General AML

Phase II study of low dose lenalidomide plus cytarabine in elderly AML patients

In the September 2017 issue of Leukemia Research, Giuseppe Visani et al. from the AORMN Hospital, Pesaro, Italy, reported results from their prospective phase II study (EudraCT Number: 2008-006790-33), which evaluated the efficacy and safety of low-dose lenalidomide plus cytarabine in elderly Acute Myeloid Leukemia (AML) patients.

Overall, 66 newly diagnosed elderly patients with AML with a median age of 76 years (range, 70–85 years), who were ineligible for standard therapy were included in this study. Patients were administered low-dose lenalidomide (10 mg/day orally, Days 1–21) plus low-dose cytarabine (10 mg/m2 subcutaneously, twice a day (Days 1–15).  The primary outcome of the study was Complete Remission (CR) rate with the lowest acceptable rate (P0) at 17% and the successful rate (PI) at 30%.

The key findings were:
  • Response
    • CR rate; 36.3% (24/66)
    • Partial Response (PR); 3% (2/66)
  • Median Overall Survival (OS) in responders and non-responders; 517 vs 70 days respectively, P = 0.01
  • Safety
    •  Death occurred in after the first cycle of therapy due to infectious complications (n = 8) and acute heart failure (n = 1)
    • Most common Grade 3–4 Adverse Events (AEs) include thrombocytopenia (71%), neutropenia (61%), neutropenic fever (18%) and anemia (30%)

The authors also aimed to identify a potential biomarker that is predictive of treatment response. The Global Expression Profile (GEP) of Peripheral Blood (PB) or Bone Marrow (BM) samples from 26 patients which were collected at diagnosis and had a clinical outcome (CR [n = 14] or no CR [n = 12]) were analyzed.

The key findings were:
  • Three hundred and nine genes were differentially expressed between samples from patients in CR versus no CR
  • A minimal gene set of 16 genes (ATF3, CHMP6, HCP5, HLAE, HOMER3, MGC21881, MID1IP1, MLF2, PAX5, PGL2, PGM1, RHOA, RTN3, TMEM44, UBE2L3, VAMP8) were identified which were sufficient enough to discriminate cases according to clinical response
  • Using an algorithm on the 16 genes, response was predicted in AML samples with an accuracy of 88%
  • Mean OS of patients classified as predicted responders were significantly better than patients that were classified as predicted non-responders; 16.24 vs 2.36 months respectively, P < 0.001

In summary, low-dose lenalidomide and cytarabine combination has “clinical activity in elderly AML patients”. Additionally, the use of GEP identified a “specific molecular signature which discriminated patients according to treatment response”.

The authors noted that an independent validation in future studies with lenalidomide and cytarabine is warranted in order to confirm the findings of their study. They further concluded by stating that the data from their study “supports the prospective use of a GEP-driven therapy in a cohort of hard-to-treat AML patients unfit for standard therapy, with an extremely poor prognosis”.


Outcome for elderly patients with acute myeloid leukemia (AML) is extremely poor. Intensive induction chemotherapy is often unsuitable. Sixty-six newly diagnosed AML patients (median age: 76 years), ineligible for standard therapy, were consecutively treated with low-dose lenalidomide (10 mg/day orally, days 1–21) plus 10 mg/m2 low-dose cytarabine, subcutaneously, twice a day (days 1–15) every six weeks, up to 6 cycles. Complete remission (CR) rate was 36.3% according to intention-to-treat. Responding patients had a longer median overall survival than non-responders (517 vs. 70 days, P < 0.001). The achievement of CR was not predicted by bone marrow blast count, cytogenetics, molecular markers, prior MDS, white blood cell count. Conversely, by studying the global gene expression profile, we identified a molecular signature, including 309 genes associated with clinical response (CR versus no CR). Based on the expression of a minimal set of 16 genes, we developed an algorithm to predict treatment response, that was successfully validated by showing an overall accuracy of 88%. We met the primary endpoint of the study, by beating the estimated successful CR rate (P1) fixed at 30%. Moreover, CR induced by this 2-drug combo was efficiently predicted by genetic profiling, identifying a biomarker that warrants validation in independent series.

  1. Visani G. et al. Low-dose lenalidomide plus cytarabine in very elderly, unfit acute myeloid leukemia patients: Final result of a phase II study. Leuk Res. 2017 Sep 25; 62 (2017): 77–83. DOI: 10.1016/j.leukres.2017.09.019.
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