Signs are clear that resistance to the cancer drug imatinib started to occur soon after the drugs approval in 2001 when early tests of the inhibitor oral tyrosine kinase; used in chronic CML treatment.

But second-generation drugs with similar mechanisms were already being used, according to studies presented at the  2005 ASH  meeting, in Atlanta. About 20% of CML chronic-phase patients relapse after three years of imatinib therapy, cancer treatments. Dasatinib  is a novel, oral, multitargeted kinase inhibitor that focuses on the chromosomal

mutations in CML can lead to cancer growth. Many cancer experts refer to it as the most promising of the new imatinib-like medicines.

“This

drug is 325-fold more potent than imatinib,” said veteran CML

researcher Charles Sawyers, M.D., Jonsson Comprehensive Cancer Center,

UCLA School of Medicine, Los Angeles. “In preclinical studies it showed

activity against 18 of 19 imatinib-resistant mutations.”

In an analysis of

imatinib resistance in 394 patients, median time from diagnosis of CML

was 63.8 months. Dasatinib was administered at 70 mg b.i.d., and

complete blood counts were obtained weekly. Within the first six

months, 90% of patients reached a complete hematologic response

(control of white cell counts), and 45% a major cytogenetic response

(elimination of cancer-carrying cells).

“This is

very encouraging news for patients, and it should be viewed as a step

forward in CML treatment,” commented lead investigator Andreas

Hochhaus, University of Heidelberg, Mannheim, Germany.

The ASH meeting featured another agent—AMN107 (Novartis), which is 10 to 50 times more potent than imatinib. In a phase I

clinical trial, 119 patients who were resistant to imatinib received AMN107; in some cases the dose was increased up to 12-fold

with no problems.

“The

range of response to AMN107 varied, depending on the form of the cancer

and the presence of genetic mutations,” reported the study’s lead

author Hagop Kantarjian, M.D., professor and chair of the department of

leukemia, M. D. Anderson Cancer Center, University of Texas. “For

example, among CML patients who harbored the cancerous mutation BCR-ABL

before treatment, 60% achieved a hematologic response and 41% a

cytogenetic response.” The results suggest that physicians will be able

to tailor leukemia therapy, “offering different treatments for subsets

of patients based on their cancer’s molecular signature,” he added.

“AMN107 looks like an option for patients who do not have a good

response to Gleevec therapy.”

In other treatment news from the ASH meeting:

Interim long-term follow-up data—up to 48 weeks—show the new targeted drug AMG-531 continuing to safely stimulate platelet

production in patients with immune thrombocytopenic purpura (ITP). Overall, 85% of patients in an open-label study (29 of

34) achieved a platelet response, i.e., doubling the baseline platelet count and at least 50,000 platelets per microliter

of blood.

“ITP is a chronic, autoimmune bleeding disorder characterized by low levels of platelets in the blood,” explained lead author

James B. Bussell, M.D., professor of pediatrics and medicine, Weill Cornell Medical Center, New York. “Some 200,000 Americans,

mostly women, have the disease. It’s exciting that most patients in this study achieved platelet counts of more than 50,000

per microliter, from a starting count of about 18,000,” he pointed out. “This suggests that AMG-531 may stimulate production

of platelets faster than the immune system can destroy them.”

The

Food & Drug Administration has granted the drug fast-track

designation “to address a serious unmet medical need,” according to the

manufacturer, Amgen. Traditional treatments of ITP—primarily

corticosteroid use and splenectomy—decrease platelet destruction by

suppressing the immune system. But side effects are numerous, and half

of patients do not respond at all.

By contrast, with AMG-531—which is an experimental thrombopoietic growth factor—the focus of treatment shifts from preventing

platelet destruction to enhancing platelet production, Bussell reiterated.

Enzastaurin

HCl, an investigational compound from Lilly Oncology, slowed the

progress of diffuse large B-cell lymphoma—the most common form of

non-Hodgkin’s lymphoma—in a small study. “The use of enzastaurin in

relapsed diffuse large B-cell lymphoma is important for two reasons,”

said senior investigator Margaret A. Shipp, M.D., director of

Dana-Farber/ Harvard Cancer Center’s lymphoma program. “First, it

represents a rational inhibitor of an identified target, and second,

several patients with aggressive disease insensitive to chemotherapy

have had prolonged responses to this single oral agent.” Enzastaurin

inhibits two kinase pathways that normally encourage cell growth. The

drug may have anti-angiogenesis effects as well.

The phase II multicenter clinical trial looked at 55 relapsed patients previously treated with other agents. Data presented

at ASH showed 22% (12 of 55) treated with enzastaurin were free of disease progression for two months. Of these patients,

25% remained progression-free with continued responses of 1.5 years to more than three years in duration. Side effects were

minimal.

“We at Lilly are excited by enzastaurin’s potential in the treatment of patients with recurrent diffuse large B-cell lymphoma,”

said Richard Gaynor, M.D., VP, cancer research.