News Center

Gleevec: Mixed Opinions Now After Initial Enthusiasm

New York City_--_After an initial wave of excitement about Gleevec (also known as imatinib mesylate or STI571), some researchers are curbing their enthusiasm about the drugís ability to cure chronic myelogenous leukemia (CML).

Opinions voiced here at the recent First International Congress on Myeloproliferative Diseases and Myelodysplastic Syndromes were mixed.

Researchers championing the drug needed only to point to remission rates far higher than those achieved with any other drug therapy, and to STI571ís safety profile as compared with bone marrow transplantation or todayís standard agents.

But others noted that resistance to the new drug is already occurring in some patients, and warned that long term use might reveal unexpected toxicities.

It is evident that considerable funding and energy are being invested in testing STI571 against various malignancies and in developing agents potentially synergistic with it.

One speaker at the meeting made a remark about the ìSTI bandwagonî: ìThose who donít get on it are going to be run over by it.î

Strong feelings may be unavoidable considering that careers have been spent developing other therapies for CML, only to se STI571 sweep the field in terms of public interest and clinical eagerness to use the drug. Eradicating or Debulking?

A lengthy discussion here focused on whether STI571 is truly capable of eradicating CML stem cells or whether it is only ìdebulkingî the tumor.

ìThere are provocative in vitro data on primitive cells in CML patients showing these are highly resistant to STI571,î said Connie J. Eaves, PhD, Deputy Director of the Terry Fox Laboratory of the British Columbia Cancer Agency in Vancouver. ìStem cells in CML may not be responsive to this agent at all.

ìWhat we are seeing clinically may be debulking of the disease,î Dr. Eaves continued. ìand we are completely swept away by responses that may not have very much to do with cure at all.î

Ayalew Tefferi, MD, Professor of Medicine and Hematology at the Mayo Clinic, said it may be premature to say that STI571 does not produce molecular cure.

ìFollow-up may be too early,î Dr. Tefferi said. ìI know of cases where reverse transcriptase polymerase chain reaction has shown no molecular evidence of disease after STI571 therapy.î

Rudiger Hehlmann, MD, of Heidelberg University in Mannheim, Germany, advised researchers to keep in mind that there are no survival data for primary STI571 yet, except for patients in blast crisis.

ìThe present data [on STI571] tend to make one very euphoric, but euphoria is a bad advisor in treatment.î he said. Basis of Resistance?

One fact becoming very clear is that STI as a single agent will not be curing the majority of patients with CML, said John Goldman, MD, Chief of Haematology Services at Hammersmith Hospital in London. ìWe do not know what the basis for resistance is. It may be acquired, or the disease may already be resistant before the drug is used.î

He has seen CML patients taking STI571 who test molecularly negative, but he said many also still test positive. Similarly, a small proportion of patients with CML will obtain Philadelphia-chromosome negativity with interferon or autografting and stay Ph-negative but will be molecularly positive at a low level for a very long period of time, he said. ìOne gets into the difficult problem of deciding whether such patients are cured or not.î

He said he and another speaker, Moshe Talpaz, MD, of the University of Texas Anderson Cancer Center, have compromised on the term ìoperationally cured.î

ìThere may be a larger proportion of patients who are ëoperationally curedí with STI571 but who by definition will have molecular evidence of disease.î Dr. Goldman said. ìThere may be a small CD34-positive stem-cell population who are highly resistant to STI571, and therefore that makes it very difficult to eradicate this disease with STI571 as the single agent.î

Researchers have to think of hitting primitive stem cells to eliminate molecular evidence of disease, he said. ìWe may need a conjunction of STI571 and a graft-versus-leukemia effect or modified graft-versus-leukemia effect if we are going to eradicate this disease.î

A speaker from STI571ís manufacturer, Renaud Capdeville, MD, in the department of clinical research at Novartis Pharmaceuticals AG in Basel, Switzerland, said in his presentation that a number of investigators have reported emergence of new mutations in the STI binding pocket of ABL. Other factors may also contribute to resistance such as overexpression of the PGP-multidrug resistence-associated protein, he said.

But on the basis of STI571ís results in CML accelerated phase and blast crisis, Novartisí next step is obviously to combine this agent with other effective agents, Dr. Capdeville said.

In spite of the ìtremendous hype about STI571 as a miracle drug, people have to be prepared for the fact that it may not be 100 percent curative,î said Malcolm A.S. Moore, PhD, Professor of Cell Biology and Head of the Laboratory of Developmental Hematopoiesis at Memorial-Sloan Kettering Cancer in New York City.

Dr. Moore said reverse transcriptase polymerase chain reaction data on STI571 patients who achieved clinical and cytogenetic remission indicated quite high levels of residual Bcr-Abl activitiy in the marrow. ìSTI571 had not eliminated all of the leukemic cells,î he said. ìThat is a cautionary issue, that those residual cells do have the potential to achieve resistance. No single-agent therapy has ever been shown to be totally curative in CML due to drug resistance, and we have to consider why STI should be any different.î Nonetheless, he expects very few physicians or patients to discount the 80 to 90 percent remission rates and 40 percent plus cytogenetic responses seen with STI571 in CML.

In an interview following the meeting, Dr. Moore said he would recommend that virtually every CML patient be given STI571 up front, with the possible exception of patients under age 40 who have close or related matches available. ìSince CML is predominantly a disease of older patients, that would involve very few patients who would not be chosen for STI571 up front,î he said. The question then becomes whether to combine up-front STI571 with another agent from the start, or hold off on a second drug until resistance to STI571 might appear.

Congress co-chairman Richard T. Silver, MD, Attending Physician at Weill Medical College of New York Presbyterian Hospital, summed up the session succinctly: ìWhen STI571 first came on the scene it seemed that the question of treating CML was almost all solved, but in the last year we have all begun to appreciate how much we have to learn about how to use this agent.î

For additional information, please contact:
Keith Muhleman, CR&T.
Phone: 212-288-6604
Fax: 212-288-7704 or 212-746-8246
e-mail: kmuhleman@crt.org