Hematopoietic cell transplantation after reduced-intensity conditioning for older adults with acute myeloid leukemia in complete remission

in Current Opinion in Hematology (2007), 14(2), 145-151

Purpose of review Allogeneic hematopoietic cell transplantation with myeloablative conditioning is a well established therapy for patients with acute myeloid leukemia. Its efficacy depends, in part, on ... [more ▼]

Purpose of review Allogeneic hematopoietic cell transplantation with myeloablative conditioning is a well established therapy for patients with acute myeloid leukemia. Its efficacy depends, in part, on the destruction of recipient acute myeloid leukemia cells by the conditioning regimen and, in part on their removal by donor immune cells contained in the graft (graft-versus-tumor effect). Due to regiment related toxicities, the use of myeloablative allogeneic hematopoietic cell transplantation has been restricted to younger patients in good condition. More recently, the introduction of allogeneic hematopoietic cell transplantation following reduced-intensity or nonmyeloablative conditioning regimens, which rely mainly on graft-versus-tumor effects for tumor cell eradication, has permitted extending hematopoietic cell transplantation to include older patients and those with medical comorbidities. Recent findings Early results with allogeneic hematopoietic cell transplantation after nonmyeloablative and reduced-intensity conditioning for patients with acute myeloid leukemia in first complete remission are encouraging, with 2-year survivals after hematopoietic cell transplantation ranging from 48 to 79% among studies. Further, retrospective studies have demonstrated similar outcomes in adult patients with acute myeloid leukemia in complete remission given either myeloablative or nonmyeloablative conditioning. Summary Prospective studies are needed to define the place of allogeneic hematopoietic cell transplantation after nonmyeloablative or reduced-intensity conditioning in patients with acute myeloid leukemia in complete remission, and to determine a role for consolidation chemotherapy before hematopoietic cell transplantation, if any. [less ▲]

Comorbidity and disease status based risk stratification of outcomes among patients with acute myeloid leukemia or myelodysplasia receiving allogeneic hematopoietic cell transplantation.

in Journal of Clinical Oncology (2007), 25(27), 4246-54

PURPOSE: Retrospective studies have shown similar survival among patients with acute myeloid leukemia (AML) and myelodysplasia (MDS) after nonmyeloablative compared with myeloablative conditioning ... [more ▼]

PURPOSE: Retrospective studies have shown similar survival among patients with acute myeloid leukemia (AML) and myelodysplasia (MDS) after nonmyeloablative compared with myeloablative conditioning. Refined risk stratification is required to design prospective trials. PATIENTS AND METHODS: We stratified outcomes among patients with AML (n = 391) or MDS (n = 186) who received either nonmyeloablative (n = 125) or myeloablative (n = 452) allogeneic hematopoietic cell transplantation (HCT) based on comorbidities, as assessed by a HCT-specific comorbidity index (HCT-CI), as well as disease status. Patients receiving nonmyeloablative conditioning were older, more frequently pretreated, more often received unrelated grafts, and more often had HCT-CI scores of 3 compared with patients who received myeloablative conditioning. RESULTS: Patients with HCT-CI scores of 0 to 2 and either low or high disease risks had probabilities of overall survival at 2 years of 70% and 57% after nonmyeloablative conditioning compared with 78% and 50% after myeloablative conditioning, respectively. Patients with HCT-CI scores of 3 and either low or high disease risks had probabilities of overall survival of 41% and 29% with nonmyeloablative conditioning compared with 45% and 24% with myeloablative regimens, respectively. After adjusting for pretransplantation differences, stratified outcomes were not significantly different among patients receiving nonmyeloablative compared with myeloablative conditioning, with the exception of lessened nonrelapse mortality (hazard ratio, 0.50; P = .05) in the highest risk group. CONCLUSION: Patients with low comorbidity scores could be candidates for prospective randomized trials comparing nonmyeloablative and myeloablative conditioning regardless of disease status. Additional data are required for patients with low-risk diseases and high comorbidity scores. Novel antitumor agents combined with nonmyeloablative HCT should be explored among patients with high comorbidity scores and advanced disease. [less ▲]

Actualités thérapeutiques en hématologie.

in Revue Médicale de Liège (2007), 62(5-6), 384-90

This article focuses on recent advances in four important areas of hematology: aggressive lymphomas, allogeneic hematopoietic stem cell transplantation, multiple myeloma, and molecular therapy of cancer.

Evaluation de la thymopoiese: applications cliniques.

in Revue Médicale de Liège (2007), 62(12), 725-9

In the precedent article, we have described how T-cell generation in the thymus (thymopoiesis) may be currently evaluated through quantification by PCR of T-cell receptor excision circles (TREC) generated ... [more ▼]

In the precedent article, we have described how T-cell generation in the thymus (thymopoiesis) may be currently evaluated through quantification by PCR of T-cell receptor excision circles (TREC) generated by intrathymic random recombination of the gene segments coding for variable parts of T-cell receptor for antigen (TCR). In hematology, TREC methodology helps in a better understanding of immune reconstitution after graft of hematopoietic stem cells: first there is a proliferation of mature T cells present in the graft, then a differentiation of naive T cells. In geriatrics, the homeostasis of the peripheral T-cell repertoire is maintained through proliferation of peripheral memory T cells rather than through thymic generation of naive T cells. In addition, TREC quantification constitutes a novel major tool for deciphering the tight control of thymopoiesis by the neuroendocrine system. [less ▲]

Unrelated donor status and high donor age independently affect immunologic recovery after nonmyeloablative conditioning

in Biology of Blood & Marrow Transplantation (2006), 12(11), 1176-1187

The risk of cytomegalovirus (CMV) infection is higher after HLA-matched unrelated donor (URD) than after HLA-matched related donor (MRD) nonmyeloablative hematopoietic cell transplantation (HCT). We ... [more ▼]

The risk of cytomegalovirus (CMV) infection is higher after HLA-matched unrelated donor (URD) than after HLA-matched related donor (MRD) nonmyeloablative hematopoietic cell transplantation (HCT). We therefore investigated factors affecting immune recovery in 94 patients given HCT from MRDs (n = 51) and URDs (n = 43) after 2-Gy total body irradiation with or without fludarabine and postgrafting immunosuppression with mycophenolate mofetil and cyclosporine. CD4 T cells counts remained below normal values during the first year after HCT in both patient groups. This included abnormally low counts each of naive CD4 T cells and memory CD4 T cells. Conversely, CD8 T cell counts reached the 10th percentile of normal 6 months after HCT in MRD and URD recipients. On day 30 after HCT, URD recipients had lower counts of B cells (P = .02), naive CD4 T cells (P = .04), memory CD4 T cells (P = .005), memory CD8 T cells (P = .005), and CMV-specific T helper cells (P = .007) than had MRD recipients. This delay in CMV-specific immune reconstitution translated into increased frequency of CMV antigenemia among URD recipients during the first 100 days after HCT. Older donor age was associated with low counts of naive CD4 T cells on days 180-365 after HCT (P = .003). Further, low numbers of T cells and CD34(+) cells in the graft and development of acute graft-versus-host disease were associated with impaired immune recovery of naive CD4 T cells and B cells. In summary, immunologic recovery was poor the first year after nonmyeloablative conditioning and was delayed among URD recipients in comparison with MRD recipients. Other factors significantly associated with delayed immune recovery were advanced donor age, low numbers of CD34 and T cells in the graft, and development of graft-versus-host disease. (C) 2006 American Society for Blood and Marrow Transplantation. [less ▲]

Factors associated with outcomes in allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning after failed myeloablative hematopoietic cell transplantation

in Journal of Clinical Oncology (2006), 24(25), 4150-4157

Purpose Several studies have investigated the feasibility of allogeneic hematopoietic cell transplantations (HCTs) after reduced-intensity conditioning in patients who experienced relapse after ... [more ▼]

Purpose Several studies have investigated the feasibility of allogeneic hematopoietic cell transplantations (HCTs) after reduced-intensity conditioning in patients who experienced relapse after myeloablative HCT. Although most studies showed relatively low nonrelapse mortality (NRM) rates and encouraging short-term results, it has yet to be defined which patients would benefit most from these approaches. Patients and Methods We analyzed data from 147 patients with hematologic malignancies who experienced treatment failure with conventional autologous (n = 135), allogeneic (n = 10), or syngeneic (n = 2) HCT and were treated with HLA-matched related (n = 62) or unrelated (n = 85) grafts after conditioning with 2 Gy of total-body irradiation with or without fludarabine. Results Three-year probabilities of NRM, relapse, and overall survival were 32%, 48%, and 27%, respectively, for related recipients, and 28%, 44%, and 44%, respectively, for unrelated recipients. The best outcomes were observed in patients with non-Hodgkin's lymphoma, whereas patients with multiple myeloma and Hodgkin's disease had worse outcomes as a result of high incidences of relapse and progression. Being in partial remission (PR) or complete remission (CR) at HCT (P = .002) and developing chronic graft-versus-host disease (GVHD; P = .03) resulted in lower risks of relapse and progression. Factors associated with better overall survival were PR or CR (P = .01) and lack of comorbidity (P = .03) at HCT and absence of acute GVHD after HCT (P = .06). Conclusion Encouraging outcomes were seen with allogeneic HCT after nonmyeloablative conditioning in selected patients who had experienced relapse after a high-dose HCT, particularly in patients with non-Hodgkin's lymphoma. Results with unrelated grafts were comparable with results with related grafts. [less ▲]

Allogeneic hematopoietic cell transplantation following nonmyeloablative conditioning as treatment for hematologic malignancies and inherited blood disorders

in Molecular therapy (2006), 13(1), 26-41

Allogeneic hematopoietic cell transplantation (HCT) after myeloablative conditioning regimens has been an effective treatment for many patients with hematologic malignancies or inherited blood disorders ... [more ▼]

Allogeneic hematopoietic cell transplantation (HCT) after myeloablative conditioning regimens has been an effective treatment for many patients with hematologic malignancies or inherited blood disorders. Unfortunately, such regimens have been associated with significant toxicity, limiting their use to otherwise healthy, relatively young patients. In an attempt to extend treatment by allogeneic HCT to older patients and those with comorbid conditions, several groups of investigators have developed reduced-intensity or truly nonmyeloablative conditioning regimens, lacking such toxicity. Analogous to conventional regimens, reduced-intensity regimens both eliminated host-versus-graft (rejection) reactions and produced major anti-tumor effects. In contrast, nonmyeloablative regimens have relied on optimizing both pre-and posttransplant immunosuppression to overcome host-versus-g raft reactions, while anti-tumor responses have depended mainly on immune-mediated graft-versus-tumor effects. In this review, we define reduced-intensity and truly nonmyeloablative regimens, describe the preclinical development and clinical application of a very low intensity nonmyeloablative regimen, and review results with reduced-intensity regimens in patients with hematologic malignancies or inherited blood disorders. [less ▲]

Extending postgrafting cyclosporine decreases the risk of severe graft-versus-host disease after nonmyeloablative hematopoietic cell transplantation

in Transplantation (2006), 81(6), 818-25

BACKGROUND: It is unknown whether the duration of systemic immunosuppressive treatment after allogeneic nonmyeloablative hematopoietic cell transplantation (HCT) might influence the incidence, severity ... [more ▼]

BACKGROUND: It is unknown whether the duration of systemic immunosuppressive treatment after allogeneic nonmyeloablative hematopoietic cell transplantation (HCT) might influence the incidence, severity, timing, and/or corticosteroid-responsiveness of graft-versus-host disease (GVHD). METHODS: We retrospectively analyzed outcomes among 185 patients with hematologic malignancies who were given grafts from HLA-matched related donors following conditioning with 2 Gy total body irradiation alone or in combination with fludarabine between December 1998 and March 2003. Postgrafting immunosuppression consisted of mycophenolate mofetil (days 0-27) in combination with 3 different cyclosporine (CSP) regimens: taper from (A) days 35 to 56 (n=107), (B) days 56 to 77 (n=35), and (C) days 56 to 180 (n=43). RESULTS: The overall incidences of grades II-IV and III-IV acute GVHD, and extensive chronic GVHD were 52%, 13%, and 56%, respectively. The duration of CSP prophylaxis did not significantly influence the overall rate of acute GVHD (grade II-IV), extensive chronic GVHD, or non-relapse mortality. However, prolonged administration of CSP (group C) was associated with a significantly decreased hazard of grades III-IV acute GVHD (HR 0.2, 95% CI [0.04, 0.9]) and with an increased likelihood of discontinuing all systemic immunosuppression (HR 2.4, 95% CI [1.1, 5.2]) when compared to the shortest course of CSP (group A). CONCLUSION: Longer CSP duration decreased the risk of severe GVHD and increased the likelihood of discontinuing all systemic immunosuppression after nonmyeloablative HCT with HLA-matched related grafts. [less ▲]

Infections after allogeneic hematopoietic stem cell transplantation with a nonmyeloablative conditioning regimen.

in Bone Marrow Transplantation (2006), 37(4), 411-8

Hematopoietic cell transplantation (HCT) following nonmyeloablative conditioning (NMSCT) may be associated with a reduced risk of infection compared to standard allogeneic HCT. We retrospectively analyzed ... [more ▼]

Hematopoietic cell transplantation (HCT) following nonmyeloablative conditioning (NMSCT) may be associated with a reduced risk of infection compared to standard allogeneic HCT. We retrospectively analyzed incidence and risk factors of infection in 62 patients undergoing NMSCT with low-dose TBI +/- fludarabine and postgrafting CsA and MMF. The proportion of patients with any infection was 77%, but the majority of infectious events occurred beyond day 30. Donor other than sibling, older age, early disease and male gender were significant risk factors. The incidence of bacteremia was 55% at 1 year and the number of bacteremic episodes was 0.9 per patient (0.08 before day 30). The risk of bacteremia increased with older age and the use of a donor other than an HLA-identical sibling, but not with neutropenia. The incidence of infections other than bacteremia correlated with the use of corticosteroids. The risk of CMV infection increased with high-risk CMV serology, and risk of CMV disease with high-risk CMV serology, older age, first transplantation and a diagnosis of lymphoma. In conclusion, after NMSCT, infections are not frequent in the first 30 days post transplant but careful long-term monitoring is necessary thereafter. [less ▲]

Immune reconstitution after CD8-depleted or unmanipulated peripheral blood stem cells transplantation with nonmyeloablative conditioning

in Acta Clinica Belgica (2006), 61(2), 113