Publications by authors named "Jaap-Jan Boelens"

122 Publications

New insights in phenotype and treatment of lung disease immuno-deficiency and chromosome breakage syndrome (LICS).

Orphanet J Rare Dis 2021 Mar 19;16(1):137. Epub 2021 Mar 19.

Department of Genetics (Center for Molecular Medicine, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands.

We report five patients with lung disease immuno-deficiency and chromosome breakage syndrome (LICS) but without recurrent infections and severe immunodeficiency. One patient had extended survival to 6.5 years. Hematopoietic stem-cell transplantation failed to cure another patient. Our findings suggest that the immunological abnormalities can be limited and do not fully explain the LICS phenotype.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13023-021-01770-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980653PMC
March 2021

Harmonization, biomarkers, disease risk index.

Authors:
Jaap Jan Boelens

Blood 2021 Feb;137(7):874-875

Memorial Sloan Kettering Cancer Center.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2020009862DOI Listing
February 2021

αβ T-cell graft depletion for allogeneic HSCT in adults with hematological malignancies.

Blood Adv 2021 Jan;5(1):240-249

Department of Hematology and.

We conducted a multicenter prospective single-arm phase 1/2 study that assesses the outcome of αβ T-cell depleted allogeneic hematopoietic stem cell transplantation (allo-HSCT) of peripheral blood derived stem cells from matched related, or unrelated donors (10/10 and 9/10) in adults, with the incidence of acute graft-versus-host disease (aGVHD) as the primary end point at day 100. Thirty-five adults (median age, 59; range, 19-69 years) were enrolled. Conditioning consisted of antithymocyte globulin, busulfan, and fludarabine, followed by 28 days of mycophenolic acid after allo-HSCT. The minimal follow-up time was 24 months. The median number of infused CD34+ cells and αβ T cells were 6.1 × 106 and 16.3 × 103 cells per kg, respectively. The cumulative incidence (CI) of aGVHD grades 2-4 and 3-4 at day 100 was 26% and 14%. One secondary graft failure was observed. A prophylactic donor lymphocyte infusion (DLI) (1 × 105 CD3+ T cells per kg) was administered to 54% of the subjects, resulting in a CI of aGVHD grades 2-4 and 3-4 to 37% and 17% at 2 years. Immune monitoring revealed an early reconstitution of natural killer (NK) and γδ T cells. Cytomegalovirus reactivation associated with expansion of memory-like NK cells. The CI of relapse was 29%, and the nonrelapse mortality 32% at 2 years. The 2-year CI of chronic GVHD (cGVHD) was 23%, of which 17% was moderate. We conclude that only 26% of patients developed aGVHD 2-4 after αβ T-cell-depleted allo-HSCT within 100 days and was associated with a low incidence of cGVHD after 2 years. This trial was registered at www.trialregister.nl as #NL4767.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2020002444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805311PMC
January 2021

Population pharmacokinetics of clofarabine for allogeneic hematopoietic cell transplantation in paediatric patients.

Br J Clin Pharmacol 2021 Jan 14. Epub 2021 Jan 14.

Department of Clinical Pharmacy, Division of Laboratory Medicine and Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.

Aims: Clofarabine has recently been evaluated as part of the conditioning regimen for allogeneic hematopoietic stem cell transplantation (HCT) in children. Pharmacokinetic (PK) exposure of different agents commonly used in conditioning regimens is strongly related to HCT outcome. Consequently, the PK of clofarabine may be important for outcome. This report describes the population PK of clofarabine in paediatric patients and one adult.

Methods: From 80 paediatric (0.5-18 years) and 1 adult patient (37 years), 805 plasma concentrations were included in pharmacokinetic analyses using nonlinear mixed effects modelling.

Results: A two-compartment model adequately described the PK of clofarabine. Body weight and estimated glomerular filtration rate (eGFR) were included as covariates. Clearance was differentiated into nonrenal and renal clearance (approximately 55% of total clearance), resulting in population estimates of 24.0 L/h (95% confidence interval [CI] 13.7-34.4) and 29.8 L/h (95% CI 23.9-36.1) for a patient of 70 kg with normal renal function, respectively. Unexplained interindividual variability in clearance was 17.8% (95% CI 14.6-22.4). A high variability in exposure was observed (range area under the curve 1.8-6.0 mg/L*h) after body surface area (BSA) based dosing. Interestingly, children with low body weight had a lower exposure than children with a higher body weight, which indicates that the currently practised BSA-based dosing is not adequate for clofarabine.

Conclusion: A clofarabine dosing algorithm based on this PK model, using body weight and eGFR, results in a more predictable exposure than BSA-based dosing. However, the exact target exposure needs to be further investigated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bcp.14738DOI Listing
January 2021

Consensus opinion on immune-mediated cytopenias after hematopoietic cell transplant for inherited metabolic disorders.

Bone Marrow Transplant 2021 Jan 13. Epub 2021 Jan 13.

Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN, USA.

Hematopoietic stem cell transplantation (HCT) has been increasingly used for patients with inherited metabolic disorders (IMD). Immune mediated cytopenias (IMCs) after HCT, manifesting as hemolytic anemia, thrombocytopenia, and/or neutropenia, are recognized as a significant complication in this patient population, yet our understanding of the incidence, risk factors, and pathophysiology is currently limited. Review of the published literature demonstrates a higher incidence in younger patients who undergo HCT for a nonmalignant disease indication. However, a few reports suggest that the incidence is even higher among those with IMD (incidence ranging from 10 to 56%). This review summarizes the literature, provides an approach to better understanding of the possible etiology of IMCs, and proposes a diagnostic and management plan for patients with IMD who develop single or multi-lineage cytopenias after HCT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41409-020-01179-5DOI Listing
January 2021

CD4+ T-cell reconstitution predicts survival outcomes after acute graft-versus-host-disease: a dual-center validation.

Blood 2021 Feb;137(6):848-855

Pediatric Stem Cell Transplant and Cellular Therapies, Memorial Sloan Kettering Cancer Center, New York, NY.

Acute graft-versus-host-Disease (aGVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). We previously showed that early CD4+ T-cell immune reconstitution (IR; CD4+ IR) predicts survival after HCT. Here, we studied the relation between CD4+ IR and survival in patients developing aGVHD. Pediatric patients undergoing first allogeneic HCT at University Medical Center Utrecht (UMC)/Princess Máxima Center (PMC) or Memorial Sloan Kettering Cancer Center (MSK) were included. Primary outcomes were nonrelapse mortality (NRM) and overall survival (OS), stratified for aGVHD and CD4+ IR, defined as ≥50 CD4+ T cells per μL within 100 days after HCT or before aGVHD onset. Multivariate and time-to-event Cox proportional hazards models were applied, and 591 patients (UMC/PMC, n = 276; MSK, n = 315) were included. NRM in patients with grade 3 to 4 aGVHD with or without CD4+ IR within 100 days after HCT was 30% vs 80% (P = .02) at UMC/PMC and 5% vs 67% (P = .02) at MSK. This was associated with lower OS without CD4+ IR (UMC/PMC, 61% vs 20%; P = .04; MSK, 75% vs 33%; P = .12). Inadequate CD4+ IR before aGVHD onset was associated with significantly higher NRM (74% vs 12%; P < .001) and inferior OS (24% vs 78%; P < .001). In this retrospective analysis, we demonstrate that early CD4+ IR, a simple and robust marker predictive of outcomes after HCT, is associated with survival after moderate to severe aGVHD. This association must be confirmed prospectively but suggests strategies to improve T-cell recovery after HCT may influence survival in patients developing aGVHD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2020007905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986048PMC
February 2021

Clinical Grade Production of Wilms' Tumor-1 Loaded Cord Blood-Derived Dendritic Cells to Prevent Relapse in Pediatric AML After Cord Blood Transplantation.

Front Immunol 2020 25;11:559152. Epub 2020 Sep 25.

Center for Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands.

Hematopoietic cell transplantation (HCT) is a last resort, potentially curative treatment option for pediatric patients with refractory acute myeloid leukemia (AML). Cord blood transplantation (CBT) results in less relapses and less graft-versus-host disease when compared to other sources. Nevertheless, still more than half of the children die from relapses. We therefore designed a strategy to prevent relapses by inducing anti-AML immunity after CBT, using a CB-derived dendritic cell (CBDC) vaccine generated from CD34+ CB cells from the same graft. We here describe the optimization and validation of good manufacturing practice (GMP)-grade production of the CBDC vaccine. We show the feasibility of expanding low amounts of CD34+ cells in a closed bag system to sufficient DCs per patient for at least three rounds of vaccinations. The CBDCs showed upregulated costimulatory molecules after maturation and showed enhanced CCR7-dependent migration toward CCL19 in a trans-well migrations assay. CBDCs expressed Wilms' tumor 1 (WT1) protein after electroporation with -mRNA, but were not as potent as CBDCs loaded with synthetic long peptides (peptivator). The WT1-peptivator loaded CBDCs were able to stimulate T-cells both in a mixed lymphocyte reaction as well as in an antigen-specific (autologous) setting. The autologous stimulated T-cells lysed not only the WT1+ cell line, but most importantly, also primary pediatric AML cells. Altogether, we provide a GMP-protocol of a highly mature CBDC vaccine, loaded with WT1 peptivator and able to stimulate autologous T-cells in an antigen-specific manner. Finally, these T-cells lysed primary pediatric AML demonstrating the competence of the CBDC vaccine strategy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2020.559152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546401PMC
September 2020

Immune Monitoring After Allogeneic Hematopoietic Cell Transplantation: Toward Practical Guidelines and Standardization.

Front Pediatr 2020 21;8:454. Epub 2020 Aug 21.

Princess Máxima Center for Pediatric Oncology and UMC Utrecht, Utrecht, Netherlands.

Hematopoietic cell transplantation (HCT) is often a last resort, but potentially curative treatment option for children suffering from hematological malignancies and a variety of non-malignant disorders, such as bone marrow failure, inborn metabolic disease or immune deficiencies. Although efficacy and safety of the HCT procedure has increased significantly over the last decades, the majority of the patients still suffer from severe acute toxicity, viral reactivation, acute or chronic graft-versus-host disease (GvHD) and/or, in case of malignant disease, relapses. Factors influencing HCT outcomes are numerous and versatile. For example, there is variation in the selected graft sources, type of infused cell subsets, cell doses, and the protocols used for conditioning, as well as immune suppression and treatment of adverse events. Moreover, recent pharmacokinetic studies show that medications used in the conditioning regimen (e.g., busulphan, fludarabine, anti-thymocyte globulin) should be dosed patient-specific to achieve optimal exposure in every individual patient. Due to this multitude of variables and site-specific policies/preferences, harmonization between HCT centers is still difficult to achieve. Literature shows that adequate immune recovery post-HCT limits both relapse and non-relapse mortality (death due to viral reactivations and GvHD). Monitoring immune parameters post-HCT may facilitate a timely prediction of outcome. The use of standardized assays to measure immune parameters would facilitate a fast comparison between different strategies tested in different centers or between different clinical trials. We here discuss immune cell markers that may contribute to clinical decision making and may be worth to standardize in multicenter collaborations for future trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fped.2020.00454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7472532PMC
August 2020

Outcome After Cord Blood Transplantation Using Busulfan Pharmacokinetics-Targeted Myeloablative Conditioning for Hurler Syndrome.

Transplant Cell Ther 2021 Jan 20;27(1):91.e1-91.e4. Epub 2020 Sep 20.

Department of Paediatric Blood and Marrow Transplant, Royal Manchester Children's Hospital, Manchester, UK. Electronic address:

We report the outcomes of cord blood transplantation (CBT) with a busulfan (Bu) pharmacokinetics-targeted myeloablative conditioning regimen in 97 children with Hurler syndrome (HS) performed between 2004 and 2016. The median age at CBT was 10.8 months (range, 0.23 to 63.2 months). The median duration of follow-up for surviving patients was 4.2 years (range, 1.0 to 12.8 years). Five-year overall survival (OS) and engrafted survival (ES) were 88% and 79%, respectively. OS was 95% in patients who received Bu/fludarabine (Flu)/antithymocyte globulin (ATG) conditioning, 90% in those who received Bu/cyclophosphamide (Cy)/ATG, and 74% in those who received Bu/Cy/alemtuzumab (P = .02). ES was 84% for recipients of Bu/Flu/ATG conditioning, 83% for recipients of Bu/Cy/ATG conditioning, and 65% for recipients of Bu/Cy/alemtuzumab conditioning (P = .34). Receipt of washed CB units (P = .03) and HLA matching ≤6/10 (P = .02) were associated with significantly lower ES. The 1-year cumulative incidence of graft failure was 11% (95% confidence interval, 6% to 21%). Five patients (5%) had grade III-IV acute GVHD, 5 patients had limited chronic GVHD, and 1 patient had extensive GVHD. The incidence of veno-occlusive disease was higher in patients conditioned with Bu/Cy compared with those conditioned with Bu/Flu (19% [n = 10] versus 5% [n = 2]: P = .03). Of the 11 patients with graft failure, 8 (73%) were aplastic, and 3 (27%) had autologous reconstitution. Of 11 patients with graft failure, 9 underwent a second CBT, and 8 (89%) survived. Full donor chimerism was observed in 89% patients after first CBT and in all patients after second CBT. Survival after CBT for HS has improved, but better strategies are still needed to improve graft outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbmt.2020.08.033DOI Listing
January 2021

Metachromatic leukodystrophy genotypes in The Netherlands reveal novel pathogenic ARSA variants in non-Caucasian patients.

Neurogenetics 2020 10 7;21(4):289-299. Epub 2020 Jul 7.

Amsterdam Leukodystrophy Center, Department of Child Neurology, Emma Children's Hospital, Amsterdam University Medical Center, VU University Amsterdam and Amsterdam Neuroscience, De Boelelaan, 1117, Amsterdam, The Netherlands.

Metachromatic leukodystrophy (MLD) is an autosomal recessively inherited sulfatide storage disease caused by deficient activity of the lysosomal enzyme arylsulfatase A (ASA). Genetic analysis of the ARSA gene is important in MLD diagnosis and screening of family members. In addition, more information on genotype prevalence will help interpreting MLD population differences between countries. In this study, we identified 31 different ARSA variants in the patient cohort (n = 67) of the Dutch expertise center for MLD. The most frequently found variant, c.1283C > T, p.(Pro428Leu), was present in 43 (64%) patients and resulted in a high prevalence of the juvenile MLD type (58%) in The Netherlands. Furthermore, we observed in five out of six patients with a non-Caucasian ethnic background previously unreported pathogenic ARSA variants. In total, we report ten novel variants including four missense, two nonsense, and two frameshift variants and one in-frame indel, which were all predicted to be disease causing in silico. In addition, one silent variant was found, c.1200C > T, that most likely resulted in erroneous exonic splicing, including partial skipping of exon 7. The c.1200C > T variant was inherited in cis with the pseudodeficiency allele c.1055A > G, p.(Asn352Ser) + ∗96A > G. With this study we provide a genetic base of the unique MLD phenotype distribution in The Netherlands. In addition, our study demonstrated the importance of genetic analysis in MLD diagnosis and the increased likelihood of unreported, pathogenic ARSA variants in patients with non-Caucasian ethnic backgrounds.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10048-020-00621-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476914PMC
October 2020

Early CD4+ T cell reconstitution as predictor of outcomes after allogeneic hematopoietic cell transplantation.

Cytotherapy 2020 09 1;22(9):503-510. Epub 2020 Jul 1.

Stem Cell Transplantation and Cellular Therapies, MSK Kids, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

Background: An association between early CD4+ T cell immune reconstitution (CD4+ IR) and survival after T-replete allogeneic hematopoietic cell transplantation (HCT) has been previously reported. Here we report validation of this relationship in a separate cohort that included recipients of ex vivo T-cell-depleted (TCD) HCT. We studied the relationship between CD4+ IR and clinical outcomes.

Methods: A retrospective analysis of children/young adults receiving their first allogeneic HCT for any indication between January 2008 and December 2017 was performed. We related early CD4+ IR (defined as achieving >50 CD4+ T cells/µL on two consecutive measures within 100 days of HCT) to overall survival (OS), relapse, non-relapse mortality (NRM), event-free survival (EFS) and acute graft-versus-host disease (aGVHD). Fine and Gray competing risk models and Cox proportional hazard models were used.

Results: In this analysis, 315 patients with a median age of 10.4 years (interquartile range 5.0-16.5 years) were included. The cumulative incidence of CD4+ IR at 100 days was 66.7% in the entire cohort, 54.7% in TCD (N = 208, hazard ratio [HR] 0.47, P < 0.001), 90.0% in uCB (N = 40) and 89.6% in T-replete (N = 47) HCT recipients. In multi-variate analyses, not achieving early CD4+ IR was a predictor of inferior OS (HR 2.35, 95% confidence interval [CI] 1.46-3.79, P < 0.001) and EFS (HR 1.80, 95% CI 1.20-2.69, P = 0.004) and increased NRM (HR 6.58, 95% CI 2.82-15.38, P < 0.001). No impact of CD4+ IR on relapse or aGVHD was found. Within the TCD group, similar associations were observed.

Conclusion: In this HCT cohort, including recipients of TCD HCT, we confirmed that early CD4+ IR was an excellent predictor of outcomes. Finding strategies to predict or improve CD4+ IR may influence outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jcyt.2020.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484404PMC
September 2020

Hearing loss in patients with mucopolysaccharidoses-1 and -6 after hematopoietic cell transplantation: A longitudinal analysis.

J Inherit Metab Dis 2020 11 9;43(6):1279-1287. Epub 2020 Jul 9.

Sylvia Toth Center for Multidisciplinary Follow up after Hematopoietic Cell Transplantation, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Hearing loss is frequently seen in mucopolysaccharidoses (MPS) patients. Although hematopoietic cell transplantation (HCT) increases overall survival, disease progression is observed in certain tissues. This study describes the course of hearing loss (HL) over time in transplanted MPS patients. Transplanted MPS patients between 2003 and 2018 were included and received yearly audiological evaluation, including auditory brainstem response (ABR) or pure tone audiometry (PTA). Twenty-eight MPS-1 and four MPS-6 patients were analyzed with a median follow-up of 5 years (range 11 months-16 years). Air conduction threshold improved significantly over time (P < .001) with a PTA 1-year post-HCT of 50 ± 0.7 dB to 23 ± 11 dB 13 years post-HCT. Bone conduction threshold worsened with a PTA 1 year post-HCT of 10 ± 7 dB to 18 ± 9 dB 13 years post-HCT (P = .34). The degree of HL varied from mainly mild-severe early after HCT to normal-mild at longer follow-up. The type of HL consisted of mainly conductive in the first years post-HCT in contrast to mainly sensorineural at longer follow-up. MRIs of the cerebellopontine angle did not show abnormalities. HL is still seen in patients with MPS despite HCT and consists of a conductive type early after HCT in contrast to a sensorineural type at longer follow-up in the majority of cases. Yearly follow-up of HL is necessary to timely intervene, as hearing is important in the speech and language development of children and their academic achievements.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jimd.12277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689745PMC
November 2020

Hurdles in treating Hurler disease: potential routes to achieve a "real" cure.

Blood Adv 2020 06;4(12):2837-2849

Sylvia Toth Center for Multidisciplinary Follow-up after Hematopoietic Cell Transplantation.

Mucopolysaccharidoses (MPSs) are multiorgan devastating diseases for which hematopoietic cell transplantation (HCT) and, to a lesser extent, enzyme replacement therapy have substantially altered the course of the disease. Furthermore, they have resulted in increased overall survival, especially for Hurler disease (MPS-1). However, despite the identification of clinical predictors and harmonized transplantation protocols, disease progression still poses a significant burden to patients, although at a slower pace. To design better therapies, we need to understand why and where current therapies fail. In this review, we discuss important aspects of the underlying disease and the disease progression. We note that the majority of progressive symptoms that occur in "hard-to-treat" tissues are actually tissues that are difficult to reach, such as avascular connective tissue or tissues isolated from the circulation by a specific barrier (eg, blood-brain barrier, blood-retina barrier). Although easily reached tissues are effectively cured by HCT, disease progression is observed in these "hard-to-reach" tissues. We used these insights to critically appraise ongoing experimental endeavors with regard to their potential to overcome the encountered hurdles and improve long-term clinical outcomes in MPS patients treated with HCT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2020001708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322951PMC
June 2020

Emerging trends in COVID-19 treatment: learning from inflammatory conditions associated with cellular therapies.

Cytotherapy 2020 09 7;22(9):474-481. Epub 2020 May 7.

Center for Cancer and Immunology Research, Center for Cancer and Blood Disorders, Children's National Hospital and the George Washington University Cancer Center, George Washington University, Washington, DC, USA.

Coronavirus disease 2019 (SARS-CoV2) is an active global health threat for which treatments are desperately being sought. Even though most people infected experience mild to moderate respiratory symptoms and recover with supportive care, certain vulnerable hosts develop severe clinical deterioration. While several drugs are currently being investigated in clinical trials, there are currently no approved treatments or vaccines for COVID-19 and hence there is an unmet need to explore additional therapeutic options. At least three inflammatory disorders or syndromes associated with immune dysfunction have been described in the context of cellular therapy. Specifically, Cytokine Release Syndrome (CRS), Immune Reconstitution Inflammatory Syndrome (IRIS), and Secondary Hemophagocytic Lymphohistiocytosis (sHLH) all have clinical and laboratory characteristics in common with COVID19 and associated therapies that could be worth testing in the context of clinical trials. Here we discuss these diseases, their management, and potential applications of these treatment in the context of COVID-19. We also discuss current cellular therapies that are being evaluated for the treatment of COVID-19 and/or its associated symptoms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jcyt.2020.04.100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7252029PMC
September 2020

Towards new long-term composite 'Quality of Survival' endpoints.

Authors:
Jaap Jan Boelens

Bone Marrow Transplant 2020 10 12;55(10):1898-1899. Epub 2020 Jun 12.

Stem Cell Transplantation and Cellular Therapies, MSK Kids, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41409-020-0883-8DOI Listing
October 2020

Low toxicity and favorable overall survival in relapsed/refractory B-ALL following CAR T cells and CD34-selected T-cell depleted allogeneic hematopoietic cell transplant.

Bone Marrow Transplant 2020 11 10;55(11):2160-2169. Epub 2020 May 10.

Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

To define the tolerability and outcome of allogeneic hematopoietic stem cell transplant (allo-HSCT) following CAR T-cell therapy, we retrospectively reviewed pediatric/young adult patients with relapsed/refractory B-ALL who underwent this treatment. Fifteen patients (median age 13 years; range 1-20 years) with a median potential follow-up of 39 months demonstrated 24-month cumulative incidence of relapse, cumulative incidence of TRM, and OS of 16% (95% CI: 0-37%), 20% (95% CI: 0-40%), and 80% (95% CI: 60-100%), respectively. Severe toxicity following CAR T cells did not impact OS (p = 0.27), while greater time from CAR T cells to allo-HSCT (>80 days) was associated with a decrease in OS. In comparing CD34-selected T-cell depleted (TCD; n = 9) vs unmodified (n = 6) allo-HSCT, the cumulative incidence of relapse, TRM, and OS at 24 months was 22% (95% CI: 0-49%) vs 0% (p = 0.14), 0% vs 50% [95% CI: 10-90%] (p = 0.02) and 100% vs 50% [95% CI: 10-90%] (p = 0.02). In this small cohort of patients, CAR T cells followed by a CD34-selected TCD allo-HSCT appears to result in less TRM and favorable OS when compared with unmodified allo-HSCT. There was no evidence that disease control was impacted by the type of consolidative allo-HSCT, which demonstrates the feasibility of this approach.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41409-020-0926-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606268PMC
November 2020

A semi-mechanistic model based on glutathione depletion to describe intra-individual reduction in busulfan clearance.

Br J Clin Pharmacol 2020 08 10;86(8):1499-1509. Epub 2020 Mar 10.

Department of Clinical Pharmacy, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands.

Aim: To develop a semi-mechanistic model, based on glutathione depletion and predict a previously identified intra-individual reduction in busulfan clearance to aid in more precise dosing.

Methods: Busulfan concentration data, measured as part of regular care for allogeneic hematopoietic cell transplantation (HCT) patients, were used to develop a semi-mechanistic model and compare it to a previously developed empirical model. The latter included an empirically estimated time effect, where the semi-mechanistic model included theoretical glutathione depletion. As older age has been related to lower glutathione levels, this was tested as a covariate in the semi-mechanistic model. Lastly, a therapeutic drug monitoring (TDM) simulation was performed comparing the two models in target attainment.

Results: In both models, a similar clearance decrease of 7% (range -82% to 44%), with a proportionality to busulfan metabolism, was found. After 40 years of age, the time effect increased with 4% per year of age (0.6-8%, P = 0.009), causing the effect to increase more than a 2-fold over the observed age-range (0-73 years). Compared to the empirical model, the final semi-mechanistic model increased target attainment from 74% to 76%, mainly through better predictions for adult patients.

Conclusion: These results suggest that the time-dependent decrease in busulfan clearance may be related to gluthathione depletion. This effect increased with older age (>40 years) and was proportional to busulfan metabolism. The newly constructed semi-mechanistic model could be used to further improve TDM-guided exposure target attainment of busulfan in patients undergoing HCT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bcp.14256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373715PMC
August 2020

Rabbit ATG/ATLG in preventing graft-versus-host disease after allogeneic stem cell transplantation: consensus-based recommendations by an international expert panel.

Bone Marrow Transplant 2020 06 22;55(6):1093-1102. Epub 2020 Jan 22.

University Hospital Eppendorf, Hamburg, Germany.

This collaborative initiative aimed to provide recommendations on the use of polyclonal antithymocyte globulin (ATG) or anti-T lymphocyte globulin (ATLG) for the prevention of graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (HSCT). A comprehensive review of articles released up to October, 2018 was performed as a source of scientific evidence. Fourteen clinically relevant key questions to the domains indication, administration, and post-transplant management were developed and recommendations were produced using the Delphi technique involving a Panel of 14 experts. ATG/ATLG was strongly recommended as part of myeloablative conditioning regimen prior to matched or mismatched unrelated bone marrow or peripheral blood allogeneic HSCT in malignant diseases to prevent severe acute and chronic GvHD. ATG/ATLG was also recommended prior to HLA-identical sibling peripheral HSCT with good but lesser bulk of evidence. In reduced intensity or nonmyeloablative conditioning regimens, ATG/ATLG was deemed appropriate to reduce the incidence of acute and chronic GvHD, but a higher risk of relapse should be taken into account. Recommendations regarding dose, application, and premedication were also provided as well as post-transplant infectious prophylaxis and vaccination. Overall, these recommendations can be used for a proper and safe application of polyclonal ATG/ATLG to prevent GvHD after allogeneic HSCT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41409-020-0792-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269907PMC
June 2020

Clinical Trial Simulation To Optimize Trial Design for Fludarabine Dosing Strategies in Allogeneic Hematopoietic Cell Transplantation.

CPT Pharmacometrics Syst Pharmacol 2020 05 21;9(5):272-281. Epub 2020 Apr 21.

Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek Hospital, Netherlands Cancer Institute, Amsterdam, The Netherlands.

Optimal fludarabine exposure has been associated with improved treatment outcome in allogeneic hematopoietic cell transplantation, suggesting potential benefit of individualized dosing. A randomized controlled trial (RCT) comparing alternative fludarabine dosing strategies to current practice may be warranted, but should be sufficiently powered for a relevant end point, while still feasible to enroll. To find the optimal design, we simulated RCTs comparing current practice (160 mg/m ) to either covariate-based or therapeutic drug monitoring (TDM)-guided dosing with potential outcomes being nonrelapse mortality (NRM), graft failure, or relapse, and ultimately overall survival (covering all three aforementioned outcomes). The inclusion in each treatment arm (n) required to achieve 80% power was calculated for all combinations of end points and dosing comparisons. The trial requiring the lowest n for sufficient power compared TDM-guided dosing to current practice with NRM as primary outcome (n = 70, NRM decreasing from 21% to 5.7%). We conclude that a superiority trial is feasible.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/psp4.12486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239337PMC
May 2020

Genetic Susceptibility to Hepatic Sinusoidal Obstruction Syndrome in Pediatric Patients Undergoing Hematopoietic Stem Cell Transplantation.

Biol Blood Marrow Transplant 2020 05 29;26(5):920-927. Epub 2019 Nov 29.

Charles-Bruneau Cancer Center, Sainte-Justine University Health Center (SJUHC), Montreal, Quebec, Canada; Department of Pharmacology and Physiology, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada; Clinical Pharmacology Unit, Sainte-Justine University Health Center (SJUHC), Montreal, Quebec, Canada; Department of Pediatrics, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada. Electronic address:

Sinusoidal obstruction syndrome (SOS) is a well-recognized and potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT). SOS arises from endothelial cell damage and hepatocellular injury mostly due to the transplantation conditioning regimens but also to other patient, disease, and treatment-related factors. Understanding risk factors associated with the development of SOS is critical for early initiation of treatment or prophylaxis. The knowledge about genetic contribution is limited; few studies investigated so far selected a set of genes. To get more comprehensive insight in the genetic component, we performed an exome-wide association study using genetic variants derived from whole-exome sequencing. The analyses were performed in a discovery cohort composed of 87 pediatric patients undergoing HSCT following a busulfan-containing conditioning regimen. Eight lead single-nucleotide polymorphisms (SNPs) were identified after correction for multiple testing and subsequently analyzed in a validation cohort (n = 182). Three SNPs were successfully replicated, including rs17146905 (P = .001), rs16931326 (P = .04), and rs2289971 (P = .03), located respectively in the UGT2B10, BHLHE22, and KIAA1715 genes. UGT2B10 and KIAA1715 were retained in a multivariable model while controlling for nongenetic covariates and previously identified risk variants in the GSTA1 promoter. The modulation of associations by conditioning regimens was noted; KIAA1715 was dependent on the intensity of the conditioning regimen, whereas the effect of UGT2B10 was equally applicable to all of them. Combined effect of associated loci was also observed (P = .00006) with a genotype-related SOS risk of 9.8. To our knowledge, this is the first study addressing the genetic component of SOS at an exome-wide level and identifying novel genetic variations conferring a higher risk of SOS, which might be useful for personalized prevention and treatment strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbmt.2019.11.026DOI Listing
May 2020

Longitudinal Analysis of Ocular Disease in Children with Mucopolysaccharidosis I after Hematopoietic Cell Transplantation.

Biol Blood Marrow Transplant 2020 05 29;26(5):928-935. Epub 2019 Nov 29.

Sylvia Toth Center for Multidisciplinary Follow-Up after Hematopoietic Cell Transplantation, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands; Section Metabolic Diseases, Department of Child Health, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands. Electronic address:

Corneal clouding, causing visual impairment, is seen in nearly all patients with mucopolysaccharidosis type 1 (MPS-1). Hematopoietic cell transplantation (HCT) is able to stabilize disease in many organs. Residual disease in several tissues is being increasingly recognized, however. Data on the effect of HCT on ocular disease in patients with MPS-1 are contradictory. With this study, we aim to clarify the long-term effects of HCT on ocular disease in these patients. Best corrected visual acuity (BCVA), refraction, intraocular pressure (IOP), and slit-lamp biomicroscopic and fundoscopic examinations, including corneal clouding, were collected prospectively from 24 patients with MPS-1 who underwent HCT successfully between 2003 and 2018 (92% with >95% chimerism and normal enzyme activity after HCT). The course of corneal clouding and BCVA after HCT were analyzed using a linear mixed model. Other parameters studied were clinical phenotype, age at time of transplantation, and hematologic enzyme activity after transplantation. Outcomes of additional ophthalmologic tests were described. In addition, IDUA and α-galactosidase A (AGAL) enzyme activity and glycosaminoglycan (GAG) concentration in tear fluid were determined. Corneal clouding stabilized in the first years after HCT but increased rapidly beyond 3 years (P < .0001). BCVA and IOP also worsened over time (P = .01 and P < .0001, respectively). IDUA activity in tear fluid remained very low (P < .0001). After initial stabilization in the cornea, ongoing ocular disease and low IDUA activity in tear fluid is seen in patients with MPS-1 despite treatment with HCT, unveiling a weak spot of current standard therapy. New therapies that overcome these shortcomings are needed to improve the late outcomes of patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbmt.2019.11.025DOI Listing
May 2020

Hematopoietic Stem Cell Transplantation in Inborn Errors of Metabolism.

Front Pediatr 2019 25;7:433. Epub 2019 Oct 25.

Metabolic and Blood and Marrow Transplant Units, Royal Manchester Children's Hospital, Manchester, United Kingdom.

Hematopoietic stem cell transplantation (HSCT) has been established as an effective therapy for selected inborn errors of metabolism. The success of HSCT in metabolic disease is best exemplified through the treatment of Hurler's syndrome, a lysosomal storage disease. Through the collaborative effort of several international centers, factors that predict successful patient and transplant outcomes have been identified. In this review, we discuss the principles that underlie the use of HSCT in metabolic diseases. We consider the clinical indications, conditioning regimens, and disease-specific follow-up for HSCT in different metabolic diseases. We highlight persisting challenges in HSCT to delay progression of certain organ systems that remain refractory to HSCT and the relatively high rates of aplastic graft failure. Finally, we evaluate the variable applicability of these principles to other inherited metabolic disorders including peroxisomal, mitochondrial, and other lysosomal storage diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fped.2019.00433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824291PMC
October 2019

Peripheral neuropathy in metachromatic leukodystrophy: current status and future perspective.

Orphanet J Rare Dis 2019 11 4;14(1):240. Epub 2019 Nov 4.

Department of Child Neurology, Emma Children's Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, and Amsterdam Neuroscience, De Boelelaan 1117, Amsterdam, the Netherlands.

Metachromatic leukodystrophy (MLD) is an autosomal recessively inherited metabolic disease characterized by deficient activity of the lysosomal enzyme arylsulfatase A. Its deficiency results in accumulation of sulfatides in neural and visceral tissues, and causes demyelination of the central and peripheral nervous system. This leads to a broad range of neurological symptoms and eventually premature death. In asymptomatic patients with juvenile and adult MLD, treatment with allogeneic hematopoietic stem cell transplantation (HCT) provides a symptomatic and survival benefit. However, this treatment mainly impacts brain white matter, whereas the peripheral neuropathy shows no or only limited response. Data about the impact of peripheral neuropathy in MLD patients are currently lacking, although in our experience peripheral neuropathy causes significant morbidity due to neuropathic pain, foot deformities and neurogenic bladder disturbances. Besides, the reasons for residual and often progressive peripheral neuropathy after HCT are not fully understood. Preliminary studies suggest that peripheral neuropathy might respond better to gene therapy due to higher enzyme levels achieved than with HCT. However, histopathological and clinical findings also suggest a role of neuroinflammation in the pathology of peripheral neuropathy in MLD. In this literature review, we discuss clinical aspects, pathological findings, distribution of mutations, and treatment approaches in MLD with particular emphasis on peripheral neuropathy. We believe that future therapies need more emphasis on the management of peripheral neuropathy, and additional research is needed to optimize care strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13023-019-1220-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829806PMC
November 2019

Toxicity and response after CD19-specific CAR T-cell therapy in pediatric/young adult relapsed/refractory B-ALL.

Blood 2019 12;134(26):2361-2368

Center For Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY.

Chimeric antigen receptor (CAR) T cells have demonstrated clinical benefit in patients with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). We undertook a multicenter clinical trial to determine toxicity, feasibility, and response for this therapy. A total of 25 pediatric/young adult patients (age, 1-22.5 years) with R/R B-ALL were treated with 19-28z CAR T cells. Conditioning chemotherapy included high-dose (3 g/m2) cyclophosphamide (HD-Cy) for 17 patients and low-dose (≤1.5 g/m2) cyclophosphamide (LD-Cy) for 8 patients. Fifteen patients had pretreatment minimal residual disease (MRD; <5% blasts in bone marrow), and 10 patients had pretreatment morphologic evidence of disease (≥5% blasts in bone marrow). All toxicities were reversible, including severe cytokine release syndrome in 16% (4 of 25) and severe neurotoxicity in 28% (7 of 25) of patients. Treated patients were assessed for response, and, among the evaluable patients (n = 24), response and peak CAR T-cell expansion were superior in the HD-Cy/MRD cohorts, as compared with the LD-Cy/morphologic cohorts without an increase in toxicity. Our data support the safety of CD19-specific CAR T-cell therapy for R/R B-ALL. Our data also suggest that dose intensity of conditioning chemotherapy and minimal pretreatment disease burden have a positive impact on response without a negative effect on toxicity. This trial was registered at www.clinicaltrials.gov as #NCT01860937.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2019001641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6933289PMC
December 2019

Choice of conditioning regimens for bone marrow transplantation in severe aplastic anemia.

Blood Adv 2019 10;3(20):3123-3131

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

Allogeneic bone marrow transplantation (BMT) is curative therapy for the treatment of patients with severe aplastic anemia (SAA). However, several conditioning regimens can be used for BMT. We evaluated transplant conditioning regimens for BMT in SAA after HLA-matched sibling and unrelated donor BMT. For recipients of HLA-matched sibling donor transplantation (n = 955), fludarabine (Flu)/cyclophosphamide (Cy)/antithymocyte globulin (ATG) or Cy/ATG led to the best survival. The 5-year probabilities of survival with Flu/Cy/ATG, Cy/ATG, Cy ± Flu, and busulfan/Cy were 91%, 91%, 80%, and 84%, respectively (P = .001). For recipients of 8/8 and 7/8 HLA allele-matched unrelated donor transplantation (n = 409), there were no differences in survival between regimens. The 5-year probabilities of survival with Cy/ATG/total body irradiation 200 cGy, Flu/Cy/ATG/total body irradiation 200 cGy, Flu/Cy/ATG, and Cy/ATG were 77%, 80%, 75%, and 72%, respectively (P = .61). Rabbit-derived ATG compared with equine-derived ATG was associated with a lower risk of grade II to IV acute graft-versus-host disease (GVHD) (hazard ratio [HR], 0.39; P < .001) but not chronic GVHD. Independent of conditioning regimen, survival was lower in patients aged >30 years after HLA-matched sibling (HR, 2.74; P < .001) or unrelated donor (HR, 1.98; P = .001) transplantation. These data support Flu/Cy/ATG and Cy/ATG as optimal regimens for HLA-matched sibling BMT. Although survival after an unrelated donor BMT did not differ between regimens, use of rabbit-derived ATG may be preferred because of lower risks of acute GVHD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2019000722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849938PMC
October 2019

Related and unrelated donor transplantation for β-thalassemia major: results of an international survey.

Blood Adv 2019 09;3(17):2562-2570

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

We studied 1110 patients with β-thalassemia major aged ≤25 years who received transplants with grafts from HLA-matched related (n = 677; 61%), HLA-mismatched related (n = 78; 7%), HLA-matched unrelated (n = 252; 23%), and HLA-mismatched unrelated (n = 103; 9%) donors between 2000 and 2016. Ninety percent of transplants were performed in the last decade. Eight-five percent of patients received ≥20 transfusions and 88% were inadequately chelated. All patients received myeloablative-conditioning regimen. Overall and event-free survival were highest for patients aged ≤6 years and after HLA-matched related and HLA-matched unrelated donor transplantation. The 5-year probabilities of overall survival for patients aged ≤6 years, 7 to 15 years, and 16 to 25 years, adjusted for donor type and conditioning regimen were 90%, 84%, and 63%, respectively ( < .001). The corresponding probabilities for event-free survival were 86%, 80%, and 63% ( < .001). Overall and event-free survival did not differ between HLA-matched related and HLA-matched unrelated donor transplantation (89% vs 87% and 86% vs 82%, respectively). Corresponding probabilities after mismatched related and mismatched unrelated donor transplantation were 73% vs 83% and 70% vs 78%. In conclusion, if transplantation is considered as a treatment option it should be offered early (age ≤6 years). An HLA-matched unrelated donor is a suitable alternative if an HLA-matched relative is not available.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2019000291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6737407PMC
September 2019

Population Pharmacokinetics of Alemtuzumab (Campath) in Pediatric Hematopoietic Cell Transplantation: Towards Individualized Dosing to Improve Outcome.

Clin Pharmacokinet 2019 12;58(12):1609-1620

Division of Stem Cell Transplantation, Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands.

Background And Objective: Alemtuzumab (Campath) is used to prevent graft-versus-host disease and graft failure following pediatric allogeneic hematopoietic cell transplantation. The main toxicity includes delayed immune reconstitution, subsequent viral reactivations, and leukemia relapse. Exposure to alemtuzumab is highly variable upon empirical milligram/kilogram dosing.

Methods: A population pharmacokinetic (PK) model for alemtuzumab was developed based on a total of 1146 concentration samples from 206 patients, aged 0.2-19 years, receiving a cumulative intravenous dose of 0.2-1.5 mg/kg, and treated between 2003 and 2015 in two centers.

Results: Alemtuzumab PK were best described using a two-compartment model with a parallel saturable and linear elimination pathway. The linear clearance pathway, central volume of distribution, and intercompartmental distribution increased with body weight. Blood lymphocyte counts, a potential substrate for alemtuzumab, did not impact clearance.

Conclusion: The current practice with uniform milligram/kilogram doses leads to highly variable exposures in children due to the non-linear relationship between body weight and alemtuzumab PK. This model may be used for individualized dosing of alemtuzumab.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s40262-019-00782-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885503PMC
December 2019

The influence of stem cell source on transplant outcomes for pediatric patients with acute myeloid leukemia.

Blood Adv 2019 04;3(7):1118-1128

Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.

When hematopoietic stem cell transplant (HSCT) is necessary for children with acute myeloid leukemia (AML), there remains debate about the best stem cell source. Post-HSCT relapse is a common cause of mortality, and complications such as chronic graft versus host disease (cGVHD) are debilitating and life-threatening. To compare post-HSCT outcomes of different donor sources, we retrospectively analyzed consecutive transplants performed in several international centers from 2005 to 2015. A total of 317 patients were studied: 19% matched sibling donor (MSD), 23% matched unrelated donor (MUD), 39% umbilical cord blood (UCB), and 19% double UCB (dUCB) recipients. The median age at transplant was 10 years (range, 0.42-21 years), and median follow-up was 4.74 years (range, 4.02-5.39 years). Comparisons were made while controlling for patient, transplant, and disease characteristics. There were no differences in relapse, leukemia-free survival, or nonrelapse mortality. dUCB recipients had inferior survival compared with matched sibling recipients, but all other comparisons showed similar overall survival. Despite the majority of UCB transplants being HLA mismatched, the rates of cGVHD were low, especially compared with the well-matched MUD recipients (hazard ratio, 0.3; 95% confidence interval, 0.14-0.67; = .02). The composite measure of cGVHD and leukemia-free survival (cGVHD-LFS), which represents both the quality of life and risk for mortality, was significantly better in the UCB compared with the MUD recipients (HR, 0.56; 95% confidence interval, 0.34-1; = .03). In summary, the use of UCB is an excellent donor choice for pediatric patients with AML when a matched sibling cannot be identified.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2018025908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6457227PMC
April 2019