	As medical oncologists, drug developers, and research scientists presented findings and novel treatment options in hematological cancers, a special session on the first day of the 56th Annual Meeting of the American Society of Hematology (ASH), held December 6-9, 2014, in San Francisco, addressed an aspect of cancer care that’s increasingly finding its way onto the agenda at clinical meetings, as was witnessed at the annual meeting of the American Society of Clinical Oncology (ASCO).

	The session, “The Rising Cost of Medical Care: Understanding the Problem and Exploring Solutions,” drew participation from hematologists and a representative from a company that provides market access support to the pharmaceutical industry. These experts came together on a common platform to discuss ways to tame the unsustainable healthcare expenditure in the United States, which touched $3.8 trillion in 2013.

	Escalating drug costs can influence patient adherence, quality of life, and overall health—an endless loop. Participants in this energetic discussion provided insight into these existing challenges and ways to address them. Kicking off the session was Hagop M. Kantarjian, MD, professor, Department of Leukemia, the University of Texas MD Anderson Cancer Center in Houston, Texas. Kantarjian presented strong views on the way the pharmaceutical industry sets drug prices during his talk, “Cancer Drug Prices in the US: Causes, Consequences and Solutions.” He said he is surprised by the high drug prices today, the triggers for him being the prices for 3 commonly used drugs for chronic myelogenous leukemia (CML): ponabinostat, bosutinib, and omacetaxine.  Each of the 3 drugs costs more than $100,000 per year. While cancer drug prices have been rapidly rising&mdash;a 10-fold increase over the past decade&mdash;the average household income, he said, has decreased by 8%. Kantarjian asked the audience to come up with solutions to help these patients who might be victimized in the process. High out-of-pocket costs, he said, are leading patients 

pharmaceutical industry for overestimating 

tax subsidy that they avail, and it’s the 

mean cost, not median,” he said. Kantarjian 

several solutions to this growing problem:

blocks all other generic drug competition 

	• allowing importing of drugs	• preventing “pay-for-delay,” which 

was Alex W. Bastian, MBA, vice president, 

in this problem; rising healthcare costs 

past half century. However, an examination 

FDA-approved drugs have steadily increased 

a long-term view of the situation, taking 

that a drug might yield,” which can reduce 

	He reiterated the importance of identifying 

professor of medicine at Duke University, 

oncologist by training, is a health service

care on patient preferences with cost-related 

	researcher with an interest in improving 

the high cost of care on cancer patients 

quality of life and diminish the quality 

of their care. He said that coupled with 

chemotherapy side effects, cancer treatment 

published last year reported that people 

2.5 times more likely to declare bankruptcy 

can also impact quality of care, as it puts 

patients at risk for cost-related nonadherence 

in patients with chronic myeloid leukemia, 

Articles

Evidence-Based Oncology

Healthcare Costs in Need of Solutions: Experts at ASH Agree

institutes are evolving simultaneously to 

allow for better patient care at reduced 

costs. That was the conclusion of presenters 

Hematology, held in San Francisco, California, 

is associated with lifelong disabilities 

SCD, a commonly inherited blood disorder 

the annual cost of medical care alone for these patients exceeds $1.1 billion.

professor, St. Jude Children’s Research 

evaluated at her institute to manage the 

transition of pediatric patients with SCD 

into adult care while avoiding the overutilization 

children with SCD survive into adulthood, 

highest following transfer to adult care. 

Episodes of acute care or emergency department 

ED visits and inpatient care in 8 states 

(18 to 30 years old) are more than twice as 

likely to visit the ED as patients aged 10 

to 17 years or adults aged 31 to 45 years. 

stays and the highest percentage of frequent 

She rationalized that the failure to establish 

pediatric care is also a driver of higher 

Methodist Sickle Cell Disease Transition 

and signifies 2 levels of overlap between 

pediatric and adult care: 1) comanagement 

in the pediatric setting at age 17 years, 

can transition into adult care as late as 

there was only a single RN available. All 

visits followed a detailed plan of care, including 

care, disease-related education, and self-management 

maintenance visits for the 2-year interval 

transfer to adult care, using a repeated 

educational session by the nurse coordinator 

care. These health literacy results were 

adults (median age 16.3 years at the beginning 

Care Plans to Reduce Healthcare Utilization in Sickle Cell Disease

scans still make sense to identify relapse 

Francisco, California, was part of an education 

managed care, and came as ASH is drawing 

to the session, surveillance imaging “is 

risks of mortality due to radiation-related 

false-positive findings, leading to unnecessary 

the use of routine scans after the second 

catch only a very small portion of relapses; 

symptoms. In fact, he noted, ASH included 

improvement in its Choosing Wisely initiative, 

non rituximab—containing combinations, 

	• In a report of 117 patients with diffuse 

that 22% of the relapses were identified 

	• A series of 100 relapsed patients with 

if imaging evaluations are not included. 

certainly be used to investigate at that 

Flowers presented a chart showing various 

costs per death avoided using surveillance 

years, which is the current recommendation, 

mark for various rates of risk reduction. 

for the first scanning protocol would be 

	On the flip side is the cost of imaging. 

ever, Flowers said. “Good clinical judgment 

Session on Survivorship Outlines Surveillance Strategies in Non-Hodgkin Lymphoma

	Hematologists received recommendations about how long to use anticoagulants, when to transfuse sickle cell patients, and when to perform surveillance scans in patients with early stage chronic lymphocytic leukemia (CLL), as the American Society of Hematology (ASH) issued its second list of tests and treatments to question under the 

	This year’s list was announced at the start of the 2014 Annual Meeting of ASH that convened at the Moscone Center in San Francisco. The first round of recommendations, numbers 1 through 5, were announced December 4, 2013, at the last ASH meeting in New Orleans. Details of recommendations 6 through 10 were presented at a session December 8, 2014.

 is the initiative of the American Board of Internal Medicine Foundation that asks each specialty to identify tests or treatments that might be overused and unnecessary, with the potential to harm patients. While saving healthcare dollars is not the only consideration of 

, its efforts will have that effect if patients and their doctors are more judicious in their medical decisions.

	The 2014 ASH Choosing Wisely recommendations are:

Don’t use anticoagulants for more than 3 months in patients with a first venous thromboembolism (VTE) occurring in the setting of a major transient risk factor.

 This was presented by Mark Crowther, MD, MSc, of McMaster University in Hamilton, Ontario, Canada, who described this recommendation as a basic calculation of benefit versus risk; a VTE triggered by a major event such as surgery presents a low risk for recurrence once the major event has passed and recovery has occurred, assuming adequate care and anticoagulant therapy. Subsequently, such patients have a low risk of thrombosis, “and have the same risk of bleeding as other patients.” The ASH recommendation does not apply to VTE linked to non-major risks, such as pregnancy or travel-associated immobility.

Don’t routinely transfuse patients with sickle cell disease for chronic anemia or an uncomplicated pain crisis without an appropriate clinical indication.

 Presented by George R. Buchanan, MD, of the University of Texas Southwestern in Dallas, this recommendation starts from the mandate, “First, do no harm.” Unnecessary red blood cell transfusions can cause iron overload and other complications that require additional treatment, and unnecessary transfusions can make it difficult for sickle cell patients to find compatible blood supplies when they are truly needed. Buchanan said it is critical to ask: is this a routine transfusion specific to a clinical indication? What is the patient’s gene type? As he discussed, and the companion paper in Hematology notes, stable patients with severe disease “can have baseline hemoglobin values between 7 and 10 g/dL and can tolerate 1 to 2 g/dL decreases withou developing symptoms of anemia.”

 Most importantly, Buchanan said, using transfusions for chronic pain management does not work.

Don’t perform baseline or routine surveillance computed tomography (CT) scans in patients with asymptomatic, early-stage CLL. 

This recommendation incorporates a theme heard this year at ASH about overuse of scans, which has been a broad theme across managed care and cancer care especially. John Byrd, MD, of Ohio State University discussed this item, which states that in these circumstances of CLL, a CT scan does not improve survival for either staging or prognostic purposes. If anything, scans uncover incidental, irrelevant findings that drive up costs. The ASH recommendation calls for blood monitoring, and Byrd was among the speakers at ASH who urged clinicians to counsel patients about the value of biomarkers instead of radiation.

Don’t test or treat for suspected heparin-induced thrombocytopenia (HIT) in patients with a low pre-test probability.

 Adam C. Cuker, MD, MS, of the University of Pennsylvania, described the “4T” score, a widely used system that allows clinicians to evaluate the timing of a degree of thrombocytopenia and whether it might be caused by heparin. Cuker said this is one of the tough calls in medicine: for one, a patient is taken off heparin, and other anticoagulants are much more expensive. What’s more, taking the test brings the risk of a false positive. Even if that turns out to be incorrect, once that information lands in a patient’s file, it can be difficult for the patient to receive heparin again. Thus, Cuker emphasized the importance of not only not treating, but not testing for HIT, unless scores call for it.

Don’t treat patients with immune thrombocytopenic purpura (ITP) in the absence of bleeding or low platelet count.

 Cindy R. Neunert, MD, of Georgia Regents University, noted that this ASH recommendation applies to adults, and that pediatric cases have difficult criteria. In all cases, treatment should be aimed at improving quality of life without exposing patients to unnecessary risks and is always conditioned on prior bleeding episodes, activity levels, and social factors. In general, ITP treatment is rarely indicated in adults if platelet counts are above 30,000/microL unless they are facing surgery or other invasive procedures. 

	1. Hicks LK, Bering H, Carson KR, et al. Five hematologic tests and treatments to question. 

ASH Presents Second Round of Tests, Treatments to Question Under Choosing Wisely Initiative

revealing how to identify who should be treated early. Promising results are expected on monoclonal antibodies, said Jesus F. San Miguel, MD, PhD, of the Clinica Universidad de Navarra

	Those who treat patients with multiple myeloma have witnessed a sea change in the past 15 years. Yet another revolution appears right around the corner, with research on risk stratification 

	On December 6, 2014, San Miguel delivered the Han-Wasserman Lecture, “Multiple Myeloma: A Modern Model for Scientific and Clinical Progress,” at the 56th Annual Meeting of the American Society of Hematology (ASH), which convened at the Moscone Center in San Francisco, California.

	During his lecture, San Miguel previewed results that came later in the meeting on daratumumab, which targets CD38. Daratumumab, which received FDA breakthrough status in May 2013, and elotuzumab, which gained the status in 2014, have been highly anticipated by multiple myeloma patients and the clinicians who treat them. One of San Miguel’s slides said results showed improved survival of 30% to 35% for daratumumab as a single agent, and 64% to 75% of patients in combination with lenalidomide and dexamethasone.

	San Miguel said it has become clear that the disease “should not be considered a single entity, but different entities,” and thus, multiple treatment options will exist. For example, he said, many thought there would be no role for melphalan after the 2013 ASH meeting in New Orleans, which saw the paradigm-shifting results from Thierry Facon, MD, on lenalidomide and low dose dexamethasone. But San Miguel said that despite those results, melphalan remains a viable treatment option.

	The talk opened with an overview of the increased understanding of the genetics behind myeloma, which is building awareness that treatments must be tailored to the individual. Identifying and measuring key “drivers” of the disease holds great promise, San Miguel said, as this will give clinicians the information to create combination therapies for more patients. While survival has increased from the abysmal rates of 1 to 3 years of years past to 5 to 7 years today, more can be done, he said.

	San Miguel spent considerable time on an area where his group, the Spanish Myeloma Group, made a major contribution in 2013: risk-stratification of those precancerous patients who show signs of “smoldering” myeloma, and identifying for early treatment those at highest risk of developing the disease.

	He was the senior investigator of the phase 3 trial published in the 

 in which patients were randomized to be treated with lenalidomide and dexamethasone or observation, the latter being the usual standard of care for patients who have an increase of plasma cells in the bone marrow that produce the monoclonal immunoglobulin, but do not have any symptoms. San Miguel outlined the prognostic factors that allowed the research team to segment out the high-risk group. “You want to give the patient what is needed, and nothing more than is needed,” he said.

especially his wife for many sacrifices. A final slide was a photo of a popular Spanish football team, with faces of his colleagues replacing those of the star players. He thanked the patients, and their families, and the pharmaceutical leaders who have contributed to the revolution in treating multiple myeloma. “This is why we become doctors; this is the reason why we are hematologists,” he concluded. 

	These results produced improved 3-year survival rates among the high-risk patients identified and treated by the Spanish team: 94% of the treated group was still alive at 5 years, compared with 78% in the untreated group.

While most of his talk involved cutting-edge science, San Miguel ended on a highly personal note. He thanked his research team in Spain, his family, and 

	1. Spanish Myeloma Group study a treatment milestone. CenterWatch Newsline. http://www.centerwatch.com/newsâ€online/article/5124/spanishâ€myelomaâ€groupstudyâ€ aâ€treatment milestone#sthash.bo7URvWm.dpbs. Published August 5, 2013. Accessed December 5, 2014.

Early Treatment, Monoclonal Antibodies Discussed in Multiple Myeloma

	In March 2014, Dana Farber Cancer Institute’s Kenneth C. Anderson, MD, raised expectations at the annual gathering of the National Comprehensive Cancer Network when he said it wouldn’t be long before patients and clinicians in multiple myeloma (MM) practice would have “a monoclonal antibody or 2,” the new class of therapy that trains the patient’s immune cells to attack the cancer.

	Based on the results presented at the 56th Annual Meeting of the American Society of Hematology (ASH) in San Francisco, Anderson’s prediction is right on schedule. On December 8, 2014, Anderson’s colleague at Dana Farber, Paul G. Richardson, MD, presented final results from a phase 1b/2 study of elotuzumab in combination with lenalidomide and dexamethasone for relapsed/refractory MM patients, including 73 who had already been treated with an average of 2 other therapies.

	Results show highly encouraging overall response rate (ORR) and progression-free survival (PFS), with the responses even better at the lower dose of 10 mg/kg of elotuzumab than the higher dose of 20 mg/kg. However, during the question-and-answer period Richardson warned, “We have to be careful how we interpret that.”

	Elotuzumab, given by intravenous infusion, is being developed by Bristol-Myers Squibb in collaboration with AbbVie. The therapy binds to signaling lymphocytic activation molecule F7 (SLAMF7), giving it a different mechanism of action from other monoclonal antibodies under study, daratumumab and SAR650984, which target the CD38 protein. These therapies were stars at ASH 2014, with studies spotlighted in a press conference and a major lecture at the conference. The FDA granted breakthrough therapy status to the combination of elotuzumab with lenalidomide and dexamethasone in May 2014, based on promising phase 1 results. Daratumumab gained breakthrough status in May 2013 as a single agent.

	The phase 2 study included patients who had 1 to 3 prior therapies, including those with at least 1 prior therapy from the phase 1 study; their median age was 63 years. Half the patients received 10 mg/kg of elotuzumab, while the other half received 20 mg/kg of the drug, and treatment was in 28-day cycles. Patients also received oral lenalidomide at 25 mg for days 1 through 21 and oral dexamethasone (28 mg, plus 8 mg on days when the elotuzumab was given). This pretreatment was designed to manage infusion reactions. Notably, ORR were 92% among patients in the 10-mg/kg group who responded to treatment compared with 76% for those in the 20-mg/kg group.Median PFS was 32 months for the 10-mg/ kg group and 25 months for the 20-mg/kg group.

	A stringent complete response or complete response was observed in 14% of patients, with a very good partial response seen in 43%; another 27% had a partial response. Richardson said researchers were struck by both the quality and durability of these responses. “It’s important to see, because many patients were on therapy for a number of years,” he noted. Common adverse events were diarrhea (66%), which Richardson described as manageable; fatigue (56%); muscle spasms (62%); constipation (51%); nausea (48%); and upper respiratory tract infections (47%). 

	1. Richardson PG, Jagannath S, Moreau P, et al. Final results for the 1703 Phase 1b/2 study of elotuzumab in combination with lenalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma. Blood. 2014;124 (21): abstract 302.

	2. Elotuzumab receives breakthrough therapy designation for multiple myeloma. http://www.myelomabeacon.com/news/2014/05/19/elotuzumab-breakthrough-therapy-designation-multiple-

	myeloma/. Published May 21, 2014. Accessed December 17, 2014.

Promising Results for Elotuzumab Presented in Session on Multiple Myeloma

	Results from a pair of phase 2 studies involving pomalidomide were reported December 8, 2014, during oral abstract sessions on treatments for multiple myeloma, as researchers continue to develop new combinations for patients who have stopped responding to earlier treatments.

	Pomalidomide, an immunomodulatory drug marketed as Pomalyst, received FDA approval in February 2013 for multiple myeloma patients whose disease is demonstrating progression despite having had at least 2 other therapies, including lenalidomide and bortezomib.

	Results presented featured 2 combinations. A phase 1/2 study found pomalidomide with bortezomib and dexamethasone to be highly effective, with confirmed responses over 80%.

 A second study determined that pomalidomide with cyclophosphamide and dexamethasone was superior to pomalidomide and dexamethasone only.

Pomalidomide, bortezomib, and dexamethasone.

	Martha Q. Lacy, MD, of the Mayo Clinic, presented results involving 50 patients who had previously been treated with 1 to 4 therapies (median 3) and were not responding to lenalidomide.

The median age of the patients was 66 years; 51% were female. The median time from diagnosis to the time of the study was 46 months, and 68% had received a stem cell transplant.

	Dosing was as follows: in phase 1, 9 patients started on 4 mg of pomalidomide on days 1 to 21, bortezomib 1 mg/m

 weekly, and 40 mg of dexamethasone weekly. For 6 patients, dosing of bortezomib was increased to 1.3 mg/m

, and this dose level was adopted for the larger group of patients in phase 2.

	At 9 months, 72% of the patients were progression free, 96% were alive, and 66% continued treatment. Common adverse events (AEs) were anemia, fatigue, leukopenia, and thrombocytopenia, with the majority grade 1/2. AEs grade 3 and higher and their total occurrences were neutropenia (29) leukopenia (15), lung infection (6), lymphopenia (8), dyspnea (3), and syncope (3). Pulmonary embolism occurred in 1 patient. Among the 42 patients who could be evaluated, confirmed responses were seen in 34, including 9 of 11 highrisk patients. Median progression-free survival (PFS) was 17.7 months.

TREATMENT WITH AND WITHOUT CYCLOPHOSPHAMIDE

	Previously reported results of pomalidomide with dexamethasone had an overall response rate (ORR) of 33% and median PFS of 4.2 months in patients who had previously been treated with bortezomib and lenalidomide. This phase 2 trial involving 70 randomly assigned patients compared 1 arm of patients receiving the pomalidomide-dexamethasone combination (median age, 63 years) with a second arm also receiving cyclophosphamide (median age, 64 years).

	Dosing of dexamethasone was adjusted by age, and patients not receiving cyclophosphamide were allowed to cross over to join that arm if their disease progressed. After a median follow up of 15 months, ORR (partial response or better) for the arm receiving pomalidomide and dexamethasone was 39%, while it was 65% for the arm also receiving cyclophosphamide. Clinical benefit (minimal response or better) was 64% for pomalidomide plus dexamethasone and 79% for the combo plus cyclophosphasmide. Median PFS was 4.4 months compared with 9.2 months for the 2 arms, respectively. Grade 3/4 AEs were more frequent in patients receiving cyclophosphamide, although the authors reported that these were not statistically significant.

12 who did. During the study, 13 patients crossed into the second arm. 

	While the study ended in March 2014, the authors reported that as of July 2014, 28 of the original 70 patients had died—16 who did not start out in the arm receiving cyclophosphamide and 

	1. Shilane J. Pomalyst: questions and answers about the FDA approval. The Myeloma Beacon. http://www.myelomabeacon.com/news/2013/02/13/pomalyst-pomalidomidequestions-and-answers-fda-approval/. Published February 13, 2013. Accessed December 9, 2014.

	2. Lacy MQ, LaPlant BR, Laumann KM, et al. Pomalidomide, bortezomib, and dexamethasone (PVD) for patients with relapsed lenalidomide refractory multiple myeloma (MM). 

	3. Baz R, Martin TG, Alsina M, et al. Pomalidomide, cyclophosphamide, and dexamethasone is superior to pomalidomide and dexamethasone in relapsed and refractory myeloma: results of a multicenter phase 2 study. 

Sessions Report Phase 2 Results of Pomalidomide Combinations

	Several research groups gathered at the 56th Annual Meeting of the American Society of Hematology in San Francisco discussed findings from trials conducted in patients suffering from chronic myelogenous leukemia (CML) to prevent disease progression to advanced stages. Their session, held December 7, 2014, was called “Chronic Myeloid Leukemia: Outcomes With TKI therapy.”

CA180-056),” he reported the results of the final 5-year analysis of DASISION. As has been published earlier, patients with newly diagnosed CML-CP were randomized to receive dasatinib 100 mg once daily (n = 259) or imatinib 400 mg once daily (n = 260). The primary end point was confirmed complete cytogenetic response (cCCyR) by 12 months. Long-term efficacy and safety data from patients with the predefined minimum 5 years of study treatment were presented.

	Jorge E. Cortes, MD, deputy department chair, Department of Leukemia, Division of Cancer Medicine, the University of Texas MD Anderson Canc Center, Houston, presented results from the DASISION trial. In his talk, “Final Study Results of the Phase 3 Dasatinib Versus Imatinib in Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Trial (DASISION, 

	Cortes reported that 61% of dasatinib-treated patients and 63% of imatinib-treated patients were still on their initial study therapy at the end of the period. Cytogenetic and molecular response rates continued to be higher for dasatinib compared with imatinib (intent-to-treat population). The rate of cCCyR by 5 years was particularly higher with dasatinib when compared with imatinib (83% vs 78%, P =.187), as were the rates of major molecular response (MMR; BCR-ABL ≤0.1%; 76% vs 64%; P=.002) and MR4.5 (BCR-ABL ≤0.0032% IS; 42% vs 33%; P = .025) by 5 years.

arm. Fewer CML-CP patients in the dasatinib cohort (4.6%) progressed to the accelerated phase (AP) and blast phase (BP) compared with imatinib (7.3%). However, 5-year progression-free survival (PFS) and overall survival (OS) rates were similar across treatment arms. Significantly greater number of patients on dasatinib achieved BCR-ABL ≤10% at 3 months (84%) compared with those on imatinib (64%). And among the patients who achieved BCRâ€‘ABL ≤10% versus >10% at 3 months, improved PFS, OS, and lower rates of transformation to AP/BP were maintained at 5 years for both drugs.

	Further, he showed data that confirmed the times to cCCyR (95% CI; HR = 1.46, P =.0001) and MMR (95% CI; HR = 1.54; P <.0001) in all randomized patients were faster with the dasatinib 

“While adverse events for both arms were as we expected, the total incidence of pleural effusion continued to increase each year in dasatinib-treated patients,” he said. Discontinuation of 

dasatinib due to pleural effusion occurred in only 15 patients. Arterial ischemic events were uncommon. However, cardiovascular (CV) ischemic events and transient ischemic attack were reported in 10 and 2 dasatinib-treated patients, respectively, while CV ischemic and peripheral arterial occlusive events were reported in 4 and 2 imatinib-treated patients, respectively.

	According to Cortes, although the number of mutations following 4 to 5 years of treatment increased slightly in dasatinib-treated patients, the spectrum of mutations remained the same. 

	Cortes concluded that at the end of 5 years, 100 mg of dasatinib once daily presented superior outcomes compared with 400 mg of imatinib once daily as initial therapy for CML. He based his conclusion on the faster time to cCCyR and MMR, with more patients achieving BCR-ABL ≤10% at 3 months, sustained higher cumulative rates of response, and a lower rate of disease progression. According to Cortes, “Dasatinib offers meaningful advantages for patients with newly diagnosed CML-CP and remains a standard of care in this setting.”

	Susanne Saussele, MD, University of Heidelberg, Mannheim, Germany, was also a participant in this session. She discussed therapy goals for MMR in CML, based on the CML-Study IV. “We sought to evaluate a failure time point for MMR using data of the CML-Study IV, a randomized 5-arm trial designed to optimize imatinib therapy, alone or in combination. We also evaluated the optimal time point to achieve an MMR,” said Saussele.

	In the current European LeukemiaNet (ELN) recommendations, the optimal time point to achieve MMR is defined at 12 months after diagnosis of CML.

 “Not achieving MMR is not recommended as failure by ELN,” said Saussele. “So there are uncertainties about when CML therapy can be altered in patients not reaching MMR after 12 months.”

remission levels (MR4 or deeper), monthly landmarks were defined between 1 and 5 years after diagnosis. A patient was considered to be in MR2, MMR, or MR4 from the first diagnosis of 

the corresponding remission level and could only change to a higher level of response. Patients were censored after a stem cell transplant. For the failure time point analysis, for each of the resulting 48 landmarks, a Cox model was used to define the time to progression with age and EUTOS score as additional prognostic factors.

	In the study, patients with valid molecular analysis on MR4 level were randomly divided into a learning sample (LS) and a validation sample (VS). For the LS, MR2, MMR, and deep molecular 

	Between 2002 and 2012, 1551 patients were randomized to LS or VS and 1358 had a valid molecular analysis on the MR4 level. Of the 1228 evaluable patients, two-thirds were randomly allocated to the LS (n = 818) and one-third to the VS (n = 410). Percentage of patients in the LS with MR2, MMR, and MR4 or deeper at 1 year were 28%, 29%, and 14%, respectively, and at 5 years were 5%, 21%, and 71%, respectively. Forty-four patients of the LS reached MMR on second-generation tyrosine kinase inhibitors. Saussele identified a significant PFS advantage for patients in MMR (P =.018). Eight years following treatment, the probability of PFS for patients in MMR was 90.8% compared with 80.5% of patients not in MMR.

	Saussele said that the results of their model show that an optimal time point to predict PFS in patients with MMR was defined at 2.25 years after diagnosis, which could be construed as being significant. Further, at any time point, patients in MMR had a lower risk of progression than patients not in MMR. “This model can help determine when MMR is a failure and when a change in therapy should be considered. However, we should be aware that the earlier MMR is achieved, the higher is the chance to achieve deep molecular response later during therapy,” concluded Saussele. 

	1. Baccarani M, Deininger MW, Rosti G, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia:2013. 

CML Updates: Defining MMR and Results of the DASISION Trial

	A poster session December 7, 2014, at the 56th Annual Meeting of the American Society of Hematology in San Francisco was dedicated to trials evaluating therapeutic options in chronic myelogenous leukemia (CML). Data presented covered safety, efficacy, managing comorbidities, and biological differences that drive response to therapy.

	One poster, “Long-Term Outcomes of First-Line Tyrosine Kinase Inhibitors for Chronic Phase Chronic Myeloid Leukemia: A Mixed-Treatment Comparison,” summarized the efficacy and safety of tyrosine kinase inhibitors (TKIs), comparing them directly and indirectly, in the mature follow-up for patients with newly diagnosed chronic phase (CP)-CML.

	The authors included data from randomized controlled trials evaluating TKIs in adults with newly diagnosed CP-CML. A TKI (imatinib, dasatinib or nilotinib) was included if used as an initial treatment. Studies on bosutinib were excluded, as it is only approved in the United States for the treatment of CP-CML after failure of initial therapy. Studies that included patients with accelerated- or blast-phase CML, intolerant or resistant patients to first-line treatment, those on IFN-α, older agents, or stem cell transplantation were excluded. Primary outcomes examined were efficacy, represented by major molecular response (MMR, ≤0.1% BCR-ABLIS) and deeper molecular responses (MR4.5, ≤0.0032% IS); survival, represented by overall survival and progression free survival; and safety, represented by medication discontinuation rate due to adverse events.

	As available trials provided direct comparison with imatinib, with no head-tohead trials to compare other TKIs, the authors conducted a mixed treatment comparison (MTC) analysis, which pools evidence from direct and indirect comparisons to facilitate simultaneous inference regarding all treatments. Bayesian mixed-treatment comparison method was used to rank TKI in terms of effectiveness. The study identified 4 landmark trials, including the DASISION and ENESTnd trials, which included 1647 patients with CP-CML. Follow-up times ranged from 3 months to 6 years. MTC analysis on these reported trials demonstrated superiority of both nilotinib and dasatinib over imatinib in terms of efficacy and safety. Nilotinib ranked first in efficacy with better MMR and MR4.5 after a 2-year followup, followed by dasatinib. Dasatinib was observed to have the highest medication discontinuation rate due to adverse events or drug-related toxicity. Among TKIs, nilotinib was found to have the best survival profile, though statistically nonsignificant.

	The authors concluded that both nilotinib and dasatinib are associated with significantly better efficacy and safety profiles compared to imatinib. After a 2-year follow-up, nilotinib ranked first to achieve MMR and MR4.5, with lower discontinuation rate due to adverse events. The authors conclude that new generation TKIs exhibit a faster and more potent response over a longer follow-up period.

	Results of the PACE trial were also presented during this poster session; the study authors presented their data as the “Long-term follow-up of ponatinib efficacy and safety in the phase 2 PACE trial.” The trial evaluated efficacy and safety of ponatinib (45 mg daily) in CML and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) patients who were resistant/intolerant to dasatinib or nilotinib or if they harbored the T315I mutation. The authors clarified that in October 2013, the trial was placed on partial clinical hold due to observation of arterial thrombotic events (ATEs) in the ponatinib clinical program, following which dose reductions were recommended. They now reported long-term follow-up analysis (minimum 23.9 month follow-up from last patient, first visit). For ATEs, exposure adjusted yearly incidence rates were calculated as (number of patients with first event in interval)/(total exposure for the \ interval)*100 [adverse events (AEs) per 100 patient years]. Rates for later intervals excluded patients with prior events.

phase (AP) CML, blast-phase (BP) CML, and Ph+ ALL, estimated OS at 3 years was 59%, 9%, and 16%, respectively. The study authors observed that responses were generally maintained after dose reduction: 99% maintained MCyR, 96% maintained complete cytogenetic response, and 90% maintained MMR. Frequent (≥20%) treatment-emergent AEs were thrombocytopenia (44%), abdominal pain (41%), rash (41%), constipation (37%), headache (37%), dry skin (35%), fatigue (29%), pyrexia (29%), nausea (28%), arthralgia (28%), hypertension (26%), neutropenia (25%), anemia (22%), myalgia (21%), diarrhea (21%), vomiting (21%), increased lipase (21%). Most common serious AEs were pneumonia (7%) and pancreatitis (6%). ATEs observed in 19% of patients included cardiovascular (10%), cerebrovascular (7%), and peripheral vascular (7%) events. Venous thromboembolic events were observed in 5% patients.

	Patients in this study group were heavily pretreated: 58% received more than 3 prior TKIs. Most common reasons for discontinuation were progressive disease (21%) and AEs. For CP-CML patients, 2-year major cytogenetic response (MCyR) duration, progression-free survival (PFS), and overall survival (OS) estimates were 87%, 67%, and 86%, respectively. For accelerated-

	The authors reported that after a 3-year follow-up, 22% of the CP-CML patients achieved MR4.5 and 83% remained in MCyR. PFS and OS at 3 years were 61% and 82%, respectively.

	Based on their trial data, the authors conclude that ponatinib continues to exhibit deep and durable responses in heavily pretreated patients with longer follow-up, particularly CP-CML. They

	recommend a benefit-risk evaluation to guide the initiation of ponatinib therapy, particularly in patients who may be at an increased risk of ATEs. The authors plan to conduct a dose-ranging trial of ponatinib in refractory CML for benefit-risk evaluation. 

Poster Presentations Cover Therapeutic Options in CML

	Results from a large phase 3 prospective randomized open-label trial comparing imatinib 400 mg daily with dasatinib 100 mg daily were presented by Stephen O’Brien, MD, professor of hematology, Newcastle University Medical School, Newcastle upon Tyne, England. He presented the results of SPIRIT 2, which compared the 2 drugs in patients with newly diagnosed chronic myelogenous leukemia, at the 56th Annual Meeting of the American Society of Hematology, held in San Francisco.

	According to O’Brien, the SPIRIT 2 trial design was similar to the DASISION trial. The trial recruited 814 patients at 172 hospitals across England and in Northern Ireland between August 2008 and March 2013. The primary end point of the trial was event-free survival at 5 years. Key secondary end points listed in the trial were the rate of achievement of a major molecular response (defined as BCR-ABL/ABL ratio of less than 0.1%), cytogenetic response, and toxicity. The trial had an even distribution of patients between the 2 arms.

(5 deaths while on treatment). Following discontinuation, an additional 11 patients from the imatinib arm and 15 from the dasatinib arm died. The research group is currently following 124 of the patients in the imatinib arm and 89 in the dasatinib arm.

	With a median follow-up of 37.4 months, O’Brien said 300 patients have discontinued the study medication: 170 in the imatinib arm (7 deaths while on treatment) and 130 in the dasatinib arm 

	While there were no unexpected side effects observed, O’Brien said that patients receiving imatinib experienced GI toxicity more often than patients receiving dasatinib; fatigue, rash, and headache were more common with dasatinib. Also, a higher rate of grade 3/4 thrombocytopenia was observed in the dasatinib arm, pleural effusions occurred in 78 of 406 (19.2%) patients on dasatinib, and 13 of 78 (16.7%) patients required drainage. No significant differences in cardiovascular adverse events were observed, he noted.

	While significant differences in major cytogenetic response and complete cytogenetic response were observed, with dasatinib presenting a better effect, O’Brien cautioned that a large amount of data was missing in this analysis. This could, in reality, render the difference insignificant.

	O’Brien concluded that dasatinib-treated patients have a higher rate of molecular response at 1 year, but, with a median follow-up of 37.4 months, there is no significant difference in rates of disease progression or overall survival. He suggested the need for additional follow-up to evaluate differences in event-free survival at 5 years, if any. 

SPIRIT 2: Dasatinib Superior to Imatinib in Newly Diagnosed CML

	Patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL) who show a deletion of the short arm of chromosome 17 (del 17p) typically see a rapid progression of their disease, with an average life expectancy of less than 2 years once the disease relapses or stops responding to treatment.

	In the largest prospective trial dedicated to treating patients with this disease profile, ibrutinib showed marked efficacy in overall response rates, according to data presented December 8, 2014, at the 56th Annual Meeting of the American Society of Hematology held in San Francisco.

	The study, led by Susan O’Brien, MD, involved 144 patients: 137 with CLL and 7 with SLL. All had del 17p, their median age was 64 years, and 63% were stage III or IV. Patients received 420 mg of oral ibrutinib once daily until progression; all patients receiving at least 1 dose were included in the analysis. The overall rate of response (ORR) was 82.6%, including 17.4% with partial response with lymphocytosis. Complete response with incomplete bone marrow recovery was reported in 3 patients. An Independent Review Committee-assessed ORR is pending.

	At a median follow-up of 13 months, the median progression-free survival and duration of response by investigator determination had not been reached. However, at 12 months, 79.3% of the patients were alive and progression-free and 88.3% of the responders were progression-free. Progressive disease was reported in 20 patients.

	The most frequent adverse events (AEs) were diarrhea (36%), fatigue (30%), cough (24%), and arthralgia (22%). Atrial fibrillation was reported in 11 patients. Seven patients reported basal or squamous cell skin cancer. One patient had plasma cell myeloma.

	The most frequent grade 3-4 AEs were neutropenia (14%), anemia (8%), pneumonia (8%), and hypertension (8%). Major hemorrhage was reported in 7 patients, all grade 2 or 3, and 16 patients stopped therapy due to AEs, with 8 later having fatal events.

	At the time of data cut off, median treatment duration was 11.1 months, and 101 of the 144 patients continued treatment with ibrutinib. 

The American Society of Hematology Annual Meeting, 2014

Healthcare Costs in Need of Solutions: Experts at ASH Agree

Care Plans to Reduce Healthcare Utilization in Sickle Cell Disease

Session on Survivorship Outlines Surveillance Strategies in Non-Hodgkin Lymphoma

ASH Presents Second Round of Tests, Treatments to Question Under Choosing Wisely Initiative

Early Treatment, Monoclonal Antibodies Discussed in Multiple Myeloma

Promising Results for Elotuzumab Presented in Session on Multiple Myeloma

Sessions Report Phase 2 Results of Pomalidomide Combinations

CML Updates: Defining MMR and Results of the DASISION Trial

Poster Presentations Cover Therapeutic Options in CML

SPIRIT 2: Dasatinib Superior to Imatinib in Newly Diagnosed CML

Ibrutinib Demonstrates Significant Responses for Patients With Hard-to-Treat CLL/SLL, Phase 2 Data Show

Results Project Savings for Payers With Novel Oral Anticoagulants

Study Suggests Method of Reducing Blood Clots Without Risking Bleeding

Best of ASH Presentations: Platelets, Lenalidomide for MDS, and Sorafenib in AML

Data Show High Response Rate to Ibrutinib Combination for Patients With Hard-to-Treat MCL

Improved Cancer Care Through Innovation

Payers Look to CER for Improved Healthcare Decisions

Bigger Regulatory Challenges in Diagnostics Than in Therapeutics, Industry Expert Says