Clinical activity of sequential flavopiridol, cytosine arabinoside, and mitoxantrone for adults with newly diagnosed, poor-risk acute myelogenous leukemia
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].
Section snippets
Patient eligibility and selection
From December 2006 through June 2008, adults ≥18 years with pathologically confirmed, newly diagnosed, previously untreated AML with poor-risk features including age ≥50, secondary AML (MDS/AML, MPD/AML, treatment-related AML) and/or known adverse cytogenetics were eligible provided they had ECOG performance status 0–2; normal bilirubin; hepatic enzymes ≤2× normal; serum creatinine ≤1.5× normal; LVEF ≥45%. All patients with MDS/AML or MPD/AML had previous documentation of the original
Patient characteristics
A total of 45 adults (median age 61, range 22–72) with newly diagnosed AML with poor-risk features were entered on study between December 2006 and June 2008. As depicted in Table 1, 37 patients (82%) had secondary AML and/or prominent trilineage dysplasia (TLD) consistent with preceding MDS and 24 (53%) had adverse cytogenetics. An additional 9 (20%) had FLT-3 mutations consisting of internal tandem duplication (ITD) in 7 (15%) or D835S point mutation in 2 (4%). Eight of the 9 had normal
Discussion
The results of this Phase II trial of TST with flavopiridol, ara-C and mitoxantrone therapy for adults with newly diagnosed, poor-risk AML expand our initial findings of a salutary CR rate and a sizable fraction of CR patients achieving lengthy DFS and OS. The 67% CR rate following a single cycle of FLAM in the current patient cohort is similar to the 75% CR rate achieved in a previously reported group of 15 newly diagnosed, poor-risk patients [22]. Moreover, all parameters of response and
Conflict of interest
None.
Acknowledgements
We wish to thanks the Johns Hopkins Department of Medicine house staff and the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center nursing staff for superb medical care, and the patients and families, without whose partnership we could never have conducted the trial and from whom we have learned critical information that will help us improve the treatment of these diseases.
This work was supported in part by the National Cancer Institute (NCI) Cooperative AgreementU01 CA70095 (J.E.K.), NCI
References (35)
- et al.
Age and acute myeloid leukemia
Blood
(2006) - et al.
Alteration of the phosphorylation state of p34cdc2 kinase by the flavone L86-8275 in breast carcinoma cells
Biochem Pharmacol
(1993) - et al.
Flavopiridol inactivates P-TEFb and blocks most RNA polymerase II transcription in vivo
J Biol Chem
(2001) - et al.
S. A two-step timed sequential treatment for acute myelocytic leukemia
Blood
(1989) - et al.
Timed sequential therapy of acute myelogneous leukemia in adults: a phase II study of retinoids in combination with the sequential administration of cytosine arabinoside, idarubicin and etoposide
Leuk Res
(2003) - et al.
End points to establish the efficacy of new agents in the treatment of acute leukemia
Blood
(2007) - et al.
Flavopiridol administered using a pharmacologically derived schedule of flavopiridol is associated with marked clinical activity in refractory, genetically high risk chronic lymphocytic leukemia
Blood
(2007) - et al.
Clinical response and pharmacokinetics from a phase I study of an active dosing schedule of flavopiridol in relapsed chronic lymphocytic leukemia
Blood
(2009) - et al.
Lysozymuria and renal tubular dysfunction in monocytic and myelomonocytic leukemia
Am J Med
(1969) - et al.
A novel molecular mechanism of primary resistance to FLT-3 kinase inhibitors in AML
Blood
(2009)
Enhanced activation of STAT pathways and overexpression of survivin confer resistance to FLT3 inhibitors and could be therapeutic targets in AML
Blood
Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461)
Blood
Acute myeloid leukemia and myelodysplastic syndromes in older patients
J Clin Oncol
Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia
N Engl J Med
Sequential response-adapted induction and consolidation regimens idarubicin/cytarabine and mitoxantrone/etoposide in adult acute myelogenous leukemia: 10 year follow-up of a study by the Canadian Leukemia Studies Group
Leuk Lymphoma
High-dose Daunorubicin in older patients with acute myeloid leukemia
N Engl J Med
Anthracycline dose intensification in acute myeloid leukemia
N Engl J Med
Cited by (63)
Myeloablative Fractionated Busulfan With Fludarabine in Older Patients: Long Term Disease-Specific Outcomes of a Prospective Phase II Clinical Trial
2021, Transplantation and Cellular TherapyFludarabine with a higher versus lower dose of myeloablative timed-sequential busulfan in older patients and patients with comorbidities: an open-label, non-stratified, randomised phase 2 trial
2018, The Lancet HaematologyCitation Excerpt :Longer regimens or regimens that use a sequence of chemotherapy agents have not been studied. Timed-sequential therapy, which consists of delivery of a second course of chemotherapy 8–10 days after the first one, was developed as induction therapy for treatment of patients with acute myeloid leukaemia to increase antitumour effects.6–8 Clinical studies of timed-sequential therapy using various chemotherapy drugs and regimens have showed promising efficacy in patients with acute myeloid leukaemia who were not having HCT.6–8
The Role of Natural Products From Plants in the Development of Anticancer Agents
2018, Natural Products and Drug Discovery: an Integrated Approach