Umbilical cord blood transplantation after nonmyeloablative conditioning: impact on transplantation outcomes in 110 adults with hematologic disease

Brunstein, Claudio G.; Barker, Juliet N.; Weisdorf, Daniel J.; DeFor, Todd E.; Miller, Jeffrey S.; Blazar, Bruce R.; McGlave, Philip B.; Wagner, John E.

doi:10.1182/blood-2007-04-067215

Cited by 477 publications

(529 citation statements)

References 37 publications

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“…The UCB selection criteria were previously published. 27,28 UCB grafts were matched at 4-6 of 6 HLA-A, -B (Ag level) and -DRB1 (allele level) to the recipient, and in patients receiving two UCB units, similarly matched to each other.…”

Section: Methodsmentioning

confidence: 99%

Achieving stringent CR is essential before reduced-intensity conditioning allogeneic hematopoietic cell transplantation in AML

Üstün

Wiseman

DeFor

et al. 2013

Bone Marrow Transplant

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Reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (allo-HCT) can cure patients with AML in CR. However, relapse after RIC allo-HCT may indicate heterogeneity in the stringency of CR. Strict definition of CR requires no evidence of leukemia by both morphologic and flow cytometric criteria. We re-evaluated 85 AML patients receiving RIC allo-HCT in CR to test if a strict definition of CR had direct implications for the outcome. These patients had leukemia immunophenotype documented at diagnosis and analyzed at allo-HCT. Eight (9.4%) had persistent leukemia by flow cytometric criteria at allo-HCT. The patients with immunophenotypic persistent leukemia had a significantly increased relapse (hazard ratio (HR): 3.7; 95% confidence interval (CI): 1.3-10.3, P ¼ 0.01) and decreased survival (HR: 2.9; 95% CI: 1.3-6.4, Po0.01) versus 77 patients in CR by both morphology and flow cytometry. However, the pre-allo-HCT bone marrow (BM) blast count (that is, 0-4%) was not significantly associated with risks of relapse or survival. These data indicate the presence of leukemic cells, but not the BM blast count affects survival. A strict morphologic and clinical lab flow cytometric definition of CR predicts outcomes after RIC allo-HCT, and therefore is critical to achieve at transplantation. Keywords: allogeneic hematopoietic cell transplantation; reduced-intensity conditioning regimen; AML; relapse; minimal residual disease; CR INTRODUCTIONAllogeneic hematopoietic SCT (allo-HCT) remains the most effective treatment for most patients with AML. 1 The two main mechanisms by which allo-HCT can cure AML are through the immunologically based GVL effect and leukemic cell cytoreduction by HCT conditioning. 2-5 Reduced-intensity conditioning (RIC) was introduced to allo-HCT more than a decade ago for patients who are older, had significant co-morbid conditions or poorer performance status. [6][7][8] The anti-neoplastic potency of these RIC HCT regimens relies primarily on the GVL effect rather than ablating all residual leukemic disease. 9 It is clear that patients with active leukemia had more relapse and worse OS after allo-HCT regardless of donor type or patient age. [10][11][12][13][14][15] Following allo-HCT, 40-60% of AML patients in CR1 enjoy long-term OS, whereas o20% of refractory or relapsed AML patients survive. 1,11 Yet even for allo-HCT during CR, relapse remains the most frequent complication of allo-HCT. 16 As relapse has been reported more frequently after RIC allo-HCT compared with myeloablative conditioning (MAC) allo-HCT in patients with AML, this suggests heterogeneity in the interpretation of a CR, which may be more important after RIC allo-HCT. [17][18][19][20][21][22][23] The CR definition updated in 2003 24 clearly requires no evidence of leukemia by flow cytometry in addition to the morphologic remission as reported: 'The presence of a unique phenotype (by flow cytometry) identical to what was found in the pretreatment specimen (for example, CD34, CD7 coexpression) should be viewed ...

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Section: Methodsmentioning

confidence: 99%

Achieving stringent CR is essential before reduced-intensity conditioning allogeneic hematopoietic cell transplantation in AML

Üstün

Wiseman

DeFor

et al. 2013

Bone Marrow Transplant

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“…Interestingly, patients who displayed mixed chimerism with both cord blood units at 6 weeks post-transplant presented with a higher incidence of chronic GvHD, a finding that may reflect an ongoing graft-versus-graft interaction. A recent report by Brunstein et al [26] further substantiates the low rates of severe GvHD, reduced TRM, and low relapse rates seen with the double UCB transplant approach. In this study of 110 patients, neutrophil engraftment was notably rapid and occurred at a median of 12 days in 92% of patients.…”

Section: Transplantation With Ucb : Clinical Studiesmentioning

confidence: 82%

Umbilical cord blood transplantation: Basic biology and clinical challenges to immune reconstitution

Brown

Boussiotis

2008

Clinical Immunology

150

111

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Allogeneic stem cell transplantation has continued to evolve as a common procedure for the treatment of hematological malignancies and bone marrow failure. Donor bone marrow and mobilized peripheral stem cells are routinely employed for the reconstitution of immune function in leukemia and lymphoma patients following radiation and/or chemotherapy. Unfortunately, only 30% of patients have an HLA identical sibling donor and the identification of matched unrelated donors, particularly for minorities, can present an exceptional challenge. The transplantation of umbilical cord blood (UCB) represents the most recent strategy to expand the potential donor pool while maintaining an acceptable level of treatment related complications. First utilized in children, UCB transplantation permits a higher degree of HLA disparity while demonstrating a reduction in the incidence and severity of graft versus host disease (GvHD) compared to previous transplantation modalities. Despite the apparent decrease in GvHD, relapse rates remain comparable to transplantation with bone marrow or mobilized peripheral blood suggesting a strong graft versus leukemia/lymphoma (GvL) effect. However, several issues complicate the use of UCB transplantation and its extension to the treatment of adults. Many infections that afflict transplant patients are particularly frequent and more severe in the context of UCB transplantation. UCB T cells are naïve and therefore display less proliferation and IFN-γ production in response to cognate antigen and also appear to demonstrate defects in signal transduction mechanisms. In addition, UCB contain T regulatory cells (Treg) with more potent suppressor function than adult Treg. Furthermore, adult patients often require more total cells and CD34+ progenitors for transplantation than a single UCB unit can provide. Thus, strategies to expand selected subpopulations from UCB and the use of multiunit transplantation are areas of active research. This review will provide a condensed summary of the clinical history of UCB transplantation and emphasize the advantages and disadvantages of this approach to hematological malignancies in comparison to other methods of hematopoietic stem cell transplantation. Subsequently, it will mainly focus on the current challenges to immune reconstitution presented by UCB transplantation, recent research into their cellular and molecular mechanisms, and experimental approaches to overcome them.

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“…CBT is now routinely utilized for the treatment of both adult [2][3][4][5] and pediatric 6 patients with hematological diseases, with similar reported outcomes as compared with hematopoietic SCT (HSCT) in which either adult BM or peripheral blood was used as a source of stem cells (non-CB HSCT). [7][8][9] Many human herpesviruses (HHVs) can be reactivated following HSCT, and have been associated with adverse outcomes in this clinical setting.…”

Section: Introductionmentioning

confidence: 91%

HHV-6 encephalitis in umbilical cord blood transplantation: a systematic review and meta-analysis

Scheurer

Pritchett

Amirian

et al. 2012

Bone Marrow Transplant

105

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Reactivation of human herpesvirus-6 (HHV-6) frequently occurs following hematopoietic SCT (HSCT), and has been associated with clinical consequences in many patient populations. HHV-6 reactivation and HHV-6 encephalitis seem to occur more frequently in patients undergoing HSCT with cord blood (CB) as the stem cell source. We have conducted a systematic literature review and meta-analysis to investigate the clinical significance of this correlation. A systematic review of publications indexed in PubMed was performed for HSCT studies published over the past 10 years that fit inclusion criteria. Data on prevalences of HHV-6 reactivation and HHV-6 encephalitis post HSCT were abstracted from 19 papers. Meta-analyses were conducted to calculate combined prevalence estimates. The prevalences of HHV-6 reactivation and encephalitis were compared among CB vs non-CB HSCT. Prevalences of HHV-6 reactivation and HHV-6 encephalitis were significantly higher in patients receiving CB as the stem cell source than in patients receiving another stem cell source (72.0% vs 37.4%, Po0.0001; 8.3% vs 0.50%, Po0.0001, respectively). HHV-6 reactivation and HHV-6 encephalitis are significant complications in the post-HSCT setting, particularly in patients receiving CB as the stem cell source. Thus, patients undergoing umbilical CB transplantation should be closely monitored for HHV-6 reactivation.

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Umbilical cord blood transplantation after nonmyeloablative conditioning: impact on transplantation outcomes in 110 adults with hematologic disease

Cited by 477 publications

References 37 publications

Achieving stringent CR is essential before reduced-intensity conditioning allogeneic hematopoietic cell transplantation in AML

Achieving stringent CR is essential before reduced-intensity conditioning allogeneic hematopoietic cell transplantation in AML

Umbilical cord blood transplantation: Basic biology and clinical challenges to immune reconstitution

HHV-6 encephalitis in umbilical cord blood transplantation: a systematic review and meta-analysis

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