Acute and Chronic Graft-Versus-Host-Disease – A Focus on Pediatric Patients

Graft-versus-host disease (GVHD), either in its acute or chronic form, is the main contributory factor for morbidity and non-relapse mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Recent advancements in the classification of this disease, with better applicability and reproducibility of standardized criteria, coupled with improvements in the management of steroid-refractory or resistant cases, have led to promising results. In 2020, the Brazilian Group for Pediatric Bone Marrow Transplantation of the Brazilian Society for Blood and Marrow Transplantation and Cellular Therapy (SBTMO) convened a task force to provide updated, evidence-based guidance for the diagnosis, classification, staging, prophylaxis, and treatment of GVHD, with a focus on the pediatric population, the results of which are presented here.

HEMATOPOIETIC STEM CELL TRANSPLANTATION IN CHILDREN WITH HEMOGLOBINOPATHIES: BRAZILIAN SOCIETY OF BONE MARROW TRANSPLANTATION CONSENSUS

THE BRAZILIAN SOCIETY FOR BLOOD AND MARROW TRANSPLANTATION (SBTMO) PRESENTS THE BRAZILIAN GUIDELINES ON HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR CHILDREN WITH HEMOGLOBINOPATHIES

Mobility and Muscle Strength in Recipients of Hematopoietic Cell Transplantation for Sickle Cell Disease: A Preliminary Report from Sickle Transplant Evaluation of Longterm and Late Effects Registry (STELLaR)

Introduction Recipients of Hematopoietic Cell Transplantation (HCT) are at risk for treatment related late effects including cardiovascular disease and diabetes. Physical fitness including mobility and muscle strength are important predictors of cardiovascular health and quality of life. Physical fitness has been described in children and adults who are long term survivors of HCT for malignant disease [1]. Patients with sickle cell disease (SCD) are likely to be subject to unique morbidity post-HCT as a consequence of the pathophysiology of SCD which is characterized by anemia, inflammation, pain, bone infarcts and neurological complications. A systematic assessment of physical fitness is required to understand some of the long-term outcomes HCT for SCD. Methods We enrolled patients with SCD ≥ 1-year post-HCT in Sickle Transplantation Evaluating Long Term And Late Effects Registry (STELLaR). We assessed physical fitness including mobility using the timed up and go (TUG) test, and muscle strength using the handgrip strength (HGS) test. TUG scores were compared with published normative data for children (mean 9.2s; SD = 0.8) and young adults (mean 10.5s, SD = 1.1) [2]. TUG scores ≥ mean+ 2SD were considered abnormal (children: ≥10.8s, young adults ≥12.7s). The HGS of each patient was compared to published normative data of children and adults [3,4]. Patients ≤12 years were abnormal if they had a HGS of two standard deviations below the mean. Patients ≥13 years were considered abnormal if they had a HGS lower than the lower limit of the 85% age-sex standard. Additionally, patients were also assessed for chronic graft versus host disease (cGvHD) by means of the Lee Chronic GvHD Symptom Scale [5]. Patients rated their extent of being bothered by cGvHD symptoms on a scale from 1 to 5, with 1 being not at all and 5 being extremely. These scores were then organized into 7 categories of cGVHD symptoms and normalized to a 0-100 scale. We report the results of an interim analysis of physical fitness in these HCT recipients. Results Out of 121 patients enrolled in the study, 37 HCT recipients were assessed for mobility using the TUG test, and for muscle strength using the HGS test. Children were defined as being below the age of 18 and young adults between 18 and 40 years of age. Patient demographic and clinical results for TUG and HGS are presented in Table 1. Young adult participants were more likely to have abnormal TUG and HGS results than pediatric study participants. Patient self-reporting of overall (summary) cGvHD symptoms was found to be statistically significant between children and young adults (p=0.037) with young adults iappearing to be slightly more bothered by GvHD symptoms. There was no correlation in length of time in years between a patient's transplant and whether or not there was abnormal physical fitness (TUG and HGS) for both the young adult and children cohorts. Conclusions These data suggest the existence of impaired physical fitness in the long term in SCD patients who are HCT recipients. They provide the rationale for systematic evaluation of physical fitness and other risk factors for cardiovascular disease post-HCT. References 1. Slater, M. E., Steinberger, J., Ross, J. A., Kelly, A. S., Chow, E. J., Koves, I. H., ... & Baker, K. S. (2015). Physical activity, fitness, and cardiometabolic risk factors in adult survivors of childhood cancer with a history of hematopoietic cell transplantation. Biology of Blood and Marrow Transplantation, 21(7), 1278-1283. 2. Mangano, G. R., Valle, M. S., Casabona, A., Vagnini, A., & Cioni, M. (2020). Age-related changes in mobility evaluated by the timed up and go test instrumented through a single sensor. Sensors, 20(3), 719. 3. Omar, M. T., Alghadir, A. H., Zafar, H., & Al Baker, S. (2018). Hand grip strength and dexterity function in children aged 6-12 years: A cross-sectional study. Journal of Hand Therapy, 31(1), 93-101. 4. Webb, A. R., Newman, L. A., Taylor, M., & Keogh, J. B. (1989). Hand grip dynamometry as a predictor of postoperative complications reappraisal using age standardized grip strengths. Journal of Parenteral and Enteral Nutrition, 13(1), 30-33. 5. Lee, S. J., Cook, E. F., Soiffer, R., & Antin, J. H. (2002). Development and validation of a scale to measure symptoms of chronic graft-versus-host disease. Biology of Blood and Marrow Transplantation, 8(8), 444-452 Figure 1 Figure 1. Disclosures Guilcher: BlueBirdBio: Research Funding; Project Sickle Cure Study: Other: Principal Investigator, Research Funding.

Comparative Study of Treosulfan Plus Fludarabine (FT14) with Busulfan Plus Fludarabine (FB4) for Acute Myeloid Leukemia in First or Second Complete Remission: An Analysis from the European Society for Blood and Marrow Transplantation (EBMT) Acute Leukemia Working Party (ALWP)

Background: Treosulfan has been increasingly used in reduced toxicity regimens, especially in older or frail patients. Different doses of treosulfan plus fludarabine have shown an advantage over reduced intensity regimens, confirmed by a randomized phase 3 trial utilizing treosulfan 30 g/m² (or FT10) in the majority of patients. However, data comparing fludarabine with higher doses of treosulfan (FT14) to fludarabine combined with myeloablative doses of busulfan are limited. Aims: We compared outcomes between treatment alternatives of similar conditioning intensity: FT14 (fludarabine 150 or 160 mg/m 2 and treosulfan 42g/m 2, or FT14) over FB4 (fludarabine 150 or 160 mg/m 2 and busulfan 12.8 mg/kg). Methods: We retrospectively studied consecutive patients from the European Society for Blood and Marrow Transplantation (EBMT) registry, meeting the following inclusion criteria: a) adults diagnosed with acute myeloid leukemia (AML), b) recipients of first allogeneic hematopoietic stem cell transplantation (HSCT) from a matched unrelated or sibling donor between 2010-2020, c) HSCT at first or second complete remission (CR), d) conditioning regimen with either FT14 or FB4. Patients with ex vivo manipulated grafts were excluded. A sub-group analysis was performed according to age (<55 years or ≥55 years). Results: In total, 2703 patients were included in the analysis comprising 2025 (75%) transplanted with FB4, and 678 (25%) with FT14. In the sub-group of patients younger than 55 years (n=1676), FT14 recipients (n=236) had a significantly increased age (p<0.001), higher rates of secondary AML (p<0.0001), unrelated donors (p<0.0001), and peripheral blood grafts (p=0.026), but a lower percentage of female donors to male recipients (p=0.008), compared to FB4 recipients (n=1440). Cumulative incidence (CI) of acute graft-versus-host disease (GVHD) grade III-IV was higher in FT14 (9.3% versus 5.8%, p=0.044), but rates of chronic GVHD were similar. With a median follow-up of 24.4 months (range 23.4-25.6), 2-year CI of relapse was higher in FT14 (35.9% versus 27.5%, p=0.025, Figure 1A), while non-relapse mortality was similar between groups (NRM 11.9% versus 7.7%, p=0.28, 1B). This led to lower 2-year leukemia-free survival (LFS 52.2% versus 62.4%, p=0.002, 1C), overall survival (OS 63.2% versus 72.9%, p=0.038, 1D), and GVHD free, relapse free survival (GRFS 41.3% versus 50%, p=0.004) in FT14. In Cox-regression multivariate analysis, conditioning regimen remained an independent predictor of CI of relapse (p=0.011), and LFS (p=0.03). Similar differences in patient characteristics were observed in patients aged ≥55 years (n=1027). FT14 recipients (n=442) had a significantly increased age (p<0.001), higher rates of secondary AML (p<0.0001), unrelated donors (p<0.0001), adverse cytogenetics (p<0.0001), peripheral blood grafts (p=0.026), but a lower percentage of female to male combinations (p=0.008) compared to FB4 (n=585). Cumulative incidence (CI) of acute graft-versus-host disease (GVHD) grade II-IV was higher in FT14 (7.6% versus 6.5%, p=0.001), with similar rates of chronic GVHD. Nevertheless, with a median follow-up of 29.6 months (range 23.9-34.1), 2-year CI of relapse, NRM, as well as LFS, OS and GFRS were similar between groups. Conclusion: With the limitations of a retrospective analysis, our large real-world multicenter study suggests that FB4 is associated with better outcomes compared to FT14 in younger patients with AML transplanted in first or second CR. The same was not true for older patients (≥55 years). It should also be noted that FT14 has been selected by treating physicians for higher risk HSCT, including patients who are older, have secondary disease, adverse cytogenetics, and unrelated donors. Therefore, further studies are needed to determine the optimal conditioning regimen for such patient populations. Figure 1 Figure 1. Disclosures Gavriilaki: Alexion, Omeros, Sanofi Corporation: Consultancy; Gilead Corporation: Honoraria; Pfizer Corporation: Research Funding. Labopin: Jazz Pharmaceuticals: Honoraria. Yakoub-Agha: Jazz Pharmaceuticals: Honoraria. Hilgendorf: Novartis: Honoraria; AbbVie: Honoraria; Jazz Pharmaceuticals: Honoraria, Other: Travel Support; Celgene: Other: Travel Support; SanofiGenzyme: Other: Travel Support. Kröger: Novartis: Research Funding; Riemser: Honoraria, Research Funding; Sanofi: Honoraria; Neovii: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Gilead/Kite: Honoraria; Celgene: Honoraria, Research Funding; AOP Pharma: Honoraria. Mielke: Gilead/KITE: Other: Travel support, Expert panel ; Novartis: Speakers Bureau; Immunicum: Other: Data safety monitoring board; Miltenyi: Other: Data safety monitoring board; DNA Prime SA: Speakers Bureau; Celgene/BMS: Speakers Bureau. Zuckerman: AbbVie: Honoraria; Orgenesis Inc.: Honoraria; Janssen: Honoraria; BioSight Ltd: Honoraria; Novartis: Honoraria; Gilead Sciences: Honoraria, Speakers Bureau; Cellect Biotechnology: Honoraria. Giebel: Janssen: Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau. Bazarbachi: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Hikma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees. Spyridonidis: Menarini: Current Employment. Mohty: Astellas: Honoraria; Amgen: Honoraria; Celgene: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Takeda: Honoraria; Jazz: Honoraria, Research Funding; Adaptive Biotechnologies: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Bristol Myers Squibb: Honoraria; Janssen: Honoraria, Research Funding; Gilead: Honoraria.