Principles of alemtuzumab immunoablation in hematopoietic cell transplantation for non-malignant diseases in children: A review

2018 ◽  
Vol 22 (2) ◽  
pp. e13142 ◽  
Author(s):  
Gregory M. T. Guilcher ◽  
Ravi Shah ◽  
Shalini Shenoy
Keyword(s):  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Malignant Diseases

scholarly journals Expanded Comorbidity Definitions Improve Application of the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) for Children and Young Adults with Non-Malignant Diseases Receiving Allogeneic Hematopoietic Cell Transplantation

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 7-8
Author(s):  
Larisa Broglie ◽  
Brian D Friend ◽  
Brent Logan ◽  
Caitrin Fretham ◽  
Gary J. Schiller ◽  
...  
Keyword(s):  
Young Adults ◽  
Renal Disease ◽  
Cell Transplantation ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Validation Cohort ◽  
Hematopoietic Cell ◽  
Malignant Diseases ◽  
Publicly Traded ◽  
C Statistic

Introduction: Allogeneic hematopoietic cell transplantation (HCT) can be employed as curative therapy for many non-malignant diseases but there is risk of transplant related complications. Pre-HCT, patient-specific factors can help inform risk using the HCT comorbidity index (HCT-CI); however, it can be difficult to apply in children and young adults, where assessment of organ function differs from those defined by the HCT-CI. We aimed to supplement the HCT-CI with pediatric-specific comorbidity definitions to broaden the use of the HCT-CI for pediatric & young adult patients with non-malignant diseases. Methods: Patients <40 years old (yo) who received first allogeneic HCT for non-malignant diseases from 2008-2017 were identified in the Center for International Blood and Marrow Transplant Research (CIBMTR) database. Separate training and validation samples were created using a 2/3, 1/3 split. Adjustment to the definition of renal disease was made, supplementing with estimated glomerular filtration rate (eGFR) and defined as mild (60-89) or moderate/severe (<60ml)/min/1.73m2. Nutritional assessment was supplemented to include obesity (body mass index (BMI) >95th percentile for <18yo) and added assessment of underweight (BMI <5th percentile for <18yo, <18kg/m2 for ≥18yo) by CDC guidelines. History of mechanical ventilation was included as an additional marker of pulmonary disease. Multivariable Cox regression analyses assessed the effect of each comorbidity, and then the modified scores, on overall survival (OS), adjusting for age, primary disease, donor, performance status, recipient CMV status, and year of HCT. We propose 2 potential scores based on modifications for pediatric and young adult patients: 1) Expanding the HCT-CI with broader definitions that can be applied to younger patients, 2) Simplifying the HCT-CI to remove certain comorbidities with hazard ratio (HR) <1.2. C-statistic was used to compare the modified scores to the original HCT-CI. Results: 2,815 patients received allogeneic HCT for non-malignant diseases (25.8% aplastic anemia, 26.5% immune deficiency, 18.2% hemoglobinopathies, 29.5% other) at a median age of 6 (<1-39)yo. 84.3% were ≤18yo and 15.7% were 19-40y. Conditioning intensity was myeloablative in 48.5%, donors were primarily matched sibling (21.2%) or well-matched unrelated donors (25.6%), and bone marrow was primary graft source (54%). Using the original HCT-CI, patients were categorized with scores of 0 (59%), 1-2 (20.8%), and ≥3 (20%). In multivariable analysis, comorbidities with pediatric-specific definitions demonstrated increased hazards of death, including in underweight patients (HR 1.55, 95% confidence interval (CI) 1.18-2.04), those with history of mechanical ventilation (HR 1.85, 95%CI 1.39-2.48), mild renal disease by eGFR (HR 1.49, 95%CI 1.11-2.0), or moderate/severe renal disease by eGFR (HR 2.04, 95%CI 1.1-3.26). Therefore, comorbidities were expanded to include these definitions in the Expanded HCT-CI. Expanding the comorbidity definitions increased the number of patients identified as having pre-HCT comorbidities: 35% were categorized with scores of 0, 32% with scores of 1-2, and 33% with scores of ≥3. Figure 1 shows the expanded comorbidity definitions and effect on OS. Arrhythmia and Psychiatric diseases were noted to have HR <1.2 and were removed in the Pediatric Simplified score. Increasing scores had increasing risk of death in the Expanded HCT-CI [validation cohort HR 1.31, 95%CI 0.81-2.02 for scores (1-2), HR 2.03, 95%CI 1.34-3.07 for (≥3), compared to scores of 0] and the Pediatric Simplified score (validation cohort HR 1.34, 95%CI 0.89-2.02 (1-2), HR 1.97, 95%CI 1.82-2.93 (≥3), compared to scores of 0]. Modifications to the HCT-CI predicted outcomes similar to the original HCT-CI (validation cohort c-statistic at 2yr - HCT-CI 64.3, expanded HCT-CI 65.8, and pediatric simplified HCT-CI 65.8). Conclusion: Modifications to definitions in the HCT-CI can create a pre-HCT risk tool that more broadly classifies organ dysfunction for children & young adults. By expanding the comorbidity definitions, 24% more patients were re-categorized as having at least 1 comorbidity, allowing for better assessment of pre-HCT risk. This expanded HCT-CI performs as well as the HCT-CI but is more broadly applicable to children & young adults with non-malignant diseases and can aid physicians in pre-HCT counseling. Disclosures Schiller: Johnson & Johnson: Current equity holder in publicly-traded company; Karyopharm: Research Funding; Sangamo: Research Funding; AstraZeneca: Consultancy; Amgen: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Agios: Consultancy, Research Funding, Speakers Bureau; Incyte: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding; Ono Pharma: Consultancy; Celgene: Research Funding, Speakers Bureau; Sanofi: Speakers Bureau; Gilead: Speakers Bureau; Stemline: Speakers Bureau; Onconova: Research Funding; Samus: Research Funding; Regimmune: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Cyclacel: Research Funding; Daiichi Sankyo: Research Funding; Deciphera: Research Funding; DeltaFly: Research Funding; Bristol-Myers Squibb: Current equity holder in publicly-traded company, Research Funding; Forma: Research Funding; FujiFilm: Research Funding; Gamida: Research Funding; Genentech-Roche: Research Funding; Geron: Research Funding; Jazz Pharmaceuticals: Research Funding; Kite Pharma: Research Funding; Mateon: Research Funding; MedImmune: Research Funding; Tolero: Research Funding; Trovagene: Research Funding; Kaiser Permanente: Consultancy; Celator: Research Funding; Constellation: Research Funding; Astellas Pharma: Honoraria, Research Funding; Ariad: Research Funding; Actinium: Research Funding; Abbvie: Research Funding. Stadtmauer:Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Novartis, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology: Consultancy. Pasquini:Bristol Myers Squibb: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Other; Novartis: Research Funding; Kite: Research Funding. Thakar:Infectious Disease Research Institute: Consultancy. Sorror:Jazz Pharmaceutical: Other: Honorarium for Advisory role. .

Emerging approaches to improve allogeneic hematopoietic cell transplantation outcomes for non-malignant diseases

Blood ◽  
2021 ◽  
Author(s):  
Zachariah DeFilipp ◽  
Mehrdad Hefazi ◽  
Yi-Bin Chen ◽  
Bruce R. Blazar
Keyword(s):  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Disease Free Survival ◽  
Hematologic Malignancies ◽  
Current Approach ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Mixed Chimerism ◽  
Malignant Diseases ◽  
Graft Versus Host

Many congenital or acquired non-malignant diseases (NMD) of the hematopoietic system can be potentially cured by allogeneic hematopoietic cell transplantation (HCT) with varying types of donor grafts, degrees of HLA matching, and intensity of conditioning regimens. Unique features that distinguish the use of allogeneic HCT in this population include higher rates of graft failure, immune-mediated cytopenias, and the potential to achieve long-term disease-free survival in a mixed chimerism state. Additionally, in contrast to patients with hematologic malignancies, a priority is to completely avoid graft-versus-host disease in patients with NMD, as there is no theoretical beneficial graft-versus-leukemia effect that can accompany graft-versus-host responses. In this review, we discuss the current approach to each of these clinical issues and how emerging novel therapeutics hold promise to advance transplant care for patients with NMD.

scholarly journals Haploidentical Hematopoietic Cell Transplantation Using Post-transplant Cyclophosphamide for Children With Non-malignant Diseases

2021 ◽  
Author(s):  
Hasan Hashem ◽  
Rula Najjar ◽  
Mayada Abu Shanap ◽  
Eman Khattab ◽  
Rawad Rihani ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Primary Immunodeficiency ◽  
Hematopoietic Cell Transplantation ◽  
Bone Marrow Failure ◽  
Chronic Gvhd ◽  
Hematopoietic Cell ◽  
Malignant Diseases ◽  
Post Transplant ◽  
Haploidentical Hematopoietic Cell Transplantation ◽  
Matched Donor

Abstract Haploidentical hematopoietic cell transplantation (HCT) is a valuable curative option for children with non-malignant diseases. Haploidentical HCT using post-transplant cyclophosphamide (PTCy) is a readily available option in the absence of an HLA- matched donor. We conducted a retrospective single-center study on the outcome of haploidentical HCT in children with non-malignant diseases. We gathered data from 44 patients underwent HCT in the period 2015 to 2020. The indications for HCT were bone marrow failure, primary immunodeficiency, metabolic disorders, and hemoglobinopathy. Median age at HCT was 4 years (range 0.7-20).The conditioning regimens were myeloablative (n=16), or reduced intensity (n=26). After a median follow-up of 20 months (range 4-71), 2-year overall survival was 89% and 2 year GvHD-free relapse-free survival (GRFS) was 66%. Incidence of primary graft failure was 13.6%. Cumulative incidence of grade II-IV acute and moderate/severe chronic GvHD were 20% and 6.4%, respectively. Younger age at HCT (<5 years) and primary immunodeficiency were significantly associated with better GRFS (p <0.05). In conclusion, haploidentical HCT using PTCy is feasible and curative in children with non-malignant diseases lacking an HLA-matched donor. Early diagnosis and referral in addition to timely treatment can further improve outcomes.

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