Nonadherence to Imatinib in 25% of CML Patients Leads to Poorer Control

Zosia Chustecka

January 13, 2010

January 13, 2009 — About 25% of patients being treated with imatinib (Gleevec, Novartis) for chronic myeloid leukemia (CML) did not take the drug as prescribed, and ended up taking less than 90% of their imatinib doses. This had an adverse effect on their cytogenic and molecular responses, and might ultimately affect long-term outcomes, say researchers in the United Kingdom.

A few details of the study were discussed by coauthor Lina Eliasson, a PhD student at the School of Pharmacy, University of London, United Kingdom, at a press briefing in London last week. The briefing focused on cancer-drug development, the subject of this year's School of Pharmacy lecture.

The extent of noncompliance seen with imatinib is similar to that seen in other studies of chronic diseases, but it was rather "surprising" in this context of a life-threatening disease, said Nick Barber, PhD, professor of practice and policy at from the School of Pharmacy, an expert on compliance, and Ms. Eliasson's PhD supervisor.

This study is very important and serves as a warning for other oral cancer drugs.

"You would think that cancer patients would be more motivated to keep taking their drug, and so the finding is rather counterintuitive," he said in an interview with Medscape Oncology. But he also said that there are other studies that suggest that noncompliance is a problem in other life-threatening disorders, and mentioned a study that found that 17% of patients who had received a kidney transplant were noncompliant with their immunosuppressive drug therapy, even though not taking these drugs would reduce the likelihood of the transplant surviving.

"This study is very important and serves as a warning for other oral cancer drugs, which have been a Holy Grail of cancer-drug development," said David Taylor, FFPH, professor of pharmaceutical and public health at the School of Pharmacy. "It shows that giving a prescription is not enough. There can be serious consequences if patients stop taking them."

Nonadherence Led to Worse Outcomes

Imatinib is used for front-line treatment in CML, and has "changed this terminal illness into a chronic illness that patients can manage at home," Ms. Eliasson noted. When imatinib is successful, it eradicates all leukemic cells from the body, and this can result in a "cure," with patients being able to stop taking imatinib without relapsing, she explained, as shown in a study published in Blood (2007;109:58-60).

However, patients plateau at different levels of response, she added. In the current study, patients who took less than 90% of their imatinib therapy (missing 3 doses in 1 month) had worse responses than those who were 100% compliant, and none of the patients who took less than 80% of the imatinib dose had a complete response in which no leukemic cells remained. This could have adverse effects on long-term outcomes, because the poorer control of CML might lead to "avoidable deaths," she suggested.

These data come from a clinical trial involving 87 patients, which was conducted by David Marin, MD, and colleagues from Imperial College London and Hammersmith Hospital, in the United Kingdom. Preliminary results were reported in a poster presentation at the recent American Society of Hematology 51st Annual Meeting, and the full results have now been submitted for publication in an oncology journal. Ms. Eliasson conducted interviews with 21 of these patients to investigate the reasons for nonadherence to therapy.

"Few patients were aware of the consequences of missing the odd dose," she explained. "They felt that missing 3 or 4 doses per month didn't really matter, but we were able to show them that it does make a difference."

Interviews with patients revealed a variety of reasons for nonadherence, but one of the most common was hoping to minimize adverse effects. One patient said that he stopped taking the drug when he went on holiday because he wanted to enjoy himself and felt he had more energy when he was not taking the drug, she said.

"Patients have a right to not take their medications, but this should be an informed decision, and they should understand the consequences of not taking the therapy exactly as prescribed," Ms. Eliasson noted. She suggested that more research is needed into cancer patients taking oral medications at home.

Dr. Barber added that in other chronic diseases, many approaches to improve compliance have been tested, but most have failed. One of the few interventions that has been shown to work is telephone calls made by the pharmacist to patients about 2 weeks after they are prescribed a new medicine, in which they are asked about how they are getting on with the new drug, he said. In studies conducted by his team, this approach halved nonadherence in a variety of chronic conditions, and has now been recommended for implementation in a British government White Paper, he said.

Vaccine That "Mops Up" Leukemic Cells

In separate research, published in the January 1 issue of Clinical Cancer Research, a pilot study with a vaccine designed to destroy circulating CML cells suggests that it could be used to "mop up" any leukemic cells left behind after treatment with imatinib.

This comes from a study of 19 CML patients who had been taking imatinib for a year but continued to have measurable levels of leukemic cells. They were treated with the experimental vaccine in 4 sessions, comprised of 10 injections every 3 weeks. After a median follow-up of 72 months, the number of remaining leukemic cells declined in 13 patients, and in 7 patients CML became undetectable.

"We want to get rid of every last cancer cell in the body, and using cancer vaccines may be a good way to mop up residual disease," said Hyam Levitsky, MD, professor of oncology, medicine, and urology at the Johns Hopkins Kimmel Cancer Center in Baltimore, Maryland, in a statement. He said more research is needed to confirm and expand the results.

The experimental vaccine, known as GVAX, is being developed under a licensing agreement between Johns Hopkins University and BioSante Pharmaceuticals. Dr. Levitsky is entitled to a share of the milestone and royalty payments that would be received by the university from any future sales of GVAX.

The researchers note that most patients with CML will need to take imatinib for the rest of their lives, but about 10% to 15% of patients cannot tolerate the drug long-term. Secondary therapies, including dasatinib and nilotinib, also have many adverse effects, they add.

"Often, patients have low blood cells counts, fluid retention, significant nausea, and other gastrointestinal problems," said coauthor B. Douglas Smith, MD, associate professor of oncology at Johns Hopkins Kimmel Cancer Center. Many patients also report fatigue as an adverse effect. "Patients often tell me that they feel about 80% to 90% of what they should and, over time, this may have a big impact on their quality of life," he added.

"Ultimately, should this vaccine approach prove to be successful, the ability to get patients off life-long imatinib therapy would be a significant advance," Dr. Levitsky said.

Ms. Eliasson, Dr. Barber, and Dr. Smith have disclosed no relevant financial relationships. Dr. Marin reports receiving consultancy and research funding from Novartis, as do 3 of his coauthors. Dr. Levitsky reports being a consultant to Cell Genesys Inc, which has been acquired by BioSante Pharmaceuticals, and 2 of his coauthors are employees of Cell Genesys; he also stands to receive milestone and royalty payments from eventual sales of the vaccine.

American Society of Hematology (ASH) 51st Annual Meeting: Abstract 3290. Presented December 7, 2009.

Clin Cancer Res. 2010;16:338-347. Abstract

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