Chronic graft-vs-host disease, an immune-mediated disorder that follows allogeneic hematopoietic cell transplantation (allo-HCT), is characterized by debilitating tissue injury with inflammatory and fibrotic pathology leading to significant morbidity and mortality. Historically, the treatment of chronic graft-vs-host disease involved broad, systemic immunosuppression, mainly with corticosteroids. As our understanding of the immune and cellular processes underlying chronic graft-vs-host disease has improved, more focused therapies have emerged.
Targeting signaling pathway effectors such as JAK1/2, ROCK2, BTK, and SYK have led to U.S. Food and Drug Administration (FDA) approval of three therapies for steroid-refractory chronic graft-vs-host disease, including ibrutinib in 2017 and two agents (ruxolitinib and belumosudil) in 2021. Numerous other agents and combinations of therapies are being investigated, and the field of chronic graft-vs-host disease has been progressing at an unprecedented rate.1
Syed Ali Abutalib, MD
Navneet Majhail, MD, MS, FASTCT
To complement The ASCO Post’s extensive coverage of the 2023 American Society of Hematology (ASH) Annual Meeting & Exposition, here are two important abstracts selected from the meeting proceedings focusing on the treatment of chronic graft-vs-host disease. For full details of the study abstracts, visit www.hematology.org.
Prevention of Chronic Graft-vs-Host Disease
Abstract 653: Maintenance ruxolitinib is associated with low rates of chronic graft-vs-host disease requiring systemic treatment in older adults (aged 60–80 years; n = 63) with acute myeloid leukemia in first complete remission (n = 55) and myelodysplastic syndromes (n = 8) undergoing reduced-intensity conditioning allo-HCT: Results of a phase II multicenter trial (ClinicalTrials.gov identifier NCT03286530).2
Background: Ruxolitinib, an oral selective inhibitor of JAK1/2, is FDA-approved for the treatment of refractory acute and chronic graft-vs-host disease. However, the clinical efficacy of JAK inhibition in preventing severe chronic graft-vs-host disease in older patients is not well characterized.
Methods: In this study, transplants could be performed using human leukocyte antigen (HLA)-matched related donors or 7/8 or 8/8 HLA-matched unrelated donors. Transplants were required to use busulfan- or melphalan-based reduced-intensity conditioning regimens and peripheral blood stem cells as the graft source. Standard graft-vs-host disease prophylaxis consisted of tacrolimus and methotrexate (5–10 mg/m2 on days 1, 3, and 6 ± 11). Ruxolitinib therapy could begin between day 30 and day 100 after meeting pretreatment criteria, which included donor engraftment, ongoing remission confirmed by biopsy, adequate hematopoietic recovery (hemoglobin ≥ 8 g/dL, platelet count ≥ 50,000/μL), and the absence of progressive acute graft-vs-host disease. Ruxolitinib was administered at 10 mg twice a day continuously in 28-day cycles (allowing for dose reductions for drug interactions or cytopenias), for up to 24 cycles.
Results: The primary objective was to evaluate the graft-vs-host disease relapse-free survival at 1 year after allo-HCT. The median follow-up of survivors was 19 months (range = 3–64 months) at last cutoff (February 14, 2023).
Key findings included the following data:
- The 12-month relapse-free survival was 70% (95% confidence interval [CI] = 56%–80%).
- The 6-month cumulative incidence of grade II to IV acute graft-vs-host disease was 14% (95% CI = 7%–24%) and grade III to IV acute graft-vs-host disease was 4.8% (95% CI = 1.3%–12%), with three cases of grade II to IV graft-vs-host disease occurring prior to initiation of ruxolitinib.
- While the 12-month incidence of all cases of chronic graft-vs-host disease was 27% (95% CI = 17%–39%), the 12-month incidence of chronic graft-vs-host disease requiring systemic therapy was 8.4% (95% CI = 3.1%–17%).
- The 18-month cumulative incidence of nonrelapse mortality was 5.6% (95% CI = 1.4%–14%), with one death attributed to graft-vs-host disease and one death due to infection (COVID-19).
- The 18-month cumulative incidence of disease relapse was 27% (95% CI = 16%–39%).
- Despite the anticipated cytopenias with therapy, most of the subjects were able to remain on treatment.
Clinical Implications: Despite recent advances in graft-vs-host disease prophylaxis, novel approaches to the effective prevention of chronic graft-vs-host disease remain of utmost importance. This is particularly true for older transplant recipients, for whom high-dose posttransplant cyclophosphamide therapy or prolonged treatment with corticosteroids may be challenging.
In this phase II trial, prolonged administration of ruxolitinib following allogeneic transplant was associated with low rates of chronic graft-vs-host disease requiring systemic treatment. The incidence of relapse was comparable to historical rates, suggesting no compromise of graft-vs-leukemia effect. The incorporation of JAK inhibition with and without posttransplant cyclophosphamide into graft-vs-host disease prevention approaches is underway.
Treatment
Abstract 1: Safety and efficacy of axatilimab (SNDX- 6352) at three different doses in patients (n = 241) with recurrent or refractory chronic graft-vs-host disease: AGAVE-201, a pivotal phase II, open-label, randomized, multicenter study (NCT04710576).3
Background: Colony-stimulating factor 1 receptor (CSF-1R)–dependent monocytes and macrophages play a key role in chronic graft-vs-host disease inflammation and fibrosis. Axatilimab is an investigational, high-affinity humanized anti–CSF-1R monoclonal antibody that targets monocytes and macrophages. Study investigators previously demonstrated the biological and clinical activity of axatilimab with organ-specific responses and symptom improvement in a phase I/II study in patients with chronic graft-vs-host disease (NCT03604692).
Methods: Eligible patients were randomly assigned 1:1:1 to receive intravenous axatilimab at 0.3 mg/kg every 2 weeks, 1 mg/kg every 2 weeks, or 3 mg/kg every 4 weeks. Randomization was stratified by severity of chronic graft-vs-host disease and prior use of ibrutinib (23%), ruxolitinib (74%), or belumosudil (31%). Concomitant use of corticosteroids, calcineurin inhibitors, sirolimus, or everolimus was allowed. Axatilimab treatment could be continued if there was clinical benefit as assessed by the investigator.
The primary efficacy endpoint was overall response rate in the first six cycles (24 weeks) as defined by the National Institutes of Health 2014 consensus criteria—a document that clarified controversies related to the diagnosis of graft-vs-host disease and the definition of disease subcategories and organ-severity scoring.4 The efficacy boundary of the overall response rate was based on the lower bound of the 95% confidence interval exceeding 30%. Safety endpoints included frequency and severity of treatment-related adverse events and treatment-emergent adverse events.
Results:
Safety: The most frequent grade ≥ 3 treatment-related adverse events included increased blood creatine kinase, periorbital edema, and pneumonia. Drug discontinuation owing to treatment-emergent adverse events occurred in 6% of patients with 0.3 mg/kg every 2 weeks, 22% with 1 mg/kg every 2 weeks, and 18% with 3 mg/kg every 4 weeks. Fatal treatment-emergent adverse events occurred in 1.3%, 8.6%, and 7.6% of patients in the three dose cohorts, respectively. The frequency of all and grade ≥ 3 treatment-related adverse events was dose-dependent, consistent with CSF-1R inhibition–mediated macrophage clearance. Most infections were mild, with three reported cytomegalovirus infections, including reactivations, in the higher-dose cohorts.
Efficacy: The overall response rate was 74% (95% CI = 63%–83%) with 0.3 mg/kg every 2 weeks, 67% (95% CI = 55%–77%) with 1 mg/kg every 2 weeks, and 50% (95% CI = 39%–61%) with 3 mg/kg every 4 weeks. Median duration of response had not been reached in any of the cohorts at the time of data cutoff (April 7, 2023).
Clinical Implications: The AGAVE-201 trial met its primary endpoint for all dose levels studied. Axatilimab treatment of refractory chronic graft-vs-host disease in heavily pretreated patients resulted in robust clinical activity and durable responses in all three dose cohorts, with the highest overall response rate and least toxicity at the 0.3 mg/kg every-2-weeks dose. Adverse events consisted primarily of transient laboratory abnormalities and other on-target effects known to be associated with axatilimab.
DISCLOSURE: Dr. Abutalib has served on an advisory board for AstraZeneca. Dr Majhail has served as a consultant for Anthem, Inc.
REFERENCES
1. Trunk A, Couriel DR: Chronic graft-versus-host disease, in Abutalib SA, Markman M, Armitage JO, et al (eds): Cancer Consult, vol 2, ch 61, pp 793-807. Hoboken, New Jersey; Wiley-Blackwell; 2023.
2. Defilipp Z, Kim H, Knight L, et al: Maintenance ruxolitinib is associated with low rates of chronic GVHD requiring systemic treatment in older adults with AML/MDS undergoing allogeneic HCT. 2023 ASH Annual Meeting & Exhibition. Abstract 653. Presented December 10, 2023.
3. Wolff D, Cutler C, Lee S, et al: Safety and efficacy of axatilimab at 3 different doses in patients with chronic graft-versus-host disease (AGAVE-201). 2023 ASH Annual Meeting & Exhibition. Abstract 1. Presented December 10, 2023.
4. Jagasia MH, Greinix HT, Arora M, et al: National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-vs-Host Disease: I. The 2014 Diagnosis and Staging Working Group Report. Biol Blood Marrow Transplant. 21:389-401, 2015.
Dr. Abutalib is Director of the Malignant Hematology and Transplantation & Cellular Therapy Programs at the Advocate/Aurora St. Luke’s Medical Center, Milwaukee, and Associate Professor at Rosalind Franklin University of Medicine and Science, Chicago. Dr. Majhail is Physician-in-Chief of Blood Cancers at the Sarah Cannon Transplant and Cellular Therapy Network and Medical Director of the Sarah Cannon Transplant and Cellular Therapy Program at TriStar Centennial Medical Center in Nashville.
