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Clinical and pharmacodynamic activity of bortezomib and decitabine in acute myeloid leukemia.

ABSTRACT: We recently reported promising clinical activity for a 10-day regimen of decitabine in older AML patients; high miR-29b expression associated with clinical response. Subsequent preclinical studies with bortezomib in AML cells have shown drug-induced miR-29b up-regulation, resulting in loss of transcriptional activation for several genes relevant to myeloid leukemogenesis, including DNA methyltransferases and receptor tyrosine kinases. Thus, a phase 1 trial of bortezomib and decitabine was developed. Nineteen poor-risk AML patients (median age 70 years; range, 32-84 years) enrolled. Induction with decitabine (20 mg/m(2) intravenously on days 1-10) plus bortezomib (escalated up to the target 1.3 mg/m(2) on days 5, 8, 12, and 15) was tolerable, but bortezomib-related neuropathy developed after repetitive cycles. Of previously untreated patients (age ? 65 years), 5 of 10 had CR (complete remission, n = 4) or incomplete CR (CRi, n = 1); 7 of 19 overall had CR/CRi. Pharmacodynamic analysis showed FLT3 down-regulation on day 26 of cycle 1 (P = .02). Additional mechanistic studies showed that FLT3 down-regulation was due to bortezomib-induced miR-29b up-regulation; this led to SP1 down-regulation and destruction of the SP1/NF-?B complex that transactivated FLT3. This study demonstrates the feasibility and preliminary clinical activity of decitabine plus bortezomib in AML and identifies FLT3 as a novel pharmacodynamic end point for future trials.

SUBMITTER: Blum W

PROVIDER: S-EPMC3383015 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Clinical and pharmacodynamic activity of bortezomib and decitabine in acute myeloid leukemia.

Blum William W Schwind Sebastian S Tarighat Somayeh S SS Geyer Susan S Eisfeld Ann-Kathrin AK Whitman Susan S Walker Alison A Klisovic Rebecca R Byrd John C JC Santhanam Ramasamy R Wang Hongyan H Curfman John P JP Devine Steven M SM Jacob Samson S Garr Celia C Kefauver Cheryl C Perrotti Danilo D Chan Kenneth K KK Bloomfield Clara D CD Caligiuri Michael A MA Grever Michael R MR Garzon Ramiro R Marcucci Guido G

Blood 20120507 25

We recently reported promising clinical activity for a 10-day regimen of decitabine in older AML patients; high miR-29b expression associated with clinical response. Subsequent preclinical studies with bortezomib in AML cells have shown drug-induced miR-29b up-regulation, resulting in loss of transcriptional activation for several genes relevant to myeloid leukemogenesis, including DNA methyltransferases and receptor tyrosine kinases. Thus, a phase 1 trial of bortezomib and decitabine was develo ...[more]

PMID: 22566605

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Project description:BackgroundPosttherapy measurable residual disease (MRD) positivity in core binding factor acute myeloid leukemia (CBF-AML) is associated with shorter relapse-free survival (RFS). Elimination of MRD measured via quantitative reverse transcription polymerase chain reaction (qRTPCR) for disease specific transcripts can potentially lead to better outcomes in CBF-AML.MethodsWe prospectively monitored the MRD using qRTPCR and flow cytometry on bone marrow samples in patients with newly diagnosed CBF-AML who received decitabine (DAC) maintenance therapy after fludarabine/cytarabine/G-CSF (FLAG)-based induction/consolidation regimen. Negative qRTPCR (CMR) was defined as fusion transcript <0.01%.ResultsThirty-one patients with CBF-AML including 14 with t(8;21) and 17 with inv(16) received parenteral DAC as maintenance therapy. Fifteen patients (48.3%) had completed FLAG-based induction/consolidation but with positive MRD (0.35%, range = 0.01%-0.91%) (Group 1). Sixteen patients (51.7%) could not complete recommended consolidations with FLAG-based regimen (due to older age or complications) and were switched to DAC maintenance (Group 2). In Group 2, eight patients (50%) had undetectable MRD (Group 2A) (all had qRTPCR ≤ 0.01%) and the other eight patients (50%) had residual fusion product by qRTPCR (0.1%, range = 0.02%-0.36%) (Group 2B) prior to starting DAC. Amongst the 23 patients who had a PCR ≥ 0.01% before maintenance therapy (Groups 1 and 2B), 12 patients (52%) attained a CMR as their best response (responders). The median pre-DAC qRTPCR amongst responders were 0.03% compared to 0.14% in nonresponders (p = .002). The median estimated molecular RFS amongst responders were 93.9 months. At a median follow-up of 59.3 months (13.2-106 months) from DAC initiation, 16 patients (51.6%) had to be initiated on a second line of therapy (40%, 25%, and 100% patients, respectively, in Groups1, 2A, and 2B). The median estimated time to new treatment between responders was 112.4 versus 5.8 months in nonresponders (hazard ratio = 0.16, 95% confidence interval = 0.04-0.54); however, there were no difference in overall survival between these groups (p = .37).ConclusionDAC is an effective maintenance therapy for CBF-AML patients with persistent fusion transcript at a low level after FLAG-based regimen. Attainment of CMR with DAC maintenance can lead to long-term remission in patients who have persistent MRD positive after FLAG-based regimen or are unable to receive the full course of consolidation therapy.

Project description:BackgroundThe molecular determinants of clinical responses to decitabine therapy in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) are unclear.MethodsWe enrolled 84 adult patients with AML or MDS in a single-institution trial of decitabine to identify somatic mutations and their relationships to clinical responses. Decitabine was administered at a dose of 20 mg per square meter of body-surface area per day for 10 consecutive days in monthly cycles. We performed enhanced exome or gene-panel sequencing in 67 of these patients and serial sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients. An extension cohort included 32 additional patients who received decitabine in different protocols.ResultsOf the 116 patients, 53 (46%) had bone marrow blast clearance (<5% blasts). Response rates were higher among patients with an unfavorable-risk cytogenetic profile than among patients with an intermediate-risk or favorable-risk cytogenetic profile (29 of 43 patients [67%] vs. 24 of 71 patients [34%], P<0.001) and among patients with TP53 mutations than among patients with wild-type TP53 (21 of 21 [100%] vs. 32 of 78 [41%], P<0.001). Previous studies have consistently shown that patients with an unfavorable-risk cytogenetic profile and TP53 mutations who receive conventional chemotherapy have poor outcomes. However, in this study of 10-day courses of decitabine, neither of these risk factors was associated with a lower rate of overall survival than the rate of survival among study patients with intermediate-risk cytogenetic profiles.ConclusionsPatients with AML and MDS who had cytogenetic abnormalities associated with unfavorable risk, TP53 mutations, or both had favorable clinical responses and robust (but incomplete) mutation clearance after receiving serial 10-day courses of decitabine. Although these responses were not durable, they resulted in rates of overall survival that were similar to those among patients with AML who had an intermediate-risk cytogenetic profile and who also received serial 10-day courses of decitabine. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT01687400 .).

Project description:BackgroundTP53 mutation (TP53mut ) confers an adverse prognosis in acute myeloid leukemia (AML). Venetoclax with hypomethylating agents is a current standard for older patients; however, recent reports suggest that TP53mut confers resistance to venetoclax. The authors investigated the outcomes of patients with TP53mut AML who were treated with a 10-day decitabine and venetoclax (DEC10-VEN) (ClinicalTrials.gov identifier NCT03404193).MethodsPatients with newly diagnosed AML received decitabine 20 mg/m2 for 10 days every 4 to 6 weeks for induction, followed by decitabine for 5 days after response. The venetoclax dose was 400 mg daily. TP53mut was identified in bone marrow samples using next-generation sequencing, with sensitivity of 5%. Outcomes were analyzed according to European LeukemiaNet 2017 guidelines.ResultsAmong 118 patients (median age, 72 years; age range, 49-89 years), 63 (53%) had secondary AML, 39 (33%) had AML with complex karyotype, and 35 (30%) had TP53mut AML. The median TP53 variant allele frequency was 32% (interquartile range, 16%-65%), 8 patients (23%) had only a single TP53 mutation, 15 (43%) had multiple mutations, and 12 (34%) had mutation and deletion. Outcomes were significantly worse in patients who had TP53mut AML compared with those who had wild-type TP53 AML, with an overall response rate of 66% vs 89% (P = .002), a complete response/complete response with incomplete hematologic recovery rate of 57% vs 77% (P = .029), and a 60-day mortality of 26% vs 4% (P < .001), respectively. Patients with TP53mut versus wild-type TP53 had shorter overall survival at 5.2 versus 19.4 months, respectively (hazard ratio, 4.67; 95% CI, 2.44-8.93; P < .0001), and shorter relapse-free survival at 3.4 versus 18.9 months (hazard ratio, 4.80; 95% CI, 1.97-11.69; P < .0001), respectively. Outcomes with DEC10-VEN in patients with TP53mut AML were comparable to historical results with 10-day decitabine alone.ConclusionsPatients with TP53mut AML have lower response rates and shorter survival with DEC10-VEN.

Dataset Information

Clinical and pharmacodynamic activity of bortezomib and decitabine in acute myeloid leukemia.

Publications

Clinical and pharmacodynamic activity of bortezomib and decitabine in acute myeloid leukemia.

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