Response as an end point in treatment trials for acute GVHD

Pavletić, Steven Z.

doi:10.1038/bmt.2011.59

Cited by 6 publications

(5 citation statements)

References 21 publications

(22 reference statements)

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“…The study did not meet its primary endpoint of durable complete resolution of all clinical signs of GVHD for at least 28 consecutive days. Furthermore, the overall response rate at day 28, currently endorsed as an appropriate endpoint for acute GVHD treatment studies [25,26], was similar between the remestemcel-L group and the placebo group. In post hoc analyses, specific patient subgroups that appear to benefit from remestemcel-L treatment compared with placebo were identified; these include pediatric patients, patients with any liver involvement, and patients with high-risk aGVHD, typically although not always involving multiple or visceral organs (Figure 2, Table 2).…”

Section: Discussionmentioning

confidence: 79%

“…Since the conclusion of the trial in 2009, consensus in the field has established that OR, defined as CR + PR, at day 28, is a more appropriate endpoint for first-line GVHD treatment studies [25,26]. We therefore conducted exploratory analysis of the OR endpoint, using data collected at week 4 and day 32 assessments, and using the following protocol-specified response criteria:…”

Section: Discussionmentioning

confidence: 99%

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A Phase 3 Randomized Study of Remestemcel-L versus Placebo Added to Second-Line Therapy in Patients with Steroid-Refractory Acute Graft-versus-Host Disease

Kebriaei

Hayes

Daly

et al. 2020

Biology of Blood and Marrow Transplantation

114

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Uncontrolled studies have suggested that bone marrow-derived mesenchymal stem cells (MSCs) may be effective against acute graft-versus-host disease (aGVHD). We conducted a multicenter, randomized study to assess the efficacy of using ex vivo cultured adult human MSC (remestemcel-L) in addition to second-line therapy to treat steroid-refractory aGVHD (NCT00366145). In total, 260 patients, 6 months to 70 years of age, were enrolled from August 2006 to May 2009 and were randomized 2:1 to receive 8 intravenous infusions of remestemcel-L or placebo, given over 4 weeks, in addition to second-line therapy according to institutional standards. Four additional infusions over 4 weeks were indicated for patients with incomplete response at day 28. Randomization was stratified by aGVHD grade. Efficacy and safety were assessed through 180 days of follow-up, with the primary endpoint being durable complete response (DCR), defined as complete resolution of aGVHD symptoms for any period of at least 28 days after beginning treatment. Remestemcel-L did not meet the primary endpoint of greater DCR in the intent-to-treat population (35% versus 30%; P = 0.42). In post hoc analyses, patients with liver involvement who received at least 1 infusion of remestemcel-L had a higher DCR, and higher overall complete or partial response rate (OR) than those who received placebo (29% versus 5%; P = .047). Among high-risk patients (aGVHD grades C and D), remestemcel-L demonstrated significantly higher OR at day 28 than placebo (58% versus 37%; P = 0.03). Furthermore, pediatric patients had a higher OR with MSCs compared with placebo (64% versus 23%; P = .05). Similar rates of adverse events were observed between treatment groups. Remestemcel-L was safe and well tolerated. Results of this study did not demonstrate superior DCR compared with placebo when added to standard of care. The favorable clinical responses seen in some patient subsets may warrant further investigation.

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Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

A Phase 3 Randomized Study of Remestemcel-L versus Placebo Added to Second-Line Therapy in Patients with Steroid-Refractory Acute Graft-versus-Host Disease

Kebriaei

Hayes

Daly

et al. 2020

Biology of Blood and Marrow Transplantation

114

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“…The primary endpoint of Study 271 was Day‐28 ORR (CR + VGPR + PR). The definition of this endpoint and its acceptance as a clinical benefit was discussed at the open public workshop on Clinical Trial Endpoints for Acute Graft‐vs‐Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation held May 19, 2009 . The definition of CR used by FDA in the current analysis (supplemental online Table 1) differed slightly from the proposed consensus definition.…”

Section: Regulatory Insightsmentioning

confidence: 99%

FDA Approval Summary: Ruxolitinib for Treatment of Steroid-Refractory Acute Graft-Versus-Host Disease

et al. 2019

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On May 24, 2019, the Food and Drug Administration approved ruxolitinib for steroid-refractory acute graft-versus-host disease (SR-aGVHD) in adult and pediatric patients 12 years and older. Approval was based on Study INCB 18424-271 (REACH-1; NCT02953678), an open-label, single-arm, multicenter trial that included 49 patients with grades 2-4 SR-aGVHD occurring after allogeneic hematopoietic stem cell transplantation. Ruxolitinib was administered at 5 mg twice daily, with dose increases to 10 mg twice daily permitted after 3 days in the absence of toxicity. The Day-28 overall response rate was 57.1% (95% confidence interval [CI]: 42.2-71.2). The median duration of response was 0.5 months (95% CI: 0.3-2.7), and the median time from Day-28 response to either death or need for new therapy for acute GVHD was 5.7 months (95% CI: 2.2 to not estimable). Common adverse reactions included anemia, thrombocytopenia, neutropenia, infections, edema, bleeding, and elevated transaminases. Ruxolitinib is the first drug approved for treatment of SR-aGVHD. The Oncologist 2020;25:e328-e334Implications for Practice: Ruxolitinib is the first Food and Drug Administration-approved treatment for steroid-refractory acute graft-versus-host disease in adult and pediatric patients 12 years and older. Its approval provides a treatment option for the 60% of those patients who do not respond to steroid therapy.

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“…Day 28 has emerged as a standard response evaluation point in aGVHD studies because it also correlates with NRM. (63) Likewise, clinical studies in cGVHD have been hampered by a failure to specify a time for response assessment, define objective criteria for response, account for concomitant treatments, or identify a historical benchmark to identify a null hypothesis. (64) Standardization of methods, response criteria, and inclusion and exclusion criteria would allow for better comparisons across studies.…”

Section: Discussionmentioning

confidence: 99%

Graft-versus-host disease

Jaglowski

Devine

2014

Current Opinion in Hematology

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Purpose of review While allogeneic hematopoietic stem cell transplantation (allo-SCT) is potentially curative for a number of hematologic malignancies, its use is limited by the development of acute and chronic graft-versus-host disease (GVHD). This potentially fatal complication occurs in approximately 50% of allo-SCT recipients. Its pathogenesis is poorly understood, methods to prevent it are largely unchanged over the past two decades, and response to front-line treatment with corticosteroids is suboptimal. Recent findings The pathogenesis of acute and chronic GVHD remains poorly understood, methods to prevent it are largely unchanged over the past two decades, and response to front-line treatment with corticosteroids is suboptimal. For patients with steroid-refractory disease, response to second-line treatment is dismal. The prospective clinical studies evaluating new agents for GVHD have been hampered by inconsistencies in design, making generalization difficult, and few multicenter studies have been conducted. Summary Advances have been made over the past decade in grading both acute and chronic GVHD, with the development of biomarkers that provide improved prognostic information in acute GVHD and NIH Consensus Criteria for improved grading of chronic GVHD. This, along with the broad understanding of the need to conduct prospective studies with uniform inclusion criteria and endpoints leading to multicenter studies will hopefully lead to advancements in the prevention of GVHD in the near future.

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Response as an end point in treatment trials for acute GVHD

Cited by 6 publications

References 21 publications

A Phase 3 Randomized Study of Remestemcel-L versus Placebo Added to Second-Line Therapy in Patients with Steroid-Refractory Acute Graft-versus-Host Disease

A Phase 3 Randomized Study of Remestemcel-L versus Placebo Added to Second-Line Therapy in Patients with Steroid-Refractory Acute Graft-versus-Host Disease

FDA Approval Summary: Ruxolitinib for Treatment of Steroid-Refractory Acute Graft-Versus-Host Disease

Graft-versus-host disease

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