Treatment Change as a Predictor of Outcome among Patients with Classic Chronic Graft-versus-Host Disease

Flowers, Mary E.D.; Storer, Barry E.; Carpenter, Paul A.; Rezvani, Andrew R.; Vigorito, Afonso Celso; Campregher, Paulo Vidal; Moravec, Carina; Kiem, Hans Peter; Fero, Matthew L.; Georges, George E.; Warren, Edus H.; Lee, Stephanie J.; Sanders, Jean E.; Appelbaum, F; Martin, Paul J.

doi:10.1016/j.bbmt.2008.09.017

Cited by 52 publications

(33 citation statements)

References 13 publications

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“…9,10 We also demonstrated that addition of a new treatment was associated with higher non-relapse and overall mortality, which is in agreement with previous studies. 15,16 Inamoto et al published two analyses of FFS in patients who received first-line 9 or second-line 10 therapy for chronic GVHD at a single institution. The median duration of FFS and the rates of FFS at 6 months and 2 years in the current study are similar to their results 9,10 despite the differences in cohort definition.…”

Section: Discussionmentioning

confidence: 99%

Failure-free survival in a prospective cohort of patients with chronic graft-versus-host disease

et al. 2015

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Failure-free survival, defined as the absence of relapse, non-relapse mortality or addition of another systemic therapy, has been proposed as a potential endpoint for clinical trials, but its use has only been reported for single-center studies. We measured failure-free survival in a prospective observational cohort of patients (n=575) with both newly diagnosed and existing chronic graft-versus-host disease from nine centers. Failure was observed in 389 (68%) patients during the observation period. The median follow up of all patients was 30.9 months, and the median failure-free survival was 9.8 months (63% at 6 months, 45% at 1 year, and 29% at 2 years). Of the variables measured at enrollment, ten were associated with shorter failure-free survival: higher National Institutes of Health 0-3 skin score, higher National Institutes of Health 0-3 gastrointestinal score, worse range of motion summary score, lower forced vital capacity (%), bronchiolitis obliterans syndrome, worse quality of life, moderate to severe hepatic dysfunction, absence of treatment for gastric acid, female donor for male recipient, and prior grade II-IV acute graft-versus-host disease. Addition of a new systemic treatment, the major cause of failure, was associated with an increased risk of subsequent non-relapse mortality (hazard ratio=2.06, 95% confidence interval: 1.29-3.32; P<0.003) and decreased survival (hazard ratio=1.51, 95% confidence interval: 1.04-2.18; P<0.03). These results show that fewer than half of patients on systemic treatment will be failure-free survivors at 1 year, and fewer than a third will reach 2 years without experiencing failure. Better treatments are needed for chronic graftversus-host disease. Clinicaltrials.gov identifier: NCT00637689. Failure-free survival in a prospective cohort of patients with chronic graft-versus-host disease ABSTRACT Statistical analysisFailure-free survival was estimated from the time of study enrollment. Cumulative incidence estimates of relapse, nonrelapse mortality and addition of a new therapy as causes of failure were derived, treating each event as a competing risk for the other two.14

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Section: Discussionmentioning

confidence: 99%

Failure-free survival in a prospective cohort of patients with chronic graft-versus-host disease

et al. 2015

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“…59 Thalidomide has diverse immune-modulating effects including: (1) reduced levels of TNF-a; (2) co-stimulation of T cells to produce IL-2 and IFN-g; (3) inhibition of other cytokines like IL-1b, IL-6, IL-12; (4) downregulation of cell surface adhesion molecules involved in leukocyte migration; and (5) anti-angiogenesis. 48,57,60 Its biological activities are contrasted with other IMiDs in Figure 1. There are seven phase-2 and three phase-3 trials of thalidomide in cGVHD.…”

Section: Imid-class Drugsmentioning

confidence: 99%

Chronic GVHD: Where are we? Where do we want to be? Will immunomodulatory drugs help?

Linhares

Pavletić

Gale

2012

Bone Marrow Transplant

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Chronic GVHD (cGVHD) is an important problem after allotransplants. Some risk factors for cGVHD are similar to those of acute GVHD (aGVHD) but others are distinct indicating sometimes overlapping but unique pathogeneses. Precise incidence and prevalence data of cGVHD are lacking because of diverse diagnostic criteria but a 50% risk is a reasonable estimate. Incidence and prevalence of cGVHD are probably growing because of increased use of unrelated donors, blood rather than bone marrow (BM) grafts, decreased early transplant-related mortality (TRM) and increasing frequency of allotransplants. Pathophysiology of cGVHD is complex and poorly understood. Notably, no reliable surrogate end point to predict mechanism(s) of cGVHD has been identified. Therapy of cGVHD is unsatisfactory. Corticosteroids are effective but other drugs are controversial and few are rigorously tested in randomized trials. Highly variable response rates are reported because of small sample sizes and inconsistencies in eligibility, diagnostic and response criteria. We focus on the possible role of immunomodulatory drugs (IMiDs), thalidomide lenalidomide and pomalidomide, in preventing and treating cGVHD. The data suggest activity of thalidomide but at doses not clinically practical in many instances. There are few data with lenalidomide. Trials of pomalidomide, which has immune activities like thalidomide but with fewer adverse effects, are beginning. Because cGVHD is not recently reviewed in Bone Marrow Transplantation, we give a brief background and discuss challenges in diagnosing, understanding and treating cGVHD including the recently proposed National Institutes of Health consensus criteria for cGVHD. 1-3 It occurs in about 50% of persons surviving 41 year post transplant and causes substantial morbidity and mortality. There has been little progress over the past 30 years in preventing and/or treating cGVHD. Moreover, incidence and prevalence are increasing because of several factors including: (1) increased use of blood cell rather than BM grafts; (2) increasing use of incompletely HLA-matched related and unrelated donors; (3) increased use of donor-lymphocyte infusions, especially in the context of reduced-intensity allotransplants; (4) increased number of transplants done each year; and (5) increased proportion of transplants in older persons. [4][5][6] The focus of our review is on the use and potential of IMiD-class drugs to prevent and/or treat cGVHD. These drugs have unique, complex immune regulatory activities. As a prelude, we review some relevant definitional, laboratory and clinical features of cGVHD.

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“…An effort to decrease corticosteroid doses has led to their use in combination with other immunosuppressants, such as cyclosporine, tacrolimus, and sirolimus, in frontline or second-line settings, despite a lack of clinical evidence supporting additional efficacy after combining these agents with corticosteroids. [7][8][9][10][11][12] Patients who have persistent cGVHD after frontline therapy and require a change in treatment have a 2.5 times increased risk of nonrelapse mortality 13 ; however, there is no standard of care or approved second-line treatment.…”

Section: Introductionmentioning

confidence: 99%

Ibrutinib for chronic graft-versus-host disease after failure of prior therapy

Miklos

Cutler

Arora

et al. 2017

Blood

393

253

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• Ibrutinib induced a high rate of sustained responses for patients with cGVHD and inadequate response to corticosteroid-containing therapy.• This trial supported the approval of ibrutinib for treatment of adult patients with cGVHD after failure of $1 lines of systemic therapy.Chronic graft-versus-host disease (cGVHD) is a serious complication of allogeneic stem cell transplantation with few effective options available after failure of corticosteroids. B and T cells play a role in the pathophysiology of cGVHD. Ibrutinib inhibits Bruton tyrosine kinase in B cells and interleukin-2-inducible T-cell kinase in T cells. In preclinical models, ibrutinib reduced severity of cGVHD. This multicenter, open-label study evaluated the safety and efficacy of ibrutinib in patients with active cGVHD with inadequate response to corticosteroid-containing therapies. Forty-two patients who had failed 1 to 3 prior treatments received ibrutinib (420 mg) daily until cGVHD progression. The primary efficacy end point was cGVHD response based on 2005 National Institutes of Health criteria. At a median follow-up of 13.9 months, best overall response was 67%; 71% of responders showed a sustained response for ‡20 weeks. Responses were observed across involved organs evaluated. Most patients with multiple cGVHD organ involvement had a multiorgan response. Median corticosteroid dose in responders decreased from 0.29 mg/kg per day at baseline to 0.12 mg/kg per day at week 49; 5 responders discontinued corticosteroids. The most common adverse events were fatigue, diarrhea, muscle spasms, nausea, and bruising. Plasma levels of soluble factors associated with inflammation, fibrosis, and cGVHD significantly decreased over time with ibrutinib. Ibrutinib resulted in clinically meaningful responses with acceptable safety in patients with ‡1 prior treatments for cGVHD. Based on these results, ibrutinib was approved in the United States for treatment of adult patients with cGVHD after failure of 1 or more lines of systemic therapy. This trial was registered at www.clinicaltrials.gov as #NCT02195869. (Blood. 2017;130(21):2243-2250

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Treatment Change as a Predictor of Outcome among Patients with Classic Chronic Graft-versus-Host Disease

Cited by 52 publications

References 13 publications

Failure-free survival in a prospective cohort of patients with chronic graft-versus-host disease

Failure-free survival in a prospective cohort of patients with chronic graft-versus-host disease

Chronic GVHD: Where are we? Where do we want to be? Will immunomodulatory drugs help?

Ibrutinib for chronic graft-versus-host disease after failure of prior therapy

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