April 2015 by McMahon Group

Independent News for the Oncologist and Hematologist/Oncologist CLINICALONCOLOGY.COM • April 2015 • Vol. 10, No. 4

Editorial Board Commentary

CURRENT PRACTICE Tips to boost adherence to oral oncology drugs .......

Debate: Are we ready for molecular profiling of GI cancers? .......................................

SOLID TUMORS MD Anderson algorithm for ovarian cancer raises optimal resection rate .........

4Kscore may reduce need for prostate biopsies ..................................

HEMATOLOGIC DISEASE Largest-ever T-ALL trial in children shows long-term event-free survival .............. 15 Study shows finding MGUS first improves survival in myeloma .............................. 16

by the

numbers Testis cancer survival by stage at diagnosis, 2004-2010

99 Local

96 Regional

73 Distant 0

100

5-year survival, % Source: American Cancer Society

April is Testicular Cancer Awareness Month See story on testicular-prostate cancer link; story on page 13.

Practicing in a New World of Molecular Cancer Medicine

uch has been written about the effect of revolutionary changes in our understanding of the fundamental biology of cancer and how this informaMaurie tion may favorably imMarkman, MD pact the management and outcomes of individual patients with malignant disease. Historic paradigm changes include the outlook for women with HER-2 positive breast cancer (adjuvant therapy or see NEW WORLD, D page 7

Preventing Oral Chemo Rx Errors: A Team Approach

Part 2 of a 3-Part Series

n recent years, oral antineoplastic agents have transformed the care of cancer patients. They have also brought new challenges, particularly in the case of medication errors. Oral cancer drugs are “some of the most toxic [compounds] on the market,” and when errors occur, they can be especially dangerous, noted Raymond Muller, MS, RPh, the associate director of the Division of Pharmacy Services at Memorial Sloan-Kettering Cancer Center (MSKCC), in New York City. Mr. Muller discussed strategies for reducing these errors during a recent webinar sponsored by the Institute for Safe Medication Practices (ISMP). Chemotherapy mishaps have multiple see CHEMO ERRORS, S page 4

New recommendations have been issued to guide the diagnosis of multiple myeloma; story on page 16.

Payment Reform: The Good, The Bad and the Ugly I

t’s high noon for payment reform. Like Gary Cooper, some oncologists are reluctantly taking it on, looking for solutions, whereas others are shuttering their doors, hoping the changes pass by without involving them. Almost all are wary—concerned about whether the new payment models will reimburse them for the cognitive work, as well as the procedural medical care they provide. “We are creatures of our economic environment,” said Sam Silver, MD, PhD, a professor of hematology at the University of Michigan, in Ann Arbor. “I think people are just concerned and confused. It’s hard to predict what the future is for oncologists because the entire environment of oncology practice is definitely changing.” Although most oncologists continue to work in a fee-for-service model (72%, according to the American Society for Clinical Oncology [ASCO]), others are experimenting with alternative payment schemes, such as capitation and bundling. In this second part of a three-part series, Clinical Oncology News discusses the various options—the good, the bad and the ugly. The one thing everyone agrees on is that payment reform has come to town. see PAYMENT REFORM, M page 9

Essential Oncology™

To download the Essential OncologyTM app go to:

essentialoncology.com 65 Cancer Types

65 Cancer Types

Cases in Hyponatremia

Minimizing Risks, Optimizing Outcomes To participate in this FREE CME activity, log on to

www.CMEZone.com/hyponatremia Release Date: November 11, 2014

Expiration Date: November 11, 2015

Faculty

Goal

Michael L. Moritz, MD

The goal of this educational activity is to provide clinicians with clinically relevant information and practice strategies concerning the assessment and management of hyponatremia.

Professor, Pediatrics Clinical Director, Pediatric Nephrology Medical Director, Pediatric Dialysis Children’s Hospital of Pittsburgh of UPMC Pittsburgh, Pennsylvania

Denise H. Rhoney, PharmD Ron and Nancy McFarlane Distinguished Professor and Chair Division of Practice Advancement and Clinical Education UNC Eshelman School of Pharmacy Chapel Hill, North Carolina

Learning Objectives At the completion of this activity, participants will be better prepared to: 1 Distinguish the various subtypes of hyponatremia. 2 Describe the comorbidities and causes commonly associated with hyponatremia and their signiﬁcance in treatment. 3 Summarize current evidence and best practices in the management of hyponatremia. 4 Explain how to mitigate adverse events secondary to treatment of hyponatremia. 5 Apply strategies to improve the management of hospitalized patients with hyponatremia.

Intended Audience The intended audience for this educational activity includes physicians (cardiologists, critical care specialists, endocrinologists, hepatologists, hospitalists, intensivists, and nephrologists), nurses, pharmacists, and other clinicians who care for individuals with hyponatremia.

Accreditation Statement This activity has been planned and implemented in accordance with the Essential Areas and policies

This activity is jointly provided by Global Education Group and Applied Clinical Education.

of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Global Education Group and Applied Clinical Education. Global Education Group is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation Global Education Group designates this activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Pharmacist Continuing Education Accreditation Statement Global Education Group is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Credit Designation Global Education Group designates this continuing education activity for 1.0 contact hour(s) (0.10 CEUs) of the Accreditation Council for Pharmacy Education. (Universal Activity Number - 0530-9999-14-061-H01-P) This is a knowledge-based activity

Accreditor Contact Information For information about the accreditation of this program, please contact Global Education Group at (303) 395-1782 or inquire@globaleducationgroup.com.

Supported by an educational grant from Otsuka America Pharmaceutical Inc.

Distributed via CMEZone

CLINICAL ONCOLOGY NEWS

CLINICAL ONCOLOGY NEWS • APRIL 2015 • CLINICALONCOLOGY.COM

EDITORIAL BOARD

Solid Tumors Bone Metastases Allan Lipton, MD Milton S. Hershey Medical Center Penn State University Hershey, PA

Hematologic Malignancies Jennifer R. Brown, MD, PhD Dana-Farber Cancer Institute Harvard Medical School Boston, MA

Andrew Seidman, MD Memorial Sloan-Kettering Cancer Center Weill Cornell Medical College New York, NY

Maura N. Dickler, MD Memorial Sloan-Kettering Cancer Center Weill Cornell Medical College New York, NY

Gastrointestinal Cancer

Paul J. Ford, PhD

University of Texas, MD Anderson Cancer Center Houston, TX

Cleveland Clinic Foundation Lerner College of Medicine of Case Western Reserve University Cleveland, OH

Pharmacy Harry Erba, MD, PhD

Breast Cancer

Michele Neskey, MMSc, PA-C

University of Alabama Birmingham, AL

Shaji Kumar, MD Mayo Clinic Rochester, MN

Richard Stone, MD Dana-Farber Cancer Institute Harvard Medical School Boston, MA

Policy and Management

Cindy O’Bryant, PharmD

Mary Lou Bowers, MBA

University of Colorado Cancer Center Denver, CO

Mitchell Cancer Institute Mobile, AL The Pritchard Group Rockville, MD

Sara S. Kim, PharmD The Mount Sinai Medical Center New York, NY

Matt Brow VP, Public Policy & Reimbursement Strategy McKesson Specialty Health The US Oncology Network Washington, DC

Bioethics Joseph P. DeMarco, PhD

Infection Control

Cleveland State University Cleveland, OH

Susan K. Seo, MD

Edward Chu, MD University of Pittsburgh Cancer Institute Pittsburgh, PA

Memorial Sloan-Kettering Cancer Center New York, NY

Syed A. Abutalib, MD Cancer Treatment Centers of America Zion, Illinois

Cathy Eng, MD University of Texas, MD Anderson Cancer Center Houston, TX

Leonard Saltz, MD Memorial Sloan-Kettering Cancer Center Weill Cornell Medical College New York, NY

Gastrointestinal Cancer and Sarcoma

Community Oncology John W. Finnie, MD Mercy Medical Center St. Louis, MO

Michael J. Fisch, MD, MPH University of Texas, MD Anderson Cancer Center Houston, TX

Ephraim Casper, MD

Steven Vogl, MD

Memorial Sloan-Kettering Cancer Center Weill Cornell Medical College New York, NY

Medical Oncologist New York, NY

Genitourinary y Cancer Ronald M. Bukowski, MD Taussig Cancer Center Cleveland Clinic Foundation Cleveland, OH

Michael Enright, Publication Sales menright@mcmahonmed.com McMahon Publishing is a 43-year-old, family-owned medical publishing and medical education company. McMahon publishes seven clinical newspapers, seven special editions, and continuing medical education and custom publications.

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CURRENT PRACTICE

CHEMO ERRORS continued from page 1

causes, Mr. Muller noted, including poor packaging/labeling, interruptions during order processing or a misunderstanding of a drug regimen’s total daily dose. A 2010 study identified 508 oral antineoplastic errors through MEDMARX and other

Table 1. Common Causes of Cancer Chemotherapy Errors Miscommunicated verbal orders Excessive interruptions during order processing Lack of patient information, such as past medications, lab data and demographics Poor packaging/labeling

CLINICAL ONCOLOGY NEWS • APRIL 2015 • CLINICALONCOLOGY.COM

(SORAFenib or SUNITinib) to help distinguish between similar drug names. As an additional safeguard against medication errors, MSKCC has a computerized prescriber order entry (CPOE) system that contains more than 3,000 customized order sets for chemotherapy, including oral agents. A CPOE system is “one of the single best things” that a cancer center can implement to reduce errors, Mr. Muller said. Indeed, one study showed that e-prescribing cut medication errors in half ((J Am Med Inform Assoc 2013;20[3]:470-476, PMID: 23425440). Having a full electronic medical record (EMR) system also can help boost medication safety, Mr. Muller noted, adding that at MSKCC, 100% of the medical records are electronic. The EMR system tracks inpatient and outpatient doses and provides cumulative dose tracking to warn clinicians when they are nearing the maximum dose allowed. “There is an

Confusion because of similarsounding drug names or the use of abbreviations

automatic interface for 125 drugs that interfere with common laboratory tests; height and weight limits are embedded,” he said. “We have an incredibly robust electronic system to report and review actual and near-miss events, which tend to improve our care.”

Comorbidities a Concern Mr. Muller noted that managing comorbidities in patients taking oral cancer medications can be tricky. Adjustments often have to be made to concomitant drugs, which could include oral anticoagulants, proton pump inhibitors, antifungals, vitamins and many others (Table 3). But those adjustments may never occur if, during the course of cancer treatment, the patient isn’t asked about other medications they may be taking, Mr. Muller noted. “There are a lot of drug interactions that we don’t see when we have a patient in a chair having IV chemo infused,” i f d” h he said. id Th Thus, ““we strongt ly encourage a comprehensive [medication] profile and have the patient record everything that they take, including

Legibility issues due to handwriting or a poor copy/fax Total course dose given every day Failure to round a dose Miscalculation in the ordering or dispensing process Drug shortages, which can lead to drug concentration changes or the use of alternative agents

databases (Cancer 2010;116[10]:245 552464, PMID: 20225328). The most co ommon reason for error was wrong dose (38.8%), followed by wrong drug (13.6%), 6%) wrong number of days supplied (11%) and missed doses (10%). Roughly one-third of the mishaps were due to pharmacy dispensing errors. “That is significantly higher than most medication safety studies,” Mr. Muller said. “Usually, if you look at [the literature], dispensing errors are typically responsible for about 15% of events.” Most errors identified in the study resulted in a near miss, but 39.3% of reports involving the wrong number of days supplied resulted in an adverse drug event, he pointed out. (For more details on common causes of oral chemotherapy errors, see Tables 1 and 2). Confusion caused by similar-sounding drug names or the use of abbreviations is a special challenge with cancer agents. “Many oral cancer agents have a common suffix of ‘nib’ and have the same size and color for all dosage strengths,” Mr. Muller said. To guard against medication errors, MSKCC uses electronic alerts and posters to educate clinicians about lookalike/sound-alike medications, refers to all drugs by their generic names, and uses the TALLman lettering system, which uses upper- and lower-case letters

alternative meds, vitamins, etc.” Poor adherence to oral cancer drug regimens is another potential problem spot that can introduce a medication error. “One patient came back and said, ‘I figured if I’m supposed to take one tablet twice a day, then two tablets twice a day might work better,’” Mr. Muller said. It is important to stress to patients that no dose adjustments can be made without a physician’s approval. Patients also must be cautioned to not crush, break or chew tablets because doing so can affect the pharmacokinetics of some drugs, he added. Mr. Muller also stressed the importance of taking a standardized approach to chemotherapy administration. In fact, he recommended that cancer centers standardize everything (e.g., order sets, calculation methods, supportive therapy approaches and emergency management of reactions) and regularly assess staff competency. When consistent consisten protocols are combined with team ccare, medication safety can improve sign nificantly, he noted. In one study, a pediattric cancer center that used a multidiscip plinary team approach involving clinicaal pharmacy specialists, oncologists and nurses, achieved a 0 0.18% actual chemottherapy error rate ((Pediatr Blood Cancer 2013;60[8]:1320-1324, PM MID: 23519908).

The e Power Of Ac ctual Events MSKCC perio odically offers educational programs ab bout medication errors using actual eventss. “Staff respond much better to [actual evvents]; they think, ‘if it

Table 2. Sample of Oral Chemotherapy Drug Errors Drug

Error

Methotrexate

Multiple deaths caused by accidental daily administration when weekly was intended

Lomustine

Given daily instead of every 6 wk; a patient took 450 mg instead of the intended 150 mg; the patient died

Idarubicin

An oral dose of 60 mg was given daily for 4 d instead of a single dose over 4 d

Temozolomide

Physician ordered 10-fold overdose that resulted in a patient death

Capecitabine

Many dispensing errors cited due to multiple dosage forms and regimens

Source: Guide to Prevention of Chemotherapy Errors 2012; Cancerr 2010;116:2455-2464; ISMP Med Safety Alert, July 17, 2014; ISMP Med Safety Alert, February 12, 2013.

Table 3. Selected Drug Interactions With Oral Antineoplastic Agents Capecitabine

Increases serum levels of oral anticoagulants and phenytoin

Dasatinib (Sprycel, Bristol-Myers Squibb)

Avoid proton pump inhibitors, H2 antagonists and St. John’s wort

Everolimus (Afinitor, Novartis)

Avoid phenytoin, carbamazepine, posaconazole (Noxafil, Merck), and voriconazole

Imatinib (Gleevec, Novartis)

Do not give with warfarin; use low-molecular-weight heparin instead

Nilotinib (Tasigna, Novartis)

Do not use in patients with hypokalemia, hypomagnesemia or long QT syndrome; avoid most cardiac medications

Sou ce J O Source: Oncol co Pract actt 2014;10(4):e255-e268; 0 ; 0( ) e 55 e 68; PMID: 24756141. 56

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • APRIL 2015 • CLINICALONCOLOGY.COM

Meeting the Challenges of Oral Cancer Agents Solving access issues, fostering adherence and managing comorbidities are major components of care Anaheim, Calif.—The past decade has seen a surge in oral cancer therapies. These agents—representing approximately 25% of all new anticancer drugs in development—provide benefits as well as present new challenges. Many of these oral agents are distributed through specialty pharmacies, in part because they require proof of Risk Evaluation and Mitigation Strategies compliance. Joseph Bubalo, PharmD, an oncology pharmacy specialist at Oregon Health & Science University, in Portland, estimates that almost half of all oral cancer agents move through specialty pharmacies. Thus, supply channel issues are often at the top of the list of challenges to resolve, not the least of which is access. For example, will a new oral chemotherapy drug even be available to patients at a given hospital or clinic, or do limited distribution networks pose barriers to access? Assuming any access issues can be resolved, the next step is to meet clinical issues head on, including monitoring disease response, managing toxicities and ensuring treatment adherence. At the American Society of Health-System Pharmacists 2014 Midyear Clinical Meeting, Ginah Nightingale, PharmD, an oncology pharmacy specialist at Thomas Jefferson University Hospital, in Philadelphia, and Susannah Koontz, PharmD, a pediatric clinical pharmacy specialist at Koontz Oncology Consulting, in Houston, addressed these issues, especially as they affect geriatric and pediatric patient populations.

Table 1. Selected Trials Evaluating Adherence to Oral Cancer Therapies Study

Patients, N

Drug

Adherence Metric

Adherence Rate

Time Period

J Clin Oncol 2012;30(suppl): abstract e11067

666

Lapatinib (Tykerb, GlaxoSmithKline)

Medication possession ratio, ≥80%

78%

J Clin Oncol 2008;26(4): 556-562

12,391

Anastrozole

Prescription refills, ≥80%

78%-86%, year 1; 62%-79%, year 3

J Clin Oncol 2010;28(27): 4120-4128

5,979

Tamoxifen, letrozole

Medical claims, ≥80%

49%

J Clin Oncol 40 2013;31(suppl 31): abstract 25

Sunitinib (Sutent, Pfizer), pazopanib (Votrient, GlaxoSmithKline), everolimus (Afinitor, Novartis)

Adherence questionnaire, eight-item Morisky Medication Adherence Scale

High adherence, 60%; Intermediate adherence, 30%; low adherence, 10%

60 d

J Clin Oncol 2011;29(suppl): abstract 7611

Erlotinib (Tarceva, Genentech)

Self-report, ≥95%

72%

2 mo

Arch Dis Child 2004;89(8): 785-788

Mercaptopurine

Patient interview, drug metabolite assay

54%

Conclusion of maintenance therapy

According to Dr. Koontz, one of the biggest challenges is that oral

chemotherapy drugs haven’t been widely studied in pediatric patients. As a result, there are knowledge gaps regarding the pharmacodynamic or pharmacokinetic profile of the medications in children. However, there are some useful clues in the literature. A study from Denmark, for example, showed that oral methotrexate and 6-mercaptopurine were more effective when children with acute lymphoblastic leukemia (ALL) took the medications in the morning or evening (J ( Pediatr Hematol Oncol 1997;19[2]:102-109, PMID: 9149738). Because older patients are underrepresented in clinical trials, just how new

drugs will work in the elderly also is unclear. “In clinical trials, you have a superstar athlete, the most healthy and functionally fit patient, compared with an 82-year-old or 87-year-old who likely has several comorbidities, underlying organ impairment and declining functional status,” Dr. Nightingale said. “It is hard to generalize what you see in a clinical study to the patient in front of you.” Studies estimate that only 20% of patients in cancer clinical trials are 70 or older, and only 9% are 75 or older ((J Clin Oncol 2004;22[22]:4626-4631, PMID: 15542812). Age-related factors can influence the

absorption, distribution and metabolism of oral agents (Drugs ( Agingg 2002;19[1]:2542, PMID: 11929325). For example, older individuals often have reduced gastric acid secretion and gastrointestinal motility, and many are on concomitant medications, all of which can change drug absorption. The decreased plasma albumin and increased fat-to-muscle mass that comes with aging can hinder drug distribution. Reduced hepatic metabolism and cytochrome P450 enzymes can decrease drug metabolism. Dr. Nightingale pointed out that there is a big difference between chronologic

can happen to one of my colleagues who I respect, it could certainly happen to me,’” Mr. Muller said. To further strengthen staff education, MSKCC provides an annual chemotherapy error prevention course for medical oncology fellows. Smaller oncology centers and practices sometimes have to come up with creative solutions when they don’t have the resources and protocols of larger centers. Robin Zon, MD, the vice president at Michiana Hematology-Oncology, in South Bend, Ind., told Clinical Oncology News that to reduce medical errors, her practice follows the American Society of Clinical Oncology/Oncology Nursing Society Chemotherapy Administration Safety Standards. This guidance was first published in 2009 and was most recently updated in 2013 ((J Oncol Practt 2013;9[2 Suppl]:5s-13s,

PMID: 23914148). The guidance includes numerous recommendations, such as having two people independently verify each order for chemotherapy prior to preparation. The 2013 updates specifically address oral chemotherapy and drive home the necessity of ascertaining that prescriptions are actually filled; the importance of patient and family education regarding administration schedules, exception procedures and disposal of unused oral medication; and aspects of continuity of care across settings. Dr. Zon echoed the sentiment that the flurry of similar-sounding drug names for different indications can add confusion. “The clinician worksheet that we use often has both the generic and the name brand, and I think this is helpful to physicians and nurses to be clear about

a drug when it comes to similar-sounding generic compounds,” said Dr. Zon. She added that at her practice, nurses are encouraged to speak to physicians or nurse practitioners without retribution, if they have any concerns or questions about a particular drug. Errors can also occur on the clinical research side, such as when patients are only supposed to be getting a drug from a specific stockpile of drug, even though the drug is already on the market and on pharmacy shelves. “To avoid this error, if a patient is on a clinical research trial, they are flagged with a green flag in our IT system,” said Dr. Zon. John Finnie, MD, a staff hematologist and a medical oncologist at the David C. Pratt Cancer Center at St. John’s Mercy Medical Center, in St. Louis, said he

“strongly believes that CPOE and electronic chemotherapy order protocols greatly minimize potential errors.” He said clinical pathways also can reduce mistakes. “Pathways, a big new idea in oncology, should further minimize potential error. The oral chemo gets checked by the outpatient pharmacist and pharmacy tech, which helps minimize error,” said Dr. Finnie. He simplifies medication instruction where he can. “In my practice,” said Dr. Finnie, “I only use the 500 mg capecitabine pill, because I find trying to use the 150 mg pill and the 500 mg pill always confuses patients.”

Drug Safety and Effectiveness

see ORAL AGENTS, page 6

—Kate O’Rourke Mr. Muller and Drs. Zon and Finnie reported no relevant financial relationships.

CURRENT PRACTICE

ORAL AGENTS continued from page 5

age and functional age. Factors predicting treatment-related morbidity or mortality in elderly cancer patients include functional status, comorbid conditions, nutritional status, cognitive function, psychological state, social support and polypharmacy. Experts recommend that older patients undergo a comprehensive geriatric assessment before starting any oral cancer agent. “A frail patient can be more at risk of cancer treatments causing harm than benefit,” Dr. Nightingale said. “We have all of our patients seen by a dietician to determine whether they have underlying malnutrition. Some of the new oral therapies are very specific in terms of dietary considerations—take the pills with food or high-fat food.” A patient with anorexia could run into problems, she added. In the elderly population, managing patient prescriptions to avoid drug– drug interactions is another challenge. “Most of the oral drugs are metabolized by liver enzymes that metabolize lots of other drugs, and some new agents change the metabolism of other drugs,” Dr. Bubalo explained. For example, sorafenib (Nexavar, Bayer) is partially metabolized by uridine diphosphate glucuronyltransferases 1A9 and cytochrome P450 3A4 isoform, both of which are involved in metabolizing many other drugs. The prostate cancer drug enzalutamide (Xtandi, Astellas/ Medivation) speeds up the metabolism of some medications, including those used to treat high cholesterol. Other oral agents, such as crizotinib (Xalkori, Pfizer) and dasatinib (Sprycel, BristolMyers Squibb), are pH-sensitive, so over-the-counter antacids and proton pump inhibitors can impair drug absorption. Assessing nutritional supplements or herbal medicines as well as foods, such as grapefruit juice, that may interact with oral antineoplastic agents also is crucial. All patients should have a portable medication list, on paper, as well as on their smartphone, to keep track of medications, Dr. Bubalo noted. Regular medication reconciliation is a must.

Treatment Adherence However, just because a drug is on a list doesn’t mean a patient is actually taking it. Suboptimal treatment adherence is one of the biggest obstacles to using oral therapies. Because studies measuring adherence use different definitions and different yardsticks (i.e., selfreport, pill counts), it is difficult to get a clear picture of the problem, but some adherence rates are under 50% (Table 1). Although a threshold of 80% often has been quoted as an adequate adherence rate, a study of imatinib (Gleevec,

CLINICAL ONCOLOGY NEWS • APRIL 2015 • CLINICALONCOLOGY.COM

Table 2. Factors in Adherence to Oral Cancer Therapies Patient-specific Age Ethnicity/race Cognitive capacity Forgetfulness and ability to establish a medication routine Cultural health beliefs Financial resources Health knowledge literacy Physical factors Social support system Coping/adaptation skills Anxiety/self-esteem

Table 3. Medication Reminder Apps

Caregiver beliefs and anxiety

My MedSchedule

Treatment-specific

MedSimple

Illness perception

RxmindMe Prescription

Side effects

MyMeds

Cost/access

Meds Agenda

Polypharmacy Regimen complexity and administration Therapy duration Provider/system-specific Provider–patient relationship Fragmented continuity of care Insurance coverage Satisfaction with care Based on presentations by Ginah Nightingale, PharmD, and Susannah Koontz, PharmD

Novartis) in chronic myeloid leukemia demonstrated that an adherence rate of less than 90% greatly decreased the sixyear probability of a major molecular response compared with an adherence rate of 90% or greater (28.4% vs. 94.5%; P<0.001) ((J Clin Oncoll 2010;28[14]:23812388, PMID: 20385986). A study of oral mercaptopurine in children with ALL showed that compared with a benchmark of at least 95% compliance, the risk for relapse rose with decreasing compliance ((J Clin Oncoll 2012;30[17]:2094-2101, PMID: 22564992). When developing a plan to improve treatment adherence, Dr. Koontz said pharmacists can rely on the American College of Preventive Medicine’s mnemonic device, SIMPLE: • S, simplify the regimen; • I, impart knowledge; • M, modify patient beliefs and behavior; • P, provide communication and trust; • L, leave the bias; and • E, evaluate adherence. To simplify, Dr. Koontz discusses schedules with patients and caregivers to identify the best time for medication administration, recommending that complex

regimens be taken when a caregiver can devote more time. “For example, maybe first thing in the morning is not the best time for a child to take a lot of medications when a grandmother is coming over to take care of the child,” she said. She stressed the importance of avoiding biases, such as assuming that single mothers will have the most problems managing a child’s medications; sometimes it is the two-parent family with a high income that struggles to comply. Dr. Koontz provides regimen information in a chart that lists the drug names; what exactly each medication does; instructions on how to take the drug, such as time and food requirements; and information on managing the four or five most common side effects. “It is not helpful to say these are 30 side effects that you might have; that can be overwhelming,” Dr. Koontz said. In contrast, empowering a patient with a manageable amount of knowledge can increase compliance. There is no standard tool for measuring adherence to oncology medications, but Dr. Nightingale said she uses the eight-item Morisky Medication Adherence Scale, which has been validated in other diseases. Open-ended questions work better than “do you take” medicine X. “I say, ‘tell me how you are taking your mercaptopurine,’ and I let them verbalize it,” Dr. Koontz said. Proactive patient education on adverse effects also can be helpful. According to Dr. Bubalo, one relatively new agent that can be challenging to manage is afatinib (Gilotrif, Boehringer Ingelheim). This lung cancer drug causes diarrhea in almost all patients and grade

3 diarrhea in roughly 15% ((J Clin Oncol 2013;31[27]:3327-3334, PMID: 23816960). “There is a lot of patient education that goes into this drug. You need to tell patients what to expect, and how to manage the side effects and watch for the danger signs that indicate they should call back for medical support,” he said. “Patients are much more successful when you have a preemptive side effect management process in place.” Melanoma agents trametinib ( Mekinist, GlaxoSmithKline) and vemurafenib (Zelboraf, Genentech) are associated with rash; patients need to be able to differentiate a normal rash from one that may require additional therapies, he pointed out. Because the reasons that patients may be nonadherent to therapy are so varied (Table 2), adherence interventions must be individualized. Financial assistance programs can help those who may be noncompliant because they can’t afford their drugs, many of which run $8,000 to $12,000 per month. Even when a patient has insurance, he or she may have high copays. Smartphone apps (Table 3) and automated texts may be helpful, but only for those comfortable with technology. Use of sticker books, with young patients being rewarded with a sticker every time they take their medication, is effective, especially for girls. “Sometimes it is a memory issue or figuring out how to integrate a medicine into the day,” Dr. Bubalo said. “Some individuals have barriers such as cost, nutrition, the inability to swallow or side effects. You have to tailor an intervention to the patient. Adherence issues are always individual.” —Kate O’Rourke Drs. Bubalo and Nightingale reported no relevant financial relationships. Dr. Koontz reported relationships with Lexicomp and Sigma Tau Pharmaceuticals.

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EDITORIAL BOARD COMMENTARY

NEW WORLD continued from page 1

management of metastatic disease) when treated with an anti-HER-2–directed antibody, the use of molecularly based treatment of chronic myelogenous leukemia, the lack of activity of anti–epidermal growth factor receptor (EGFR) antibody therapy in colon cancer in the presence of a KRAS mutation, and the critical recognition that certain lung cancers (EGFR ( mutations, Alk rearrangements) and melanomas (BRAF ( mutations) are “driven by” the presence of specific genomic abnormalities. More recently, the excitement regarding precision medicine reached the White House with President Obama actually noting in his State of the Union address the fundamental relevance of current and future efforts to establish a role for this strategy in multiple areas of medicine.1 Plans are underway to substantially accelerate government-funded efforts to discover molecular abnormalities that may be actionable in multiple clinical conditions, including cancer. However, it has been acknowledged that the concept of precision cancer medicine (also called “personalized cancer medicine”) can be confusing. Furthermore, it is not a simple task to articulate clearly for patients with cancer, their families, and the general public the differences between germline abnormalities (routinely employed for a number of decades in assessments of genetic risk for the presence or development of certain serious malignant and nonmalignant medical

conditions) and somatic molecular changes, which only are observed within the cancer. The situation is made even more complex when both types of abnormalities may be relevant in a particular clinical setting (eg, BRCA mutations in epithelial ovarian cancer). Although the concerns of patients regarding the complexity of genomic information are increasingly and appropriately being recognized, it is my opinion that there has been less than adequate attention paid to another key

existing paradigm of care once the strategy leaves the “non-real world” of clinical trials, is it any wonder that this rapidly accelerating new era represents a serious challenge for the practitioner? A recent report from an “academic cancer center” emphasized both the relevance and magnitude of this concern.2 Of 160 physicians (57% medical oncologists) who participated in a survey regarding advanced genomic testing, fully 22% reported “low confidence regarding genomic knowledge.” The program

It is the practicing oncologist who, ultimately, will be responsible for translating the research paradigm into clinical practice. group of individuals whose thorough understanding of these revolutionary changes is absolutely required to fully transition current routine oncologic care into the new paradigm of precision cancer medicine. And this group is the community of practicing oncologists. For although genuinely exciting, highly clinically relevant reports written and presented by academic investigators regularly appear in the peer-reviewed medical literature or are presented at national and international meetings, it is the practicing oncologist who, ultimately, will be responsible for translating the research paradigm into clinical practice. Considering the number of these publications, the speed at which novel approaches are entering the clinical domain, and the need to rationally determine if (and how) a given novel approach should fit within the

where the surveyed physicians worked is regarded as a top-tier research center as well as a National Cancer Institute–designated comprehensive cancer center. One can only imagine the resulting response to this survey if it had been conducted among physicians with less research exposure, interest, and support. Only 25% of the respondents said they planned to obtain multiplex genomic testing on the majority (>90%) of their patients at the current time and almost 20% stated they would order this type of testing in a small minority (<10%) of their patient population. Of considerable interest to the future of advanced molecular testing, a strong association was observed between an individual physician’s selfreported “confidence” with genomic knowledge and their stating in the survey that they would consider ordering

Maurie Markman, MD Cancer Treatment Centers of America Drexel University College of Medicine Philadelphia, Pennsylvania

this type of test for most patients under their care. These results, although clearly representing a limited survey sample, provide strong evidence that considerable efforts will be required to ensure an adequate comfort level for practicing oncologists as they attempt to provide optimal care for their patients in the coming era of precision cancer medicine.

References 1. Deng B, Monastersky R, Morello L, et al. Obama seeks science boost. Nature. 2015; 518(7537):13-15, PMID: 25652973. 2. Gray SW, Hicks-Courant K, Cronin A, et al. Physicians’ attitudes about multiplex tumor genomic testing. J Clin Oncol. 2014;32(13):1317-1323, PMID: 24663044.

See related debate on profiling on page 8 and profiling of biliary tract cancers on page 10.

Comments or feedback on Dr. Markman’s column? Please write to Clinical Oncology News managing editor Sarah Tilyou at

smtilyou@mcmahonmed.com

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Gastrointestinal Cancers:

Are We Ready for Molecular Profiling: A Debate San Francisco—In a debate at the 2015 Gastrointestinal Cancers Symposium, Peter J. O’Dwyer, MD, the program leader in developmental therapeutics at the University of Pennsylvania’s Abramson Cancer Center, in Philadelphia, advocated the merits of ordering molecular profiling for patients, whereas Neal J. Meropol, MD, the associate director of clinical programs at University Hospital’s Seidman Cancer Center, in Cleveland, argued that such testing is unnecessary and costly. The following is a summary of the debate. Highlighting the decreasing costs and increasing availability of molecular profiling, Dr. O’Dwyer said that next-generation sequencing panels have been made available at many academic and commercial institutions due to a dramatic reduction in sequencing costs. “We’re currently around the area of $5,000 to $6,000 per test for comprehensive genomic sequencing,” he said. “We’re well within the range of feasibility already, and we expect them to become less expensive.”

Whom To Test? Acknowledging that clinicians can’t at this point recommend “who should get tested,” Dr. O’Dwyer said, “Genetic analysis is not really standard of care and hasn’t been validated yet to contribute to the overall benefit of patients.” However, he did recommend who shouldn’t get tested. “Patients who don’t need treatment or those too sick to avail [themselves] of a treatment are not good candidates because testing can’t do them any good,” he said. “I

‘Sensitivity for base substitution is in excess of 99.9% positive predictive value for these assays, which is very high ....’ —Peter J. O’Dwyer, MD

He emphasized the flexible nature of the technology, which allows for broad coverage of the whole expressed panel or highly targeted areas of sequence. “Is it valid?” he rhetorically asked the audience. “Sensitivity for base substitution is in excess of 99.9% positive predictive value for these assays, which is very high indeed. … So, yes, I think the technology is robust and reliable.”

Finding Actionable Mutations Dr. O’Dwyer described his center’s experience with personalized diagnostics for colorectal cancer to support the idea that such testing provides information that can be clinically useful. Of the 101 patients sequenced using Illumina MiSeq platform, 95% had at least one mutation, with a median of two and a mean of 2.46 mutations. “We conservatively used about seven abnormalities that we defined as actionable, either through standard therapies or clinical trials,” he said, “and we determined 42% of patients could have a therapy that was directed by the assay.” According to Dr. O’Dwyer, the distribution found at the University of Pennsylvania was similar to databases with much larger numbers of colorectal cancer, and there also is applicability outside colon cancer, across other malignancies.

think it’s also important to recognize that positive findings are not equally likely across all [gastrointestinal] malignancies.” He concluded that given that response to therapy based on genomic profiling currently is anecdotal, the key benefit to a patient is the potential eligibility for a research trial.

Limitations and Risks In opposition to Dr. O’Dwyer’s position, Dr. Meropol outlined reasons why clinicians should hesitate before succumbing to pressure to routinely test all tumors. One item on his list of concerns was assay platform limitations. He noted potential variability in the sensitivity and specificity of numerous platforms being promoted. “How are the genes selected for these panels?” he asked. “Does the platform look at the transcriptome or just the genome? Are we looking at epigenomic changes? What’s the turnaround time for results? Who is interpreting? Who is annotating? And what is the cost?” Dr. Meropol also cited the complexity and heterogeneity of tumors as a concern. Depending on where one biopsies the tumor, the mutations identified may differ among sites. “Not all of these tumors are the same,” he said. “Although they may look the same under a microscope, colon cancers and gastric cancers are extremely

complex and extremely heterogenous in terms of their molecular profile.” According to Dr. Meropol, definitions used for identifying drivers in a clinical trial are not yet good enough for routine clinical care. Nor does finding a single driver mutation guarantee a single, effective drug intervention because of “crosstalk” between pathways that occurs downstream of a key mutation. “These are costly interventions,” he said. “They may not work, and they have side effects. This should not be our routine approach with patients.” For Dr. Meropol, the limited availab bility of investigational drugs and cliniccal trial sites provided further evidence of the drawbacks to genetic profiling.. “Not everybody lives in close proxim-ity to a research center,” he said, “and d getting compassionate access to a new w drug in development is a logisticallly complicated process.”

Costly Interventions, Unintended Consequences Payment also is a problem, Dr. Meropol argued. Increasingly, payors are scrutinizing off-label use of expensive targeted agents, resulting in costs falling on patients. “Recommending cancer

After both speakers completed their presentations, the audience response shifted somewhat. After the presentations, fewer participants stated that they would routinely order genomic tests than

‘These are costly interventions. They may not work and they have side effects. This should not be our routine approach with patients.’ —Neal J. Meropol, MD drugs with high copays may not be ethical without strong evidence that they are going to help that individual patient,” he said. Given the potential for confusion over interpretation, Dr. Meropol stressed the importance of knowing who is interpreting the data and making recommendations. He concluded his talk with a focus on the patients. “We don’t want to give our patients false hope,” he said. “We don’t want to subject them to the risks of needless biopsies, and we don’t want to subject them to the financial burden of therapies and procedures that are not destined to help.”

had indicated they would in a baseline survey before the debate. Nevertheless, 60% of the audience polled still said they would recommend an assay for a patient with metastatic colon cancer refractory to treatment if the gene-sequencing panel was covered by insurance. —Chase Doyle Dr. Meropol reported that he has consulted for Biomotiv. Dr. O’Dwyer reported no relevant financial relationships.

See related commentary on page 7 and related story on profiling of biliary tract cancers on page 10.

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PAYMENT REFORM continued from page 1

“Certainly when Medicare steps into the arena, it is a big deal,” said Marcus Neubauer, MD, referring to Medicare’s new oncology payment initiative. “I think this pretty much means that innovative payment models or attempts at payment reform have arrived,” added Dr. Neubauer, the medical director of Oncology Services for McKesson Specialty Health and The US Oncology Network. The Centers for Medicare & Medicaid Services (CMS) has oncology in its sights because 50% of the more than 1.6 million Americans diagnosed with cancer each year are Medicare beneficiaries, explained Laura Mortimer, MPP, a public health analyst with the Center for Medicare and Medicaid Innovation, during a CMS webinar on the program. (See the webinar at http://innovation.cms. gov/resources/OCMintro.html.) “As you all know, cancer is a very complex disease that can also be very expensive for patients and other payors,” she said. Cost is the driver as payors and policymakers focus on better ways to push value over volume. The average cost of cancer treatment in America is more than $10,000 a month, and a handful of treatments push those costs upward to $100,000, according to an analysis by IMS Institute for Healthcare Informatics. Most oncologists are focused on the best treatment of a particular cancer patient, not on how much it costs, explained Jeffrey Ward, MD, a medical oncologist/hematologist at Swedish Cancer Institute in Edmonds, Wash. “But I think that there has to be a balance between the two. So, value in my mind is not just cost; value is quality per cost.” The current fee-for-service models encourage the delivery of more services: more tests, more procedures, more drugs, which do not necessarily equate to improved outcomes and quality of life. Alternative models are trying to address this shortfall. “New payment models stand the best chance of being successful if payors and providers collaborate,” Dr. Neubauer said. “If [a model] is too one-sided in favor of payors, it will be punitive to practices, and perhaps patients. If it is too favorable to practices, it won’t bend the cost curve.” Most alternatives do not scrap the feefor-service model—that just would not be practical—but it is being phased out. Instead they are an amalgam of fee for services, global payments and extra incentives based on specific metrics, according to Dr. Silver. They focus on clinical pathways, management fees, bundled payments and the oncology medical home.

Reviewing the Evidence Clinical pathways, which are a subset of all the treatment regimens for a particular

cancer that have evidence to prove they provide the best outcomes, fewer toxicities, and are less expensive are being used more and more. Oncologists who follow clinical pathways receive an extra monthly per-patient fee. The idea is that not only is treatment cheaper, but the patient should experience fewer hospitalizations, emergency department (ED) visits and a better quality of life, explained Jennifer L. Malin, MD, PhD, the medical director for oncology at Anthem Inc., the largest Blue Cross Blue Shield Association licensee. Despite genetic and tumor differences, clinical pathways that are evidencebased should be applicable to at least

Pathways do have their drawbacks, according to Dr. Ward. They will require frequent updating, and there is no national body to create or certify pathways. The biggest worry among oncologists is that each payor and many institutions are developing their own. This means a community oncologist might have to follow six or more different pathways for each tumor type.

Can’t Find My Way Home The oncology medical home is a physician-led approach that aims to coordinate patient care to reduce ED visits and hospitalizations. Again, there nor-

‘If [a model] is too one-sided in favor of payors, it will be punitive to practices, and perhaps patients. If it is too favorable to practices, it won’t bend the cost curve.’ —Marcus Neubauer, MD 80% of patients, she explained, and the pathways usually give physicians leeway to deviate when necessary for particular patients. The US Oncology Network began a clinical pathways program in 2005, so it has experience, and, with a network of 1,000 oncologists, a lot of data, too. “We have been able to show that if you adhere to clinical pathways, you preserve quality and outcomes, and also are able to reduce costs,” Dr. Neubauer said. But pathways are only as good as the panel that makes them. “People think pathways themselves are going to save money, and I’m not sure that’s the case,” said Barbara L. McAneny, MD, CEO, of the New Mexico Cancer Center, in Gallup, “but what they do is assure that we as a group decide what is high-quality care, what is the right thing to do for a patient with a specific tumor and cancer stage.”

mally is a payment for reaching quality and cost targets. This payment structure is called “sharing the risk” because the payments go down if patients need costly services. “In an oncology medical home, we are aggressively managing the side effects of cancer and its treatment, and we save money by keeping people out of the emergency department and out of the hospital, which makes patients happy because they don’t want to spend the time that’s left in a hospital,” said Dr. McAneny. Medical homes need an infrastructure that is able to triage patients. They need to be able to provide a broader array of services and they need weekend and night hours for patient consultation. That infrastructure is expensive to put into place. Dr. McAneny said that oncologists have an advantage over primary care physicians because some of that

infrastructure is already in place. However, there are expenses even for larger oncology practices, Dr. McAneny said. Patient issues tend not to occur 9 to 5 Monday to Friday. That means a health care professional has to be available by telephone to triage patient issues, and if a problem can be managed by the practice, someone has to be on site to treat the patient, which means having weekend and night hours so the patient does not have to be sent to the ED.

Bundling It All Up Bundled payments provide a single fee for a specific cluster of oncology services that are delivered for a predefined episode of care. This is a less popular payment alternative. “Oncology is not conducive to a bundled payment like you see with a hip replacement. There are two hips, so hip replacement is pretty uniform,” said Dr. Neubauer. “However, there are more than 50 different types of cancer and more than 100 oncology drugs, sometimes with huge variations in price,” he said. Dr. McAneny said she is not opposed to bundled payments “as long as they are adequate to cover the cost of care.” She likes the idea of being able to manage how the money is spent. “Let me spend it wisely on the things that the patient truly needs and work to keep him or her out of the emergency department and out of the hospital,” she said, adding that this would save money and improve the patient’s quality of life. Although physicians can work harder to improve patient outcomes and assure that they provide the best and most cost-effective treatments, these efforts will only go so far to control costs if nothing is done about cancer drug pricing. However, when speaking about that area of the payment story, most just throw up their hands. “One of the only things that we can keep under control is how we manage the side effects. I can’t control the price of the drug. They are my tools, and I have to use them,” said Dr. McAneny. The cost of drugs might seem like a separate issue, but really, it’s the primary issue, said Dudley Adams, MD, a professor at the University of California in San Francisco. Although Dr. Adams is not an oncologist, he writes and speaks about health care reform and policy. “We need to change the way that we as physicians are paid, but we also need to make sure that we do it in a way that takes into account all the ways we spend [including the cost of drugs],” he said. Debates continue on the alternative payment method. In the final installment of this series, we look at the cost of cancer drugs, as well as some of these models in action to see how they are working. —Marie Rosenthal

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Biliary Tract Ca Shows Tumor-Specific Genomic Features San Francisco—Two-thirds of biliary tract cancer patients harbored genomic alterations that could soon guide the selection of approved targeted therapies or access to novel therapies available in clinical trials, according to findings presented at the 2015 Gastrointestinal Cancers Symposium. “Given the limited treatment options and poor prognosis of patients with biliary tract cancers, and the diversity of clinically relevant alterations that have been identified in this study … comprehensive genomic profiling [has] significant potential to maximize the identification of new treatment paradigms and meet an unmet clinical need for this devastating disease,” said investigator Jeffrey Ross, MD, the medical director of Foundation Medicine and the chair of the Department of Pathology and Laboratory Medicine at Albany Medical College, in New York. According to Dr. Ross, biliary tract cancers—including intrahepatic cholangiocarcinoma (IHCCA), extrahepatic cholangiocarcinoma (EHCCA) and gallbladder carcinomas (GBCA)—typically present at an advanced stage and are refractory to conventional cytotoxic chemotherapy. The study’s goal was to determine whether comprehensive genomic profiling of IHCCA, EHCCA and GBCA would reveal distinctive patterns of genomic alterations and identify clinically relevant alterations that could lead to targeted therapies. The study used a hybrid capture-based next-generation sequencing assay that evaluated the coding exons of 315 cancer-related genes and 47 introns in genes commonly rearranged in cancer. DNA was extracted from 554 biliary tract carcinomas, including 412 cases of IHCCA, 57 cases of EHCCA and 85 cases of GBCA. The overall number of genomic alterations per patient was similar among the various types of biliary tract carcinomas (Table). Additionally, the clinically relevant alterations—the so-called “actionable alterations” per patient—were the same: two for all three tumor types. For patients with IHCCA, Dr. Ross said, “There was a wide diversity in the type of alterations,” with TP53 being the most commonly altered gene, followed by P16, KRAS and others. For the GBCA group, TP53 also was the most commonly altered gene, and Dr. Ross singled out HER2 in fifth place. KRAS was the most commonly altered gene for EHCCA, followed by TP53 and P16. IHCCA, EHCCA and GBCA all were noted to have frequent genomic alterations associated with cell cycle regulation (CDKN2B) and chromatin remodeling ( (ARID1A ). IHCCA was further characterized by FGFR fusions, IDH1/2 substitutions, BRAF F substitutions and MET

These ‘results validate some others that have looked at the biliary tract, so it’s very exciting— there’s huge promise here. However, we still need to do this in a clinical trial, because a mutation does not necessarily mean it will benefit with an agent that hits the mutation.’ —Laura A. Dawson, MD

Table. Genomic Alterations in Biliary Tract Cancers Genomic Profiling Findings

EHCCA

GBCA

IHCCA

Overall genomic alterations per patient

4.4

3.6

Clinically relevant genomic alterations per patient

2.1

ERBB2 2 amplification, %

BRAF F substitutions, %

KRAS S substitutions, %

PI3KCA substitutions, %

FGFR1-3 3 fusions and amplifications, %

CDKN2A/B loss, %

IDH1/2 2 substitutions, %

ARID1A alterations, %

MET T amplification, %

EHCCA, extrahepatic cholangiocarcinoma; GBCA, gallbladder carcinoma; IHCCA, intrahepatic cholangiocarcinoma a

amplification, with a low KRAS mutation frequency. IHCCA and GBCA had frequent ERBB2 amplifications and PI3KCA/ MTOR pathway alterations. KRAS mutation frequency was high in EHCCA and low in GBCA. Dr. Ross noted that amplification of the

ERBB2 gene—potentially the same as in breast and upper gastroesophageal carcinomas—was found in 16% of patients with GBCA. The ERBB2 amplification rate was lower in patients with EHCCA (11%) and even lower in patients with IHCCA (4%). Dr. Ross highlighted several cases in

which patients responded to targeted therapies in each of the three tumor types. For example, one patient with an EGFR-amplification GBCA responded to neoadjuvant erlotinib (Tarceva, Genentech) therapy when it was combined with systemic chemotherapy. In another case, a GBCA patient with FGFR3 fusion demonstrated disease stability after four months of the investigational agent dovitinib. “This suggests,” Dr. Ross hypothesized, “that targeting the FGFR fusion has clinical efficacy for this tumor type.” When asked by a member of the audience about a relationship to outcome, however, Dr. Ross clarified that the findings were preliminary and were meant to identify potential therapeutic targets. “We did not use this study as a prognostic test; it was only done to search for therapy targets. We do not have the kind of outcomes data for the entire cohort to be able to put prognostic results into the study at this point, but we’re hoping to get that kind of follow-up.”

Clinical Trials Needed Laura A. Dawson, MD, a researcher for the Cancer Clinical Research Unit at the Princess Margaret Cancer Centre, in Toronto, Canada, told Clinical Oncology News, “I think moving forward, we need to change the way we make treatment decisions, and I think this is the way of the future—to look at not only pathological or anatomical histology but profiling as well. [These] results validate some others that have looked at the biliary tract, so it’s very exciting—there’s huge promise here. However, we still need to do this in a clinical trial, because a mutation does not necessarily mean it will benefit with an agent that hits the mutation. So, I strongly believe we need to incorporate profiling into trials.” Although Dr. Dawson said she would use profiling with her patients, she cautioned that it would be unethical to do so without the proper mechanism to treat the patient, e.g., a clinical trial. “And for trials that aren’t using profiling,” she concluded, “I strongly recommend the archiving of tissue—or to look for serum and circulating DNA—so we can learn in a prospective setting whether targeting actual mutations should differ from standard care.” —Chase Doyle Dr. Ross is the medical director of Foundation Medicine, whose assay was used in the study y Dr. Dawson reported no relevant financial relationships.

See related commentary on page 7 and a debate on the role of molecular profiling for GI cancers on page 8.

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Shooting at the Moon To Improve Ovarian Cancer MD Anderson algorithm helps surgeons remove all visible ovarian tumors

surgical algorithm developed and implemented by ovarian cancer specialists at the University of Texas MD Anderson Cancer Center, in Houston, dramatically increased the frequency of optimal resection, a milestone strongly tied to improved survival during to a recent study ((Nat Rev Clin Oncol 2015 Feb 24. [Epub ahead of print], PMID: 25707631). “Our algorithm allows us to be much smarter about whom we operate on up front, providing a more individualized approach to surgery that’s led to better results for our patients,” said investigator Anil Sood, MD, a professor of gynecologic oncology and reproductive medicine and the lead investigator of the study. The multistep process (Figure)—focusing on how to optimize surgery to achieve optimal resection—was developed through MD Anderson’s Moon Shots Program, launched in 2012 to dramatically reduce cancer deaths. “Achieving the greatest clinical impact that we can with existing knowledge is an important aspect of MD Anderson’s Moon Shots Program,” said Dr. Sood. “We worked hard to develop this algorithm, but all of it is based on existing knowledge.” A combination of surgery and chemotherapy is used to treat the disease, but the sequence of those therapies has been at issue due to the lack of clear indication of which should be used first. A major clinical trial randomizing patients to either initial surgery followed by chemotherapy, or chemotherapy then surgery, revealed no significant difference in overall survival (OS) between the groups ((N Engl J Med 2010;363[10]:943-953, PMID: 20818904). However, those who achieved complete resection within either group did much better. Other studies have shown that achieving good margins to eliminate residual disease after surgery is the strongest independent variable predicting OS. For example, data from seven multi-institutional U.S. clinical trials showed patients who had no visual residual disease had a median survival of 64 months compared with 29 months for those with minimal residual cancer, noted Dr. Sood and his colleagues. Practice at MD Anderson has varied, Dr. Sood said. Since surgeons began to apply the MD Anderson algorithm two years ago, the algorithm has sorted half of patients to each mode of treatment, with faculty adhering to the algorithm 95% of the time. The rate of complete resection for patients who have surgery first has gone from approximately

To improve the odds for patients with advanced-stage ovarian cancer undergoing complete cytoreduction, the approach at MD Anderson is as follows: • Screen and track all patients with suspected diagnosis of advanced-stage ovarian cancer • Educate surgeons about the improvement in PFS and OS with R0 resection • Develop a consensus recommendation to offer NACT to patients unlikely to achieve complete gross resection • Use a multidisciplinary assessment of disease distribution • Use diagnostic laparoscopy for peritoneal disease assessment to determine resectability of diseasea

Figure. The MD Anderson algorithm. a All patients who are appropriate for surgery are offered diagnostic laparoscopy for peritoneal disease assessment with two surgeons independently scoring the abdomen to determine resectability of disease. Those with a PIV <8 are offered primary cytoreductive surgery; those with a PIV ≥8 are offered NACT and subsequent interval TRS as indicated

iQIc, internal quality improvement consultant; NACT, neoadjuvant chemotherapy; 2OS, second opinion surgeon; OS, overall survival; PFS, progression-free survival; PIV, predictive index value; PS, primary surgeon; QI, quality improvement; TRS, tumor reductive surgery Based on Nat Rev Clin Oncoll 2015 Feb 24. [Epub ahead of print], PMID: 25707631; used with permission from MD Anderson Cancer Center.

20% to 88%, and for those receiving chemotherapy first, it has improved from 60% to 86%. Because computed tomography (CT) imaging and analysis of bloodborne proteins associated with ovarian cancer,

such as CA-125, have so far failed to predict which patients would benefit from surgery first, the algorithm calls for diagnostic laparoscopy for all surgically fit patients with suspected advancedstage ovarian cancer, according to Alpa

Nick, MD, an assistant professor of gynecologic oncology at MD Anderson. Dr. Nick noted that research has shown that laparoscopic findings are highly predictive of the likelihood of achieving optimal tumor resection. “Ovarian cancer spreads like a coating over other organs, which is one of the reasons CT scans are less effective,” she said. “Laparoscopy allows a better visual assessment of the disease.” To predict the likelihood of optimal resection, clinicians at MD Anderson use an index based on the extent of laparoscopy-identified disease in seven other organs that was developed by Anna Fagotti, MD, and her colleagues at Catholic University of the Sacred Heart, in Rome. An index score below 8 indicates surgery should be performed first, whereas a score of 8 or above indicates the patient should receive presurgical chemotherapy. Two surgeons independently score the disease with respect to the potential to remove all visible tumor, and a third scores the disease if the first two disagree in their assessment. To date, the first two surgeons have agreed 98% of the time. Experts in liver, thoracic, colorectal and urologic oncology also assess disease in those organs when indicated. The algorithm recommends presurgical chemotherapy for patients in whom complete surgical removal is unlikely. Such patients typically undergo three rounds of chemotherapy, with responders then undergoing surgery. Maurie Markman, MD, the president of CTCA Medicine and Science and a clinical professor of medicine at Drexel University College of Medicine, in Philadelphia, called the report interesting, but said other groups have attempted to develop similar ovarian cancer cytoreduction algorithms that have not gained widespread acceptance. “The novelty of this particular report is that laparoscopic assessment with direct visualization of the cancer is included, which is almost certainly a superior approach to any external imaging strategy,” he said, adding that being able to determine whether other groups of gynecologic oncologists can replicate the results (including use of the scoring system) will be important. “It is also critical to acknowledge that this report does not indicate the strategy actually improves clinical outcomes,” Dr. Markman said. “Rather, it may be possible to more critically define the patient populations most appropriate for primary surgical cytoreduction versus a neoadjuvant approach.” —Marie Rosenthal

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4Kscore Can Reduce Need for Risky Prostate Biopsies Orlando, Fla.—Costly and invasive biopsies may soon be obsolete for most men screened for prostate cancer. According to results from a prospective clinical trial presented at the 2015 Genitourinary Cancers Symposium, a blood test called the 4Kscore can predict the personal risk of Gleason 3+4 or higher aggressive cancer with a 94% rate of accuracy (abstract 1). “The role of the 4Kscore,” explained Sanoj Punnen, MD, an assistant professor in the Department of Urology at the University of Miami Miller School of Medicine and Sylvester Comprehensive Cancer Center, in Florida, “is to determine which patients are most likely to have an aggressive cancer and would, therefore, benefit from … biopsy. This allows us to forgo biopsies in men who are unlikely to ever suffer any serious consequences from a high-grade cancer.” Although Dr. Punnen acknowledged the reduction in prostate cancer mortality shown in previous screening trials involving prostate-specific antigen (PSA), he was also quick to stress the costs of said reduction—namely, overdetection and overtreatment. “To save one man’s life,” Dr. Punnen said, “we need to screen over 1,000 men … ” According to Dr. Punnen, much of this screening culminates in a prostate biopsy, which in addition to increased costs, can result in urinary complications, emotional stress and an increased trend for quinolone resistance. Additionally, he said, “75% of biopsies are either negative for cancer or show an indolent or low-grade cancer, which … is unlikely to ever affect the quantity or quality of anyone’s life.”

First Prospective Study Of Kallikrein Panel The 4Kscore, a blood test based on the four-kallikrein panel, incorporates total PSA, free PSA, intact PSA and human kallikrein (hK2), as well as clinical information, including digital rectal exam results, prior biopsy status and the patient’s age. “When you take all of these factors together,” Dr. Punnen said, “you obtain a personalized risk prediction of a Gleason 3 or higher cancer of the prostate.” Although a previous study, the European Randomized Study of Screening

for Prostate Cancer, examined the kallikrein panel, it was a retrospective study ( (Lancet 2014.6;384[9959]:2027-2035, PMID: 25108889). “This test has never been analyzed prospectively, and it’s never been performed in the United States,” Dr. Punnen said. “So that was the goal of this current study.” From October 2013 to April 2014, Dr. Punnen and his co-investigators studied 1,012 patients from 26 different sites around the United States. All the men

cancers using the 4Kscore,” said Dr. Punnen. “The calibration plot shows that the 4Kscore pretty much approximated the actual observed risk of a Gleason 3+4 cancer (area under the curve 0.82)” (Figure). The investigators also examined the clinical utility of the 4Kscore with a decision-curve analysis of the net benefit at various thresholds for performing a biopsy, which was useful in providing a personalized risk prediction to

Patients with high-grade cancer 1.0

0.8

0.6

Actual

0.4

0.2

0.0 0.0

0.2

0.4

0.6

0.8

1.0

Predicted

Figure. Correlation of 4Kscore with biopsy.

were referred by their urologists to undergo a biopsy of the prostate; there were no restrictions based on age or PSA values; all patients underwent a minimum of 10 core biopsies; and all patients gave samples of blood, which were tested for kallikrein levels. Among the 1,012 men enrolled in the trial, the majority (77.2%) had either no prostate cancer or a Gleason 6 low-grade cancer; 231 men (22.8%) had a Gleason 3+4 or higher cancer. “The idea of this test was to see how well we could predict the high-grade

facilitate informed and shared decision making. “For a very risk-averse person—a young person, for example—you may use a very low threshold in order to perform a biopsy,” he explained. “Anything 6% or higher may be your threshold. If you did that, you would avoid 30% of biopsies that you normally would [perform] and only about 1.3% of Gleason 3+4 or higher cancers would be missed. But, if you have an older man with more comorbidities, you may take a 15% threshold before you’re willing to

undergo a biopsy. With this threshold, you’d avoid almost 60% of biopsies you would otherwise [perform].” Although such a strategy carries some risk for missing high-grade cancers (4.7% with the aforementioned threshold), Dr. Punnen suggested that most of those cancers were Gleason 3+4 and unlikely to progress quickly and would probably be detected in subsequent screenings. “The likelihood of missing an actual high-grade Gleason 4+4 or higher cancer is less than 1% at all of those thresholds,” Dr. Punnen concluded. Co-investigator Daniel W. Lin, MD, the chief of urologic oncology at the University of Washington Medical Center, in Seattle, underscored the value of the findings. He said, although “we can detect prostate cancer with PSA screening alone, the problem is it detects prostate cancers that might not need to be detected because they’re indolent. The value of the 4Kscore is to identify those men who have a higher likelihood of having high-grade prostate cancer. At the same time, it spares men the burden of having to get an unnecessary prostate biopsy.” Oliver Sartor, MD, a professor of cancer research in the Departments of Medicine and Urology at Tulane School of Medicine, and the director of the Tulane Cancer Center, in New Orleans, commented on the study. “The study presented by Dr. Punnen helps to provide valuable new data,” Dr. Sartor said. “The 4Kscore test appears to correlate well with the presence of high-grade cancer on biopsy, much better than PSA. Though it is not perfect, it does represent a new step forward in the assessment of men at risk for prostate cancer.” —Chase Doyle Drs. Punnen and Lin reported no relevant financial relationships.

Get the Essential Oncology™ App For the new Prostate Cancer chapter GO TO EssentialOncology.com

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • APRIL 2015 • CLINICALONCOLOGY.COM

Testicular Cancer Pts at High Risk for Prostate Cancer Orlando, Fla.—A new study has concluded that the rate of intermediateand high-risk prostate cancer is sixfold higher in men with a history of testicular cancer than in those who never had the disease. The findings were reported at the recent 2015 Genitourinary Cancers Symposium (abstract 177). “A history of testicular cancer was associated with an increased risk of both all prostate cancer and intermediate- to high-grade prostate cancer,” said lead author Mohummad Siddiqui, MD, an assistant professor in the Department of Surgery and the Division of Urology, and the director of urologic robotic surgery at the University of Maryland Medical Center, in Baltimore. “Based on these findings, we believe that men with a history of testicular cancer should consider discussion regarding the risks and benefits of prostate cancer screening with their physicians.” Dr. Siddiqui said that previous studies have shown that men who have a history of testicular cancer have up to a threefold higher rate of prostate cancer than men with no history of testicular cancer. The new study is the first to specifically examine whether a heightened risk exists for intermediate- or high-risk prostate cancer. The researchers analyzed data from the Surveillance, Epidemiology, and End Results (SEER) database to compare the rate of prostate

cancer in 32,435 men with a history of testicular cancer and a control group that consisted of 147,044 men with a history of melanoma. “We chose melanoma because it has no known association with prostate cancer,” said Dr. Siddiqui.

incidence of prostate cancer by age 80 was much higher in men with testicular cancer than the control group (12.6% vs. 2.8%; P<0.001). The cumulative incidence of intermediate- to high-grade prostate cancer by age 80 also was

‘Based on these findings, we believe that men with a history of testicular cancer should consider discussion regarding the risks and benefits of prostate cancer screening with their physicians.” —Mohummad Siddiqui, MD “Only men older than 40 were examined to allow a sufficient age for prostate cancer diagnosis.” Intermediate-risk prostate cancer was defined as a Gleason score of 7; high-risk was defined as a Gleason score of 8 or greater. The cumulative

much higher in patients with testicular cancer than in controls (5.8% vs. 1.1%; P<0.001). “The increased risk was still observed after controlling for alternate risk factors such as age, race and radiation history,” Dr. Siddiqui said. Philip Kantoff, MD, the director of the

Excerpt From Prostate Cancer App

Dana-Farber Cancer Institute’s Lank Center for Genitourinary Oncology, in Boston, who was not involved with the research, called the study compelling. “We need to figure out a biologic rationale for this association,” he said. Timothy Gilligan, MD, a medical oncologist and testicular cancer expert at the Cleveland Clinic in Ohio, said that if the significantly elevated risk is true, then it is important for testicular cancer patients to be made aware because it may affect their decision making about prostate cancer screening. However, he said, the findings were a “little surprising” in terms of the specific rate of prostate cancer diagnosis. “According to SEER data, which is what the authors used to conduct their study, 15% to 16% of men will be diagnosed with prostate cancer in their lifetime,” Dr. Gilligan said. “Therefore, the figure reported in this study, that only 2.8% of men in the control group [with a history of melanoma] were diagnosed with prostate cancer by age 80, seems extremely low, and the 12% figure for testis cancer survivors is still lower than the rate in the general population” from the overall SEER data. —Kate O’Rourke Drs. Siddiqui, Kantoff and Gilligan reported no relevant financial relationships.

For the full chapter, GO HERE:

The following has been excerpted from Essential OncologyTM Prostate Cancer, by Leonard Gomella, MD.

EssentialOncology.com

Stage Active surveillance

Gleason grade Informed decision

PSA

RP Active treatment

Health status/ life expectancy

RT Clinical trial

Patient preference/QoL

Figure. Current initial approach: localized prostate cancer.a-c a

The best treatment is controversial and must be individualized considering tumor characteristics, age, overall health, life expectancy, and patient and physician preferences. No treatment has demonstrated unequivocal superiority in localized low-risk disease. Each treatment is associated with unique side-effect profiles

>70 y who may be likely to die of other causes • Ideal patient: PSA <10 ng/mL, T1c, Gleason ≤6; <3 positive biopsy cores (<50% cancer in any core); PSA density <0.15 ng/mL/g

• Option for many patients due to the slow progression of prostate cancer, especially in men aged

• Move to active treatment regimen with change in parameters

• RT: external beam RT, interstitial RT (low or high dose), proton; for intermediate- and high-risk disease treated by external beam RT the addition of androgen deprivation (6 mo or ≤2-3 y) is advocated

Active treatment options for low-risk disease:

• Cryotherapy

• Follow-up biopsy at 6-12 mo, with periodic longterm monitoring and PSA testing

Active surveillance for very-low-risk disease c

• RP: retropubic, perineal, laparoscopic, robotically assisted laparoscopic; following RP, pathologic evaluation for extraprostatic disease may indicate the need for adjuvant RT1

• High-intensity focused ultrasound; investigational focal ablative therapy in use outside of US PSA, prostate-specific antigen; RP, radical prostatectomy; RT, radiation therapy

Reference 1. Thompson IM, Valicenti RK, Albertsen P, et al. Adjuvant and salvage radiotherapy after prostatectomy: AUA/ASTRO Guideline. J Urol. 2013;190(2):441-449, PMID: 23707439.

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • APRIL 2015 • CLINICALONCOLOGY.COM

Clinical Conundrums Updates in Hematology from Blood, JCO, JAMA, Lancet, Ann Intern Med, and the FDA Prepared by

Syed A. Abutalib, MD Assistant Director Hematology & Stem Cell Transplantation Program Cancer Treatment Centers of America Zion, Illinois

QUESTIONS

Primum non nocere. (First, do no harm.)

2. In a randomized, double-blind trial,

prophylactic valganciclovir was not superior to a conventional preemptive strategy for the prevention of complications of late cytomegalovirus (CMV) infection after allogeneic hematopoietic cell transplantation (allo-HCT). True or false?

3. In a study published in JAMA,

bicin-vincristine-prednisone) immunochemotherapy, the addition of entecavir compared with lamivudine resulted in a lower incidence of HBV-related hepatitis and HBV reactivation. True or false?

4. The German Hodgkin Study Group

HD13 trial shows for the first time that omission of bleomycin from ABVD (doxorubicin-bleomycin-vinblastinedacarbazine) does not decrease freedom from treatment failure (FFTF) at 5 years in patients with classical Hodgkin lymphoma (HL). True or false?

The Therapeutic Intensification in De Novo Leukaemia (TIDEL)-II study supports the feasibility and efficacy of an imatinib (Gleevec, Novartis)-based approach with selective, early switching to nilotinib (Tasigna, Novartis). True or false?

1. Dose

among patients seropositive for the hepatitis B surface antigen (HBsAg) with diffuse large B-cell lymphoma receiving R-CHOP (rituximab [Rituxan, Genentech]-cyclophosphamide-doxoru-

6. The TIDEL-II study failed to show

ANSWERS

95% confidence interval, 4.7%-21.9%; P=0.003).

assessed against molecular targets: BCRABL1 10% or less, 1% or less, and 0.1% or less at 3, 6, and 12 months, respectively. Cohort 1 patients failing any target were escalated to imatinib 800 mg per day, and subsequently were switched to nilotinib 400 mg twice daily for failing the same target 3 months later. Cohort 2 patients failing any target switched to nilotinib directly, as did patients with intolerance or loss of response in either cohort.

modification of ibrutinib (Imbruciva, Phamacyclics/Janssen) is not required for patients with mild liver impairment. True or false?

1. False. Dose modifications have been

added to the package insert for ibrutinib based on emerging information about the metabolism and toxicity of this new agent. Ibrutinib is metabolized by the liver; for patients with mild liver impairment (Child-Pugh class A), the starting dose is reduced to 140 mg daily. Imbruvica (ibrutinib) prescribing information. Horsham, PA: Janssen Biotech, Inc. January 2015. http://www.accessdata.fda.gov/drugsatfda_ docs/label/2015/205552s002lbl.pdf. Accessed March 15, 2015.

2. True. In a multicenter trial, allo-

HCT recipients at high risk for late CMV disease were randomly assigned to receive 6 months of valganciclovir prophylaxis or placebo at a median of approximately 97 days after transplant. The primary composite end point— death, CMV disease (not seroconversion), or other invasive bacterial or fungal infections by 270 days after alloHCT—occurred at similar frequencies in both groups. No significant differences were seen in other secondary outcomes. Boeckh M, Nichols WG, Chemaly RF, et al. Valganciclovir for the prevention of complications of late cytomegalovirus infection after allogeneic hematopoietic cell transplantation: a randomized trial. Ann Intern Med. 2015;162(1):1-10, PMID: 25560711.

3. True. In this randomized controlled

trial, daily entecavir (0.5 mg) or lamivudine (100 mg) was started 1 week before the initiation of R-CHOP treatment and stopped 6 months after completion of chemotherapy. The incidence of HBVrelated hepatitis was significantly lower in the entecavir group than in the lamivudine group (0% vs 13.3%, respectively; difference between groups, 13.3%;

Huang H, Li X, Zhu J, et al. Entecavir vs lamivudine for prevention of hepatitis B virus reactivation among patients with untreated diffuse large B-cell lymphoma receiving R-CHOP chemotherapy: a randomized clinical trial. JAMA. 2014;312(23):25212530, PMID: 25514302.

False. The open-label, randomized, multicenter HD13 trial compared 2 cycles of ABVD with 2 cycles of the reduced-intensity regimen variants ABV (doxorubicin-bleomycin-vinblastine), AVD (doxorubicin-vinblastine-dacarbazine), and AV (doxorubicin-vinblastine) in patients with newly diagnosed, histologically proven, classic or nodular, lymphocyte-predominant HL. In each treatment group, 30 Gy of involved-field radiotherapy (IFRT) was given after both cycles of chemotherapy were completed. Of the 1,502 qualified patients, 566, 198, 571, and 167 were randomly assigned to receive ABVD, ABV, AVD, or AV, respectively. The 5-year FFTF was 93%, 81%, 89%, and 77% with ABVD, ABV, AVD, and AV, respectively. The investigators concluded “standard of care” for those with early-stage favorable HL should remain ABVD followed by IFRT. Behringer K, Goergen H, Hitz F, et al. Omission of dacarbazine or bleomycin, or both, from the ABVD regimen in treatment of early-stage favourable Hodgkin’s lymphoma (GHSG HD13): an openlabel, randomised, non-inferiority trial. Lancet. 2014, PMID: 25539730.

5. True.

This study enrolled 210 patients with CP-CML in 2 equal, sequential cohorts. All started treatment with imatinib 600 mg per day (note the higher starting dose). An imatinib plasma trough level was measured at day 22; if it was less than 1,000 ng/mL, imatinib 800 mg per day was given. Patients were then

higher rates of major molecular response (MMR) with a higher imatinib dose. True or false?

Yeung DT, Osborn MP, White DL, et al. TIDEL-II: first-line use of imatinib in CML with early switch to nilotinib for failure to achieve time-dependent molecular targets. Blood. 2015;125(6):915-923, PMID: 25519749.

6. False. The Australasian Leukaemia

and Lymphoma Group’s TIDEL-I trial used a higher imatinib starting dose of 600 mg per day for all patients and set a series of time-dependent treatment targets. These included complete hematologic response, major cytogenetic response, complete cytogenetic response (CCR), and BCR-ABL1 0.01% or less (on the International scale [IS]) at 3, 6, 9, and 12 months, respectively. Patients failing to achieve these targets were treated with an increased daily imatinib dose of 800 mg. Subsequently, in the TIDEL-II study, they also escalated the imatinib daily dose to 800 mg in patients with trough serum concentration less than 1,000 ng/mL on day 22 and switched to the more potent tyrosine kinase inhibitor nilotinib for either imatinib intolerance or a suboptimal response, as defined by molecular targets. The cumulative incidence of MMR was 47% at 12 months and 73% at 24 months. By comparison, the 12-month MMR rate was 40% and 55% at these time points in the IRIS study. Yeung DT, Osborn MP, White DL, et al. Blood. 2015;125(6):915-923, PMID: 25519749.

7. The

International Randomized Study of Interferon Vs STI571 (IRIS) reported an 8-year overall survival (OS) of 85% in patients with chronic phase chronic myeloid leukemia (CP-CML) treated with imatinib in the first-line setting. True or false?

8. In the TIDEL-II trial, failure to

achieve BCR-ABL1 of 10% or less at 3 months influenced OS. True or false?

A retrospective study published in JCO suggests that complete remission (CR) without platelet recovery does not portend an increase in the risk for relapse compared with CR in individuals with a new diagnosis of acute myeloid leukemia (AML). True or false?

10. A retrospective study published

in JCO shows that a favorable-impact NPM1-positive/FLT3-ITD / -negative genotype is maintained in older adults with AML (aged >65 years). True or false?

True. Landmark analysis of the IRIS cohort demonstrated superior 5- and 7-year outcomes for patients achieving CCR at 12 months and MMR at 18 months compared with those who did not achieve these goals, a finding confirmed subsequently by other cohorts. The prognostic significance of these targets has been confirmed in patients treated with nilotinib and dasatinib (Sprycel, BristolMyers Squibb) in the first-line setting. On the basis of these results together with similar findings from other studies, in 2009 the European LeukemiaNet recommended achievement of partial cytogenetic response, CCR, and MMR by 6, 12, and 18 months of treatment, respectively, as being optimal responses for CP-CML patients. Druker BJ, Guilhot F, O’Brien SG, et al. Fiveyear follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355(23):2408-2417, PMID: 17151364.

8. True. The 12% of the patients (n=25)

who failed to achieve an early molecular response defined as BCR-ABL1 10% or less at 3 months had inferior OS. Of interest, only 10 of the 25 patients had an imatinib plasma trough level less than 1,000 ng/mL at day 22. Patients starting treatment with either dasatinib (16%) or nilotinib (9%) are more likely to achieve this target compared with those receiving the standard daily imatinib dose of 400 mg (33%-36%). Higher starting doses of imatinib (800 mg/d) have also been associated with a reduced rate of early molecular response failure in the Southwest Oncology Group S0325 study. Yeung DT, Osborn MP, White DL, et al. Blood. 2015;125(6):915-923, PMID: 25519749.

9. False. Both presence of minimal

residual disease and achievement of CR

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • APRIL 2015 • CLINICALONCOLOGY.COM

Protocol Generates Long-Term EFS in T-ALL San Francisco—A highly effective treatment protocol appears to eliminate the adverse prognostic effect of the early thymic precursor (ETP) immunophenotype in children and adolescents with T-lymphoblastic leukemia (T-ALL). At five years, the event-free survival (EFS) was approximately 87%, independent of ETP status. Although data from a postinduction randomization of this ongoing Phase III trial are not yet available, the study results are recharacterizing the disease. “T-ALL is no longer a poor-risk disease,” reported Brent L. Wood, MD, PhD, the director of the Hematopathology Laboratory at the University of Washington, in Seattle. Presenting the study on behalf of the Children’s Oncology Group (Trial COG AALL0434) during the 2014 annual meeting of the American Society of Hematology (abstract 1), Dr. Wood noted that relapses more than 12 months after induction are rare in those who achieved negative minimal residual disease (MRD) status. COG AALL0434, the largest T-ALL trial ever conducted in a pediatric population, enrolled and evaluated 1,144 patients beginning in January 2007. The patients received a standard fourdrug induction regimen that included pegaspargase, prednisone, daunorubicin and vincristine. On intent-to-treat analysis, there were no statistically significant differences in the probability of five-year EFS or overall survival among those with ETP, without ETP or with a near-ETP status (consistent with early differentiation arrest but did not meet classic criteria of ETP). ETP status was not a predictor of longterm outcome despite differences in the proportions of patients who achieved MRD-negative status after induction. MRD overall and higher levels of MRD on day 29 after induction were both predictors of failure of the induction regimen. These data reemphasize the

with incomplete platelet recovery rather than CR after induction therapy predict relapse in AML. Chen X, Xie H, Wood BL, et al. Relation of clinical response and minimal residual disease and their prognostic impact on outcome in acute myeloid leukemia. J Clin Oncol. 2015, PMID: 25732155.

10. False. NPM1-positive/FLT3-ITD-

negative genotype remains a relatively favorable prognostic factor for patients with AML aged 55 to 65 years but not in those older than age 65 years. Ostronoff F, Othus M, Lazenby M, et al. Prognostic significance of NPM1 mutations in the absence of FLT3-internal tandem duplication in older patients with acute myeloid leukemia: a SWOG and UK National Cancer Research Institute/Medical Research Council Report. J Clin Oncol. 2015, PMID: 25713434.

importance of MRD-negative status. Although the effect of the postinduction randomizations has not yet been measured, the data so far predict that the relative ability of these therapies to achieve MRD-negative status are likely to predict their benefit in providing sustained remissions. Several previously published studies have found the ETP phenotype of T-ALL to be a predictor of poor prognosis, but the treatment protocol employed in COG

AALL0434 appears to reduce or eliminate this as a factor in long-term outcomes. Putting these data into perspective, Lewis B. Silverman, MD, the director of the Pediatric Hematologic Malignancy Center at Dana-Farber Cancer Institute/Boston Children’s Hospital, suggested that these data confirm an important change in the prognosis of T-ALL. “Twenty to 30 years ago, T-ALL was considered a high-risk subtype of the disease, associated with an inferior

prognosis compared with B-ALL,” Dr. Silverman explained. “But we have made great strides in improving the outcome for this group of patients over the past several years. The COG AALL0434 study … confirms that. With contemporary therapy, the outcome of children and adolescents with T-ALL is quite favorable and now appears to be as good as that observed in B-ALL.” —Ted Bosworth Drs. Wood and Silverman reported no relevant financial relationships.

CTCA® FORUM 2015

Cancer Treatment Centers of America®

SYMPOSIUM

Advances & Controversies in Malignant Hematology & Oncology Saturday, July 25, 2015 8:00 AM to 5:30 PM Radisson Blu Aqua Hotel Chicago, Illinois REGISTER NOW AT ctcaforumhemonc.org This CME program will efficiently discuss the most recent clinical advances and trials in the rapidly evolving field of malignant hematology and oncology by addressing the questions and controversies that have emerged from the latest data presented at both the American Society of Hematology (ASH) and American Society of Clinical Oncology (ASCO) annual conferences.* Complimentary for hematology/oncology and oncology fellows. #CTCAForum Education Group gratefully acknowledge an educational grant from Cancer Treatment Centers of America® in support of this continuing medical education activity. *This educational program is not an official program of ASH or ASCO, nor is it endorsed by ASH or ASCO.

PROGRAM CHAIRS Syed A. Abutalib, MD Assistant Director, Stem Cell Transplant and Cell Therapy Program Cancer Treatment Centers of America Zion, Illinois Maurie Markman, MD President of Medicine and Science Cancer Treatment Centers of America Philadelphia, Pennsylvania Faculty Al B. Benson III, MD Jennifer Brown, MD, PhD Jan C. Buckner, MD Timothy Kuzel, MD Hillard Lazarus, MD Edith Perez, MD

Jerald Radich, MD Paul Richardson, MD Richard Riedel, MD Ravi Salgia, MD, PhD John Sweetenham, MD Everett Vokes, MD Anas Younes, MD

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • APRIL 2015 • CLINICALONCOLOGY.COM

New IMWG Criteria Reflect Change in Practice A

recent redefinition of multiple myeloma (MM) allows patients to be diagnosed and treated before they show signs of the disease’s most problematic characteristics. The new guidelines also lift the burden of what to do with some patients who were considered to have smoldering MM (SMM) but now fall into the category of MM. The guidelines, authored by members of the International Myeloma Working Group (IMWG), represent a paradigm shift away from an era in which patients needed to show end-organ damage, hypercalcemia, anemia and bone lesions (i.e., CRAB features; see box) before their condition is considered a cancer and treated as such (Lan( cet Oncol 2014;15[12]:e538-e548, PMID: 25439696).

“The criteria now allow early diagnosis, prior to symptoms,” said S. Vincent Rajkumar, MD, a professor of medicine at Mayo Clinic in Rochester, Minn, and the lead author of the guidelines. The new guidelines add three new criteria to the existing definition of MM. These new myeloma-defining events are the presence of 60% or more bone marrow plasma cells, abnormal free light change ratio of 100 or more and more than one focal lesion found on magnetic resonance imaging. “These three new multiple myeloma– defining events were adopted based on evidence from two or more independent studies showing that their presence is associated with an ultra-high risk of developing end-organ damage from the malignancy (approximately

80% within two years), that there was no major reason to delay therapy for such patients, and that treating such patients would prevent serious endorgan damage,” Dr. Rajkumar said. The IMWG also clarified that bone disease in MM can be determined not just by skeletal survey but also by computed tomography (CT) or positron emission tomography CT scans, and that renal disease can be identified not only by serum creatinine levels but also by creatinine clearance. “As a result of all these changes, we believe that myeloma will be diagnosed in a timely manner and that patients will be spared the trauma of having to wait until organ damage happens before therapy can begin,” Dr. Rajkumar told Clinical Oncology News.

Finding MGUS First Improves Survival in MM

atients with multiple myeloma (MM) appear to have better rates of survival if the precursor state monoclonal gammopathy of undetermined significance (MGUS)— detectable M protein without evidence of end-organ damage or other related plasma cell or lymphoproliferative disorders—is found first, according to a study conducted in Sweden (JAMA Oncoll March 5, 2015 [Epub ahead of print]; doi:10.1001/jamaoncol.2015.23). Current guidelines recommend, depending on a patient’s risk score, lifelong monitoring of people with MGUS to detect progression to MM or related disorders. Investigators from Sweden, Iceland and the United States estimated the effect of prior knowledge of MGUS diagnosis and coexisting illnesses on MM survival. The study included all patients diagnosed with MM in Sweden (N=14,798) from 1976 to 2005; 394 patients (2.7%) had previously diagnosed MGUS. The results showed that although patients with prior knowledge of their MGUS status had more coexisting illnesses, they had 14% better overall survival than patients with MM who did not know they had MGUS (2.8 vs. 2.1 years; P<0.01). Low M-protein concentration at MGUS diagnosis was associated with poorer MM survival among patients with prior knowledge of MGUS. Speculating on the reasons for prolonged survival found in their study, the investigators noted that patients with MGUS are evaluated more often for signs of progression to MM and might be diagnosed and started on therapy for myeloma at an earlier stage. “Our results reflect the importance of lifelong follow-up for individuals diagnosed as having MGUS, independent of risk score, and highlight the need for better risk models

based on the biology of the disease. Patients should receive balanced information stressing not only the overall very low risk of progression to malignant neoplasm but also the symptoms that could signal such development and the need to consult their physician,” the investigators wrote. Because most MGUS is never diagnosed, or physicians find it while doing a medical workup for another reason, Robert A. Kyle, MD, and S. Vincent Rajkumar, MD, of Mayo Clinic in Rochester, Minn., who wrote a commentary accompanying the study, said this study begs the question of whether there should be population-based screening and suggested that more studies be done to assess the feasibility of this intervention. The cost-effectiveness of screening would be a big factor, they said, because only a small proportion of MGUS (0.5%-1%) progresses to malignancy. They suggested that the costs, inconvenience and anxiety such screening could produce, plus the low risk for progression among MGUS patients, would “probably override the possible potential benefit of screening for MGUS.” Drs. Kyle and Rajkumar also said the study had a shortcoming because it showed an association but could not be used to determine a causal relationship. “It is interesting to note that patients with a lower M-protein concentration were found to have shorter survival following the diagnosis of MM,” they wrote. “However, as noted, it is not possible from the present study to determine any causal relationship between close follow-up or lack thereof of these patients and outcome of MM.” —Marie Rosenthal The researchers and commenters reported no relevant financial relationships.

Earlier Treatment for SMM With the redefinition of MM, the definition of SMM has changed as well. Patients are now considered to have SMM if they have 10% to 60% clonal plasma cells without evidence of CRAB or other MM-defining characteristics. The rationale for this update in definitions stemmed from the fact that MM remained unique among cancers in that it required patients to develop end-organ damage before they could be diagnosed and treated. “Part of the reason myeloma lagged behind was the thought that many patients with SMM could go years without needing therapy,” Dr. Rajkumar said. “Another concern was over the toxicity of the treatment.” Today, however, both concerns are mitigated by the fact that researchers have identified biomarkers to more accurately pinpoint which SMM patients are likely to progress, and that current therapies are well tolerated and can more than double the survival of MM patients. “Also, we had a randomized trial in high-risk SMM patients that showed early therapy can improve survival, further alleviating concerns about overtreatment,” Dr. Rajkumar said, referring to a Spanish trial that compared lenalidomide with observation ((N Engl J Med 2013;369[5]:438-447, PMID: 23902483). With the bar lowered for diagnosing MM, some of the controversy over what to do with SMM patients has lightened. “The highest-risk SMM patients are now considered multiple myeloma patients,” Dr. Rajkumar said. “The extension of the multiple myeloma diagnostic criteria takes the pressure off treatment decisions for patients with SMM, but there will still be some patients for whom we are nervous about waiting and watching,” Dr. Rajkumar said. The median interval to progression for SMM patients is approximately five years, although it varies considerably in this heterogeneous population. The patients who cause concern are those at risk for progressing to MM within two years, and they are identifiable by a number of risk factors. “There is the size of the monoclonal protein, the proportion of plasma cells in the marrow, the immunophenotype of these plasma cells, the suppression of uninvolved immunoglobulins, the proliferative rate of the plasma cells and cytogenetic abnormalities,” Dr. Rajkumar said. “In patients with SMM who have multiple high-risk factors, we do wonder whether or not to treat. The standard of care remains observation, and clinical trials are preferred. There are

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Table. Selected Ongoing Clinical Trials in SMM ClinicalTrials.gov Identifier

Trial Name A Pilot Study of Novel Imaging Modalities in MGUS, SMM, and MM

NCT01237054

Large-Scale Study of DNA Copy Numbers Variations and Gene Expression Profile of Bone Marrow Plasma Cells From MGUS and Indolent Myeloma (SMM)

NCT01079429

Natural History Study of MGUS and SMM

NCT01109407

A Prospective Study Of Circulating MM Cells As A Biomarker Of Progression In Myeloma Precursor States (MGUS And SMM)

NCT01958528

A Phase II Trial of IPH2101 (Anti-KIR) in SMM

NCT01248455

A Randomized Phase II Trial to Evaluate 3 Daratumumab Dose Schedules in SMM

NCT02316106

Carfilzomib, Lenalidomide, and Dexamethasone in High-Risk SMM: A Clinical and Correlative Study

NCT01572480

Genomic and Psychosocial Effects of the Relaxation Response Resiliency Program (3RP) on Patients With MGUS and SMM

NCT01955395

A Phase 2, Randomized, Blinded, Placebo-controlled, Multicenter Study of Siltuximab (Anti IL 6 Monoclonal Antibody) in Subjects With High-risk SMM

NCT01484275

MGUS, monoclonal gammopathy of undetermined significance, SMM, smoldering smolderring multiple myeloma

two schools of thought on this. One is to do prophylactic therapy with one or two agents to try and delay progression, and the other is to go ahead and treat them as myeloma patients.” That said, Dr. Rajkumar said that he suspects very few SMM patients will require treatment. The recommendation for the rest is observation or enrollment in clinical trials. “The reason for that is that we really need data that such

Defining CRAB

alcium elevation in the blood: serum calcium >11.5 mg/dL enal insufficiency: serum creatinine >2 mg/dL nemia: hemoglobin <10 g/dL or 2 g/dL below normal one: (lytic) lesions or osteoporosis

patients will benefit from early therapy, more data than the Spanish trial gave us,” Dr. Rajkumar said. Syed Abutalib, MD, an assistant director of the Hematology and Stem Cell Transplant Program at the Midwestern Regional Medical Center, in Chicago, is generally in support of the new guidelines, particularly regarding the redefinition of MM, but he cautioned that there are some unanswered questions about SMM. “There still needs to be work done to identify ‘high-risk’ groups of patients who are identified as ‘smoldering’ MM patients, even with the new guideline. Due to well-recognized biological and clinical heterogeneity, certain proportions of patients with SMM still have a more aggressive disease course.” he said. “No doubt, the so-called ‘ultra-high-risk SMM’ has been grouped with MM, which makes it low-risk MM (considering tempo of the disease only), but still there is a high-risk group that needs to be dissected out from the new definition of smoldering MM.” Dr. Abutalib also concurs with the guideline’s recommendation that SMM patients should not undergo treatment and should be handled by observation or preferably, in his opinion, enrollment in clinical trials. “We cannot improve on outcomes,” he said, “unless patients are enrolled in wellconstructed clinical trials.” Emphasizing the complexity of this area, he said all patients with SMM should be given the opportunity to seek advice from a myeloma expert. “Selection of a clinical trial among numerous options is not easy. When you have

MRI Is Beneficial Tool for Multiple Myeloma Management

agnetic resonance imaging (MRI) is a useful tool for diagnosing, staging and following patients with multiple myeloma (MM), according to Evangelos Terpos, MD, PhD, who was a member of a consensus panel that recently reviewed the role of this advanced imaging modality in managing MM patients (J Clin Oncoll 2015;33[6]:657-664; PMID: 25605835). These recommendations, from an International Myeloma Working Group (IMWG) consensus panel, support the group’s recently published criteria for the diagnosis of myeloma (see story, page 16), explained Dr. Terpos, an associate professor of hematology at the University of Athens School of Medicine, Alexandra General Hospital, and an honorary senior lecturer in the Faculty of Medicine at Imperial College London. One important use of MRI in MM, according to Dr. Terpos, is for patients with focal lesions. “The re-evaluation of the patient after treatment using MRI will give important information about the response of the disease,” he said. The panel designed the MRI recommendations for everyday clinical practitioners. “Generally, there is a lag period and learning curve whenever a new diagnostic tool is introduced in the management of cancer patients,” explained another panel member, Saad Z. Usmani, MD, FACP, the director of the Plasma Cell Disorders Program and Clinical Research in Malignancies at Levine Cancer Institute/Carolinas Healthcare System, in Charlotte, N.C. Thus, the goal is to facilitate appropriate use of MRI in this setting. Among its recommendations, the consensus panel said that MRI is more sensitive than whole-body radiography in detecting bone involvement in symptomatic MM; therefore, it should be the gold standard for symptomatic disease and also should be used to evaluate painful lesions and spinal cord compression. “The MRI recommendations align well with the IMWG’s updated diagnostic criteria because they emphasize the utility of whole-body MRI to assess MM bone involvement and provides clinicians [with] guidance on when and how to use this imaging tool,” Dr. Usmani said. The panel stressed that MRI detects bone marrow involvement but not bone destruction. “MRI is particularly useful in the evaluation of collapsed vertebrae, especially when myeloma is not active, where the possibility of osteoporotic fracture is high,” the panel wrote. MRI also is helpful in evaluating when asymptomatic patients should be considered to have active disease and require treatment, according to the IMWG. Those with equivocal lesions should be re-evaluated by MRI after three to six months; if the MRI shows progression, then they should be treated. Although MRI is not recommended as part of a routine workup of patients with monoclonal gammopathy of undetermined significance (MGUS), it should be considered if the clinical presentation leads the clinician to suspect that the MGUS has progressed. In addition, it can be used to stage disease in patients with a solitary bone plasmacytoma. Following these recommendations will increase the use of MRI, Dr. Terpos conceded; however, he said, “MRI is a useful tool for the diagnosis of active myeloma and offers important information for the follow-up of myeloma patients.” “The main take-home messages from these recommendations,” Dr. Usmani added, “are that [whole-body] MRI is a time-efficient imaging tool that provides better disease burden assessment for MM patients and [that it] will serve the oncology community better than regular x-rays [for] taking care of their MM patients.” —Marie Rosenthal Dr. Usmani reported relationships with Celgene, Millennium, Onyx and Sanofi-Aventis. Dr. Terpos reported relationships with Acetylon, Amgen, Celgene, Genesis, Janssen-Cilag, Medtronic, Novartis, Onyx, Roche and Teva.

so many options, it makes you wonder—if there is such a lack of consensus among experts, how do you make the right choice? Additionally, it makes the patient nervous and definitely does not make it easier for the community oncologist, the primary referral source.” It is prudent that oncologists selecting a trial keep in mind the needs of their patients, carefully calculate the risks and benefits and fully understand what the trial is trying to achieve (e.g., primary end point, duration of therapy, type of therapy), he said. “You have

to select the trial that best suits your patient’s need, and the toxicity of any intervention should be balanced with primary outcome.” Although the drugs may have improved, he said, there is still toxicity, and there are other factors to consider, such as inconvenience to the patient and impact of the therapy on quality of life. —Monica J. Smith Drs. Rajkumar and Abutalib reported no relevant financial relationships.

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HIV Doesn’t Preclude Benefit of Lymphoma Transplant San Francisco—A study that received funding from the National Heart, Lung, and Blood Institute (NHLBI) has provided evidence that patients with HIVrelated lymphoma (HRL) can tolerate and benefit from autologous hematopoietic cell transplantation (auto-HCT). Although the study was small and did not directly compare those with HIV to those without HIV, it suggests that transplant just as readily can be considered in patients with HIV if they otherwise meet standard transplant criteria. “Transplant is still largely limited to centers with HIV-specific expertise, but we wanted to evaluate whether [autoHCT] could be extended to nonspecialty centers,” explained the principal investigator Joseph C. Alvarnas, MD, the director of medical quality, risk, and regulatory management at City of Hope Medical Center, in Duarte, Calif. The answer was yes, according to results of the Phase II trial, which were presented at the 2014 annual meeting of the American Society of Hematology (abstract 674). During the study, 40 patients with HRL and HIV that was well controlled with combination antiretroviral therapy (cART) underwent a modified BEAM (carmustine-etoposide-cytarabine-melphalan) regimen followed by auto-HCT. Antiretroviral therapies were stopped during BEAM until nausea and vomiting resolved. None of the patients experienced difficulty in cell engraftment. The primary end point was overall survival (OS). With a median follow-up of 24 months after auto-HCT, the estimated probabilities of one-year OS and progression-free survival (PFS) were 86.6% (95% confidence interval [CI], 70.8%-94.2%) and 82.3% (95% CI,

66.3%-91.1%), respectively. These ese outco outcomes es we weree not ot ssignificantg ca t ly different from those for 151 casematched controls without HIV drawn from the Center for International Blood and Marrow Transplant Research database. In the control group, matched for age, performance score and disease stage, the 12-month OS was 87.7% or just 1.1% higher ((P=0.56). There was a trend for lower PFS in patients with HIV relative to controls (P ( =0.06), but there was no difference in treatmentrelated mortality ((P=0.97). This latter result is important because it supports the ability of HIV-positive patients to tolerate auto-HCT, which was a major conclusion of the trial. Relative to patients without HIV, the toxicities associated with the regimen were not remarkable.

In addition to confirming high OS rates ates from o auto-HCT, auto C , which w c has been used for more than a decade in centers that are experienced in managing HRL, a major trial objective was to confirm that this now should be considered a standard of care rather than an experimental procedure. HIV infection has been an exclusion criteria for clinical trials, Dr. Alvarnas reported. “We believe this is no longer justified.” Referring back to the pre-cART era, Dr. Alvarnas recalled that the median survival for HRL was measured in months. The introduction of cART is permitting many patients with HIV to achieve a normal life expectancy, but Dr. Alvaranas noted that the risk for lymphoma in HIV-positive patients remains elevated. “The key message is that patients with

chemotherapy-sensitive relapsed or refractory HRL may be treated successfully with the modified BEAM regimen and should be considered candidates for [auto-HCT] if they meet standard transplant criteria,” Dr. Alvarnas said. On the basis of this and other experience, it is reasonable to conclude that HCT in HIV patients does not require specialty centers, agreed Wyndam H. Wilson, MD, PhD, the head of the Lymphoma Therapeutics Section of the National Cancer Institute’s Center for Cancer Research, in Bethesda, Md. However, when asked to comment on the data presented at ASH, he noted that the high PFS rates are not consistent with those presented elsewhere and he cautioned that results should not be overinterpreted. Published studies suggest that autoHCT “in sensitive relapses of DLBCL [diffuse large B-cell lymphoma] in nonHIV patients have a long-term PFS of at most 25%, and this is dependent on follow-up time, selection criteria and prior treatment,” Dr. Wilson suggested. “HIV-associated DLBCL that fails EPOCH-R [etoposide-prednisone-vincristine-cyclophosphamide-doxorubicin-rituximab], which is a standard for these tumors, is rarely salvaged with [auto-HCT].” HIV should not be a contraindication for auto-HCT, Dr. Wilson said, “but it would not be proper to suggest that [auto-HCT] will achieve such outcomes observed in this small and non– peer-reviewed abstract.” —Ted Bosworth Drs. Alvarnas and Wilson reported no relevant financial relationships.

Halted EPIC Trial Supports Front-Line Ponatinib for CML San Francisco—When — a Phase III trial of patients with chronic phase chronic myeloid leukemia (CP-CML) was terminated prematurely in 2013, ponatinib was producing deeper and more rapid responses than imatinib as first-line therapy, according to a final summary of the results. Adverse events (AEs) were more common with ponatinib than imatinib, but activity was greater on every marker associated with improvement in survival. The relative advantage of ponatinib (Iclusig, Ariad) over imatinib (Gleevec, Novartis) for such measures as major molecular response (MMR) was “as good as any second-generation agent” evaluated so far, according to Jeffrey Lipton, MD, a professor of medicine at the University of Toronto, in Canada. Speaking

Table. Molecular Response Rates in EPIC Trial 3 months

6 months

12 months

Measure of Activity

Ponatinib N=109

Imatinib Ponatinib N=114 N=69

Imatinib N=73

MMR, n (%)

34 (31)

3 (3)

43 (62)

16 (22)

8 (80)

5 (39)

MR4, n (%)

8 (7)

22 (32)

1 (1)

6 (60)

MR4.5, n (%)

5 (5)

11 (16)

6 (60)

Ponatinib N=10

Imatinib N=13

MMR, major molecular response; MR4, major response achieving 4 log reduction of BCR-ABL transcripts; MR4.5, major response resp ponse achieving 4.5 log reduction reducttion of BCR-ABL BCR ABL L transcripts

at the 2014 annual meeting of the American Society of Hematology (ASH, abstract 519), Dr. Lipton reported that 307 patients

had been randomized in the EPIC trial at the time it was terminated. The median follow-up was 5.1 months.

Ponatinib is approved for T315I-positive and T315II Philadelphia chromosome–positive CML, but the EPIC trial was designed to compare ponatinib with imatinib as first-line therapy. Early termination of the trial was not directly related to any data generated from the trial itself. Rather, an association between ponatinib and increased rates of arterial thrombosis made independent of the EPIC trial led to its early termination, which occurred too soon for investigators to evaluate clinically significant outcomes. The advantage of ponatinib relative to imatinib was large and consistent and grew when the most rigorous measures of activity were applied. For example, more patients on ponatinib

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had achieved MMR at six months (62%) than those taking imatinib had at 12 months (39%), when 80% of ponatinibtreated patients had an MMR. Few imatinib-treated patients ever achieved a 4 log reduction (MR4), whereas 60% of ponatinib-treated patients achieved a MR4.5 by 12 months (Table). Risk stratification also emphasized the greater activity of ponatinib. In lowrisk patients, the percentage of patients with less than 10% BCR-ABL at three months was 76% and 98% (P ( =0.002) for the imatinib and ponatinib arms, respectively. The relative advantage for ponatinib grew progressively for the intermediate-risk (69% vs. 96%; P=0002) and high-risk groups (42% vs. 85%; P=0.008). Although the AE profiles differed, ponatinib produced more serious treatment-emergent AEs. No such event was observed in more than three patients taking imatinib, but there were three cases of atrial fibrillation, three cases of thrombocytopenia and five cases of pancreatitis associated with ponatinib. Only one imatinib-treated patient developed a serious arterial thrombotic event compared with 10 ponatinib-treated patients. The only serious venous thromboembolic event was observed in the ponatinib arm.

The data suggest that ponatinib is an active alternative to imatinib in the front-line for CML, particularly in patients with high-risk features, but the termination of EPIC has eliminated the data necessary to provide evidence-based guidance on relative efficacy. —Jeffrey Lipton, MD The data suggest that ponatinib is an active alternative to imatinib in the front-line for CML, particularly in patients with high-risk features, but the termination of EPIC has eliminated

the data necessary to provide evidencebased guidance on relative efficacy. Dr. Lipton suggested that future trials in the front-line setting, if ever resumed, might best consider efficacy in the context of

baseline risk characteristics and in consideration of how dose modifications might reduce safety concerns. In the discussion that followed Dr. Lipton’s presentation at the 2014 ASH meeting, several hematologists suggested that early termination of EPIC might not have been appropriate, particularly as the decision to terminate it was made on the basis of data independent of the trial. However, Mark L. Heaney, MD, PhD, an associate professor in the Division of Hematology/Oncology at Columbia University Medical Center, in New York City, told Clinical Oncology News the decision was justified. “While the safety and efficacy data from the EPIC trial might have provided a significant contribution to the understanding of how to deploy agents in the CML armamentarium,” he said, “I think that the safety data cited by the FDA were of enough concern that the knowledge gap left by the premature termination of EPIC is one that the oncology community is probably best served by tolerating.” —Ted Bosworth Dr. Lipton reported financial relationships with Bristol-Myers Squibb, Novartis, Pfizer and Teva. Dr. Heaney reported no relevant financial relationships.

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