Secondary Graft-Versus-Host Disease (GVHD) Prophylaxis with Oral Proteasome Inhibitor Ixazomib Is Associated with Low Incidence of Recurrent, Late Acute and Chronic GVHD and Facilitated Calcineurin Inhibitor Taper within the First Year Post Allogeneic Stem Cell Transplantation

Media type: E-Article

Title: Secondary Graft-Versus-Host Disease (GVHD) Prophylaxis with Oral Proteasome Inhibitor Ixazomib Is Associated with Low Incidence of Recurrent, Late Acute and Chronic GVHD and Facilitated Calcineurin Inhibitor Taper within the First Year Post Allogeneic Stem Cell Transplantation

Contributor: Rodriguez, Natasia; Lee, Jasme; Flynn, Lisa; Murray, Fiona; Devlin, Sean; Soto Izquierdo, Cristina; Cho, Christina; Dahi, Parastoo B.; Giralt, Sergio A.; Sauter, Craig S.; Perales, Miguel-Angel; Ponce, Doris M

imprint: American Society of Hematology, 2020

Language: English

DOI: 10.1182/blood-2020-139666

ISSN: 0006-4971; 1528-0020

Keywords: Cell Biology ; Hematology ; Immunology ; Biochemistry

Origination:

Footnote:

Description: Background. GVHD is a frequent complication within the 1st year after allogeneic stem cell transplantation (allo-HCT). Recipients of reduced intensity (RI) and non-myeloablative (NMA) conditioning combined with calcineurin inhibitor (CNI)-based GVHD prophylaxis, frequently develop GVHD in the context of immunosuppression taper. Ixazomib is an oral proteasome inhibitor (PI) that has demonstrated immunomodulatory properties, inhibition of pro-inflammatory cytokines, anti-tumor activity, and has a wide safety profile. We hypothesized that secondary GVHD prophylaxis using ixazomib, will facilitate CNI taper without increase in GVHD frequency and severity, maintaining graft-versus-tumor (GVT) effect, and a safety profile. Methods. We conducted an open label, prospective, single-center pilot study between 11/16 and 03/19. Eligible patients were &gt; 18 yrs old, had a hematologic malignancy treated with RI or NMA conditioning allo-HCT, received CNI-based GVHD prophylaxis, and were within day 100 to 150 post-HCT. Patients with active acute and/or chronic GVHD were excluded. Patients were treated with ixazomib 4 mg orally once weekly, each cycle consisting of 3 weeks on and 1 week off therapy, until completion of taper from prophylactic CNI or 1-year post-HCT was reached, whichever occurred first. Patients who developed grade II-IV acute GVHD, chronic GVHD, or died of transplant-related mortality (TRM) were deemed treatment failure. The primary endpoint was the efficacy of ixazomib for the prevention of recurrent or late grade II-IV acute GVHD or chronic GVHD at 1-year post-HCT. Additional endpoints included TRM, relapse rate, survival analysis, safety evaluation, and immune reconstitution. Results. A total of 18 patients (median age of 58 yrs) were accrued in the study. The majority were male, had a diagnosis of NHL, and received RI conditioning (Table 1). All patients had a PBSC graft, and 16 (89%) were 10/10 HLA-matched. The median time for initiation of ixazomib was 141.5 days post-HCT. Fourteen patients had no GVHD during the study period. The 4 patients who developed GVHD had severe overlap syndrome (n = 2), mild de novo chronic GVHD (n = 1), and recurrent grade II acute GVHD (n = 1). Notably, patients with severe overlap syndrome had limited chronic GVHD involvement affecting the mouth and/or eyes, and the severity score was driven by acute manifestations affecting the skin and GI tract. Six patients successfully discontinued CNI and 4 patients were tapering immunosuppression close to the end of study at 1-year post-HCT. The cumulative incidence (CI) of grade II-IV acute and chronic GVHD at 1-year post-HCT was 25% (95%CI: 7.2-48.1) (Fig. 1A). No patients died during the study and therefore, the CI of TRM at 1-year was 0%, and only 1 patient had malignant relapse (NHL). The CI of PFS and the composite endpoint GVHD-free/relapse-free survival (GRFS) at 1-year were 83% (95%CI: 58-100) and 73% (95%CI: 49-100, Fig 1B), respectively. All patients experienced at least 1 TEAE of any grade. Most AEs were grade 1 or 2, with the most common being cytopenia and elevation in ALT/AST. Drug-related SAEs were reported in 9 patients and included neutrophil and decreased WBC. Seven patients required ixazomib dose reduction due to side effects, and 5 patients were removed from the study due to toxicity (1 neutropenia, 3 GI, 1 skin rash). Of those, 1 had subsequent GVHD by day 365 post-HCT. Immune recovery at 3, 6 and 12 months post-HCT was evaluated. There was a rapid and sustained recovery in T-cell subpopulations and B cell reconstitution Fig 2. Conclusions. Secondary GVHD prophylaxis with ixazomib was associated with low incidence of recurrent and late acute and chronic GVHD within the 1st year post-HCT. This approach allowed CNI taper while preserving GVT effect without aggravating GVHD. No deaths occurred during the study period and the 1-year GRFS was high. Ixazomib was overall well tolerated and favored immune reconstitution post-HCT. Our findings support further development of this approach and provide a proof-of-concept for secondary GVHD prophylaxis. Disclosures Dahi: Kite: Consultancy. Giralt:TAKEDA: Research Funding; JAZZ: Consultancy, Honoraria; CELGENE: Consultancy, Honoraria, Research Funding; AMGEN: Consultancy, Research Funding; MILTENYI: Consultancy, Research Funding; KITE: Consultancy; NOVARTIS: Consultancy, Honoraria, Research Funding; OMEROS: Consultancy, Honoraria; ACTINUUM: Consultancy, Research Funding. Sauter:Bristol-Myers Squibb: Research Funding; GSK: Consultancy; Gamida Cell: Consultancy; Celgene: Consultancy, Research Funding; Kite - a Gilead Company: Consultancy; Precision Biosciences: Consultancy, Research Funding; Genmab: Consultancy; Novartis: Consultancy; Spectrum Pharamaceuticals: Consultancy; Sanofi-Genzyme: Consultancy, Research Funding; Juno Therapeutics: Consultancy, Research Funding. Perales:Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Medigene: Membership on an entity's Board of Directors or advisory committees, Other; NexImmune: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Other; Cidara Therapeutics: Other; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; Miltenyi Biotec: Research Funding; Kite/Gilead: Honoraria, Research Funding; Incyte Corporation: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ponce:Ceramedix: Membership on an entity's Board of Directors or advisory committees; Generon: Membership on an entity's Board of Directors or advisory committees; Kadmon: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding.

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