes of family haploidentical hematopoietic stem cell transplantation in hematological malignancies are not associated with patient age

Abstract

Haploidentical hematopoietic cell transplantation (HCT) has been used to treat hematologic malignancies but it is unknown whether the procedure is more effective in adults or children. To address this question, we analyzed patients aged 1–65 years old receiving myeloablative conditioning regimens followed by family 2 to 3 antigen HLA-mismatched HCT and reported to the Center for International Blood and Marrow Transplant Research (CIBMTR, n=137) or performed in Dao-Pei Hospital in Beijing, China (n=181). The Dao-Pei cohort had more acute and chronic GVHD, less relapse, lower transplant related mortality (TRM) and better leukemia-free survival (LFS) than the CIBMTR cohort. Overall survival (OS) and outcomes were similar between adults and children. In the CIBMTR cohort receiving ex vivo T cell depletion (TCD), adults had higher TRM (RR 2.71, 95% CI 1.29–5.69, p=0.008) and lower overall survival (RR 1.75, 95%CI 1.08–2.84, p=0.023) than children. In the CIBMTR subset that did not receive ex vivo TCD, relapse was lower in adults compared to children (RR 0.24, 95% CI 0.07–0.80, p=0.020) but TRM, LFS and OS were similar. We conclude that outcomes in adults and children are similar overall, although children have better survival than adults if ex vivo TCD is used.

Keywords: HLA-mismatched, haploidentical, blood and marrow transplantation, leukemia, antithymocyte globulin

Introduction

Family human leukocyte antigen (HLA)-mismatched/haploidentical hematopoietic cell transplantation (HCT) has been used as an alternative donor source in patients who lack an appropriate HLA-matched related or unrelated donor for 30 years since the first clinical trial was performed in 1980.1,2 The advantages of family donors, even if partially mismatched, are: (1) family donors are better matched on shared complete haplotypes, including tested and untested HLA and minor histocompatibility loci; (2) almost all patients have at least one haploidentical donor readily available, a particular advantage for patients with advanced/resistant disease who need urgent HCT; and (3) recent reports suggest that haploidentical HCT can achieve nearly comparable therapeutic effects as HLA matched sibling transplantation35 and may induce more potent graft-versus-tumor effect.69 Most articles have reported the results of haploidentical transplantation separately in adults10,11 and in children1215 or combined them into single reports without comparing the two age groups. The goal of this study was to investigate whether the outcome of haploidentical HCT differs in adults and children, and to identify the patient or transplant characteristics that favor positive outcomes and survival in children and adults undergoing haploidentical HCT.

Methods

Patients

Patients with the diagnosis of ALL, AML, CML, or MDS, receiving myeloablative conditioning regimens with 2 to 3 antigen HLA-mismatched family member donors between 2000–2005 were included. (Table 1) Adults were age 21 years or older and children were less than 21 years old at the time of HCT. 137 patients (50 children and 87 adults) were reported to Center for International Blood and Marrow Transplant Research (CIBMTR), and 181 patients (68 children and 113 adults) were from Dao-Pei Hospital in China.

Table 1
Patients, disease, transplant characteristics.

CIBMTR cohort

The CIBMTR is 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) established in 2004 that comprises a voluntary working group of more than 450 transplantation centers worldwide that contribute detailed data on consecutive allogeneic and autologous HCT to a Statistical Center at the Medical College of Wisconsin in Milwaukee and the NMDP Coordinating Center in Minneapolis. Participating Centers are required to report all transplants consecutively; compliance is monitored by on-site audits. Patients are followed longitudinally, with yearly follow-up. 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 the Privacy Rule (HIPAA) as a Public Health Authority, and in compliance with all applicable federal regulations pertaining to the protection of human research participants as determined by continuous review of the Institutional Review Boards of the National Marrow Donor Program and the Medical College of Wisconsin since 1985. Donor-recipient histocompatibility was determined by results of serologic typing for HLA-A, -B, and -DR antigens as reported by institutions performing the transplants. A variety of conditioning and GVHD prophylaxis regimens were used (Table 1).

Dao-Pei cohort

All patients were treated on the same protocols approved by the institutional review board (IRB) at Beijing Dao-Pei Hospital, and all patients or their guardians signed consent forms. HLA typing has been described previously.2,15 Family members were tested for HLA compatibility using serology and intermediate-resolution DNA typing for HLA-A, -B, and -C antigens and high resolution DNA typing for HLA-DRB1 antigens. Donors carrying non-inherited maternal antigens were preferentially selected. Conditioning regimens and GVHD prophylaxis have been described previously3,16,17 Briefly, patients received combinations of cytarabine, oral busulfan, cyclophosphamide, and methyl CCNU prior to graft infusion. GVHD prophylaxis consisted of ATG, cyclosporine, methotrexate and mycophenolate mofetil. Approximately half of the patients in the current report were also reported in the Lu et al 2006 Blood paper, 3 but the length of follow-up is significantly longer in the present study (4 years vs. 1.2 years).

Endpoints

Absolute neutrophil count (ANC) was defined as recovery of the blood ANC to ≥0.5×109/L on 3 consecutive days. Platelet recovery was defined as the time after transplantation needed to maintain a platelet count ≥20 ×109/L without transfusion support for 7 consecutive days. The acute GVHD end-point referred to the development of grades 2–4 and grades 3–4 according to the Glucksberg criteria.18 Chronic GVHD was diagnosed according to Seattle definitions.19 Transplant-related mortality (TRM) was defined as death resulting from causes other than relapse. Leukemia-free survival (LFS) was defined as survival without recurrent malignancy.

Statistical Analysis

CIBMTR and Dao-Pei data were analyzed separately because of differences in patient and transplant characteristics and major outcomes. Clinical variables considered for inclusion in the models included: recipient age and sex; Karnofsky performance score at transplant, diagnosis, disease stage, time from diagnosis to transplant, stem cell source, ex vivo T-cell depletion, use of anti-thymocyte globulin (ATG) in the conditioning regimen or GVHD prophylaxis, donor relationship, number of antigen incompatibilities, donor/recipient gender match, ABO matching, donor age, and year of transplantation. Cumulative incidence of neutrophil recovery, acute and chronic GVHD, TRM, and relapse were calculated to accommodate competing risks. Probabilities of survival and LFS were calculated using the Kaplan-Meier estimate. Patients were not censored for second transplant or donor leukocyte infusion (DLI) for the endpoints of TRM, relapse, DFS or OS. The log-rank test was used for univariate comparisons.

Cox proportional hazards regression models were applied for TRM, relapse, LFS and overall mortality using time dependent covariates when appropriate. The proportional hazard assumption was assessed for each variable. Stepwise forward-backward selection was used to build the models from the prognostic variables under consideration. The main effect of adults vs. children was kept in all models, and significant other variables with p<0.05 were retained. SAS software version 9.1 (SAS Institute, Cary, NC) was used.

Results

Patient, disease and transplant characteristics

The patient and transplant characteristics are shown in Table 1. Comparing baseline characteristics, the CIBMTR cohort differed from the Dao-Pei cohort in that the adults were older (p=0.021), more patients were in advanced stage for both children and adults (p=0.024 and p<0.001 respectively), more pediatric patients waited longer than 12 months before receiving a transplantation (p=0.033), more patients had transplantation in the earlier time period (during 2000~2003) (p<0.001), and there were more cases of AML and fewer CML cases in the adult group. All Dao-Pei patients received ATG without ex vivo TCD whereas 70% children and 63% adult patients in the CIBMTR cohort had ex vivo TCD. 32% children and 15% adults in CIBMTR cohort received stem cells derived from bone marrow only whereas 94% children and 96% adults received both bone marrow and peripheral blood in the Dao-Pei cohort.

Outcomes for all patients

Table 2 shows the univariate analyses. Despite the differences in clinical characteristics between the CIBMTR and Dao-Pei cohorts, within each cohort there were no statistically significant differences in engraftment, acute and chronic GVHD, TRM, relapse, LFS and OS between adults and children. Table 3 summarizes the clinical variables considered in the multivariate analyses. Table 4 presents the multivariate analysis results for the CIBMTR and the Dao-Pei cohort separately, which are summarized below.

Table 2
Univariate analysis.
Table 3
Variables tested in the multivariate analysis.
Table 4
Age effect in patients undergoing related HLA-Mismatched/Haploidentical transplantation

CIBMTR cohort

In the multivariate analysis in the CIBMTR cohort, a significant interaction between age and ex vivo TCD for OS and DFS was detected so four subgroups (Adult-No TCD, Adult-TCD, Child-No TCD and Child-TCD) were compared (Table 4). No other interactions were present. When ex vivo TCD was used, there were statistically significant differences between the outcomes of adults and children. Adult-TCD was associated with a higher risk of TRM (RR 2.71, 95% CI 1.29 – 5.69, p=0.008) and lower OS (RR 1.75, 95% CI 1.08–2.84, p=0.023) than Child-TCD. When ex vivo TCD was not employed, there was a lower risk of relapse in Adult-No TCD compared with Child-No TCD, (RR 0.24, 95% CI 0.07 – 0.80, p=0.020) and a suggestion of a higher LFS (RR 0.44, 95% CI 0.19–1.04, p=0.060) and overall survival (RR 0.46, 95% CI 0.20–1.02, p=0.056) which were not statistically significant according to the p=0.05 cutoff. There was no difference in TRM. Among all patients, advanced disease was associated with higher TRM, higher relapse and lower LFS and OS. Transplantation more than 12 months from diagnosis was associated with higher TRM, while use of ATG was associated with a lower relapse rate.

Influence of TCD and No-TCD in CIBMTR cohort

Given these results, we performed a post-hoc comparison of transplant outcomes according to TCD status. Adult-TCD had a higher cumulative incidence of TRM (RR 3.18, 95% CI 1.38–7.37, p=0.007) and relapse (RR 4.28, 95% CI 1.52–12.05; p=0.006) as well as higher rates of graft failure (RR 3.25, 95% CI 1.71–6.18, p<0.001) and increased mortality (RR=3.81, 95% CI 2.01–7.22, p<0.001) compared to Adult-No TCD. Among the non-TCD patients, adult-No TCD had a lower relapse rate (RR 0.24, p=0.02) and almost had better survival (RR 0.46, p=0.056) and better LFS (RR 0.44, p=0.06) than children. For children, there was no difference in outcomes between TCD and No-TCD (Figure 1).

Figure 1
(A) Cumulative incidence of TRM, (B) Cumulative incidence of relapse, (C) Adjusted probability of LFS and (D) Adjusted probability of OS (Adults vs. children with no TCD/with TCD) from CIBMTR cohort.

Dao-Pei cohort

In the Dao-Pei cohort, we observed no differences between adults and children in TRM, relapse, LFS or OS (Figure 2). Karnofsky score ≥ 90 was associated with lower TRM, lower relapse and higher LFS and OS. Disease type also predicted relapse. ALL was associated with higher relapse rate than other diagnoses.

Figure 2
(A) Cumulative incidence of TRM, (B) Cumulative incidence of relapse, (C) Adjusted probability of LFS and (D) Adjusted probability of OS (Adults vs. children) from Dao-Pei cohort.

Discussion

Our study confirms that haploidentical transplantation for hematologic malignancies in adults and children using myeloablative conditioning and standard GVHD prophylaxis is a reasonable treatment option, although we did not find that outcomes in children were superior to those seen in adults among the Dao-Pei cohort or within the non-TCD subset of the CIBMTR. Only among the ex vivo TCD recipients reported to the CIBMTR did we see better outcomes in the children compared to the adults. In this group, children had lower rates of TRM and trends towards better LFS and OS.

The apparent better outcomes seen in the Dao-Pei cohort overall compared to the CIBMTR cohort could be due to inherent differences in the patient populations, differences in clinical management or the fact that the Dao-Pei data were all derived from a single center, compared to the CIBMTR cohort where 25 Centers contributed data for children and 32 (Table 1) Centers provided data for adults. All patients in the Dao-Pei cohort received in vivo ATG based on the belief that ATG reduces the incidence of graft-versus-host disease without damaging the hematopoietic cell precursor population or impeding immune reconstitution. The Dao-Pei cohort also preferentially used non-inherited maternal antigen complementary haploidentical donors. In 108 patients with parent donors (see Table 1), mothers were used as the donor in 76 (70%) pairs, since this combination has been associated with improved outcomes, based on presumed maternal-fetal microchimerism and resulting tolerance.20,21

Children in the CIBMTR cohort who received ex vivo TCD had better outcomes than similarly treated adults, adjusting for other clinical characteristics. One contributing factor may be that children were more likely to achieve “megadose” CD34+ cells than adults due to their lower weight, and the CD34+ dose may be more important in the TCD setting. 22 Modern haploidentical transplant protocols using high doses of CD34+ purified cells and myeloablative conditioning report sustained engraftment rates of over 90%. In addition, full donor chimerism and low rates of acute and chronic GVHD are seen.2326 In adults, a relatively lower CD34+cell dose per kg may be a major cause of unstable chimerism and incomplete immunologic reconstitution after transplantation, although we did not see statistically significant differences in engraftment or recurrent malignancy.

Post-hoc analysis of the CIBMTR cohort suggested that adults should not receive a TCD graft, since TRM and relapse were higher, and LFS and survival lower in adults with TCD compared to adults who did not receive TCD, adjusted for other clinical features. However, we consider this a hypothesis-generating analysis that requires additional study, ideally in a randomized trial.

Since virtually almost every patient has a haplo-identical family member donor available, there has been great interest in developing transplant approaches that permit this degree of HLA disparity during transplantation. Only approximately 50% of patients with an indication for unrelated donor HCT may ultimately receive the intended allograft. That percentage may be even lower for patients with a nonwhite background.27 Our study suggests that in most settings, the outcomes of adults and children appear comparable so age should not automatically be considered an adverse prognostic factor. Rather, other traditional clinical factors such as disease stage, disease type, time from diagnosis to HCT, and Karnofsky performance status appear to be much stronger predictors of transplantation success. Research to help identify the optimal combinations of conditioning agents and GVHD approaches and to select the optimal donors may continue to improve outcomes.

Treatment approaches to haploidentical transplantation vary greatly and continue to evolve. These include modifications to donor selection such as consideration of feto-maternal michrochimerism,2830 non-inherited maternal antigens (NIMA),20,21,31 or killer immunoglobulin-like receptor (KIR) status,32,33 as well as use of non-myeloablative conditioning regimens, 1,3436 or alteration of the GVHD prophylaxis approach with post transplant cyclophosphamide.37 Studies to date show 2-year survival rates of 50±20%.38

Our study has a number of limitations. First, the overall study numbers are relatively low although they do represent the largest report of haploidentical transplantation using traditional GVHD prophylaxis approaches. The small subsets limit the power to detect differences, although evaluation of the figures suggests that this was not the reason for the failure to find differences. Second, although the original intention was to combine the CIBMTR and Dao-Pei cohorts, the inherent differences in patient characteristics, transplant approaches and outcomes did not make this possible. We are left without clear understanding of why the outcomes differed so greatly. Finally, despite the readily available donor source, haploidentical transplantation is still relatively uncommon and approaches are rapidly evolving. Further study and larger numbers of more homogenously treated patients would enhance our understanding of clinical and transplant factors associated with better outcomes.

Acknowledgments

The CIBMTR is supported by Public Health Service Grant/Cooperative Agreement U24-CA76518 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 5U01HL069294 from NHLBI and NCI; a contract HHSH234200637015C with Health Resources and Services Administration (HRSA/DHHS); two Grants N00014-06-1-0704 and N00014-08-1-0058 from the Office of Naval Research; and grants from AABB; Aetna; American Society for Blood and Marrow Transplantation; Amgen, Inc.; Anonymous donation to the Medical College of Wisconsin; Astellas Pharma US, Inc.; Baxter International, Inc.; Bayer HealthCare Pharmaceuticals; Be the Match Foundation; Biogen IDEC; BioMarin Pharmaceutical, Inc.; Biovitrum AB; BloodCenter of Wisconsin; Blue Cross and Blue Shield Association; Bone Marrow Foundation; Canadian Blood and Marrow Transplant Group; CaridianBCT; Celgene Corporation; CellGenix, GmbH; Centers for Disease Control and Prevention; Children’s Leukemia Research Association; ClinImmune Labs; CTI Clinical Trial and Consulting Services; Cubist Pharmaceuticals; Cylex Inc.; CytoTherm; DOR BioPharma, Inc.; Dynal Biotech, an Invitrogen Company; Eisai, Inc.; Enzon Pharmaceuticals, Inc.; European Group for Blood and Marrow Transplantation; Gamida Cell, Ltd.; GE Healthcare; Genentech, Inc.; Genzyme Corporation; Histogenetics, Inc.; HKS Medical Information Systems; Hospira, Inc.; Infectious Diseases Society of America; Kiadis Pharma; Kirin Brewery Co., Ltd.; The Leukemia & Lymphoma Society; Merck & Company; The Medical College of Wisconsin; MGI Pharma, Inc.; Michigan Community Blood Centers; Millennium Pharmaceuticals, Inc.; Miller Pharmacal Group; Milliman USA, Inc.; Miltenyi Biotec, Inc.; National Marrow Donor Program; Nature Publishing Group; New York Blood Center; Novartis Oncology; Oncology Nursing Society; Osiris Therapeutics, Inc.; Otsuka America Pharmaceutical, Inc.; Pall Life Sciences; PDL BioPharma, Inc; Pfizer Inc; Pharmion Corporation; Saladax Biomedical, Inc.; Schering Corporation; Society for Healthcare Epidemiology of America; StemCyte, Inc.; StemSoft Software, Inc.; Sysmex America, Inc.; Teva Pharmaceutical Industries;; THERAKOS, Inc.; Thermogenesis Corporation; Vidacare Corporation; Vion Pharmaceuticals, Inc.; ViraCor Laboratories; ViroPharma, Inc.; 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, or any other agency of the U.S. Government.

Footnotes

Authorship

Contributions: L.J. Dong, D.P. Lu, and T. Wu, designed and supervised the study (IB06-04, CIBMTR). L.J. Dong and T. Wu compiled clinical data. F. Kan, M. J. Zhang and L.J. Dong performed the statistical analysis. L.J. Dong, M.J. Zhang and S.J.Lee drafted the manuscript. All authors provided critical feedback and approved the final manuscript.

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