Publications by authors named "Haydar Frangoul"

109 Publications

CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia. Reply.

N Engl J Med 2021 06;384(23):e91

Children's Hospital Regensburg, Regensburg, Germany

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMc2103481DOI Listing
June 2021

Safety, Tolerability, and Population Pharmacokinetics of Intravenous and Oral Isavuconazonium Sulfate in Pediatric Patients.

Antimicrob Agents Chemother 2021 07 16;65(8):e0029021. Epub 2021 Jul 16.

Weill Cornell Medicine, Cornell University, New York, New York, USA.

Isavuconazole, administered as the water-soluble prodrug isavuconazonium sulfate, is a new triazole agent used to treat invasive fungal infections. This phase 1 study evaluated the pharmacokinetics (PK), safety, and tolerability of isavuconazole in 46 immunocompromised pediatric patients, stratified by age (1 to <6 [intravenous (i.v.) only], 6 to <12, and 12 to <18 years), receiving 10 mg/kg body weight (maximum, 372 mg) isavuconazonium sulfate either i.v. or orally. A population PK model using weight-based allometric scaling was constructed with the pediatric i.v. and oral data plus i.v. data from a phase 1 study in adults. The best model was a 3-compartment model with combined zero-order and first-order input, with linear elimination. Stepwise covariate modeling was performed in Perl-speaks-NONMEM version 4.7.0. None of the covariates examined, including age, sex, race, and body mass index, were statistically significant for any of the PK parameters. The area under the concentration-time curve at steady state (AUC) was predicted for pediatric patients using 1,000 Monte Carlo simulations per age cohort for each administration route. The probability of target attainment (AUC range, 60 to 233 μg · h/ml) was estimated; this target range was derived from plasma drug exposures in adults receiving the recommended clinical dose. Predicted plasma drug exposures were within the target range for >80% and >76% of simulated pediatric patients following i.v. or oral administration, respectively. Intravenous and oral administration of isavuconazonium sulfate at the studied dosage of 10 mg/kg was well tolerated and resulted in exposure in pediatric patients similar to that in adults. (This study has been registered at ClinicalTrials.gov under identifier NCT03241550).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/AAC.00290-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8284446PMC
July 2021

Impact of depth of clinical response on outcomes of acute myeloid leukemia patients in first complete remission who undergo allogeneic hematopoietic cell transplantation.

Bone Marrow Transplant 2021 Sep 16;56(9):2108-2117. Epub 2021 Apr 16.

Haematology Research Centre, Department of Immunology and Inflammation, Imperial College London, London, UK.

Acute myeloid leukemia (AML) patients often undergo allogeneic hematopoietic cell transplantation (alloHCT) in first complete remission (CR). We examined the effect of depth of clinical response, including incomplete count recovery (CRi) and/or measurable residual disease (MRD), in patients from the Center for International Blood and Marrow Transplantation Research (CIBMTR) registry. We identified 2492 adult patients (1799 CR and 693 CRi) who underwent alloHCT between January 1, 2007 and December 31, 2015. The primary outcome was overall survival (OS). Multivariable analysis was performed to adjust for patient-, disease-, and transplant-related factors. Baseline characteristics were similar. Patients in CRi compared to those in CR had an increased likelihood of death (HR: 1.27; 95% confidence interval: 1.13-1.43). Compared to CR, CRi was significantly associated with increased non-relapse mortality (NRM), shorter disease-free survival (DFS), and a trend toward increased relapse. Detectable MRD was associated with shorter OS, shorter DFS, higher NRM, and increased relapse compared to absence of MRD. The deleterious effects of CRi and MRD were independent. In this large CIBMTR cohort, survival outcomes differ among AML patients based on depth of CR and presence of MRD at the time of alloHCT. Further studies should focus on optimizing post-alloHCT outcomes for patients with responses less than CR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41409-021-01261-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425595PMC
September 2021

Molecular and phenotypic diversity of CBL-mutated juvenile myelomonocytic leukemia.

Haematologica 2020 12 30;Online ahead of print. Epub 2020 Dec 30.

Department of Pediatrics, Benioff Children's Hospital, University of California, San Francisco, San Francisco, CA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco.

Mutations in the gene CBL were first identified in adults with various myeloid malignancies. Some patients with juvenile myelomonocytic leukemia (JMML) were also noted to harbor mutations in CBL, but were found to have generally less aggressive disease courses compared to other forms of Ras pathway-mutant JMML. Importantly, and in contrast to most reports in adults, the majority of CBL mutations in JMML patients are germline with acquired uniparental disomy occurring in affected marrow cells. Here, we systematically studied a large cohort of 33 JMML patients with CBL mutations and found this disease to be highly diverse in presentation and overall outcome. Moreover, we discovered somatically-acquired CBL mutations in 15% of pediatric patients who presented with more aggressive disease. Neither clinical features nor methylation profiling were able to distinguish somatic CBL patients from germline CBL patients, highlighting the need for germline testing. Overall, we demonstrate that disease courses are quite heterogeneous even among germline CBL patients. Prospective clinical trials are warranted to find ideal treatment strategies for this diverse cohort of patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3324/haematol.2020.270595DOI Listing
December 2020

CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia.

N Engl J Med 2021 01 5;384(3):252-260. Epub 2020 Dec 5.

From the Sarah Cannon Center for Blood Cancer at the Children's Hospital at TriStar Centennial, Nashville (H.F., J.D.), and St. Jude Children's Research Hospital, Memphis (A.S.) - both in Tennessee; Vertex Pharmaceuticals (D.A., B.K.E., J.L.-H., A.Y.) and Boston University School of Medicine (M.H.S.), Boston, and CRISPR Therapeutics, Cambridge (Y.-S.C., T.W.H., A. Kernytsky, S. Soni) - both in Massachusetts; the University of Milan, Milan (M.D.C.), and Ospedale Pediatrico Bambino Gesù Rome, Sapienza, University of Rome, Rome (F.L.); the University of Regensburg, Regensburg (J. Foell, S.C.), and Children's University Hospital, University of Tübingen, Tübingen (R.H.) - both in Germany; Imperial College Healthcare NHS Trust, St. Mary's Hospital, London (J. de la Fuente); Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia (S.G.); the University of Athens, Athens (A. Kattamis); BC Children's Hospital, University of British Columbia, Vancouver (A.M.L.), and the Hospital for Sick Children-University of Toronto, Toronto (D.W.) - both in Canada; Columbia University (M.Y.M.) and the Joan and Sanford I. Weill Medical College of Cornell University (S. Sheth), New York; Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, University of Paris, Paris (M.M.); and the University of Illinois at Chicago, Chicago (D.R.).

Transfusion-dependent β-thalassemia (TDT) and sickle cell disease (SCD) are severe monogenic diseases with severe and potentially life-threatening manifestations. BCL11A is a transcription factor that represses γ-globin expression and fetal hemoglobin in erythroid cells. We performed electroporation of CD34+ hematopoietic stem and progenitor cells obtained from healthy donors, with CRISPR-Cas9 targeting the erythroid-specific enhancer. Approximately 80% of the alleles at this locus were modified, with no evidence of off-target editing. After undergoing myeloablation, two patients - one with TDT and the other with SCD - received autologous CD34+ cells edited with CRISPR-Cas9 targeting the same enhancer. More than a year later, both patients had high levels of allelic editing in bone marrow and blood, increases in fetal hemoglobin that were distributed pancellularly, transfusion independence, and (in the patient with SCD) elimination of vaso-occlusive episodes. (Funded by CRISPR Therapeutics and Vertex Pharmaceuticals; ClinicalTrials.gov numbers, NCT03655678 for CLIMB THAL-111 and NCT03745287 for CLIMB SCD-121.).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMoa2031054DOI Listing
January 2021

Neighborhood poverty and pediatric allogeneic hematopoietic cell transplantation outcomes: a CIBMTR analysis.

Blood 2021 01;137(4):556-568

CIBMTR, National Marrow Donor Program/Be The Match, Minneapolis, MN.

Social determinants of health, including poverty, contribute significantly to health outcomes in the United States; however, their impact on pediatric hematopoietic cell transplantation (HCT) outcomes is poorly understood. We aimed to identify the association between neighborhood poverty and HCT outcomes for pediatric allogeneic HCT recipients in the Center for International Blood and Marrow Transplant Research database. We assembled 2 pediatric cohorts undergoing first allogeneic HCT from 2006 to 2015 at age ≤18 years, including 2053 children with malignant disease and 1696 children with nonmalignant disease. Neighborhood poverty exposure was defined a priori per the US Census definition as living in a high-poverty ZIP code (≥20% of persons below 100% federal poverty level) and used as the primary predictor in all analyses. Our primary outcome was overall survival (OS), defined as the time from HCT until death resulting from any cause. Secondary outcomes included relapse and transplantation-related mortality (TRM) in malignant disease, acute and chronic graft-versus-host disease, and infection in the first 100 days post-HCT. Among children undergoing transplantation for nonmalignant disease, neighborhood poverty was not associated with any HCT outcome. Among children undergoing transplantation for malignant disease, neighborhood poverty conferred an increased risk of TRM but was not associated with inferior OS or any other transplantation outcome. Among children with malignant disease, a key secondary finding was that children with Medicaid insurance experienced inferior OS and increased TRM compared with those with private insurance. These data suggest opportunities for future investigation of the effects of household-level poverty exposure on HCT outcomes in pediatric malignant disease to inform care delivery interventions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2020006252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845011PMC
January 2021

The Impact of Donor Type on Outcomes and Cost of Allogeneic Hematopoietic Cell Transplantation for Pediatric Leukemia: A Merged Center for International Blood and Marrow Transplant Research and Pediatric Health Information System Analysis.

Biol Blood Marrow Transplant 2020 09 25;26(9):1747-1756. Epub 2020 May 25.

Cancer Care Manitoba, University of Manitoba, Winnipeg, Manitoba, Canada.

Allogeneic hematopoietic stem cell transplantation (alloHCT) may be associated with significant morbidity and mortality, resulting in increased healthcare utilization (HCU). To date, no multicenter comparative cost analyses have specifically evaluated alloHCT in children with acute leukemia. In this retrospective cohort study, we examined the relationship between survival and HCU while investigating the hypothesis that matched sibling donor (MSD) alloHCT has significantly lower inpatient HCU with unrelated donor (URD) alloHCT, and that among URDs, umbilical cord blood (UCB) alloHCT will have higher initial utilization but lower long-term utilization. Clinical and transplantation outcomes data from the Center for International Blood and Marrow Transplant Research (CIBMTR) were merged with inpatient cost data from the Pediatric Health Information System (PHIS) database using a probabilistic merge methodology. The merged dataset comprised US patients age 1 to 21 years who underwent alloHCT for acute leukemia between 2004 and 2011 with comprehensive CIBMTR data at a PHIS hospital. AlloHCT was analyzed by donor type, with specific analysis of utilization and costs using PHIS claims data. The primary outcomes of overall survival (OS), leukemia-free survival (LFS), and inpatient costs were evaluated using Kaplan-Meier curves and Cox and Poisson models. A total of 632 patients were identified in both the CIBMTR and PHIS data. The 5-year LFS was 60% for MSD alloHCT, 47% for well-matched matched unrelated donor bone marrow (MUD) alloHCT, 48% for mismatched unrelated donor alloHCT, and 45% for UCB alloHCT (P = .09). Total adjusted costs were significantly lower for MSD alloHCT versus MUD alloHCT by day 100 (adjusted cost ratio [ACR], .73; 95% confidence interval [CI], .62 to .86; P < .001), and higher for UCB alloHCT versus MUD alloHCT (ACR, 1.27; 95% CI, 1.11 to 1.45; P < .001). By 2 years, total adjusted costs remained significantly lower for MSD alloHCT compared with MUD alloHCT (ACR, .67; 95% CI, .56 to .81; P < .001) and higher for UCB alloHCT compared with MUD alloHCT (ACR, 1.25; 95% CI, 1.02 to 1.52; P = .0280). Our data show that UCB and MUD alloHCT provide similar survival outcomes; however, MUD alloHCT has a significant advantage in cost by day 100 and 2 years. More research is needed to determine whether the cost difference among URD alloHCT approaches remains significant with a larger sample size and/or beyond 2 years post-alloHCT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbmt.2020.05.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7518194PMC
September 2020

Impact of autologous blood transfusion after bone marrow harvest on unrelated donor's health and outcome: a CIBMTR analysis.

Bone Marrow Transplant 2020 11 30;55(11):2121-2131. Epub 2020 Apr 30.

Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

Pre-harvest autologous blood collection from bone marrow (BM) donors is performed to meet potential post-operative transfusion needs. This study examines the impact of autologous blood transfusion on BM donor's health and safety. The study included first-time unrelated BM donors from the United States whose BM harvest was facilitated by the National Marrow Donor Program (NMDP) centers between 2006 and 2017. Examination of 7024 BM donors revealed that 60% received at least one unit of autologous blood. The donors who received autologous blood were older, had lower hemoglobin pre-harvest, underwent longer duration of anesthesia, and higher volume BM harvest. Only donors who underwent high-volume BM harvest, defined as a BM harvest volume >27% of donor's blood volume, benefited from autologous transfusion. After a high-volume BM harvest, autologous blood transfusion was shown to decrease grade 2 to 4 collection-associated toxicities within 48 h of BM donation (p = 0.010) and shorten the time to donor-reported "complete" recovery from donation-associated symptoms (p < 0.001). Therefore, autologous transfusion could be avoided as support of marrow donation in the majority of unrelated BM donors and should be limited to cases where the planned BM harvest volume is expected to exceed 27% of donor's blood volume.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41409-020-0911-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606543PMC
November 2020

Infantile Myelofibrosis and Myeloproliferation with CDC42 Dysfunction.

J Clin Immunol 2020 05 17;40(4):554-566. Epub 2020 Apr 17.

Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.

Studies of genetic blood disorders have advanced our understanding of the intrinsic regulation of hematopoiesis. However, such genetic studies have only yielded limited insights into how interactions between hematopoietic cells and their microenvironment are regulated. Here, we describe two affected siblings with infantile myelofibrosis and myeloproliferation that share a common de novo mutation in the Rho GTPase CDC42 (Chr1:22417990:C>T, p.R186C) due to paternal germline mosaicism. Functional studies using human cells and flies demonstrate that this CDC42 mutant has altered activity and thereby disrupts interactions between hematopoietic progenitors and key tissue microenvironmental factors. These findings suggest that further investigation of this and other related disorders may provide insights into how hematopoietic cell-microenvironment interactions play a role in human health and can be disrupted in disease. In addition, we suggest that deregulation of CDC42 may underlie more common blood disorders, such as primary myelofibrosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10875-020-00778-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253386PMC
May 2020

HLA-Haploidentical Hematopoietic Cell Transplantation for Treatment of Nonmalignant Diseases Using Nonmyeloablative Conditioning and Post-Transplant Cyclophosphamide.

Biol Blood Marrow Transplant 2020 07 28;26(7):1332-1341. Epub 2020 Mar 28.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington; Division of Hematology and Oncology, Seattle Children's Hospital, Seattle, Washington. Electronic address:

Allogeneic hematopoietic cell transplant (HCT) is often the only curative therapy for patients with nonmalignant diseases; however, many patients do not have an HLA-matched donor. Historically, poor survival has been seen after HLA-haploidentical HCT because of poor immune reconstitution, increased infections, graft-versus-host disease (GVHD), and graft failure. Encouraging results have been reported using a nonmyeloablative T cell-replete HLA-haploidentical transplant approach in patients with hematologic malignancies. Here we report the outcomes of 23 patients with various nonmalignant diseases using a similar approach. Patients received HLA-haploidentical bone marrow (n = 17) or granulocyte colony-stimulating factor-mobilized peripheral blood stem cell (n = 6) grafts after conditioning with cyclophosphamide 50 mg/kg, fludarabine 150 mg/m, and 2 or 4 Gy total body irradiation. Postgrafting immunosuppression consisted of cyclophosphamide, mycophenolate mofetil, tacrolimus, ± sirolimus. Median patient age at HCT was 10.8 years. Day 100 transplant-related mortality (TRM) was 0%. Two patients died at later time points, 1 from intracranial hemorrhage/disseminated fungal infection in the setting of graft failure and 1 from infection/GVHD. The estimated probabilities of grades II to IV and III to IV acute GVHD at day 100 and 2-year National Institutes of Health consensus chronic GVHD were 78%, 26%, and 42%, respectively. With a median follow-up of 2.5 years, the 2-year overall and event-free rates of survival were 91% and 78%, respectively. These results are encouraging and demonstrate favorable disease-specific lineage engraftment with low TRM in patients with nonmalignant diseases using nonmyeloablative conditioning followed by T cell-replete HLA-haploidentical grafts. However, additional strategies are needed for GVHD prevention to make this a viable treatment approach for patients with nonmalignant diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbmt.2020.03.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7306430PMC
July 2020

Impact of cytogenetic abnormalities on outcomes of adult Philadelphia-negative acute lymphoblastic leukemia after allogeneic hematopoietic stem cell transplantation: a study by the Acute Leukemia Working Committee of the Center for International Blood and Marrow Transplant Research.

Haematologica 2020 05 26;105(5):1329-1338. Epub 2019 Sep 26.

Oncology Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Cytogenetic risk stratification at diagnosis has long been one of the most useful tools to assess prognosis in acute lymphoblastic leukemia (ALL). To examine the prognostic impact of cytogenetic abnormalities on outcomes after allogeneic hematopoietic cell transplantation, we studied 1731 adults with Philadelphia-negative ALL in complete remission who underwent myeloablative or reduced intensity/non-myeloablative conditioning transplant from unrelated or matched sibling donors reported to the Center for International Blood and Marrow Transplant Research. A total of 632 patients had abnormal conventional metaphase cytogenetics. The leukemia-free survival and overall survival rates at 5 years after transplantation in patients with abnormal cytogenetics were 40% and 42%, respectively, which were similar to those in patients with a normal karyotype. Of the previously established cytogenetic risk classifications, modified Medical Research Council-Eastern Cooperative Oncology Group score was the only independent prognosticator of leukemia-free survival (=0.03). In the multivariable analysis, monosomy 7 predicted post-transplant relapse [hazard ratio (HR)=2.11; 95% confidence interval (95% CI): 1.04-4.27] and treatment failure (HR=1.97; 95% CI: 1.20-3.24). Complex karyotype was prognostic for relapse (HR=1.69; 95% CI: 1.06-2.69), whereas t(8;14) predicted treatment failure (HR=2.85; 95% CI: 1.35-6.02) and overall mortality (HR=3.03; 95% CI: 1.44-6.41). This large study suggested a novel transplant-specific cytogenetic scheme with adverse [monosomy 7, complex karyotype, del(7q), t(8;14), t(11;19), del(11q), tetraploidy/near triploidy], intermediate (normal karyotype and all other abnormalities), and favorable (high hyperdiploidy) risks to prognosticate leukemia-free survival (=0.02). Although some previously established high-risk Philadelphia-negative cytogenetic abnormalities in ALL can be overcome by transplantation, monosomy 7, complex karyotype, and t(8;14) continue to pose significant risks and yield inferior outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3324/haematol.2019.220756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193485PMC
May 2020

Survival Trends in Infants Undergoing Allogeneic Hematopoietic Cell Transplant.

JAMA Pediatr 2019 05 6;173(5):e190081. Epub 2019 May 6.

Division of Blood and Marrow Transplantation, Center for Cancer and Blood Disorders, Children's National Health System, Washington, DC.

Importance: Studies demonstrating improved survival after allogeneic hematopoietic cell transplant generally exclude infants.

Objective: To analyze overall survival trends and other outcomes among infants who undergo allogeneic hematopoietic cell transplant.

Design, Setting, And Participants: In this cohort study, we used time-trend analysis to evaluate 3 periods: 2000 through 2004, 2005 through 2009, and 2010 through 2014. The study was conducted in a multicenter setting through the Center for International Blood and Marrow Transplant Research, which is made up of a voluntary working group of more than 450 transplant centers worldwide. Two groups of infants aged 1 year or younger in 2 cohorts were included: those with malignant conditions, such as leukemia, and those with nonmalignant disorders, including immunodeficiencies. Data analysis was conducted from July 2017 to December 2018.

Exposures: Allogeneic hematopoietic cell transplant.

Main Outcomes And Measures: Survival trends, disease relapse, and toxicity.

Results: A total of 2498 infants with a median age of 7 months (range, <1-12 months) were included. In the nonmalignant cohort (n = 472), survival rates improved from the first to the second period (hazard ratio, 0.77 [95% CI, 0.63-0.93]; P = .007) but did not change after 2004. Compared with infants with nonmalignant diseases (n = 2026; 3-year overall survival: 2000-2004, 375/577 [65.0%]; 2005-2009, 503/699 [72.0%]; and 2010-2014, 555/750 [74.0%]), those with malignant conditions had poorer survival rates, without improvement over time (3-year overall survival: 2000-2004, 109/199 [54.8%]; 2005-2009, 104/161 [64.6%]; and 2010-2014, 66/112 [58.9%]). From 2000 through 2014, relapse rates increased in infants with malignant conditions (3-year relapse rate: 2000-2004, 19% [95% CI, 14%-25%]; 2005-2009, 23% [95% CI, 17%-30%]; 2010-2014, 36% [95% CI, 27%-46%]; P = .01). Sinusoidal obstruction syndrome was frequent, occurring with a cumulative incidence of 13% (95% CI, 11%-16%) of infants with nonmalignant diseases and 32% (95% CI, 22%-42%) of those with malignant diseases. Generally, recipients of human leukocyte antigen-identical sibling bone marrow grafts had the best outcomes.

Conclusions And Relevance: Survival rates have not improved for infants with malignant diseases over the 15-year study period. Infants with nonmalignant diseases had improved survival rates in the earlier but not the later study period. Higher relapses for the malignant cohort and toxicities for all infants remain significant challenges. Strategies to reduce relapse and toxicity and optimize donor and graft selection may improve outcomes in the future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamapediatrics.2019.0081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503511PMC
May 2019

The impact of the graft-versus-leukemia effect on survival in acute lymphoblastic leukemia.

Blood Adv 2019 02;3(4):670-680

UCSD Moores Cancer Center, University of California San Diego Medical Center, La Jolla, CA.

Allogeneic hematopoietic cell transplant is a potential curative therapy for acute lymphoblastic leukemia (ALL). Delineating the graft-versus-leukemia (GVL) effect as a function of graft-versus-host disease (GVHD) offers the potential to improve survival. We examined 5215 transplant recipients with ALL reported to the Center for International Blood and Marrow Transplant Research registry. Overall survival (OS) was compared according to the presence and severity of GVHD and evaluated in 3 cohorts: 2593 adults in first or second complete remission (CR1/CR2), 1619 pediatric patients in CR1/CR2, and 1003 patients with advanced (CR ≥3 or active disease) ALL. For patients in CR1/CR2, development of acute GVHD (aGVHD) or chronic GVHD (cGVHD) was associated with lower risk of relapse than no GVHD (hazard ratio [HR], 0.49-0.69). Patients with advanced ALL developing grades III and IV aGVHD or cGVHD were also at lower risk of relapse (HRs varied from 0.52 to 0.67). Importantly, adult and children in CR1/CR2 with grades I and II aGVHD without cGVHD experienced the best OS compared with no GVHD (reduction of mortality with HR, 0.83-0.76). Increased nonrelapse mortality accompanied grades III and IV aGVHD (HRs varied from 2.69 to 3.91) in all 3 cohorts and abrogated any protection from relapse, resulting in inferior OS. Patients with advanced ALL had better OS (reduction in mortality; HR, 0.69-0.73) when they developed cGVHD with or without grades I and II aGVHD. In conclusion, GVHD was associated with an increased GVL effect in ALL. GVL exerted a net beneficial effect on OS only if associated with low-grade aGVHD in CR1/CR2 or with cGVHD in advanced ALL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2018027003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391668PMC
February 2019

The Concentration of Total Nucleated Cells in Harvested Bone Marrow for Transplantation Has Decreased over Time.

Biol Blood Marrow Transplant 2019 07 2;25(7):1325-1330. Epub 2019 Feb 2.

Clinical Haematology at Peter MacCalluma Cancer Centre and The Royal Melbourne Hospital, Victoria, Australia.

Bone marrow (BM) is an essential source of hematopoietic stem cell grafts for many allogeneic hematopoietic cell transplant (HCT) recipients, including adult patients (for specific diseases and transplantation strategies) and the majority of pediatric recipient. However, since the advent of granulocyte colony-stimulating factor-mobilized peripheral blood stem cell (PBSC) grafts, there has been a significant decrease in the use of BM in HCT, thought to be due mainly to the increased logistical challenges in harvesting BM compared with PBSCs, as well as generally no significant survival advantage of BM over PBSCs. The decreased frequency of collection has the potential to impact the quality of BM harvests. In this study, we examined >15,000 BM donations collected at National Marrow Donor Program centers between 1994 and 2016 and found a significant decline in the quality of BM products, as defined by the concentration of total nucleated cells (TNCs). The mean TNC concentration in BM donations dropped from 21.8 × 10 cells/mL in the earliest era (1994 to 1996) to 18.7 × 10 cells/mL in the most recent era (2012 to 2016) (means ratio, .83; P < .001). This decline in BM quality was seen despite the selection of more donors perceived to be optimal (eg, younger and male). Multivariate regression analysis showed that higher-volume centers (performing >30 collections per era) had better-quality harvests with higher concentrations of TNCs collected. In conclusion, we have identified a significant decrease in the quality of BM collections over time, and lower-volume collection centers had poorer-quality harvests. In this analysis, we could not elucidate the direct cause for this finding, suggesting the need for further studies to investigate the key factors responsible and to explore the impact on transplant recipients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbmt.2019.01.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615955PMC
July 2019

Veno-occlusive disease after high-dose busulfan-melphalan in neuroblastoma.

Bone Marrow Transplant 2020 03 4;55(3):531-537. Epub 2018 Sep 4.

Department of Pediatrics, University of California San Francisco Benioff Children's Hospital, San Francisco, CA, USA.

Survival for high-risk neuroblastoma patients is still suboptimal. Although stem cell transplantation (SCT) is used, there is no consensus as to which conditioning regimen has the greatest efficacy and fewest toxicities. We assessed the incidence of and risk for hepatic veno-occlusive disease (VOD) for neuroblastoma patients who underwent autologous SCT with busulfan and melphalan (BuMel) at eight centers following Children's Oncology Group (COG)-based induction chemotherapy. Data regarding the patients, SCT characteristics, busulfan steady-state concentrations, incidence of VOD, and survival were evaluated. VOD was defined using the modified Seattle criteria. Possible factors associated with VOD (age, busulfan-pharmacokinetic parameters, history of hepatic dysfunction, and day of neutrophil engraftment) were evaluated. Seventy five patients were included and 23 children (31%) developed VOD at a median of 19 days after SCT (range 14-27 days). VOD was the cause of death in 4 patients (5%). In a multivariable analysis, young age (OR 1.7 (95% CI: 1.16-2.56; p = 0.012)) and early day of neutrophil engraftment (OR 1.4 (95% CI: 1.08-2.14; p = 0.041) were associated with the development of VOD. Initial or cumulative busulfan steady-state concentration were not associated with VOD. We found that despite the use of intravenous busulfan with adjusted serum levels, the incidence of VOD remains high in pediatric neuroblastoma patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41409-018-0298-yDOI Listing
March 2020

Molecular and epidemiologic characterization of Wilms tumor from Baghdad, Iraq.

World J Pediatr 2018 12 28;14(6):585-593. Epub 2018 Aug 28.

Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, USA.

Background: Wilms tumor (WT) is the most common childhood kidney cancer worldwide, yet its incidence and clinical behavior vary according to race and access to adequate healthcare resources. To guide and streamline therapy in the war-torn and resource-constrained city of Baghdad, Iraq, we conducted a first-ever molecular analysis of 20 WT specimens to characterize the biological features of this lethal disease within this challenged population.

Methods: Next-generation sequencing of ten target genes associated with WT development and treatment resistance (WT1, CTNNB1, WTX, IGF2, CITED1, SIX2, p53, N-MYC, CRABP2, and TOP2A) was completed. Immunohistochemistry was performed for 6 marker proteins of WT (WT1, CTNNB1, NCAM, CITED1, SIX2, and p53). Patient outcomes were compiled.

Results: Mutations were detected in previously described WT "hot spots" (e.g., WT1 and CTNNB1) as well as novel loci that may be unique to the Iraqi population. Immunohistochemistry showed expression domains most typical of blastemal-predominant WT. Remarkably, despite the challenges facing families and care providers, only one child, with combined WT1 and CTNNB1 mutations, was confirmed dead from disease. Median clinical follow-up was 40.5 months (range 6-78 months).

Conclusions: These data suggest that WT biology within a population of Iraqi children manifests features both similar to and unique from disease variants in other regions of the world. These observations will help to risk stratify WT patients living in this difficult environment to more or less intensive therapies and to focus treatment on cell-specific targets.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12519-018-0181-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6236303PMC
December 2018

Comparison of pediatric allogeneic transplant outcomes using myeloablative busulfan with cyclophosphamide or fludarabine.

Blood Adv 2018 06;2(11):1198-1206

Mount Sinai Medical Center, New York, NY.

Busulfan combined with cyclophosphamide (BuCy) has long been considered a standard myeloablative conditioning regimen for allogeneic hematopoietic cell transplantation (HCT), including both nonmalignant conditions and myeloid diseases. Substituting fludarabine for cyclophosphamide (BuFlu) to reduce toxicity without an increase in relapse has been increasingly performed in children, but without comparison with BuCy. We retrospectively analyzed 1781 children transplanted from 2008 to 2014 to compare the effectiveness of BuCy with BuFlu. Nonmalignant and malignant disease populations were analyzed separately. Overall mortality was comparable for children with nonmalignant conditions who received BuFlu or BuCy (relative risk [RR], 1.14, = .52). Lower incidences of sinusoidal obstruction syndrome ( = .04), hemorrhagic cystitis ( = .04), and chronic graft-versus-host disease ( = .02) were observed after BuFlu, but the influence of the conditioning regimen could not be assessed by multivariate analysis because of the low frequency of these complications. Children transplanted for malignancies were more likely to receive BuFlu if they had higher hematopoietic cell transplantation-comorbidity index scores ( < .001) or their donor was unrelated and HLA-mismatched ( = .004). Nevertheless, there were no differences in transplant toxicities and comparable transplant-related mortality (RR, 1.2; = .46), relapse (RR, 1.2; = .15), and treatment failure (RR, 1.2; = .12). BuFlu was associated with higher overall mortality (RR, 1.4; = .008) related to inferior postrelapse survival ( = .001). Our findings demonstrated that outcomes after BuFlu are similar to those for BuCy for children, but for unclear reasons, those receiving BuFlu for malignancy may be at risk for shorter postrelapse survival.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2018016956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5998928PMC
June 2018

Haploidentical hematopoietic stem cell transplant for patients with sickle cell disease using thiotepa, fludarabine, thymoglobulin, low dose cyclophosphamide, 200 cGy tbi and post transplant cyclophosphamide.

Bone Marrow Transplant 2018 05 16;53(5):647-650. Epub 2018 Jan 16.

Pediatric Stem Cell Transplant Program Children's Hospital at TriStar Centennial and Sarah Cannon Research Institute, Nashville, TN, 37203, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41409-017-0077-1DOI Listing
May 2018

Influence of Age on Acute and Chronic GVHD in Children Undergoing HLA-Identical Sibling Bone Marrow Transplantation for Acute Leukemia: Implications for Prophylaxis.

Biol Blood Marrow Transplant 2018 03 16;24(3):521-528. Epub 2017 Nov 16.

Division of Hematology/Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama.

Relapse remains the major cause of mortality after hematopoietic cell transplantation (HCT) for pediatric acute leukemia. Previous research has suggested that reducing the intensity of calcineurin inhibitor-based graft-versus-host disease (GVHD) prophylaxis may be an effective strategy for abrogating the risk of relapse in pediatric patients undergoing matched sibling donor (MSD) HCT. We reasoned that the benefits of this strategy could be maximized by selectively applying it to those patients least likely to develop GVHD. We conducted a study of risk factors for GVHD, to risk-stratify patients based on age. Patients age <18 years with leukemia who received myeloablative, T cell-replete MSD bone marrow transplantation and calcineurin inhibitor-based GVHD prophylaxis between 2000 and 2013 and were entered into the Center for International Blood and Marrow Transplant Research registry were included. The cumulative incidence of grade II-IV acute GVHD (aGVHD) was 19%, that of grade II-IV aGVHD 7%, and that of chronic GVHD (cGVHD) was 16%. Compared with age 13 to 18 years, age 2 to 12 years was associated with a lower risk of grade II-IV aGVHD (hazard ratio [HR], .42; 95% confidence interval [CI], .26 to .70; P = .0008), grade II-IV aGVHD (HR, .24; 95% CI, .10 to .56; P = .001), and cGVHD (HR, .32; 95% CI, .19 to .54; P < .001). Compared with 2000-2004, the risk of grade II-IV aGVHD was lower in children undergoing transplantation in 2005-2008 (HR, .36; 95% CI, .20 to .65; P = .0007) and in 2009-2013 (HR, .24; 95% CI. .11 to .53; P = .0004). Similarly, the risk of grade III-IV aGVHD was lower in children undergoing transplantation in 2005-2008 (HR, .23; 95% CI, .08 to .65; P = .0056) and 2009-2013 (HR, .16; 95% CI, .04 to .67; P = .0126) compared with those doing so in 2000-2004. We conclude that aGVHD rates have decreased significantly over time, and that children age 2 to 12 years are at very low risk for aGVHD and cGVHD. These results should be validated in an independent analysis, because these patients with high-risk malignancies may be good candidates for trials of reduced GVHD prophylaxis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbmt.2017.11.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5826854PMC
March 2018

Allogeneic Hematopoietic Cell Transplantation Using Treosulfan-Based Conditioning for Treatment of Marrow Failure Disorders.

Biol Blood Marrow Transplant 2017 Oct 7;23(10):1669-1677. Epub 2017 Jun 7.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington; Department of Medicine, University of Washington School of Medicine, Seattle, Washington; Hematology-Oncology, Seattle Children's Hospital, Seattle, Washington.

Hematopoietic cell transplantation (HCT) is effective in the treatment of inherited marrow failure disorders and other nonmalignant diseases. Conventional myeloablative conditioning regimens have been associated with high transplant-related mortality, particularly in patients with comorbid conditions. Here we report on 14 patients with marrow failure disorders (Shwachman-Diamond syndrome, n = 3; Diamond Blackfan anemia, n = 4; GATA2 deficiency, n = 2; paroxysmal nocturnal hemoglobinuria, n = 4; and an undefined marrow failure disorder, n = 1) who underwent HCT on a prospective, phase II, multicenter clinical trial. Patients were given HLA-matched related (n = 2) or unrelated (n = 12) grafts after conditioning with treosulfan (42 g/m), fludarabine (150 mg/m), ± thymoglobulin (n = 11; 6 mg/kg). All patients engrafted. At a median follow-up of 3 years, 13 patients are alive with complete correction of their underlying disease. These results indicate that the combination of treosulfan, fludarabine, and thymoglobulin is effective at establishing donor engraftment with a low toxicity profile and excellent disease-free survival in patients with marrow failure disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbmt.2017.06.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5605451PMC
October 2017

Phase I Study of Clofarabine and 2-Gy Total Body Irradiation as a Nonmyeloablative Preparative Regimen for Hematopoietic Stem Cell Transplantation in Pediatric Patients with Hematologic Malignancies: A Therapeutic Advances in Childhood Leukemia Consortium Study.

Biol Blood Marrow Transplant 2017 Jul 7;23(7):1134-1141. Epub 2017 Apr 7.

The Children's Hospital, TriStar Centennial and Sarah Cannon Research Institute, Nashville, Tennessee.

Clofarabine is a purine nucleoside analog with immunosuppressive and antileukemic activity and its inclusion in reduced-intensity regimens could potentially improve outcomes. We performed a prospective phase I study of clofarabine combined with 2 Gy total body irradiation (TBI) as a nonmyeloablative preparative regimen for allogeneic stem cell transplantation in pediatric patients who were considered at high risk of mortality from standard myeloablative regimens. The main goal of the study was to delineate the maximum feasible dose (MFD) of clofarabine in combination with 2 Gy TBI. Eighteen patients, 1 to 21 years of age and in complete remission, were enrolled in 2 strata (matched related donor and unrelated donor) and evaluated for day100 dose-limiting events (DLE) (nonengraftment, nonrelapse mortality [NRM], and severe renal insufficiency) after receiving clofarabine at the starting dose level of 40 mg/m. All 6 patients (3 in each stratum) engrafted with no day 100 DLE seen in the first cohort. The dose was increased to 52 mg/m in the next and an expanded cohort (total of 12 patients) and no DLE were observed at day 100 and at the 1-year study endpoint. The regimen was well tolerated with transient transaminitis and gastrointestinal and skin reactions as the common reversible toxicities observed with clofarabine. The dose of 52 mg/m of clofarabine was deemed the MFD. Disease relapse led to mortality in 6 (33%) patients during follow-up with 1-year event-free survival and overall survival of 60% (95% confidence interval [CI], 34 to 79) and 71% (95% CI, 44 to 87), respectively. This regimen leads to successful engraftment using both related and unrelated donors with exceptionally low rates of NRM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbmt.2017.03.037DOI Listing
July 2017

Disparity in Outcomes for Adolescent and Young Adult Patients Diagnosed With Pediatric Solid Tumors Across 4 Decades.

Am J Clin Oncol 2018 05;41(5):471-475

Department of Radiation Oncology, Washington University School of Medicine, St Louis, MO.

Objective: Cancer mortality is a leading cause of disease-related death in the adolescent and young adult (AYA) population. Compared with older and younger patients, AYA patients often experience worse cancer-specific outcomes. Here, we compare AYA and pediatric overall survival (OS) in the most common pediatric extracranial solid tumors.

Materials And Methods: Using the US Surveillance, Epidemiology, and End Results database, we studied patients (age, 0 to 39 y) diagnosed with Ewing sarcoma, neuroblastoma, osteosarcoma, rhabdomyosarcoma, and Wilms tumor.

Results: A total of 12,375 patients (age, 0 to 39 y) were diagnosed between 1973 and 2010 (8247 pediatric and 4128 AYA patients). AYA patients with rhabdomyosarcoma and Ewing sarcoma were more likely to present with metastatic disease. OS was significantly worse in the AYA cohort for all tumor types (P<0.001) with the exception of osteosarcoma (P=0.29). Across 2 treatment time periods (1973 to 1989 and 1990 to 2010), there was significant improvement in 5-year OS in all tumor types with the exception of rhabdomyosarcoma; however, AYA patients continued to experience worse OS in the modern treatment cohort with the exception of osteosarcoma patients. There was no improvement in OS among AYA patients with Ewing sarcoma, neuroblastoma, rhabdomyosarcoma, or Wilms tumor over the 2 treatment eras.

Conclusions: For the most common pediatric extracranial solid tumors, AYA patients experience significantly worse OS compared with pediatric patients. Although improvements in therapy have led to gain in survival for pediatric patients, with the exception of osteosarcoma, AYA experienced no increase in survival over the study period. This investigation demonstrates the importance for further research in the AYA population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/COC.0000000000000304DOI Listing
May 2018

Incidence and risk factors of bacterial infections in children following autologous hematopoietic stem cell transplantation: Single-center experience from Jordan.

Pediatr Transplant 2016 Aug 6;20(5):683-6. Epub 2016 Jun 6.

Pediatric Stem Cell Transplant Program, TriStar Children's Hospital and Sarah Cannon Research Institute, Nashville, TN, USA.

Bacterial infection is a serious sequela following AHSCT; however, limited data are available regarding pediatric recipients, especially in developing countries. We retrospectively analyzed the incidence and risk factors of bacterial infections during the first 100 days after AHSCT in children at KHCC in Amman, Jordan between January, 2005 and September, 2013. A total of 65 patients were identified, with median age of four yr (1-17). Forty-seven patients (72.3%) had solid tumors and 18 (27.7%) had lymphoma. Bacterial infections were documented in 33 patients (50%), with a total of 63 episodes. Gram-negative infection (57.1%) was more prevalent than Gram-positive infection (38%). The risk of bacterial infections was higher among patients less than five yr of age (p = 0.028) and those who developed hypogammaglobulinemia requiring IVIG replacement (p = 0.001). Patients with solid tumors developed more bacterial infections compared to patients with lymphoma (p = 0.0057). No deaths were attributed to bacterial infection. Bacterial infection rate is high among recipients of AHSCT in Jordan with Gram-negative bacteria being the most common.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/petr.12727DOI Listing
August 2016

Effects of Race/Ethnicity and Socioeconomic Status on Outcome in Childhood Acute Lymphoblastic Leukemia.

J Pediatr Hematol Oncol 2016 07;38(5):350-4

*Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, MO †Department of Radiation Oncology, Vanderbilt University School of Medicine ‡The Children's Hospital at TriStar Centennial and Sarah Cannon Research Institute, Nashville, TN.

With modern therapy, overall survival (OS) for children with acute lymphoblastic leukemia approaches 90%. However, inferior outcomes for minority children have been reported. Data on the effects of ethnicity/race as it relates to socioeconomic status are limited. Using state cancer registry data from Texas and Florida, we evaluated the impact of neighborhood-level poverty rate and race/ethnicity on OS for 4719 children with acute lymphoblastic leukemia. On multivariable analysis, patients residing in neighborhoods with the highest poverty rate had a 1.8-fold increase in mortality compared with patients residing in neighborhoods with the lowest poverty rate (hazard ratio [HR], 1.8; 95% confidence interval [CI], 1.41-2.30). Hispanic and non-Hispanic black patients also had increased risk of mortality compared with non-Hispanic white patients (Hispanic: HR, 1.18; 95% CI, 1.01-1.39; non-Hispanic black: HR, 1.31; 95% CI, 1.03-1.66). On subgroup analysis, there was a 21.7% difference in 5-year OS when comparing non-Hispanic white children living in the lowest poverty neighborhoods (5-year OS, 91.2%; 95% CI, 88.6-93.2) to non-Hispanic black children living in the highest poverty neighborhoods (5-year OS, 69.5%; 95% CI, 61.5-76.1). To address such disparities in survival, further work is needed to identify barriers to cancer care in this pediatric population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MPH.0000000000000591DOI Listing
July 2016

Hematopoietic stem cell transplantation from non-sibling matched family donors for patients with thalassemia major in Jordan.

Pediatr Transplant 2016 Feb 23;20(1):120-3. Epub 2015 Oct 23.

Pediatric Stem Cell Transplant Program, TriStar Children's Hospital and Sarah Cannon Research Institute, Nashville, TN, USA.

There are limited data on the outcome of patients with thalassemia receiving HSCT from non-sibling matched family donors. Of the 341 patients with thalassemia major that underwent donor search at our center from January 2003 to December 2011, 236 (69.2%) had fully matched family donor of which 28 patients (8.2%) had non-sibling matched family donors identified. We report on seven patients with a median age of eight yr (4-21) who underwent myeloablative (n = 4) or RIC (n = 3) HSCT. The median age of the donors was 33 yr (4-47), three were parents, two first cousins, one paternal uncle, and one paternal aunt. All patients achieved primary neutrophil and platelet engraftment at a median of 18 (13-20) and 16 days (11-20), respectively. One patient developed grade II acute GVHD, and two patients developed limited chronic GVHD. One patient experienced secondary GF requiring a second transplant. At a median follow-up of 69 months (7-110), all patients are alive and thalassemia free. Our data emphasize the need for extended family HLA typing for patients with thalassemia major in regions where there is high rate of consanguinity. Transplant from non-sibling matched family donor can result in excellent outcome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/petr.12622DOI Listing
February 2016

Transplant Outcomes for Children with T Cell Acute Lymphoblastic Leukemia in Second Remission: A Report from the Center for International Blood and Marrow Transplant Research.

Biol Blood Marrow Transplant 2015 Dec 29;21(12):2154-2159. Epub 2015 Aug 29.

Stem Cell Transplant Program, Department of Pediatrics, Vanderbilt University, Nashville, TN.

Survival for children with relapsed T cell acute lymphoblastic leukemia (T-ALL) is poor when treated with chemotherapy alone, and outcomes after allogeneic hematopoietic cell transplantation (HCT) is not well described. Two hundred twenty-nine children with T-ALL in second complete remission (CR2) received an HCT after myeloablative conditioning between 2000 and 2011 and were reported to the Center for International Blood and Marrow Transplant Research. Median age was 10 years (range, 2 to 18). Donor source was umbilical cord blood (26%), matched sibling bone marrow (38%), or unrelated bone marrow/peripheral blood (36%). Acute (grades II to IV) and chronic graft-versus-host disease occurred in, respectively, 35% (95% confidence interval [CI], 27% to 45%) and 26% (95% CI, 20% to 33%) of patients. Transplant-related mortality at day 100 and 3-year relapse rates were 13% (95% CI, 9% to 18%) and 30% (95% CI, 24% to 37%), respectively. Three-year overall survival and disease-free survival rates were 48% (95% CI, 41% to 55%) and 46% (95% CI, 39% to 52%), respectively. In multivariate analysis, patients with bone marrow relapse, with or without concurrent extramedullary relapse before HCT, were most likely to relapse (hazard ratio, 3.94; P = .005) as compared with isolated extramedullary disease. In conclusion, HCT for pediatric T-ALL in CR2 demonstrates reasonable and durable outcomes, and consideration for HCT is warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbmt.2015.08.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4654112PMC
December 2015

Systemic granulocyte colony-stimulating factor (G-CSF) enhances wound healing in dystrophic epidermolysis bullosa (DEB): Results of a pilot trial.

J Am Acad Dermatol 2015 Jul 5;73(1):56-61. Epub 2015 May 5.

Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee.

Background: Chronic nonhealing wounds are the norm in patients with inherited epidermolysis bullosa (EB), especially those with dystrophic EB (DEB). A possible benefit in wound healing after subcutaneous treatment with granulocyte colony-stimulating factor (G-CSF) was suggested from an anecdotal report of a patient given this during stem cell mobilization before bone-marrow transplantation.

Objective: We sought to determine whether benefit in wound healing in DEB skin might result after 6 daily doses of G-CSF and to confirm its safety.

Methods: Patients were assessed for changes in total body blister and erosion counts, surface areas of selected wounds, and specific symptomatology after treatment.

Results: Seven patients with DEB (recessive, 6; dominant, 1) were treated daily with subcutaneous G-CSF (10 μg/kg/dose) and reevaluated on day 7. For all patients combined, median reductions of 75.5% in lesional size and 36.6% in blister/erosion counts were observed. When only the 6 responders were considered, there were median reductions of 77.4% and 38.8% of each of these measured parameters, respectively. No adverse side effects were noted.

Limitations: Limitations include small patient number, more than 1 DEB subtype included, and lack of untreated age-matched control subjects.

Conclusions: Subcutaneous G-CSF may be beneficial in promoting wound healing in some patients with DEB when conventional therapies fail.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaad.2015.04.015DOI Listing
July 2015
-->