BMS-354825 Overcomes Imatinib Resistance in CML

SAN DIEGO, California—An investigational drug, BMS-354825, overcame resistance to imatinib (Gleevec) in Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) patients in two small but dramatic phase I trials presented at the 46th Annual Meeting of the American Society of Hematology (ASH). After up to 9 months of treatment with BMS-354825, 31 of 36 chronic-phase patients (86%) had a complete hematological response, Charles L. Sawyers, MD, a Howard Hughes Medical Institute researcher at UCLA, reported (abstract 1). Among 29 patients who reached 3 months on treatment and could be evaluated for cytogenetic response, 13 responses were observed overall, including 8 major cytogenetic responses (28%), of which 5 were complete.

Co-investigator Moshe Talpaz, MD, professor of medicine, Department of Experimental Therapeutics, M.D. Anderson Cancer Center, reported that responses were nearly as good for accelerated- and blast-phase patients in the second trial (abstract 20). He said that 19 of 21 blast-phase patients had some hematological response. Of 15 patients for whom cytogenetic data were available, more than half (53%) had a major benefit. No cytogenetic responses have so far been observed in eight accelerated-phase patients, but six (75%) had a hematological response.

Based on these results, Bristol-Myers Squibb Company, developer of BMS-354825, announced it is working with regulatory authorities to start global phase II trials as soon as possible. Dr. Sawyers said these would be in all phases of CML and Ph+ acute lymphoblastic leukemia (ALL). "In 1 year, we should really have a good idea how the drug is performing," Dr. Sawyers told ONI.

In a press briefing, Dr. Sawyers hailed the development of BMS-354825 as an example of "how precise molecular understanding of a disease and how knowledge of a drug can lead you rapidly to a second drug."

Like imatinib, BMS-354825 is a kinase inhibitor, but it is less specific, hitting a broader number of targets in and around the fused BCR-ABL gene whose hybrid ever-active enzyme hyperdrives white blood cells in CML. "This BMS compound is actually an SRC inhibitor, as well as an ABL inhibitor. SRC is closely related to ABL, but it’s not ABL," Dr. Sawyers said.

The drug is clearly working in patients who had mutations, he said, reporting activity against all but one of the BCR-ABL mutations known to play a role in imatinib resistance. The exception, T3151, may require another agent.

In an interview, Dr. Talpaz said that BMS-354825 may be more potent than imatinib and could possibly inhibit other cancers.

Only two patients in the original chronic-phase study are off trial. Both had previously been in blast crisis and developed progressive disease while on BMS-354825. Three others who have not responded are continuing on study. All responses were durable, Dr. Sawyers said, and major cytogenetic responses correlated with a 1 to 2 log reduction in BCR-ABL transcripts.

Dr. Sawyers described BMS-354825 as generally well tolerated with toxicity that was easily managed. The most serious events reported in the chronic-phase trial were grade 4 thrombocytopenia in three patients and grade 3 neutropenia in seven. One patient developed a duodenal ulcer, but is still on study. Tumor lysis syndrome was reported in two of Dr. Talpaz’s blast-phase patients, and pneumonia in one accelerated-phase patient.

Maximum tolerated dose has not been reached and is still being investigated. Dr. Sawyers reported his trial has so far gone from 15 mg to 180 mg per day in one or two oral doses 5 to 7 days a week.

Introducing Dr. Sawyers at the plenary session, Brian J. Drucker, MD, of Oregon Health Sciences University, Portland, said the compound was "very, very good news for patients with CML." Not only does BMS-354825 have immediate application for patients with imatinib resistance, he said, but also it might yield higher response rates than imatinib in newly diagnosed patients. "Sequential combination therapy may yield a higher response rate, prolong remission, or prevent relapse," Dr. Drucker added.