Founded in 1958, the American Society of Hematology (ASH) is considered the premier professional society for physicians and scientists specializing in benign and malignant blood disorders. The organization is comprised of more than 16 000 members representing close to 100 countries, and is recognized by many as integral to the establishment of hematology as a discrete specialty within internal medicine. Blood—ASH’s peer-reviewed publication—is the most highly cited journal within hematology.
ASH’s stated mission is to “further the understanding, diagnosis, treatment, and prevention of disorders affecting the blood, bone marrow, and the immunologic, hemostatic, and vascular systems, by promoting research, clinical care, education, training, and advocacy in hematology.” In recent years, ASH’s mission has increasingly highlighted the need for health services and outcomes research, and the society’s annual meeting has become a place for hematologists to present informative research on clinical pathways development and value-based care. “Our health services section has grown by leaps and bounds, and now really includes a broad range of topics,” said Stephanie J Lee, MD, MPH, ASH secretary, professor of medicine at University of Washington Medical School, and member of Fred Hutchinson Cancer Research Center (Seattle, WA). “ASH is becoming very involved in the process of developing guidelines, and we are committed to the Choosing Wisely campaign, which attempts to help practitioners understand which services might not have a high value.”
One highlight of the 58th ASH Annual Meeting & Exposition—which was held in San Diego, CA, from December 3 to December 6—was the society’s recently released State of Sickle Cell Disease: 2016 Report. Issued in September, the report aimed to standardize and improve the care of individuals with sickle cell disease (SCD), a chronic, inherited blood disorder affecting approximately 100 000 individuals in the United States. Once considered strictly a disease of childhood, patients with SCD now commonly survive into adulthood, which has introduced issues surrounding appropriate health care as patients transition into the adult medical system. The report serves as a tool to inform adult hematologists about the complexities of the disorder and to educate them on optimal treatment practices, in the hopes that standardized procedures will result in decreased hospitalizations, pain crises, and premature deaths from SCD.
Conference participants offered more than 350 presentations on health services research, outcomes research, and value-based care. Topics included the applicability of American Society of Clinical Oncology and European Society of Medical Oncology value frameworks to the treatment of hematologic malignancies; whether hematologists have integrated Choosing Wisely recommendations into their daily practices; the appropriate utilization of palliative care for patients with terminal blood cancers; and the development of treatment pathways for patients experiencing chemotherapy-induced nausea and vomiting.
“Outcomes research is growing dramatically, and I am delighted to see that ASH is committed to studying the impact that new developments will have in real time,” said Joseph R Mikhael, MD, MEd, FRCPC, chair of ASH’s Committee on Communications, associate dean of Mayo School of Graduate Medical Education, and deputy director of education at Mayo Clinic Cancer Center (Phoenix, AZ).
ASCO, ESMO Value Frameworks Imperfectly Apply to Hematology
Current value frameworks issued by leading medical societies may not be easily generalizable to the treatment of hematologic malignancies, according to two studies presented at the 2016 ASH Annual Meeting & Exposition.
The American Society of Clinical Oncology (ASCO) and European Society of Medical Oncology (ESMO) have issued value frameworks in recent years to combat the rising costs associated with cancer treatment. However, these guidelines were primarily derived from data on the treatment of solid tumors, and their applicability to hematologic cancers remains unclear.
Matthew C Cheung, MD, SM, FRCPC, associate scientist at Sunnybrook Health Sciences Centre’s Odette Cancer Centre (Toronto, ON), and colleagues conducted a retrospective review of randomized controlled trials (RCTs) investigating new therapies in hematologic malignancies to determine if they met the threshold for value by ASCO and/or ESMO standards. Erlene K Seymour, MD, hematologist at Barbara Ann Karmanos Cancer Institute (Detroit, MI), and Jonas de Souza, MD, MBA, assistant professor of medicine at The University of Chicago Medicine (Chicago, IL), evaluated the ASCO value framework within the scope of novel therapies developed for chronic lymphocytic leukemia (CLL).
To determine whether hematology RCTs adhered to the ASCO and ESMO frameworks, independent reviewers scored trial outcomes based on published guidelines. These included two versions of the ASCO framework (version 1 scoring range, -20 to 130; version 2, lower range undefined to 180) and the ESMO Magnitude of Clinical Benefit Scale (range, 1-5).
Dr Cheung and colleagues reviewed 23 RCTs, noting that seven studies used hematology-specific endpoints—including time-to-progression, cytogenetic response, and symptomatic response—that differed from overall survival and progression-free survival, the main endpoints used to design the ASCO and ESMO frameworks. The median ASCO framework scores were 24 (interquartile range [IQR], 22-40; minimum, 6; maximum, 53) by version 1 and 26.7 (IQR, 17.4-37.6; minimum, -33.3; maximum, 116.3) by version 2. The median ESMO score was 2 (IQR, 2-3; minimum, 1; maximum, 4).
Scoring disagreements occurred for 10 RCTs under version 1 of the ASCO framework and for 14 RCTs under version 2; scoring disagreements occurred for 12 RCTs using ESMO’s framework. Divergent interpretations of the scoring system served as the primary driver of disagreement for version 1 of the ASCO framework, whereas differences in scoring toxicities served as the most commonly cited reason for version 2. For the ESMO framework, divergent scoring interpretations or missing progression-free survival data served as the primary reasons for disagreement. Further, two studies could not be evaluated under version 1 of the ASCO model, and two studies could not be evaluated using the ESMO scale.
The researchers observed a correlation coefficient of 0.10 (95% CI, -0.37 to 0.53) between version 1 of the ASCO model and the ESMO model, and a coefficient of -0.21 (95% CI, -0.59 to 0.24) between version 2 and ESMO. The coefficient for version 1 of the ASCO model vs version 2 was 0.30 (95% CI, -0.15 to 0.65).
“When studies could be scored, the correlations between ASCO (version 1 and version 2) and ESMO results were poor, suggesting that these frameworks may not reliably identify the value of therapies in hematology,” wrote Dr Cheung and colleagues. “Consideration for the unique outcomes and toxicities in this population is warranted. The ASCO and ESMO frameworks continue to evolve, and a partnership with societies representing hematologists and their patients would be fruitful.”
Drs Seymour and de Souza compared the most current version of the ASCO framework to current National Comprehensive Cancer Network (NCCN) CLL guidelines to determine whether ASCO’s value models for efficacy, toxicity, and cost of therapy could be applied to novel CLL therapies.
The study included data from 39 CLL RCTs, of which 20% (n = 8) could be assessed using the ASCO framework. The researchers found that they were able to assess clinical benefit in contrast to cost for certain therapies. “When comparing ibrutinib (Imbruvica; Pharmacyclics, Janssen) plus bendamustine (Treanda, Teva Oncology) and rituximab (Rituxan; Genentech, Biogen Idec) to bendamustine and rituximab alone, the framework is able to demonstrate a high clinical benefit of ibrutinib along with its high cost-sharing,” Seymour and de Souza wrote. “It is also able to demonstrate that alemtuzumab (Lemtrada; Sanofi, Genzyme) has lower clinical benefit compared to other regimens studied against chlorambucil with a higher drug acquisition cost.”
The researchers found that toxicity scores varied by drug, and that net health benefit scores were affected by the clinical variable used. They noted that six evaluable studies included control arms that, although cheaper, were “among the lowest preferred NCCN recommendations.” They concluded that because an RCT directly comparing ibrutinib to chemoimmunotherapy is lacking, one would need to be performed in order to better understand the cost difference between the strategies.
“The ASCO Value Framework is a promising tool that helps compare costs and net health benefits,” Drs Seymour and de Souza wrote. “Major limitations when applied to CLL include limited number of trials that could be evaluated by the Framework, and lack of trials comparing stronger control arms. To optimize application of this Framework, we would urge investigators and sponsors to consider the assessment and reporting of the required variables to determine the net health benefit of therapies in clinical trials.”
The Slow Implementation of Value-Based Care in Hematology
In 2012, the American Board of Internal Medicine launched the Choosing Wisely campaign, which attempts to curb wasteful medical spending by limiting the use of potentially unnecessary tests and procedures. Prominent medical societies were invited to issue recommendations that clinicians and providers could use to reduce costs while individualizing patient care. Since 2013, ASH has drafted 10 Choosing Wisely recommendations and endorsed five further recommendations from other medical societies. Many hematologists have wondered to what degree these guidelines have affected day-to-day practice within the subspecialty.
The answer—according to three abstracts presented at the 2016 ASH Annual Meeting & Exposition—appears to be not much. Researchers found that despite ASH’s initial Choosing Wisely recommendations, hematologists have continued to inappropriately transfuse red blood cells (RBCs) and perform aggressive computed tomography (CT) scanning on asymptomatic patients following aggressive lymphoma treatment. Additionally, despite a decrease in repeated testing for heparin-induced thrombocytopenia (HIT), physicians have not widely adapted a scoring system used to recommend patients for initial thrombocytopenia testing.
ASH discourages liberal RBC transfusions, recommending instead that only the minimum number of units be transfused to alleviate anemia symptoms and maintain a safe hemoglobin range. Shoshana Revel-Vilk, MD, MSc, pediatric hematologist at Haddassah-Hebrew University Medical Center (Jerusalem, Israel), and colleagues reviewed 584 RBC transfusions to determine the percentage of which occurred off-protocol, which they defined as receiving more than one consecutive unit or any transfusion in a nonbleeding, nonactive cardiac patient with a stable hemoglobin range.
In total, 48.1% of RBC transfusions were considered off-protocol. Factors associated with off-protocol transfusion included older patient age (odds ratio [OR] = 1.02; 95% CI, 1.01-1.03), treatment in the surgical department (OR = 7.4; 95% CI, 3.7-14.7), undergoing a major invasive or surgical procedure (OR = 1.7; 95% CI, 1.1-2.8), and receipt of antithrombotic therapy (OR = 1.7; 95% CI, 1.2-2.4). Other factors—including underlying diseases or pre-transfusion factors such as blood pressure or pulse rate—did not significantly increase the odds of receiving inappropriate transfusion.
“Although clinical considerations, such as underlying diseases or patients’ pre-transfusion signs, may explain non-adherence to guidelines, no clear pattern was observed in the current study to support this explanation,” Dr Revel-Vilk and colleagues wrote. “The study findings highlight the need to further our understanding of clinical decision making leading to RBC transfusion and call for establishing clear guidelines to facilitate wise-transfusion related choices.”
Patients with diffuse large B-cell lymphoma (DLBCL) frequently undergo CT surveillance while in remission, despite high testing costs and a lack of demonstrated benefit. ASH has recommended that DLBCL patients who were treated with rituximab (Rituxan; Genentech, Biogen Idec) plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) discontinue CT surveillance after 2 years if they are asymptomatic.
Matthew C Cheung, MD, SM, FRCPC, of Sunnybrook Health Sciences Centre’s Odette Cancer Centre (Toronto, ON), and colleagues reviewed administrative data from 2838 adult DLBCL patients to determine rates of CT surveillance, finding that 55.6% (95% CI, 38.3-41.9) continued to receive imaging up to 5 years beyond the end of R-CHOP treatment. Factors associated with increased imaging likelihood included age older than 65 years and higher comorbidity burdens (P < .01 for both). The researchers, however, observed a decrease in inappropriate CT screening as the follow-up period progressed (2006 vs 2013, 65.5% vs 47.4%; P < .01).
“During a time-frame in which surveillance imaging is deemed unnecessary by the Choosing Wisely campaign, the practice in a large population remains excessive,” Dr Cheung and colleagues wrote. “This study represents a real-world baseline from which future efforts to reduce surveillance imaging can be benchmarked.”
Hospitalized patients receiving heparin frequently develop HIT, which is confirmed by thrombocytopenia testing. However, because thrombocytopenia testing can needlessly interrupt heparin treatment or lead to overtreatment with other anticoagulants, ASH recommended that patients with a low pretest probability of HIT not undergo testing. A four-question scoring system (4T) can aid in predicting pretest HIT probability; external validation showed that it is accurate in nearly 100% of cases.
Anmol Baranwal, MBBS, and Sindhu Joseph, MD, both of MacNeal Hospital (Berwyn, IL), reviewed data from randomly selected patients who underwent HIT testing at their institution, in periods preceding and following ASH’s Choosing Wisely issuance. The study included data from 257 patients, tested prior to January 2015 (pre-recommendation, n = 129) or between January 2015 and March 2016 (post-recommendation, n = 128).
The researchers determined that 24% of patients (n = 31) tested pre-recommendation would be considered at intermediate or high risk for HIT based on 4T testing, as would 20.3% (n = 26) of patients tested post-recommendation. Despite the lack of significant differences in testing, the researchers observed that repeated HIT testing decreased following ASH’s recommendation (P = .038).
“More efforts need to be taken to improve the quality of care in this population,” they wrote.
Few Blood Cancer Patients Receive Recommended CINV Prophylaxis
Many patients with hematologic cancers receiving highly emetic chemotherapy regimens do not achieve adequate control of chemotherapy-induced nausea and vomiting (CINV), according to study results presented at the 2016 ASH Annual Meeting & Exposition.
The lack of acceptable CINV control may be caused by a variety of factors, including inadequate prophylaxis receipt or physician misunderstanding, said Lee S Schwartzberg, MD, FACP, executive director of West Cancer Center and chief of the division of hematology and oncology at University of Tennessee Health Science Center (Memphis, TN).
“Outcomes are variable due to the small amounts of clinical trials investigating highly emetogenic multiday chemotherapy regimens, as well as the variability of chemotherapy regimens,” Dr Schwartzberg told Journal of Clinical Pathways. “It is also possible that hematologists have not focused as much on the evidence base associated with CINV prophylaxis as solid tumor oncologists.”
Patients with high-grade hematologic malignancies and those undergoing pre-conditioning for stem cell transplants (SCTs) frequently receive highly emetic, multiday chemotherapy. Guidelines recommend that patients receiving such therapies utilize a three-drug prophylaxis comprised of a 5-HT3 receptor antagonist, an NK-1 receptor antagonist, and corticosteroids; however, the utilization of such regimens in blood cancer patients had not been studied.
Dr Schwartzberg and colleagues conducted a prospective observational study to determine rates of prophylaxis receipt and CINV control in this patient population. Their study included data from 76 patients (median age, 58 years; 68% men) undergoing SCT pre-conditioning (n = 72) or receiving a multiday chemotherapy regimen that included at least one highly emetic drug (n = 4). The most commonly observed diseases in the patient population included non-Hodgkin lymphoma (n = 27), multiple myeloma (n = 19), and acute myeloid leukemia (n = 15).
Patients kept a diary during treatment, and were asked to fill out Functional Living Index-Emesis (FLIE) questionnaires daily. Surveys began at the time of screening and continued for up to 5 days following final chemotherapy treatment. The researchers recorded daily use of scheduled antiemetic and rescue medications.
A total of 71 patients completed all surveys, all of whom received one or more highly emetic therapies on their first day of treatment. The most common chemotherapy regimen among study participants was carmustine, etoposide, cytarabine, and melphalan (n = 28); 18 patients received high-dose melphalan, and eight patients received melphalan, fludarabine, and campath.
Thirty-seven percent (n = 28) received the recommended three-drug prophylaxis combination, and 32% (n = 24) received a 5-HT3 receptor antagonist with dexamethasone. Nine patients (12%) received 5-HT3 receptor antagonists alone and two patients (3%) received 5-HT3 receptor antagonists in combination with metoclopramide. The remaining patients received other combinations (n = 10; 13%) or had no regimens documented (n = 3; 4%).
Twenty percent (n = 15) of patients achieved a complete response, which the researchers defined as no vomiting and no use of rescue medication. Dr Schwartzberg and colleagues observed significant differences in complete response by date, from 95% on day 1 of treatment to 46% by the end of the study period (P = .041). Mean FLIE scores significantly increased from 19.9±3.1 before chemotherapy to 22.4±3.3 overall (P = .0031).
“We need more clinical research, but there are a lot of things that can already be fixed,” Dr Schwartzberg said. “The majority of patients did not receive the recommended three-drug prophylactic regimen at all. This is not guideline-concordant. The scheduling of drugs was also unclear. No patients on study received second-generation NK-1 receptor antagonists or newer 5-HT3 receptor antagonists like palonosetron [Aloxi; Eisai, Helsinn]. It is also possible that patients are not receiving appropriate supportive care, because doctors feel that the patients are receiving so many drugs in their chemotherapy regimens. That is a matter of attitude that can be changed.”
