Abstract: Patient age, 18 to 54 years: comparable survival after transplants from an HLA-matched sibling and a haploidentical sibling. Patient age, 55 to 76 years: better survival after transplants from an HLA-matched sibling compared with offspring.

Abstract: Patients with sickle cell disease (SCD) are now routinely living into adulthood, but SCD has deleterious effects on multiple organ systems which can lead to increased complications from illness. SCD patients generally auto-splenectomize in childhood secondary to infarctions from their hemoglobinopathy, thus increasing their risk of infection with encapsulated organisms such as S. pneumoniae. Although there are data to demonstrate that vaccination has drastically decreased the incidence of invasive pneumococcal disease (i.e. bacteremia or meningitis) in children, the situation for adults is less clear. There are no data to guide the decision to use conjugated and/or polysaccharide pneumococcus vaccines in adults. In addition, there are few data available on the efficacy of pneumococcal vaccination on non-invasive disease such as pneumonia. Two landmark studies have demonstrated the efficacy of polysaccharide-based pneumococcal vaccines in the general adult population to be approximately 56%. However, there are data to suggest that immune responses in SCD patients may be impaired, and thus responses to vaccines may be suboptimal. Current sickle cell guidelines for pneumococcal vaccination, which are based on expert opinion, recommend one dose of Prevnar 13 (conjugated vaccine) followed by one dose of Pneumovax 23 (polysaccharide vaccine) with a booster of Pneumovax 23 at age 65. However, some clinicians choose to vaccinate every 5 years due to fear of waning immunity. There is a lack of data on which to base guidelines, and there are also no data nor any guidelines to help decide if patients needs additional boosters of vaccine. Besides the potential for suboptimal immune responses in sickle cell patients, the standard definition used to define a responder to pneumococcal vaccine may not translate to protection from disease in the real world. Most studies define a responder as having a protective titer to 50-70% of the serotypes tested. However, this definition has no consideration for the prevalence of serotypes causing disease in the community. Therefore it's possible to have a patient who responds to 50% of the serotypes in the assay and is considered immune, but if those serotypes are all uncommon, then the patient may still be at high risk for serious disease. Determining a better way to identify patients at risk for pneumococcal disease and optimizing vaccination strategies to prevent this disease would help to improve the lives of patients. We performed a retrospective study to investigate immunity to pneumococcus in adult patients with SCD. We used the electronic medical record and collected data on patient demographics, sickle cell genotype, dates of previous pneumococcal vaccination (both conjugated and polysaccharide vaccines), quantitative antibody levels to individual pneumococcus serotypes, as well as information on comorbidities. In our sample of n=28 patients with SCD and available antibody data, 68% met a commonly accepted definition of immunity, which we defined by having an antibody concentration ≥ 1 mcg/mL for at least 50% of any of the serotypes tested. Immunity was inversely correlated with time from last pneumococcal vaccination, and it did not matter whether the most recent vaccine was the conjugated or polysaccharide product (Fig 1a). We then sought to analyze the data with consideration for the prevalence of various serotypes based on epidemiologic data published in The Lancet Infectious Diseases15,301-309 (2015). Interestingly, only 21% of patients who met the traditional definition of being a vaccine responder had protective titers to all 3 of the most prevalent serotypes tested, and 10% of patients who would traditionally be characterized as vaccine responders did not have sufficient antibody production to any of the 3 most prevalent serotypes tested in the assay (Fig. 1b, left). Of the 9 patients who were categorized as vaccine nonresponders based on the traditional definition, one subject was actually immune to all 3 of the most common serotypes in the community (Fig 1b, right), suggesting that he may actually be well-covered for pneumococcus in the real world. This study raises concern about the definition of immunity following vaccination, and highlights the challenge to identify which patients are at risk for disease. Future studies should examine how immunity wanes post vaccination and how the lack of immunity to prevalent serotypes might lead to clinical disease. Disclosures Lanzkron: Pfizer: Research Funding; Global Blood Therapeutics: Research Funding; Ironwood: Research Funding; HRSA: Research Funding; NIH: Research Funding; PCORI: Research Funding.

Abstract: An HLA-matched sibling has been considered the optimal donor for allogeneic hematopoietic cell transplantation (HSCT). However, several potential transplant recipients may have a haploidentical sibling or an offspring who may also serve as donors. In this study, we sought to determine the optimal alternative related donor (haploidentical sibling or an offspring) as compared to an HLA-matched sibling. The primary objective was comparison of chronic graft-versus-host disease (GVHD). Secondary outcomes included acute GVHD, non-relapse mortality (NRM), relapse, treatment failure (relapse or death, inverse of relapse-free survival) and overall mortality. The study population included 4540 donor-recipient pairs (n=218 haploidentical sibling; n=218 offspring; n=4104 HLA-matched sibling) with acute myeloid (n=3617) and acute lymphoblastic (n=923) leukemia transplanted in 2008 to 2015. There were few offspring (n=87) who donated to patients aged 18-54 years and haploidentical siblings (n=61) who donated to patients aged 55-76 years and were excluded from the analysis. Post-transplant cyclophosphamide (PT-Cy) with calcineurin inhibitor (CNI) and mycophenolate was used for GVHD prophylaxis for all haploidentical HSCTs. HLA-matched siblings received CNI-containing GVHD prophylaxis; CNI with methotrexate was the predominant prophylaxis regimen. Patient age was correlated with donor age and donor-recipient relationship. Bone marrow was the predominant graft for haploidentical HSCTs (64%) and peripheral blood (89%) for HLA-matched sibling HSCTs. Younger patients (age 18-54 years) of were more likely to receive reduced intensity conditioning regimens for haploidentical HSCTs compared to HLA-matched sibling HSCTs (22%). Among older patients, conditioning regimen intensity did not differ by donor type. Exploratory analysis confirmed differences in survival by patient age. Therefore, based on differences in survival by patient age, two age groups were created: 18 - 54 years and 55 - 76 years and within each patient age group, donor-recipient relationship and its effect on transplant outcomes were tested using Cox regression models. In addition to the standard Cox regression model, we also performed a matched-pair analysis. Recipients of haploidentical HSCT (cases; n=436) were matched to HLA-matched siblings (controls; n=1707) on age, disease and disease risk index. 88% of patients aged 18-54 years were matched to 4 controls and 96% of patients aged 55-76 years were matched to 4 controls. The median difference in age between cases and controls were 0.08 (range 0-9.9) years for patients aged 18-54 years and 0.05 (0 - 9.5) years for patients aged 55-76 years. The results of multivariate Cox regression and matched-pair analysis are shown in Tables 1, 2. Among patients aged 18-54 years, chronic GVHD risks were lower after haploidentical sibling compared to HLA-matched sibling HSCT. There were no differences in acute GVHD, NRM, relapse, treatment failure or overall mortality. Among patients aged 55-76 years, acute and chronic GVHD risks were lower after offspring compared to HLA-matched sibling HSCT. But risks for NRM, treatment failure and overall mortality were higher after offspring compared to HLA-matched sibling HSCT. The 2-year probabilities of overall survival, adjusted for disease risk index and sex are shown in Figure 1. In summary, chronic GVHD rates were lower after haploidentical HSCT with PT-Cy containing GVHD prophylaxis regimens compared to HLA-matched sibling HSCT for all patients. Whether this can be attributed solely to the GVHD prophylaxis regimen or in part attributed to use of peripheral blood grafts for HLA-matched sibling HSCT must be studied further in a setting in which PT-Cy containing GVHD prophylaxis is used for HLA-matched sibling HSCT. Despite lower chronic GVHD with haploidentical sibling donor HSCT with PT-Cy, NRM and overall survival did not differ by donor type for patients aged 18-54 years. However, for patients aged 55 - 76 years, despite lower chronic GVHD with offspring donor HSCT with PT-Cy, NRM was higher and overall survival was lower compared to HLA-matched sibling HSCT. Definitive proof of these findings would require a prospective randomized trial. Disclosures Ciceri: GSK: Other: B-thalassemia gene therapy was developed by Fondazione Telethon and Ospedale San Raffaele and has been inlicenced by GSK that provides funding for the clinical trial, Research Funding. Mohty: Sanofi: Honoraria, Speakers Bureau.

Abstract: Allogeneic hematopoietic stem cell transplantation (aHSCT) is hampered by chronic graft-versus-host disease (cGVHD), which results in multi-organ fibrosis and loss of function. In particular, bronchiolitis obliterans (BO) and scleroderma resulting from fibrotic bronchiolar and cutaneous response, respectively, are two devastating outcomes for cGVHD patients. Fibrotic manifestations often are considered irreversible and progressive. Therefore, new therapies targeting fibrosis are urgently needed. Pirfenidone (5-methyl-1-phenyl-2- (1H)-pyridone) exhibits a well-documented anti-inflammatory and anti-fibrosis function in multiple pre-clinical models and is the first and only FDA-approved drug for idiopathic pulmonary fibrosis. For this study, Pirfenidone was synthesized as a crystalline solid and found to be pure both by melting point and NMR spectroscopy. We evaluated Pirfenidone's anti-fibrosis function in 2 pathophysiologically distinct cGVHD murine models: 1. a major mismatched multi-organ system model (C57BL/6 to B10.BR) that induces BO as a result of a cGVHD-induced germinal center (GC) reaction, antibody deposition and fibrosis in the lung; and 2. a minor antigen mismatched model (B10.D2 to BALB/c) in which severe scleroderma is the major disease manifestation. In the BO model, pulmonary function loss in cGVHD mice (as reflected by increased resistance, elastance and decreased compliance of the lung) was restored by Pirfenidone treatment (400mg/kg) during both the early (day28-56) (Fig A, representative of 3 experiments with 5-8 mice per group) and late stages (day56-84) of the disease. Pathologic changes in the lung, such as collagen deposition and narrowing of bronchioles, were significantly reduced by Pirfenidone. The size and frequency of GCs in the spleen, and the frequency of GC B cells (Fig B, representative of 2 experiments with 5-8 mice per group) and T follicular helper cells were all significantly reduced in Pirfenidone- treated groups. To determine whether GCs were directly affected by Pirfenidone, we evaluated Pirfenidone in C57BL/6 mice immunized with sheep red blood cells (SRBC) to induce GCs. Interestingly, Pirfenidone did not reduce the SRBC-induced GC reaction (Fig C) (comparable frequencies of splenic GC B cells, T follicular helper cells and serum IgG levels were seen between Pirfenidone and vehicle-treated groups). These results suggested that Pirfenidone suppresses the GC reaction through a cGVHD-specific mechanism, rather than through immune regulation. Mechanistically, Pirfenidone administration attenuated the sequestration of pro-fibrogenic F4/80+ macrophages (Fig D, representative of 2 experiments) and TGF-β (Fig E, representative of 2 experiments) production within the lung. These results have led us to elucidate a potential mechanism of cGVHD: antibody deposition in the lung results in the activation of macrophages and TGF-β that drive fibrotic change and tissue damage, resulting in the exposure of auto- and allo- antigens to the immune system that support and sustain pathologic GC reactions. In the B10.D2 to BALB/c sclerodermatous cGVHD model, Pirfenidone treatment (400mg/kg, day21-55) improved clinical signs of scleroderma and reduced macrophage infiltration in the skin (Fig F). In summary, this is the first study evaluating a commercially available anti-fibrosis drug on pathologically distinct pre-clinical cGVHD models. Our data suggests Prifenidone reversed cGVHD in the BO model and, to a lesser extent, in the scleroderma model. Thus, Pirfenidone is a novel therapeutic agent for treating cGVHD patients with fibrosis that have been typically refractory to therapies. A. Resistance of lungs was measured on day56 of transplantation; Elastance and compliance correlated with resistance but were not shown here. B. Flow cytometry analysis of GC B cells of no cGVHD vs cGVHD mice treated with Pirfenidone or vehicle; C. Flow cytometry analysis of GC B cells from SRBC-immunized mice treated with Pirfenidone or vehicle; D and E. Macrophage F4/80 and TGF-β quantification of day56 lungs of no cGVHD vs cGVHD mice treated as indicated; F. Skin GVHD scores were recorded on indicated dates of irradiated BALB/c mice transplanted with B10.D2 donor BM alone or with T cells and treated as indicated. Unpaired student T test was used for statistical analysis. ****:P 〈 0.0001; ***: P 〈 0.001; **: P 〈 0.01; *: P 〈 0.05; ns: not significant. Figure Figure. Disclosures No relevant conflicts of interest to declare.

Abstract: Introduction. Valoctocogene roxaparvovec (AAV5-hFVIII-SQ) is an adeno-associated virus gene therapy that transfers a B-domain deleted factor VIII (FVIII) cDNA to hepatocytes. The open-label, single-arm, multicenter phase 3 GENEr8-1 trial (NCT03370913) evaluated valoctocogene roxaparvovec in 134 men with severe hemophilia A (HA) and demonstrated an 83.8% reduction in annualized treated bleeding rate (ABR) and superiority to FVIII prophylaxis (P & lt;0.001). The relationship between baseline FVIII activity and ABR was estimated in congenital HA (den Uijl, et al. Haemophilia 2011;17[1]:41-4); it is unknown if a similar relationship exists after gene transfer. We present here post-hoc analyses of transgene-derived FVIII activity and bleeds in GENEr8-1. Methods. Men ≥18 years of age with severe HA previously on FVIII prophylaxis who were negative for FVIII inhibitors and anti-AAV5 antibodies received one 6x10 13 vg/kg infusion of valoctocogene roxaparvovec. FVIII activity was measured by chromogenic substrate (CSA; lower limit of quantitation [LLOQ], 3.0 IU/dL) and one stage assays (OSA; LLOQ, 1.0 IU/dL); median FVIII activity in every 4- or 6-week window was assessed. Self-reported treated bleeds were counted after week 4, when routine prophylaxis was scheduled to end. The relationship between number of treated joint bleeds and matched median FVIII activity levels in each 4- or 6-week window was modeled using negative binomial regression. Results. As of the data cut date, mean follow-up was 71.6 weeks; 1 participant was lost to follow-up at week 66. At weeks 49-52 (latest time with data for all participants; intent-to-treat population), 9% (12/134) had CSA FVIII activity & lt;3 IU/dL, 3% (4/134) had median FVIII activity ≥3- & lt;5 IU/dL, 17% (23/134) had median FVIII activity ≥5- & lt;15 IU/dL, and 71% (95/134) had median FVIII activity ≥15 IU/dL. While on FVIII prophylaxis prior to gene transfer, 32% of participants (43/134) had an ABR of 0. Following gene transfer, 75% of participants (101/134) were bleed-free through their last follow-up prior to the data cut. The remaining 33 participants reported 149 treated bleeds total, 62% (93/149) as traumatic and 38% (56/149) as spontaneous. By location, 53% (79/149) occurred in joints, 19% (28/149) in muscle, 14% (21/149) in soft tissue, and 14% (21/149) in other or unspecified locations. Relative to FVIII level, 54% of treated bleeds (80/149) occurred when CSA FVIII was & lt;3 IU/dL (LLOQ), 12% (18/149) when FVIII was ≥3- & lt;5 IU/dL, 23% (35/149) when FVIII was ≥5- & lt;15 IU/dL, and 11% (16/149) when FVIII was ≥15 IU/dL. Of 16 treated bleeds that occurred when FVIII was ≥15 IU/dL, 13 were traumatic. Treated joint bleeds followed a similar pattern: 51% (40/79) occurred when FVIII was & lt;3 IU/dL, 15% (12/79) when FVIII was ≥3- & lt;5 IU/dL, 27% (21/79) when FVIII was ≥5- & lt;15 IU/dL, and 8% (6/79) when FVIII was ≥15 IU/dL. A negative binomial regression model based on these data and matched FVIII activity levels predicts & lt;1 treated joint bleed in 2 years for individuals treated with valoctocogene roxaparvovec with FVIII activity ≥15 IU/dL (CSA; Figure). Clinical value of the CSA at low FVIII levels is limited by its LLOQ of 3 IU/dL. Of 12 participants with median FVIII levels below the CSA LLOQ at weeks 49-52, 9 had improved or the same ABR post-gene therapy relative to prophylaxis. The OSA, with its LLOQ of 1 IU/dL, provided important information here. By OSA, 1 had FVIII & lt;1 IU/dL, 5 had FVIII ≥1- & lt;5 IU/dL, and 3 had FVIII ≥5 IU/dL. The remaining 3 participants who had increased ABR after gene transfer had FVIII levels by OSA of 0, 2.1, and 4.8 IU/dL. For participants with OS FVIII & lt;5 IU/dL at week 52 (n = 11), median (IQR) ABR was 1.2 (0-7.9), similar to the median (IQR) ABR of 1.6 (0.6-3.5) reported for people with moderate HA (Abdi, et al. J Throm Haemost 2020;18[12]:3203-10). Conclusions. Gene transfer with valoctocogene roxaparvovec led to sustained endogenous FVIII production and reduced ABR in this phase 3 trial. After gene transfer, the majority of bleeds were traumatic. When FVIII was ≥15 IU/dL, reports of treated bleeds, including joint bleeds, were rare. CSA FVIII activity was predictive of bleeding risk post-gene transfer, as for epidemiologic congenital HA results. At FVIII levels below the CSA LLOQ, the OSA provided clinically relevant information; bleeding with OSA FVIII & lt;5 IU/dL was similar to observations in people with moderate HA, though further exploration with more data is needed. Figure 1 Figure 1. Disclosures Pipe: Biomarin: Consultancy, Other: Clinical trial investigator; Regeneron/ Intellia: Consultancy; uniQure: Consultancy, Other; Spark Therapeutics: Consultancy; Takeda: Consultancy; Sanofi: Consultancy, Other; Sangamo Therapeutics: Consultancy; Roche/Genentech: Consultancy, Other; Pfizer: Consultancy; Novo Nordisk: Consultancy; Freeline: Consultancy, Other: Clinical trial investigator; HEMA Biologics: Consultancy; CSL Behring: Consultancy; Catalyst Biosciences: Consultancy; Genventiv: Consultancy; Grifols: Consultancy; Bayer: Consultancy; ASC Therapeutics: Consultancy; Apcintex: Consultancy; Octapharma: Consultancy; Shire: Consultancy. Ozelo: BioMarin Pharmaceutical Inc.: Consultancy, Other: Clinical trial investigator, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Novo Nordisk: Consultancy, Other: Clinical trial investigator, Travel support, Speakers Bureau; Pfizer: Consultancy, Other: Clinical trial investigator, Research Funding; Roche: Consultancy, Other: Clinical trial investigator, Travel support, Research Funding, Speakers Bureau; Sanofi: Consultancy, Other: Clinical trial investigator; Takeda: Consultancy, Other: Clinical trial investigator, Travel support, Research Funding, Speakers Bureau; Grifols: Other: Grants review. Kenet: Takeda: Consultancy; Roche: Consultancy; Novo Nordisk: Consultancy; Shire: Research Funding; Pfizer: Consultancy, Research Funding; Opko Biologics: Research Funding; Bayer: Consultancy, Research Funding; Alnylam: Consultancy, Research Funding. Reding: Bayer, CSL Behring, Sanofi Genzyme, Takeda: Speakers Bureau; Bayer, Biomarin (institutional research funding): Research Funding; Bayer, CSL Behring, NovoNordisk, Sanofi Genzyme, Takeda: Honoraria; Bayer, CSL Behring, NovoNordisk, Sanofi Genzyme, Takeda (advisory committees): Membership on an entity's Board of Directors or advisory committees. Mason: BioMarin Pharmaceutical Inc.: Other: Participation as a clinical trial investigator; Roche: Other: Participation as a clinical trial investigator, Travel support, Speakers Bureau. Leavitt: Syntimmune: Research Funding; Sangamo Therapeutics: Research Funding; Pfizer: Research Funding; Merck: Consultancy; CSL DOVA: Consultancy; Catalys: Consultancy; BioMarin: Consultancy, Research Funding; BPL: Consultancy; Behring: Consultancy; HEMA Biologics: Consultancy; Rigel: Consultancy. Laffan: Shire: Membership on an entity's Board of Directors or advisory committees; Leo-Pharma: Speakers Bureau; Alexion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Speakers Bureau; AstraZeneca: Consultancy; Sobi: Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Bayer: Other: Travel support, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BioMarin Pharmaceutical Inc.: Research Funding. Quon: Orthopaedic Institute for Children: Current Employment. von Drygalski: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Hematherix, Inc: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Super FVa; Novo Nordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Research Funding; CSL Behring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Biomarin: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; uniQure: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Chou: Bayer: Other: Clinical trial investigator, Speakers Bureau; Novo Nordisk: Consultancy, Other: Clinical trial investigator, Speakers Bureau; BioMarin: Other: Clinical trial investigator; Sanofi: Consultancy, Other: Clinical trial investigator, Speakers Bureau; Chugai: Consultancy, Other: Clinical trial investigator, Speakers Bureau; Pfizer: Other: Clinical trial investigator, Speakers Bureau; CSL: Consultancy, Other: Clinical trial investigator, Speakers Bureau. Shapiro: Sobi: Consultancy; Shire: Consultancy; Pfizer: Consultancy, Speakers Bureau; Bayer: Other: Travel support, Speakers Bureau; Takeda: Speakers Bureau; Roche: Speakers Bureau; CSL Behring: Other: travel support. Dunn: Genentech/Roche: Consultancy, Speakers Bureau; ATHN: Research Funding; Biomarin: Consultancy, Research Funding; Freeline: Research Funding; Takeda: Research Funding; World Federation of Hemophilia USA: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy; Uniqure: Consultancy; Sanofi: Research Funding; Kedrion: Consultancy. Wang: Bioverativ: Consultancy, Other: Clinical trial investigator; CSL Behring: Consultancy, Other: Clinical trial investigator; Novo Nordisk: Consultancy, Other: Clinical trial investigator; Genentech: Consultancy, Other: Clinical trial investigator; Takeda: Consultancy, Other: Clinical trial investigator; Hema Biologics: Consultancy, Other: Clinical trial investigator; uniQure: Consultancy, Other: Clinical trial investigator; Pfizer/Spark: Other: clinical trial investigator; Octapharma: Other; Bayer: Consultancy, Other: Clinical trial investigator; BioMarin: Consultancy, Other: Clinical trial investigator. Key: Grifols: Research Funding; Takeda: Research Funding; BioMarin: Honoraria, Other: Participation as a clinical trial investigator; Sanofi: Consultancy; Uniqure: Consultancy, Other: Participation as a clinical trial investigator. Kaczmarek: Bayer: Research Funding. Symington: Biomarin: Research Funding; CSL Behring: Other: Travel support; Novonordisk: Other: Travel support. Lawal: BioMarin Pharmaceutical Inc.: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Mahajan: BioMarin Pharmaceutical: Current Employment, Current equity holder in publicly-traded company. Chavele: BioMarin Pharmaceutical: Current Employment, Current equity holder in publicly-traded company. Reddy: BioMarin Pharmaceutical: Current Employment, Current equity holder in publicly-traded company. Yu: BioMarin Pharmaceutical: Current Employment, Current equity holder in publicly-traded company. Wong: BioMarin Pharmaceutical Inc.: Current Employment, Current equity holder in publicly-traded company. Robinson: BioMarin Pharmaceutical Inc.: Current Employment, Current equity holder in publicly-traded company. Kim: BioMarin Pharmaceutical Inc.: Current Employment, Current equity holder in publicly-traded company.

Abstract: Introduction. Severe hemophilia A (HA) negatively impacts health-related quality of life (HRQOL) through joint pain and disability, treatment burden, and effects on mental and emotional health; chronic pain and mental health are core outcomes for hemophilia gene therapy trials (Iorio, et al. Haemophilia 2018;24[4]:e167-72). In the phase 3 trial GENEr8-1 (NCT03370913), men with severe HA who received valoctocogene roxaparvovec (AAV5-hFVIII-SQ) gene therapy experienced a significant increase in endogenous FVIII activity that resulted in reduced bleeding events and FVIII utilization from baseline through 52 weeks (Ozelo, et al. Res Pract Thromb Haemost 2021;5). Here, we analyzed the impact of valoctocogene roxaparvovec on HRQOL. Methods. Men ≥18 years of age with FVIII ≤1 IU/dL previously receiving standard-of-care FVIII prophylaxis and without history of FVIII inhibitors received one 6x10 13 vg/kg valoctocogene roxaparvovec infusion. This analysis included HIV-negative participants who completed the weeks 49-52 visit. Participants completed QOL questionnaires at baseline and weeks 4, 12, 26, and 52 post-gene therapy infusion. Change from baseline was assessed with a two-sided t-test without multiplicity control. Missing data were not imputed. Measures included the hemophilia-specific Haemo-QOL-A questionnaire, which consists of 6 domain scores (Physical Functioning, Role Functioning, Consequences of Bleeding, Worry, Emotional Impact, Treatment Concern) and Total Score ranging from 0-100 (Rentz, et al. Haemophilia 2008;14[5]:1023-34); and the EQ-5D-5L, a general measure of HRQOL that assesses functional dimensions (Mobility, Self-Care, Usual Activities) as well as Pain/Discomfort and Anxiety/Depression (Herdman, et al. Qual Life Res 2011;20[10] :1727-36). EQ-5D-5L results are reported as visual analog scale (VAS; range, 0-100) and Utility Index Score (range, 0-1), which is calculated from population norms (Janssen, et al. Qual Life Res 2013;22[7]:171-27). Higher scores indicate better HRQOL. The anchor-based clinically important differences (CID) used for the Haemo-QOL-A were 5.5 for Total Score and 6 for domain scores (Quinn, et al. Abstract, Hemophilia Federation of America Virtual Conference, Aug 2020). For the EQ-5D-5L Index, 0.03 was considered a CID (Kaplan. COPD 2005;2[1] :91-7). However, use of general population norms, together with the presence of a disability paradox in hemophilia, causes the EQ-5D-5L to underestimate the negative impact of hemophilia on HRQOL (O'Hara, et al. Haemophilia 2021;27[2]:245-52), likely leading to underestimation of changes in HRQOL. Results. This analysis included 132 participants. At baseline, mean ± standard deviation (SD) Haemo-QOL-A Total Score was 75.7 ± 16.7 (n = 130); at weeks 26 and 52, mean change from baseline in Total Score demonstrated improvement (P & lt;0.0001) at or above the CID threshold (Table). Improvement in Total Score was noted as early as 4 weeks (change from baseline, 3.0 ± 8.5; P = 0.0001) and by week 12 had reached the CID (5.5 ± 8.4; P & lt;0.0001). Domain scores for Physical Function, Role Functioning, and Consequences of Bleeding also improved from baseline (P & lt;0.0001), exceeding the CID at weeks 26 and 52 (Table). Treatment Concern demonstrated improvement from baseline (P & lt;0.001) at weeks 26 and 52, exceeding the CID at week 52. Improvements below the CID were noted for Worry at weeks 26 and 52 (P & lt;0.01) and Emotional Impact at week 52 (P & lt;0.05; Table). At baseline, EQ-5D-5L VAS mean ± SD was 80.1 ± 15.3 (n = 131), which increased by 2.5 ± 13.7 (n = 129) at week 26 and 4.5 ± 13.3 (n = 129) at week 52. Mean ± SD EQ-5D-5L Index Score at baseline was 0.78 ± 0.17 (n = 131); mean ± SD changes from baseline at both week 26 (0.04 ± 0.14 [n = 128]) and 52 (0.04 ± 0.16 [n = 129] ) demonstrated improvement (P ≤0.002), exceeding the CID of 0.03. Conclusions. These data demonstrate improvement in core outcomes of mental health (EQ-5D-5L Anxiety/Depression, Haemo-QOL-A Consequences of Bleeding) and pain and discomfort (EQ-5D-5L Pain/Discomfort, Haemo-QOL-A Physical Functioning) as well as ability to perform activities of daily living (EQ-5D-5L Self-Care and Mobility, Haemo-QOL-A Physical Functioning and Role Functioning) for participants with HA following treatment with valoctocogene roxaparvovec compared with their values on standard-of-care FVIII prophylaxis. Figure 1 Figure 1. Disclosures O'Mahony: Freeline: Consultancy; Uniqure: Speakers Bureau; BioMarin Pharmaceutical Inc.: Consultancy. Mahlangu: Baxalta: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Catalyst Biosciences: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Biomarin: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Univeristy of the Witwatersrand: Current Employment; Spark: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Unique: Research Funding; Sanofi: Research Funding, Speakers Bureau; Takeda: Speakers Bureau; WFH: Speakers Bureau; ISTH: Speakers Bureau; Springer: Speakers Bureau. Peerlinck: SOBI: Consultancy, Research Funding; Octapharma: Consultancy; NovoNordisk: Consultancy, Research Funding; Pfizer: Consultancy; Roche: Other: Clinical trial investigator, Research Funding; CSL Behring: Research Funding; Uniqure: Other: Clinical trial investigator; BIoMarin: Other: Clinical trial investigator. Lowe: Biomarin: Research Funding; Novartis: Honoraria; Sobi: Honoraria; Leo: Honoraria; Alexion: Honoraria; Takeda: Honoraria; NovoNordisk: Honoraria. Giermasz: Bayer: Consultancy; ATHN: Consultancy; NovoNordisk: Consultancy; UniQure: Consultancy, Research Funding; Sanofi Genzyme: Consultancy; Bioverativ/Sanofi: Consultancy, Research Funding, Speakers Bureau; Sangamo Therapeutics,: Research Funding; Pfizer: Consultancy; Genentech/Roche: Consultancy, Research Funding, Speakers Bureau; BioMarin: Consultancy, Research Funding. Cockrell: Takeda: Consultancy; CSL Behring: Consultancy; HEMA Biologics: Consultancy; Sanofi: Consultancy; BioMarin: Consultancy; Novo Nordisk: Consultancy; Genentech: Consultancy, Speakers Bureau. Pepperell: Pfizer: Other: Travel support. Chambost: Bayer: Consultancy; BioMarin: Consultancy, Other: Clinical trial investigator; travel support, Speakers Bureau; Roche: Consultancy, Other: Clinical trial investigator; travel support, Speakers Bureau; Sobi: Consultancy, Other: Clinical trial investigator; travel support, Speakers Bureau; Bioverativ: Other: Clinical trial investigator; CSL Behring: Other: Clinical trial investigator; travel support; LFB: Other: Clinical trial investigator; Octapharma: Other: Clinical trial investigator; travel support; Pfizer: Other: clinical trial investigator, Speakers Bureau. Majerus: BioMarin Pharmaceutical Inc.: Consultancy, Other: Clinical trial investigator, Travel support. Skinner: Bayer: Consultancy; BioMarin: Consultancy, Research Funding; Pfizer (DMC): Consultancy; Roche/Genentech: Consultancy, Research Funding; Sanofi: Consultancy; Spark (DMC): Consultancy; Takeda: Consultancy, Research Funding; Freeline: Research Funding; uniQure: Research Funding. Klamroth: Bayer: Consultancy, Other: Clinical trial investigator, Travel support, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Other: Clinical trial investigator, Travel support, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Other: Clinical trial investigator, Travel support, Research Funding, Speakers Bureau; Pfizer: Consultancy, Other: Clinical trial investigator, Travel support, Research Funding, Speakers Bureau; Shire (a Takeda company): Consultancy, Other: Clinical trial investigator, Travel support, Research Funding, Speakers Bureau; BioMarin: Consultancy, Other: Clinical trial investigator, Travel support, Speakers Bureau; Biotest: Consultancy, Other: Travel support, Speakers Bureau; Roche/Cugai: Consultancy, Other: Clinical trial investigator, Travel support, Speakers Bureau; Octapharma: Consultancy, Other: Clinical trial investigator, Travel support, Speakers Bureau; Sanofi: Consultancy, Other: Clinical trial investigator, Travel support, Speakers Bureau; Sobi: Consultancy, Other, Speakers Bureau; Uniqure: Consultancy, Other; LEO: Other, Research Funding, Speakers Bureau; Daiichi Sankyo: Other, Speakers Bureau; Grifols: Speakers Bureau. Quinn: BioMarin Pharmaceutical: Current Employment, Current equity holder in publicly-traded company. Yu: BioMarin Pharmaceutical: Current Employment, Current equity holder in publicly-traded company. Wong: BioMarin Pharmaceutical Inc.: Current Employment, Current equity holder in publicly-traded company. Lawal: BioMarin Pharmaceutical Inc.: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Robinson: BioMarin Pharmaceutical Inc.: Current Employment, Current equity holder in publicly-traded company. Kim: BioMarin Pharmaceutical Inc.: Current Employment, Current equity holder in publicly-traded company.

Abstract: Pirfenidone ameliorates cGVHD in murine models with distinct pathophysiology. The efficacy of pirfenidone is associated with inhibition of macrophage infiltration and TGF-β production.

Abstract: Despite the increasing use of cytokines to circumvent the acute dose-limiting myelotoxicity of cancer treatment, little is known about the combined effects of cytotoxic agents and cytokines on the primitive stem cells responsible for long-term hematopoiesis. In an experimental model, we administered cytotoxic agents that have variable effects on primitive stem cells in C57BL/6 (B6)-mice. Mice received six every-other-week doses of cyclophosphamide (CY, 84 mg/kg), VP-16 (24 mg/kg) + cisplatinum (2.4 mg/kg), carboplatinum (50 mg/kg), chlorambucil (12 mg/kg), BCNU (13.2 mg/kg), or TBI (80 cGy). Granulocyte colony-stimulating factor (G-CSF; 250 μg/kg/day) was administered subcutaneously twice daily on days 3 to 6 after each dose of the cytotoxic agent. Comparison with animals receiving the cytotoxic agent alone was made to investigate the effects of G-CSF on long-term hematopoiesis. Hematopoiesis was measured 20 weeks after the last dose of the cytotoxic agent by assessment of peripheral blood counts, marrow cellularity, progenitor cell content (colony-forming units-spleen; CFU-S), and primitive stem cell number (long-term repopulating ability and day 28 and day 35 cobblestone area-forming cell [CAFC] frequencies). Exposure to cytotoxic agents alone resulted in a significant decrease in primitive stem cells (as measured by repopulating units [RU] and day 28 and day 35 CAFC content) in animals given carboplatinum, chlorambucil, BCNU, and TBI, but not in animals treated with cyclophosphamide or VP-16 and cisplatinum. The addition of G-CSF resulted in a significant decrease in stem cell content when compared with no G-CSF administration in animals treated with chlorambucil, BCNU, or TBI. Thus, G-CSF administered after repeated exposure to cytotoxic agents, appeared to damage the primitive stem cell compartment when used in combination with agents known to damage primitive stem cells. These results, although obtained in an experimental model, should raise concerns for the indiscriminate use of G-CSF in the clinic. © 1998 by The American Society of Hematology.

Abstract: Despite the increasing use of cytokines to circumvent the acute dose-limiting myelotoxicity of cancer treatment, little is known about the combined effects of cytotoxic agents and cytokines on the primitive stem cells responsible for long-term hematopoiesis. In an experimental model, we administered cytotoxic agents that have variable effects on primitive stem cells in C57BL/6 (B6)-mice. Mice received six every-other-week doses of cyclophosphamide (CY, 84 mg/kg), VP-16 (24 mg/kg) + cisplatinum (2.4 mg/kg), carboplatinum (50 mg/kg), chlorambucil (12 mg/kg), BCNU (13.2 mg/kg), or TBI (80 cGy). Granulocyte colony-stimulating factor (G-CSF; 250 μg/kg/day) was administered subcutaneously twice daily on days 3 to 6 after each dose of the cytotoxic agent. Comparison with animals receiving the cytotoxic agent alone was made to investigate the effects of G-CSF on long-term hematopoiesis. Hematopoiesis was measured 20 weeks after the last dose of the cytotoxic agent by assessment of peripheral blood counts, marrow cellularity, progenitor cell content (colony-forming units-spleen; CFU-S), and primitive stem cell number (long-term repopulating ability and day 28 and day 35 cobblestone area-forming cell [CAFC] frequencies). Exposure to cytotoxic agents alone resulted in a significant decrease in primitive stem cells (as measured by repopulating units [RU] and day 28 and day 35 CAFC content) in animals given carboplatinum, chlorambucil, BCNU, and TBI, but not in animals treated with cyclophosphamide or VP-16 and cisplatinum. The addition of G-CSF resulted in a significant decrease in stem cell content when compared with no G-CSF administration in animals treated with chlorambucil, BCNU, or TBI. Thus, G-CSF administered after repeated exposure to cytotoxic agents, appeared to damage the primitive stem cell compartment when used in combination with agents known to damage primitive stem cells. These results, although obtained in an experimental model, should raise concerns for the indiscriminate use of G-CSF in the clinic. © 1998 by The American Society of Hematology.