This month in the American Journal of Hematology, Daniel J. DeAngelo from the Dana-Farber Cancer Institute, Boston, MA, and Andrew M. Brunner from the Massachusetts General Hospital, Boston, MA, and co-authors published the results of the phase I dose-escalation study (NCT01681537) of lenalidomide (LEN), a novel immunomodulatory agent, combined with mitoxantrone, etoposide and cytarabine (MEC) reinduction in Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML). Their aim was to evaluate the safety and tolerability of LEN at different doses in combination with MEC.
In total, 35 R/R AML patients with a median age of 61 years were enrolled in this study. LEN dose escalation ranged from 5–50 mg/day using cohorts of three or more patients in a 3 + 3 design. Initially, nine patients were enrolled in a 14-day schedule at 10 mg/d (n =6) and 5 mg/d of LEN (n =3) and MEC (Days 4–8). Due to delayed count recovery, the protocol was modified to a 10-day schedule during the dose-escalation phase of the study with the dose starting at 5 mg/d (n = 3), 10 mg/d (n = 3), 25 mg/d (n = 3) and 50 mg/d (n = 7). Patients in the expansion cohort (n = 10) were treated at the Maximum Tolerated Dose (MTD).
The primary outcomes of the study were to determine the safety, MTD and the recommended phase 2 dose (R2PD).
- Dose limited toxicities (DLT) occurred in patients at 10 mg/d 1–14 (n = 2) and 50 mg/d 1–10 (n = 1) due to delayed count recovery beyond Day 45
- MTD of LEN plus MEC; 50 mg/d on Days 1–10
- In patients treated at the MTD (n = 17), grade 3 or higher, mostly hematologic adverse events (AEs) occurred including thrombocytopenia (2/17), anemia (1/17), febrile neutropenia (9/17) and infection (5/17)
- 60-day mortality rate; 13%
- Complete Remission (CR) rate in all patients (n = 35); 34% (12/35)
- CR rate in patients treated at the MTD; 41% (7/17)
- 1-year Overall Survival (OS) in all patients; 39%
- 1-year OS in patients treated at the MTD; 61%
In summary, LEN given for ten days in combination with MEC reinduction was “well tolerated” and led to a remission rate of 34% in patients with R/R AML. The authors highlighted that their efficacy data is limited due to the fact that it is a phase I study and enrolled patients had diverse clinical course prior to study with a spectrum of underlying mutations.
DeAngelo and Brunner et al. concluded by noting that the LEN and MEC combination achieved a favorable remission rate and 1-year OS which was comparable to historical controls and indicated that a phase II study which would further explore the efficacy and the immunomodulatory effect of this treatment at the R2PD (50 mg/d Days 1–10) is planned.
Patients with relapsed AML have a poor prognosis and limited responses to standard chemotherapy. Lenalidomide is an immunomodulatory drug that may modulate anti-tumor immunity. We performed a study to evaluate the safety and tolerability of lenalidomide with mitoxantrone, etoposide and cytarabine (MEC) in relapsed/refractory AML. Adult patients with relapsed/refractory AML were eligible for this phase I dose-escalation study. We enrolled 35 patients using a ‘3 + 3' design, with a 10 patient expansion cohort at the maximum tolerated dose (MTD). Lenalidomide was initially given days 1-14 and MEC days 4-8; due to delayed count recovery, the protocol was amended to administer lenalidomide days 1-10. The dose of lenalidomide was then escalated starting at 5 mg/d (5-10-25-50). The primary objective was tolerability and MTD determination, with secondary outcomes including overall survival (OS). The MTD of lenalidomide combined with MEC was 50mg/d days 1-10. Among the 35 enrolled patients, 12 achieved complete remission (CR) (34%, 90%CI 21-50%); 30-day mortality was 6% and 60-day mortality 13%. The median OS for all patients was 11.5 months. Among 17 patients treated at the MTD, 7 attained CR (41%); the median OS was not reached while 12-month OS was 61%. Following therapy with MEC and lenalidomide, patient CD4+ and CD8+ T-cells demonstrated increased inflammatory responses to autologous tumor lysate. The combination of MEC and lenalidomide is tolerable with an RP2D of lenalidomide 50mg/d days 1-10, yielding encouraging response rates. Further studies are planned to explore the potential immunomodulatory effect of lenalidomide and MEC.