General AML

Combination of everolimus and LDAC was not effective in elderly AML patients – a phase Ib study

In Acute Myeloid Leukemia (AML), aberrant mammalian Target of Rapamycin (mTOR) signaling occurs in approximately 50–80% of patients and it is associated with poor outcomes and therapy resistance.1

In a Letter to the Editor of Leukemia & Lymphoma, Ing S. Tiong from the Alfred Hospital, Melbourne, Australia, et al. reported results from their phase Ib dose-escalation study (NCT00636922), which aimed to determine the efficacy and tolerability of everolimus (inhibitor of Mammalian Target of Rapamycin Complex 1 [mTORC1]) in combination with Low Dose cytarabine (LDAC) in elderly patients with AML who are unfit for intensive chemotherapy.2

In total, 24 AML patients (median age = 74 years) were enrolled in this study between March 2008–July 2009. Patients were administered subcutaneous LDAC 20mg twice daily for 10 days every 28–42 day for four cycles and continuous oral everolimus at one of three dose levels including 2.5 mg (n = 8), 5mg (n = 8) or 10 mg (n = 8) for up to 3 months.

The key results of the study were:
  • Dose Limiting Toxicities (DLTs) were observed in patients in the 2.5 mg (leukocytosis flare, n = 1), 5 mg (heart failure, n = 1) and in the 10 mg (cough [n = 1], mouth ulcers [n = 1] and sepsis [n = 2]) cohort
  • Grade 4 adverse events occurred including thrombocytopenia (58%) and neutropenia (67%)
  • Overall Response Rate (ORR); 25% (6/24)
  • Median Overall Survival (OS)
    • All patients; 6.0 months
    • In patients administered 2.5, 5.0 and 10 mg everolimus; 7.1 vs 6.3 vs 4.6 months
    • Responders and non-responders; 18.9 vs 5.5 months, P = 0.041
    • Poor risk and standard-risk patients; 5.7 vs 8.0 months, P = 0.028

In summary, the findings of the study did not “reveal an efficacy signal for the combination of LDAC with the mTORC1 inhibitor everolimus”. Additionally, the “combination might increase toxicity, with DLTs encountered with 10 mg everolimus in combination with LDAC”.

The authors concluded by suggesting that future studies should investigate the combination of mTOR inhibitors with other novel agents in the therapy for AML in order to answer biologically targeted questions.

References
  1. Dinner S. & Platanias L. C. Targeting the mTOR Pathway in Leukemia. J Cell Biochem. 2016 Aug; 117(8): 1745–52. DOI: 10.1002/jcb.25559. Epub 2016 Apr 6.
  2. Tiong I. S. et al. Phase Ib study of the mTOR inhibitor everolimus with low dose cytarabine in elderly acute myeloid leukemia. Leuk Lymphoma. 2017 Jun 8: 1–4. DOI: 10.1080/10428194.2017.1334122. [Epub ahead of print].