Updates on ASH Clinical Practice Guidelines in Development

In 2019, the American Society of Hematology (ASH) continued its efforts to develop and publish evidence-based clinical practice guidelines to help practicing hematologists and other clinicians improve the quality of care for patients with various hematologic conditions.

As of late 2019, the first 7 guidelines for the management of venous thromboembolism (VTE) had been published in the Society’s online-only peer-reviewed journal Blood Advances, with 3 more guidelines in development.

Following commencement of the VTE guidelines initiative, ASH announced the development of evidence-based recommendations for several other areas, including: von Willebrand disease (VWD), sickle cell disease (SCD), immune thrombocytopenia (ITP), cancer-associated anemia, and acute myeloid leukemia (AML).

To update hematologists about the status of these guideline development efforts, the 2019 ASH Annual Meeting featured a series of Special Education Sessions in which representatives from relevant guideline panels reviewed key recommendations from available guidelines and provided an inside look at the guideline development process.

Venous Thromboembolism

VTE was selected as the first condition for which ASH would develop guidelines because it is a commonly encountered clinical concern for hematologists and for other medical specialties and disciplines, including emergency medicine, internal medicine, surgery, oncology, and pharmacology. ASH is serving as the sponsoring organization and providing all funding for the work, while McMaster University’s GRADE Centre has offered expertise in systematic evidence review and guideline development methods.

Seven guidelines are now available to the public, covering the topics of prophylaxis in medical patients, diagnosis of VTE, VTE in the context of pregnancy, optimal management of anticoagulation, heparin-induced thrombocytopenia, pediatric VTE, and prophylaxis in surgical patients. Three additional guidelines are under development: treatment of VTE, cancer-associated VTE, and thrombophilia. The recommendations are the result of discussions among the guideline panels, which include more than 100 U.S.-based and international hematologists, clinicians from other specialties, and scientists with expertise in evidence synthesis and appraisal and guideline development methodology.

At the special session, experts walked through case-based discussions of 4 published recommendations, including the most recently published guidelines on VTE prophylaxis in surgical patients (available in the December 3, 2019, edition of Blood Advances). According to David Anderson, MD, Dean of the Faculty of Medicine of Dalhousie University in Halifax, Nova Scotia, panelists tasked with developing this guideline made more than 30 recommendations about the use of mechanical or pharmacologic VTE prophylaxis.

In general, Dr. Anderson explained, the reasons for recommendations for or against VTE prophylaxis vary with the type of planned procedure. For example, pharmacologic prophylaxis is recommended for general or orthopedic surgery, such as total hip/knee arthroplasty, but not for neurosurgical procedures, total prostatectomy, or laparoscopic cholecystectomy due to the “potentially catastrophic consequences of major surgical site bleeding,” particularly in the neurosurgical setting.

The panel’s task was made more difficult by the paucity of evidence in this setting. “Most of the recommendations are conditional and based on low- or very low–quality evidence,” Dr. Anderson said. “We often were using ‘indirect evidence’ or extrapolating information from one setting to another.” Important areas of further research include studies to better inform the baseline risk of VTE and evaluate prophylaxis strategies in the modern surgical setting. “We also need to focus on doing research that is outside the arthroplasty realm, which has been the focus of research study in this field for the past 15 years or so,” he added.

In his remarks, Adam Cuker, MD, MS, from the University of Pennsylvania, and chair of the ASH VTE Guidelines Coordination Panel, described the dissemination efforts for the published guidelines. “Guidelines are not even worth the paper they are printed on if they do not achieve our ultimate goal, which is to improve the quality of patient care and improve outcomes for patients,” he said. The recommendations are now available in ASH’s guidelines app, through pocket guides, and as teaching slide sets. The Society also is developing quality measures, electronic clinical decision support, patient decision aids, and an adaptation of the VTE guidelines in Spanish for Latin American practitioners.

Immune Thrombocytopenia

In 2015, ASH began efforts to update the 2011 guidelines on ITP, appointing an international panel of methodologists, clinicians, and patient representatives to review evidence and form 24 recommendations on the management of adult and pediatric patients. Systematic evidence review was supported by the University of Oklahoma Health Sciences Center.

Panelists discussed the need for rigorous, comprehensive guidelines for this condition at
another Special Education Session. “Due to significant interpatient variability, differences in treatment modalities, and a lack of randomized trials, controversy exists regarding the management of patients with ITP,” explained Cindy Neunert, MD, from New York-Presbyterian Hospital, who serves as chair of the ASH ITP guideline panel. The recommendations cover such areas as the decision between observation or treatment and the selection of a treatment agent; however, they do not cover the emergent treatment of ITP and therapies introduced after 2017, she added.

Several recommendations were discussed during the session, with Wendy Lim, MD, of McMaster University, walking audience members through the guidelines for second-line treatment of adults whose disease is unresponsive to corticosteroids. Each of the 3 options – splenectomy, rituximab, or thrombopoietin receptor agonists (TPO-RAs; such as eltrombopag and romiplostim) – carries risks and benefits, Dr. Lim explained, and there are no head-to-head comparisons between the options.

Given the lack of data, the panelists acknowledged that the treatment choice is heavily influenced by patients’ individual goals and preferences. For example, splenectomy and TPO-RAs were found to have similar efficacy, but patients may want to avoid a surgical option associated with lifelong risks of infection and other complications.

There also is a strong preference to avoid splenectomy in patients who have had ITP for <12 months, due to the possibility of disease remittance, Dr. Lim added. “The publication of these guidelines includes a flow diagram that will hopefully guide clinicians in this decision,” she said.

The decision aid is largely based on the duration of ITP and guided by patient values and preferences. For example, in patients who are not surgical candidates or who wish to avoid surgery, the choice between TPO-RAs and rituximab can come down to patient goals. “For those who value achieving a durable response, TPO-RA may be an optimal choice, [while] those who wish to avoid a long-term medication may elect for rituximab,” she explained. “There is no single second-line treatment that is optimal for all patients with ITP. The choice of treatment ultimately will be based on patient and disease-related factors.”

Sickle Cell Disease

In 2016, ASH began development of 5 clinical practice guidelines on acute and chronic complications of SCD, with systematic evidence review supported by Mayo Clinic’s Evidence-Based Practice Center. Five guideline panels, which included more than 70 SCD experts and 10 patient representatives, reviewed evidence and formulated more than 50 recommendations for cardiopulmonary and kidney disease, transfusion support, transplantation, cerebrovascular disease, and pain management in patients with SCD. The first of these, covering cardiopulmonary and kidney disease in patients with SCD, was published in the December 3, 2019 issue of Blood Advances.

After an introduction from Robert Liem, MD, Director of the Comprehensive Sickle Cell Program at Ann & Robert H. Lurie Children’s Hospital of Chicago, who serves as chair of the ASH SCD guideline panel, Ankit Desai, MD, a cardiologist from Indiana University School of Medicine, reviewed the recommendations for cardiopulmonary disease management in SCD. He focused on the choice of treatment for pulmonary hypertension (PH) and pulmonary arterial hypertension (PAH) in various patient settings – ranging from vasodilators to chronic transfusions.

As with other guideline panelists who presented during these special sessions, Dr. Desai noted that there is very little high-quality evidence guiding many decisions. As a result, most recommendations are “conditional,” rather than “strong,” and accompanied by Good Practice Statements that contain descriptions and caveats based on available data. These Good Practice Statements suggest consulting a specialist before referring a patient for PH based on abnormal echocardiography results, as well as defining thresholds of isolated peak tricuspid regurgitant jet velocity (TRJV) or other biomarkers to inform decisions about catheterization.

Acute Myeloid Leukemia

In 2017, after a formal topic nomination and selection process, ASH initiated its first guideline development effort on a malignant topic: AML in older adults. The topic was selected for its clinical importance and because it is largely unaddressed by existing guidelines.

As Mikkael Sekeres, MD, MS, from Cleveland Clinic, and chair of this guideline panel remarked in his presentation, “Treating older adults with AML is not easy. Anyone who has treated an older patient knows that, from the very moment a person receives the diagnosis and as we try to discuss treatment options, there are a lot of things going through [his or her] head.”

“Guidelines are not even worth the paper they are printed on if they do not achieve our ultimate goal … to improve the quality of patient care and improve outcomes for patients.”

—Adam Cuker, MD, MS

So, in 2018, a guideline panel composed of research experts, clinicians, and a patient representative began prioritizing clinical questions, eventually selecting 6 questions that were deemed important to patients and clinicians. Panel members represented a wide swath of specialties, including leukemia, epidemiology, palliative medicine, methodology, and geriatric oncology. Systematic evidence review is again supported by the McMaster University GRADE Centre.

Recommendations were formed in 2019. The public comment period is now open, with publication expected later this year.

The recommendations include a section on the decision-making process and patient goals of care. “We felt like this was the most crucial part of these guidelines, and something that is unique about them compared with other guidelines that are out there,” Dr. Sekeres said.

He also highlighted the inclusion of guidance on the use of blood products in palliative or hospice settings in adults who are not receiving antileukemic therapy, which was discussed in-depth by Mark Litzow, MD, from Mayo Clinic in Rochester, Minnesota. These patients, who may be receiving end-of-life or hospice care, are often dependent on red blood cell (RBC) transfusions, platelet transfusions, or both, but many hospice centers may refuse to admit transfusion-dependent patients, largely because of cost.

In his remarks, Dr. Litzow noted that the discussions about transitioning to comfort care after therapy has stopped working come after spending months with patients scrutinizing their blood counts. When the conversation then shifts to, “‘no more transfusions, no more blood counts,’ it must be challenging as a patient to make that sudden transition,” he said.

Again, there were no comparative studies addressing this question, so, after reviewing lower-quality and indirect evidence from non-AML populations, the panel recommended that RBC and platelet transfusions be made available for these patients. “The potential burden, costs, and feasibility concerns were judged to be less important than the desirable consequences of [transfusion],” Dr. Litzow commented.

The recommendation echoes a recent statement issued by the ASH Committee on Practice, which supported palliative blood transfusions in the hospice setting. As part of the effort to remove transfusion dependence as a barrier to hospice enrollment, representatives from the committee are working with hospice agencies and providers to create innovative reimbursement models (such as allowing transfusions to be paid for separately under Medicare Part B) and explore novel ways to access transfusions (such as at-home transfusions).

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