Hematopoietic stem cell transplant for younger patients with sickle cell disease will get a boost in new American Society of Hematology (ASH) guidelines to be formally released next month, according to a preview presented here at the group’s
annual meeting.
That’s just one from a suite of recommendations
slated for publication by ASH in the next few weeks covering four major areas of sickle disease management. Besides stem cell transplant, these include transfusion support, cerebrovascular disease, and pain management.
Few of the forthcoming recommendations highlighted here will surprise clinicians who treat sickle cell patients, although some patients may be unhappy with the conclusions regarding opioid therapy.
Stem Cell Transplant
Like all the speakers, Courtney Fitzhugh, MD, of the National Heart, Lung, and Blood Institute in Bethesda, Maryland, led ASH attendees through the guideline panel’s recommendations on hematopoietic stem cell transplant (HSCT) using the so-called
PICO approach. It begins with a patient vignette to illustrate a particular clinical question and, after walking through the evidence for each aspect raised in the case, presenting the guideline panel’s final recommendation.
In this case, Fitzhugh began with the case of a 19-year-old African-American male with numerous severe complications related to sickle cell disease, including a history of stroke, moyamoya disease, occasional vaso-occlusive crises, and iron overload from the more than 200 transfusion he’s received.
That was the basis for questions on HSCT: which type of preparative regimen (myeloablative, reduced-intensity myeloablative, or nonmyeloablative) as well as the available donor options.
Fitzhugh couldn’t address every permutation to these considerations in her allotted 10 minutes, but as an example, she went through the evidence regarding nonmyeloablative HSCT for patients with no matched sibling donor. It showed good outcomes, with 88% 2-year survival across 16 observational studies, with rates of acute and chronic graft-versus-host disease both in the 20% range.
Given that as late as 2015, median age of death for adults with sickle cell disease was still just 46, she said the guideline panel gave HSCT in this situation a “conditional recommendation,” meaning that most patients would probably accept it but many would reasonably not, and that the pros and cons should be discussed in detail with shared decision-making. She also noted the recommendation came with “very low certainty” regarding outcomes.
However, she also noted that age is a huge consideration. The weight of evidence indicates that outcomes are much better in patients younger than about 16. Thus, the guideline panel gave a strong recommendation (meaning few patients would be expected to reject the option) for transplant in these younger patients, though also with very low certainty.
Cerebral Infarct Screening
One common but often overlooked complication of sickle cell disease is “mini-strokes” triggered by clumping of sickled blood cells. Accumulation of these silent infarcts can eventually impair cognition, which in turn can have serious real-life problems.
As reviewed by Allison King, MD, MPH, PhD, of Washington University in St. Louis, pooled data from 10 studies of children with sickle cell disease showed a 5-point IQ deficit among those screening positive for silent infarcts compared with those with negative screens. The clinical result is that children can be classified as slow or lazy and adults may have trouble holding jobs, she said.
Silent infarcts are also strongly prognostic for future full-blown stroke, she noted.
Both effects are important because propensity to silent infarcts is treatable. A
landmark trial of blood transfusions published in 2014 demonstrated that these significantly reduced incidence of infarcts. Thus, screening can produce actionable results.
That and other evidence led the guideline panel to give a strong recommendation, with moderate evidence quality, in favor of “a one-time, unsedated, MRI screening” for early school-age children with sickle cell disease or sickle “beta-zero” thalassemia who can otherwise tolerate such screening. Because the benefit of screening is less well established in adults with these conditions, it got only a conditional recommendation for patients beyond school age, King said.
Pain Management
In reviewing the forthcoming guideline on pain management, Patrick Carroll, MD, of Johns Hopkins University in Baltimore, spent most of his talk on the challenging — and controversial — topic of chronic pain management. He noted that many sickle cell patients who aren’t in “crisis” still complain of ongoing pain. These patients often wind up on opioids.
The lack of solid evidence for benefit from opioids in chronic non-cancer pain is legendary across medicine, and the ASH guideline panel found nothing to suggest one in chronic sickle cell pain. In fact, said Carroll, “no randomized controlled trials [are] available for any pharmacologic intervention for chronic pain” in sickle cell disease.
As a result, the guideline panel made no affirmative recommendation to use opioids for chronic sickle cell pain. The panel did leave the door open to use them in patients whose “pain is refractory to multiple other treatments,” meaning they should be prescribed only as a last resort (conditional recommendation, very low certainty).
However, the panel agreed that patients already on opioids to treat chronic sickle cell pain and who are doing well on them, i.e., able to perform activities of daily living and who support a pain reduction benefit, can stay on them (conditional recommendation, very low certainty), as long as clinicians stay on top of the situation. That includes developing a plan in collaboration with the patient to periodically evaluate how the drugs are working, with criteria for determining treatment failure and a roadmap for eventual cessation.
When opioids do fail, Carroll stressed, it’s important to withdraw them carefully, with patients’ full knowledge and support. And tapering opioids intended for chronic pain should not preclude using them to treat acute pain crises, he noted.
Transfusion Support
With blood transfusions a staple therapy for sickle cell disease, ASH recognized that this treatment brings with it a number of clinical questions. One of them is how closely the donor cells should match the patient’s, as mismatches can lead to a range of adverse effects.
Ross Fasano, MD, of Emory University in Atlanta, reviewed this challenge as addressed in the new guideline. His clinical vignette described a toddler whose test results covered 18 different measures of red blood cell phenotype — the question being, how many of these need to be matched? Is simple ABO/Rh matching good enough?
The answer, according to the panel, is that the latter is not good enough. The recommendation calls for prophylactic red cell matching for Rh (C, E, or C/c, E/e) and K antigens for patients receiving transfusions (strong, moderate certainty).
That’s not without limitations, Ross noted, including that no study has directly compared Rh-/K- antigen matching to ABO/RhD alone for alloimmunization risk or for patient-centered outcomes.
The panel also suggested that patients undergo “an extended red cell antigen profile by genotype or serology,” not just ABO/RhD typing, ideally prior to the first transfusion (conditional recommendation, very low certainty).
Next Steps
Robert Liem, MD, of the Lurie Children’s Hospital of Chicago, who co-chaired the guideline coordination panel that oversaw these efforts, said ASH had a multi-part plan to get the new guidelines into physicians’ hands and practice, for which publication in Blood Advances is only the beginning.
The society will produce teaching slide sets, infographics, webinars, and other materials for providers — including non-physicians — to aid in their practices. Also in development are lay-language patient education materials and decision aids for key recommendations.
ASH also plans to release an app-based version of the guidelines along with “pocket guides.” And where appropriate, ASH staff will use the guidelines in the group’s efforts to influence policy.
Liem noted that each panel included patient representatives who participated in every stage of the development process.
Liem, Fitzhugh, Carroll, and Fasano disclosed no relevant relationships with industry. King disclosed relevant relationships with Magenta Therapeutics, Incyte, Cell Works, Celgene, Bioline, Amphivena Therapeutics, Tioma Therapeutics, Novimmune, and WUGEN.
