Antilymphocyte Globulin for Prevention of Chronic Graft-versus-Host Disease

Kröger, Nicolaus; Solano, Carlos; Wolschke, Christine; Bandini, Giuseppe; Patriarca, Francesca; Pini, Massimo; Nagler, Arnon; Selleri, Carmine; Risitano, Antonio M.; Messina, Giuseppe; Bethge, Wolfgang; Oteiza, Jaime Pérez de; Duarte, Rafael F.; Carella, Angelo Michele; Cimminiello, Michele; Guidi, Stefano; Finke, Jürgen; Mordini, Nicola; Ferrà, Christelle; Sierra, Jorge; Russo, Domenico; Petrini, Mario; Milone, Giuseppe; Benedetti, Fabio; Heinzelmann, Marion; Pastore, Domenico; Jurado, Manuel; Terruzzi, Elisabetta; Narni, Franco; Völp, Andreas; Ayuk, Francis; Ruutu, Tapani; Bonifazi, Francesca

doi:10.1056/nejmoa1506002

Cited by 467 publications

(401 citation statements)

References 36 publications

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“…domized study. 37 ATG prophylaxis is likely to have detrimental effects after single CBT due to increased risks of death and relapse, a result that agrees with a recent study using the European transplant registry database. 38 This study has several limitations.…”

Section: Discussionsupporting

confidence: 89%

Comparison of graft-versus-host disease-free, relapse-free survival according to a variety of graft sources: antithymocyte globulin and single cord blood provide favorable outcomes in some subgroups

Inamoto¹,

Kimura

Kanda

et al. 2016

Haematologica

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G raft-versus-host disease-free relapse-free survival, which is defined as the absence of grade III-IV acute graft-versus-host disease, systemically treated chronic graft-versus-host disease, relapse, and death, is a novel, meaningful composite end point for clinical trials. To characterize risk factors and differences in graft-versus-host disease-free relapse-free survival according to a variety of graft sources, we analyzed 23,302 patients with hematologic malignancy that had a first allogeneic transplantation from 2000 through 2013 using the Japanese national transplant registry database. The 1-year graft-versus-host disease-free relapsefree survival rate was 41% in all patients. The rate was higher after bone marrow transplantation than after peripheral blood stem cell transplantation due to the lower risks of III-IV acute and chronic graft-versus-host disease. The rate was highest after HLA-matched sibling bone marrow transplantation. The rate after single cord blood transplantation was comparable to that after HLA-matched unrelated bone marrow transplantation among patients aged 20 years or under, and was comparable or better than other alternative graft sources among patients aged 21 years or over, due to the low risk of chronic graft-versus-host disease. Other factors associated with better graft-versus-host disease-free relapse-free survival include female patients, antithymocyte globulin prophylaxis (for standard-risk disease), recent years of transplantation, sex combinations other than from a female donor to a male patient, the absence of prior autologous transplantation, myeloablative conditioning, negative cytomegalovirus serostatus, and tacrolimus-based prophylaxis. These results provide important information to guide the choice of graft sources and are benchmarks for future graft-versus-host disease prophylaxis studies.

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Section: Discussionsupporting

confidence: 89%

Comparison of graft-versus-host disease-free, relapse-free survival according to a variety of graft sources: antithymocyte globulin and single cord blood provide favorable outcomes in some subgroups

Inamoto¹,

Kimura

Kanda

et al. 2016

Haematologica

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“…Recent randomized trials, performed mainly in myeloid malignancies, strongly supported the use of ATG as GVHD 248 prophylaxis in patients receiving alloSCT not only from unrelated donors (26), but also from HLA-identical siblings 249 (27). The benefit was mainly related to a reduction of the severe forms of chronic GVHD.…”

mentioning

confidence: 99%

Allogeneic Stem Cell Transplantation for Relapsed/Refractory B Cell Lymphomas: Results of a Multicenter Phase II Prospective Trial including Rituximab in the Reduced-Intensity Conditioning Regimen

Dodero

Milone

Sarina

et al. 2017

Biology of Blood and Marrow Transplantation

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The graft versus host disease free, relapse free survival is 34% after transplantation in 2 lymphomas; 3Reduced extensive chronic GVHD with a combination of ATG and Rituximab in recipients of 4 unrelated graft 5One Rituximab Infusion prevents EBV-related lymphoproliferative disorders 6 Abstract 7The treatment of patients with refractory/relapsed B-Cell non-Hodgkin lymphoma (NHL) is evolving due to the 8 availability of novel drugs. Allogeneic stem cell transplantation (alloSCT) can be curative, but its morbidity and 9 mortality remain a matter of concern. We conducted a multicentre prospective phase II trial to evaluate the benefit of 10 including only one dose of Rituximab (R) in the conditioning regimen before alloSCT. The primary end-point was 11 progression-free survival. The study enrolled 121 patients with relapsed/refractory B-cell lymphomas. The conditioning 12 regimen consisted of thiotepa, cyclophosphamide, fludarabine and R (500 mg/ms). Rabbit anti-thymocyte globulin 13(ATG) was administered only in case of unrelated donors. Sixty-seven (55%) and fifty-four (45%) patients received 14 grafts from related and unrelated donors, respectively. The crude cumulative incidence (CCI) of non-relapse mortality 15(NRM) was 21% at 3-years. The CCI of chronic GVHD at 3-years was 54% and 31% in recipients of matched sibling 16 and unrelated grafts, respectively. At a median follow-up of 41 months, the estimated 3-years progression-free and 17 overall survival were 50% and 61%, respectively. Long-term outcome was also evaluated with the composite end-point 18 of graft-versus-host disease-free and relapse-free survival (GRFS). This is the first work evaluating the GRFS in a 19 prospective trial of lymphomas patients: the 1 and 3-years GRFS were 40% and 34%, respectively. AlloSCT can cure a 20 fraction of patients with rather low NRM and an encouraging PFS and GRFS.

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“…In particular, there is now strong evidence, stemming from 4 randomized clinical trials, that adult patients with hematological malignancies transplanted from either an unrelated donor (UD) [1][2][3] or with peripheral blood stem cells (PBSC) from an HLA-identical sibling [4] benefit from pre-transplantation treatment with ATLG. The use of an UD and of PBSC are notoriously both associated with an increased risk for the recipient to develop GvHD, especially the chronic form of the disease.…”

Section: Rabbit Anti-human T-lymphocyte Globulin and Hematopoietic Trmentioning

confidence: 99%

“…The use of an UD and of PBSC are notoriously both associated with an increased risk for the recipient to develop GvHD, especially the chronic form of the disease. These 4 controlled trials, clearly showing that chronic GvHD in patients receiving HSCT can be effectively reduced through ATLG prophylaxis, with a substantial increase in the long-term quality of life, have compared either rabbit-antihuman thymocyte globulin (Thymoglobulin®, Genzyme) versus no ATLG [1,3] or rabbit-antihuman T-cell line (Jurkat) globulin (Grafalon®, Neovii Biotech) versus no ATLG [2,4]. None of these trials, however, had focused on a pediatric population, as well as on the identification of a dose of rabbit ATLG able to prevent GvHD, while maintaining the capacity of effectively controlling/eradicating life-threatening infections and leukemia re-growth.…”

Section: Rabbit Anti-human T-lymphocyte Globulin and Hematopoietic Trmentioning

confidence: 99%

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2017

Oncotarget

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Rabbit anti-human T-lymphocyte globulin (ATLG) is used in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) to reduce the incidence and severity of the 2 main immune-mediated complications of the procedure, namely graft rejection and acute/chronic graft-versus-host disease (GvHD) ( Figure 1). In particular, there is now strong evidence, stemming from 4 randomized clinical trials, that adult patients with hematological malignancies transplanted from either an unrelated donor (UD) [1][2][3] or with peripheral blood stem cells (PBSC) from an HLA-identical sibling [4] benefit from pre-transplantation treatment with ATLG. The use of an UD and of PBSC are notoriously both associated with an increased risk for the recipient to develop GvHD, especially the chronic form of the disease. These 4 controlled trials, clearly showing that chronic GvHD in patients receiving HSCT can be effectively reduced through ATLG prophylaxis, with a substantial increase in the long-term quality of life, have compared either rabbit-antihuman thymocyte globulin (Thymoglobulin®, Genzyme) versus no ATLG [1,3] or rabbit-antihuman T-cell line (Jurkat) globulin (Grafalon®, Neovii Biotech) versus no ATLG [2,4]. None of these trials, however, had focused on a pediatric population, as well as on the identification of a dose of rabbit ATLG able to prevent GvHD, while maintaining the capacity of effectively controlling/eradicating life-threatening infections and leukemia re-growth. For addressing these issues, we decided to conduct an open-label, randomized trial comparing two different dosages of ATLG Grafalon® (30 vs 15 mg/Kg, given intravenously over 3 days, from day -4, to -2) in children (aged 0-18) with hematological malignancies receiving, after myeloablative preparation, either bone marrow-or PBSC-derived HSCT from an UD selected using high-resolution HLA typing. We found that low-dose ATLG (15 mg/Kg) can spare life-threatening infections, without significantly affecting the incidence of acute and chronic GvHD, as well as that of recurrence of the original disease [5]. This observation is further corroborated by the cumulative incidence of both EBV and adenovirus reactivation, documenting that children allocated to the low-dose arm had a reduced incidence of viral infections in comparison to those receiving ATLG at a dose of 30 mg/Kg. Preserving recovery of pathogenspecific immunity translated into a lower risk of nonrelapse mortality (NRM), which, in turn, was associated with a better probability of event-free survival [5]. The composite endpoint of survival free from both chronic GvHD and relapse did not differ between children given either high-or low-dose ATLG, suggesting that a lower dose of serotherapy does not affect the quality of life of surviving patients. Overall, the results of our study, thus, provide a clear and clinically useful message, namely that children with hematological malignancies given UD-HSCT after myeloablative preparation should receive lowdose (15 mg/kg) rabbit ATLG in order to avoid th...

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Antilymphocyte Globulin for Prevention of Chronic Graft-versus-Host Disease

Cited by 467 publications

References 36 publications

Comparison of graft-versus-host disease-free, relapse-free survival according to a variety of graft sources: antithymocyte globulin and single cord blood provide favorable outcomes in some subgroups

Comparison of graft-versus-host disease-free, relapse-free survival according to a variety of graft sources: antithymocyte globulin and single cord blood provide favorable outcomes in some subgroups

Allogeneic Stem Cell Transplantation for Relapsed/Refractory B Cell Lymphomas: Results of a Multicenter Phase II Prospective Trial including Rituximab in the Reduced-Intensity Conditioning Regimen

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