Continuous high dosing of lenalidomide in relapsed, refractory or older newly diagnosed acute myeloid leukemia patients not suitable for other treatment options - results from a phase I study

Hütter-Krönke, Marie Luise; Fiedler, Walter; Kündgen, Andrea; Krauter, Jürgen; Lilienfeld‐Toal, Marie von; Döhner, Hartmut; Schlenk, Richard F.

doi:10.3324/haematol.2018.199794

Cited by 4 publications

(3 citation statements)

References 9 publications

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“…This thalidomide derivative is an antiangiogenic and immunomodulatory drug with a decreasing effect on VEGF expression. However, clinical relevance for AML treatment is controversially discussed ( 120 , 121 ).…”

Section: Antiangiogenic Therapy Of Amlmentioning

confidence: 99%

Acute Myeloid Leukemia and the Bone Marrow Niche—Take a Closer Look

2018

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The bone marrow is the home of hematopoiesis and is therefore a hotspot for the development of hematopoietic diseases. Complex interactions between the bone marrow microenvironment and hematopoietic stem cells must find a balance between proliferation, differentiation and homeostasis of the stem cell compartment. Changes in this tightly regulated network can provoke malignant transformation, leading to hematopoietic diseases. Here we focus on acute myeloid leukemia (AML), since this is the most frequent acute leukemia in adulthood with very poor overall survival rates and where relapse after chemotherapy continues to be a major challenge, driving demand for new therapeutic strategies. Current research is focusing on the identification of specific interactions between leukemic blasts and their niche components, which may be exploited as novel treatment targets along with induction chemotherapy. Significant progress has been gained over the last few years in the field of high-resolution imaging. Confocal ex vivo and intravital microscopy have revealed a detailed map of bone marrow structures and components; as well as identifying numerous alterations in the stem cell niche that correspond to disease progression. However, the underlying mechanisms are still not completely understood and due to the complexity, their elucidation remains a challenging. This review discusses the constitution of the AML niche in the bone marrow, the improvement in visualization of the complex three-dimensional niche structures and points out new therapeutic strategies to increase the overall survival of AML patients.

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Section: Antiangiogenic Therapy Of Amlmentioning

confidence: 99%

Acute Myeloid Leukemia and the Bone Marrow Niche—Take a Closer Look

2018

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“…Acute myeloid leukemia (AML) is a major type of hematological malignancies with the highest prevalence among all kinds of leukemias [1,2]. Relapsed disease has always been a predominant challenge in AML treatment, and most of the relapsed patients are at an older age, which obviously enhances the difficulty of management [3][4][5]. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an important curative therapy for the eligible AML patients; however, although treated by allo-HSCT, there are still approximately 40% patients who relapse post treatment [6].…”

Section: Introductionmentioning

confidence: 99%

Venetoclax plus azacitidine and donor lymphocyte infusion in treating acute myeloid leukemia patients who relapse after allogeneic hematopoietic stem cell transplantation

Zhao

et al. 2021

Ann Hematol

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This study aimed to evaluate the efficacy and safety of venetoclax plus azacitidine and donor lymphocyte infusion (DLI) in treating patients with relapsed acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Twenty-six AML patients who relapsed after allo-HSCT were enrolled and treated with venetoclax plus azacitidine and DLI. Complete remission with incomplete recovery (CRi), partial remission (PR), and objective remission rate (ORR) were assessed, and then event-free survival (EFS) and overall survival (OS) were evaluated. Besides, adverse events were documented. Additionally, whole exome sequencing was performed in bone marrow samples. The CRi, PR, and ORR rates were 26.9%, 34.6%, and 61.5%, respectively. The median time of EFS and OS was 120 (95% CI: 71–610) days and 284.5 (95% CI: 81–610) days, respectively. The most common adverse events were hematologic system adverse events including agranulocytosis, anemia, and thrombocytopenia, while the adverse events of other systems were relatively less and milder. In addition, no serious adverse events existed. Of note, there were 6 (23.1%) patients who developed GVHD. As for gene mutation, 49 mutated genes were found, which were categorized as first-, second-, and third-class mutations, and then further analysis revealed that the first-class mutations were not correlated with EFS or OS. Additionally, the most frequent mutated genes were FLT3, CEBPA, DNMT3A, KIT, KRAS, and NRAS. Venetoclax plus azacitidine and DLI is efficient and tolerant in treating patients with relapsed AML after allo-HSCT, implying this combined therapy as a potential treatment option in the studied patients.

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“…Later, a randomized phase II trial of bevacizumab did not show any improvement in the therapeutic outcome of elderly AML patients, either (NTR904) [ 126 ]. Clinical trials on other VEGF inhibitors like lenalidomide and thalidomide displayed neither limited nor controversial efficacy in patients with relapsed/refractory AML [ 127 – 129 ]. VEGF mediates downstream effects through VEGFR-2, a receptor which exhibits tyrosine-kinase activity.…”

Section: Strategies Targeting Bmm In Amlmentioning

confidence: 99%

Leukemia stem cell-bone marrow microenvironment interplay in acute myeloid leukemia development

Yao

Huang

et al. 2021

Exp Hematol Oncol

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Despite the advances in intensive chemotherapy regimens and targeted therapies, overall survival (OS) of acute myeloid leukemia (AML) remains unfavorable due to inevitable chemotherapy resistance and high relapse rate, which mainly caused by the persistence existence of leukemia stem cells (LSCs). Bone marrow microenvironment (BMM), the home of hematopoiesis, has been considered to play a crucial role in both hematopoiesis and leukemogenesis. When interrupted by the AML cells, a malignant BMM formed and thus provided a refuge for LSCs and protecting them from the cytotoxic effects of chemotherapy. In this review, we summarized the alterations in the bidirectional interplay between hematopoietic cells and BMM in the normal/AML hematopoietic environment, and pointed out the key role of these alterations in pathogenesis and chemotherapy resistance of AML. Finally, we focused on the current potential BMM-targeted strategies together with future prospects and challenges. Accordingly, while further research is necessary to elucidate the underlying mechanisms behind LSC–BMM interaction, targeting the interaction is perceived as a potential therapeutic strategy to eradicate LSCs and ultimately improve the outcome of AML.

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Continuous high dosing of lenalidomide in relapsed, refractory or older newly diagnosed acute myeloid leukemia patients not suitable for other treatment options - results from a phase I study

Cited by 4 publications

References 9 publications

Acute Myeloid Leukemia and the Bone Marrow Niche—Take a Closer Look

Acute Myeloid Leukemia and the Bone Marrow Niche—Take a Closer Look

Venetoclax plus azacitidine and donor lymphocyte infusion in treating acute myeloid leukemia patients who relapse after allogeneic hematopoietic stem cell transplantation

Leukemia stem cell-bone marrow microenvironment interplay in acute myeloid leukemia development

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