Pembrolizumab and decitabine for refractory or relapsed acute myeloid leukemia

Gulley, James L.; Hughes, Thomas E.; Marté, Jennifer L.; Calvo, Katherine R.; Goswami, Mousumi; Hourigan, Christopher S.; Gui, Gege; Dillon, Laura W.; Lindblad, Katherine E.; Thompson, Julie L.; Valdez, Janet; Kim, Dong-Yun; Ghannam, Jack; Oetjen, Karolyn A.; DeStefano, Christin B.; Smith, Dana M; Tekleab, Hanna; Li, Yeusheng; Dagur, Pradeep K.; Rivero, Jaydira Del; Klubo-Gwiezdzinksa, Joanna; Lai, Catherine

doi:10.1136/jitc-2021-003392

Cited by 47 publications

(34 citation statements)

References 80 publications

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“…In line with the previous study, responses were observed in six patients; one achieved a morphologic leukemia-free state, three with stable disease, and two achieved CR [ 43 ]. The combination was found to be safe with a median OS of 10 months [ 43 ].…”

Section: Pd-1/pdl-1 Blockadesupporting

confidence: 87%

“…The combination was well tolerated and particularly active in the newly diagnosed setting [ 42 ]. In another study conducted by Goswami et al, pembrolizumab plus 10 days of decitabine was tested in 10 patients with R/R AML [ 43 ]. In line with the previous study, responses were observed in six patients; one achieved a morphologic leukemia-free state, three with stable disease, and two achieved CR [ 43 ].…”

Section: Pd-1/pdl-1 Blockadementioning

confidence: 99%

“…In another study conducted by Goswami et al, pembrolizumab plus 10 days of decitabine was tested in 10 patients with R/R AML [ 43 ]. In line with the previous study, responses were observed in six patients; one achieved a morphologic leukemia-free state, three with stable disease, and two achieved CR [ 43 ]. The combination was found to be safe with a median OS of 10 months [ 43 ].…”

Section: Pd-1/pdl-1 Blockadementioning

confidence: 99%

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Immune Checkpoint Inhibition in Acute Myeloid Leukemia and Myelodysplastic Syndromes

Abaza

Zeidan

2022

Cells

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Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of many solid tumors, with limited progress made in the area of myeloid malignancies. The low mutational burden of acute myeloid leukemia (AML) is one potential reason behind the lack of activity of T-cell harnessing ICIs, particularly CTLA-4 and PD-1 inhibitors. Innate immune checkpoints play a critical role in the immune escape of AML and myelodysplastic syndromes (MDS). The CD47 targeting agent, magrolimab, has shown promising activity when combined with azacitidine in early phase trials conducted in AML and higher-risk MDS, especially among patients harboring a TP53 mutation. Similarly, sabatolimab (an anti-TIM-3 monoclonal antibody) plus hypomethylating agents have shown durable responses in higher-risk MDS and AML in early clinical trials. Randomized trials are currently ongoing to confirm the efficacy of these agents. In this review, we will present the current progress and future directions of immune checkpoint inhibition in AML and MDS.

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Section: Pd-1/pdl-1 Blockadesupporting

confidence: 87%

Section: Pd-1/pdl-1 Blockadementioning

confidence: 99%

Section: Pd-1/pdl-1 Blockadementioning

confidence: 99%

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Immune Checkpoint Inhibition in Acute Myeloid Leukemia and Myelodysplastic Syndromes

Abaza

Zeidan

2022

Cells

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“…4), the few studies performed so far with anti-PD-L1 antibodies in AML patients have shown only modest clinical activity. Their impact has been evaluated also in combination with hypomethylating agents [132][133][134], since they induce the expression of several immune-related genes, including HLA-I and HLA-II, leukemia-associated antigens (e.g., PRAME, WT1) [135], PD-1 and PD-L1 [136]. Despite most studies did not specifically evaluate NPM1-mutated AML, they showed that patients who might benefit more from these drug combinations are those who are naïve for hypomethylating agents or have <20% blasts and a higher pretherapy infiltration of bone marrow by CD3+, CD4+ Teff, and CD8+ T cells [132].…”

Section: Antibodies Against Cd33 and Cd123mentioning

confidence: 99%

Current status and future perspectives in targeted therapy of NPM1-mutated AML

et al. 2022

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Nucleophosmin 1 (NPM1) is a nucleus-cytoplasmic shuttling protein which is predominantly located in the nucleolus and exerts multiple functions, including regulation of centrosome duplication, ribosome biogenesis and export, histone assembly, maintenance of genomic stability and response to nucleolar stress. NPM1 mutations are the most common genetic alteration in acute myeloid leukemia (AML), detected in about 30–35% of adult AML and more than 50% of AML with normal karyotype. Because of its peculiar molecular and clinico-pathological features, including aberrant cytoplasmic dislocation of the NPM1 mutant and wild-type proteins, lack of involvement in driving clonal hematopoiesis, mutual exclusion with recurrent cytogenetic abnormalities, association with unique gene expression and micro-RNA profiles and high stability at relapse, NPM1-mutated AML is regarded as a distinct genetic entity in the World Health Organization (WHO) classification of hematopoietic malignancies. Starting from the structure and functions of NPM1, we provide an overview of the potential targeted therapies against NPM1-mutated AML and discuss strategies aimed at interfering with the oligomerization (compound NSC348884) and the abnormal traffic of NPM1 (avrainvillamide, XPO1 inhibitors) as well as at inducing selective NPM1-mutant protein degradation (ATRA/ATO, deguelin, (-)-epigallocatechin-3-gallate, imidazoquinoxaline derivatives) and at targeting the integrity of nucleolar structure (actinomycin D). We also discuss the current therapeutic results obtained in NPM1-mutated AML with the BCL-2 inhibitor venetoclax and the preliminary clinical results using menin inhibitors targeting HOX/MEIS1 expression. Finally, we review various immunotherapeutic approaches in NPM1-mutated AML, including immune check-point inhibitors, CAR and TCR T-cell-based therapies against neoantigens created by the NPM1 mutations.

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“…A clinical trial combining the PD-1 inhibitor nivolumab with the hypomethylating agent azacitidine, performed against this background, showed remarkable efficacy; the ORR was 58% in HMA–naïve patients [ 154 ]. Recent clinical trials combining immune checkpoint inhibitors and conventional drugs for the treatment of AML and/or MDS are summarized in Table 4 [ 155 , 156 , 157 , 158 ].…”

Section: Icismentioning

confidence: 99%

Therapeutic Advances in Immunotherapies for Hematological Malignancies

Nogami

Sasaki

2022

IJMS

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Following the success of immunotherapies such as chimeric antigen receptor transgenic T-cell (CAR-T) therapy, bispecific T-cell engager therapy, and immune checkpoint inhibitors in the treatment of hematologic malignancies, further studies are underway to improve the efficacy of these immunotherapies and to reduce the complications associated with their use in combination with other immune checkpoint inhibitors and conventional chemotherapy. Studies of novel therapeutic strategies such as bispecific (tandem or dual) CAR-T, bispecific killer cell engager, trispecific killer cell engager, and dual affinity retargeting therapies are also underway. Because of these studies and the discovery of novel immunotherapeutic target molecules, the use of immunotherapy for diseases initially thought to be less promising to treat with this treatment method, such as acute myeloid leukemia and T-cell hematologic tumors, has become a reality. Thus, in this coming era of new transplantation- and chemotherapy-free treatment strategies, it is imperative for both scientists and clinicians to understand the molecular immunity of hematologic malignancies. In this review, we focus on the remarkable development of immunotherapies that could change the prognosis of hematologic diseases. We also review the molecular mechanisms, development processes, clinical efficacies, and problems of new agents.

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Pembrolizumab and decitabine for refractory or relapsed acute myeloid leukemia

Cited by 47 publications

References 80 publications

Immune Checkpoint Inhibition in Acute Myeloid Leukemia and Myelodysplastic Syndromes

Immune Checkpoint Inhibition in Acute Myeloid Leukemia and Myelodysplastic Syndromes

Current status and future perspectives in targeted therapy of NPM1-mutated AML

Therapeutic Advances in Immunotherapies for Hematological Malignancies

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