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A novel regimen for relapsed/refractory adult acute myeloid leukemia
Table 1. Treatment Dose and Schedule.
Dose level
1
2
3
4
DLTs: dose limiting toxicities.
(ELN) favorable risk subtypes.1 Despite recent advances in understanding of leukemogenesis, the initial treatment for most AML patients remains largely unchanged over the past 30 years and salvage regimens also remain similar in their use of a cytarabine backbone. However, targeted therapeutics for specific molecular subsets of AML are beginning to emerge including inhibitors for patients with FLT3-ITD/TKD, IDH1 or IDH2 mutations.2,3 Another potential targetable population in AML includes patients with partial tandem duplication (PTD) in the lysine methyltransferase 2A (KMT2A) gene which was formerly known as mixed lineage leukemia 1 (MLL1). The KMT2A gene is located on Chromosome 11q23 and KMT2A PTD occurs in a single allele of this gene. This alteration occurs more commonly in AML with normal cytogenetics and trisomy 11 and is associated with an adverse prognosis.4-6 Multiple mechanisms are attributed to these adverse out- comes including hypermethylation of gene promoters leading to the silencing of potential tumor suppressors.7,8
Our published data show that the KMT2A wild type (WT) allele is epigenetically silenced in AML with KMT2A PTD.9 We have shown that re-expression of the KMT2A WT allele can be induced with DNA methyltransferase (DNMT) and/or histone deacetylase (HDAC) inhibitors.10,11 Indeed, we demonstrated that epigenetic silencing of KMT2A WT contributes to KMT2A PTD- associated leukemogenesis and that pharmacologic re- expression of this gene with DNMT and HDAC inhibitors attenuates the KMT2A PTD leukemogenic potential and activates apoptotic mechanism important to enhance chemosensitivity, in vitro. Re-expression of KMT2A WT following exposure to decitabine, followed by an HDAC inhibitor, was associated with a lower apoptotic threshold and sensitized KMT2A PTD cells to chemotherapy- induced cytotoxicity. In order to develop a regimen that might be effective in the subset of patients with AML and KMT2A PTD, we conducted a phase 1 study of a novel regimen of combined epigenetic and chemotherapies in relapsed and refractory AML patients. Because of the rela- tively low frequency of KMT2A PTD AML, the initial dose finding portion of this study was conducted in any patient with relapsed/refractory AML regardless of their molecular subtype but was enriched for KMT2A PTD.
Methods
Decitabine Vorinostat (mg/m2/day) (mg/day) Days 1-10 Days 5-10
Cytarabine Number Number (g/m2/q12hr) treated of DLTs Days 12,14,16
20 400 1.5 6 2
20 400 2 3 0 20 400 2.5 3 0 20 400 3 5 0
Eligibility criteria
history of neurological toxicity with cytarabine or vorinostat were ineligible (See Appendix 1 for full Eligibility Criteria). Informed written consent approved by The Ohio State University Humans Studies Committee was obtained on all patients prior to enroll- ment, in accordance with the Declaration of Helsinki.
Treatment
The regimen consisted of epigenetic priming with decitabine followed by vorinostat, then high dose cytarabine (which was dose-escalated). The dosing regimen was based on pre-clinical data showing the myeloid apoptotic threshold decreased most sig- nificantly compared to other therapeutic sequences. Decitabine was given intravenously over 1 hour at a dose of 20mg/m2/day on Days 1-10. Vorinostat was given orally at a dose of 400mg/day on Days 5-10. Cytarabine was administered intravenously over 2 hours every 12 hours on Days 12, 14, and 16 for 6 doses total. Cytarabine was dose escalated as follows: dose level 1, 1.5g/m2/q12hr; dose level 2, 2g/m2/q12hr; dose level 3, 2.5g/m2/q12hr; and dose level 4, 3g/m2/q12hr (Table 1). The study was designed in classic 3+3 phase I design schema to determine the maximum tolerated dose (MTD) and define dose limiting tox- icity (DLT). Adverse events were graded according to National Cancer Institute Common Toxicity Criteria for Adverse Events, version 4.0. Responses were defined according to International Working Group (IWG) Criteria for AML, including complete remission (CR) and CR with incomplete count recovery (CRi), par- tial remission (PR), and treatment failure.12 Next generation sequencing using MiSeq platform assessed over 80 AML-associat- ed gene mutations as previously described.13 KMT2A PTD and FLT3-ITD mutations were performed by PCR testing.14,15
Definition of dose limiting toxicity
Grade 4 non-hematological toxicity attributable to any of the therapeutic agents, with exception of line-associated venous thrombosis, infection, fatigue, or nausea and vomiting controllable with anti-emetic therapy were defined as DLT. Hematologic toxi- city was initially defined as failure to recover peripheral blood counts by Day 42 in patients with <5% blasts in the bone marrow, absence of myelodysplastic changes, and/or absence of disease by flow cytometry in the bone marrow. However, 2 patients at dose level 1 experienced delayed count recovery (beyond day 42) meet- ing the hematological DLT definition but both patients achieved CR with no long-term sequelae. It was felt disadvantageous to reduce chemotherapy doses due to high risk nature of the disease, and the protocol was modified to extend duration of hematologic DLT to Day 56 with G-CSF permitted to hasten neutrophil recov- ery in patients with hypoplastic bone marrow after treatment.
Statisticalanalysis
A standard method 3 + 3 phase I design of dose escalation using 3 patients per dose level cohort and a minimum of 6 patients at the MTD was performed. As an exploratory, phase I study, no infer-
Eligible patients were adults (≥18 and <60 years) with relapsed/refractory non-M3 AML with adequate organ function and ECOG performance status ≤2. Patients with previous expo- sure to high-dose cytarabine were eligible. Patients with previous
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