General AML

Phase I study evaluating a KMT2A partial tandem duplication targeted regimen in R/R AML

Acute myeloid leukemia (AML) patients with lysine methyltransferase 2A (KMT2A) partial tandem duplication (PTD) have poor outcomes.1  Alice S. Mims from the Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA, and colleagues previously showed that KMT2A wild type (WT) allele is epigenetically silenced in KMT2A PTD AML patients, moreover, allele re-expression of KMT2A can be augmented with DNA methyltransferase (DNMT) and HDAC inhibitors. With the aim of developing a therapy regimen for KMT2A PTD AML patients, the study group conducted a phase I trial (NCT01130506) evaluating the combination of decitabine and vorinostat prior to high dose cytarabine in relapsed and refractory (R/R) AML patients. The results of the study were published ahead of print in Haematologica.2

Overall, 17 adult R/R AML patients were enrolled (median age = 46 years, 21–59) and four of them had KMT2A PTD. Patients were administered decitabine (20 mg/m2/day IV) on Days 1–10, vorinostat (400 mg/day orally) on Days 5–10, and cytarabine which was dose escalated (dose level 1: 1.5 g/m2/q12hr; dose level 2: 2 g/m2/q12hr; dose level 3: 2.5 g/m2/q12hr; and dose level 4: 3g/m2/q12hr IV) and was given twice a day on Days 12, 14, and 16.

Key findings:
Safety
  • At dose level 1, DLTs of prolonged mylosuppression occurred in two patients
  • Most common side effects included diarrhoea (41%), nausea (29%), fatigue (29%), febrile neutropenia (35%), and elevated alanine aminotransferase (35%)
  • Most common grade >3 toxicities were febrile neutropenia (35%) and catheter-related infections (24%)
Efficacy
  • Complete remission (CR) rate: 35% (6/17)
  • Two of the four patients harboring KMT2A PTD mutations achieved cytogenetic CR

In conclusion, decitabine, vorinostat prior to high-dose cytarabine regimen was well tolerated in R/R AML patients with KMT2A PTD and should be further investigated in a phase II setting.

The authors added that “the small number of patients limits the interpretation of these findings” and that “the study provides a framework for larger efficacy studies for AML patients with the uncommon but biologically distinct molecular feature of KMT2A PTD.”

References
  1. Döhner H. et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129(4):424-447. DOI:  10.1182/blood-2016-08-733196.
  2. Mims A.S. et al. A novel regimen for relapsed/refractory adult acute myeloid leukemia using a KMT2A partial tandem duplication targeted therapy: results of phase 1 study NCI 8485. Haematologica. 2018 March 22. DOI: 10.3324/haematol.2017.186890. [Epub ahead of print].
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