A phase I clinical trial of avelumab in combination with decitabine as first line treatment of unfit patients with acute myeloid leukemia.
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ABSTRACT:
SUBMITTER: Zheng H
PROVIDER: S-EPMC7894154 | biostudies-literature | 2021 Feb
REPOSITORIES: biostudies-literature
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A phase I clinical trial of avelumab in combination with decitabine as first line treatment of unfit patients with acute myeloid leukemia.
Zheng Hong H Mineishi Shin S Claxton David D Zhu Junjia J Zhao Chenchen C Jia Bei B Ehmann W Christopher WC Rybka Witold B WB Naik Seema S Songdej Natthapol N Drabick Joseph J JJ Hohl Raymond J RJ
American journal of hematology 20201123 2
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Project description:The treatment of acute myeloid leukemia of older, medically non-fit patients still poses a highly unmet clinical need, and only few large, prospective studies have been performed in this setting. Given the established activity of hypomethylating agents such as 5-aza-2'-deoxycytidine (decitabine) in myelodysplastic syndromes and acute myeloid leukemia with 20-30% bone marrow blasts, we investigated whether this drug is also active in patients with more than 30% blasts.To evaluate the efficacy and toxicity of decitabine in patients over 60 years old with untreated acute myeloid leukemia ineligible for induction chemotherapy, 227 patients (median age, 72 years), many with comorbidities, adverse cytogenetics and/or preceding myelodysplastic syndrome were treated with this hypomethylating agent. During the initial decitabine treatment (135 mg/m(2) total dose infused intravenously over 72 hours every 6 weeks), a median of two cycles was administered (range, 1-4). All-trans retinoic acid was administered to 100 patients during course 2. Fifty-two patients who completed four cycles of treatment subsequently received a median of five maintenance courses (range, 1-19) with a lower dose of decitabine (20 mg/m(2)) infused over 1 hour on 3 consecutive days every 4-6 weeks.The complete and partial remission rate was 26%, 95% CI (20%, 32%), and an antileukemic effect was noted in 26% of patients. Response rates did not differ between patients with or without adverse cytogenetics; patients with monosomal karyotypes also responded. The median overall survival from the start of decitabine treatment was 5.5 months (range, 0-57.5+) and the 1-year survival rate was 28%, 95%CI (22%,34%). Toxicities were predominantly hematologic.Decitabine is well tolerated by older, medically non-fit patients with acute myeloid leukemia; myelosuppression is the major toxicity. The response rate and overall survival were not adversely influenced by poor-risk cytogenetics or myelodysplastic syndrome. Because of these encouraging results, randomized studies evaluating single-agent decitabine versus conventional treatment are warranted. The study is registered with the German Clinical Trials Registry, number DRKS00000069.
| S-EPMC3291594 | biostudies-literature
Project description:PurposeDecitabine, a DNA hypomethylating agent, was recently approved for use in Korea for older adults with acute myeloid leukemia (AML) who are not candidates for standard chemotherapy. This study aimed to evaluate the role of decitabine as a first-line treatment for older adults with AML.Materials and methodsTwenty-four patients with AML who received at least one course of decitabine (20 mg/m²/d intravenously for 5 days every 4 weeks) as a first-line therapy at Severance Hospital were evaluated retrospectively.ResultsThe median age of the patients was 73.5 years. The longest follow-up duration was 502 days. A total of 113 cycles of treatment were given to 24 patients, and the median number of cycles was four (range, 1-14). Thirteen patients dropped out because of death, no or loss of response, patient refusal, or transfer to another hospital. Twenty-one (87.5%) and 12 (50%) patients completed the second and fourth cycles, respectively, and responses to treatment were evaluated in 17. A complete response (CR) or CR with incomplete blood-count recovery was achieved in six (35.3%) patients, and the estimated median overall survival was 502 days. Ten patients developed grade >2 hematologic or non-hematologic toxicities. In univariate analysis, bone marrow blasts, lactate dehydrogenase, serum ferritin level, and bone marrow iron were significantly associated with response to decitabine.ConclusionFive-day decitabine treatment showed acceptable efficacy in older patients with AML who are unfit for conventional chemotherapy, with a CR rate 35.3% and about a median overall survival of 18 months.
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Project description:The hypomethylating agents, decitabine (DEC) and azacitidine (AZA), allowed more elderly acute myeloid leukemia (AML) patients to be treated. However, there are little direct comparative data on AZA and DEC. This multicenter retrospective study compared the outcomes of AZA and DEC in terms of response and overall survival (OS). Potential predictors associated with response and OS were also evaluated. A total of 626 AML patients were included (487 treated with AZA and 139 with DEC). Response rates were similar in both groups: CR was 18% with AZA vs. 23% with DEC (p = 0.20), CR/CRi was 20.5% vs. 25% (p = 0.27) and ORR was 32% vs. 39.5% (p = 0.12), respectively. Patients with leukocytes < 10 × 109/L, bone marrow blasts < 50% and ECOG ≥ 2 had higher ORR with DEC than with AZA. OS was similar in both groups: 10.4 months (95% CI: 9.2-11.7) vs. 8.8 months (95% CI: 6.7-11.0, p = 0.455), for AZA and DEC, respectively. Age (≥80 years), leukocytes (≥ 10 × 109/L), platelet count (<20 × 109/L) and eGFR (≥45 mL/min/1.73 m2) were associated with higher OS with AZA compared to DEC. In conclusion, we found no differences in response and OS rates in AML patients treated with AZA or DEC.
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Project description:Current treatment options for older and relapsed or refractory (R/R) acute myeloid leukemia (AML) patients are limited and represent an unmet need. Based on preclinical studies showing strong anti-leukemic effects in vivo, this phase I dose-escalation study assessed the safety and preliminary clinical activity of the oral exportin-1 inhibitor, selinexor, in combination with the hypomethylating agent, decitabine 20 mg/m2, in adults with R/R AML and in older (age ≥ 60) untreated AML patients. There were no protocol-defined dose limiting toxicities. The recommended phase 2 dose of selinexor was 60 mg (∼35 mg/m2) given twice-weekly. Notable grade ≥3 toxicities included asymptomatic hyponatremia (68%), febrile neutropenia (44%), sepsis (44%), hypophosphatemia (36%), and pneumonia (28%). In 25 patients, the overall response rate was 40%. Modification of selinexor to a flat dose of 60 mg, twice-weekly for two weeks after decitabine, improved tolerability of the regimen and demonstrated preliminary clinical activity in poor-risk patients with AML.
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Project description:This phase I trial sought to determine a biologically safe and effective dose of AR-42, a novel histone deacetylase inhibitor, which would lead to a doubling of miR-29b prior to decitabine administration. Thirteen patients with previously untreated or relapsed/refractory AML were treated at 3 dose levels (DL): AR-42 20 mg qd on d1,3,5 in DL1, 40 mg qd on d1,3,5 in DL2 and 40 mg qd on d1,3,4,5 in DL3. Patients received decitabine 20 mg/m2 on d6-15 of each induction cycle and 20 mg/m2 on d6-10 of each maintenance cycle. One DLT of polymicrobial sepsis and multi-organ failure occurred at DL3. Two patients achieved a CRi and one patient achieved a CR for an ORR of 23.1%. The higher risk features of this patient population and the dosing schedule of AR-42 may have led to the observed clinical response and failure to meet the biologic endpoint.
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Project description:Azacytidine (AzaC) and decitabine (AzadC) are cytosine analogs that covalently trap DNA methyltransferases, which place the important epigenetic mark 5-methyl-2'-deoxycytidine by methylating 2'-deoxycytidine (dC) at the C5 position. AzaC and AzadC are used in the clinic as antimetabolites to treat myelodysplastic syndrome and acute myeloid leukemia and are explored against other types of cancer. Although their principal mechanism of action is known, the downstream effects of AzaC and AzadC treatment are not well understood and the cellular prerequisites that determine sensitivity toward AzaC and AzadC remain elusive. Here, we investigated the effects and phenotype of AzaC and AzadC exposure on the acute myeloid leukemia cell line MOLM-13. We found that while AzaC and AzadC share many effects on the cellular level, including decreased global DNA methylation, increased formation of DNA double-strand breaks, transcriptional downregulation of important oncogenes and similar changes on the proteome level, AzaC failed in contrast to AzadC to induce apoptosis efficiently in MOLM-13. The only cellular marker that correlated with this clear phenotypical outcome was the level of hydroxy-methyl-dC, an additional epigenetic mark that is placed by TET enzymes and repressed in cancer cells. Whereas AzadC increased hmdC substantially in MOLM-13, AzaC treatment did not result in any increase at all. This suggests that hmdC levels in cancer cells should be monitored as a response toward AzaC and AzadC and considered as a biomarker to judge whether AzaC or AzadC treatment leads to cell death in leukemic cells.
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Project description:PurposePatients with acute myeloid leukemia (AML) unfit for, or resistant to, intensive chemotherapy are often treated with DNA methyltransferase inhibitors (DNMTi). Novel combinations may increase efficacy. In addition to demethylating CpG island gene promoter regions, DNMTis enhance PARP1 recruitment and tight binding to chromatin, preventing PARP-mediated DNA repair, downregulating homologous recombination (HR) DNA repair, and sensitizing cells to PARP inhibitor (PARPi). We previously demonstrated DNMTi and PARPi combination efficacy in AML in vitro and in vivo. Here, we report a phase I clinical trial combining the DNMTi decitabine and the PARPi talazoparib in relapsed/refractory AML.Patients and methodsDecitabine and talazoparib doses were escalated using a 3 + 3 design. Pharmacodynamic studies were performed on cycle 1 days 1 (pretreatment), 5 and 8 blood blasts.ResultsDoses were escalated in seven cohorts [25 patients, including 22 previously treated with DNMTi(s)] to a recommended phase II dose combination of decitabine 20 mg/m2 intravenously daily for 5 or 10 days and talazoparib 1 mg orally daily for 28 days, in 28-day cycles. Grade 3-5 events included fever in 19 patients and lung infections in 15, attributed to AML. Responses included complete remission with incomplete count recovery in two patients (8%) and hematologic improvement in three. Pharmacodynamic studies showed the expected DNA demethylation, increased PARP trapping in chromatin, increased γH2AX foci, and decreased HR activity in responders. γH2AX foci increased significantly with increasing talazoparib doses combined with 20 mg/m2 decitabine.ConclusionsDecitabine/talazoparib combination was well tolerated. Expected pharmacodynamic effects occurred, especially in responders.
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Project description:Despite advancements in cancer therapeutics, acute myeloid leukemia patients over 60 years old have a 5-year survival rate of less than 8%. In an attempt to improve this, epigenetic modifying agents have been combined as therapies in clinical studies. In particular combinations with Decitabine and Vorinostat have had varying degrees of efficacy. This study therefore aimed to understand the underlying molecular mechanisms of these agents to identify potential rational epi-sensitized combinations. Combined Decitabine-Vorinostat treatment synergistically decreased cell proliferation, induced apoptosis, enhanced acetylation of histones and further decreased DNMT1 protein with HL-60 cells showing a greater sensitivity to the combined treatment than OCI-AML3. Combination therapy led to reprogramming of unique target genes including AXL, a receptor tyrosine kinase associated with cell survival and a poor prognosis in AML, which was significantly upregulated following treatment. Therefore targeting AXL following epi-sensitization with Decitabine and Vorinostat may be a suitable triple combination. To test this, cells were treated with a novel triple combination therapy including BGB324, an AXL specific inhibitor. Triple combination increased the sensitivity of OCI-AML3 cells to Decitabine and Vorinostat as shown through viability assays and significantly extended the survival of mice transplanted with pretreated OCI-AML3 cells, while bioluminescence imaging showed the decrease in disease burden following triple combination treatment. Further investigation is required to optimize this triple combination, however, these results suggest that AXL is a potential marker of response to Decitabine-Vorinostat combination treatment and offers a new avenue of epigenetic combination therapies for acute myeloid leukemia.
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Project description:The azanucleotide decitabine is used in the treatment of acute myeloid leukemia (AML). Studies have shown conflicting results with 10-day regimens used in previously untreated AML patients. Additionally, there is little data on 10-day decitabine regimens in the relapsed setting. This study investigated outcomes of 108 adult patients with AML in the upfront and relapsed setting treated with a 10-day decitabine regimen. In the upfront group, the overall response rate (ORR, CR + CRi) was 36.1% and the median overall survival (OS) was 6.6 months, while the relapsed/refractory group had an ORR of 25% with an OS of 4.8 months. When analyzed with respect to cytogenetics, the upfront group featured an ORR of 28.1% with an OS of 9.4 months in the intermediate cytogenetic cohort compared to a 40.5% ORR and an OS of 5.4 months in the unfavorable cytogenetic cohort. An analysis of the relapsed/refractory group demonstrated an ORR of 26.3% with an OS of 7.9 months for intermediate cytogenetics versus 25.0% with an OS of 1.8 months in the unfavorable cohort. While these response rates are similar to previously published data, the median OS appears shorter.
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