A Randomized Phase II Trial of Three Novel Regimens for Relapsed/ Refractory Acute Myeloid Leukemia (AML) Demonstrates Encouraging Results with a Flavopiridol-Based Regimen: Results of Eastern Cooperative Oncology Group (ECOG) Trial E1906

Introduction: The therapy of relapsed/refractory AML remains poor and new treatment options are sorely needed. The Leukemia Committee of ECOG devised a randomized phase II trial of 3 novel regimens to determine overall response rates could be improved.

Methods: Patients between the ages of 18 and 70 years with a prior diagnosis of AML who relapsed <1 year after initial achievement of complete remission (CR) or who were refractory to initial induction therapy (<2 courses) or to first reinduction after a relapse (<1 course) were eligible for this trial. Eligible patients were randomized equally to one of three regimens described in Table 1 below.

The primary endpoint was achievement of a morphologic complete remission (CR) or a CR with incomplete blood count recovery (CRi). A 2 stage statistical design was planned with 18 patients (assuming 16 eligible) to be accrued in the first stage. If at least 3 CR+CRi were seen among the 16 eligible patients, an additional 19 patients (assuming 17 eligible) would be entered in the second stage. If 8 or more CR+CRi were seen in the 33 eligible patients, this would be considered evidence of a promising response rate.

Results: This study activated October 16, 2008 and closed August 2, 2013 with a total of 92 patients accrued (91 eligible). The eligibility criteria were amended during the study to lower the upper age limit from 70 to 65 years because 6 treatment related deaths occurred in the initial 27 patients accrued to the FLAM regimen. All of these patients died of septic shock or multi-organ failure and 5 of the 6 died within 1 month of the start of therapy. Most of these patients were over age 65 ( 53, 62, 67, 68, 69 and 69 years).

At the first stage analysis, of the first 16 eligible patients accrued to each arm there were 2 CR and 2 CRi in the CT arm, 2 CR and 2 CRi in the FLAM arm and 2 CR in the sirolimus-MEC arm. Thus, the sirolimus-MEC arm was closed to accrual with a total of 20 eligible patients and second stage accrual continued for the CT and FLAM arms. Among the 35, 36 and 20 eligible patients accrued to arms A, B and C, respectively, there were 2 CR and 3 CRi in the CT arm, 6 CR and 4 CRi in the FLAM arm, and 2 CR and 1 CRi in the sirolimus-MEC arm. All 10 CR or CRi of the FLAM arm were among the first 33 eligible patients, therefore FLAM was the only regimen to achieve our target. The overall response rates for arms A, B and C were 14% (90% CI 7.1% - 34.7%), 28% (90% CI 16.1% - 43.0%) and 15% (90% CI 4.2% - 34.4%), respectively. Among the 92 patients accrued, there were 5, 10 and 2 grade 5 events within 30 days of the end of therapy in arms A, B and C, respectively. The vast majority of these deaths were attributed to infection and multi-organ failure except two which were secondary to disease.

Conclusion: In this high risk group of AML patients the FLAM regimen showed an encouraging response rate. A randomized phase II trial has also recently been completed exploring its use in the front-line setting with newly diagnosed high-risk AML. While the FLAM regimen was excessively toxic in elderly patients with relapsed or refractory disease, it is a suitable option for younger patients in this setting.

Arm A: CT

Carboplatin 150 mg/m²/day over 24 hours by continuous infusion IV for 5 days (days 1-5)

Topotecan 1.6 mg/m²/day over 24 hours by continuous infusion IV for 5 days (days 1-5)

Arm B: FLAM

Flavopiridol 30 mg/m² for ½ hour followed by 60 mg/m² over 4 hours IV per day for 3 days

Cytarabine 667 mg/m² over 24 hours by continuous infusion IV for 3 days (days 6-8)

Mitoxantrone 40 mg/m² IV over 1-2 hours (day 9)

Arm C: Sirolimus-MEC

Sirolimus 12 mg by mouth on day 1, followed by 4 mg by mouth daily for 8 days (days 2-9)

Mitoxantrone 8 mg/m²/day over 15 minutes IV for 5 days (days 4-8)

Etoposide 100 mg/m²/day over 1 hour IV for 5 days (days 4-8)

Cytarabine 1000 mg/m²/day over 3 hours IV for 5 days (days 4-8)

Table 2. Responses