New Drugs Overcome Gleevec Resistance In Chronic Myeloid Leukemia

HOUSTON, June 14 - Two drugs are waiting in the wings if Gleevec (imatinib) fails or is too toxic for patients with chronic myeloid leukemia (CML).

Both are safe and active against CML in patients resistant to or intolerant Gleevec, according to reports in the June 15 issue of the New England Journal of Medicine.

One of the new drugs - Tasigna (nilotinib) - is a more potent analog of Gleevec, which is the current standard of care for the disease, according to Hagop Kantarjian M.D., of the M.D. Anderson Cancer Center here.

The other - Sprycel (dasatinib) - has a different mechanism of action from either Tasigna or Gleevec, although all three drugs target the BCR-ABL tyrosine kinase whose unregulated activity is the hallmark of CML, according to Moshe Talpaz,, M.D., also of M.D. Anderson.

Earlier this month, the FDA's Oncologic Drugs Advisory Committee, on the basis of phase I data, unanimously recommended approval of Sprycel for CML patients who are refractory or intolerant to Gleevec.

The reports of the two phase I clinical studies are of "fundamental importance," according to Brian Druker, M.D., of Oregon Health and Science University Cancer Institute in Portland. Dr. Druker was the driving force in the clinical development of Gleevec.

In the first place, Dr. Druker wrote in an accompanying editorial, the studies offer hope to patients whose disease has become resistant to Gleevec, or who can't take it because of adverse effects. But also, he wrote, they demonstrate that the progress of drug development can be impressively rapid because it is only five years since phase I data on Gleevec were published.

Also, Dr. Druker said, the studies demonstrate the clinical importance of understanding the molecular basis of drug resistance.

In the first case, researchers at Novartis - knowing that Gleevec binds to the inactive conformation of the kinase domain on the BCR-ABL protein - designed Tasigna to bind more tightly, preventing the conformational changes that create resistance to Gleevec. In the second case, researchers at Bristol-Myers Squibb designed Sprycel to bind to the ABL kinase domain regardless of its conformation.

Dr. Kantarjian and colleagues enrolled 119 patients with Gleevec-resistant CML or acute lymphoblastic leukemia (ALL). They were treated with Tasigna at doses ranging from 50 to 1,200 milligrams daily or from 400 to 600 milligrams twice daily.

The most common side effects were myelosuppression, transient indirect hyperbilirubinemia, and rashes, the researchers found, adding the drug appears to prolong the QTcF interval in some patients.

The maximum tolerated dose appeared to be 600 milligrams twice daily, but the lower dose of 400 milligrams twice daily had a better safety profile and a similar response rate, Dr. Kantarjian and colleagues said.

Patients in chronic phase CML had a complete hematologic response rate of 92% (their blood counts returned to normal) and a complete cytogenetic response (absence of the Philadelphia chromosome, which produces the BCR-ABL tyrosine kinase) of 35%.

The rates of hematologic response were 75% for patients in the accelerated phase and 39% for those in the blast phase; and cytogenetic response rates were 55% and 27%, respectively. Only two of the 13 ALL patients had a response of any kind.

In the Sprycel study, Dr. Talpaz and colleagues enrolled 84 patients with CML or ALL. Seventy-two were resistant to Gleevec and 12 could not tolerate Gleevec because of abnormal liver-function tests, rash, bone pain, fatigue, or depression. The patients were treated with doses ranging from 15 to 240 milligrams a day.

The major adverse effect was reversible myelosuppression. Nonmalignant pleural effusions developed in 15 patients, often in the absence of edema, but periorbital edema - often seen in Gleevec-treated patients -- was less frequent. Patients who could not tolerate Gleevec did not have a recurrence of nonhematologic toxic effects, such as liver-function abnormalities and rash, that were associated with the older drug, the researchers said.

In 37 of 40 patients with chronic phase CML, Sprycel led to a complete hematologic response; complete or major hematologic responses were seen in 31 of 44 patients with accelerated-phase CML, CML with blast crisis, or ALL. Rates of complete or partial cytogenetic response were 45% patients in chronic phase and 43% for those in the other phases or with ALL, respectively.

"The main message is that this drug is extremely effective in CML patients who have failed all standard therapy including Gleevec," said Charles Sawyers, M.D., of Jonsson Comprehensive Cancer Center at the University of California at Los Angeles, the senior author of the Sprycel study.

But, he added, the results shows that understanding the molecular basis of resistance is key to circumventing it.

"This shows that if you have a precise molecular understanding of a drug target you can very quickly decipher the reasons for response and failure to therapy and quickly come up with backup treatment strategies," he said in a statement.

Gleevec is likely to remain the standard of care because more than 90% of CML patients respond well to it and continue to have their disease in check after five years. But, Dr. Sawyers said, it may be that Gleevec and Sprycel could be used together as a one-two punch.