Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects

McSweeney, Peter A.; Niederwieser, Dietger; Shizuru, Judith A.; Sandmaier, Brenda M.; Molina, A.; Maloney, David G.; Chauncey, Thomas R.; Gooley, Theodore A.; Hegenbart, Ute; Nash, Richard A.; Radich, Jerald P.; Wagner, John L.; Minor, Steven T.; Appelbaum, Frederick R.; Bensinger, William I.; Bryant, Eileen; Flowers, Mary E.D.; Georges, George E.; Grumet, F. Carl; Kiem, Hans Peter; Torok‐Storb, Beverly; Yu, Cong; Blume, Karl G.; Storb, Rainer

doi:10.1182/blood.v97.11.3390

Cited by 1,295 publications

(1,073 citation statements)

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“…Initial preclinical studies of MMF in canine models of HCT demonstrated synergy with CSA in preventing GVHD and improving survival [6]. In reduced-intensity canine studies, CSA and MMF prevented graft rejection, and this combination is now commonly used in patients undergoing reduced-intensity allogeneic HCT [7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Cyclosporine in combination with mycophenolate mofetil versus methotrexate for graft versus host disease prevention in myeloablative HLA‐identical sibling donor allogeneic hematopoietic cell transplantation

et al. 2014

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Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality in allogeneic hematopoietic cell transplantation (HCT) despite current prophylaxis. Methotrexate (MTX) with a calcineurin inhibitor (CNI) is the current standard, however, has several toxicities. Mycophenolate mofetil (MMF) is frequently used in reduced-intensity HCT, but data in myeloablative transplants is limited. We thus retrospectively identified 241 patients who underwent myeloablative HCT from an HLA-identical sibling donor; 174 patients received cyclosporine (CSA) 1 MMF and 67 received CSA1MTX. Patients receiving MMF 1 CSA had rapid neutrophil (median 11 vs. 19 days with MTX1CSA), and platelet recovery (median 19 vs. 25 days), lower incidence of severe mucositis by OMAS (19% vs. 53%), and shorter length of hospital stay (median 25 vs. 36 days) (P < 0.001 for all comparisons). There were no significant differences in incidence of grade 2-4 (MMF1CSA 37% vs. MTX1CSA 39%) or 3-4 acute GVHD (17% vs. 12%), chronic GVHD (46% vs. 56%), relapse (28% vs. 27%), non-relapse mortality (20% vs. 27%), or overall survival (47% vs. 44%) (P 5 NS for all). However, in multivariable analysis, the use of MMF1CSA was associated with an increased risk of severe grade 3-4 acute GVHD (HR 2.92, 95% CI 1.2-7.15, P 5 0.019). There were no differences between the two regimens in multivariable analyses for other survival outcomes. This analysis demonstrates that the use of MMF in myeloablative sibling donor transplantation is well tolerated. However, there may be an increased risk of severe GVHD with MMF1CSA compared to MTX1CSA. Further studies evaluating optimal dosing strategies are needed.

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Section: Introductionmentioning

confidence: 99%

Cyclosporine in combination with mycophenolate mofetil versus methotrexate for graft versus host disease prevention in myeloablative HLA‐identical sibling donor allogeneic hematopoietic cell transplantation

et al. 2014

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“…Two of the first four patients rejected the donor graft, leading to the addition of fludarabine, which provided additional immunosuppression. [19] There were no further occurrences of rejection following the addition of fludarabine to the regimen. Although only one of 18 died of transplant-related toxicities, complete responses occurred in only two patients, and only three others achieved partial responses.…”

Section: Non-ablative Allogeneic Transplantsmentioning

confidence: 92%

Is there still a role for allogeneic stem-cell transplantation in multiple myeloma?

Bensinger

2007

Best Practice & Research Clinical Haematology

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Despite significant improvements in survival for multiple myeloma patients through autologous stem-cell transplantation (SCT) and the introduction of novel drugs, the disease remains incurable for all but a small fraction of patients. Only allogeneic SCT is potentially curative, due in part to a graft-versus-myeloma effect. High transplant-related mortality with allogeneic SCT is currently the major limitation to wider use of this potentially curative modality. Mortality can be reduced through the use of lower-intensity conditioning regimens which allow engraftment of allogeneic stem cells, but this comes at a cost of higher rates of disease progression and relapse. Promising studies to improve outcomes of allogeneic transplants include the use of more intensive nonmyeloablative conditioning regimens, tandem transplants, peripheral blood cells, graft engineering to improve the graft-versus-myeloma activity while reducing graft-versus-host disease (GVHD), post-transplant maintenance, and targeted conditioning therapies such as bone-seeking radioisotopes. Keywords multiple myeloma; allogeneic stem-cell transplantationThe treatment of multiple myeloma has dramatically improved in the last 10 years. Highdose therapy followed by autologous stem-cell support has emerged as a promising means for increasing remission rates and improving survival. As such, autologous stem-cell transplantation has become the standard of care for many patients with multiple myeloma. In addition, insights into the biology and genetics of myeloma cells have resulted in the rapid introduction of new drugs with unique mechanisms of action. These drugs -which include thalidomide, lenalidomide and bortezomib -have shown significant activity in multiple myeloma, and when these new agents are combined with more traditional drugs, the response and complete remission rates are as high as responses achieved with autologous stem-cell transplantation. [1,2] Despite these advances, long-term survival after treatment with stem-cell transplantation or the newly developed drugs is rare, and disease recurs in virtually all patients.Stem-cell transplantation from allogeneic donors may be curative for 10-20% of patients with chemotherapy-resistant, refractory hematologic malignancies, and for up to 80% of . E-mail address: wbensing@fhcrc.org. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. patients who are transplanted in remission. Much of the high response and curative potential of allografts is attributed to a 'graft-versus-tumor' effect. In patients with multiple myeloma this effect has been well documented...

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“…McSweeney et al reported a 20% graft rejection rate 2-4 months after HSCT with TBI alone as nonmyeloablative conditioning regimen [17]. High levels (>50%) of donor T-and NK-cell chimerism one month after transplantation are associated with a lower risk of graft rejection [13].…”

Section: Engraftment: Mixed Chimerism and Risk Of Graft Rejectionmentioning

confidence: 99%

“…Most have shown a lower incidence of acute GVHD (when acute GVHD was defined as GVHD occurring before day 100) but a similar incidence of chronic GVHD with RIC regimens [18]. The relatively reduced incidence and severity of acute GVHD after RIC transplantation can be explained by the combination of low-intensity pre-transplant conditioning and the initial mixed chimerism that may favor both host-versus-graft and graft-versus-host tolerance [17,18]. However, a number of patients given RIC conditioning experience late acute GVHD (i.e.…”

Section: Graft-versus-host Disease (Gvhd)mentioning

confidence: 99%

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Allogeneic hematopoietic stem cell transplantation (HSCT) after reduced intensity conditioning

Servais¹,

Baron²,

Béguin³

2011

Transfusion and Apheresis Science

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a b s t r a c tAllogeneic hematopoietic stem cell transplantation (HSCT) following myeloablative (conventional) conditioning regimen is associated with a high incidence of transplant-related morbidity and mortality, limiting its use to younger patients without medical co-morbidities. Over the past few years, it has become more evident that the alloreactivity of transplanted donor immunocompetent cells against host tumor cells (graft-versus-tumor effects, GVT effects) plays a major role in eradicating malignancies after allogeneic HSCT. Based on these observations, several groups of investigators have developed reduced intensity conditioning (RIC) regimens allowing patients who are ineligible for conventional HSCT to benefit from the potentially curative GVT effects of allogeneic transplantation. Retrospective studies have suggested that, in comparison with myeloablative allogeneic HSCT, in patients aged 40-60 years, RIC HSCT was associated with a higher risk of relapse but a lower incidence of transplant-related mortality leading to similar progression-free and overall survivals. Prospective studies are ongoing to define which patients might most benefit from RIC HSCT, and to increase the anti-tumoral activity of the procedure while reducing the incidence and the severity of acute graft-versus-host disease (GVHD). In this article, we review the current status and perspectives of RIC HSCT.

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Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects

Cited by 1,295 publications

References 52 publications

Cyclosporine in combination with mycophenolate mofetil versus methotrexate for graft versus host disease prevention in myeloablative HLA‐identical sibling donor allogeneic hematopoietic cell transplantation

Cyclosporine in combination with mycophenolate mofetil versus methotrexate for graft versus host disease prevention in myeloablative HLA‐identical sibling donor allogeneic hematopoietic cell transplantation

Is there still a role for allogeneic stem-cell transplantation in multiple myeloma?

Allogeneic hematopoietic stem cell transplantation (HSCT) after reduced intensity conditioning

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