Prophylaxis of graft-versus-host disease with cyclosporine–prednisone is associated with increased risk of chronic graft-versus-host disease

Kumar, Shaji; Mg, Chen; Da, Gastineau; Gertz, MA; Inwards, DJ; Lacy, M. Q.; Tefferi, Ayalew; Ws, Harmsen; Mr, Litzow

doi:10.1038/sj.bmt.1703053

Cited by 10 publications

(5 citation statements)

References 34 publications

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“…All cases (11/11) of lower tract GI-GvHD with severe crypt had a pathologic appearance on endoscopy. Our series confirms a prior study that showed that more severe histological changes are associated with a higher prevalence of a pathologic appearance on endoscopy while milder forms of histological GI-GvHD are more likely to have a normal endoscopic appearance [13].…”

Section: Discussionsupporting

confidence: 80%

“…In our study, we evaluated the extent and severity of crypt loss using a validated pathology scoring system and adapted an endoscopic grading system [11,13]. First, we found that crypt loss was not evident in the absence of accompanying apoptosis.…”

Section: Discussionmentioning

confidence: 96%

“…Survival in patients with GvHD is negatively impacted by the presence of gut involvement [13]. Definitive diagnosis of GI-GvHD is based on exclusion of other causes of GI pathology and the presence of the hallmark histological finding of GI-GvHD which is apoptosis [8,10].…”

Section: Discussionmentioning

confidence: 99%

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Crypt loss is a marker of clinical severity of acute gastrointestinal graft‐versus‐host disease

et al. 2007

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Background: Crypt loss is a histological finding in acute gastrointestinal Graft‐Versus‐Host Disease (GI‐GvHD) of undefined clinical significance. Methods: Colonic crypt loss was graded in twenty‐three patients treated for GI‐GvHD following stem cell transplantation and then correlated with clinical parameters of disease severity and mortality. Results: Crypt loss was present in 17/23 cases, and in 11/23 cases crypt loss was deemed severe by the presence of contiguous areas of crypt loss. Nine of 11 patients with severe crypt loss had daily stool volumes in excess of 1000 ml/day, while only 3/12 of those with minimal or no crypt loss had this level of severe diarrhea. All 11 patients with severe crypt loss had a pathologic appearance at endoscopy and 10/11 had steroid refractory disease. Diarrhea resolved in only 3/9 patients with severe crypt loss. Five out of 10 patients (50%) with severe crypt loss expired within 15 months of diagnosis. All five deaths were attributable to the progression of GvHD itself or infection in the presence of continued GI‐GvHD. Conversely, only 1 of 12 patients (8%) with mild or no crypt loss had a death attributable to GvHD or infection. Conclusions: This study shows that severe colonic crypt loss predicts severe clinical GI‐GvHD that is more likely to be refractory to steroid treatment. In addition, crypt loss severity appears associated with higher mortality related to GvHD. Crypt loss can serve as a tool to predict clinically severe GI‐GvHD. Am. J. Hematol. 82:881–886, 2007. © 2007 Wiley‐Liss, Inc.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 96%

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Crypt loss is a marker of clinical severity of acute gastrointestinal graft‐versus‐host disease

et al. 2007

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“…37 Prior attempts to replace methotrexate have had mixed results. In randomized studies where methotrexate was omitted or replaced with corticosteroids, acute 1,[42][43][44] and chronic GVHD 45,46 rates were higher. When mycophenolate is given in combination with cyclosporine without methotrexate, the time to engraftment has generally been demonstrated to be shortened; however, rates of acute GVHD range between 38% and 62%, which is no different than historical controls.…”

Section: Figure 2 Rfs and Os (A) Rfsmentioning

confidence: 99%

Extended follow-up of methotrexate-free immunosuppression using sirolimus and tacrolimus in related and unrelated donor peripheral blood stem cell transplantation

Cutler¹,

Ho³

et al. 2006

Blood

173

138

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We assessed the combination of sirolimus and tacrolimus without methotrexate after myeloablative allogeneic stem cell transplantation from 53 matched related donors (MRDs) and 30 unrelated donors (URDs). All patients received cyclophosphamide and total body irradiation conditioning followed by transplantation of mobilized peripheral blood stem cells. The median time to neutrophil engraftment was 14 days. The median time to platelet engraftment was 12 days. No differences between MRD and URD cohorts was noted. The incidence of grade II-IV and III-IV acute graft-versus-host disease (GVHD) were 20.5% and 4.8%. The cumulative incidence of chronic GVHD was 59.1%. There were no differences in acute or chronic GVHD incidence between MRD and URD cohorts. The omission of methotrexate was associated with low transplant-related toxicity, with 30-day and 100-day treatment-related mortality rates of 0% and 4.8%. Relapse-free survival at 1 and 2 years was 72.3% and 68.5%, respectively. Overall survival at 1 and 2 years was 77.1% and 72.2%, respectively. There were no differences in relapse-free or overall survival between MRD and URD cohorts. The substitution of sirolimus for methotrexate as GVHD prophylaxis is associated with rapid engraftment, a low incidence of acute GVHD, minimal transplant-related toxicity, and excellent survival. Differences between MRD and URD cohorts are not evident when effective GVHD prophylaxis is used. IntroductionAcute graft-versus-host disease (GVHD) and transplant-related toxicity are 2 of the most critical barriers to successful allogeneic stem cell transplantation. The combination of a calcineurininhibitor and methotrexate has been the standard GVHD prophylactic regimen for the past 20 years, 1 but despite these 2 agents, acute GVHD occurs after 35% to 50% of matched, related donor (MRD) transplantation and occurs even more frequently after unrelated donor (URD) transplantation. 2 One-year transplantation-related mortality after MRD transplantation ranges from 27% to 37% 3 and is higher after URD transplantation. Although some of this mortality is due to acute GVHD, other important factors include infection and organ toxicity. Some of this mortality can be attributed to methotrexate, which delays hematopoietic engraftment, 1,4,5 causes epithelial tissue injury, and thus contributes to infection, oral mucositis, 6 and organ toxicity. 7,8 Sirolimus is the first available inhibitor of the mammalian target of rapamycin (mTOR), a critical regulator of eukaryotic cellular homeostasis. 9 Sirolimus binds uniquely to FK-binding protein 12 (FKBP12) and forms a complex with mTOR and the raptor/rictor proteins. 10,11 Although there is theoretical competition for FKBPbinding sites between sirolimus and calcineurin inhibitors, these agents appear to work synergistically, 12,13 because sirolimus does not interact with calcineurin or its downstream effectors. The sirolimus-FKBP12-mTOR complex inhibits several biochemical pathways, resulting in a reduction in DNA transcription, DNA translation, protein synth...

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“…For instance, trials using prednisone in combination with cyclosporine and/or methotrexate have not demonstrated improved GVHD prophylaxis [ 107 ]. On the contrary, studies using cyclosporine and prednisone has been associated with increased risk of cGVHD [ 111 ].…”

Section: Prevention Of Graft- Versus -Host Disementioning

confidence: 99%

Therapeutics for Graft-versus-Host Disease: From Conventional Therapies to Novel Virotherapeutic Strategies

Villa

Rahman

McFadden

et al. 2016

Viruses

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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has a curative potential for many hematologic malignancies and blood diseases. However, the success of allo-HSCT is limited by graft-versus-host disease (GVHD), an immunological syndrome that involves inflammation and tissue damage mediated by donor lymphocytes. Despite immune suppression, GVHD is highly incident even after allo-HSCT using human leukocyte antigen (HLA)-matched donors. Therefore, alternative and more effective therapies are needed to prevent or control GVHD while preserving the beneficial graft-versus-cancer (GVC) effects against residual disease. Among novel therapeutics for GVHD, oncolytic viruses such as myxoma virus (MYXV) are receiving increased attention due to their dual role in controlling GVHD while preserving or augmenting GVC. This review focuses on the molecular basis of GVHD, as well as state-of-the-art advances in developing novel therapies to prevent or control GVHD while minimizing impact on GVC. Recent literature regarding conventional and the emerging therapies are summarized, with special emphasis on virotherapy to prevent GVHD. Recent advances using preclinical models with oncolytic viruses such as MYXV to ameliorate the deleterious consequences of GVHD, while maintaining or improving the anti-cancer benefits of GVC will be reviewed.

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Prophylaxis of graft-versus-host disease with cyclosporine–prednisone is associated with increased risk of chronic graft-versus-host disease

Cited by 10 publications

References 34 publications

Crypt loss is a marker of clinical severity of acute gastrointestinal graft‐versus‐host disease

Crypt loss is a marker of clinical severity of acute gastrointestinal graft‐versus‐host disease

Extended follow-up of methotrexate-free immunosuppression using sirolimus and tacrolimus in related and unrelated donor peripheral blood stem cell transplantation

Therapeutics for Graft-versus-Host Disease: From Conventional Therapies to Novel Virotherapeutic Strategies

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