Publications by authors named "Brandon M Triplett"

29 Publications

  • Page 1 of 1

Outcomes of pediatric patients who relapse after first HCT for acute leukemia or MDS.

Bone Marrow Transplant 2021 Mar 19. Epub 2021 Mar 19.

Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN, USA.

Disease relapse remains a major cause of treatment failure in patients receiving allogeneic hematopoietic cell transplantation (alloHCT) for high-risk acute leukemias or myelodysplastic syndromes (MDS). Comprehensive data on outcomes after post-transplant relapse are lacking, especially in pediatric patients. Our objective was to assess the impact of various transplant-, patient-, and disease-related variables on survival and outcomes in patients who relapse after alloHCT. We describe our institutional experience with 221 pediatric patients who experienced disease relapse after their first alloHCT for acute leukemias or MDS between 1990 and 2018. In a multivariable model, being in first complete remission at first alloHCT, longer duration of remission after alloHCT, experiencing GVHD and receiving a transplant in a more recent time period were significantly associated with a higher likelihood of receiving a second alloHCT after post-transplant relapse. Of these variables, only longer interval from alloHCT to relapse, receiving a second alloHCT or DLI, and receiving a transplant in a more recent time period were associated with improved overall survival. Our data support pursuing second alloHCT for patients who have experienced relapse after their first transplant, as that remains the only salvage modality with a reasonable chance of inducing long-term remission.
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http://dx.doi.org/10.1038/s41409-021-01267-0DOI Listing
March 2021

Hematopoietic cell transplant for reversal of liver fibrosis in a pediatric patient with erythropoietic protoporphyria.

Pediatr Transplant 2021 Jan 6:e13966. Epub 2021 Jan 6.

Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN, USA.

Background: EPP is a rare disorder of heme biosynthesis in which patients present with disabling photosensitivity. A subset of patients develop severe liver disease with progressive liver failure necessitating an OLT. A HCT can potentially cure EPP by replacing the native bone marrow, which is the primary site of heme synthesis. However, due to concerns for inherent risks of treatment-related toxicities, the use of HCT has been reserved for patients undergoing an OLT to avoid disease recurrence in the hepatic graft. Data for HCT in EPP are lacking, particularly in the pediatric population.

Case (methods/results): We present the case of a 12-year-old patient with EPP photosensitivity and cirrhosis, whom we successfully treated with pre-emptive allogeneic HCT, significantly improving the patient's quality of life. We used a matched-unrelated donor bone marrow-derived graft. Our patient achieved full donor peripheral blood chimerism and has not had any evidence of GVHD. In addition to resolution of photosensitivity, our patient had reversal of liver fibrosis which we feel was largely due to intervention at an early stage of compensated cirrhosis.

Conclusion: Our case highlights the successful application of a known RIC regimen to this rare disorder that was well tolerated with sustained donor engraftment. It also emphasizes the importance of timing for HCT in patients with EPP and liver fibrosis. HCT should be considered early in pediatric patients with EPP-hepatopathy to prevent progression to liver failure and need for OLT with lifelong immunosuppression.
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http://dx.doi.org/10.1111/petr.13966DOI Listing
January 2021

Diagnostic approach to the evaluation of myeloid malignancies following CAR T-cell therapy in B-cell acute lymphoblastic leukemia.

J Immunother Cancer 2020 11;8(2)

Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA

Immunotherapeutic strategies targeting B-cell acute lymphoblastic leukemia (B-ALL) effectively induce remission; however, disease recurrence remains a challenge. Due to the potential for antigen loss, antigen diminution, lineage switch or development of a secondary or treatment-related malignancy, the phenotype and manifestation of subsequent leukemia may be elusive. We report on two patients with multiply relapsed/refractory B-ALL who, following chimeric antigen receptor T-cell therapy, developed myeloid malignancies. In the first case, a myeloid sarcoma developed in a patient with a history of myelodysplastic syndrome. In the second case, two distinct events occurred. The first event represented a donor-derived myelodysplastic syndrome with monosomy 7 in a patient with a prior hematopoietic stem cell transplantation. This patient went on to present with lineage switch of her original B-ALL to ambiguous lineage T/myeloid acute leukemia. With the rapidly evolving field of novel immunotherapeutic strategies, evaluation of relapse and/or subsequent neoplasms is becoming increasingly more complex. By virtue of these uniquely complex cases, we provide a framework for the evaluation of relapse or evolution of a subsequent malignancy following antigen-targeted immunotherapy.
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http://dx.doi.org/10.1136/jitc-2020-001563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7703409PMC
November 2020

Neurocognitive functioning in long-term survivors of pediatric hematopoietic cell transplantation.

Bone Marrow Transplant 2021 Apr 14;56(4):873-882. Epub 2020 Nov 14.

Department of Psychology, St. Jude Children's Research Hospital, Memphis, TN, USA.

Survivors of pediatric hematopoietic cell transplantation (HCT) are at risk for impairment in cognitive and academic function. Most research to date has focused on the first years following transplant, and less is known about the long-term effects. We examined global and specific neurocognitive functioning in long-term (>5 years post HCT) survivors in comparison to both normative data and a sample of demographically similar healthy peers. A comprehensive battery of neurocognitive measures was obtained from 83 long-term survivors and 50 healthy comparisons. Analyses were conducted to assess for differences in neurocognitive functions between survivors, normative means, and healthy comparisons, and to examine the impact of medical and demographic variables on neurocognitive performance. Survivors' performance was within the Average range across most measures, although significantly lower than both test norms and healthy comparisons on several measures. Despite generally intact neurocognitive functioning in the survivor group as a whole, survivors who experienced graft-vs.-host disease demonstrated slower processing speed and weaker verbal learning. Use of total body irradiation was not associated with any performance-based measure of neurocognitive functioning. Although subgroups of patients may be at relatively higher risk of neurocognitive impairment, the long-term neurocognitive impact for most survivors is relatively small.
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http://dx.doi.org/10.1038/s41409-020-01125-5DOI Listing
April 2021

Pharmacokinetics of alemtuzumab in pediatric patients undergoing ex vivo T-cell-depleted haploidentical hematopoietic cell transplantation.

Cancer Chemother Pharmacol 2020 Dec 10;86(6):711-717. Epub 2020 Oct 10.

Department of Bone Marrow Transplantation and Cell Therapy, St. Jude Children's Research Hospital, MS 1130, Room I3305, 262 Danny Thomas Place, Memphis, TN, 38105, USA.

Purpose: Alemtuzumab is a humanized monoclonal antibody against CD52 which is predominantly present on T and B lymphocytes. Alemtuzumab has been used as part of conditioning regimens for prophylaxis against rejection and GVHD. While the mechanism of action is well understood, the pharmacokinetics of this drug in children needed to be studied in more detail especially in the setting of ex vivo T-cell-depleted hematopoietic cell transplantation (HCT).

Methods: Serum alemtuzumab levels were measured at various time points in 13 patients who underwent haploidentical HCT utilizing ex vivo donor T-cell depletion. Alemtuzumab was administered subcutaneously at a cumulative dose of 45 mg/m from days - 13 to - 11. A one-compartmental model was used to fit the data using non-linear mixed effects modeling.

Results: We determined the median half-life to be 11 days. Alemtuzumab clearance increased with increasing baseline lymphocyte count (p = 0.008). Additionally, clearance increased with weight and age (p ≤ 0.035). AUC of alemtuzumab did not have any significant relationship with type of leukemia, overall survival, engraftment, immune reconstitution, mixed chimerism or GVHD, although the number of subjects in this pilot study was limited.

Conclusion: Absolute lymphocyte count and body weight affect alemtuzumab clearance. We also demonstrate feasibility of body-surface area-based dosing of alemtuzumab in pediatric HCT patients. Further studies are needed to evaluate the role of monitoring alemtuzumab serum concentrations to balance the prevention of graft rejection and GVHD with the promotion of rapid donor immune reconstitution.
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http://dx.doi.org/10.1007/s00280-020-04160-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735192PMC
December 2020

Autologous hematopoietic cell transplantation for the treatment of relapsed/refractory pediatric, adolescent, and young adult Hodgkin lymphoma: a single institutional experience.

Bone Marrow Transplant 2020 07 9;55(7):1357-1366. Epub 2020 Apr 9.

Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN, USA.

Pediatric, adolescent, and young adult patients with relapsed or refractory Hodgkin lymphoma receive multimodal therapy, including autologous hematopoietic cell transplantation (AutoHCT). Despite aggressive therapy, historical outcomes for this patient population have been poor. This paper describes a single institutional experience utilizing AutoHCT in 74 patients treated from 1988-2015. Our results demonstrate significantly improved outcomes over time. Compared with patients treated in the earlier era (1988-2001), 5-year overall survival improved from 62.5 ± 9.6% to 91.8 ± 4.4% (p < 0.001) and event free survival improved from 41.7 ± 9.6% to 87.7 ± 5.3% (I < 0.001) for patients treated in a later era (2002-2015). Improvements in survival are multifactorial, including reductions in both relapse and nonrelapse mortality. Further investigation is needed to determine the role of AutoHCT in a modern treatment cohort that includes frequent use of targeted immunotherapies. In addition, as the use and availability of effective novel therapeutics increases for this patient population there may be an opportunity for the reduction of standard cytotoxic therapies, including in AutoHCT preparative regimens, thereby mitigating late effects.
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http://dx.doi.org/10.1038/s41409-020-0879-4DOI Listing
July 2020

Longitudinal NK cell kinetics and cytotoxicity in children with neuroblastoma enrolled in a clinical phase II trial.

J Immunother Cancer 2020 03;8(1)

Oncology Department, St. Jude Children's Research Hospital, Memphis, Tennessee, USA

Background: Natural killer (NK) cells are one of the main effector populations of immunotherapy with monoclonal antibody and cytokines, used in combination with chemotherapy to treat children with high-risk neuroblastoma on this phase II trial. However, the impact of chemoimmunotherapy on NK cell kinetics, phenotype, and function is understudied.

Methods: We prospectively examined NK cell properties from 63 children with newly diagnosed neuroblastoma enrolled in a phase II trial (NCT01857934) and correlated our findings with tumor volume reduction after 2 courses of chemoimmunotherapy. NK cell studies were conducted longitudinally during chemoimmunotherapy and autologous hematopoietic cell transplantation (autoHCT) with optional haploidentical NK cell infusion and additional immunotherapy.

Results: Chemoimmunotherapy led to significant NK cytopenia, but complete NK cell recovery reliably occurred by day 21 of each therapy course as well as after autoHCT. Haploidentical NK cell infusion elevated the NK cell count transiently during autoHCT. NK cell cytotoxicity increased significantly during treatment compared with diagnosis. In addition, NK cells maintained their ability to respond to cytokine stimulation in culture longitudinally. Unsupervised cluster analysis of CD56 NK cell count and tumor volume at diagnosis and after two courses of chemoimmunotherapy identified two patient groups with distinct primary tumor sizes and therapy responses.

Conclusion: After profound NK cytopenia due to chemoimmunotherapy, endogenously reconstituted NK cells exhibit enhanced NK cytotoxicity compared with pretherapy measurements. Our data suggest a relationship between CD56 expression and tumor size before and after two courses of chemoimmunotherapy; however, future studies are necessary to confirm this relationship and its predictive significance.

Trial Registration Number: NCT01857934.
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http://dx.doi.org/10.1136/jitc-2019-000176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7206969PMC
March 2020

Improved survival rate in T-cell depleted haploidentical hematopoietic cell transplantation over the last 15 years at a single institution.

Bone Marrow Transplant 2020 05 18;55(5):929-938. Epub 2019 Nov 18.

Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN, USA.

T-cell depletion of an HLA-haploidentical (haplo) graft is often used to reduce the risk of graft-versus-host disease (GVHD), but the lack of donor T cells in the infused product may lead to graft failure, slow T-cell reconstitution, infections, and relapse. More selective T-cell depletion targeting CD45RA can effectively deplete naive T cells but preserve large numbers of memory T cells leading to robust engraftment of diverse T-cell populations and reduction of viremia in the early posttransplant period. Herein, we report the outcome of 143 pediatric and young adult hematologic malignancy patients receiving a first allogeneic hematopoietic cell transplantation (HCT) on six consecutive ex vivo T-cell depleted haploHCT protocols over the past 15 years at a single institution-including the first 50 patients on an active CD45RA-depleted haploHCT study in which patients also received NK-cells and pharmacological GvHD prophylaxis post transplant. Our data demonstrated an increase in the 3-year overall survival and event-free survival in nonchemorefractory recipients receiving CD45RA-depleted grafts (78.9% and 77.7%, respectively) compared with historic T-cell depleted haploHCT cohorts (46.7% and 42.7%, respectively, p = 0.004, and 0.003). This improvement was primarily due to a reduction in transplant related mortality without significant increase in the rates of GVHD.
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http://dx.doi.org/10.1038/s41409-019-0750-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202974PMC
May 2020

Outcomes after Second Hematopoietic Cell Transplantation in Children and Young Adults with Relapsed Acute Leukemia.

Biol Blood Marrow Transplant 2019 02 19;25(2):301-306. Epub 2018 Sep 19.

Center for International Blood and Marrow Transplant Research, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin. Electronic address:

Children with acute leukemia who relapse after hematopoietic cell transplantation (HCT) have few therapeutic options. We studied 251 children and young adults with acute myelogenous or lymphoblastic leukemia who underwent a second HCT for relapse after their first HCT. The median age at second HCT was 11 years, and the median interval between first and second HCT was 17 months. Most of the patients (n = 187; 75%) were in remission, received a myeloablative conditioning regimen (n = 157; 63%), and underwent unrelated donor HCT (n = 230; 92%). The 2-year probability of leukemia-free survival (LFS) was 33% after transplantation in patients in remission, compared with 19% after transplantation in patients not in remission (P = .02). The corresponding 8-year probabilities were 24% and 10% (P = .003). A higher rate of relapse contributed to the difference in LFS. The 2-year probability of relapse after transplantation was 42% in patients in remission and 56% in those in relapse (P = .05). The corresponding 8-year probabilities were 49% and 64% (P = .04). These data extend the findings of others showing that patients with a low disease burden are more likely to benefit from a second transplantation. Late relapse led to a 10% decrement in LFS beyond the second year after second HCT. This differs from first HCT, in which most relapses occur within 2 years after HCT.
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http://dx.doi.org/10.1016/j.bbmt.2018.09.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6339844PMC
February 2019

Clonal dynamics of donor-derived myelodysplastic syndrome after unrelated hematopoietic cell transplantation for high-risk pediatric B-lymphoblastic leukemia.

Cold Spring Harb Mol Case Stud 2018 10 1;4(5). Epub 2018 Oct 1.

Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.

Donor-derived hematologic malignancies are rare complications of hematopoietic cell transplantation (HCT). Although these are commonly either a myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), in general, they are a heterogeneous group of diseases, and a unified mechanism for their development has remained elusive. Here we report next-generation sequencing, including whole-exome sequencing (WES), whole-genome sequencing (WGS), and targeted sequencing, of a case of donor-derived MDS (dMDS) following HCT for high-risk B-lymphoblastic leukemia (B-ALL) in an adolescent. Through interrogation of single-nucleotide polymorphisms (SNPs) in the WGS data, we unequivocally prove that the MDS is donor-derived. Additionally, we sequenced 15 samples from 12 time points, including the initial B-ALL diagnostic sample through several post-HCT remission samples, the dMDS, and representative germline samples from both patient and donor, to show that the MDS-related pathologic mutations, including a canonical (p.Y700*) mutation, were detectable nearly 3 yr prior to the morphological detection of MDS. Furthermore, these MDS mutations were not detectable immediately following, and for >1 yr post-, HCT. These data support the clinical utility of comprehensive sequencing following HCT to detect donor-derived malignancies, while providing insights into the clonal progression of dMDS over a 4-yr period.
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http://dx.doi.org/10.1101/mcs.a002980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6169831PMC
October 2018

Defibrotide for the treatment of hepatic veno-occlusive disease/sinusoidal obstruction syndrome following nontransplant-associated chemotherapy: Final results from a post hoc analysis of data from an expanded-access program.

Pediatr Blood Cancer 2018 10 6;65(10):e27269. Epub 2018 Jun 6.

Pediatric Oncology, The Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Background: Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially fatal complication of conditioning for hematopoietic stem cell transplantation (HSCT) but can occur after nontransplant-associated chemotherapy. Following HSCT, VOD/SOS with multi-organ dysfunction (MOD) may be associated with >80% mortality. Defibrotide is approved to treat severe hepatic VOD/SOS post-HSCT in patients aged >1 month in the European Union and hepatic VOD/SOS with renal or pulmonary dysfunction post-HSCT in the United States. Prior to US approval, defibrotide was available to treat VOD/SOS through an expanded-access treatment (T-IND) program. A post hoc analysis of nontransplant-associated VOD/SOS patients treated with defibrotide initiated within 30 days of starting chemotherapy and followed for 70 days is presented.

Procedure: Patients were diagnosed by Baltimore or modified Seattle criteria or biopsy, and received defibrotide 25 mg/kg/day in four divided doses (≥21 days recommended).

Results: Of the 1,154 patients in the T-IND, 137 had nontransplant-associated VOD/SOS, 82 of whom developed VOD/SOS within 30 days of starting chemotherapy. Of them, 66 (80.5%) were aged ≤16 years. Across all the 82 patients, Kaplan-Meier estimated day +70 survival was 74.1%, 65.8% in patients with MOD (n = 38), and 81.3% in patients without MOD (n = 44). By age group, Kaplan-Meier estimated day +70 survival was 80.1% in pediatric patients (n = 66) and 50.0% in adults (n = 16). Treatment-related adverse events occurred in 26.8%.

Conclusions: In this post hoc analysis of 82 patients initiating defibrotide within 30 days of starting chemotherapy, Kaplan-Meier estimated survival was 74.1% at 70 days after defibrotide initiation. Safety profile was consistent with prior defibrotide studies.
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http://dx.doi.org/10.1002/pbc.27269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685707PMC
October 2018

Defibrotide sodium for the treatment of hepatic veno-occlusive disease/sinusoidal obstruction syndrome.

Expert Rev Clin Pharmacol 2018 Feb 5;11(2):113-124. Epub 2018 Jan 5.

f Hematology Department , Hôpital Saint Antoine, AP-HP, Université Pierre & Marie Curie , Paris , France.

Introduction: Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is an unpredictable condition associated with endothelial-cell damage due to conditioning for hematopoietic stem-cell transplantation (HSCT) or chemotherapy without HSCT. Mortality in patients with VOD/SOS and multi-organ dysfunction (MOD) may be >80%. Areas covered: Defibrotide is the only approved drug for the treatment of severe hepatic VOD/SOS after HSCT in the European Union and hepatic VOD/SOS with renal or pulmonary dysfunction in the United States. Its efficacy in patients with VOD/SOS with MOD post-HSCT was demonstrated in a clinical-trial program that included a historically controlled treatment study, a phase 2 trial, and a large T-IND expanded-access program that also included patients without MOD and who received chemotherapy without HSCT. Expert commentary: Defibrotide appears to protect endothelial cells and restore the thrombolytic-fibrinolytic balance. It addresses a significant clinical need and has demonstrated favorable Day +100 survival and overall adverse-event rates that seem similar to control groups receiving supportive care alone. Currently, defibrotide is under investigation for the prevention of VOD/SOS in high-risk pediatric and adult patients.
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http://dx.doi.org/10.1080/17512433.2018.1421943DOI Listing
February 2018

Chronic disease burden and frailty in survivors of childhood HSCT: a report from the St. Jude Lifetime Cohort Study.

Blood Adv 2017 Nov 7;1(24):2243-2246. Epub 2017 Nov 7.

Department of Epidemiology and Cancer Control.

Outcomes of hematopoietic stem cell transplantation (HSCT) have markedly improved over the past 2 decades, underscoring a need to better understand the long-term health effects of this intensive treatment modality. We describe the burden of chronic medical conditions and frail health among St. Jude Lifetime Cohort Study participants treated for childhood hematologic malignancies with HSCT (n = 112) or with conventional therapy (n = 1106). Chronic conditions and frail health were ascertained clinically and classified according to a modified version of the Common Terminology Criteria for Adverse Events (version 4.03) and the Fried Frailty Criteria. Seventy-nine transplants were allogeneic (41 from a sibling donor, 34 unrelated, and 4 others from related donor). Twenty-five allogeneic donor recipients had a history of chronic graft-versus-host disease. Compared to those treated with conventional therapy, a higher percentage of HSCT survivors had severe, disabling, or life threatening (grade 3-4) chronic conditions (81.3% vs 69.2%, = .007). By age 25 years, HSCT survivors experienced 148 grade 3-4 events/100 compared to 60 among conventional therapy survivors ( < .001). Percentages of survivors with second neoplasms (17.0% vs 7.9%, = .003), grade 3-4 cardiovascular (19.6% vs 10.2%, = .004) and pulmonary (16.1% vs 4.6%, < .001) conditions, and frail health (7.1% vs 1.6%, < .001) were higher after HSCT than conventional therapy. These results underscore the need for clinical follow-up and provide data to guide the development of prevention and/or intervention strategies for this vulnerable population.
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http://dx.doi.org/10.1182/bloodadvances.2017010280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5737129PMC
November 2017

Selective T-cell depletion targeting CD45RA reduces viremia and enhances early T-cell recovery compared with CD3-targeted T-cell depletion.

Transpl Infect Dis 2018 Feb 16;20(1). Epub 2018 Jan 16.

Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN, USA.

Background: T-cell depletion (TCD) effectively reduces severe graft-versus-host disease in recipients of HLA-mismatched allografts. However, TCD is associated with delayed immune recovery and increased infections. We hypothesized that specific depletion of CD45RA+ naive T cells, rather than broad depletion of CD3+ T cells, can preserve memory-immunity in the allografts and confer protection against important viral infections in the early post-transplant period.

Methods: Sixty-seven patients who received TCD haploidentical donor transplantation for hematologic malignancy on 3 consecutive trials were analyzed.

Results: Patients receiving CD45RA-depleted donor grafts had 2000-fold more donor T cells infused, significantly higher T-cell counts at Day +30 post transplant (550/μL vs 10/μL; P < .001), and higher T-cell diversity by Vbeta spectratyping at Day +100 (P < .001). Importantly, these recipients experienced a significant reduction in both the incidence (P = .002) and duration (P = .02) of any viremia (cytomegalovirus, Epstein-Barr virus, or adenovirus) in the first 6 months post transplant. Specifically, recipients of CD3-depleted grafts were more likely to experience adenovirus viremia (27% vs 4%, P = .02).

Conclusion: CD45RA-depletion provided a large number of donor memory T cells to the recipients and was associated with enhanced early T-cell recovery and protection against viremia.
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http://dx.doi.org/10.1111/tid.12823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5809307PMC
February 2018

Consolidation Therapy for Newly Diagnosed Pediatric Patients with High-Risk Neuroblastoma Using Busulfan/Melphalan, Autologous Hematopoietic Cell Transplantation, Anti-GD2 Antibody, Granulocyte-Macrophage Colony-Stimulating Factor, Interleukin-2, and Haploidentical Natural Killer Cells.

Biol Blood Marrow Transplant 2017 Nov 18;23(11):1910-1917. Epub 2017 Jul 18.

Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee. Electronic address:

The treatment of pediatric high-risk neuroblastoma is intensive and multimodal. Despite the introduction of immunotherapy for minimal residual disease, survival rates remain suboptimal and new therapies are needed. As part of a phase 2 trial, we are using a consolidation therapy regimen that combines a busulfan/melphalan conditioning schema, autologous hematopoietic cell transplantation (AHCT), and experimental immunotherapy with hu14.18K322A (a humanized anti-GD2 monoclonal antibody), granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-2, with or without the adoptive transfer of haploidentical natural killer cells (NKs). Here we report on 30 patients who have undergone AHCT with this experimental immunotherapy regimen, 21 of whom received haploidentical NKs. The median time to neutrophil engraftment was 13 days (range, 10 to 28 days) and to platelet engraftment of at least 20  ×  103/mm was 36.5 days (range, 0 to 102 days); no clinical difference was seen in those who did or did not receive NKs. Eight patients developed veno-occlusive disease, with 3 having multiorgan dysfunction. Toxicities were similar for patients who did or did not receive NKs. We conclude that this consolidation regimen is feasible and has an acceptable acute toxicity profile.
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http://dx.doi.org/10.1016/j.bbmt.2017.07.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5682204PMC
November 2017

Decreased relapsed rate and treatment-related mortality contribute to improved outcomes for pediatric acute myeloid leukemia in successive clinical trials.

Cancer 2017 Oct 30;123(19):3791-3798. Epub 2017 May 30.

Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.

Background: Outcomes for children with acute myeloid leukemia (AML) have improved over the past 20 years even though the medications used for induction therapy have not changed.

Methods: This study analyzed data from patients with AML who were enrolled in successive protocols (AML97 and AML02) to determine the contributors to the improved outcomes of the latter clinical trial.

Results: There were significant improvements in 5-year overall survival (48.9% vs 71.2%; P < .0001) and event-free survival (43.5% vs 61.8%; P = .002) from AML97 to AML02. The 5-year cumulative incidence of early death (ED)/treatment-related mortality (TRM) was reduced for patients treated in AML02 (18.5% vs 7.9%; P = .007). Although the overall incidence of refractory disease (6.5% vs 5.6%; P = .736) and relapse (29.3% vs 21.0%; P = .12) did not differ between the 2 studies, patients with low-risk AML who were treated in AML02 had a reduced incidence of relapse (27.3% vs 8.8%; P = .036).

Conclusions: The improved outcomes of the AML02 trial resulted from improved disease control for low-risk patients and overall decreased ED/TRM. These results emphasize the importance of supportive-care measures throughout chemotherapy courses and hematopoietic cell transplantation and the value of treatment intensity for patients with low-risk AML while underscoring the need for novel therapy, rather than increased therapy intensity, for children with high-risk AML. Cancer 2017;123:3791-3798. © 2017 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5610607PMC
October 2017

Human memory CD8 T cell effector potential is epigenetically preserved during in vivo homeostasis.

J Exp Med 2017 06 10;214(6):1593-1606. Epub 2017 May 10.

Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105

Antigen-independent homeostasis of memory CD8 T cells is vital for sustaining long-lived T cell-mediated immunity. In this study, we report that maintenance of human memory CD8 T cell effector potential during in vitro and in vivo homeostatic proliferation is coupled to preservation of acquired DNA methylation programs. Whole-genome bisulfite sequencing of primary human naive, short-lived effector memory (T), and longer-lived central memory (T) and stem cell memory (T) CD8 T cells identified effector molecules with demethylated promoters and poised for expression. Effector-loci demethylation was heritably preserved during IL-7- and IL-15-mediated in vitro cell proliferation. Conversely, cytokine-driven proliferation of T and T memory cells resulted in phenotypic conversion into T cells and was coupled to increased methylation of the CCR7 and Tcf7 loci. Furthermore, haploidentical donor memory CD8 T cells undergoing in vivo proliferation in lymphodepleted recipients also maintained their effector-associated demethylated status but acquired T-associated programs. These data demonstrate that effector-associated epigenetic programs are preserved during cytokine-driven subset interconversion of human memory CD8 T cells.
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http://dx.doi.org/10.1084/jem.20161760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5461005PMC
June 2017

Earlier defibrotide initiation post-diagnosis of veno-occlusive disease/sinusoidal obstruction syndrome improves Day +100 survival following haematopoietic stem cell transplantation.

Br J Haematol 2017 07 26;178(1):112-118. Epub 2017 Apr 26.

Stem Cell/Bone Marrow Transplantation Program, Division of Hematologic Malignancy, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a progressive, potentially fatal complication of conditioning for haematopoietic stem cell transplant (HSCT). The VOD/SOS pathophysiological cascade involves endothelial-cell activation and damage, and a prothrombotic-hypofibrinolytic state. Severe VOD/SOS (typically characterized by multi-organ dysfunction) may be associated with >80% mortality. Defibrotide is approved for treating severe hepatic VOD/SOS post-HSCT in the European Union, and for hepatic VOD/SOS with renal or pulmonary dysfunction post-HSCT in the United States. Previously, defibrotide (25 mg/kg/day in 4 divided doses for a recommended ≥21 days) was available through an expanded-access treatment protocol for patients with VOD/SOS. Data from this study were examined post-hoc to determine if the timing of defibrotide initiation post-VOD/SOS diagnosis affected Day +100 survival post-HSCT. Among 573 patients, defibrotide was started on the day of VOD/SOS diagnosis in approximately 30%, and within 7 days in >90%. The relationship between Day +100 survival and treatment initiation before/after specific days post-diagnosis showed superior survival when treatment was initiated closer to VOD/SOS diagnosis with a statistically significant trend over time for better outcomes with earlier treatment initiation (P < 0·001). These results suggest that initiation of defibrotide should not be delayed after diagnosis of VOD/SOS.
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http://dx.doi.org/10.1111/bjh.14727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5635854PMC
July 2017

Defibrotide for Patients with Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome: Interim Results from a Treatment IND Study.

Biol Blood Marrow Transplant 2017 Jun 8;23(6):997-1004. Epub 2017 Mar 8.

Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.

Hepatic veno-occlusive disease, or sinusoidal obstruction syndrome (VOD/SOS), is a serious and potentially fatal complication of conditioning for hematopoietic stem cell transplantation (HSCT) or of chemotherapy regimens alone. Defibrotide is a complex mixture of single-stranded polydeoxyribonucleotides that is approved in the United States for treating hepatic VOD/SOS with renal or pulmonary dysfunction post-HSCT and in the European Union, Israel, and South Korea for treating severe hepatic VOD/SOS post-HSCT. Defibrotide was previously available in the United States as an investigational drug through a treatment protocol (treatment IND) study. Interim results of that large, treatment IND study of patients with VOD/SOS and with or without multiorgan dysfunction (MOD; also known as multiorgan failure) are presented here. Defibrotide was administered i.v. at 6.25 mg/kg every 6 hours (25 mg/kg/day), with a recommended treatment duration of at least 21 days. Enrolled patients (n = 681) were diagnosed with VOD/SOS based on Baltimore or modified Seattle criteria or liver biopsy analysis. Among the 573 HSCT recipients, 288 (50.3%; 95% confidence interval [CI], 46.2% to 54.4%) were alive at day +100 post-HSCT. Day +100 survival for the pediatric (≤16 years) and adult (>16 years) subgroups was 54.5% (95% CI, 49.1% to 60.0%; n = 174 of 319) and 44.9% (95% CI, 38.8% to 51.0%; n = 114 of 254), respectively. In the MOD subgroup, 159 of 351 patients (45.3%; 95% CI, 40.1% to 50.5%) of patients were alive at day +100 post-HSCT. Treatment with defibrotide was generally well tolerated, and drug-related toxicities were consistent with previous studies. Adverse events were reported in 69.6% of safety-evaluable patients (399 of 573). Other than VOD/SOS and associated MOD symptoms, the most commonly reported treatment-emergent adverse event was hypotension (13.8%). Day +100 survival results observed in this trial were consistent with results seen in previous trials of defibrotide for VOD/SOS in adult and pediatric patients. These data support the potential benefit of defibrotide in treating a VOD/SOS patient population that includes those with and without MOD.
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http://dx.doi.org/10.1016/j.bbmt.2017.03.008DOI Listing
June 2017

Escalation to High-Dose Defibrotide in Patients with Hepatic Veno-Occlusive Disease.

Biol Blood Marrow Transplant 2015 Dec 14;21(12):2148-2153. Epub 2015 Aug 14.

Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, Tennessee; Department of Pediatrics, University of Tennessee Health Science Center, College of Medicine, Memphis, Tennessee.

Hepatic veno-occlusive disease (VOD) is a serious complication of high-dose chemotherapy regimens, such as those used in hematopoietic cell transplantation recipients. Defibrotide is considered a safe and effective treatment when dosed at 25 mg/kg/day. However, patients who develop VOD still have increased mortality despite the use of defibrotide. Data are limited on the use of doses above 60 mg/kg/day for persistent VOD. In this prospective clinical trial 34 patients received escalating doses of defibrotide. For patients with persistent VOD despite doses of 60 mg/kg/day, doses were increased to a maximum of 110 mg/kg/day. Increased toxicity was not observed until doses rose beyond 100 mg/kg/day. Patients receiving doses between 10 and 100 mg/kg/day experienced an average of 3 bleeding episodes per 100 days of treatment, whereas those receiving doses >100 mg/kg/day experienced 13.2 bleeding episodes per 100 days (P = .008). Moreover, dose reductions due to toxicity were needed at doses of 110 mg/kg/day more often than at lower doses. Defibrotide may be safely escalated to doses well above the current standard without an increase in bleeding risk. However, the efficacy of this dose-escalation strategy remains unclear, because outcomes were similar to published cohorts of patients receiving standard doses of defibrotide for VOD.
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http://dx.doi.org/10.1016/j.bbmt.2015.08.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4639417PMC
December 2015

Natural killer cell therapy in children with relapsed leukemia.

Pediatr Blood Cancer 2015 Aug 30;62(8):1468-72. Epub 2015 Apr 30.

Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, Tennessee.

Background: Novel therapies are needed for children with relapsed or refractory leukemia. We therefore tested the safety and feasibility of haploidentical natural killer cell therapy in this patient population.

Procedure: Twenty-nine children who had relapsed or refractory leukemia were treated with chemotherapy followed by the infusion of haploidentical NK cells. Cohort 1 included 14 children who had not undergone prior allogeneic hematopoietic cell transplantation (HCT), whereas Cohort 2 included 15 children with leukemia that had relapsed after HCT.

Results: Twenty-six (90%) NK donors were KIR mismatched (14 with one KIR and 12 with 2 KIRs). The peak NK chimerism levels were >10% donor in 87% of the evaluable recipients. In Cohort 1, 10 had responsive disease and 12 proceeded to HCT thereafter. Currently, 5 (36%) are alive without leukemia. In Cohort 2, 10 had responsive disease after NK therapy and successfully proceeded to second HCT. At present, 4 (27%) are alive and leukemia-free. The NK cell infusions and the IL-2 injections were well-tolerated.

Conclusions: NK cell therapy is safe, feasible, and should be further investigated in patients with chemotherapy-resistant leukemia.
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http://dx.doi.org/10.1002/pbc.25555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4634362PMC
August 2015

Haploidentical stem cell transplantation augmented by CD45RA negative lymphocytes provides rapid engraftment and excellent tolerability.

Pediatr Blood Cancer 2015 Apr 5;62(4):666-73. Epub 2015 Jan 5.

Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, Tennessee 38105; Department of Pediatrics, University of Tennessee Health Science Center, College of Medicine, Memphis, Tennessee 38163.

Background: Haploidentical donors are being increasingly used for allogeneic hematopoietic cell transplantation (HCT). However, the requisite T-cell depletion results in a profound and often long-lasting immunocompromised state, and donor lymphocyte infusions bring a risk of graft-versus-host disease (GVHD). Naïve T-cells are believed to be among the most alloreactive T-cell subset and can be identified by CD45RA expression. Allogeneic HCT using CD45RA depletion has not been previously described for haploidentical donors.

Procedure: Eight children with relapsed or refractory solid tumors were transplanted following myeloablative conditioning. Each patient received two cell products, one created by CD3 depletion and the other through CD45RA depletion.

Results: Median CD34 recovery was 59.2% with CD45RA depletion, compared to 82.4% using CD3 depletion. Median CD3+ T-cell dose after CD45RA reduction was 99.2 × 10(6)  cells/kg, yet depletion of CD3+ CD45RA+ cells exceeded 4.5 log. CD45RA depletion also resulted in substantial depletion of B-cells (median 2.45 log). All eight patients engrafted within 14 days and rapidly achieved 100% donor chimerism. No acute GVHD or secondary graft failure was observed.

Conclusions: CD45RA depletion is a novel approach to haploidentical HCT that offers rapid engraftment with minimal risk of GVHD.
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http://dx.doi.org/10.1002/pbc.25352DOI Listing
April 2015

Phase I study of the safety and pharmacokinetics of plerixafor in children undergoing a second allogeneic hematopoietic stem cell transplantation for relapsed or refractory leukemia.

Biol Blood Marrow Transplant 2014 Aug 23;20(8):1224-8. Epub 2014 Apr 23.

Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, Tennessee; Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee.

The safety, pharmacokinetics, and biological effect of plerixafor in children as part of a conditioning regimen for chemo-sensitization in allogeneic hematopoietic stem cell transplantation (HSCT) have not been studied. This is a phase I study of plerixafor designed to evaluate its tolerability at dose of .24 mg/kg given intravenously on day -4 (level 1); day -4 and day -3 (level 2); or day -4, day -3, and day -2 (level 3) in combination with fludarabine, thiotepa, melphalan, and rabbit antithymocytic globulin for a second allogeneic HSCT in children with refractory or relapsed leukemia. Immunophenotype analysis was performed on blood and bone marrow before and after plerixafor administration. Twelve patients were enrolled. Plerixafor at all 3 levels was well tolerated without dose-limiting toxicity. Transient gastrointestinal side effects of National Cancer Institute-grade 1 or 2 in severity were the most common adverse events. The area under the concentration-time curve increased proportionally to the dose level. Plerixafor clearance was higher in males and increased linearly with body weight and glomerular filtration rate. The clearance decreased and the elimination half-life increased significantly from dose level 1 to 3 (P < .001). Biologically, the proportion of CXCR4(+) blasts and lymphocytes both in the bone marrow and peripheral blood increased after plerixafor administration.
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http://dx.doi.org/10.1016/j.bbmt.2014.04.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631218PMC
August 2014

Successful allogeneic hematopoietic cell engraftment after a minimal conditioning regimen in children with relapsed or refractory solid tumors.

Biol Blood Marrow Transplant 2013 Feb 9;19(2):291-7. Epub 2012 Oct 9.

Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, Tennessee 38105-3678, USA.

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 pretreated patients. We sought to determine the feasibility of HCT in a cohort of 24 children with incurable solid tumors using human leukocyte antigen-matched sibling or unrelated donors and a minimal conditioning regimen. Before stem cell infusion, all patients received 3 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 4 patients, all of whom had either improved chimerism or apparent tumor response. Graft-versus-host disease was comparable across donor sources and did not affect survival. Relapse remains a substantial barrier, although objective graft-versus-tumor effect was observed in several patients. Four patients with detectable disease before HCT achieved a complete response for at least 30 days after HCT, and two remain long-term survivors. Three patients were in complete response before HCT and 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.
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http://dx.doi.org/10.1016/j.bbmt.2012.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4689143PMC
February 2013

Longitudinal changes in body mass and composition in survivors of childhood hematologic malignancies after allogeneic hematopoietic stem-cell transplantation.

J Clin Oncol 2012 Nov 1;30(32):3991-7. Epub 2012 Oct 1.

Department of Bone Marrow Transplantation and Cellular Therapy, MS 1130, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105-3678, USA.

Purpose: To measure longitudinal changes in body mass and composition in survivors of childhood hematologic malignancies after allogeneic hematopoietic stem-cell transplantation (HSCT).

Patients And Methods: Body mass index (BMI) was analyzed in 179 survivors by category (underweight, healthy-weight, overweight, and obese) and by z score. Fat and lean body mass measured by dual-energy x-ray absorptiometry was analyzed as z scores.

Results: Over a median 6.6 years of follow-up, BMI z scores diminished significantly (0.32 pre-HSCT v -0.60 at 10 years post-HSCT; P < .001). Mean z scores for fat mass stayed within population norms, but those for lean mass remained below normal levels and diminished significantly over time (P = .018). Pre-HSCT BMI category and/or z score were strongly predictive of post-HSCT BMI (P < .001) and of fat and lean mass z scores (both P < .001). Survivors with extensive chronic graft-versus-host disease were more likely than others to have low BMI (P = .004) and low lean mass (P < .001) post-HSCT. Older age at HSCT (P = .015) and T-cell-depleted graft (P = .018) were predictive of lower post-HSCT BMI. Female patients had higher body fat (P = .002) and lower lean mass (P = .013) z scores than male patients, and black patients had higher fat mass z scores than white patients (P = .026).

Conclusion: BMI declines significantly after allogeneic HSCT for childhood hematologic malignancies, reflecting primarily a substantial decrease in lean mass but not fat mass. Monitoring and preservation of BMI and lean mass are vital, especially in those with the identified risk factors.
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http://dx.doi.org/10.1200/JCO.2011.40.0457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3675688PMC
November 2012

Effects of conditioning regimens and T cell depletion in hematopoietic cell transplantation for primary immune deficiency.

Biol Blood Marrow Transplant 2012 Dec 27;18(12):1911-20. Epub 2012 Jul 27.

Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

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.
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http://dx.doi.org/10.1016/j.bbmt.2012.07.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3496815PMC
December 2012

Detectable minimal residual disease before hematopoietic cell transplantation is prognostic but does not preclude cure for children with very-high-risk leukemia.

Blood 2012 Jul 19;120(2):468-72. Epub 2012 Apr 19.

Department of Bone Marrow Transplantation and Cellular Therapy, St Jude Children's Research Hospital, 262 Danny Thomas Pl, Memphis, TN 38105-2794, USA.

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.
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http://dx.doi.org/10.1182/blood-2012-02-409813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3398757PMC
July 2012

Longitudinal analysis of antibody response to immunization in paediatric survivors after allogeneic haematopoietic stem cell transplantation.

Br J Haematol 2012 Jan 24;156(1):109-17. Epub 2011 Oct 24.

Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105-3678, USA.

The long-term antibody responses to re-immunization in recipients of allogeneic haematopoietic stem cell transplantation (allo-HSCT) have not been well studied. We prospectively and longitudinally evaluated the antibody responses to eight vaccine antigens (diphtheria, tetanus, pertussis, measles, mumps, rubella, hepatitis B, and poliovirus) and assessed the factors associated with negative titres in 210 allo-HSCT recipients at St. Jude Children's Research Hospital. Antibody responses lasting for more than 5 years after immunization were observed in most patients for tetanus (95.7%), rubella (92.3%), poliovirus (97.9%), and, in diphtheria-tetanus-acellular pertussis (DTaP) recipients, diphtheria (100%). However, responses to pertussis (25.0%), measles (66.7%), mumps (61.5%), hepatitis B (72.9%), and diphtheria in tetanus-diphtheria (Td) recipients (48.6%) were less favourable, with either only transient antibody responses or persistently negative titres. Factors associated with vaccine failure were older age at immunization; lower CD3, CD4 or CD19 counts; higher IgM concentrations; positive recipient cytomegalovirus serology; negative titres before immunization; acute or chronic graft-versus-host disease; and radiation during preconditioning. These response patterns and clinical factors can be used to formulate re-immunization and monitoring strategies. Patients at risk for vaccine failure should have long-term follow-up; those with loss of antibody response or no seroconversion should receive booster immunizations.
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http://dx.doi.org/10.1111/j.1365-2141.2011.08913.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3237834PMC
January 2012

High success rate of hematopoietic cell transplantation regardless of donor source in children with very high-risk leukemia.

Blood 2011 Jul 25;118(2):223-30. Epub 2011 May 25.

Department of Oncology, St Jude Children's Research Hospital, Memphis, TN 38105-2794, USA.

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.
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http://dx.doi.org/10.1182/blood-2011-01-333070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3138677PMC
July 2011