CD52 antibodies for prevention of graft-versus-host disease and graft rejection following transplantation of allogeneic peripheral blood stem cells

Hale, Geoff; Jacobs, Peter; Wood, Lucille; Fibbe, W. E.; Barge, Rmy; Novitzky, Nicolás; Toit, Cdu; Abrahams, Lameze; Thomas, Valda; Bunjes, Donald; Duncker, Christian; Wiesneth, Markus; Selleslag, Dominik; Hidajat, M.; Starobinski, Michel; Bird, P.; Waldmann, Herman

doi:10.1038/sj.bmt.1702477

Cited by 153 publications

(84 citation statements)

References 28 publications

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“…12,20,21 However, these regimens necessitated the use of subsequent DLI to establish full donor chimerism with the increased risk of subsequent GVHD. [38][39][40]44 The high response rate and OS in this high-risk population demonstrates that this RIT regimen was effective for disease control, even in patients with active disease at the time of the transplant. Surprisingly, neither age nor donor type (sibling or unrelated donor) had an impact on the incidence or severity of aGVHD or survival.…”

Section: Survival and Disease Responsementioning

confidence: 99%

“…21,40,43 However, in contrast to the T-cellmodified transplants, we did not observe a high incidence of infectious complications, mixed chimerism, or disease relapse. 21,40,43,44 Moreover, the patients in our study were at high risk for the development of aGVHD: 31% received either an unrelated donor or mismatched related donor transplant, 43% were recipients of a sex-mismatched transplant, 44% were over the age of 50 years, and 66% were heavily pretreated or had refractory disease (Table 2). 41 It is unclear as to which components of our preparative regimen contributed to the low incidence of aGVHD.…”

Section: Survival and Disease Responsementioning

confidence: 99%

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A novel reduced intensity regimen for allogeneic hematopoietic stem cell transplantation associated with a reduced incidence of graft-versus-host disease

Miller

Roberts

Chan

et al. 2004

Bone Marrow Transplant

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Summary:In all, 55 patients at high risk or ineligible for a conventional allogeneic hematopoietic stem cell transplant (HSCT) received a regimen consisting of extracorporeal photopheresis, pentostatin, and reduced dose total body irradiation. The median age was 49 years (18-70 years); 44 received a sibling and 11 an unrelated HSCT; 44% were over the age of 50 years and 31% had undergone a prior HSCT. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and methotrexate. Full donor chimerism was documented in 98% by day þ 100. The 1000-day nonrelapse mortality was 11%. The median follow-up is 502 days (154-1104 days). The 1-and 2-year overall survival (OS) and event-free survival (EFS) are 67, 58 and 55%, and 47%, respectively. Patients who had not received a prior HSCT or had less than three prior chemotherapy regimens had a 71% OS and 67% EFS at 1 year. Greater than grade II aGVHD developed in 9% and chronic GVHD (cGVHD) in 43%, and extensive in 12% and limited in 31%. Of the patients, 86% who engrafted had a disease response, 72% had complete and 14% partial responses. This novel reduced intensity preparative regimen was well tolerated and associated with a low incidence of transplant-related mortality and serious acute and cGVHD. pentostatin Current allogeneic hematopoietic stem cell transplant (HSCT) preparative regimens are designed to administer the maximally tolerated doses of chemotherapy and/or radiation therapy in an attempt to eradicate residual disease, ablate host hematopoiesis, and immune suppress the recipient to ensure engraftment of donor hematopoietic stem cells (HSC). While this approach is curative for many patients, it is also associated with 30-50% transplantrelated mortality (TRM) in patients over the age of 50 years. 1 While advances in supportive care and the management of acute graft-versus-host disease (aGVHD) have decreased the TRM and morbidity associated with an allogeneic HSCT, its application remains limited to patients who are able to tolerate the side effects of high-dose chemotherapy administered as part of a conventional preparative regimen. 2 Recent studies suggest that disease control and engraftment of allogeneic HSCT can be achieved following nonablative doses of chemoradiotherapy. [3][4][5] Moreover, in various diseases, the beneficial effects of the allogeneic HSCT result from an immune-mediated graft-versus-malignancy (GVM) effect and not from the high doses of chemotherapy administered in the preparative regimen. [5][6][7][8] Stable full or partial donor stem cell engraftment following the administration of a nonablative, reduced intensity preparative (RIT) regimen may also provide a platform for subsequent immune modulation to augment the GVM effect. [7][8][9] Compared to conventional, ablative preparative regimens, RIT regimens are generally associated with a decrease in TRM and other transplant-related complications. 3,7,10,11 However, despite a decrease in regimen-related toxicities, serious aGVHD and cGVHD remain a major cause of TRM and morbidi...

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Section: Survival and Disease Responsementioning

confidence: 99%

Section: Survival and Disease Responsementioning

confidence: 99%

A novel reduced intensity regimen for allogeneic hematopoietic stem cell transplantation associated with a reduced incidence of graft-versus-host disease

Miller

Roberts

Chan

et al. 2004

Bone Marrow Transplant

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“…15,17,18 The in vivo administration of alemtuzumab results in profound immunosuppression, significantly reducing GVHD when compared with T-cell replete transplants for a variety of haematological malignancies. 12,13,[18][19][20][21][22][23][24][25] Conversely, as a result of the depletion of the lymphocytes and APCs involved in GVL as well as GVHD, alemtuzumab has been associated with increased risk of relapse 26 In addition, alemtuzumab is associated with poor immune recovery post transplant, 26 and it is now apparent that an increased risk of infections after transplant with alemtuzumab is a significant cause of morbidity and mortality. 27,28 Balancing these competing effects in favour of low non-relapse mortality is the goal of the effective use of alemtuzumab.…”

Section: Introductionmentioning

confidence: 99%

Alemtuzumab markedly reduces chronic GVHD without affecting overall survival in reduced-intensity conditioning sibling allo-SCT for adults with AML

Malladi

Peniket

Littlewood

et al. 2008

Bone Marrow Transplant

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By retrospective analysis of 88 patients from the British Society of Blood and Marrow Transplantation registry, we investigated the effect of in vivo T-cell depletion in HLA-identical sibling reduced-intensity conditioning (RIC) allografts for adult AML by comparing patients who received alemtuzumab with those without alemtuzumab conditioning. Both groups were equivalent for age, sex, karyotype and disease status at transplant. With a median follow-up of 27 months (3-72 months) and 48 months (7-72 months), the 2-and 5-year overall survival, with or without alemtuzumab, is 60 and 60% (P ¼ 0.80) and 61 and 53%, respectively (P ¼ 0.85). The 2-year nonrelapse mortality is 12% with alemtuzumab, and 17% without alemtuzumab (P ¼ 0.49). The 2-year relapse rate is 35% with alemtuzumab compared with 19% without alemtuzumab (P ¼ 0.28). Grades II-IV acute GVHD occurred in 22% (8/37) without alemtuzumab compared with 14% (7/51) given alemtuzumab (P ¼ 0.25). Extensive chronic GVHD occurred in 47% (14/30) not given alemtuzumab compared with 4% (2/45) who were given alemtuzumab (P ¼ 0.001). Among evaluable patients, the risk of infections was higher in those treated with alemtuzumab compared with those not treated with alemtuzumab (79 vs 57%, respectively, P ¼ 0.02). In conclusion, alemtuzumab has a beneficial effect by reducing chronic GVHD without affecting overall survival. Further studies are warranted before alemtuzumab can be recommended as standard in RIC allografts for AML.

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“…The use of the monoclonal anti-CD52 antibody alemtuzumab has also been rather extensively explored to reduce the incidence of GvHD, either by the so-called treatment "in the bag" or by systemic intravenous infusion before the conditioning. 57 Alemtuzumab reduced GvHD, but at the same time its use remarkably affected response rates and response duration. These findings further confirm the pivotal role of donor T cells in providing graft-versus-myeloma activity.…”

Section: Gvhd and T-cell Depletionmentioning

confidence: 99%

Role of Allogeneic Stem Cell Transplantation in Multiple Myeloma

Bruno¹,

Giaccone²,

Sorasio³

et al. 2009

Seminars in Hematology

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High-dose chemotherapy with autologous stem cell rescue has been regarded as the standard of care for young newly diagnosed myeloma patients. Moreover, the development of new agents with potent anti-tumor activity has further improved survival. However, relapse is a continuous risk primarily due to the inability of current therapies to eradicate all myeloma cells. Allografting is the only potentially curative treatment at least for a subset of multiple myeloma patients due to its well documented graft-versus-myeloma effects. Given the high transplant mortality of the high-dose myeloablative conditionings used until recently, allografting has for a long time been limited to younger relapsed/refractory patients. These limitations have been reduced significantly by the use of reduced-intensity conditionings. Although results of recent trials are encouraging, the subset of patients who may benefit most from an allograft remains to be determined. An overview of the clinical outcomes obtained with allografting and possible future developments are reported. Multiple myeloma remains a fatal plasma cell disorder, although progress in the understanding of its pathogenesis has identified mechanisms that have recently become targets of new agents with potent anti-myeloma activity such as thalidomide and its derivatives, and bortezomib. 1, 2, 3, 4 and 5 However, high-dose chemotherapy and autologous stem cell rescue with/without these newer agents is still regarded as standard treatment for newly diagnosed myeloma patients younger than 65 years. 6, 7, 8, 9 and 10 Patients are almost universally at continuous risk of relapse and only a minority live disease-free for longer than 10-15 years. 8 and 9 In at least a subset of patients, allografting from a human leukocyte antigen (HLA)-identical sibling or an unrelated donor appears to be the only potentially curative strategy due to the well-documented graft-versus-myeloma effects. 11 Given the high transplant-related mortality and toxicity related to the intense myeloablative conditioning regimens employed until recently, allografting has frequently been limited to younger patients at relapse or who are refractory to chemotherapy. 12, 13 and 14 Since the early 2000s, these limitations have been dramatically reduced through the introduction of so-called reduced-intensity or nonmyeloablative conditioning regimens. 15 These regimens allowed an increase in the eligible age for allografting up to 65-70 years, even in patients with nonhematological comorbidities, and have shifted the burden of tumor eradication from chemotherapy to donor T cells. 16 and 17 In this article we will review the current evidence of graft-versus-myeloma effects, and the results obtained with conventional myeloablative regimens, and also summarize the results of recent trials with reducedintensity conditioning regimens. Allografting and Graft-Versus-Myeloma Effects

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CD52 antibodies for prevention of graft-versus-host disease and graft rejection following transplantation of allogeneic peripheral blood stem cells

Cited by 153 publications

References 28 publications

A novel reduced intensity regimen for allogeneic hematopoietic stem cell transplantation associated with a reduced incidence of graft-versus-host disease

A novel reduced intensity regimen for allogeneic hematopoietic stem cell transplantation associated with a reduced incidence of graft-versus-host disease

Alemtuzumab markedly reduces chronic GVHD without affecting overall survival in reduced-intensity conditioning sibling allo-SCT for adults with AML

Role of Allogeneic Stem Cell Transplantation in Multiple Myeloma

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