A phase II trial of decitabine, bortezomib and pegylated liposomal doxorubicin for the treatment of relapsed or refractory AML

Jonas, Brian A.; Potter, Laura A.; Galkin, Maria; Tuscano, Joseph M.

doi:10.1016/j.lrr.2023.100374

Cited by 2 publications

(6 citation statements)

References 7 publications

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“…For the same reason, newly developed and potentially more efficient drugs are now available, that begin to be tested in this context. [13][14][15][16][17] In conclusion, the BSC group here confirms the dismal prognosis of AML-MRC patients. Although ICT and allo-HSCT appear currently to be the best choice for R/R AML-MRC patients, AZA could be considered a feasible option for patients ineligible to ICT.…”

Section: Discussionsupporting

confidence: 78%

“…Indeed, molecular data are lacking, that would have helped to better classify the patient. For the same reason, newly developed and potentially more efficient drugs are now available, that begin to be tested in this context 13–17 …”

Section: Discussionmentioning

confidence: 99%

“…A significant improvement of the remission rate was confirmed for patients who received CPX‐351 (47.7% vs 33.3%; p = 0.016) as well as a better median OS (9.5 months vs 5.9 months; p = 0.003). Since then, more recently developed drugs have been tested in the context of R/R AML, 13 , 14 , 15 , 16 yet without singling out patients with MRC‐AML.…”

Section: Introductionmentioning

confidence: 99%

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Dismal outcome of refractory or relapsing patients with myelodysplasia‐related acute myeloid leukemia partially alleviated by intensive chemotherapy

Leroy,

Gadaud,

Bérard

et al. 2024

Cancer Medicine

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BackgroundAcute myeloid leukemia (AML) with myelodysplasia‐related characteristics is a heterogeneous subset of AML that has been challenged throughout the history of myeloid malignancies classifications, considered to have similar outcomes as intermediate‐ or adverse‐risk AML depending on the subgroup. However, little is known about the fate of these patients in refractory or relapsed situation (R/R) after first line therapy.MethodsA large series of R/R AML patients, recorded in the French DATAML registry, have received either intensive chemotherapy (ICT), azacitidine (AZA) as single agent, or best supportive care (BSC). A cohort of 183 patients (median age 63‐year‐old) with what was called at the time AML‐MRC has been explored, and data are reported here.ResultsPatient status was refractory for 93, while 90 had relapsed. Respectively, 88, 34, and 61 were included in the three treatment arms. The median OS of the whole cohort was 4.2 months (95%CI: 3.1–5.6) with a mean 1‐year overall survival of 24% ± 3.2%. There was no significant survival difference between refractory and relapsed patients. The BSC group had overall a significantly worse outcome (p = 0.0001), and this remained true in both refractory (p = 0.01) and relapsed (p = 0.002) patients. Similar survivals were observed in both groups comparing ICT and AZA.ConclusionsThese data, reporting about an ill‐explored population, indicate the poor prognosis of this condition where both ICT and AZA can be proposed. The latter, which was demonstrated here to be a feasible option, should be added to new targeted therapies.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dismal outcome of refractory or relapsing patients with myelodysplasia‐related acute myeloid leukemia partially alleviated by intensive chemotherapy

Leroy,

Gadaud,

Bérard

et al. 2024

Cancer Medicine

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“…9 In addition, BTZ may be effective in treating other haematological neoplastic diseases, such as T-cell acute lymphoblastic leukaemia, 10 lymphoma 10 and AML. 11 BTZ has been reported to inhibit the stemness features of AML, including AML with lysine [K]-methyltransferase 2A (KMT2A)/ mixed-lineage leukaemia 1 (KMT2A/MLL) rearrangements, a type of aggressive AML, via NF-ĸB-dependent inhibition of CDK6. 12,13 In this work, we investigated the anti-AML activity of BTZ, emphasizing its anti-LSC potential, using KG-1a cells, an AML cell line with stem-like properties.…”

Section: Introductionmentioning

confidence: 99%

“…Bortezomib (BTZ, Figure 1A) is a FDA‐approved treatment of multiple myeloma, and mantle cells lymphoma that act as a selective and reversible inhibitor of the 26S proteasome 9 . In addition, BTZ may be effective in treating other haematological neoplastic diseases, such as T‐cell acute lymphoblastic leukaemia, 10 lymphoma 10 and AML 11 . BTZ has been reported to inhibit the stemness features of AML, including AML with lysine [K]‐methyltransferase 2A (KMT2A)/mixed‐lineage leukaemia 1 (KMT2A/MLL) rearrangements, a type of aggressive AML, via NF‐ĸB‐dependent inhibition of CDK6 12,13 …”

Section: Introductionmentioning

confidence: 99%

Bortezomib suppresses acute myelogenous leukaemia stem‐like KG‐1a cells via NF‐κB inhibition and the induction of oxidative stress

Costa,

Oliveira,

Rodrigues

et al. 2024

J Cellular Molecular Medi

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Acute myelogenous leukaemia (AML) originates and is maintained by leukaemic stem cells (LSCs) that are inherently resistant to antiproliferative therapies, indicating that a critical strategy for overcoming chemoresistance in AML therapy is to eradicate LSCs. In this work, we investigated the anti‐AML activity of bortezomib (BTZ), emphasizing its anti‐LSC potential, using KG‐1a cells, an AML cell line with stem‐like properties. BTZ presented potent cytotoxicity to both solid and haematological malignancy cells and reduced the stem‐like features of KG‐1a cells, as observed by the reduction in CD34‐ and CD123‐positive cells. A reduction in NF‐κB p65 nuclear staining was observed in BTZ‐treated KG‐1a cells, in addition to upregulation of the NF‐κB inhibitor gene NFΚBIB. BTZ‐induced DNA fragmentation, nuclear condensation, cell shrinkage and loss of transmembrane mitochondrial potential along with an increase in active caspase‐3 and cleaved PARP‐(Asp 214) level in KG‐1a cells. Furthermore, BTZ‐induced cell death was partially prevented by pretreatment with the pancaspase inhibitor Z‐VAD‐(OMe)‐FMK, indicating that BTZ induces caspase‐mediated apoptosis. BTZ also increased mitochondrial superoxide levels in KG‐1a cells, and BTZ‐induced apoptosis was partially prevented by pretreatment with the antioxidant N‐acetylcysteine, indicating that BTZ induces oxidative stress‐mediated apoptosis in KG‐1a cells. At a dosage of 0.1 mg/kg every other day for 2 weeks, BTZ significantly reduced the percentage of hCD45‐positive cells in the bone marrow and peripheral blood of NSG mice engrafted with KG‐1a cells with tolerable toxicity. Taken together, these data indicate that the anti‐LSC potential of BTZ appears to be an important strategy for AML treatment.

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A phase II trial of decitabine, bortezomib and pegylated liposomal doxorubicin for the treatment of relapsed or refractory AML

Cited by 2 publications

References 7 publications

Dismal outcome of refractory or relapsing patients with myelodysplasia‐related acute myeloid leukemia partially alleviated by intensive chemotherapy

Dismal outcome of refractory or relapsing patients with myelodysplasia‐related acute myeloid leukemia partially alleviated by intensive chemotherapy

Bortezomib suppresses acute myelogenous leukaemia stem‐like KG‐1a cells via NF‐κB inhibition and the induction of oxidative stress

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