Expanded Comorbidity Definitions Improve Applicability of the Hematopoietic Stem Cell Transplantation-Comorbidity Index for Children, Adolescents, and Young Adults with Hematologic Malignancies Undergoing Allogeneic Stem Cell Transplantation
Authors: Friend Brian D , Broglie Larisa , Logan Brent , Fretham Caitrin , Schiller Gary J. , Savani Bipin N. , Stadtmauer Edward , Chhabra Saurabh , Pasquini Marcelo C. , Thakar Monica , Sorror Mohamed 
Published: November 2020

Introduction:
Allogeneic hematopoietic cell transplantation (HCT) is curative for children &young adults with hematologic malignancies but is associated with a significant risk of morbidity and mortality. The HCT-comorbidity index (HCT-CI) is a prognostic tool that can predict non-relapse mortality (NRM) based on pre-HCT risk factors; however, it is less applicable for pediatric and young adult patients as some comorbidities are age-related while others are defined differently in this younger population. The objective of this study was to test each component of HCT-CI and additional pediatric-specific comorbidity definitions on NRM in children, adolescents, and young adults with hematologic malignancies, with the aim of supplementing the HCT-CI to create a broader risk score for this younger population.
Methods:
Using the Center for International Blood and Marrow Transplant Research (CIBMTR) registry, patients &lt;40 years of age (yo) with hematologic malignancies that underwent first allogeneic HCT between 2008-2017 were identified. Separate training and validation samples were created using a 2/3, 1/3 split. Definitions for 4 comorbidities included in the HCT-CI were broadened based on additional age-appropriate information. Mild renal disease used HCT-CI-defined creatinine levels or estimated glomerular filtration rate (eGFR, ml/min/1.73m2) 60-89, and moderate/severe renal disease by eGFR &lt;60ml.CDC-based body mass index (BMI) was expanded to include the assessment of obesity based on age (&lt;18yo: BMI &gt;95th percentile, ≥18yo: &gt;35kg/m2) and underweight (&lt;18yo: BMI &lt;5th percentile, ≥18yo: &lt;18kg/m2 for). Pulmonary disease was defined by FEV1 and DLCO values as in HCT-CI, but severe disease could also include a history of mechanical ventilation. In addition, history of fungal infection was combined with the comorbidity for infection. The primary outcome of this study was NRM. Multivariable models for NRM were fit on the training data using a Fine-Gray model to identify the effect of each HCT-CI defining comorbidity and their modifications on NRM, after adjusting for age, conditioning regimen, disease, donor type, KPS, race, recipient CMV status, and year of HCT. From these models, new risk scores were built on the training dataset and then validated on an independent test sample. C-statistics were used to compare the new scores to the original HCT-CI.
Results:
5,790 patients were included in this study. The median age was 22 (0-39)yo. HCT indications were primarily acute myeloid leukemia (43%) and acute lymphoblastic leukemia (31%). Conditioning was mostly myeloablative (85%). Most common donor types were cord blood (35%), matched unrelated (28%) and matched sibling (18%). Donor source was peripheral blood stem cells (41%), umbilical cord blood (35%), or bone marrow (24%). Using the HCT-CI resulted in scores of 0, 1-2, and ≥3 for 45%, 26%, and 29% of the patient population, respectively. By adding pediatric-specific definitions to the HCT-CI, we developed the Expanded HCT-CI, with scores of 0, 1-2, and ≥3 translating to 31%, 28%, and 33% of the patients, respectively. Further, comorbidities with HR &lt;1.2 were removed to create a Pediatric simplified HCT-CI (Table 1).
The Expanded HCT-CI discriminated risk of NRM, with scores of 1-2 and ≥3 demonstrating hazard ratios (HR) of 1.02 (95%CI 0.75-1.38) and 1.52 (95%CI 1.16-1.99), respectively, vs. score of 0 (p&lt;0.002). Similarly, higher scores on the Pediatric simplified HCT-CI corresponded to a greater risk of NRM, with scores of 1-2, and ≥3 exhibiting HRs of 1.44 (95%CI 1.09-1.90) and 1.72 (95%CI 1.33-2.22), respectively, vs. score of 0 (p&lt;0.001). Compared to the original HCT-CI, the Expanded HCT-CI and Pediatric simplified HCT-CI performed similarly, as validated C-statistics (68.0 vs. 68.1 vs. 67.7) at 2 years were no different.
Conclusion:
The Expanded HCT-CI is a more comprehensive and practical pre-HCT risk score to predict NRM in children, adolescents, and young adults with hematologic malignancies, improving the sensitivity of the original HCT-CI while retaining the same level of specificity. This novel model can be widely used by transplant physicians to better assess HCT risks when counseling patients and improve study designs targeting the younger patient population.

Disclosures
Schiller: Agios: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Abbvie: Research Funding; Karyopharm: Research Funding; Jazz Pharmaceuticals: Research Funding; AstraZeneca: Consultancy; Incyte: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding; Stemline: Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Sanofi: Speakers Bureau; Ono Pharma: Consultancy; Gilead: Speakers Bureau; Constellation: Research Funding; Cyclacel: Research Funding; Celator: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Regimmune: Research Funding; Johnson & Johnson: Current equity holder in publicly-traded company; Onconova: Research Funding; Daiichi Sankyo: Research Funding; Samus: Research Funding; Kite Pharma: Research Funding; Geron: Research Funding; FujiFilm: Research Funding; Forma: Research Funding; Bristol-Myers Squibb: Current equity holder in publicly-traded company, Research Funding; DeltaFly: Research Funding; Deciphera: Research Funding; Astellas Pharma: Honoraria, Research Funding; Ariad: Research Funding; Actinium: Research Funding; Mateon: Research Funding; Genentech-Roche: Research Funding; Gamida: Research Funding; Tolero: Research Funding; Kaiser Permanente: Consultancy; Trovagene: Research Funding; Sangamo: Research Funding; MedImmune: Research Funding. Stadtmauer:Bristol Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy; AbbVie: Research Funding; Sanofi: 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. .