Sirolimus for treatment of steroid-refractory acute graft-versus-host disease

Hoda, Daanish; Pidala, Joseph; Salgado-Vila, N; Kim, J; Perkins, Janelle; Bookout, Ryan; Field, Teresa; Perez, Lia; Ayala, Ernesto; Ochoa-Bayona, José L.; Raychaudhuri, Jyotishankar; Alsina, Melissa; Jn, Greene; Janssen, William E.; Fernandez, Hugo F.; Anasetti, Claudio

doi:10.1038/bmt.2009.343

Cited by 62 publications

(45 citation statements)

References 25 publications

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“…In a study of 21 steroid-refractory grade III/ IV aGVHD patients, treatment with sirolimus was associated with responses in 57 % patients (CR 24 %), but treatment was discontinued in 10 patients due to no response in GVHD or toxicity [109]. Similar results were observed in retrospective studies as well [110]. It should be noted that in the GVHD prophylaxis study conducted by BMT-CTN which compared sirolimus/tacrolimus combination with methotrexate/tacrolimus combination, the option using busulfan/cyclophosphamide as conditioning regimen in sirolimus/tacrolimus arm was closed due to excessive occurrence of veno-occlusive disease (VOD) [111].…”

Section: Sirolimussupporting

confidence: 70%

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State-of-the-art acute and chronic GVHD treatment

Jamil

Mineishi

2015

Int J Hematol

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owing to the advancement in reduced intensity conditioning (RIC) and in patients without HLA-matched donors due to the use of cord blood and haploidentical HSCT [4][5][6]. Although marked improvement has been made in supportive care, immunosuppressive therapy and DNA-based Human Leukocyte Antigen (HLA) typing, graft vs host disease (GVHD) remains a major cause of morbidity and non-relapse mortality among allogeneic HSCT recipients. It was first described by Billingham in 1966 as a syndrome where immunocompetent T cells from the donor recognize and damage the host tissue in an immunocompromised recipient. It presents with heterogeneous symptoms involving multiple organ systems including gastrointestinal tract, skin, mucosa, liver and lungs [7]. In the past clinical features occurring within 100 days after HSCT was called acute GVHD (aGVHD) and those happening after 100 days were labeled chronic GVHD (cGVHD) [8,9]. This definition was rather unsatisfactory thus National Institute of Health (NIH) consensus criteria were developed and have been revised. The criteria have added new categories such as late-onset aGVHD (acute GVHD occurring after 100 days) and overlap syndrome which includes features of both acute and chronic GVHD to the classification, and also have introduced new definitions for organ system involvement [10][11][12]. The categorization of acute vs chronic GVHD is based on the combination of clinical symptoms rather than the time of onset. Depending upon a number of variables associated with patients, donors, and types of transplant, the incidence of aGVHD varies with incidence of grade II-IV GVHD at 40 % in matched related donor (MRD) transplant to 50 % in MUD transplant. The main risk factors for aGVHD include degree of HLA mismatch, age of the patient, previous all immunization of the donor and the kind of GVHD prophylaxis used. About 30-70 % of allogeneic HSCT recipients alive after 100 days will Abstract Graft-versus-host disease (GVHD) remains as the major obstacle for successful hematopoietic stem cell transplant (HSCT). Roughly half of the patients undergoing HSCT develop GVHD which requires treatment, and above 10 % of the patient may die because of it. However, GVHD presents with anti-tumor activity, called graft-versus-tumor (GVT) effect, and it carries significant anti-tumor activity, thus suppressing GVHD completely may increase the relapse of original disease. Thus, it is important to control GVHD to the appropriate level.

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Section: Sirolimussupporting

confidence: 70%

“…Sirolimus is a mammalian-target-of-rapamycin (mTOR) inhibitor which has been used in the treatment of steroidrefractory aGVHD as well as in GVHD prophylaxis studies [109,110]. Concerns have been raised over potential side effects of sirolimus which could include seizures, hyperlipidemia, thrombotic microangiopathy and myelosuppression.…”

Section: Sirolimusmentioning

confidence: 99%

State-of-the-art acute and chronic GVHD treatment

Jamil

Mineishi

2015

Int J Hematol

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“…Initial treatment remains the administration of systemic corticosteroids, which can achieve response rates of approximately 50% as reported in large registry studies, 1,2 with Ͻ 40% of patients maintaining a durable remission. 3,4 There is no standard secondline therapy for patients who do not respond to the initial treatment with steroids although many agents are used, including antithymocyte globulin (ATG), 5 sirolimus, 6 etanercept, 7 denileukin diftitox, 8 and mycophenolate mofetil. 9 Novel therapeutic approaches are needed, and the ideal therapy would be able to specifically suppress aGVHD without increasing a patient's susceptibility to opportunistic infections as well as maintaining an intact graft-versusmalignancy effect.…”

Section: Introductionmentioning

confidence: 99%

Expression of CD30 in patients with acute graft-versus-host disease

Chen

McDonough

Hasserjian

et al. 2012

Blood

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“…These include antithymocyte globulin (ATG), 15 sirolimus, 16 etanercept, 17 denileukin diftitox, 18 extracorporeal pheresis, 19 mycophenolate mofetil, 20 mesenchymal stem cells, 21 and tocilizumab. 22 Most of these trials have been small single-arm studies and have generally shown historic response rates of ;30% and 6-month survival rates of around 40% to 45%, 4 which are comparable to the results observed in this study.…”

mentioning

confidence: 99%

Phase 1 multicenter trial of brentuximab vedotin for steroid-refractory acute graft-versus-host disease

Chen

Perales

Li³

et al. 2017

Blood

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• BV has activity for SR-aGVHD.• The MTD of BV was 0.8 mg/kg every 2 weeks for 4 doses.Therapy for steroid-refractory acute graft-versus-host disease (SR-aGVHD) remains suboptimal. Preclinical data demonstrate increased CD30 expression on activated CD8 1 T cells during aGVHD. Brentuximab vedotin (BV) is an antibody-drug conjugate targeting CD30. We conducted a multicenter phase 1 trial in 34 patients to establish the maximum tolerated dose (MTD) of BV for SR-aGVHD treatment. A 313 cohort design was conducted initially with BV given weekly 3 3 doses followed by maintenance dosing (initial dose 0.6 mg/kg IV weekly). Six patients were treated with the initial weekly dosing scheme; 2 of these patients died of neutropenic sepsis complications. The trial was subsequently revised to escalating cohorts of 5 patients treated every 2 weeks 3 4 doses with a 4-week dose-limiting toxicity (DLT) period. Twenty-eight patients were treated with every-2-week dosing (n 5 10 at 0.6 mg/kg; n 5 18 at 0.8 mg/kg). MTD was defined at 0.8 mg/kg with 1 DLT observed (sepsis). At day 28, the overall response rate was 38.2% with 5 complete responses (CRs; 14.7%) and 8 very-good-partial responses (23.5%). An additional 7 patients achieved CR by day 56. With 12 months' follow-up on all patients, overall survival was 41% (95% confidence interval [CI], 25%-57%) at 6 months and 38% (95% CI, 22%-54%) at 12 months. CD30 expression on central memory CD81 , central memory CD4 1 , and regulatory T-lymphocyte subsets at enrollment was not associated with clinical response. BV is tolerable and has activity in SR-aGVHD and merits further investigation. This trial was registered at www.clinicaltrials.gov as #NCT01940796. (Blood. 2017;129(24):3256-3261)

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Sirolimus for treatment of steroid-refractory acute graft-versus-host disease

Cited by 62 publications

References 25 publications

State-of-the-art acute and chronic GVHD treatment

State-of-the-art acute and chronic GVHD treatment

Expression of CD30 in patients with acute graft-versus-host disease

Phase 1 multicenter trial of brentuximab vedotin for steroid-refractory acute graft-versus-host disease

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