LACK OF SLEEP LINKED TO MORE AGGRESSIVE BREAST CANCER

For the first time, lack of sleep has been associated with more aggressive breast cancers, according tofindings published in the August issue of Breast Cancer Research and Treatment.
The study was conducted in 101 women with early-stage estrogen-receptor-positive breast cancer who were assessed with the Oncotype DX test, which guides treatment in early-stage breast cancer by predicting the likelihood of recurrence.
The worst scores on the recurrence probability test were found in women who reported having the least sleep at night. Specifically, having fewer than 7 hours of sleep a night during the 2 years before the diagnosis was associated with a greater risk for recurrence.
However, this association between less sleep and breast cancers that are more aggressive and more likely to recur was strong only in postmenopausal women (P = .0011), not in premenopausal women (P = .80).
"This is the first study to suggest that women who routinely sleep fewer hours may develop more aggressive breast cancers than women who sleep longer hours," said lead author Cheryl Thompson, PhD, in a press statement. She and her coauthor, Li Li, MD, PhD, are from Case Western Reserve University in Cleveland, Ohio.
The study findings are limited by the "relatively modest sample size," the authors acknowledge.
Nevertheless, the study adds to the literature on sleep duration and breast cancer. Four previous studies, all of which assessed breast cancer risk and did not specifically look at breast cancer aggressiveness, have had "mixed results," according to the authors. Three of these have suggested that sleep can reduce the risk for breast cancer and 1 found no association at all.
Medscape Medical News asked Simone P. Pinheiro, ScD, from the Center for Drug Evaluation and Research at the US Food and Drug Administration (FDA), for her opinion on this study.
Before joining the FDA, Dr. Pinheiro was the lead author of the large prospective study that "did not find convincing evidence to support an association between habitual duration of sleep and subsequent development of breast cancer" (Cancer Res. 2006;66:5521-5525). However, information on habitual sleep duration was obtained prior to the development of breast cancer in that study, she emphasized.
The study by Drs. Thompson and Li "suggests" a "significant inverse correlation" between sleep duration and breast cancer aggressiveness among women diagnosed with breast cancer, Dr. Pinheiro noted.

"These results could also reflect the effect of subclinical (not yet diagnosed) breast cancer on sleep duration," she said in an email. In other words, a woman's nascent breast cancer might have caused sleep disturbance, she explained.
So, is lack of sleep a new risk factor for aggressive breast cancers?
The authors believe it might be. "Our data suggest that lack of sufficient sleep may cause biologically more aggressive tumors," they write. But they note that "further work will need to be done to more thoroughly characterize the biology underlying this epidemiological association."
Less Sleep and Recurrence Scores Defined 
All of the study participants are enrolled in a larger 412-patient case–control breast cancer study. As such, they were recruited at diagnosis and asked about lifestyle matters, including average sleep duration in the previous 2 years. Many of the breast cancer patients in the study underwent Oncotype DX testing.
The authors designated 3 levels of nightly sleep: 6 hours or less, 6 to 7 hours, and 7 or more hours.
Using previously published data on the recurrence probability test, they determined that scores below 18 predict a low risk for recurrence, scores of 18 to 30 predict an intermediate risk, and scores of 31 or higher predict a high risk.
Overall, less sleep was found to be correlated with a higher score. Risk for recurrence was intermediate in patients who slept 6 hours or less (mean recurrence score, 27.8) or 6 to 7 hours (mean recurrence score, 18.0) and low for patients who slept 7 or more hours (mean recurrence score, 16.4).
Thus, getting an average of less than 7 hours of sleep a night was associated with an intermediate risk and getting 7 or more hours was associated a with low risk. However, this finding was only statistically significant in the subset of postmenopausal women.
The lack of a strong association in premenopausal women is explainable, say the authors.
"It is well known that there are different mechanisms underlying premenopausal and postmenopausal breast cancers," they explain. "Our data suggest that sleep may affect carcinogenic pathway(s) specifically involved in the development of postmenopausal breast cancer, but not premenopausal cancer."
The positive findings in postmenopausal women remained statistically significant after adjustment for possible confounders, including age, physical activity, smoking status, and body mass index.
"Effective intervention to increase duration of sleep and improve quality of sleep could be an underappreciated avenue for reducing the risk of developing more aggressive breast cancers and recurrence," said Dr. Li in a press statement.
This study adds to the literature on lifestyle factors that can affect breast cancer and its related risk. These studied factors are increasingly diverse and include night-shift work, light in the bedroom, and more obvious variables such as obesity.

RISK OF HEART FAILURE WITH TRASTUZUMAB

Clinical trials have already shown that breast cancer patients who receive treatment with anthracyclines and trastuzumab (Herceptin, Genentech/Roche) are at increased risk for heart failure and cardiomyopathy.

Now, an observational cohort study conducted in a "real-world" setting suggests that this risk might be much higher.

The study, led by Erin J. Aiello Bowles, MPH, from the Group Health Research Institute in Seattle, Washington, was published online August 31 in the Journal of the National Cancer Institute.

This study adds to the understanding of the association between trastuzumab and heart failure, writes Ann M. Geiger, MPH, PhD, from Wake Forest School of Medicine in Winston-Salem, North Carolina, in an accompanying editorial. In this study, the median follow-up time is a year longer than that of previous clinical trials, and the incidence of heart failure appears to increase with longer follow-up.

"These results provide additional evidence that heightened risk of heart failure is a long-term effect of previous trastuzumab use rather than a short-term increase associated with current or recent use," she writes.

"This justifies long-term surveillance for congestive heart failure in women who have received trastuzumab, as well as extended follow-up of women enrolled in trials," Dr. Geiger notes.

Real-World Community Setting

"Clinical trials have shown that anthracyclines and trastuzumab are not only effective at improving survival, but are also associated with an increased risk of heart failure. However, these studies typically exclude older women and women with chronic diseases, so we really don't know what the real-world estimate of heart failure risk associated with these drugs is," Bowles told Medscape Medical News.

"Our goal was to describe not only the population of women with breast cancer who do and who do not receive these drugs, but also to estimate the risk of heart failure associated with these drugs in a real-world community practice," she said.

In this population-based retrospective study, Bowles and her colleagues from the Cancer Research Network analyzed data from 12,500 women diagnosed with incident invasive breast cancer from January 1, 1999 to December 31, 2007.

The women were patients for at least 12 months before their diagnosis at 6 health maintenance organizations in different areas of the United States.

The risk for heart failure and cardiomyopathy with anthracycline alone, trastuzumab alone, anthracycline followed by trastuzumab, and other chemotherapy was compared with no chemotherapy.

Among the women in the analysis, 5807 (46.5%) received no chemotherapy, 3697 (29.6%) received anthracycline-based chemotherapy alone, 112 (0.9%) received trastuzumab-based therapy without anthracycline, 442 (3.5%) received anthracycline plus trastuzumab, and 2442 (19.5%) received other chemotherapy.

The mean age of the population was 60 years (range, 22 to 99 years), 85.8% were white, and the median follow-up time was 4.4 years (interquartile range, 2.6 to 6.9 years).

The researchers found that women who received anthracycline or anthracycline plus trastuzumab were younger. Of the women who received anthracycline alone, 86.4% were younger than 65 years, as were 89.6% of the women who received both anthracycline and trastuzumab.

Younger women were also diagnosed at later stages, had fewer comorbidities, and were slightly more likely to receive radiation therapy than women who received other chemotherapy or no chemotherapy.

The small proportion of women who received trastuzumab without anthracycline were older (more than 65 years) and had more comorbidities.

The researchers also found that the risk for heart failure was higher among women who received anthracycline alone than among those who received no chemotherapy, and that the magnitude of that risk was similar to what has been reported in clinical trials.

For that population, the risk for heart failure or cardiomyopathy was higher than among those who received no anthracycline (adjusted hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.11 to 1.76). The increased risk was similar to that seen with other chemotherapy (adjusted HR, 1.49; 95% CI, 1.25 to 1.77).

However, the risk for heart failure associated with trastuzumab following anthracycline was much higher than has been reported in clinical trials (adjusted HR, 4.12; 95% CI, 2.30 to 7.42)

Overall, for anthracycline, the cumulative incidence at 5 years was 4.3%. But for the women who received anthracycline and then trastuzumab, the 5-year cumulative incidence was 20.1%.

"It is a lot bigger than what has been reported from the clinical trials," said Bowles. "But keep in mind that this is a much broader population that we looked at. We have a lot more older women who are already at an increased risk for heart failure, so that is going to drive up our results."

Bowles said this study can be generalized to other women, whereas the results from clinical trials are only applicable to the populations in those trials.

"We know clinical trials are very well done, they're very controlled and have great internal validity because they control any kind of confounding for age and other characteristics, but their generalizability to people who many not be included in those trials is really limited," she explained.

"Our results are much more generalizable, but at the expense of the internal validity. But we did our best to control for age, comorbidities, and any other things that we thought would affect the results. I think our study provides a nice complement to clinical trials," she said.

Long-term Follow-up

In her editorial, Dr. Geiger notes that the results of this study add to the evidence that anthracycline and trastuzumab (in particular) increases the risk for heart failure or cardiomyopathy as a long-term effect.

Dr. Geiger concludes that there is a need to monitor women who have received trastuzumab on an ongoing basis, and calls for prudence in using trastuzumab outside of clinical trials.

She also highlights a role for observational studies. This study "illustrates how observational studies complement randomized controlled trials by capturing valuable information about treatment outcomes for the vast majority of women who are unable to access a trial."

RADIATION THERAPY BENEFITS SOME OLDER PATIENTS WITH BREAST CANCER

Clinicians might want to offer radiation therapy to some older women (70 to 79 years of age) with early breast cancer because it lowers the risk for recurrence and subsequent mastectomy, according to a new American observational study.

The study of women in a "real-world" setting shows a benefit for radiation therapy after lumpectomy in this older patient population. This finding is in contrast to findings from a previous clinical trial, which prompted clinical guidelines to no longer recommend radiation therapy in this group.

The study, published online August 13 in Cancer, showed that at 10 years, radiation therapy was associated with a lower absolute risk for mastectomy in the same breast, compared with no radiation therapy (3.2% vs 6.3%).

This translates into a statistically significant relative reduction of two thirds in the risk for subsequent mastectomy (hazard ratio, 0.33; P < .001).

Most of the women (87.6%) in the 7403-patient cohort, derived from the Surveillance, Epidemiology, and End Results (SEER)–Medicare database, were treated with radiation therapy. A small percentage of the total population had a recurrence; only 174 patients (2.4%) underwent mastectomy in the same breast after initial surgery during the study period (1992 to 2002), which had a median follow-up of 7.2 years.

These findings led the study authors to conclude that radiation therapy is "associated with a greater likelihood of ultimate breast preservation for most older women with early breast cancer."

The study did not assess overall survival. Instead, it was designed to determine whether adjuvant radiation therapy reduced the risk for mastectomy in women with stage I estrogen-receptor (ER)-positive breast cancer.

In effect, the study is an analysis of radiation therapy in routine practice. The use of radiation therapy in older women with early breast cancer was also studied in the major clinical Cancer and Leukemia Group (CALGB) 9343 trial.

In that randomized trial, radiation therapy resulted in a statistically nonsignificant 50% relative reduction in the risk for subsequent mastectomy. The absolute risk at 10 years was 4% for those who did not receive radiation therapy, compared with 2% for patients who did receive radiation therapy. There was no significant difference in survival between the 2 groups.

On the basis of the CALGB findings, the influential National Comprehensive Cancer Network (NCCN) adjusted its treatment guidelines, and now no longer recommends radiation therapy after lumpectomy in older women with ER-positive early breast cancer who are receiving endocrine therapy.

However, Benjamin Smith, MD, from the University of Texas M.D. Anderson Cancer Center in Houston, lead author of the current study, stopped short of saying the NCCN guidelines need to be reversed.

"I think the national guidelines, while well intended and important, may gloss over the certain nuances needed for making critical decisions with patients," he said in a press statement. "Our study may shed additional light on some of those nuances, and provides data that physicians can use when talking to their patients about whether to go forward with radiation."

Dr. Smith and his coauthors also acknowledge that randomized trials such as CALGB 9343 are "the gold standard of clinical evidence." But they point out that such trials "often do not have sufficient power to permit meaningful subgroup analyses, making it difficult to determine which subgroups of patients are more or less likely to benefit from the therapy under consideration."

The study authors suspect that there are differences between a "motivated clinical trial population" and the "general population" of women with ER-positive early breast cancer. For example, poor compliance with endocrine therapy is "common" in the general population, the authors report. Thus, they hypothesized (correctly) that radiation therapy would be even more beneficial in routine practice than it was in the CALGB trial.

Selecting Patients

The findings from the current study, with its subset analyses of clinicopathologic features, can help clinicians identify which patients are more or less likely to benefit from radiation therapy, suggest the authors.

For instance, in subset analyses, the study authors found that radiation therapy provided no benefit for patients 75 to 79 years of age without high-grade tumors who had a pathologic lymph node assessment (P = .80); however, for all other subgroups, radiation therapy was associated with an absolute reduction in risk for mastectomy that ranged from 4.3% to 9.8% at 10 years.

Which patient groups are more likely to benefit?

The study authors highlighted several groups, including patients with high-grade early breast cancers, who had a 6.7% absolute reduction in the 10-year risk for mastectomy; patients who undergo the less sophisticated clinical lymph node assessment (4.9% absolute reduction); and any patient 70 to 74 years of age (3.8% absolute reduction). These types of patients had some of the most pronounced benefits from radiation therapy, followed by most patients with other clinicopathologic features.

This study is not the only recent effort on radiation therapy in older women with early breast cancer by the study authors.

They recently published a paper on a nomogram that converts clinical data into estimates of mastectomy-free survival, as reported by Medscape Medical News (J Clin Oncol. 2012;30: 2837-2843). The tool aims to help clinicians refine their advice about radiation therapy to older women with early breast cancer.

In an editorial that accompanied the nomogram paper (J Clin Oncol. 2012;30:2809-2811), an expert suggested that nomograms might be a step forward in the ongoing effort to refine decision making about radiation therapy in this setting.

However, the nomogram needs validation, said David Wazer, MD, from the Tufts University School of Medicine in Boston, Massachusetts, and the Alpert Medical School of Brown University in Providence, Rhode Island.

In the meantime, Dr. Wazer advised clinicians to check out the modeling tool on the IBTR! Web site, which predicts 10-year risk for in-breast recurrence both with and without radiation therapy. The modeling tool, which uses clinical trial (randomized and not) data but not observational study data, is the "most reliable" of the available risk-assessment tools, he said.

A portion of this study was funded by a research grant from Varian Medical Systems. The study was also supported by the Department of Health and Human Services and the National Cancer Institute. The authors have disclosed no relevant financial relationships. Dr. Wazer reports being a consultant to Advanced Radiation Therapy.

BOUTIS SPEAKING-IMAGING IN ADVANCED CANCER

The use of high-cost diagnostic imaging "steadily increased" in Medicare patients with advanced cancers from 1995 to 2006, which raises concerns about overuse in this setting, according to a new study.

In the second half of the study period (2002 to 2006), the use of scanning was especially zealous, with 95.9% of patients undergoing a high-cost diagnostic imaging procedure and an average of 9.79 scans per patient, despite their limited survival times, report the study authors, led by Yue-Yung Hu, MD, MPH, from Brigham and Women's Hospital in Boston, Massachusetts.

The analysis, which was restricted to patients with stage IV breast, colorectal, lung, or prostate cancer, waspublished online July 31 in the Journal of the National Cancer Institute.

The types of scans analyzed were computed tomography, magnetic resonance imaging, positron emission tomography, and nuclear medicine.

The increasing use of big-ticket scans is not simply the result of vulnerable patients being overscanned, suggest a pair of experts in an accompanying editorial"The use of high-cost imaging found in this study may seem excessive," write K. Robin Yabroff, PhD, and Joan L. Warren, PhD, from the National Cancer Institute in Bethesda, Maryland. "Yet, assessing the appropriateness of care for patients with advanced disease is complex."

Part of the problem, say the editorialists, is that guidelines in the United States are "largely silent about the use of advanced imaging tests for ongoing evaluation" of patients with these advanced cancers "in the absence of symptoms."

This is in stark contrast to guidelines for early-stage disease, which make recommendations about "when to use (and when not to use)" advanced imaging for surveillance, they write.

Not surprisingly, the study authors found that from 1995 to 2006, the proportion of stage IV cancer patients imaged increased by 4.6% and the proportion of early-stage (stages I and II) cancer patients imaged decreased by 2.5%.

Evidence-based guidelines for these newer imaging technologies are needed, the editorialists assert. This is especially true because there is "limited evidence that advanced imaging improves patient outcomes, compared with older less expensive technologies," they note, referring to ultrasound and radiograph.

Nevertheless, guidelines can be developed.

In the United Kingdom, the National Institute for Clinical Excellence has issued "do not do" recommendations for some high-cost imaging in patients with advanced cancer, the editorialists report.

In their study, Dr. Hu and colleagues shed some light on the current situation in the United States.

It does not appear that physicians with financial incentives to scan are running up medical bills. In a previous study (Health Aff. 2008;27:1491-1502), increases in advanced imaging were observed in managed care, where there is no profit motive, according to the editorialists. Thus, the trend toward increased use is probably a combination of the "widespread availability of imaging machines, malpractice concerns, patient demand, and critically, the technological imperative," they write.

Costs for Imaging Rising Faster Than for Total Cancer Care

The study authors were inspired to review patterns of use in the United States because previous research found that "Medicare expenditures for high-cost diagnostic imaging have risen faster than those for total cancer care."

Dr. Hu and colleagues reviewed claims data from the Surveillance, Epidemiology, and End Results (SEER)–Medicare database for the 4 types of big-ticket scans. They found more than 100,000 patients diagnosed with stage IV breast, colorectal, lung, or prostate cancer during the study period.

They looked at imaging performed during 3 periods of time during the course of the disease: the diagnostic period, the last month of life, and the continuing-care phase (the interval between the diagnosis period and the last month of life).

The majority of patients with stage IV cancer received advanced imaging in the diagnostic (90.4%) and continuing-care (75.3%) phases. About a third of patients received advanced imaging in the last month of life (34.3%).

The purposes of scanning in the continuing-care phase of advanced care are "more diverse" than in the other 2 phases, according to the editorialists.

Imaging results can inform decisions about the continuation or modification of treatment, symptom management, and hospice referral, they write. "The incremental benefits of advanced imaging compared with older less expensive technologies for informing clinical decisions may vary for each of these different purposes," they add.

"In situations where high-cost imaging is used to evaluate response to third- or fourth-line therapies, evaluation of appropriateness extends to the decision to continue treatment of patients with poor prognoses," the editorialists explain.

Thus, identifying the appropriateness of advanced imaging for these clinical decisions requires a better understanding of how imaging can improve care, the editorialists explain. In other words, there is much work to be done in this field.

Despite many areas of concern, there is some good news, say the editorialists. In 2009 and 2010, the period after that evaluated by Dr. Hu and colleagues, the use of high-cost imaging for Medicare beneficiaries has declined slightly, according to recent report on Medicare payment policy.

NEW TREATMENTS IN CML

he outlook has never been better for patients with chronic myeloid leukemia (CML). Clinicians have an increasingly wide choice of drugs, between imatinib (Gleevec), dasatinib (Sprycel), nilotinib (Tasigna), bosutinib, and very likely ponatinib too, if it receives U.S. Food and Drug Administration (FDA) approval later this year.

The 17th Congress of the European Hematology Association (EHA), recently held in Amsterdam, The Netherlands, presented a wealth of new data on these second- and third-line tyrosine kinase inhibitors (TKIs).

"It's phenomenal. The overall survival has improved, with 93 to 95% of patients alive after 7 to 8 years of follow-up," said Daniel DeAngelo, MD, associate professor of medicine at Harvard Medical School, and clinical director of Adult Leukemia at the Dana-Farber Cancer Institute, Boston, Massachusetts, in an interview with Medscape Medical News. "There has been a dramatic improvement in outcome over the decade."

Data Round-Up on New Drugs

The EHA saw long-term follow-up and comparison data on bosutinib, dasatinib, nilotinib, and ponatinib presented.

Dasatinib data (Bristol-Myers Squibbs) showed that first-line treatment at 100 mg resulted in faster and deeper response rates compared with imatinib 400 mg, according to 3-year follow-up of the DASISION (Dasatinib versus Imatinib Study in Treatment-Naïve CML-CP Patients) trial. The median time to complete cytogenic response (CCyR) for dasatinib was 3.2 months, versus 6.0 months for imatinib. The median time to major molecular response (MMR) was 15 versus 36 months, respectively. By 3 years, MMR was achieved in 68% of dasatinib-treated patients and in 55% of imatinib-treated patients (P < .0001). Long-term follow-up for 5 years is planned as part of the original DASISION study design.

Pfizer's BELA trial compared bosutinib with imatinib and reported that after at least 30 months of follow-up, 79% of patients on bosutinib showed CCyR versus 81% on imatinib; 61% on bosutinib versus 52% on imatinib achieved MMR; and 30% on bosutinib versus 22% on imatinib achieved complete molecular response (CMR), according to an intent-to-treat analysis. The BELA trial is a phase 3 open-label comparison of the efficacy and safety of bosutinib combined with imatinib in patients with newly diagnosed chronic phase CML.

Nilotinib data (Novartis) showed superior results compared with imatinib in newly diagnosed patients in the ENESTnd 3-year follow-up. A significantly lower rate of progression to accelerated/blast phase CML, lower rates of mutation, and significantly higher rates of MMR and molecular response were observed for nilotinib versus imatinib. Differences in rates of molecular response between nilotinib and imatinib increased over time. Another study presented at EHA showed that nilotinib induced deeper molecular responses versus continued imatinib in patients with CML with detectable disease after 2 years on imatinib as seen in the ENESTcmr 12-month results.

Data on ponatinib (Ariad), an investigational pan-BCR-ABL inhibitor, showed that 54% of chronic-phase CML patients who were pretreated and were refractory to other TKIs, including 70% with a T315I mutation, achieved a major CyR (MCyR). CCyR was achieved by 44% of patients. The median follow-up of chronic phase CML patients is 10.1 months. Data were updated from the pivotal PACE trial in CML patients who were resistant or intolerant to dasatinib or nilotinib, or who had the T315I mutation.

Imatinib Sets the Stage

Imatinib was the first oral targeted drug in cancer therapy and the first in CML. "Imatinib sets the bar very high," reflects Dr. DeAngelo, "but that doesn't mean it's the best drug."

Patients who experience significant side effects, develop resistance to imatinib, or become intolerant warrant discontinuation of the drug. "These categories represent a small number of patients, but it is important to have alternative second- and now third-generation drugs available for patients," added Dr. DeAngelo.

In 2006, dasatinib received U.S. Food and Drug Administration (FDA) approval for CML in patients who were refractory or intolerant to imatinib; in 2010, it received approval for use in patients newly diagnosed with CML. Nilotinib (Tasigna) received FDA approval for previously treated CML in 2007, and for newly diagnosed patients in 2010. These 2 drugs represent the first 2 second-generation drugs for CML. They are more potent inhibitors of BCR-ABL than imatinib, and they exhibit significant activity against all resistant mutations except the T315Imutation.

Bosutinib Holds Long-Term Promise

Bosutinib is another second-generation TKI. Dr. Carlo Gambacorti, MD, hematologist-oncologist, from the University of Milano Bicocca, Monza, Italy, who presented findings at the EHA, commented on the BELA comparison trial with imatinib and noted that results reflected findings with other second-generation TKIs in that you get faster and deeper molecular remissions. "This translates into a reduced number of progressions to accelerated or blast/crisis phase, usually within the first year of treatment," said Dr. Gambacorti in an interview with Medscape Medical News.

At 30 months, 4% of patients in the bosutinib group progressed to accelerated or blast/crisis phase, compared with 6% of those taking imatinib. Overall survival at 30 months was achieved by 97% of patients in the bosutinib group versus 95% in the imatinib group, with 5 of 250 versus 10 of 252 drug-related deaths in each group, respectively.

"The comparator imatinib is a very effective drug, and most patients are well served by it. However, the small number who fail imatinib show a better response to bosutinib," pointed out Dr. Gambacorti.

It is notable that a small proportion of patients could not tolerate bosutinib and discontinued in the first few weeks. "Most discontinued because the physician was unfamiliar with the drug or the management of gastrointestinal effects like nausea and vomiting, but these can be effectively treated."

Because of these dropouts, the trial did not reach its primary endpoint of CCyR at 12 months but did show significant differences in MMR and CMR at 12 months. "The CMR is theoretically the response which could open the door for drug discontinuation," Dr. Gambacorti commented, and he added that no serious adverse toxicity was seen with bosutinib, unlike with other second-generation TKIs.

Reflecting more generally on CMR, Dr. Gambacorti stated that if a patient remained in CMR for an extended time, the patient would be likely to have a normal life expectancy, based on other data on imatinib. "This is the first disease in which we can return a patient to normal life expectancy. Patients on bosutinib with CMR at 24 months may have a similarly positive outlook."

Dr. Gambacorti concluded that bosutinib is most likely to be used in the approximately 20% of patients who do not respond well when taking imatinib. "In patients with a bad prognosis, bosutinib, like other second-generation TKIs, is likely to return over 50% of them to cytogenetic remission," said Dr. Gambacorti. "This is where these drugs are going."

However, he stood by the effectiveness of imatinib as first-line therapy. "It's difficult to beat a Ferrari, especially when it is a Ferrari that does not harm the patient," Dr. Gambacorti commented.

Ponatinib: A T315I Inhibitor

Ponatinib is a third-generation pan-BCR-ABL inhibitor drug. It marks another turning point in the therapeutic history of CML in that, in addition to other cases of refractory CML, it is under investigation for the treatment of patients with the gatekeeper T315I mutation, for which no other drug is currently available.

The study presented at this year's EHA represented patients who had failed treatment with a second-generation drug—dasatinib or niliotinib. Most had failed imatinib too.

"Imatinib, dasatinib, nilotinib, and bosutinib all fail to be effective in patients with the T315I mutation," commented Dr. DeAngelo. "Also, there are other mutations which render nilotinib ineffective, and others which render dasatinib ineffective; however, these mutations are sensitive to ponatinib."

Ariad, the company developing ponatinib, expects to file for regulatory approval of ponatinib in the European Union and in the United States in the third quarter of 2012 for patients who have failed dasatinib and nilotinib; it will also include patients who have the T315I mutation.

At some point in the near future, a randomized clinical trial (RCT) of ponatinib versus imatinib will be conducted in newly diagnosed patients; additional information will be obtained on toxicity profiles, and this will potentially lead to a first-line indication.

Asked where he would envisage using ponatinib if approval is granted, Dr. DeAngelo said, "Ponatinib offers a new approach in patients who fail dasatinib or nilotinib, as we currently have no good alternative option for them. With the exception of low-risk chronic phase CML, I typically use one of the second-generation TKIs as first line in the majority of my patients."

Dr. DeAngelo added that if a patient progressed while receiving imatinib and was found to have a T315I mutation, he would move straight to ponatinib. Mutation analysis still is not recommended in treatment-naïve patients.

Head-to-Head Comparisons

Three head-to-head RCTs have compared the following treatment agents: imatinib and niliotinib, imatinib and dasatinib, and imatinib and bosutinib. This information was presented at EHA.

Commenting on the dasatinib-imatinib trial results (3-year follow-up of the DASISION trial), Dr. DeAngelo said that dasatinib seemed to be better tolerated. "There was, in general, a slightly greater number of patients with pleural effusions in the dasatinib arm, but all other side effects were higher in the imatinib arm. Patients had a more rapid time to response, achieving complete cytogenetic remission on dasatinib, which was almost twice as fast," he said.

Furthermore, he added that more patients on dasatinib achieved an MMR. "On the face of it, dasatinib appears to be superior with these endpoints to imatinib."

Dr. DeAngelo said that the bosutinib BELA trial was powered to look at CCyR, and it was found identical to imatinib, but MMR was better in the bosutinib group. "Bosutinib had a higher MMR and complete molecular response rate, but the endpoint of CCyR was identical at 79% for bosutinib and 80% for imatinib. My assumption is that the drug is more active than imatinib, but CCR rate was the study's primary endpoint, and there was no difference," he said.

Dr. DeAngelo added that more patients experienced diarrhea in the bosutinib than in the imatinib group, but greater numbers of musculoskeletal issues and cases of edema were reported in the imatinib group. "It works in patients who fail imatinib, but also has a different toxicity profile to dasatinib and nilotinib. It would [be] good to have this as another treatment option."

Dr. DeAngelo has disclosed that he sat on the Novartis advisory board and received an honorarium from Ariad. Dr. Gambacorti has received research funding from Pfizer.