Full-intensity and reduced-intensity allogeneic stem cell transplantation in AML

Craddock, Charles

doi:10.1038/sj.bmt.1705975

Cited by 46 publications

(30 citation statements)

References 95 publications

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“…21,22,2 In our previous studies of full-haplotype mismatched HSCTs, mortality from causes other than leukemia relapse was 40% 1 and 36.5%. 2 In the present study, the 50% transplantation-related mortality needs to be viewed in light of these outcomes and of the clinical characteristics of this cohort.…”

Section: Discussionmentioning

confidence: 92%

Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation

Ianni

Falzetti

Carotti

et al. 2011

Blood

954

802

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IntroductionA viable option for high-risk, acute leukemia patients without matched donors is hematopoietic stem cell transplantation (HSCT) from human leukocyte antigen (HLA)-haploidentical 3-locimismatched family members who were readily available for almost all patients. 1,2 Until the 1990s, full-haplotype-mismatched, T cell-replete transplantations were unsuccessful because donoralloreactive T cells triggered a high incidence of severe graft-versushost disease (GVHD) despite posttransplantation immune suppression. 3,4 The breakthrough came with the use of a megadoses of extensively ex vivo T cell-depleted peripheral blood hematopoietic progenitor cells and a highly myeloablative conditioning regimen containing antithymocyte globulin (ATG), which exerts additional T-cell depletion in vivo. This approach ensures a high rate of primary engraftment in the absence of GVHD, 5 with more than 40% long-term event-free survival and excellent quality of life. 1,2 However, extensive ex vivo and in vivo T-cell depletion delays the recovery of immune responses against pathogens, leading to a high incidence of life-threatening infections. 1,2 Strategies to hasten posttransplantation immune reconstitution without triggering GVHD have included infusion of donor T cells after engineering with a suicide gene, 6 photodynamic purging, 7 and the use of an anti-CD25 monoclonal antibody (mAb) 8 to remove alloreactive cells. An alternative strategy might be based on donor CD4 ϩ CD25 ϩ T-regulatory cells (Tregs). In murine models of HSCT across major histocompatibility complex barriers, CD4 ϩ CD25 ϩ Tregs suppressed lethal GVHD 9 and favored posttransplantation immune reconstitution when coinfused with conventional T cells (Tcons). 10 The main obstacle to clinical application of human Tregs is their paucity in the peripheral blood. Although ex vivo-expanded polyclonal 11 or recipient-specific Tregs 12 were proposed to circumvent this potential barrier, we opted for closed, automated immunoselection 13 of naturally occurring Tregs. In the present study, for the first time in humans, we show that the early infusion of freshly isolated donor Tregs followed by Tcons at the time of full-haplotypemismatched HSCT prevented GVHD while favoring Tconmediated posttransplantation immune reconstitution. MethodsStudy design, conditioning regimen, stem cell mobilization, and supportive careIn 2008, the Umbria Regional Hospital Ethics Committee (CEAS Umbria) approved the protocol entitled "Adoptive Immunotherapy with Natural Regulatory T cells (Treg) and Effector T Cells in Allogeneic Hematopoietic Stem Cell Transplantation from 2-3 Loci Mismatched HLA-Haploidentical Family Donors for Patients with High Risk Haematologic Malignancies" (Protocol No 01/08). Written informed consent was obtained for all patients and donors in accordance with the Declaration of Helsinki. Inclusion criteria were: acute myeloid leukemia (AML) or acute lymphoid leukemia (ALL) in remission at high risk of relapse; acute leukemia with primary induction failure, in chemoresist...

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Section: Discussionmentioning

confidence: 92%

Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation

Ianni

Falzetti

Carotti

et al. 2011

Blood

954

802

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“…1 However post-HSCT relapse remains an important cause of treatment failure with relapse rates ranging from 30% to 70%, [2][3][4][5] depending on a number of factors such as disease status at the time of transplantation, donor source, conditioning regimen, and T-cell content of the graft. 4,6 Extramedullary relapses are known to occur post-HSCT, either as isolated sites of relapse or in combination with marrow relapse, [7][8][9] and usually result in death.…”

Section: Introductionmentioning

confidence: 99%

Extramedullary relapse of acute myeloid leukemia following allogeneic hematopoietic stem cell transplantation: incidence, risk factors and outcomes

et al. 2012

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Articleshaematologica | 2013; 98 (2) 179 IntroductionAllogeneic hematopoietic stem cell transplantation (HSCT) is increasingly used as a potentially curative treatment for acute myeloid leukemia (AML).1 However post-HSCT relapse remains an important cause of treatment failure with relapse rates ranging from 30% to 70%, 2-5 depending on a number of factors such as disease status at the time of transplantation, donor source, conditioning regimen, and T-cell content of the graft. 4,6 Extramedullary relapses are known to occur post-HSCT, either as isolated sites of relapse or in combination with marrow relapse, 7-9 and usually result in death. 10,11 Although risk factors for extramedullary disease/relapse have been described in newly diagnosed leukemia patients, 12 there have been few studies supporting the extrapolation of these factors to the post-HSCT setting. Despite the potential importance of post-HSCT extramedullary relapse as a determinant of outcomes, the incidence, risk factors, and treatment of this condition are not well understood, especially in light of the many changes in HSCT strategies over the past 20 years.Given the need for a better understanding of post-HSCT extramedullary relapse, we performed a retrospective analysis of patients who underwent HSCT for AML at the Design and MethodsDisease-, transplant-and outcome-related data were collected using protocols approved by the Institutional Review Board. Patients were treated according to clinical protocols approved by our Institutional Review Board and/or institutional care practice guidelines.Information on the patients and their transplants are shown in Table 1. Patients were classified as having high risk cytogenetics if they had any of the following: 5q-, monosomy 7/7q-, complex cytogenetics or FLT-3 positivity. Myeloablative conditioning regimens included busulfan (12.8 mg/kg IV or oral equivalent) combined with cyclophosphamide (120-200 mg/kg) ± cytarabine (6 g/m 2 ), fludarabine (140 mg/m 2 ), or clofarabine (150 mg/m 2 ), or total body irradiation (1200 cGy) combined with cyclophosphamide (120 mg/kg). Reduced intensity regimens included fludarabine (140 mg/m 2 ) and either busulfan (6.4 mg/kg IV or oral equivalent) or melphalan (140 mg/m 2 ). Immunosuppression primarily consisted of a calcineurin inhibitor (tacrolimus or cyclosporine) with methotrexate (5 mg/m 2 on days 1, 3, 6, and 11; n=211) or mycophenolate (20-30 mg/kg/day, maximum 3000 mg/day on days 0-28; n=46). Patients enrolled in graft-versus-host (GVHD) prevention clinical trials (n=29) received sirolimus in lieu of methotrexate, or etanercept as additional pro- Ferrata Storti Foundation. This is an open-access paper. doi:10.3324/haematol.2012.073189 Manuscript received on June 29, 2012.Manuscript accepted on September 12, 2012 Extramedullary relapse after allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia is a contributor to post-transplant mortality but risk factors for, and outcomes of, this condition are not well characterized. We analyzed 257 cons...

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“…Although some advances in intensive chemotherapeutic and transplant procedures have been made (e.g. the introduction of reduced intensity conditioning, 1,2 only a subgroup of patients aged over 60 years are considered fit for induction, and the percentage drops for older individuals. 3,4 Parameters for allocating treatment include both disease-specific parameters such as cytogenetics 5 and new biomarkers, 6 as well as patient-specific variables such as numerical age, performance status 7 and comorbidities.…”

Section: Introductionmentioning

confidence: 99%

Parameters detected by geriatric and quality of life assessment in 195 older patients with myelodysplastic syndromes and acute myeloid leukemia are highly predictive for outcome

et al. 2012

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Myelodysplastic syndromes and acute myeloid leukemia exemplify the complexity of treatment allocation in older patients as options range from best supportive care, non-intensive treatment (e.g. hypomethylating agents) to intensive chemotherapy/hematopoietic cell transplantation. Novel metrics for non-disease variables are urgently needed to help define the best treatment for each older patient. We investigated the feasibility and prognostic value of geriatric/quality of life assessments aside from established disease-specific variables in 195 patients aged 60 years or over with myelodysplastic syndromes/acute myeloid leukemia. These patients were grouped according to treatment intensity and assessed. Assessment consisted of eight instruments evaluating activities of daily living, depression, mental functioning, mobility, comorbidities, Karnofsky Index and quality of life. Patients with a median age of 71 years (range 60-87 years) with myelodysplastic syndromes (n=63) or acute myeloid leukemia (n=132) were treated either with best supportive care (n=47), hypomethylating agents (n=73) or intensive chemotherapy/hematopoietic cell transplantation (n=75). After selection of variables, pathological activities of daily living and quality of life/fatigue remained highly predictive for overall survival in the entire patient group beyond disease-related risk factors adverse cytogenetics and blast count of 20% or over. In 107 patients treated non-intensively activities of daily living of less than 100 (hazard ratio, HR 2.94), Karnofsky Index below 80 (HR 2.34) and quality of life/'fatigue' of 50 or over (HR 1.77) were significant prognosticators. Summation of adverse features revealed a high risk of death (HR 9.36). In-depth evaluation of older patients prior to individual treatment allocation is feasible and provides additional information to standard assessment. Patients aged 60 years or over with newly diagnosed myelodysplastic syndromes/acute myeloid leukemia and impairments in activities of daily living, Karnofsky Index below 80%, quality of life/'fatigue' of 50 or over, are likely to have poor outcomes.Parameters detected by geriatric and quality of life assessment in 195 older patients with myelodysplastic syndromes and acute myeloid leukemia are highly predictive for outcome

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Full-intensity and reduced-intensity allogeneic stem cell transplantation in AML

Cited by 46 publications

References 95 publications

Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation

Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation

Extramedullary relapse of acute myeloid leukemia following allogeneic hematopoietic stem cell transplantation: incidence, risk factors and outcomes

Parameters detected by geriatric and quality of life assessment in 195 older patients with myelodysplastic syndromes and acute myeloid leukemia are highly predictive for outcome

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