Graft-versus-leukemia effect with a WT1-specific T-cell response induced by azacitidine and donor lymphocyte infusions after allogeneic hematopoietic stem cell transplantation

Ishikawa, Tadataka; Fujii, Nobuharu; Imada, Masahide; M, Aoe; Meguri, Yusuke; Inomata, Tomoko; Nakashima, Hiromi; Fujii, Keiko; Yoshida, Shohei; Nishimori, Hisakazu; Matsuoka, Ken; Kondo, Eisei; Maeda, Yoshinobu; Tanimoto, Mitsune

doi:10.1016/j.jcyt.2016.12.007

Cited by 23 publications

(19 citation statements)

References 30 publications

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“…While WT1 mutations are not relapse‐specific, they are recurrently gained at relapse pointing towards a role in disease progression. WT1 constitutes an important epitope for immune response to leukemia, mediating the graft‐vs‐leukemia effect and providing the rationale for vaccination strategies . However, somatic mutations may disrupt the immunogenic potential of WT1, thereby contributing to immune escape after allogeneic transplantation.…”

Section: Aml Relapse After Allogeneic Stem Cell Transplantationmentioning

confidence: 99%

Clonal evolution of acute myeloid leukemia from diagnosis to relapse

Vosberg

Greif

2019

Genes Chromosomes & Cancer

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Based on the individual genetic profile, acute myeloid leukemia (AML) patients are classified into clinically meaningful molecular subtypes. However, the mutational profile within these groups is highly heterogeneous and multiple AML subclones may exist in a single patient in parallel. Distinct alterations of single cells may be key factors in providing the fitness to survive in this highly competitive environment. Although the majority of AML patients initially respond to induction chemotherapy and achieve a complete remission, most patients will eventually relapse. These points toward an evolutionary process transforming treatment‐sensitive cells into treatment‐resistant cells. As described by Charles Darwin, evolution by natural selection is the selection of individuals that are optimally adapted to their environment, based on the random acquisition of heritable changes. By changing their mutational profile, AML cell populations are able to adapt to the new environment defined by chemotherapy treatment, ultimately leading to cell survival and regrowth. In this review, we will summarize the current knowledge about clonal evolution in AML, describe different models of clonal evolution, and provide the methodological background that allows the detection of clonal evolution in individual AML patients. During the last years, numerous studies have focused on delineating the molecular patterns that are associated with AML relapse, each focusing on a particular genetic subgroup of AML. Finally, we will review the results of these studies in the light of Darwinian evolution and discuss open questions regarding the molecular background of relapse development.

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Section: Aml Relapse After Allogeneic Stem Cell Transplantationmentioning

confidence: 99%

Clonal evolution of acute myeloid leukemia from diagnosis to relapse

Vosberg

Greif

2019

Genes Chromosomes & Cancer

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“…Table 1 summarizes the publications regarding the use of Aza as salvage treatment for relapse after allo-SCT: until now a total of 601 patients with AML, MDS and other related myeloid malignancies have been published with varying schedules and dosages of Aza. These included 3 prospective, non-randomized trials and the majority of patients reported retrospectively [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25]. Furthermore, Aza was the first treatment of relapse and combined with DLI in some of these patients, while other patients had previously received other salvage therapies or did not receive DLI.…”

Section: Azacitidine For the Treatment Of Relapsementioning

confidence: 99%

Hypomethylating agents for treatment and prevention of relapse after allogeneic blood stem cell transplantation

et al. 2017

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Despite the curative potential of allogeneic stem cell transplantation (allo-SCT) in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), many patients will relapse. Until recently therapeutic options mainly consisted of palliative care, chemotherapy, donor lymphocyte infusions and second transplantation in selected cases. Still many patients either do not tolerate intensive therapies or do not achieve durable remissions and will finally succumb. Given this unmet medical need the hypomethylating agents (HMA), Azacitidine (Aza) and Decitabine (DAC) have been tested as salvage therapy in patients with myeloid malignancies relapsing after allo-SCT. Furthermore, they have also been incorporated into prophylactic and pre-emptive approaches to avoid haematological relapse. In this review, we summarize the evidence from retrospective studies but also from a few prospective trials regarding the use of HMA after transplant. To aid clinicians in their daily clinical practice, we also comment on some practical aspects such as dosing and schedule, the choice of HMA and the use of complementary cellular therapies. Finally, this review also gives an overview on potential mechanisms mediating the efficacy of HMA after transplant as well as ongoing preclinical research and clinical activities aiming to further improve this treatment approach.

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“…29 Moreover, Dec may be a promising epi-immunotherapeutic agent against solid tumors and hematologic cancers. 28,30,31 Studies have also demonstrated a critical role of Dec in promoting the graft versus tumor (GvT) effect. The underlying mechanisms may be as follows: firstly, it may upregulate the expressions of antioncogenes that are silenced because of hypermethylation.…”

Section: Discussionmentioning

confidence: 99%

Decitabine Containing Conditioning Regimen for Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Intermediate- and High-Risk Myelodysplastic Syndrome/Acute Myeloid Leukemia: Potential Decrease in the Incidence of Acute Graft Versus Host Disease

Wang

Liang

et al. 2019

Blood

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These authors contributed equally to this work Purpose: To evaluate the role of Decitabine in the allo-HSCT conditioning regimen for intermediate-and high-risk patients with MDS or AML. Patients and methods: Retrospective analysis of data pertaining to 76 intermediate-and high-risk patients with MDS or AML who underwent allo-HSCT between December 2005 and June 2018 at the Peking University First Hospital. Forty patients received Decitabinecontaining conditioning regimen before transplantation, while thirty-six patients received regimen without Decitabine.Results: Over a median follow-up of 40 months (range, 1 to 155), the cumulative incidence of grade II to IV acute graft versus host disease was 12.4% [95% confidence interval (CI) 4.9-30.9%] in the Decitabine group and 41.5% (95% CI 28.1-61.2%) in the non-Decitabine group (P=0.005). On multivariate analysis, Decitabine-containing conditioning regimen was found to protect against grade II to IV aGVHD (HR=0.279, 95% CI 0.102-0.765, P=0.013). Incidence of respiratory infection in the Decitabine and non-Decitabine groups was 22.5% and 52.78%, respectively (P=0.012). No significant between-group difference was observed with respect to 3-year OS, DFS, or RR (P=0.980, 0.959, and 0.573, respectively), while the median relapse time was longer in the Decitabine group [7 months (range, 2-12) versus 3 months (range, 2-4), P=0.171]. Decitabine-containing conditioning showed a tendency for lower relapse rate among higher risk patients, as assessed by IPSS R; however, the betweengroup difference was not statistically significant (P=0.085). Conclusion: Inclusion of Decitabine in the conditioning regimen for allo-HSCT in intermediate-and high-risk patients may lower the incidence of aGVHD and respiratory infections, and contribute to longer median relapse time.

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Graft-versus-leukemia effect with a WT1-specific T-cell response induced by azacitidine and donor lymphocyte infusions after allogeneic hematopoietic stem cell transplantation

Cited by 23 publications

References 30 publications

Clonal evolution of acute myeloid leukemia from diagnosis to relapse

Clonal evolution of acute myeloid leukemia from diagnosis to relapse

Hypomethylating agents for treatment and prevention of relapse after allogeneic blood stem cell transplantation

Decitabine Containing Conditioning Regimen for Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Intermediate- and High-Risk Myelodysplastic Syndrome/Acute Myeloid Leukemia: Potential Decrease in the Incidence of Acute Graft Versus Host Disease

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