Page 84 - Haematologica June

A.S. Mims et al.
Discussion
Table 4. Non-hematological toxicities possibly attributable.
Epigenetic deregulation is felt to contribute to the under- lying pathobiology of AML and both aberrant DNA methylation and histone acetylation have been explored as potential therapeutic targets in this disease.16 Monotherapy with hypomethylating agents, azacitidine and decitabine, that target DNMTs have shown some suc- cess in regards to clinical activity and are currently used in the treatment of AML, though neither are considered cur- ative therapies in this patient population.17 These agents have become the standard of care for elderly patients who are unfit to undergo intensive induction chemotherapy. With regards to HDAC inhibition, though preclinical find- ings in AML have been exciting, these results have yet to translate into significant clinical responses in AML both as monotherapy and in combination with hypomethylating agents or with cytotoxic chemotherapy.18-21 However, priming with both hypomethylating agents and HDAC inhibitors prior to salvage chemotherapy has shown some promise.22
A dose-finding study of decitabine and valproic acid in 25 patients in both relapsed/refractory and untreated, unfit AML populations has been previously performed. Due to the major DLT of the study of encephalopathy in older patients attributed to valproic acid, this current study of combination therapy with HDAC inhibitors was limited to those <60 years old. It was also felt a different HDAC inhibitor, such as vorinostat, might be better toler- ated.23
As mentioned, vorinostat has also been studied in com- bination with other agents in AML, including hypomethy- lating agents and cytotoxic chemotherapies. Kirschbaum, et al. randomized patients with untreated (n=31) and relapsed/refractory AML (n=29) along with myelodysplas- tic syndrome (MDS) (n=31) to concurrent decitabine plus vorinostat versus sequential decitabine followed by vorinostat. Both schedules were felt to be well-tolerated but more objective responses (CRs plus PRs) were seen in the concurrent schedule (46% vs. 14% in untreated AML, 15% vs. 0% in relapsed/refractory AML, and 60% vs. 0% in MDS).24 Gojo et al. assessed the ability to add vorinostat prior to etoposide and cytarabine in relapsed/refractory AML or acute lymphoblastic leukemia, newly diagnosed secondary AML, or chronic myeloid leukemia in acceler- ated or blastic phase failing or intolerant of tyrosine kinase inhibitor therapy. The MTD was found to be vorinostat 200mg orally twice a day (Days 1-7) followed by cytara- bine and etoposide on Days 11-14 with DLTs of hyper- bilirubinemia/septic death and anorexia/fatigue at higher dosing. In the 21 patients treated, there were 7 CRs (n=5) or CRi’s (n=2) all in the AML population (2 newly diag- nosed high-risk and 5 relapsed/refractory patients).25 A phase II trial combined vorinostat 500mg orally 3 times a day (Days 1-3) followed by idarubicin and cytarabine induction chemotherapy in younger untreated AML and higher-risk MDS patients and saw no excess in vorinostat- related toxicities with an overall response rate of 85% including 76% CR and 9% CRi rates.20 A Phase III ran- domized intergroup study assessed the benefit of vorino- stat in addition to high dosed cytarabine-based induction chemotherapy vs. induction chemotherapy alone and did not show any differences in CR, event-free survival, or overall survival with the addition of vorinostat. Toxicity was considered similar between groups.26 However, the
Toxicity
Diarrhea
Nausea
Fatigue
Catheter-related infection
Lung infection
Hypoxia
Febrile neutropenia
Blood bilirubin increased
Peripheral sensory neuropathy
Dyspnea
Lymph node pain
Abdominal pain
Colitis
Dry mouth
Mucositis oral
Proctitis
Rectal pain
Vomiting
Sinusitis
Prolonged PTT
Increased ALT
Increased AST
Creatinine increased
Anorexia
Urinary incontinence
Cough
Weight loss
Headache
Proteinuria
All grades number of events
7
5
5
4
2
1
6
1
1
2
1
2
1
1
1
1
1
1
1
1
6
3
1
4
1
2
1
1
1
Grade 3 or greater number
of events
2
4 2 1 6
1
1
1 1
986
ALT: alanine aminotransferase; AST: aspartate aminotransferase; PTT: partial thrombo- plastin time.
effect of epigenetic priming, particular for subsets of dis- ease that may be sensitive to the approach, remains an area of interest for clinical development.
In this phase I study, we evaluated the combination of decitabine and vorinostat priming prior to high-dose cytarabine in a cohort of younger AML patients with relapsed or refractory AML. We developed a regimen for subsequent phase 2 testing in the select population that may be sensitive to the approach (KMT2A PTD). The treatment was generally well-tolerated with exception of the initial prolonged myelosuppression identified in dose level 1 and there were otherwise no DLTs. The most com- mon toxicities seen including febrile neutropenia, nausea, and diarrhea are all common side effects that can be seen with high-dose cytarabine alone. Neurotoxicity that was seen previously with valproic acid in combination with decitabine was not seen in this patient population.23 This combination therapy resulted in CR in 6 patients with an overall response rate of 35%. Although the small number of patients limits the interpretation of these findings, prior
haematologica | 2018; 103(6)