Bortezomib, tacrolimus, and methotrexate for prophylaxis of graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation from HLA-mismatched unrelated donors

Abstract Graft-versus-host disease (GVHD) is a significant complication of allogeneic stem cell transplantation (alloSCT). The proteasome inhibitor bortezomib has immunomodulatory properties of potential benefit for GVHD control. We undertook a phase 1 trial of bortezomib, tacrolimus, and methotrexate for GVHD prophylaxis after reduced-intensity conditioning alloSCT using human leukocyte antigen–mismatched unrelated donors. Twenty-three patients were enrolled. Bortezomib dose levels of 1, 1.3, and 1.5 mg/m2 were evaluated with 5, 3, and 5 patients, respectively. Ten additional patients were accrued at the 1.3 mg/m2 bortezomib dose level. Bortezomib-related toxicity was minimal. With a 12-month median follow-up, grade II-IV acute GVHD occurred in 3 patients, a 180-day cumulative incidence of 13%. Chronic GVHD occurred in 9 patients, a 1-year cumulative incidence of 41%. At 1-year, the nonrelapse mortality was zero, cumulative incidence of relapse/progression was 29%, and overall, progression-free, and event-free survival were 75%, 64%, and 59%, respectively. Bortezomib is a promising novel immunomodulatory agent in allogeneic transplantation. This study was registered at http://www.clinicaltrials.gov as #NCT00369226.

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Allogeneic stem cell transplantation after reduced-intensity conditioning in patients with myelofibrosis: a prospective, multicenter study of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation

Blood ◽

10.1182/blood-2009-07-234880 ◽

2009 ◽

Vol 114 (26) ◽

pp. 5264-5270 ◽

Cited By ~ 227

Author(s):

Nicolaus Kröger ◽

Ernst Holler ◽

Guido Kobbe ◽

Martin Bornhäuser ◽

Rainer Schwerdtfeger ◽

...

Keyword(s):

Stem Cell ◽

Confidence Interval ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Graft Versus Host Disease ◽

Allogeneic Stem Cell Transplantation ◽

Cumulative Incidence ◽

Reduced Intensity Conditioning ◽

Graft Versus Host ◽

Reduced Intensity

Abstract From 2002 to 2007, 103 patients with primary myelofibrosis or postessential thrombocythemia and polycythemia vera myelofibrosis and a median age of 55 years (range, 32-68 years) were included in a prospective multicenter phase 2 trial to determine efficacy of a busulfan (10 mg/kg)/fludarabine (180 mg/m2)–based reduced-intensity conditioning regimen followed by allogeneic stem cell transplantation from related (n = 33) or unrelated donors (n = 70). All but 2 patients (2%) showed leukocyte and platelet engraftment after a median of 18 and 22 days, respectively. Acute graft-versus-host disease grade 2 to 4 occurred in 27% and chronic graft-versus-host disease in 43% of the patients. Cumulative incidence of nonrelapse mortality at 1 year was 16% (95% confidence interval, 9%-23%) and significantly lower for patients with a completely matched donor (12% vs 38%; P = .003). The cumulative incidence of relapse at 3 years was 22% (95% confidence interval, 13%-31%) and was influenced by Lille risk profile (low, 14%; intermediate, 22%; and high, 34%; P = .02). The estimated 5-year event-free and overall survival was 51% and 67%, respectively. In a multivariate analysis, age older than 55 years (hazard ratio = 2.70; P = .02) and human leukocyte antigen–mismatched donor (hazard ratio = 3.04; P = .006) remained significant factors for survival. The study was registered at www.clinicaltrials.gov as #NCT 00599547.

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Methotrexate Reduces the Incidence of Severe Acute Graft-versus-Host Disease without Increasing the Risk of Relapse after Reduced-Intensity Allogeneic Stem Cell Transplantation from Unrelated Donors

Biology of Blood and Marrow Transplantation ◽

10.1016/j.bbmt.2010.06.013 ◽

2011 ◽

Vol 17 (1) ◽

pp. 93-100 ◽

Cited By ~ 2

Author(s):

Stéphane Vigouroux ◽

Reza Tabrizi ◽

Cyril Melot ◽

Joelle Coiffard ◽

Xavier Lafarge ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Graft Versus Host Disease ◽

Allogeneic Stem Cell Transplantation ◽

Graft Versus Host ◽

Unrelated Donors ◽

Reduced Intensity ◽

Risk Of Relapse ◽

Acute Graft

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Inflammatory cytokines and acute graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation

Blood ◽

10.1182/blood-2005-07-2919 ◽

2005 ◽

Vol 106 (13) ◽

pp. 4407-4411 ◽

Cited By ~ 52

Author(s):

Mohamad Mohty ◽

Didier Blaise ◽

Catherine Faucher ◽

Norbert Vey ◽

Reda Bouabdallah ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Inflammatory Cytokines ◽

Graft Versus Host Disease ◽

Allogeneic Stem Cell Transplantation ◽

Reduced Intensity Conditioning ◽

Graft Versus Host ◽

Reduced Intensity ◽

Acute Graft

This study investigated the role of inflammatory cytokines in acute graft-versus-host disease (aGVHD) incidence and severity in 113 patients who underwent reduced-intensity conditioning (RIC) allogeneic stem cell transplantation (allo-SCT). Among all tested cytokines in the first 3 months after allo-SCT, only interleukin-12 p70 (IL-12p70) levels in the first month were significantly associated with grades II to IV aGVHD development (P < .001). IL-12p70 levels were directly correlated with aGVHD severity grade (P < .001). Before aGVHD onset, blood monocytes, the main precursor pool of IL12p70-secreting dendritic cells, recovered more rapidly in patients with grades II to IV aGVHD (P = .005). Similarly, at the effector level, there was a more robust reconstitution of naive CD3+CD4+CD45RA+CD27+ T cells in patients developing grades II to IV aGVHD (P = .006). In multivariate analysis, IL-12p70 level measured in the first month was the strongest predictive factor for aGVHD development (P < .001). These findings, reconstituting a TH1 loop, support a model in which aGVHD reflects a type 1 alloreaction after RIC allo-SCT.

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