Measuring Therapeutic Response in Chronic Graft-versus-Host Disease. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IV. The 2014 Response Criteria Working Group Report

Lee, Stephanie J.; Wolff, Daniel; Kitko, Carrie L.; Koreth, John; Inamoto, Yoshihiro; Jagasia, Madan; Pidala, Joseph; Olivieri, Attilio; Martin, Paul J.; Przepiorka, Donna; Pusic, Iskra; Dignan, Fiona L.; Mitchell, Sandra A.; Lawitschka, Anita; Jacobsohn, David A.; Hall, Anne M.; Flowers, Mary E.D.; Schultz, Kirk R.; Vogelsang, Georgia B.; Pavletić, Steven Z.

doi:10.1016/j.bbmt.2015.02.025

Cited by 299 publications

(271 citation statements)

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“…Nonresponders were defined as those patients who had stable disease, had progressive disease, or were not evaluable. The response criteria were based on those provided by the 2005 NIH cGVHD Consensus Panel 27 and subsequently modified to include the following 2 changes based on publication of the 2014 NIH response criteria 28 : a change in organ score from 0 to 1 was not considered progression, and an organ was deemed nonevaluable for response when the organ response was confounded by a non-cGVHD-related factor. Under the original protocol, response assessments were conducted every 12 weeks.…”

Section: Study End Points and Evaluationsmentioning

confidence: 99%

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

Miklos

Cutler

Arora

et al. 2017

Blood

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355

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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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Section: Study End Points and Evaluationsmentioning

confidence: 99%

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

Miklos

Cutler

Arora

et al. 2017

Blood

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355

227

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“…"Trivial" intestinal increase (score 0→1) was not deemed progression, per the 2014 NIH consensus update. 24 We assessed patient-reported outcomes (PRO) using the Lee cGVHD Symptom Score. 25 …”

Section: Clinical Assessmentsmentioning

confidence: 99%

Efficacy, durability, and response predictors of low-dose interleukin-2 therapy for chronic graft-versus-host disease

Koreth

Kim

Jones

et al. 2016

Blood

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• Low-dose IL-2 is efficacious in steroid-refractory cGVHD, with objective responses in .50% of patients, and durable disease control.• IL-2 initiation earlier after cGVHD onset, prior to severe impairment of Treg:Tcon ratios, improves likelihood of clinical response.Chronic graft-versus-host disease (cGVHD) is associated with inadequate reconstitution of tolerogenic CD4 1 CD25 1 FOXP3 1 regulatory T cells (Tregs). Previous phase 1 studies identified a low daily dose of interleukin-2 (IL-2) that was well tolerated, did not exacerbate alloimmunity, augmented Treg in vivo, and was associated with improvement of active cGVHD. In the current phase 2 study, 35 adults with steroid-refractory cGVHD received daily IL-2 (1 3 10 6 IU/m 2 ) for 12 weeks. Median time from transplantation and cGVHD onset was 616 days (range, 270-2145 days) and 317 days (range, 28-1880 days), respectively. Two patients withdrew and 5 required IL-2 dose reductions due to side effects. Twenty of 33 evaluable patients (61%) had clinical responses at multiple cGVHD sites (liver, skin, gastrointestinal tract, lung, joint/muscle/fascia). Three patients (9%) had progressive cGVHD. Compared with pretreatment levels, Treg and natural killer cell counts rose >fivefold (P < .001) and >fourfold (P < .001), respectively, without significant change in conventional CD4 T cells (Tcons) or CD8 T cells. The Treg:Tcon ratio rose >fivefold (P < .001). Clinical responders initiated IL-2 earlier (508 vs 917 days after transplantation, P 5 .005; 249 vs 461 days after cGVHD onset; P 5 .03). Treg:Tcon ratios ‡0.07 at baseline and ‡0.2 at week 1 also predicted clinical response (P 5 .003; P 5 .0003, respectively). After a 4-week treatment hiatus, clinical responders were eligible to continue IL-2 therapy indefinitely. During 2 years of extended IL-2 therapy, clinical and Treg immune responses persisted, while Tcon count and Treg:Tcon ratio gradually normalized. Lowdose IL-2 provides durable clinical improvement in active cGVHD and extended therapy is well-tolerated. (Blood. 2016;128(1):130-137)

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“…4,5 In 2014, the National Institutes of Health (NIH) Consensus Development Project on Criteria for Clinical Trials in cGVHD published an updated series of articles to help standardize the clinical approach to treating these patients, thereby promoting new interest in this important post-transplantation complication and motivating the development of well-defined biomarkers for future use as an aid in clinical trials. [6][7][8][9][10] The development of acute graft-versus-host disease (aGVHD) biomarkers [11][12][13][14] has increased interest in identifying biomarkers that provide meaningful information for cGVHD. Several studies have reported the discovery of cGVHD biomarkers, 9,15 but verification studies of these biomarkers in independent cohorts are currently lacking.…”

Section: Introductionmentioning

confidence: 99%

Biomarker Panel for Chronic Graft-Versus-Host Disease

Storer

Kushekhar

et al. 2016

JCO

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113

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To identify diagnostic and prognostic markers of chronic graft-versus-host disease (cGVHD), the major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). Patients and MethodsUsing a quantitative proteomics approach, we compared pooled plasma samples obtained at matched time points after HCT (median, 103 days) from 35 patients with cGVHD and 18 without cGVHD (data are available via ProteomeXchange with identifier PXD002762). Of 105 proteins showing at least a 1.25-fold difference in expression, 22 were selected on the basis of involvement in relevant pathways and enzyme-linked immunosorbent assay availability. Chemokine (C-X-C motif) ligand 9 (CXCL9) and suppression of tumorigenicity 2 (ST2) also were measured on the basis of previously determined associations with GVHD. Concentrations of the four lead biomarkers were measured at or after diagnosis in plasma from two independent verification cohorts (n = 391) to determine their association with cGVHD. Their prognostic ability when measured at approximately day +100 after HCT was evaluated in plasma of a second verification cohort (n = 172). ResultsOf 24 proteins measured in the first verification cohort, nine proteins were associated with cGVHD, and only four (ST2, CXCL9, matrix metalloproteinase 3, and osteopontin) were necessary to compose a four-biomarker panel with an area under the receiver operating characteristic curve (AUC) of 0.89 and significant correlation with cGVHD diagnosis, cGVHD severity, and nonrelapse mortality. In a second verification cohort, this panel distinguished patients with cGVHD (AUC, 0.75), and finally, the panel measured at day +100 could predict cGVHD occurring within the next 3 months with an AUC of 0.67 and 0.79 without and with known clinical risk factors, respectively. ConclusionWe conclude that the biomarker panel measured at diagnosis or day +100 after HCT may allow patient stratification according to risk of cGVHD.

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Measuring Therapeutic Response in Chronic Graft-versus-Host Disease. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IV. The 2014 Response Criteria Working Group Report

Cited by 299 publications

References 114 publications

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

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

Efficacy, durability, and response predictors of low-dose interleukin-2 therapy for chronic graft-versus-host disease

Biomarker Panel for Chronic Graft-Versus-Host Disease

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