Impact of donor source on hematopoietic cell transplantation outcomes for patients with myelodysplastic syndromes (MDS)

Saber, Wael; Cutler, Corey; Nakamura, Ryotaro; Zhang, Mei Jie; Atallah, Ehab; Rizzo, J. Douglas; Maziarz, Richard T.; Cortes, Jorge; Kalaycio, Matt; Horowitz, Mary M.

doi:10.1182/blood-2013-04-496778

Cited by 91 publications

(74 citation statements)

References 46 publications

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“…[1][2][3][4] However, acute graft-versus-host disease (GVHD) remains a significant cause of morbidity and mortality. 2 Despite standard immunosuppressive prophylaxis, acute GVHD develops in 50% to 70% of the patients receiving allogeneic HCT from unrelated donors (URDs), [5][6][7][8][9][10][11] and GVHD accounts for 13% to 16% of the mortality in this type of HCT. 10,12 The incidence of severe (grade 3-4) acute GVHD after myeloablative, non-total-body irradiation (TBI)-based conditioning, URD HCT is as high as 32% at 100 days after transplant 13 and carries a 75% to 100% mortality rate.…”

Section: Introductionmentioning

confidence: 99%

Vorinostat plus tacrolimus/methotrexate to prevent GVHD after myeloablative conditioning, unrelated donor HCT

Choi

Braun

Henig

et al. 2017

Blood

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Key Points• Grade 2 to 4 acute GVHD in URD HCT patients who received vorinostat and tacrolimus/methotrexate after myeloablative conditioning was 22%.• HDAC inhibition with vorinostat shows potential efficacy for GVHD prevention and should be investigated in a randomized phase 3 trial.The oral histone deacetylase (HDAC) inhibitor (vorinostat) is safe and results in low incidence of acute graft-versus-host disease (GVHD) after reduced-intensity conditioning, related donor hematopoietic cell transplantation (HCT). However, its safety and efficacy in preventing acute GVHD in settings of heightened clinical risk that use myeloablative conditioning, unrelated donor (URD), and methotrexate are not known. We conducted a prospective, phase 2 study in this higher-risk setting. We enrolled 37 patients to provide 80% power to detect a significant difference in grade 2 to 4 acute GVHD of 50% compared with a reduction in target to 28%. Eligibility included adults with a hematological malignancy to receive myeloablative HCT from an available 8/8-HLA matched URD. Patients received GVHD prophylaxis with tacrolimus and methotrexate. Vorinostat (100 mg twice daily) was started on day 210 and continued through day 1100 post-HCT. Median age was 56 years (range, 18-69 years), and 95% had acute myelogenous leukemia or high-risk myelodysplastic syndrome. Vorinostat was safe and tolerable. The cumulative incidence of grade 2 to 4 acute GVHD at day 100 was 22%, and for grade 3 to 4 it was 8%. The cumulative incidence of chronic GVHD was 29%; relapse, nonrelapse mortality, GVHD-free relapse-free survival, and overall survival at 1 year were 19%, 16%, 47%, and 76%, respectively. Correlative analyses showed enhanced histone (H3) acetylation in peripheral blood mononuclear cells and reduced interleukin 6 (P 5 .028) and GVHD biomarkers (Reg3, P 5 .041; ST2, P 5 .002) at day 30 post-HCT in vorinostat-treated subjects compared with similarly treated patients who did not receive vorinostat. Vorinostat for GVHD prevention is an effective strategy that should be confirmed in a randomized phase 3 study. This trial was registered at www.clinicaltrials.gov as #NCT01790568. (Blood. 2017;130(15):1760-1767

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Section: Introductionmentioning

confidence: 99%

Vorinostat plus tacrolimus/methotrexate to prevent GVHD after myeloablative conditioning, unrelated donor HCT

Choi

Braun

Henig

et al. 2017

Blood

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“…92 Thus despite the lack of prospective, randomized data, and given the consistency of findings across all decision analyses, we continue to recommend HCT early after diagnosis of higher-risk MDS when feasible, with recent data supporting no decrement in early survival and a long-term survival rate of 40% to 50%. [93][94][95] In the 60-yearold male patient, long-term success could be enhanced by his low HCT-CI (irrespective of age) but worsened by poor-risk cytogenetics. 96,97 Should MDS patients be treated while awaiting HCT?…”

Section: What Is the Most Appropriate Timing Of Hct?mentioning

confidence: 99%

“…108 For patients who do not have available MRD, a URD search must be done. In a study of 701 adult patients with MDS who underwent transplantation between 2002 and 2006, 94 MRD recipients and 8 of 8 URD recipients had similar disease-free and overall survival, both superior to the disease-free and overall survival rates of patients undergoing 7 of 8 URD transplantation, for whom the likelihood of 3-year disease-free survival was only 29%.…”

Section: What Investigational Approaches Are Being Used After Hct?mentioning

confidence: 99%

How we treat higher-risk myelodysplastic syndromes

Sekeres

Cutler

2014

Blood

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Higher-risk myelodysplastic syndromes (MDS) are defined by patients who fall into higher-risk group categories in the original or revised International Prognostic Scoring System. Survival for these patients is dismal, and treatment should be initiated rapidly. Standard therapies include the hypomethylating agents azacitidine and decitabine, which should be administered for a minimum of 6 cycles, and continued for as long as a patient is responding. Once a drug fails in one of these patients, further treatment options are limited, median survival is <6 months, and consideration should be given to clinical trials. Higher-risk eligible patients should be offered consultation to discuss hematopoietic stem cell transplantation close to the time of diagnosis, depending on patient goals of therapy, with consideration given to proceeding to transplantation soon after an optimal donor is located. In the interim period before transplantation, hypomethylating agent therapy, induction chemotherapy, or enrollment in a clinical trial should be considered to prevent disease progression, although the optimal pretransplantation therapy is unknown.

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“…Nonetheless, with 1 prospective registration trial completed and 2 trials ongoing, it remains our current practice to continue to recommend HSCT for those patients who are eligible for the procedure and who have HLA-matched, related or unrelated donors. HSCT from mismatched or alternative donors should be considered investigational given the poorer results noted in registry trials 10 and should be reserved for special circumstances.…”

Section: What Is the Most Appropriate Timing Of Hct?mentioning

confidence: 99%

Timing of allogeneic stem cell transplantation for myelodysplastic syndromes and aplastic anemia

Cutler

2014

Hematology

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Allogeneic hematopoietic stem cell transplantation (HSCT) for myelodysplastic syndrome (MDS) is a potentially curative procedure, but is associated with a significant risk of morbidity and mortality. With the recent approval of disease-modifying agents, the appropriate timing of allogeneic HSCT needs to be addressed. Similarly, the optimal use of these disease-modifying agents before HSCT needs to be determined. In severe aplastic anemia, HSCT is a proven cure, but HLA-matched sibling donors are found in fewer than 25% of newly diagnosed patients. The use of early unrelated donor HSCT is an evolving concept that will become more accepted as improvements in HSCT outcomes continue. Learning Objectives• To understand the role of transplantation for myelodysplastic disorders (MDS) and severe aplastic anemia (SAA) • To understand the appropriate timing of transplantation for MDS and SAA in the context of alternative available therapies

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Impact of donor source on hematopoietic cell transplantation outcomes for patients with myelodysplastic syndromes (MDS)

Abstract: . 2013;122(11):1974-1982)

Cited by 91 publications

References 46 publications

Vorinostat plus tacrolimus/methotrexate to prevent GVHD after myeloablative conditioning, unrelated donor HCT

Vorinostat plus tacrolimus/methotrexate to prevent GVHD after myeloablative conditioning, unrelated donor HCT

How we treat higher-risk myelodysplastic syndromes

Timing of allogeneic stem cell transplantation for myelodysplastic syndromes and aplastic anemia

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