Clinical activity of sequential flavopiridol, cytosine arabinoside, and mitoxantrone for adults with newly diagnosed, poor-risk acute myelogenous leukemia

Abstract

Flavopiridol, a cyclin-dependent kinase inhibitor, is cytotoxic to leukemic blasts. In a Phase II study, flavopiridol 50 mg/m² was given by 1-h infusion daily × 3 beginning day 1 followed by 2 g/m²/72 h ara-C beginning day 6 and 40 mg/m² mitoxantrone on day 9 (FLAM) to 45 adults with newly diagnosed acute myelogenous leukemia (AML) with multiple poor-risk features. Thirty patients (67%) achieved complete remission (CR) and 4 (9%) died. Twelve (40%) received myeloablative allogeneic bone marrow transplant (BMT) in first CR. Median OS and DFS are not reached (67% alive 12.5–31 months, 58% in CR 11.4–30 months), with median follow-up 22 months. Sixteen received FLAM in CR, with median OS and DFS 9 and 13.1 months, and 36% alive at 21–31 months. Short OS and DFS correlated with adverse cytogenetics, regardless of age or treatment in CR. The addition of allogeneic BMT in CR translates into long OS and DFS in the majority of eligible patients.

Introduction

Adults with newly diagnosed acute myelogenous leukemia (AML) with specific risk features have a poor prognosis in terms of achievement and duration of complete remission (CR). Diverse independent studies have identified secondary AML – i.e., treatment-related or arising from myelodysplasia (MDS) or myeloproliferative disorder (MPD) – and AML presenting with adverse genetics (including chromosome 3 abnormalities, −5/5q, −7/7q, +8, 11q23 abnormalities, 20q−, complex karyotypes, FLT-3 mutations), among others, as particularly poor risk [1], [2], [3]. For such patients, despite intensive multiagent chemotherapy, CR is achieved in ≤30% with 3–5-year survival in <10%, while the CR rate for patients without poor-risk features is ≥70% with 3–5-year survival of 30–40%.

CR rate and duration also decrease with increasing age (i.e., ≥60), with CR rates <50%, even without overt poor-risk features, and a 3–5-year survival ≤10–15% [2], [4]. Even in a study of non-cross-resistant, response-adapted therapy by van der Jagt et al. [5] where the CR rate was 67% in 42 adults over age 60 with de novo AML, the 5-year overall survival (OS) and disease-free survival (DFS) of CR patients were only 9.7% and 8.3%. Mortality during induction therapy in the older age group was 26% [6]. Along similar lines, Lowenberg et al. [6] demonstrated that doubling the Daunorubicin dose during induction therapy for “fit” AML patients age 60 and older improved the CR rate from 54% to 64%, with achievement of CR following a single induction cycle in 52% of high-dose vs. 35% of conventional dose group. High-dose Daunorubicin yielded improvement in 2-year OS and event free survival (EFS) in the younger patient subgroup (ages 60–65), but did not have a major impact on OS and EFS in patients with adverse cytogenetics, independent of age [6]. In contrast, Fernandez's et al. study of high-dose Daunorubicin in younger adults under age 60 yielded increases in both CR rate (71% vs. 57%) and OS (23.7 months vs. 15.3 months) [7]. However, there was no apparent benefit for patients age 50–60 or those with unfavorable cytogenetics or FLT-3 mutations.

Flavopiridol [8], [9] inhibits growth and induces apoptosis in diverse hematopoietic cell lines [10], [11], [12]. This apoptosis results at least in part from inhibition of multiple serine-threonine cyclin-dependent kinases (CDKs) with cell cycle arrest in G1 and G2 [13], [14], [15]. Inactivation of the CDK9/cyclin T complex (PTEF-b) inhibits phosphorylation of RNA polymerase II, diminishes mRNA synthesis [16], [17] and blocks production of polypeptides such as cyclin D1 [9], [18] and the pro-survival protein MCL-1 [12], [19].

We previously reported on longitudinal clinical-laboratory studies of flavopiridol followed in a timed sequential manner by the cell cycle-dependent, antileukemia drugs cytosine arabinoside (ara-C) and mitoxantrone [20], [21], [22]. The hypothesis-driven regimen (“FLAM”) was generated based on in vitro modeling where administration of flavopiridol to marrow leukemic blasts followed sequentially by ara-C resulted in synergistic enhancement of ara-C-related blast cell apoptosis [20], [23]. In a recent Phase II trial of FLAM, 15 patients had newly diagnosed, poor-risk AML with multiple poor-risk features including older age (100% > 50 years), secondary AML (100%), and adverse genetic features (53%) [22]. Twelve (75%) achieved CR, with a 2-year disease-free survival (DFS) of 50%. These results compared favorably with historical timed sequential therapy (TST) regimens using sequential ara-C, anthracycline and either amsacrine [24] or VP-16 [25], in which CR rates are 40–45% for patients ≥55 years of age and 30–40% for patients with adverse cytogenetics.

We have now expanded our investigation of FLAM to establish a more accurate estimate of efficacy in inducing durable CRs in this patient population. Further, we evaluated the ability for this regimen to achieve a CR without severe toxicity and, in turn, permit successful allogeneic bone marrow transplantation (BMT) in eligible patients in first CR [26].