Clinical Insights: January/February, 2013


CE lesson worth 1.0 contact hour that is focused on research from the 2012 American Society of Hematology Annual Meeting and the San Antonio Breast Cancer Symposium.


The overall goal is to update the healthcare professional’s knowledge of cancer detection and prevention and to understand current and new research regarding state-of-the art care for those with or at risk for cancer.


Intended for advanced practice nurses, registered nurses, and other healthcare professionals who care for cancer patients.


Upon completion, participants should be able to:

  • Describe new preventive options and treatments for cancer patients
  • Identify options for individualizing the treatment for cancer patients
  • Review new evidence to facilitate survivorship and supportive care for cancer patients


Dannemiller is approved by the California Board of Registered Nursing, Provider Number 4229, for 1.0 contact hours. RNs outside California must verify with their licensing agency for approval of this course.


The planners and authors of this CE activity have disclosed no relevant financial relationships with any commercial companies pertaining to this activity.


  • Read the articles in this section in its entirety.
  • Go to
  • Complete and submit the CE posttest and activity evaluation.
  • Print your Certificate of Credit.

This activity is provided free of charge to participants.

2012 CTRC-AACR San Antonio Breast Cancer Symposium (SABCS)

Cognitive Impairment May Originate

Before Treatment

By Jason M. Broderick

The mental toll and stress of a breast cancer diagnosis might factor into the cognitive impairment experienced during chemotherapy treatment, commonly referred to as “chemo brain.” At the 35th Annual San Antonio Breast Cancer Symposium, Bernadine Cimprich, PhD, RN, presented data suggesting that pretreatment neurocognitive compromise and fatigue contribute to cognitive issues formerly associated solely with chemotherapy.

“Our [previous] work and the work of others has shown that cognitive complaints and deficits have occurred even before chemotherapy, so these [problems] could not be attributed to the treatment,” said Cimprich, who is an associate professor emerita at the University of Michigan School of Nursing in Ann Arbor. “It’s important to find solutions because even subtle cognitive changes can have a considerable negative impact on a person’s functioning and quality of life. And, further, concern over ‘chemo brain’ may result in patient reluctance to accept life-saving therapy.”

In their latest study, Cimprich and her colleagues analyzed neurocognitive responses in 66 women with localized breast cancer (stages 0-IIIa), as well as in 32 healthy controls. Patients were receiving either an anthracyline-based adjuvant chemotherapy combination (n = 29) or radiotherapy (n = 37).

Cimprich explained the design of the trial: “Functional magnetic resonance imaging was used to directly test brain function while a woman was performing a working memory task in the scanner before adjuvant treatment and then 1 month after adjuvant treatment.”

After each scan, patients self-reported on levels of cognitive functioning and fatigue.

In both patient groups, pretreatment brain imaging revealed lower functioning versus the control arm in frontal regions of the brain that were necessary to the performance of the working memory task. The cognitive impairment was most severe in women awaiting chemotherapy. “The chemotherapy group actually had the lowest level of activation [before treatment] and [results] with the radiation group fell between the prechemotherapy and the controls,” said Cimprich.

Cimprich said the study demonstrates the need for increased awareness of the vulnerability of women awaiting chemotherapy to cognitive problems related to worry and fatigue.

Cimprich noted that the findings suggest that “chemo brain” might be an inappropriate term to describe cognitive problems in patients with cancer. Abstract S6-3

Nurse Perspective on Cognitive Impairment

Janice Famorca Tran, RN, MS, AOCNP®, CBCN®, ANP-CTexas OncologyHouston, TX

Cognitive impairment as a result of cancer treatment occurs in a majority of patients, with most patients experiencing improvement after treatment completes; however, for a subset of this population, the problem may persist.

The presence of cognitive impairment, both in its severity and duration, can cause a significant amount of distress. The majority of studies have examined the effects of cancer treatment on cognitive impairment; however, the study performed by Cimprich and colleagues took a different approach in studying this relationship. They concluded that decreased brain function prior to treatment predicted lower levels of cognitive functioning and increased levels of fatigue. Additionally, the pre-chemotherapy group had higher levels of cognitive impairment compared to controls.

These results suggest that feelings such as stress, worry, and anxiety about treatment and cancer may potentially contribute to increased cognitive impairment and fatigue. This study implicates the importance of pre-psychological screening of all cancer patients in order to identify high-risk patients so that appropriate interventions can be undertaken early in order to assist patients with this problem. These interventions may include emotional support by the nurse, professional counseling, patient involvement in peer support groups, and spiritual activities.

Adjuvant Chemotherapy Improves Survival

in Women With Recurrent Breast Cancer

By Jason M. Broderick

Adjuvant chemotherapy improved survival rates in women with isolated local or regional breast cancer recurrence, according to results from the CALOR trial presented by Stefan Aebi, MD, at the 2012 SABCS. Aebi, head of the division of Medical Oncology at Luzerner Kantonsspital in Luzern, Switzerland, said the greatest benefit was observed in patients with estrogen receptor (ER)—negative disease.

Aebi and colleagues from the Breast International Group, the National Surgical Adjuvant Breast and Bowel Project, and the International Breast Cancer Study Group randomized 162 patients (median age, 56 years) with recurrent tumors to chemotherapy (n = 85) or no chemotherapy (n = 77). “The choice of chemotherapy was determined by the patient’s treating oncologist based on her prior therapy,” Aebi said. A minimum of four cycles of a multidrug chemotherapy regimen was recommended.

Patients were evenly distributed between the two trial arms in terms of location of recurrence (breast, chest wall/mastectomy scar, or lymph nodes), ER status, and menopause status. Sixty-eight percent and 58% of patients in the control and treatment arms, respectively, had prior adjuvant chemotherapy. The median time between patient surgeries for primary and recurrent disease was 5 years in the treatment group and 6 years in the control group.

At 4.9 years’ follow-up, the overall survival (OS) rate for patients receiving adjuvant chemotherapy was 88% versus 76% in the control arm (hazard ratio [HR] = 0.41; 95% CI, 0.19-0.89; P = .02). Five-year disease-free survival (DFS) rates were 69% and 57% with and without chemotherapy, respectively (HR = 0.59; 95% CI, 0.35-0.99; P = .046). The data remained statistically significant in statistical analyses controlling for recurrent disease location, ER-status, prior adjuvant chemotherapy, and interval between primary and recurrent surgeries.

In women with ER-negative disease, 5-year DFS was 67% in the treatment arm versus 35% in the control group (HR = 0.32; 95% CI, 0.14-0.73; P = .007). Fiveyear OS in ER-negative patients was 79% with adjuvant chemotherapy versus 69% without (HR = 0.43; 95% CI, 0.15-1.24; P = .12).

DFS at 5 years in patients with ER-positive recurrent tumors was 70% and 69%, respectively, with and without treatment (HR = 0.94; 95% CI, 0.47-1.89; P = .87). OS rates were 94% and 80%, respectively (HR = 0.40; 95% CI, 0.12-1.28; P = .12). Aebi commented that the ER-positive data are not yet mature. “When I say now that we found no statistically significant benefit in the ER-positive group, this does not mean that it will stay this way with further follow-up. We need to observe these patients for a longer period of time.”

Regarding side effects, Aebi said nothing abnormal was observed in the treatment arm. “Toxicity-wise, we observed what is expected from these chemotherapies.”

Aebi said the next step with his research in this setting is unclear, as patient recruitment for clinical studies has been difficult. “You’ve seen that recruitment for the [CALOR] trial was very challenging. So, at the moment, we are still struggling with how to follow up this trial. We have to be realistic and find out a way to go on that is acceptable to patients and clinicians, so that we do not run into the same problem. This is still an unresolved challenge.” Abstract S3-2

Nurse Perspective on Adjuvant Chemotherapy

Laura Zimmerman, MA, OCN®, RN-BC, HN-BC, CRRNManager OncologyMeridian Health SystemNeptune, NJ

As we continue to expand our research into specific genetic markers and utilize those markers in identifying patients for appropriate therapy, the more we uncover regimens that improve the overall survival rates of women with recurrent breast cancer, as this study demonstrated.

Researchers noted that the greatest survival benefit from adjuvant chemotherapy occurred in patients with ER-negative disease, with follow-up and continued observation needed for ER-positive patients.

One of the issues the lead author also discussed was the challenge of recruitment for clinical trials. How do we engage clinicians and our patients to participate in open clinical trials? What are the issues surrounding recruitment?

In our local community in New Jersey, we have a fairly diverse patient population. We often struggle with numerous challenges in recruitment related to cultural, psychosocial, spiritual, and religious beliefs. We also struggle with time—the clinician’s time to spend with the patients or even the patient’s perception of the length of study. Many of our patients feel that when they are ‘done’ with treatment, they are ‘done’ and do not want to continue participating.

Our multidisciplinary team has been doing a great job in improving our research participant numbers and engaging everyone in the research clinical trial recruitment; navigators, social workers, genetic counselors, clinicians, and research team members all meet weekly and monthly to discuss patients on treatment and on studies. They even hand off information to one another after meeting with one of our patients. We also have engaged with our community cultural centers and have begun to offer lectures and sessions to open those discussions. At the leadership level our corporate medical director drives us to open more clinical trials and improve our participant numbers.

I think the challenge will continue, but with patience, positivity, and persistence we can begin to close that gap.

10 Years of Tamoxifen Found Better Than 5

in ER-Positive Breast Cancer

Extending the duration of adjuvant tamoxifen treatment to 10 years was more effective than the standard 5 years of treatment in protecting against recurrence and death among women with estrogen receptor—positive (ER+) breast cancer, according to findings from the international ATLAS study which showed that 10 years of tamoxifen reduced the risk of dying by 29% during the second decade after diagnosis compared with 5 years of treatment.

“We already knew that 5 years of tamoxifen was very effective and has a carryover effect after stopping, with about a 30% reduction in mortality over the next 5 years. We wanted to do a longer-term treatment trial on tamoxifen to see if we could beat the carryover effect of 5 years of treatment,” said Richard Gray, MSc, Clinical Trial Service Unit, University of Oxford, Oxford, UK. Gray presented the results at SABCS on behalf of lead author Christina Davies, MD, also of the University of Oxford.

ATLAS enrolled 6846 women with ER+ breast cancer between 1996 and 2005. Approximately half of the women had node-positive disease, and all had been taking tamoxifen for 5 years. Women were randomized to 5 more years of tamoxifen or no more tamoxifen.

After about 8 years of follow-up, 1328 recurrences and 728 deaths after recurrence were reported. Treatment assignment had little or no effect on rates of recurrence or death in the period 5 to 9 years after diagnosis. However, in the second decade after diagnosis, women who continued on tamoxifen had a 25% lower recurrence rate and 29% lower breast cancer mortality rate compared with women who stopped after 5 years of tamoxifen.

The risk of dying due to breast cancer 5-14 years after diagnosis was 12.2% for continuing tamoxifen users versus 15% for those who only had 5 years of treatment, representing an absolute gain of 2.8% favoring continuing treatment with tamoxifen for 10 years.

“Little effect was seen for longer duration of tamoxifen during the years 5-9 after diagnosis,” Gray said. “The greatest benefit was observed during 10-14 years after diagnosis.”

Based on the results of this trial, the estimated effect that 10 years of tamoxifen versus no tamoxifen in ER+ breast cancer could have is to cut the rate of breast cancer deaths by 48% 10 years after diagnosis, Gray said.

Receiving tamoxifen for a longer period of time can increase side effects, including endometrial cancer. The cumulative risk of death from endometrial cancer between 5-14 years after diagnosis was 0.4% for the continuing tamoxifen users versus 0.2% for those who did not continue.

Gray said that the reduction in breast cancer deaths outweighs the risk of endometrial cancer and other side effects of tamoxifen. To put this in perspective, Gray said that the absolute mortality gain of 10 years of tamoxifen at 15 years after diagnosis is 12% or 1 in 8 balanced against 1 in 250 cases of endometrial cancer deaths.

“Women and their doctors should be aware of the evidence from ATLAS when deciding how long to continue tamoxifen or other endocrine treatment,” he said. Abstract S1-2

Nurse Perspective on Adjuvant Tamoxifen

A. Nicole Spray, APRNHays Med Breast Care CenterHays, KS

The international ATLAS (Adjuvant Tamoxifen Longer Against Shorter) trial showed that 10 years of tamoxifen reduced the risk of dying by 29% during the second decade after diagnosis compared with 5 years of treatment. Additionally, women who continued tamoxifen for 10 years were found in the second decade after diagnosis to have a 25% lower recurrence rate.

These findings are exciting—perhaps more so for young women with high-risk features such as larger tumors or positive lymph nodes. The ATLAS results offer these premenopausal women, who are unable to take an aromatase inhibitor, options for extended treatment that may be able to positively impact their recurrence and mortality rate.

Perhaps the most important key phrase we must remember is that these findings may be practice changing for patients for whom tamoxifen is indicated. As we all know, tamoxifen has tolerability issues (hot flashes, fluid retention, vaginal dryness/discharge, hair loss, cataracts), and for some, more serious side effects (thrombosis, strokes, and endometrial cancer). Certainly, tamoxifen is not a “one drug fits all” medication. We must know a patient’s history and comorbidities to determine if the risk/benefit ratio of therapy favors an individual patient. Studies have indicated that as many as 50% of women on tamoxifen tolerate it with minimal toxicity; certainly these women are likely to continue treatment for the additional 5 years.

The ATLAS study did show that taking tamoxifen for a longer period of time can increase endometrial cancer ever so slightly. This information gives us a unique opportunity as nurses and midlevel providers to emphasize to patients the importance of an annual gynecologic exam and symptom monitoring for dysfunctional uterine bleeding while on tamoxifen in order to catch endometrial complications early.

Future research will hopefully elucidate the optimal duration and sequence of endocrine therapy for women with breast cancer.

Sentinel Lymph Node Surgery After Chemotherapy Shows Accuracy in Nodal Staging in Breast Cancer

By Ben Leach

Sentinel lymph node (SLN) surgery may provide a less-invasive alternative to axillary lymph node dissection (ALND) for nodal staging in node-positive breast cancer, according to data collected from the American College of Surgeons Oncology Group (ACOSOG) Z1071 study. These results were presented at the 35th Annual San Antonio Breast Cancer Symposium.

Most women with node-positive breast cancer undergo ALND as a treatment, while SLN surgery is typically used for patients initially diagnosed with node-negative disease. Many patients who receive neoadjuvant chemotherapy become node-negative as the disease is eradicated in the lymph nodes. The Z1071 study was performed to determine whether SLN surgery could be a safe method to use in patients with node-positive breast cancer who receive neoadjuvant chemotherapy.

“Many of those women will convert from node-positive disease to node-negative with the use of neoadjuvant chemotherapy,” said Judy C. Boughey, MD, associate professor of Surgery at the Mayo Clinic in Rochester, Minnesota, and lead author of the study. “These women often will ask, ‘Can I avoid the morbidity of an axillary lymph node dissection? Can I preserve some of my lymph nodes and undergo a less extensive procedure in the axilla?’”

Among the 689 patients in the study, SLNs were detected in 639 patients (92.7%). Among these patients, 637 received neoadjuvant chemotherapy, and if they were found to be node-positive, they received both SLN surgery with identification and removal of the sentinel nodes and ALND to remove lymph nodes in the axilla. The study found that 255 patients (40%) tested node-negative after receiving chemotherapy. Among the remaining 382 patients who had residual nodal disease, SLN surgery correctly identified nodal status in 326 patients; however, 56 patients who were SLN-negative tested node-positive with ALND. Thus, SLN surgery correctly identified nodal status in 581 (255 + 326) of 637 patients (91.2%).

Boughey and her colleagues noted that the false-negative rate (FNR) representing patients who tested SLN-negative but tested positive when they received ALND was 12.6%. A number of factors reduced the FNR, including the combined use of a blue dye mapping agent and a radiolabeled colloid (FRN = 10.8%) and the number of SLNs examined, with patients who had more than two SLNs examined having a lower FNR, including three lymph nodes (FNR = 9.0%), four lymph nodes (FNR = 6.7%), and five or more lymph nodes (FNR = 11.0%).

Boughey said the FNR observed in this study was encouraging, especially since this study was performed across several different institutions.

“This false-negative rate was hopefully going to be clinically acceptable to surgeons utilizing this procedure,” Boughey said. “In particular, women are very interested in trying to minimize their axillary surgery, so it is important for us to be able to have this information to give them as part of their decision-making, and to discuss what potential surgery they wish to go with.” Abstract S2-1

New Agent Improves Survival in Advanced

ER-Positive Breast Cancer

Combining an investigational agent called PD 0332991 with letrozole as first-line therapy extended progression-free survival (PFS) in women with advanced estrogen—receptor positive (ER+) breast cancer in a phase II study presented at SABCS.

The combination achieved median PFS of 26.1 months compared with 7.5 months for letrozole alone (P = .006).

PD 0332991 is a novel oral selective inhibitor of cyclin-dependent kinase (CDK) 4/6 that prevents cellular DNA synthesis by blocking tumor cell progression.

“The dramatic improvement in progression-free survival with the combination is very encouraging and clinically meaningful,” said Richard S. Finn, MD, associate professor of Medicine at the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles (UCLA) and lead author of the study. “These data represent a potential major advancement in our efforts to identify new medicines that target patients most likely to have an optimal response.”

The phase II study had two parts. In both parts, postmenopausal women with ER+/HER2- advanced breast cancer were randomized 1:1 to receive letrozole plus PD 0332991 or letrozole alone. At the conference, pooled results from both part 1 and 2 of the trial were presented, based on a total of 165 patients. In this pooled analysis, median PFS was 26.1 months (95% CI, 12.7-26.1) with the combination versus 7.5 months (95% CI, 5.6-12.6) with letrozole alone, representing a 63% improvement in risk of progression (hazard ratio [HR]=0.37; 95% CI, 0.21-0.63, P < .001).

In patients with measurable disease, response rates were 45% for the combination versus 31% for letrozole alone. Clinical benefit rate (complete and partial response rates plus stable disease) was 70% versus 44%, respectively.

The most commonly observed treatment-related adverse events in the combination arm were neutropenia, leukopenia, anemia, and fatigue.

“Importantly this was uncomplicated neutropenia,” Finn said. “There was no evidence of febrile neutropenia.” A phase III trial of the investigational agent in this patient population will be mounted in 2013. Abstract S1-6

Study Supports Hypofractionated Radiotherapy in Patients With Early-Stage Breast Cancer

Researchers presented 10-year follow-up data from the START trials at SABCS further supporting the use of hypofractionated radiotherapy—a lower total dose administered in fewer, larger fractions&mdash;in early-stage breast cancer.

“What our trials have shown is that you can be gentler on the normal tissue and produce fewer adverse effects if you give a slightly lower total dose [of radiation] in fewer, slightly larger fractions without losing the ability to eradicate the cancer,” said John Yarnold, MBBS, professor of Clinical Oncology at the Institute of Cancer Research in London and honorary consultant at the Royal Marsden NHS Foundation Trust.

The START trials randomized 4451 women with invasive breast cancer (T1-3, N0-1, M0) to various radiotherapy schedules following primary surgery. Yarnold said that START A was exploratory and START B was a pragmatic trial designed to determine a schedule that would work in clinical practice.

In START A, 2236 patients were randomized 1:1:1 to 50 Gy in 25 Fr (2.0 Gy) over 5 weeks, or 41.6 Gy or 39 Gy in 13 Fr (3.2 Gy and 3.0 Gy, respectively) over 5 weeks. In START B, 2215 patients were randomized 1:1 to 50 Gy in 25 Fr (2.0 Gy) over 5 weeks or 40 Gy in 15 Fr (2.67 Gy) over 3 weeks.

Long-term follow-up results showed that the hypofractionated regimens were as effective as the 50-Gy standard, and in both trials, the safety profiles were similar between the hypofractionated and standard arms.

Yarnold said that the 3-week 40 Gy 15 Fr regimen established in the START B trial is the current treatment standard in the United Kingdom, but other countries, including the United States, still use the traditional standard. Abstract S5-2

2012 American Society of Hematology (ASH) Annual Meeting

High Response Rates for Ponatinib

in Treatment-Resistant Leukemias

By Beth Fand Incollingo

Researchers have demonstrated that ponatinib, a new oral tyrosine kinase inhibitor (TKI), can overcome a wide range of mutations that cause treatment resistance, including the stubborn T315I mutation, in all stages of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), while also working in cases where no mutations have been detected.

“We have simply never had any treatment produce such high rates of durable response in such a heavily treated group of patients,” said Jorge Cortes, MD, lead author and professor of Medicine, deputy chair of the Department of Leukemia, and chief of the CML and AML Sections at the University of Texas MD Anderson Cancer Center, in Houston.

Cortes presented the phase II study results during the 54th Annual Meeting and Exposition of the American Society of Hematology (ASH). Following a priority review, the FDA approved ponatinib (Iclusig) on December 14, 2012, for treatment of adult patients with chronic-, accelerated-, or blast-phase CML that is resistant or intolerant to prior TKI therapy or for PH+ ALL that is resistant or intolerant to prior TKI therapy.

Revolutionary improvement in the treatability of the two diseases came with the FDA’s 2001 approval of imatinib, the first TKI for the conditions. That and more recently developed TKIs, including dasatinib and nilotinib, work by binding to the BCR-ABL tyrosine kinase and turning off its signal, Cortes said. The treatments have turned CML, which once had a prognosis of 3 to 5 years, into a condition that can be successfully managed for decades.

But 5% to 20% of patients with CML and Ph+ ALL have the T315I mutation, making their disease resistant to those treatments, according to ASH. The only alternative is a hematopoietic stem cell transplant, which has toxic side effects, according to the organization.

Researchers in the United States and Europe embarked on the phase II study of ponatinib, enrolling 449 patients with CML or Ph+ ALL who had the T315I mutation and/or a history of resistance to dasatinib or nilotinib. Nearly all of the patients had been treated with multiple TKIs—90% with three such drugs and 60% with two, Cortes said. The patients were separated into six cohorts based on their disease resistance or genetic profile, and then treated with ponatinib.

The primary endpoint was major cytogenetic response within 12 months of treatment for those with chronic-phase CML, and major hematologic response within 6 months after treatment for those with advanced-phase CML or Ph+ALL. Results exceeded those criteria.

Major cytogenetic response was observed in 56% of all chronic-phase CML patients (70% of those with the T315I mutation and 51% of those with other mutations). Major hematologic response was observed in 57% of patients with accelerated-phase CML (50% of those with T315I and 58% of those with other reasons for resistance or intolerance) and 34% of those with blast-phase CML or Ph+ ALL (33% of those with the T315I mutation and 35% of resistant/intolerant patients), Cortes said.

Complete cytogenetic response was achieved in 46% of patients with chronic-phase CML, with higher response rates observed in patients who were exposed to fewer prior TKIs and those with shorter disease duration.

The portion of responders estimated to maintain their primary endpoint at 1 year was 91% in chronic-phase CML, 42% in accelerated-phase CML, and 35% in blast-phase CML or Ph+ ALL, Cortes reported.

Ponatinib was well tolerated in all cohorts. The most common adverse events were skin toxicity (including rash or dry skin), elevation of pancreatic enzymes and/or pancreatitis, and myelosuppression (a side effect of cancer treatment that lowers blood cell count).

Ongoing at MD Anderson are a study of ponatinib as initial therapy and a trial of the drug in comparison to imatinib, Cortes said. Studies to start soon, he added, will involve combining ponatinib and chemotherapy in Ph+ ALL; using the novel drug in patients who have failed just one prior therapy; and administering ponatinib to patients with acute myeloid leukemia, a strategy that showed promise in phase I trials. Abstract 163

Nurse Perspective on Ponatinib

Jayshree Shah, APN-C, AOCN®, RN, MSN, BSN, BS, CCRPJohn Theurer Cancer CenterHackensack, NJ

In chronic myeloid leukemia (CML) and in Philadelphia chromosomepositive acute lymphoblastic leukemia (Ph+ALL), the overproduction of BCR-ABL protein results in an abnormal growth of leukemia cells. We now have new players entering the market as potential options to treat patients with CML or Ph+ ALL who have a specific T315I mutation. This mutation can be deadly if treatment is not initiated immediately.

One of those players is a new tyrosine kinase inhibitor (TKI), ponatinib. The data so far for this drug suggest it is a positive contender for the treatment of adult patients with CML and Ph+ALL resistant to prior TKI therapy.

This oral therapy requires close monitoring of blood counts, and routine bone marrow biopsy with cytogenetics should be done prior to and during treatment. Findings so far are encouraging with positive results reported for CML and Ph+ALL cancers, and it will be even more exciting to see the preliminary results when ponatinib is compared with imatinib.

As a hematology nurse practitioner, it is very important to have knowledge of all the different options available to treat CML and Ph+ALL that have resulted in positive findings. In addition to knowing the clinical trial results, it will be important to know how to manage these therapies appropriately by doing the proper testing to monitor response, utilizing proper symptom management, addressing adherence issues, providing proper education related to the medicine the patient is currently taking, and assisting patients in obtaining the medicine at a reasonable cost.

Pomalidomide Labeled an Advance

in Multiple Myeloma

By Anita T. Shaffer

The combination of pomalidomide and a steroid significantly improved outcomes for patients with multiple myeloma who have exhausted other novel therapies, marking what researchers say is a notable advancement for a sizable proportion of those treated for the disease.

In a phase III trial, pomalidomide given with lowdose dexamethasone nearly doubled median progression- free survival (PFS) to 15.7 weeks when compared with high-dose dexamethasone at a median PFS of 8.0 weeks (HR = 0.45; P < .001), according to findings discussed at the 2012 ASH meeting.

Median overall survival (OS) had not yet been reached in the pomalidomide arm, but is expected to be about 11-12 months, said Meletios A. Dimopoulos, MD, lead author and professor and chair of the Department of Clinical Therapeutics at Alexandra Hospital in Athens, Greece. The median OS was 34 weeks in the control arm (HR = 0.53; P < .001).

Dimopoulos said in an interview that researchers are excited to have an option for patients who become resistant to lenalidomide (Revlimid) and bortezomib (Velcade), which often are combined with dexamethasone as frontline therapy in the United States.

He said that although novel therapies have dramatically improved the median survival of the average patient with multiple myeloma from no more than 3 years approximately a decade ago to more than 7 or 8 years today, patients ultimately relapse. Currently, patients who are resistant or refractory to the novel agents often are offered high-dose dexamethasone as a palliative treatment because there are no alternatives, he said.

Patients who enrolled in the clinical trial, which was conducted from March 2011 to September 2012, had been heavily pretreated. “The median number of prior therapies was five,” Dimopoulos said.

In all, 455 patients were randomized 2:1 to receive pomalidomide plus low-dose dexamethasone (n = 302) versus high-dose dexamethasone (n = 153). In the experimental arm, each 28-day cycle consisted of pomalidomide daily on days 1-21 at a dosage of 4 mg/day plus dexamethasone on days 1, 8, 15, and 22 at 40 mg for participants age 75 or younger and 20 mg for those over age 75. In the control arm, patients received dexamethasone on days 1-4, 9-12, 17- 20 at the same age-stratified dosages.

The combination regimen was well tolerated, Dimopoulos said, although there were toxicities reported in both arms. The frequency of grade 3/4 hematologic toxicities was higher in the pomalidomide arm compared with the control group for neutropenia (42% vs 15%, respectively) and febrile neutropenia (7% vs 0%), but lower for thrombocytopenia (21% vs 24%).

Of those who discontinued therapy, progressive disease was the primary reason, with 35% of patients who took pomalidomide discontinuing and 49% in the control group. In all, 25% of patients in the pomalidomide group and 38% in the control group died, primarily due to progressive disease and infections.

In October, the Data Safety Monitoring Board determined that the pomalidomide study met its primary endpoint of improvement in PFS and crossed the superiority boundary for OS.

On February 8, 2013, the FDA announced its approval of pomalidomide for the treatment of multiple myeloma after patients have relapsed or become refractory to other cancer drugs. The drug is marketed by Celgene, which also has applied to the European Medicines Agency for marketing authorization and anticipates a decision in the second half of 2013. Abstract LBA-6

Genes Predispose Some Anthracycline Patients to Heart Failure

Researchers have identified a genetic profile of the patients who are most likely to develop congestive heart failure after being treated with anthracyclines and then undergoing hematopoeitic stem cell transplant (HCT) for a range of blood cancers.

The results of the study, presented at the 54th Annual Meeting and Exposition of the American Society of Hematology (ASH), will help oncologists decide which bloodcancer patients are good candidates for anthracyclines, and which should either avoid the drugs or take them in combination with frequent heart screening and/or medication to prevent heart failure, said Smita Bhatia, MD, MPH, chair of the Department of Population Sciences at City of Hope in Duarte, California, and a coauthor of the paper.

“We all know that, first and foremost, we have to cure our patients,” Bhatia said. “But if we have to use anthracyclines in these patients, we may also consider using a cardio protectant.”

In conducting the study, lead author Saro Armenian, DO, MPH, and colleagues sought to explain the wide variability in the risk of heart failure among blood-cancer patients who receive anthracycline treatment followed by HCT, by determining if some have a genetic susceptibility to the condition. The investigators followed patients who had undergone HCT at City of Hope between 1988 and 2008 and survived at least 1 year. From that group, Bhatia said, the researchers chose 77 patients who developed heart failure and 178 who did not.

The researchers compared the frequency with which certain genes, known to be associated with heart failure, were expressed in the subjects. “We found three genes that were independently associated with risk,” Bhatia said—specifically, MRP2, RAC2, and HFE. “Then, we looked at them in combinations of two or more of the genes versus less than two genes. We found that, if the patient was female and had more than two of the genes, her risk of developing congestive heart failure was tremendously increased; it was 17-fold higher than for males with less than two of the genes.”

Combined with clinical factors, the gene signature makes it possible to predict with 79% certainty whether patients like those in the study will develop congestive heart failure, as compared with a 69% probability based on clinical factors alone, Bhatia said. Abstract 589

Ibrutinib Performance in CLL Patients Hailed

By Anita T. Shaffer

The novel targeted agent ibrutinib has demonstrated dramatic activity in hard-to-treat patients with chronic lymphocytic leukemia (CLL) when used alone and in combination with rituximab (Rituxan), raising the prospect of a promising new therapy for elderly and frail patients who currently have few viable options, according to findings from two studies into the drug reported at the 2012 ASH meeting.

Ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor, is the most advanced in a new class of anticancer agents, and researchers were clearly excited about its potential.

The drug is an oral, well-tolerated medication that produces “excellent responses,” without the need for the more intensive chemotherapy regimens that serve as first-line treatments for younger and fitter patients, said Claire E. Dearden, MD, consultant hematologist and head of the CLL Unit at The Royal Marsden NHS Foundation Trust in London, who served as moderator for the briefing.

“There’s a lot of excitement about the possibility of the landscape changing and leaning toward having chemotherapy-free treatments for patients with CLL that are as effective as giving them chemotherapy agents,” said Dearden. “It’s hugely exciting for us as clinicians, but also for the patient community.”

The median age for diagnosis of CLL is 72 years, but such patients often are not able to tolerate the primary treatment regimen that includes the chemotherapy agents fludarabine and cyclophosphamide, along with the humanized monoclonal antibody rituximab, researchers noted.

Ibrutinib is an irreversible inhibitor of BTK, an enzyme that plays an essential role in B-cell receptor signaling and several other pathways, said John C. Byrd, MD, lead author of one of the studies and director of the Division of Hematology at The Ohio State University Comprehensive Cancer Center—James Cancer Hospital and Solove Research Institute in Columbus.

So far, he said, there is no indication that inhibiting BTK activates other cancer-causing pathways.

Responses High in Elderly Patients

Ibrutinib, formerly known as PCI-32765, was evaluated in a phase IB/II study in patients with CLL or small lymphocytic leukemia (SLL). The primary goal of the study was to determine the safety of the low and high doses; secondary objectives included response rates and progression-free survival (PFS).

Results were reported for 116 patients who were stratified into three cohorts: treatment-naïve ≥65 years (n = 31), relapsed/refractory (RR; n = 61), and high-risk RR (n = 24). Participants in the first two groups received dosages of either 420 mg/day or 840 mg/day, while those in the third group received the dosage of 420 mg/day. High risk was defined as progression of disease within 24 months of initiation of prior treatment or failure to respond to previous therapy.

The overall response rates, which included partial and complete responses, were 68% in the treatment-naïve group at 20.3 months’ follow-up and 71% in the combined results for the two RR groups at follow-up ranging from 14.7 months for the high-risk RR patients and 22.1 months for the RR group.

Among previously untreated patients, there was a 96% estimated rate of both PFS and overall survival (OS) at 22 months’ follow-up. For patients in the RR groups, there was a 76% PFS rate and an 85% OS rate at 22 months.

The majority of adverse events were grade ≤2, with diarrhea (54%), fatigue (29%), and upper respiratory tract infection (29%) the most frequently reported, according to the abstract. The incidence of hematologic toxicity ≥grade 3 was “relatively infrequent,” and there was no evidence of long-term safety concerns, the abstract indicates.

“There’s rarely something that comes along that you see helping patients so much,” said Byrd. “The quicker we get this across the finish line to patients, the better it’s going to be. This is a special therapy that all of us have seen really helps patients.” The drug is being developed under the FDA’s Fast Track program for patients with CLL/SLL who have relapsed or refractory disease after at least one prior therapy, according to Pharmacyclics, Inc, which is developing ibrutinib in collaboration with Janssen Biotech, Inc. Abstract 189

Rituximab Combination Helps High-Risk Group

In a second study, researchers sought to accelerate response to ibrutinib by pairing the drug with rituximab in 40 patients with CLL/SLL considered high risk, including those harboring the del17p/TP53 mutation or del11q deletion, or those with <3 years remission after first-line chemo-immunotherapy. The median age was 65 (ages 35—82), and nearly 28% had early-stage disease while the remainder were stage III or IV.

Participants received continuous daily ibrutinib at 420 mg/day in combination with weekly rituximab (375 mg/m2) for the first 4 weeks, and then monthly rituximab until cycle 6. Daily single-agent ibrutinib continued until progression. In all, 38 of 40 patients continued on therapy without disease progression. The overall response rate was 83%, with one patient exhibiting a complete response and the others achieving partial responses. In addition, three patients had a partial response with lymphocytosis, two participants did not exhibit any response, and results were too early to evaluate in two other patients.

The most common adverse event was diarrhea, followed by bone pain/myalgias, and fatigue.

Jan A. Burger, MD, PhD, lead author and associate professor of Medicine in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston, said larger-scale studies of the ibrutinib-rituximab combination are needed. He also said the rate of complete remissions might increase with more effective combination therapies. Abstract 187

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