Factors Associated With Successful Discontinuation of Immune Suppression After Allogeneic Hematopoietic Cell Transplantation

Abstract

IMPORTANCE Immune suppression discontinuation is routinely attempted after allogeneic hematopoietic cell transplantation (HCT) and under current practices may lead to graft-vs-host disease (GVHD)-associated morbidity and death. However, the likelihood and predictive factors associated with successful immune suppression discontinuation after HCT are poorly understood.OBJECTIVES To examine factors associated with successful immune suppression discontinuation and risk for immune suppression discontinuation failure under conventional HCT approaches and develop a practical tool to estimate successful immune suppression discontinuation likelihood at the clinical point of care. DESIGN, SETTING, AND PARTICIPANTS Using long-term follow-up data from 2 national Blood and Marrow Transplant Clinical Trial Network studies (N = 827), a multistate model was developed to investigate the probability and variables associated with immune suppression discontinuation success. The study began in July 2015, and analyses were completed in August 2019. MAIN OUTCOMES AND MEASURES Immune suppression discontinuation and immune suppression discontinuation failure. RESULTSOf the 827 patients included in the analysis, 456 were men (55.1%). Median age at transplant was 44 (range, <1-67) years. With median follow-up of 72 (range, 11-124) months, 20.0% of the patients were alive and not receiving immune suppression at 5 years. Older recipient age (adjusted odds ratio [aOR] of >50 vs <30 years, 0.27, 99% CI, 0.14-0.50; P < .001), mismatched unrelated donor (aOR, mismatched unrelated vs matched related, 0.37; 99% CI, 0.14-0.97; P = .008), peripheral blood graft (aOR of peripheral blood graft vs bone marrow, 0.46; 99% CI, 0.26-0.82; P < .001), and advanced stage disease (aOR of advanced vs early disease, 0.45; 99% CI, 0.23-0.86, P = 0.002), were significantly associated with decreased odds of immune suppression discontinuation. Failed attempts at immune suppression discontinuation (127 patients [37.1% of total immune suppression discontinuation events]) resulting in GVHD were significantly associated with use of peripheral blood stem cells (HR, 2.62; 99% CI, 1.30-5.29; P < .001), prior GVHD, and earlier immune suppression discontinuation attempts. Earlier immune suppression discontinuation was not associated with protection from cancer relapse after HCT (adjusted hazard ratio for discontinuation vs not, 1.95; 99% CI, 0.88-4.31; P = .03). Dynamic prediction models were developed to provide future immune suppression discontinuation probability according to individual patient characteristics.CONCLUSIONS AND RELEVANCE Successful immune suppression discontinuation is uncommon in the setting of peripheral blood stem cell grafts. The data suggest earlier attempts at ISD conferred no long-term benefit, given frequent ISD failure, limited subsequent success after initial failed ISD attempt, and no evidence of relapse reduction. Using a risk model-based clinical application, physicians may be able to identify individual patients' probability of successful immu...

Initial therapy for chronic graft-versus-host disease: analysis of practice variation and failure-free survival

“…Chronic graft vs. host disease (GVHD) is a common complication of allogeneic hematopoietic cell transplantation (HCT), 1 and is associated with increased risk of death, morbidity, impaired quality of life, and prolonged immune suppressive (IS) therapy. [2][3][4][5][6][7] Based on evidence arising from prior clinical trials as well as practice recommendations, initial therapy for chronic GVHD remains prednisone (generally starting at 1mg/kg/day) with or without a calcineurin inhibitor. Previous work has demonstrated that this approach fails to provide durable control of chronic GVHD, as failure-free survival (a composite failure endpoint including death, malignancy relapse, or additional systemic IS therapy) following initial steroid therapy is 68% by 6 months, and 54% by 12 months.…”

Post-Transplant Cyclophosphamide and Tacrolimus—Mycophenolate Mofetil Combination Governs GVHD and Immunosuppression Need, Reducing Late Toxicities in Allogeneic Peripheral Blood Hematopoietic Cell Transplantation from HLA-Matched Donors

“…In traditional calcineurin-based regimens, it is uncommon to discontinue IS (20%) and relatively common for other IS forms (including steroids) to be used for long periods after transplantation. Additionally, in newer strategies, the burden of IS persists— albeit significantly less pronounced [ 25 , 33 , 46 , 47 ]. After PTCy-BMT, the cumulative incidence of steroid use at three years ranges between 46& and 68%; the probability of being alive and free from IS ranges between 48–56%, with 10–20% of patients conditioned with busulfan/fludarabine still on IS at 3 years [ 33 ].…”

Evolving Therapeutic Options for Chronic Graft‐versus‐Host Disease

“…Another analysis examined successful discontinuation of IST and incidence of GVHD recurrence in 827 patients enrolled in two phase III clinical trials using CNI-based GVHD prophylaxis. 124 Only 20% of patients were alive and off IST completely at 5 years. A total of 41.4% of patients were able to discontinue IST initially; however, 37.1% had discontinuation failure and had to restart IST for GVHD.…”