CC BY-NC-ND
0ASBMI
American Society for Blood and Marrow Transplantation
Haploidentical Hematopoietic Stem Cell Transplantation without In Vitro T Cell Depletion for Treatment of Hematologic Malignancies in Children
Xiaojun Huang, Daihong Liu, Kaiyan Liu, Lanping Xu, Huan Chen, Wei Han, Yuhong Chen, Yu Wang, Xiaohui Zhang
Objective: To evaluate the efficacy and safety of haploidentical (from family member donors) hematopoietic stem cell transplantation (HSCT) for children. Patients and methods: Fifty-eight children under fourteen years old with hematological malignancies underwent haploidentical HSCT. Outcomes were analyzed. Results: Of Fifty-eight patient/donor pairs, seven (12.1%) were mismatched in two HLA loci, twenty (34.5%) in three loci, and thirty-one (53.4%) in four loci. Follow-ups were performed for a median of 915 (227-1898) days after transplantation. All patients achieved stable engraftments. The cumulative incidence of acute graft-versus-host disease (GVHD) of grade 2-4 was 54.8%7.6%, and that of grade 3-4 was 11.4%4.8%. The cumulative incidence of chronic GVHD was 45.6%7.8% for total and 19.6%6.5% for extensive. Fourty patients survived with a 3-year probability of leukemia-free survival (LFS) 44.7%13.9%. Eighteen patients died, five from infection, eight from relapse of leukemia, two from heart failure, two from GVHD, and one from lymphoproliferative disorders. Conclusion: The results encourage extending haploidentical HSCT without T-cell depletion treatments to children with an indication for transplantation. Biol Blood Marrow Transplant 15: 91-94 (2009) © 2009 American Society for Blood and Marrow Transplantation
KEY WORDS: haploidentical, hematopoietic stem cell transplantation, hematological malignancy, children
INTRODUCTION
Despite recent advances in the diagnosis and treatment of childhood hematologic malignancies, there are several subgroups of children that are at high risk of failing current chemotherapy regimens and require allogeneic hematopoietic stem cell transplantation (HSCT) to cure their disease [1,2]. In this study, we report the results of 58 children under 14 years old that have no HLA-identical sibling donors and received HSCT from haploidentical family donors within 6 consecutive years. The toxicity and efficacy of this transplantation method for children were investigated.
PATIENTS AND METHODS
Fifty-eight children under 14 (3-14) years old with hematologic disorders underwent haploidentical
From the Peking University Institute of Hematology, People's Hospital, 11 South Street of Xizhimen, Xicheng District, Beijing, 100044, People's Republic of China. Financial disclosure: See Acknowledgments on page 94. Correspondence and reprint requests: Prof. Xiao-Jun Huang, Peking University Institute of Hematology, People's Hospital, 11 South Street of Xizhimen, Xicheng District, Beijing, 100044, P.R. China (e-mail: xjhrm@medmail.com.cn). 1083-8791/09/151S-0001$36.00/0 doi:10.1016/j.bbmt.2008.10.019
HSCT between January 2002 and December 2007 at a median of 780 (180-2738) days after diagnosis. None of the patients had HLA-identical related or unrelated donors, or a source ofstem cells from umbilical cord blood. Thirty-two patients had acute lymphoblas-tic leukemia (ALL), 15 patients had acute myeloid leukemia (AML), and 8 patients had chronic myelogenous leukemia (CML), 2 had myelodisplastic syndrome with refractory anemia with excess blasts (MDS-RAEB), and 1 had acute biphenotypic leukemia before HSCT.
Donors were primed with granulocyte-colony stimulating factor (G-CSF; Filgrastim, Kirin, Japan; 5 mg/kg per day) injected subcutaneously for 5 consecutive days. The target mononuclear cell count (MNC) was 4-6 x 108 cells/kg recipient weight. On the fourth day, bone marrow cells were harvested. On the fifth day, peripheral blood stem cells (PBSC) were collected. 49 patients received G-CSF-primed bone marrow combined with PBSC at transplantation, 5 patients received the G-CSF-primed bone marrow, and 4 patients received PBSC. The day of transplantation was designated day 0. The conditioning regimen consisted of arabinoside (Ara-C, 4 g/m2/day, i.v.) given on days -10 and -9; busulfan (Bu, 12 mg/kg, p.o. in 12 doses) given on days -8, -7, and -6; cyclophosphamide (Cy, 1.8 g/m2/day, i.v.) given on days -5 and -4; Simus-tine (Me-CCNU, 250 mg/kg, i.v.) given on day-3; and
Figure 1. (a) Cumulative incidence of aGVHD grade 2-4 with HLA disparity after haploidentical HSCT for children. (b) Cumulative incidence of aGVHD grade 3-4 with HLA disparity after haploidentical HSCT for children.
antihuman thymocyte immunoglobulin (ATG, 2.5mg/ kg/d of the Sangstat, i.v.) given on days -5 through -2. All transplant recipients received cyclosporine A (CsA), mycophenolate mofetil (MMF), and short-term methotrexate (MTX) for graft-versus-host disease (GVHD) prophylaxis. DNA fingerprinting of short tandem repeats was used for confirmation of en-graftment and determination of chimerism. Chromosomal fluorescent in situ hybridization (FISH) was also used to detect chimerism in patients with a donor of a mismatched gender.
High-risk candidates included patients with acute leukemia (AL) in the first complete remission (CRi), those in CR2 with a cytogenetic marker of "poor risk,'' such as the Philadelphia chromosome, those in complete remission after CR 3, those in nonremission or in a relapse state before transplantation, and those with chronic myelogenous leukemia (CML) beyond the first chronic phase (CPi). All other patients were
stratified into a standard-risk group. Thirty children with AL presented with clinical and biologic features that indicated a very high risk of relapse with conventional chemotherapy. The primary endpoint of the study was the overall survival (OS) rate at 3 years from transplantation. Secondary endpoints included leukemia-free survival (LFS, defined as survival in continuous complete remission after transplantation), nonrelapse mortality (NRM), incidence of relapse, and incidence and severity of acute and chronic GVHD (aGVHD, cGVHD). The date of the last follow-up for all surviving patients was August 1, 2008. All reported P values were based on 2-sided hypothesis tests. Alpha was set at 0.05. The SPSS-13.0 software package was used for data analysis.
RESULTS
Thirty-six donors were mothers and 17 donors were fathers of the patients. The other 3 donors were an uncle, a sister, and a brother; both were haploidentical according to the familial spectrum of genetics analysis. The median age of the donors was 36 (16-50) years old. All patients were mismatched at the allele level for HLA-A, HLA-B, HLA-C, and HLA-DRB1. Thirty-one (53.4%) patients were mismatched in 4 loci, 20 (34.5%) patients were mismatched in 3 loci, and 7 (12.1%) in 2 loci. The patients were followed up with a median of 915 (227-1898) days after transplantation. The median numbers ofMNC infused at transplantation were 7.9 (1.1-15.4) x 108/kg. All patients achieved stable engraftment and whole donor chime-rism. The median times of myeloid and platelet recovery were 14 (9-22) days and 21 (8-90) days after transplantation, respectively. There was no significant association between the extent of HLA disparity and the time of myeloid or platelet recovery.
Forty-one patients developed aGVHD, with grade 1 in 15 patients, grade 2 in 21 patients, and grade 4 in 5 patients. The cumulative incidence of aGVHD grade
2-4 was 54.8% 6 7.6%, and that of aGVHD grade
3-4 was 11.4% 6 4.8%. (Figure 2) Of the 5 patients that developed aGVHD grade 4, 2 died and the remaining 3 recovered. However, 1 patient died of subsequent pneumonia 1.5 years after transplantation. One of the surviving 2 patients remained free of GVHD through the last follow-up of 904 days after transplantation, and the other 1 developed limited cGVHD at 484 days after transplantation and recovered 2 months later. Fifty-two patients that survived longer than 100 days after transplantation were evaluated for cGVHD. Of 29 patients that had no cGVHD, 21 survived without relapse. Of 14 patients that developed limited cGVHD, 11 survived. Of 9 patients that developed extensive cGVHD, 7 survived. The cumulative incidence of cGVHD was 45.6% 6 7.8%, and that
Biol Blood Marrow Transplant 15:91-94, 2009 Hapliodentical HSCT fir Treatment of Hematologic Malignancies in Children 93
Figure 2. Cumulative incidence of cGVHD after haploidentical stem cell transplantation for children.
Figure 3. LFS in different risk groups after haploidentical HSCT for children.
of extensive cGVHD was 19.6% 6 6.5% (Figure 2). The development of aGVHD grade 3-4, and extensive cGVHD was not associated with the age or gender of the patients or donors, numbers of MNC, CD3+, CD34+ cells infused at transplantation, the extent of HLA disparity, or the stage of disease before transplantation.
Nineteen opportunistic infections were observed within the follow-up time. The causes ofopportunistic infection were pneumonia (12 cases), varicella zoster virus (VZV) (3 cases), bacteremia (2 cases), infection in the gastrointestinal tract (2 case), and infection in the central nervous system (1 case). The causes of pneumonia were CMV in 7 cases, fungi in 1 case, bacteria in 1 case, and idiopathic interstitial pneumonia in 3 cases. CMV antigenemia was detected in 24 patients; however, only 7 case of interstitial pneumonia (IP) was associated with CMV. Epstein-Barr virus (EBV) anti-genemia was detected in 2 children, and 1 of these died of EBV-associated lymphoproliferative disorder. Hemorrhagic cystitis developed in 9 children at 15 to 160 (median 40) days after transplantation, and lasted for 2 to 6 (median 3.5) weeks. Seizures occurred in 5 cases within 2 months after transplantation.
At 3 months after transplantation for 5 children without GVHD, the median CD41 and CD81 cell counts were 149 and 310 cells/mL, respectively. At 1 year, data were only obtained in 3 children and CD41 and CD81 cell counts were 382 and 1066 cells/mL, respectively.
Up to August 1,2008,40 patients survived. Thirty-five were free of leukemia. Fourteen of the 35 patients were classified as high-risk candidates before transplantation with a 22.6% 6 16.7% probability of LFS. The 3-year probability of LFS for all patients was 44.7% 6 13.9%. The quality of life of the survivors was evaluated with the Lansky Play performance
scale. Six patients who scored 70% were under treatment for extensive GVHD. Of 3 patients who scored 80%, 2 developed cGVHD. Sixteen patients scored 90% and 15 patients scored 100%. Eighteen patients died. Eight patients died from relapse of leukemia at a median of 340 (120-706) days after HSCT. Five patients died from infection: 3 from pneumonia on day 184, 300 and 463, 1 from cytomegalovirus interstitial pneumonia on day 68, and 1 from cerebral fungal infection on day 170. Two patients died from heart failure on days 40 and 184; both had received chemotherapy before transplantation for 2 and 4 years, respectively. One died from severe aGVHD on day 67; 1 died of infection associated with extensive cGVHD at 4 years after transplantation. Another died from EBV-associated lymphoproliferative disorder on day 55. The transplantation-related mortality (TRM) was 8.6% 6 3.7% at 100 days, 14.3% 6 4.7% at 1 year,
Figure 4. Leukemia-free survival with different diagnosis after haploi-dentical HSCT for children.
and 37.6% 6 18.4% at 3 years after transplantation. All 13 of the patients that relapsed after HSCT were diagnosed with ALL before transplantation, and 10 were from the high-risk group. The probability of relapse for high-risk patients was 44.6% 6 10.8% and that for standard-risk patients was 11.3% 6 6.1% at 2 years after transplantation. Three patients with he-matologic relapse and 2 with relapse in central nervous system received chemotherapy or radiotherapy followed by donor lymphocyte infusion. These 5 patients achieved remission and survived free of relapse with the follow-up 438, 452, 486, 1200, and 1247 days, respectively. The diagnosis of ALL was associated with a lower probability of LFS (P = .004) and a higher probability of relapse (P = .008) after transplantation.
The occurrence of cGVHD was associated with a lower rate of relapse after transplantation (P = .019).
CONCLUSION
The results encourage extending haploidentical HSCT without ex vivo T cell depletion treatments to children with an indication for transplantation.
ACKNOWLEDGMENTS
Financial disclosure: The authors have nothing to disclose.
