Azacitidine augments expansion of regulatory T cells after allogeneic stem cell transplantation in patients with acute myeloid leukemia (AML)

Goodyear, Oliver; Dennis, Mike; Jilani, Nadira; Loke, Justin; Siddique, Shamyla; Ryan, Gavin; Nunnick, Jane; Khanum, Rahela; Raghavan, Manoj; Cook, Mark; Snowden, John A.; Griffiths, Mike; Russell, Nigel H.; Yin, John; Crawley, Charles; Cook, Gordon; Vyas, Paresh; Moss, Paul; Malladi, Ram; Craddock, Charles

doi:10.1182/blood-2011-09-377044

Cited by 355 publications

(279 citation statements)

References 32 publications

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“…Another strategy used to prevent AML relapse after alemtuzumab-based RIC has been based on the pre-emptive administration of azacitidine which can likely favor the GVT effect without excessive GVHD. 36,37 Besides the impact of in vivo T-cell depletion on outcomes, this study also confirmed the negative impact of poor risk cytogenetics, 23,38,39 of being transplanted with a female donor in case of male recipients, 40 and of being transplanted in low-activity centers 18,22 on OS and PFS, as previously observed by our group 18,22,38,41 and by other groups of investigators. 39,40 Further, in contrast to what was observed in a recent CIBMTR study, 39 current data suggest that older patient age at transplantation is associated with higher NRM translating to worse LFS and OS in multivariate analyses.…”

Section: Discussionsupporting

confidence: 77%

Impact of in vivo T-cell depletion on outcome of AML patients in first CR given peripheral blood stem cells and reduced-intensity conditioning allo-SCT from a HLA-identical sibling donor: a report from the Acute Leukemia Working Party of the European group for Blood and Marrow Transplantation

Baron

Labopin

Blaise³

et al. 2014

Bone Marrow Transplant

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The impact of in vivo T-cell depletion on transplantation outcomes in patients transplanted with reduced-intensity conditioning (RIC) remains controversial. This study assessed the outcome of 1250 adult patients with de novo AML in first CR (CR1) given PBSC from HLA-identical siblings after chemotherapy-based RIC. A total of 554 patients did not receive any form of in vivo T-cell depletion (control group), whereas antithymocyte globulin (ATG) and alemtuzumab were given in 444 and 252 patients, respectively. The incidences of grade II-IV acute GVHD were 21.4, 17.6 and 10.2% in control, ATG and alemtuzumab patients, respectively (Po0.001).In multivariate analysis, the use of ATG and the use of alemtuzumab were each associated with a lower risk of chronic GVHD (Po0.001 each), but a similar risk of relapse, and of nonrelapse mortality, and similar leukemia-free survival and OS. Further, among patients given BU-based RIC, the use of o6 mg/kg ATG did not increase the risk of relapse (hazard ratio, HR ¼ 1.1), whereas there was a suggestion for higher relapse risk in patients given X6 mg/kg ATG (HR ¼ 1.4, P ¼ 0.08). In summary, these data suggest that a certain amount of in vivo T-cell depletion can be safely used in the conditioning of AML patients in CR1 given PBSC after chemotherapy-based RIC. INTRODUCTIONThe use of PBSC instead of BM in patients receiving grafts from HLA-matched donors after myeloablative conditioning has been associated with faster hematological recovery, lower relapse risk in patients with advanced disease (due to higher immune-mediated graft-versus-tumor (GVT) effects), but also higher incidence extensive chronic GVHD. 1-4 These observations prompted several groups of investigators to study in vivo T-cell depletion of the graft with antithymocyte globulin (ATG) or alemtuzumab as a way to reduce severe GVHD in patients given PBSC after highdose myeloablative conditioning regimen. [5][6][7] These studies demonstrated that the use of ATG or alemtuzumab was successful at preventing severe GVHD without apparently increasing the relapse incidence (RI). [5][6][7] In contrast to patients given grafts after myeloablative conditioning who benefit from both the high-dose chemo/radiotherapy given as part of the conditioning regimen and the GVT effect for tumor eradication,

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Section: Discussionsupporting

confidence: 77%

Impact of in vivo T-cell depletion on outcome of AML patients in first CR given peripheral blood stem cells and reduced-intensity conditioning allo-SCT from a HLA-identical sibling donor: a report from the Acute Leukemia Working Party of the European group for Blood and Marrow Transplantation

Baron

Labopin

Blaise³

et al. 2014

Bone Marrow Transplant

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“…[59][60][61][62][63] These agents also have the potential to harness an immunomodulatory effect that could synergize with the GVL effect, making them of additional interest. 64,65 The notion of administering these agents at a lower dose/intensity to harness their immunomodulatory effects, which include the upregulation of cancer testis antigens and augmentation of T-regulatory cells, following allo-SCT is additionally attractive. 66 At present there are several ongoing clinical trials, assessing a combination of JAK inhibitors and epigenetic modulators in both Transplantation for myelofibrosis in the JAK inhibitor era R Tamari et al transplant and non-transplant settings, based on preclinical evidence of synergy.…”

Section: Impact Of Targeting the Jak/signal Transducers And Activatormentioning

confidence: 99%

Allo-SCT for myelofibrosis: reversing the chronic phase in the JAK inhibitor era?

Tamari

Mughal

Rondelli

et al. 2015

Bone Marrow Transplant

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At present, allogeneic hematopoietic stem cell transplantation (allo-SCT) is the only curative treatment for patients with myelofibrosis (MF). Unfortunately a significant proportion of candidate patients are considered transplant ineligible due to their poor general condition and advanced age at time of diagnosis. The approval of the first JAK inhibitor, Ruxolitinib, for patients with advanced MF in 2011 has had a qualified impact on the treatment algorithm. The drug affords substantial improvement in MF-associated symptoms and splenomegaly but no major effect on the natural history. There has, therefore, been considerable support to assess the drug’s candidacy in the peri-transplant period. The drug’s precise impact on clinical outcome following allo-SCT is currently not known; nor is the drug’s long term efficacy and safety known. Considering the rarity of MF and the small proportion of patients who are undergoing allo-SCT, well designed collaborative efforts are required. In order to address some of the principal challenges, an expert panel of laboratory and clinical experts in this field was established, and an independent workshop held during the 54th American Society of Hematology’s meeting in New Orleans, USA, on 6th December 2013 and the European Hematology Association meeting in Milan, Italy on 13th June 2014. This document summarizes the results of these efforts.

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“…Demethylating agents 14,23 -Direct antileukemic activity -Hematological toxicity -Induce expression of tumor antigens by AML blasts -Induction of regulatory T cells that might affect GVT effects. FLT3 inhibitors 15 -Direct antileukemic activity -Hematological toxicity -Only efficient in FLT3-mutated AML?…”

Section: Mechanisms Of Action Potential Limitationsmentioning

confidence: 99%

“…11,12 Given the poor prognosis of patients who experience relapse after allo-HCT, several groups of investigators have assessed various post-transplant approaches aimed at preventing disease relapse in high-risk AML patients (Table 1). These approaches include decreasing the level of post-grafting immunosuppression, 13 preemptive (i.e., administered in patients with post-transplant evidence of minimal residual disease or low / decreasing donor chimerism levels) or prophylactic administration of diseasespecific medications such as demethylating agents 14 or FLT3 inhibitors, 15 or preemptive 16,17 or prophylactic DLI. 18,19 In this issue of Bone Marrow Transplantation, Jedlickova et al 20 report the results of a retrospective analysis assessing the safety and efficacy of prophylactic DLI in a cohort of 46 high-risk AML patients given grafts following a sequential treatment consisting of chemotherapy (FLAMSA) followed by RIC allo-HCT.…”

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confidence: 99%

Prophylactic donor lymphocyte infusion in patients with high-risk acute myeloid leukemia: ready for prime time?

Baron

Béguin

2016

Bone Marrow Transplant

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Azacitidine augments expansion of regulatory T cells after allogeneic stem cell transplantation in patients with acute myeloid leukemia (AML)

Cited by 355 publications

References 32 publications

Impact of in vivo T-cell depletion on outcome of AML patients in first CR given peripheral blood stem cells and reduced-intensity conditioning allo-SCT from a HLA-identical sibling donor: a report from the Acute Leukemia Working Party of the European group for Blood and Marrow Transplantation

Impact of in vivo T-cell depletion on outcome of AML patients in first CR given peripheral blood stem cells and reduced-intensity conditioning allo-SCT from a HLA-identical sibling donor: a report from the Acute Leukemia Working Party of the European group for Blood and Marrow Transplantation

Allo-SCT for myelofibrosis: reversing the chronic phase in the JAK inhibitor era?

Prophylactic donor lymphocyte infusion in patients with high-risk acute myeloid leukemia: ready for prime time?

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