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ABSTRACT: Human leukocyte antigen (HLA) matched related donor (MRD) hematopoietic stem cell transplant (HSCT) for patients with sickle cell disease (SCD) has been well established, however experience using alternative donors, including haploidentical donors for treatment of SCD is limited. We report the long-term outcome of 22 pediatric patients who underwent a related donor HSCT for SCD at St. Jude Children's Research Hospital. Patients received a myeloablative MRD from a sibling (14) or reduced intensity parental haploidentical (8) HSCT. The medianageforthe patients who underwent a MRD and haploidentical donor HSCT were11.0±3.9 yrs. and9.0±5.0 yrs., respectively. The median time to follow up for the MRD cohort was 9.0 ± 2.3 yrs. withan overallsurvival (OS) of93%andrecurrence/graftfailureof0%. The median follow up for the haploidentical donor cohort was 7.4 ± 2.4 years with an OSof75%, disease free survival of 38%anddisease recurrence of 38%. We report the long-term hematological response and organ function in patients undergoing a MRD and haploidentical donor HSCT for severe SCD. Our data demonstrate long-term hematologic improvements after HSCT for our patients with sustained engraftment. In summary, our dataconfirmsthatHSCT offerslong--termprotectionfromcomplicationsthat commonlydevelopinpatientswithSCDsuchasstroke,pulmonaryhypertension, acutechest and nephropathy, regardless of donor source.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 02/2013; · 3.15 Impact Factor
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ABSTRACT: Children with relapsed or refractory solid tumors face dismal prognoses and novel therapies are desperately needed. Allogeneic hematopoietic cell transplantation (HCT) offers potential for cell-based therapy, but the toxicity of myeloablation limits this approach in heavily pre-treated patients. We sought to determine the feasibility of HCT in a cohort of 24 children with incurable solid tumors, using HLA-matched sibling or unrelated donors and a minimal conditioning regimen. Prior to stem cell infusion, all patients received three daily doses of 30 mg/m(2) fludarabine followed by 2 Gy of total body irradiation. Hematopoietic cell recovery was rapid and reliable. Median time to neutrophil engraftment was 13.5 days for sibling donors and 12 days for unrelated donors. Donor lymphocyte infusions were used safely in four patients, all of whom had either improved chimerism or apparent tumor response. Graft-versus-host disease was comparable across donor sources and did not impact survival. Relapse remains a substantial barrier, although objective graft-versus-tumor effect was observed in several patients. Four patients with detectable disease prior to HCT achieved a complete response (CR) for at least 30 days after HCT, and two remain long-term survivors. Three patients were in CR before HCT, and they remained in remission for 3, 6, and 74 months after HCT. Early disease response was associated with improved survival. Allogeneic HCT using this conditioning regimen offers a potential platform for novel immunotherapies.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 10/2012; · 3.15 Impact Factor
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ABSTRACT: Detection of respiratory viruses by molecular methods, in children without respiratory symptoms undergoing hematopoietic cell transplantation (HCT), has not been well described. A prospective study of 33 asymptomatic children detected respiratory viruses in 8 of 33 (24%) patients before HCT. Human rhinovirus (HRV) was detected in five patients, and human adenovirus (hADV) in three patients. Two additional patients shed HRV, and one shed human coronavirus (hCoV), post-HCT. Two patients had co-infections. Of the 11 asymptomatic patients where respiratory virus was detected, 3 (27%) later developed an upper respiratory tract infection, from the same virus. Pediatr Blood Cancer © 2012 Wiley Periodicals, Inc.
Pediatric Blood & Cancer 09/2012; · 1.89 Impact Factor
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Brandon M Triplett,
Chong Wang,
Jie Yang,
Mari Dallas, Christine Hartford,
Vanessa Howard,
Asha Pillai,
David Shook,
Ashok Srinivasan,
Joseph Laver,
Wing Leung
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ABSTRACT: This study analyzes the hematopoietic cell transplantation experience in patients with immune deficiency at a single institution. The objective is to comprehensively evaluate the short-term and long-term outcomes with various preparative regimens, donor grafts, and ex vivo manipulations to identify transplantation approaches that most likely favor early donor immune competency without generating excessive toxicity. Clinical outcomes were evaluated in 52 consecutive patients with immune deficiencies. Thirty-seven of the 52 patients (71%) survived with attenuation of their underlying disease. The use of a melphalan-based reduced-intensity conditioning preparative regimen and immunomagnetic CD3(+) T cell depletion techniques (when T cell depletion was indicated) were associated with improved event-free survival. Survivors who received a preparative regimen other than a melphalan-based reduced-intensity regimen suffered from therapy-related morbidities or chronic/recurrent infections. Our findings indicate that melphalan-based reduced-intensity conditioning regimens and immunomagnetic CD3(+) T cell depletion limit therapy-related toxicity, and demonstrate promising results for the early establishment of donor immune competency.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 07/2012; · 3.15 Impact Factor
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Wing Leung,
Ching-Hon Pui,
Elaine Coustan-Smith,
Jie Yang,
Deqing Pei,
Kwan Gan,
Ashok Srinivasan, Christine Hartford,
Brandon M Triplett,
Mari Dallas,
Asha Pillai,
David Shook,
Jeffrey E Rubnitz,
John T Sandlund,
Sima Jeha,
Hiroto Inaba,
Raul C Ribeiro,
Rupert Handgretinger,
Joseph H Laver,
Dario Campana
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ABSTRACT: In patients with acute leukemia, detection of minimal residual disease (MRD) before allogeneic hematopoietic cell transplantation (HCT) correlates with risk of relapse. However, the level of MRD that is most likely to preclude cure by HCT is unclear, and the benefit of further chemotherapy to reduce MRD before HCT is unknown. In 122 children with very-high-risk acute lymphoblastic leukemia (ALL; n = 64) or acute myeloid leukemia (AML, n = 58), higher MRD levels at the time of HCT predicted a poorer survival after HCT (P = .0019); MRD was an independent prognostic factor in a multivariate analysis (P = .0035). However, the increase in risk of death associated with a similar increment of MRD was greater in ALL than in AML, suggesting that a pretransplantation reduction of leukemia burden would have a higher impact in ALL. At any given MRD level, survival rates were higher for patients treated in recent protocols: the 5-year overall survival for patients with ALL was 49% if MRD was detectable and 88% if it was not and the corresponding rates for patients with AML were 67% and 80%, respectively. Although MRD before HCT is a strong prognostic factor, its impact has diminished and should not be regarded as a contraindication for HCT.
Blood 04/2012; 120(2):468-72. · 9.90 Impact Factor
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ABSTRACT: To assess whether a tolerance-induction regimen could be applied for unrelated (MUD) HCT in SAA, we retrospectively reviewed our HCT experience using unmanipulated 10/10 HLA-matched bone marrow grafts from MSD vs. MUD donors. Conditioning was CTX 200 mg/kg (CTX) + rabbit ATG 10 mg/kg (ATG) for MSD (n = 9) and TLI (800 cGy) + CTX/ATG for MUD HCT ( n = 5). Immunoprophylaxis was CSA and short-course MTX. Median patient age was 14.7 yr, median time to HCT 1.5 yr, and median follow-up 3 yr. Outcome measures included EFS, time to engraftment, and cumulative incidence of GVHD (CIN of GVHD) for MSD and MUD cohorts. EFS and stable engraftment rate were 100%. CIN of acute GVHD was: MSD, Grade I-II: 1 (11%), Grade III-IV: 0%; MUD, Grade I-II: 1 (20%), Grade III-IV: 1 (20%). CIN of chronic GVHD was: MSD, limited: 1 (11%), extensive: 0%; MUD, limited: 0%, extensive: 0%. All immunosuppressive-compliant patients successfully weaned immunosuppression. Although in limited patients, our results suggest that immunomodulatory TLI added to backbone CTX/ATG conditioning is a promising option for MUD HCT in SAA patients, which we will examine in a prospective clinical trial.
Pediatric Transplantation 07/2011; 15(6):628-34. · 1.48 Impact Factor
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Amit K Mitra,
Kristine R Crews,
Stanley Pounds,
Xueyuan Cao,
Tanya Feldberg,
Yogita Ghodke,
Varsha Gandhi,
William Plunkett,
M Eileen Dolan, Christine Hartford,
Susana Raimondi,
Dario Campana,
James Downing,
Jeffrey E Rubnitz,
Raul C Ribeiro,
Jatinder K Lamba
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ABSTRACT: Cytosolic 5'-nucleotidase II (NT5C2) is involved in the development of 1-β-d-arabinofuranosylcytosine (ara-C) resistance and has been associated with clinical outcome in patients receiving ara-C-based chemotherapy. NT5C2 inactivates ara-C by dephosphorylating ara-C monophosphate to ara-C. In this study, we sequenced NT5C2 in genomic DNA samples from International HapMap project panels with European [Centre d'Etude du Polymorphisme Humain (CEU); n = 90] or African [Yoruba people in Ibadan, Nigeria (YRI); n = 90] ancestry. We identified 41 genetic variants [one insertion-deletion and 40 single nucleotide polymorphisms (SNPs)], including three nonsynonymous SNPs (Y3A, K47R, and Q136R). Twenty-five SNPs were novel and 16 overlapped with the HapMap data. Subjects with African ancestry had NT5C2 mRNA expression levels that was significantly higher than those with European ancestry (p = 0.005). Furthermore, there was a correlation between NT5C2 mRNA expression and ara-C sensitivity in CEU but not in YRI cell lines. None of the nonsynonymous SNPs demonstrated any effect on NT5C2 activity. The genotypes of several SNPs were significantly associated with NT5C2 mRNA expression and/or ara-C sensitivity in CEU cell lines, but very few were significant in YRI cell lines. Of most interest, SNPs (linkage disequilibrium group CEU.12) in the 5'-untranslated region were associated with NT5C2 expression and ara-C sensitivity in HapMap cell lines and with NT5C2 mRNA expression and ara-C sensitivity in diagnostic leukemic blasts from pediatric patients with acute myeloid leukemia. Functional genomics analysis demonstrated that the promoter SNP rs11191612 was associated with altered luciferase activation in reporter assays and altered DNA-protein binding in gel shift assays. These results suggest that genetic variations in NT5C2 influence its expression and, potentially, cellular responses to nucleoside analogs.
Journal of Pharmacology and Experimental Therapeutics 06/2011; 339(1):9-23. · 3.83 Impact Factor
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Wing Leung,
Dario Campana,
Jie Yang,
Deqing Pei,
Elaine Coustan-Smith,
Kwan Gan,
Jeffrey E Rubnitz,
John T Sandlund,
Raul C Ribeiro,
Ashok Srinivasan, Christine Hartford,
Brandon M Triplett,
Mari Dallas,
Asha Pillai,
Rupert Handgretinger,
Joseph H Laver,
Ching-Hon Pui
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ABSTRACT: We evaluated 190 children with very high-risk leukemia, who underwent allogeneic hematopoietic cell transplantation in 2 sequential treatment eras, to determine whether those treated with contemporary protocols had a high risk of relapse or toxic death, and whether non-HLA-identical transplantations yielded poor outcomes. For the recent cohorts, the 5-year overall survival rates were 65% for the 37 patients with acute lymphoblastic leukemia and 74% for the 46 with acute myeloid leukemia; these rates compared favorably with those of earlier cohorts (28%, n = 57; and 34%, n = 50, respectively). Improvement in the recent cohorts was observed regardless of donor type (sibling, 70% vs 24%; unrelated, 61% vs 37%; and haploidentical, 88% vs 19%), attributable to less infection (hazard ratio [HR] = 0.12; P = .005), regimen-related toxicity (HR = 0.25; P = .002), and leukemia-related death (HR = 0.40; P = .01). Survival probability was dependent on leukemia status (first remission vs more advanced disease; HR = 0.63; P = .03) or minimal residual disease (positive vs negative; HR = 2.10; P = .01) at the time of transplantation. We concluded that transplantation has improved over time and should be considered for all children with very high-risk leukemia, regardless of matched donor availability.
Blood 05/2011; 118(2):223-30. · 9.90 Impact Factor
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BMC Bioinformatics. 01/2008;
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ABSTRACT: The recessive deficiency in thiopurine methyltransferase (TPMT), caused by germ-line polymorphisms in TPMT, can cause severe toxicity after mercaptopurine. However, the significance of heterozygosity and the effect of the polymorphism on thioguanine or in the absence of thiopurines is not known. To address these issues, we created a murine knockout of Tpmt. Pharmacokinetic and pharmacodynamic studies of mercaptopurine and thioguanine were done in Tpmt(-/-), Tpmt(+/-), and Tpmt(+/+) mice and variables were compared among genotypes. Methylated thiopurine and thioguanine nucleotide metabolites differed among genotypes after treatment with mercaptopurine (P < 0.0001 and P = 0.044, respectively) and thioguanine (P = 0.011 and P = 0.002, respectively). Differences in toxicity among genotypes were more pronounced following treatment with 10 daily doses of mercaptopurine at 100 mg/kg/d (0%, 68%, and 100% 50-day survival; P = 0.0003) than with thioguanine at 5 mg/kg/d (0%, 33%, and 50% 15-day survival; P = 0.07) in the Tpmt(-/-), Tpmt(+/-), and Tpmt(+/+) genotypes, respectively. Myelosuppression and weight loss exhibited a haploinsufficient phenotype after mercaptopurine, whereas haploinsufficiency was less prominent with thioguanine. In the absence of drug challenge, there was no apparent phenotype. The murine model recapitulates many clinical features of the human polymorphism; indicates that mercaptopurine is more affected by the TPMT polymorphism than thioguanine; and provides a preclinical system for establishing safer regimens of genetically influenced antileukemic drug therapy.
Cancer Research 05/2007; 67(10):4965-72. · 7.86 Impact Factor
