Adult acute leukemia: demand for innovative drugs that prolong survival

Rlapse rates high

Unfortunately, relapse rates following treatment for AML and ALL are high, and current treatments offer little chance of long-term survival for most patients. While developmental drugs in this area have the opportunity to garner orphan drug designation and fast track approval status by the FDA, given the niche nature of treatments for this form of cancer, the return on investment for developers of novel acute leukemia treatment may not be as lucrative as that seen in other tumor types. 

The incidence of acute leukemia increases with age, particularly for AML, in which the mean age of diagnosis is 65 years. Thus, AML is predominantly a disease of the elderly, with a dramatic rise in incidence beyond the age of 60 years. However, the epidemiology of ALL exhibits a bimodal distribution, with peak incidences in early childhood and then again in old age.

ALL is the most frequently diagnosed childhood cancer and represents 23% of cancer cases in children under 15 years of age. The incidence peaks in early childhood before plateauing throughout adulthood and then gradually increasing after the age of 60.

The significance of this trend is that the biology of both AML and ALL differs between young and old adults and this is reflected in different responses to therapy.

Older patients most at risk

The increased incidence of AML in the over-60 population also presents additional challenges, as the increased likelihood of co-morbid illness and the decreased capacity of elderly patients to cope with the adverse effects of cytotoxic therapy may restrict available treatment options. 

Cytarabine in combination with an anthracycline remains the gold standard for AML remission-induction treatment. While this regime can induce complete remission in an impressive 65-80% of younger patients, this number falls to 40-60% in elderly patients with AML. The duration of this remission, and the ability to maintain long-term control of AML, remains problematic and one of the most significant unmet needs within the adult acute leukemia market. Consequently, five-year overall survival is bleak; being in the range of 5-15% for elderly-AML and approximately 30% in younger adults.

While allogeneic stem cell transplantation offers the only potentially curative treatment strategy in acute leukemia, the high morbidity and mortality associated with the technique - along with the scarcity of eligible donors - means the utility of this approach is limited.

Allogeneic transplantation techniques are expected to improve in the future and, as the associated rates of treatment-related morbidity and mortality decline, the application of this approach will become more common, particularly the use of the 'low-intensity' or 'mini-transplant' procedure in elderly AML, which has recently been shown to confer survival benefit.

However, efforts to enhance the rates of disease remission and prolong survival among the broader patient population look likely to rely on the integration of novel developmental agents into existing treatment paradigms. With regard to AML, the most promising of these agents are Genzyme's Clolar and Cephalon's FMS-like tyrosine kinase-3 (flt-3) inhibitor CEP-701. 

Given the dismal prognosis associated with AML in the elderly, together with the fact that they comprise the majority of patients, developers should ensure that new agents have toxicity profiles that this cohort will be able to tolerate. Efficient agents that can be used in elderly patients can expect to obtain considerable uptake.

On the fast-track

In December 2005, Novartis filed a supplementary new drug approval (sNDA) for the approval of Gleevec in adult Philadelphia positive ALL. While this has improved the outlook for patients with Philadelphia positive disease, key opinion leaders were unanimous in their belief that all such patients would eventually develop Gleevec resistance, reflecting the aggressiveness of this disease and poor prognosis indicated by the presence of the Philadelphia chromosome.

Agents with the ability to delay or overcome this resistance are eagerly awaited. As such, there is much excitement surrounding the next generation of Bcr-Abl tyrosine kinase inhibitors, including Bristol-Myers Squibb's (BMS) Sprycel (dasatanib) and Novartis' AMN107. The former will be the first such product to be subject to regulatory review when it goes before the FDA's Oncologic Drugs Advisory Committee on June 2, 2006.

Key opinion leaders are undecided as to which molecule holds the most promise, but Datamonitor believes that BMS' slight lead in terms of clinical development may mean that Sprycel wins the race to commercialization. 

The significant unmet clinical need in hematological malignancies is reflected by an examination of recent FDA approvals of oncology drugs. Of the 31 FDA-approved oncology drugs that received approval up to and including 2005, 14 were approved for the treatment of hematological indications.10 of these drugs received marketing authorization under the FDA's accelerated approval program, a designation assigned to promising therapies for serious or life-threatening diseases. Thus, the FDA recognizes the leukemia market as one with significant unmet needs.

Unfortunately, the relatively small size of the acute leukemia market dictates that the potential financial rewards offered by developing drugs for these patients may not be as attractive as those for one of the four major tumor types - breast, lung, prostate and colorectal cancer. However, in an attempt to encourage developers to target smaller patient populations, like adult AML or ALL, the FDA provides incentives for investment into niche markets.

There are currently nine compounds in phase III development for AML and ALL, and all of these drugs have been awarded either orphan drug status or fast track status or both. Thus, developers can reap returns on their investment by a potentially faster route to market and longer periods of exclusivity. 

Vion Pharmaceutical's Cloretazine (VNP-40101M) obtained fast track status for poor-risk AML patients aged 60-plus in October 2005. Positive results from the resulting pivotal phase II trial in elderly AML may mean that Cloretazine will enter the market three to nine months earlier than would have been expected, based on the ongoing phase III trial examining Cloretazine in relapsed AML.

However, developers also need to be aware of the prevailing increase in regulatory vigilance, as demonstrated by the rejection of accelerated approval for Johnson & Johnson's Zarnestra. 

The FDA's Oncologic Drug Advisory Committee (ODAC) stated that they wanted a more explicit definition of which patient cohorts would benefit most from Zarnestra. Further, reflecting increased regulator scrutiny of the accelerated approval procedure, an ODAC member also expressed concern that if accelerated approval had been granted for Zarnestra based on the available phase II data, there was no guarantee that the drug would be withdrawn if confirmatory phase III trials failed to demonstrate the drug's clinical benefit.

Thus, despite significant unmet needs, the FDA still requires well designed trials with definitive end points that demonstrate clinical benefit. 

Related research:

 §          Stakeholder Opinions: Acute Leukemias - Persistent unmet needs confer significant commercial opportunity

§          Stakeholder Opinions: Chronic Leukemias - Curative Intent Raises the Bar