Chronic leukemias: different forms, different problems, different solutions
SummaryTreatment of chronic myeloid leukemia (CML) and chronic lymphocytic leukemia (CLL) presents unique problems. While treatments for both leukemias have advanced significantly in recent years, Datamonitor research shows that drug resistance to the gold standard treatment for CML is emerging, while current immunotherapeutic treatment for CLL is hampered by prognostic difficulties.
An estimated 300,000 new cases of leukemia are diagnosed worldwide each year, with over 220,000 deaths attributable to the disease. While each type of leukemia has its own distinctive epidemiological profile, incidence rates are generally higher for males than females and increase with age for all subtypes except acute lymphoblastic leukemia (ALL).
The treatment of CML was transformed with the launch of Novartis' Gleevec in December 2002. Gleevec's unequivocal efficacy, coupled with its favorable toxicity profile, resulted in an inexorable shift toward a trial period of Gleevec for most, if not all, newly diagnosed CML patients. However, despite its impressive efficacy and widespread use, Gleevec resistance is now an emerging problem. Resistance, along with Gleevec's relatively modest response rate among patients with advanced disease indicate the need for novel, efficacious second-line treatment strategies to counter these challenges.
Studies have shown that patients treated with Gleevec in first-line therapy survive on average six years longer than those treated with the previous gold standard, interferon-alpha. However, Gleevec resistance is developing in a reported 4% of newly diagnosed early-stage patients with each year of treatment, and up to 50% of CML patients with advanced disease are refractory to treatment. This highlights the need for novel, efficacious second-line treatment strategies both for patients with Gleevec-resistant chronic-phase CML and for virtually all advanced-stage patients.
Two second-generation tyrosine kinase inhibitors, Bristol Myers Squibb's (BMS) dasatinib and Novartis' AMN-107, are in a close race to realize accelerated approval, with the ultimate goal of replicating the outstanding commercial and clinical success of Novartis' Gleevec. Both drugs are currently in phase II clinical trials.
Should the ongoing phase II studies confirm dasatinib's clinical benefit in Gleevec-resistant or -intolerant patients, it is likely to garner accelerated approval from the FDA. Similarly, should phase II data consolidate the demonstrable phase I activity of AMN-107, Novartis also has the opportunity to benefit from accelerated approval.
The experience and expertise that Novartis has gained since the launch of Gleevec will be invaluable in the future development and commercialization of AMN-107. If Novartis is able to counter the challenge of BMS's dasatinib and establish AMN-107 as a new standard in Gleevec-refractory CML, the company will gain a strong foothold across two lines of the CML treatment paradigm, providing a lucrative additional source of revenue and further bolstering its advantageous position within the market.
Refinement is the way forward
In contrast to CML, in the CLL market, refinements to existing chemo-immunotherapy approaches, rather than any specific new drug entity, appear to hold the greatest promise for prolonging disease-free survival.
CLL is the most commonly diagnosed form of adult leukemia in the western world, accounting for up to 35% of all adult leukemia's. Although immunotherapeutic agents exist to treat the malignancy, an opportunity exists to employ biological markers that can facilitate the identification of high-risk patients who may benefit from more aggressive front-line treatment strategies.
Because of the heterogeneity or variability of CLL in terms of disease progression and response to treatment, there is a need to identify biological markers that will provide a more robust and reliable prediction of patient outcomes to current and evolving treatment strategies.
The identification and application of molecular markers to facilitate prognosis is becoming integral to the treatment decision-making process.
A significant limitation of both the existing staging systems for CLL is that they do not allow for any reliable prediction of the rate of disease progression for an individual diagnosed with low- or intermediate-risk disease. Since the vast majority of newly diagnosed CLL patients fall into this category, there is an urgent need to identify prognostic markers that can help refine outcome prediction for these patients.