Propensity Score Matching Analysis Comparing Extracorporeal Photopheresis (ECP) Vs Best Available Therapy in Third Line or Later Treatment of Chronic Graft-Versus-Host Disease (cGVHD)

*DB and DK contributed to the work equally Background Prospective randomized controlled data comparing extracorporeal photopheresis (ECP) to other treatments for chronic graft vs host disease (cGvHD) as third-line or later therapy are limited, despite its clinical benefit observed in patients (pts) who failed ≥ 2 lines of previous therapy. Our single-center experience has reported promising results, including 68.3% failure-free survival (FFS) and 85.9% overall survival (OS) at 12 months in 75 heavily pre-treated cGvHD pts treated with ECP (ASH 2021 Abstract ID 152640). The present study compared outcomes, using propensity-score matching (PSM), between ECP ("ECP group", n=74) and a historical cohort treated with best available therapy (BAT) as third-line or later treatment from 2007 to 2021 ("BAT group", n=132). Statistical endpoints such as FFS and OS, as well as steroid dose reduction were evaluated instead of overall response due to limited response assessment data available from retrospective chart review. Patients and methods The BAT group received MMF (n=71, 53.8%), prednisone (n=37, 28.0%), prednisone/cyclosporine (n=7, 5.3%), rituximab (n=7, 5.3%), and others (n=10, 7.6%). There was an imbalance in characteristics between the two groups, as expected; the ECP group had more pts with severe cGVHD (91.1% vs 20.5%; p<0.001), fewer with a previous history of acute GVHD (aGvHD: 60.8% vs 78.0%; p=0.008), and fewer on a prednisone dose ≥0.5mg/kg/day (37.8% vs. 90.5%; p<0.001). PSM analysis was applied to adjust risk factors imbalanced between groups, including cGVHD grade (mild/moderate vs severe), aGVHD history, and baseline prednisone dose (<0.5 vs. ≥ 0.5 mg/kg/day). A total of 54 pts (27 case-control pairs) were selected via PSM within 0.2 of a calliper difference, resulting in the balancing of risk factors between groups: cGVHD severity (p=0.941), aGVHD history (p=0.75) and prednisone dose ≥ 0.5 mg/kg/day (p=0.788). FFS and OS were calculated from the day of starting ECP or BAT, and were compared using Cox's hazard model. Daily prednisone dose at months 0, 3 and 6 were calculated divided by body weight (kg), and the proportions of pts on prednisone ≤ 0, 0.1, 0.2 and 0.5mg/kg/day were compared. Results In the overall cohort (n=206), with a median 29 months of follow-up, 114 treatment failures (55.3%) occurred. While the non-relapse mortality (NRM) was similar in both groups, the ECP group showed a lower rate of resistance requiring therapy switch. Failure was noted in 27 ECP pts (36.4%) due to causes including resistance/intolerance requiring a switch to other therapy (n=15; 20.3%), NRM (n=11, 14.8%), and relapse (n=1; 1.4%), while 87 failures (65.9%) were noted in BAT pts due to resistance requiring a switch to other therapy (n=63; 47.7%), NRM (n=7; 5.3%), and relapse (n=17; 12.9%). In the overall cohort, the 12-month FFS was 68.3% and 32.0% in ECP and BAT groups (p<0.0001; Fig 1A), while OS was 86.2% and 82.2% in ECP and BAT groups, respectively (p=0.333; Fig 1B). In the PSM cohort (n=54), the ECP group showed a survival benefit at 12 months: FFS was 65.8% in the ECP group vs. 30.5% in the BAT group (p=0.00226; Fig 2A), and OS was 76.6% in the ECP group vs. 67.1% in the BAT group (p=0.0977; Fig 2B). Multivariate analysis in the PSM cohort confirmed that ECP was superior to BAT for FFS (p=0.024, HR 0.317 [0.117-0.859]) when adjusted for other risk factors including cGVHD severity, aGvHD history, age, HCT-CI score and prednisone dose ≤0.5mg/kg/day. Prednisone doses were gradually reduced over time; the median doses of prednisone at months 0, 3, and 6 were 0.35, 0.22 and 0.11 mg/kg/day, respectively, in the ECP group vs. 0.96, 0.24 and 0.19mg/kg/day in the BAT group. ECP also showed better kinetics of steroid dose reduction over time; the proportions of pts who discontinued prednisone at months 0, 3 and 6 were 16.2, 17.6% and 32.4% in ECP group vs. 0.8%, 0% and 2.5% in BAT group (Fig 3). The differences in the proportion of pts (delta) who discontinued prednisone in the ECP vs. BAT groups were 15.4%, 17.6% and 29.9% at 0, 3, and 6 months, respectively. Conclusion In the current study using PSM analysis, use of ECP was associated with a superior FFS to BAT when used as third-line or later therapy in cGVHD patients who failed at least 2 lines of previous therapy. Use of ECP also allowed for better steroid tapering in comparison to BAT. Figure 1 Figure 1. Disclosures Patriquin: Alexion: Consultancy, Honoraria, Speakers Bureau; BioCryst Pharmaceuticals: Honoraria; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Apellis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria. Law: Novartis: Consultancy; Actinium Pharmaceuticals: Research Funding. Lipton: Bristol Myers Squibb, Ariad, Pfizer, Novartis: Consultancy, Research Funding. Mattsson: MattssonAB medical: Current Employment, Current holder of individual stocks in a privately-held company. Kim: Novartis: Consultancy, Honoraria, Research Funding; Paladin: Consultancy, Honoraria, Research Funding; Bristol-Meier Squibb: Research Funding; Pfizer: Honoraria.

Extracorporeal Photopheresis Induces Netosis in Neutrophils Derived from Patients with Graft-Versus-Host Disease

Introduction Extracorporeal photopheresis (ECP) serves as a second line treatment for patients with acute or chronic graft versus host disease (GVHD) and demonstrates efficacy in ameliorating GVHD in this setting. The mechanism by which ECP acts against GVHD has not been fully elucidated yet. Preliminary data point to an association between GVHD and increased neutrophil extracellular trap (NET) formation (NETosis) although much is unknown regarding the pathologic implication of this association. In this study we performed a preliminary assessment of the influence of ECP on NETosis among patients with GVHD. Methods Six patients after allogeneic transplantation treated with ECP for severe GVHD post allogeneic transplant at the Rabin Medical Center in Israel were enrolled to the study. Blood samples were obtained at 3 different time points: before an ECP cycle, immediately after the end of the ECP and 24h after the initiation of the ECP cycle. Neutrophils were obtained from whole blood samples using a percoll gradient. NETosis was assessed by measurement of neutrophil elastase activity using a commercial NETosis assay kit by Cayman Chemical and by immunofluorescence staining for DNA (DAPI (4',6-diamidino-2-phenylindole)) and for citrullinated H3 (H3Cit), a marker of NET formation. All assessments were executed in unstimulated neutrophils and in neutrophils that were stimulated with phorbol myristate acetate (PMA)(100nmol) for 4 hours. Results Six patients (4 males) with chronic GVHD were included in the study. The underlying hematologic disease was acute myeloid leukemia (AML) in four patients, B-cell acute lymphocytic leukemia (B-ALL) and myelodysplastic syndrome (MDS) each in one patient. ECP was executed for moderate to severe GVHD. We observed a sharp increase in the formation of NETs following treatment with ECP among all study participants. The level of neutrophil elastase activity was significantly elevated from a mean value of 2.21mU/mL (±0.6mU/mL) at baseline to a mean value of 13.82mU/mL (±5.54mU/mL) immediately after the treatment (p-value=0.0022). The mean level of neutrophil elastase activity was significantly elevated to a mean peak value of 17.35mU/mL (±10.74mU/mL) 24h following the initiation of the ECP cycle (p-value 0.0063 for the difference between the first and the last time points). Pre-incubation of the neutrophils with PMA yielded similar results, as the mean neutrophil elastase activity was 6.05mU/mL (±3.63mU/mL), 20.16mU/mL (±6.72mU/mL), and 24.57mU/mL (±13.59mU/mL) before the ECP cycle initiation, immediately after treatment, and 24h following ECP onset, respectively (Figure 1). In agreement, the expression of H3cit was also increased in neutrophils derived from patients with GVHD after ECP treatment (Figure 2). Conclusion Our preliminary data indicate that ECP induces NET formation among patients with GVHD. NETosis might play a role in the therapeutic effects of ECP in this setting. These initial results might set the stage for future studies in this field. Figure 1 Figure 1. Disclosures Goldberg: MSD Israel: Consultancy. Yeshurun: Astellas: Consultancy; Janssen: Consultancy. Wolach: Janssen: Consultancy; Abbvie: Consultancy, Honoraria, Research Funding; Astellas: Consultancy; Amgen: Research Funding; Novartis: Consultancy; Neopharm: Consultancy.

Budget Impact Analysis of Belumosudil for Chronic Graft-Versus-Host Disease Treatment in the United States

Introduction: Chronic graft-versus-host disease (cGVHD) is a common complication post allogeneic hematopoietic cell transplant. The goal of cGVHD treatment is symptom relief and long-term control of disease progression, with minimal toxicity/adverse events. Available treatments, including corticosteroids, mTOR inhibitors, calcineurin inhibitors, extracorporeal photopheresis, mycophenolate mofetil, ibrutinib, and ruxolitinib, are associated with adverse events (AEs) that may limit compliance or lead to treatment discontinuation. Belumosudil is a selective Rho-associated coiled-coil kinase 2 (ROCK2) inhibitor that is approved for the treatment of cGVHD for adult and pediatric patients 12 years and older after failure of at least two prior lines of systemic therapy (i.e., 3L/4L+). Belumosudil has been well tolerated in clinical trials, with a low incidence of grade ≥3 AEs, including cytopenias and infections, which may lead to increased compliance to treatment and lower overall costs. The present analysis estimated the budget impact of increasing utilization of belumosudil in 3L/4L+ cGVHD in three scenarios using a United States (US) payer perspective. Methods: A 5-year budget impact model was developed to estimate annual healthcare resources utilization (HCRU) and budget impact for a 10 million member US payer plan. Epidemiology, market share, treatment cost, adverse events, and HCRU inputs were incorporated in the model in a user-modifiable manner. US cGVHD prevalence rates were incorporated based on literature and secondary sources (Bachier et al. 2021). In addition to belumosudil, treatments that can potentially be accounted for in the model include corticosteroids, calcineurin inhibitors, mTOR inhibitors, mycophenolate mofetil, extracorporeal photopheresis, ibrutinib, and ruxolitinib (off-label), with proportions based on current and projected market share. Belumosudil use was modeled in three different scenarios based on projections of branded agent shares (i.e., source of share from ibrutinib only, ruxolitinib only, or both ibrutinib and ruxolitinib in a market with branded agents only). Grade 3/4 adverse events and their rates in cGVHD were sourced from prescribing information, clinical trials, or published literature and were monetized using Medicare Diagnosis Related Groups costs, with conversion to commercial plan costs utilizing ratios from the Congressional Budget Office. Drug costs were sourced from Redbook. HCRU and costs per visit were derived from a prior cGVHD claims analysis. The overall percentage reduction and per member per month (PMPM) savings were calculated. Results: When belumosudil share is taken only from ibrutinib, by 2026, the model estimates a 0.9% reduction in the plan's budget and a PMPM savings of $0.01 versus a market without belumosudil. Percentage cost offsets due to reductions in AE and HCRU costs with belumosudil adoption were 34.3% and 13.5%, respectively. In a scenario where belumosudil share is taken only from ruxolitinib, an estimated reduction in budget of 1.9% and a savings of $0.01 PMPM would be observed by 2026, largely due to cost reductions of 76.2% and 27.9% in AEs and HCRU, respectively. If belumosudil share is derived from both ibrutinib and ruxolitinib similar results were observed, with a 1.9% reduction in budget and $0.01 in PMPM savings by 2026. AE and HCRU cost reductions versus a scenario without belumosudil were 71.2% and 27.7%, respectively. Conclusions: The introduction of belumosudil as a therapy for 3L/4L+ cGVHD patients resulted in a budget reduction in this model for US health plans. In each of the three scenarios examined, focusing on patients receiving existing branded agents in 3L/4L+ cGHVD, belumosudil demonstrated 0.9-1.9% in overall and $0.01 in PMPM savings, likely driven by the favorable safety profile of belumosudil reducing AEs and HCRU. The model indicates that belumosudil may provide an alternative to existing cGVHD treatments while also offering cost savings to a US health plan. Patients who enter 3L/4L+ cGVHD treatment may benefit from recently approved therapies for cGVHD like belumosudil that offer a well tolerated treatment option for patients who are cycling through cGVHD therapies. Figure 1 Figure 1. Disclosures Bachier: BMS: Membership on an entity's Board of Directors or advisory committees; CRISPR: Membership on an entity's Board of Directors or advisory committees; Autolus: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Mana: Membership on an entity's Board of Directors or advisory committees; Nkarta: Membership on an entity's Board of Directors or advisory committees. Skaar: Trinity Life Sciences: Current Employment; Kadmon Corporation: Consultancy. Dehipawala: Trinity Life Sciences: Current Employment; Kadmon Corporation: Consultancy. Miao: Trinity Life Sciences: Current Employment; Kadmon Corporation: Consultancy. Ieyoub: Kadmon Corporation: Current Employment. Taitel: Kadmon Corporation: Current Employment.

Response to Extracorporeal Photopheresis in Patients with Cutaneous T-Cell Lymphoma: A Retrospective Medical Chart Review

INTRODUCTION Extracorporeal photopheresis (ECP) is an immunomodulatory therapy that has been used in the treatment of cutaneous T-cell lymphoma (CTCL) for over 30 years. Clinical trials of newer agents for the treatment of CTCL have shown response rates of approximately 30% in heterogeneous patient populations. The objective of this study was to assess the effectiveness of ECP in the treatment of CTCL patients in real-world clinical practice. METHODS This is an interim analysis of a retrospective medical chart review study conducted at clinical sites in the United States, in which treating physicians were responsible for patient selection and data collection via structured case report forms. Patients with a confirmed diagnosis of CTCL who initiated ECP between January 1, 2017 and February 28, 2019 were included in the study. In addition, patients must have initiated ECP at age ≥18 years with no ECP treatment received within the year prior to data collection, have received at least 3 months of ECP treatment, and have response data available in the patient chart. Data collected included patient demographics, clinical characteristics, and treatments received prior to and concomitantly with ECP. Clinical outcomes were collected every 3 months during treatment for up to 18 months, and included the body surface area (BSA) affected, appearance of new skin lesions, and the physician-rated Clinical Global Impression-Improvement (CGI-I) scores. Response to ECP was defined as >50% reduction in BSA affected at any point during the follow-up period, consisting of the time from ECP initiation through the time of data collection. Data analysis was descriptive in nature. RESULTS Four clinical sites participated in the study and enrolled a total of 26 patients for the interim analysis. Patients were predominantly female (53.8%) and White (88.5%). Mean age at CTCL diagnosis was 68.4 years, and the majority patients were diagnosed with Sézary syndrome (57.5%) or mycosis fungoides (30.8%). Nearly half of patients (46.1%) had stage IV disease at diagnosis (IVA, 26.9%; IVB, 19.2%) and half of patients (50.0%) had lymph node involvement at diagnosis. Median BSA involvement with plaques/patches at diagnosis was 80% (interquartile range [IQR], 20% to 90%). Six patients (23.1%) achieved >50% reduction in BSA affected, and among those, median time to response was 6.0 months (IQR, 2.9 to 15.0 months). New skin lesions appeared in 5 patients (19.2%). Among those with available data, the percentage of patients rated as minimally improved, much improved, or very much improved on the CGI-I was 57.7% at 3 months (N=26), 50.0% at 6 months (N=18), and 60.0% at 9 months (N=15) after ECP initiation. CONCLUSIONS This retrospective observational study describes patient characteristics and clinical outcomes among CTCL-diagnosed patients initiating therapy with ECP. Despite the population treated with ECP in real-world practice being older and having more advanced-stage disease compared to recent clinical trials, response rate was comparable. Disclosures Girardi: Transimmune: Patents & Royalties: Inventor/IP; Helsinn: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Research Funding; Soligenix: Research Funding; Mallinckrodt Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Stradefy Biosciences Inc: Patents & Royalties: Inventor/IP; Actelion: Membership on an entity's Board of Directors or advisory committees, Research Funding. Huang: Mallinckrodt Pharmaceuticals: Current Employment. Corman: Mallinckrodt Pharmaceuticals: Consultancy. Edmundson: Mallinckrodt Pharmaceuticals: Consultancy. Kale: Mallinckrodt Pharmaceuticals: Consultancy. Rusibamayila: Mallinckrodt Pharmaceuticals: Consultancy. Foss: Kura: Honoraria; Daiichi Sankyo: Honoraria; Seattle Genetics: Honoraria, Speakers Bureau; Acrotech: Honoraria, Speakers Bureau; Mallinckrodt: Honoraria; Kyowa: Honoraria.

Single Centre, Retrospective Analysis of Extracorporeal Photopheresis (ECP) Therapy in the Patients Who Are Heavily Pre-Treated for Steroid Resistant Chronic Graft-Versus-Host Disease (GVHD)

*DB and DK contributed to the work equally. Background Extracorporeal photopheresis (ECP) is a recommended second or later line of therapy for chronic GVHD (cGVHD), and is beneficial not only because of increased response but also for its lack of adverse effects, specifically systemic immune suppression, mainly from steroids. In this single centre study, we attempted to evaluate not only therapeutic efficacy of ECP, but also its steroid-sparing effect by regularly analyzing steroid dose per body weight. We also attempted to identify any predictors of response or survival after ECP, which was not well defined before. Patients and methods A total of 75 cGVHD patients (pts) who received ECP for cGVHD from 2007 to 2021 at Princess Margaret Cancer Centre were included and evaluated retrospectively. Patients and disease characteristics are as follows: median age 48.5 years (range 17-70); male 42/75 (56%); organ involvement at the time of ECP: skin (93%), oral (53%), eye (51%), gastrointestinal (25%), liver (49%), lung (57%), and musculoskeletal (n=50, 67%). Sixty-eight (91%) and 7 pts (9%) had severe and moderate grade cGVHD, respectively. Sixty-eight pts (91%) received ECP as 4 th line or beyond. They were heavily pretreated with prednisone (98%), cyclosporine (57%), tacrolimus (24%), mycophenolate mofetil (64%), azathioprine (65%), rituximab (7%), imatinib (8%), ibrunitib (3%) and ruxolitinib (1%). ECP was started twice weekly for the first 12 weeks, then twice every 2 weeks in 2012-2021, while the schedule was twice every 2 weeks from 2007-2012. If there was no response or clinical benefit noted in first 24 treatments, then ECP was discontinued. In general, we attempted to provide up to around 60 sessions based on the clinicians' discretion. The overall response rate (ORR) and clinical benefit (CB) were assessed at months 3, 6 and 12 after staring ECP. As part of standard clinical practice, NIH consensus criteria were used for grading and response assessment. CB was assessed considering clinical response as well as steroid dose reduction. Treatment failure was defined as 1) resistance to ECP requiring treatment switch, 2) non-relapse mortality (NRM), 3) relapse, 4) intolerance to ECP. Failure free survival (FFS) and overall survival (OS)were calculated from the day of ECP initiation until the endpoints of failure or death, respectively. Results ECP was started a median of 28 months (range 1-125) after development of cGVHD. ECP was performed a median of 35 times (range 6-174) with a median duration of 11 months (range 1-53). Out of 75 pts, 48 completed planned ECP successfully and 27 stopped due to no response or benefit including, of whom 14 required additional therapy, 1 stopped due to line infection, and 1 stopped due to relapse of AML. With a median 72 months of follow-up, ORR was attained in 21% (16/75), 57% (36/63) and 70% (32/46) at month 3, 6 and 12, respectively. At 6 months, ORR was observed in 47-64% across all organs assessed. No difference in ORR was noted according to the cGVHD grade; at 6 months, severe cGVHD showed similar ORR (57%) to those with moderate cGVHD (60%) (p=0.893). CB was noted in 23% (17/75), 62% (39/63), and 76% (35/46) at month 3, 6 and 12, respectively. A total of 27/75 failures (36%) and 20/75 death (27%) occurred, due to the following: ECP resistance requiring switch to other therapy (n=14, 19%), NRM (n=11, 15%), relapse of primary disease (n=1, 1%) or ECP-related complication (n=1, 1%, line infection). In the overall cohort, FFS and OS at 12 months were 68.3% and 85.9%, respectively (Figure 1). More than a half of pts stopped steroids completely within 12 months after starting ECP. The proportion of pts off steroids was 16%, 17%, 32%, and 64% at month 0, 3, 6 and 12 after starting ECP, respectively (Figure 2). Risk factor analysis did not show any predictive markers for ORR at 6 months, while prognostic factor analysis suggested the development of musculoskeletal involvement as favorable prognostic factor for FFS (p=0.003, HR 0.315 [0.147, 0.673]) even with multivariate analysis. Conclusion Our study showed that: 1) ECP is a very effective treatment for heavily pre-treated cGVHD pts who have failed other therapies; 2) More than a half of pts can stop steroids completely within 12 months after starting ECP, thus avoiding long-term toxicity risk. Further study is warranted comparing ECP with other cGVHD treatment modalities. Figure 1 Figure 1. Disclosures Patriquin: BioCryst Pharmaceuticals: Honoraria; Alexion: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Apellis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria. Law: Novartis: Consultancy; Actinium Pharmaceuticals: Research Funding. Lipton: Bristol Myers Squibb, Ariad, Pfizer, Novartis: Consultancy, Research Funding. Mattsson: MattssonAB medical: Current Employment, Current holder of individual stocks in a privately-held company. Kim: Paladin: Consultancy, Honoraria, Research Funding; Bristol-Meier Squibb: Research Funding; Pfizer: Honoraria; Novartis: Consultancy, Honoraria, Research Funding.