Graft-versus-leukemia effect in hematopoietic stem cell transplantation for pediatric acute lymphoblastic leukemia: significantly lower relapse rate in unrelated transplantations

Gassas, Adam; Sung, Lillian; Saunders, E F; Doyle, John

doi:10.1038/sj.bmt.1705853

Cited by 32 publications

(16 citation statements)

References 21 publications

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“…However, only incidence of relapse was significantly lower in the unrelated group because of higher incidence of GVHD, proving that GVL is important in pediatric ALL. 16 Furthermore, the very-high-risk infant ALL who benefited from a KIR (killer-cell immunoglobulin-like receptor) mismatch HSCT also proves that GVL is important in ALL. 17 Our understanding of GVL is still limited and there is no good measure for GVL, and although, historically, GVL has been more associated with chronic myeloid leukemia and AML, and may be least effective in ALL based on DLI response, this may be explained by the different disease kinetics of myeloid compared with lymphoid leukemia.…”

Section: Discussionmentioning

confidence: 99%

“…AML subtypes were classified using the FAB (French-American-British) system. Risk definition and cytogenetic abnormalities were classified according to the United Kingdom Medical research Council (UK-MRC) criteria, favorable if t(8;21), t (15)(16)(17) or inversion 16 were present, unfavorable if À5, À7, del (5q), abn (3q), and complex cytogenetics and standard risk for the remaining.…”

Section: Conditioning Regimensmentioning

confidence: 99%

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Early lymphocyte recovery after allogeneic hematopoietic SCT is associated with significant GVL effect in pediatric ALL but not acute myelogenous leukemia—Update study

Afzal

Ishaqi

Dupuis

et al. 2009

Bone Marrow Transplant

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We earlier published data on 136 children who received hematopoietic SCT (HSCT) for ALL, and showed that early lymphocyte recovery is a powerful indicator for survival by GVL effect without increase in GVHD. To answer the question whether this is true for AML, we extended our cohort to 207 consecutive children with acute leukemia by adding 71 children with AML who received 75 HSCT's between 1994 and 2005. For the AML cohort, all patients at time of HSCT were in complete morphological remission (CR) except for one patient in CR1, who had 8% blasts in the BM before HSCT. All patients received myeloablative regimens. Stem cell sources were: matched sibling donor in 40 patients, mismatched related donor in eight patients, matched unrelated donor in 25 children and two children received cord progenitor stem cells. ALL results were published with significant P-values. In AML, absolute lymphocyte count o0.3 Â 10 9 /l or 40.3 Â 10 9 /l on days 21 and 30 were not predictive of relapse with a hazard ratio at day 21 ¼ 0.88; P ¼ 0.8, and hazard ratio at day 30 ¼ 0.5; P ¼ 0.2.

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Section: Discussionmentioning

confidence: 99%

Section: Conditioning Regimensmentioning

confidence: 99%

Early lymphocyte recovery after allogeneic hematopoietic SCT is associated with significant GVL effect in pediatric ALL but not acute myelogenous leukemia—Update study

Afzal

Ishaqi

Dupuis

et al. 2009

Bone Marrow Transplant

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“…5 Clinical GVL effect has been associated with a fast recovery of alloreactive effector cells, such as NK cells in HP settings and T cells in MUD settings. 6,7 A recent report has described a delay in T-cell reconstitution using CD3/CD19-depleted grafts and RIC in the HP setting. 8 Furthermore, Dulphy et al 9 have described an immature NK-cell population during the early post-transplant period following unmanipulated HLA-matched HSCTs.…”

Section: Introductionmentioning

confidence: 99%

Early evaluation of immune reconstitution following allogeneic CD3/CD19-depleted grafts from alternative donors in childhood acute leukemia

Pérez‐Martínez

González‐Vicent

Valentín

et al. 2012

Bone Marrow Transplant

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Graft engineering procedures for hematopoietic SCT (HSCT) may improve the chance of success in matched unrelated donor (MUD) and haploidentical donor transplantations. Successful donor immune reconstitution is important to mediate GVL effects in reduced-intensity conditioning (RIC) HSCT. We prospectively investigated early immune reconstitution and clinical outcome in 30 CD3/CD19-depleted MUD (n ¼ 15) or HP (n ¼ 15) HSCTs for high-risk childhood leukemia using a fludarabine-based RIC without serotherapy. The graft consisted of a mean of 10.5 Â 10 6 /kg CD34 þ , 77 Â 10 3 /kg CD3 þ and 39 Â 10 6 /kg CD56 þ cells. After transplantation, 86% of the patients engrafted. In all, 13% of patients had 4grade 3 acute GVHD. Natural killer (NK) cell, DC and T-cell recovery achieved normal values within the first 60 days after transplantation. DC recovery was dominated by the DC2 À subset. NK-cell phenotype was altered and cytotoxicity was lower compared with their donors. EFS was 50 ± 9% (73 ± 11% for those in CR1 and 26 ± 11% for those with advanced disease). Faster DC2 À recovery was associated with better outcome, especially in the MUD setting. In summary, CD3/CD19-depleted HSCT with fludarabine-based RIC without serotherapy resulted in favorable patient survival, and rapid NK, DC and T-cell recovery. T-cell-depleted grafts have been proposed as a strategy to avoid GVHD. For example, CD34-selected HSCT followed by DLI has been proposed to maximize the effects of GVL with low rates of GVHD in HLA-matched HSCT. 3 However, secondary graft rejection is an important problem, especially in the MUD transplant setting. To facilitate engraftment, CD3/CD19-depleted grafts containing different pools of cells have been proposed to be preferable to T-cell-depleted grafts in MUD and HP HSCT in our unit. 4 In addition to T-cell depletion, B-cell depletion was used to prevent EBV-related lymphoproliferative disease. To reduce toxicity, we developed a reduced intensity conditioning (RIC) with i.v. BU, fludarabine and thiotepa. In addition, a high-dose steroid was used to further suppress recipient T-cell function to prevent graft rejection. We did not use antithymocyte globulin because of its long half-life and its potential to suppress T cells and natural killer (NK) cells, resulting in a high risk of infection and reduced GVL. 5 Clinical GVL effect has been associated with a fast recovery of alloreactive effector cells, such as NK cells in HP settings and T cells in MUD settings. 6,7 A recent report has described a delay in T-cell reconstitution using CD3/CD19-depleted grafts and RIC in the HP setting. 8 Furthermore, Dulphy et al. 9 have described an immature NK-cell population during the early post-transplant period following unmanipulated HLA-matched HSCTs. Apart from effector cells, the reconstitution of other immune cells such as DCs has not been systematically studied after T-cell-depleted HSCTs.

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“…1,2 Despite several advances over the last decade which led to significantly reduced transplantrelated mortality, relapse rates are still high and represent the major cause of death in these patient cohorts. [3][4][5][6] Level of pre-transplant minimal residual disease (MRD) has been shown to be an important adverse prognostic parameter for estimating the risk of relapse; MRD, therefore, influences long-term event-free survival after allogeneic stem cell transplantation. [7][8][9][10][11][12] In particular, patients who relapsed posttransplant have an extremely poor prognosis and need to achieve another hematologic remission or an even more advantageous very low or negative MRD level before proceeding to a subsequent SCT.…”

Section: Introductionmentioning

confidence: 99%

Pediatric posttransplant relapsed/refractory B-precursor acute lymphoblastic leukemia shows durable remission by therapy with the T-cell engaging bispecific antibody blinatumomab

et al. 2014

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Graft-versus-leukemia effect in hematopoietic stem cell transplantation for pediatric acute lymphoblastic leukemia: significantly lower relapse rate in unrelated transplantations

Cited by 32 publications

References 21 publications

Early lymphocyte recovery after allogeneic hematopoietic SCT is associated with significant GVL effect in pediatric ALL but not acute myelogenous leukemia—Update study

Early lymphocyte recovery after allogeneic hematopoietic SCT is associated with significant GVL effect in pediatric ALL but not acute myelogenous leukemia—Update study

Early evaluation of immune reconstitution following allogeneic CD3/CD19-depleted grafts from alternative donors in childhood acute leukemia

Pediatric posttransplant relapsed/refractory B-precursor acute lymphoblastic leukemia shows durable remission by therapy with the T-cell engaging bispecific antibody blinatumomab

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