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Originally published as JCO Early Release 10.1200/JCO.2006.08.6462 on December 4 2006 © 2007 American Society of Clinical Oncology.
On the Road to New Drugs in Acute Myeloid Leukemia
Department of Hematology, Erasmus University Medical Center, Rotterdam, the Netherlands The outcome of therapy for acute myeloid leukemia (AML) has improved over the years, mainly in patients of younger age. There is no question, however, that the challenges in the area of developmental therapeutics in AML have remained considerable. These challenges relate to patients who from the start of treatment, fail to respond to currently available drugs or combinations of drugs. The outlook of these primarily refractory patients is notably dismal. The majority of patients (75%) age 60 years or younger, however, do attain an initial complete remission. Unfortunately, most of these responders (on average, 60%) will ultimately present with disease relapse, usually occurring within the first 2 years. Both groups, initial nonresponders and secondary nonresponders, represent the notorious difficulty of chemotherapy resistance. Age of the patient and certain acquired genetic characteristics of the leukemia are important predictors of failure. The unmet therapeutic need is by any measure greatest among the large population of patients with AML of older age, in whom response rates are comparatively low (average 50% for those older than 60 years of age), relapse rates are exceedingly high (more than 85%), and long-term survival rates are less than 10%. The traditional chemotherapeutic approach to the patient with AML has been based on treatment with a combination of an anthracycline or anthracenedione (daunorubicin, idarubicin, mitoxantrone) with cytarabine. Scientists are permanently on the road to discover new drugs with different modes of action that can overcome the limitations of the current selection of drugs. Numerous new drugs are currently in early clinical development with the aim of circumventing chemotherapy resistance. In the coming years, some of these compounds are expected to become members of the standard armamentarium of drugs available to the patient with AML. New drugs may be designed with the deliberate objective of affecting a known molecular lesion or signaling pathway in the neoplastic cell, thus critically inhibiting leukemia cell survival. These therapeutic compounds may tackle distinct molecular subsets of leukemia; researchers anticipate that their greater specificity will allow for application with enhanced effect and reduced toxicity. Another class of drugs is being developed through redesign of the chemical structure of currently available chemotherapeutic agents in an effort to accomplish a better efficacy profile of the drug. The two reports1,2 published in this issue of the Journal of Clinical Oncology are representatives of the latter category, describing the early clinical results of two chemotherapeutic analogs. Troxacitabine is a nucleoside analog with special pharmacologic properties allowing prolonged exposure. It also has special features of cellular uptake and intracellular metabolism, bypassing the resistance mechanism imposed by nucleoside-specific membrane transporters. Phase I/II studies of troxacitabine had already demonstrated clinical activity in AML. Notably, skin and bone marrow toxicities have been reported in those studies. In the phase I/II study of troxacitabine reported in this issue,1 the investigators pursued a new schedule of continuous infusion. Patients for whom prior therapy had failed were enrolled, and many patients had gone through multiple lines of treatment during successive relapses. Eighty-five percent of the study group had had an initial complete remission (CR) duration of less than 12 months and one third of the patients had AML with poor-risk cytogenetics. Thus, the study group unquestionably reflected a category of adverse prognostic risk. The investigators reported that using the continuous intravenous schedule was feasible with a higher dose intensity of 12.0 mg/m2 for 5 days, compared with the previously used bolus regimen. The new continuous schedule of troxacitabine produced seven remissions among 48 patients and the pharmacologic data suggested a relationship between response and troxacitabine plasma concentration. The response rate of 15% in this poor-risk category of AML warrants additional study of troxacitabine. The second study2 dealt with the development of another interesting drug, cloretazine (VNP40101M; Vion Pharmaceuticals Inc, New Haven, CT; [101M, 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-(methylamino)carbonylhydrazine]). Cloretazine is a 1,2-bis(sulfonyl)-hydrazine, a new alkylator that is related to the nitrosoureas. It undergoes activation to yield an active chloroethylating species that specifically targets the O6 position of guanine. In contrast to the nitrosoureas, it generates considerably more DNA cross-links and avoids the undesired N7 alkylations as well as hydroxyl alkylations at O6 of guanine. In a previous phase I study, cloretazine combined with cytarabine had demonstrated significant antileukemic activity in refractory AML. In their article in this issue, Giles et al2 pursue the development of cloretazine at a selected dose level of 600 mg/m2 intravenous bolus in previously untreated patients with AML who are older than 60 years. A priori, merely because of age older than 60 years, eligible patients were considered of unfavorable risk. Median age of the study cohort was 72 years. There were frequent comorbidities among the study patients, and 46 of 105 AMLs exhibited an unfavorable cytogenetic risk profile. Hydroxyurea was applied adjunctively to support leukemia cytoreduction. Eighty-nine patients with AML and 15 patients with high-risk myelodysplasia were enrolled. Twenty-nine patients achieved CR after one course of treatment. If one also includes patients with complete marrow responses but with incomplete platelet recovery, and the nine patients with an opportunity of receiving a second cycle of treatment, the overall CR plus CR with incomplete platelet recovery rate was 31% (33 of 105 patients). Considering the poor-risk profile of the patients, these outcome data are interesting and promising. This drug also deserves additional study. At present, along the road of clinical drug development, one can discern a remarkable variety of new agents. Currently, it is probable that more new drugs and drugs with greater diversity are emerging than ever before. These compounds include kinase inhibitors (peptides, antibodies), which act as inhibitors of oncogenes (eg, fms-like tyrosine kinase mutations or kit mutations) or inhibitors that target critical cellular signaling substrates (eg, vascular endothelial growth factor receptor inhibitors, farnesyl transferase inhibitors), proteosome inhibitors, demethylating agents, and many others. Response assessments in phase II allow for the initial establishment of antileukemic activity. Yet, at the early point of a phase II screening, it remains virtually impossible to discover at the horizon the ultimate merits of a new drug. The key question is whether the new drug makes a difference. The ultimate test relates to prolonged survival or better survival quality. Only few of the agents demonstrating antileukemic activity in early phase II studies will ultimately break through with sufficient added value to gain a position as part of standard of care. Thus, the merits of troxacitabine and cloretazine will need to be clarified in subsequent trials. These future studies will need to be done in the context of combination therapy. An additional step would be to integrate these new drugs at different points in an overall treatment plan and assess their effect on outcome. Considering the significant ongoing explorative activities in the area, the odds are that the road through the discovery field of new drugs for AML will lead to a spectrum of novel agents embedded in new schedules of treatment that will fill the deficits of current therapeutics. Studies like the two trials reported here feed the optimism about a future of clinical practice with a greater selection of active drugs that will allow for a more individualized choice, benefit patients with notoriously unresponsive subtypes of AML, and last—but not least—create the badly needed improved treatment opportunities for the older patient with AML. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author indicated no potential conflicts of interest. NOTES published online ahead of print at www.jco.org on December 4, 2006. REFERENCES
1. Roboz GJ, Giles FJ, Ritchie EK, et al: Phase I/II study of continuous-infusion troxacitabine in refractory acute myeloid leukemia. J Clin Oncol 25:10-15, 2007 2. Giles F, Rizzieri D, Karp J, et al: Cloretazine (VNP40101M), a novel sulfonylhydrazine alkylating agent, has significant activity in patients age 60 years or older with previously untreated acute myeloid leukemia. J Clin Oncol 25:25-31, 2007 This article has been cited by other articles:
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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