Coverage from the 64th Annual American Society of Hematology Meeting and Exposition, December 10-13, 2022, New Orleans, Louisiana.
Some patients with acute myeloid leukemia (AML) could have a faster path to allogenic stem cell transplant—and less toxic chemotherapy—based on new findings that challenge conventional thinking about the best way to make a transplant successful.
The phase 3 study, called ASAP, asked whether all patients must achieve complete remission (CR) prior to allogenic hematopoietic cell transplant (allo-HCT), given the development of sequential conditioning methods with cytarabine or melphalan in the 2 weeks prior to transplant. If requiring patients to undergo intensive “salvage” chemotherapy to achieve remission doesn’t produce better results than sequential conditioning, a rethinking is in order, reasoned scientists from University of Muenster and Technical University/University Hospital, Dresden, Germany.
Johannes Schetelig, MD, MSc, professor of medicine at Technical University in Dresden, outlined the findings at a news conference before presenting them at a plenary session December 11, 2022.1
It’s not that attaining CR has no link to a successful transplant. Failure to do so is a risk factor. But bombarding a patient with chemotherapy to achieve CR works only about half the time, and doing so can delay getting a patient to allo-HCT when that process would produce the best outcome, especially in an aggressive disease such as AML.2 The transplant process can be challenging; if a relative is not a donor match, transplant centers must search for a donor through human leukocyte antigen (HLA) matching, a process far more complex and uncertain than blood type matching.
Despite the logic of this hypothesis, investigators were amazed by the findings. For the patients not receiving salvage therapy, time to transplant was cut in half, resulting in success rates that slightly favored those who skipped salvage therapy after 8 weeks and held up after 3 years.
“We were astonished—we never expected these results,” Schetelig, the abstract’s senior author, said in a statement.3 “Patients did not gain additional benefit from salvage chemotherapy at all. It suggests we should think about starting the process of allo-transplantation as soon as possible.”
Of interest to payers, the patients who skipped salvage chemotherapy had fewer high-grade adverse events and spent less time in the hospital, Schetelig said. “Yet time to discharge and in-hospital mortality after transplantation did not differ between the 2 arms,” he said.
Joseph Alvarnas, MD, vice president of government affairs for City of Hope, Duarte, California, whose area of clinical expertise is in bone marrow and stem cell transplantation, called the findings “extraordinarily important.”
“These data show very clearly that sequential treatment that culminates in transplant represents a highly effective strategy for caring for patients with relapsed/refractory AML,” said Alvarnas, who is editor in chief of Evidence-Based Oncology.™ This should provoke us to think more strategically and prospectively about getting patients HLA-typed and referred for transplant services as part of a coordinated episode of care that minimizes delays and maximizes the chances for survival for this vulnerable population.”
Study Approach and Methods
The approach was straightforward: Investigators identified adult patients with non-favorable risk AML and randomly assigned them 1:1 to pursue either a remission induction strategy, receiving treatment with cytarabine twice a day for 3 days followed by mitoxantrone before receiving allo-HCT; or a disease control strategy prior to sequential conditioning and allo-HCT.
In the second arm, a watchful waiting approach was recommended; however, low-dose cytarabine was permitted with single doses of mitoxantrone for disease control. The primary end point was treatment success based on a measure of CR on day 56 (8 weeks) after transplant; investigators measured noninferiority within a margin of 5%. Secondary end points were overall survival (OS) and leukemia-free survival.
A total of 281 patients were enrolled and 276 were analyzed; 138 patients were in the disease control arm and 134 were in remission induction arm. In the disease control arm, 105 of the 138 patients stayed on watchful waiting until sequential conditioning, with 33 (24%) needing disease control treatment. In the remission induction arm, 62 patients (46%) achieved a CR and 5 patients needed a second round of chemotherapy. The rest continued to transplant without additional attempts to induce complete remission.
Median time to transplant was 4 weeks in the disease control arm and 8 weeks in the remission induction arm. At 24 weeks post randomization, 98% and 96% of the patients had received transplants in the disease control and remission induction arms, respectively.
The primary end point was reached when 84.1% of the patients in the disease control arm and 81.3% of those in the remission induction arm; the test for inferiority was P = .047. One-year leukemia-free survival from 8 weeks posttransplant was 71.5% in the disease control arm and 69.6% in the remission induction arm.
Schetelig noted that the primary end point missed statistical significance but he highlighted the importance of the long-term outcomes. After a median follow-up from randomization of 37 months, 1 year OS was 69.1% (95% CI, 60.6-76.1) for disease control vs 71.9% (95% CI, 63.3-78.9) for remission induction. Three-year OS rates were 51.0% (95% CI, 41.8-59.8) and 54.2% (95% CI, 44.4-62.9), respectively.
1. Stellies M, Middeke JM, Bug G, et al. In patients with relapsed/refractory AML Sequential conditioning and immediate allogeneic stem cell transplantation (allo-HCT) results in similar overall and leukemia-free survival compared to intensive remission induction chemotherapy followed by allo-HCT: results from randomized phase 3 ASAP trial. Presented at: 64th American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA. Abstract 4. https://ash.confex.com/ash/2022/webprogram/Paper159962.html
2. Acute myeloid leukemia. Leukemia & Lymphoma Society. Accessed December 11, 2022. https://www.lls.org/leukemia/acute-myeloid-leukemia
3. New studies challenge the dogma of blood cancer care. News release. American Society of Hematology. December 10, 2022. Accessed December 10, 2022. https://www.hematology.org/newsroom/press-releases/2022/new-studies-challenge-the-dogma-of-blood-cancer-care
Federico Stella, MD, a hematology resident at the University of Milan, Italy, discusses study results demonstrating no significant difference in infection rates between patients following restrictive vs nonrestrictive neutropenic diets after undergoing hematopoietic stem cell transplantation. These phase 3 data were presented at the 64th American Society of Hematology Annual Meeting and Exposition.
This transcript has been lightly edited for clarity.
EBO: Can you give a summary of the study design?
Stella: We designed a multicenter, randomized study trying to demonstrate that the use of a restrictive neutropenic diet is basically useless for preventing infections in our patients undergoing hematopoietic stem cell transplantation. We designed and conducted a randomized noninferiority trial that compared the 2 arms. Patients randomized in the standard arm received during the period of neutropenia—so low blood cell counts—a restrictive diet consisting of only foods cooked above 80 °C. That is, more or less, 175 °F. Patients randomized in the experimental arm received during the period of neutropenia no restrictive diet. So it’s a diet compliant to hospital hygiene standards that allows patients to eat fresh fruit, fresh vegetables, cold cuts, and sausages that were forbidden in the standard arm.
EBO: Did you have any pushback when designing this study, which challenges a long-held belief that the neutropenic diet is necessary?
Stella: It is a very long-lasting belief, as you have correctly highlighted, but several centers have the feeling that restrictive diet is basically not capable to prevent infections. It was a widespread idea, even because we have observational data that highlighted a paradoxical link between the use of neutropenic diet and higher incidence of infection. And it will be explained from the impact of diet on our microbiota, so the content of bacteria in our gut. It was challenging the status quo, it’s true. But it was a status quo that, thanks to other observational studies and studies in other settings rather than hematopoietic stem cell transplantation, was already challenged. And I think that the merit of these studies is to demonstrate something that everyone already thought but [was] never tested prospectively. In 2016, when Professor Paolo Corradini—that is the mind behind this study—read over this observational data [and] said we have to stop restricting the diet of our patients; it is useless. But on the other side methodologically, scientifically, the right thing to do to stop the use of this diet safely is to conduct a randomized trial that definitely demonstrates that the use of it because prospective data was lacking. We wanted to, and he wanted to fill this gap and to put a cross on the use of a nonrestrictive diet in the most methodologically correct way. So we designed this randomized study.
EBO: Can you explain the distinction between testing for noninferiority vs superiority?
Stella: This distinction is crucial basically for a statistical design because, if you want to test the hypothesis of noninferiority, we need a lower number of patients to be enrolled. We wanted to test the noninferiority because we want to be sure that we are not exposing our patients to a higher risk of infection, obviously. We don’t want to demonstrate the superiority of nonrestrictive diet because it’s quite obvious that if you understand that 2 things are equal and one is more complex than the other, you will choose the easy path. So that’s the rationale behind the design of the study.
Stella F, Marasco V, Levatti GV, et al. Non-restrictive diet does not increase infections in patients with neutropenia after stem cell transplantation: final analysis of the neutrodiet multicenter, randomized trial. Presented at: 64th American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA. Abstract 169. https://ash.confex.com/ash/2022/webprogram/Paper158662.html
Quality improvement in health care is not easy. It takes buy-in from many stakeholders, and progress can be hard won. For the first time, the American Society of Hematology (ASH) singled out those who are making these efforts work.1 During ASH’s 64th annual meeting and exposition in December 2022, a session chaired by Rachel Rosovsky, MD, MPH, director, Thrombosis Research, Division of Hematology at Massachusetts General Hospital in Boston, featured 3 Guideline Implementation Champions who led efforts to ensure ASH Clinical Guidelines were being met within or across institutions.
According to criteria from ASH, each project had to have a measurable impact and incorporate a unique change strategy. The speakers discussed collaboration across departments, any barriers to change, and how they overcame them. The 3 champions were able to improve health outcomes while reducing days or hours of hospitalization—achievements of interest to managed care.
E-consults for Heparin-Induced Thrombocytopenia
Jori E. May, MD, an assistant professor of hematology/oncology at the University of Alabama at Birmingham (UAB), outlined how a cross-disciplinary team developed a system for e-consults to address frequent deviations from guideline-supported care for patients with suspected and confirmed heparin-induced thrombocytopenia (HIT). May noted that HIT is associated with high resource utilization because of higher rates of bleeding and thrombosis.2 Guidelines published in 2018 are divided into those specific to the diagnosis phase and those that are situation specific, May said. Of primary importance, May said, was that when patients with suspected HIT have a low probability 4T score, the ASH guideline recommends against laboratory testing.
“[What] we saw at our institution—which unfortunately I think is pretty prevalent in most institutions—is frequent testing without consideration of a 4T score,” May said. Going further, an audit revealed frequent use of bivalirudin when 4T scores suggested it was not indicated, going against another guideline. Unnecessary bivalirudin use can result in bleeding and extended hospitalizations, May said. In addition, May said, “Warfarin was primarily used in our patients with HIT, with little use of direct oral anticoagulants [DOACs].”
To better comply with guidelines regarding HIT, an electronic consultation process was implemented to ensure a hematologist consulted in all cases involving suspected HIT and a positive enzyme immunoassay (EIA). In a 1200-bed hospital, there were 645 such tests a year, of which 101 were positive.
Eliminating 645 EIAs seemed overwhelming, but managing the 101 positive cases seemed doable, May said. “We identified advocates in pharmacy, our client division laboratory, and clinical services that were frequently testing for it. That included our cardiovascular surgery colleagues, intensive care unit, and hospitalist colleagues [who] were interested in engaging on this issue,” she said.
Defining desire outcomes based on ASH guidelines was key. “Where did we think we could make a difference?” May asked. The first goal was to decrease unnecessary bivalirudin use, and a second goal was to improve use of DOACs—especially among patients with confirmed HIT. Finally, the team sought to decrease length of stay among patients with HIT with an improved protocol, she said.
The new protocol allowed providers to order EIAs, as they had in the past. But to reduce bivalirudin use, a positive EIA automatically triggered an electronic consultation with the hematology team. This was a review of the medical record and a written recommendation in the chart. Hematologists did not see the patients, but sometimes they talked to the treating physician and made anticoagulation recommendations, May said, “particularly if we felt there was another cause of thrombocytopenia that might need attention.”
A positive EIA would prompt a serotonin release assay (SRA) to confirm suspected HIT, and the e-consult service would review the SRA to offer a final recommendation, both written and verbal—including additional evaluation for thrombosis or deep vein thrombosis as needed. The process was kept efficient: consult responses took an average of 76 minutes to complete.
After 12 months, the results were impressive: The hematology team ended up providing final recommendations for 89 patients. The number of days of bivalirudin use dropped from 148 days per month across the institution to 92.8 days per month (patient counts on bivalirudin also dropped). May noted that in many cases the patient lacked a low probability 4T score, and the hematology team offered assurances that nonheparin anticoagulation was not indicated.
The initiative made progress in following the ASH guideline to promote DOAC use as well. A year prior to the e-consult effort, 12 patients with HIT were discharged with warfarin (63%), compared with 7 on a DOAC (37%); after the change, 11 patients (85%) with HIT were discharged on a DOAC, compared with 2 (15%) on warfarin.
Most impressively, the average length of stay for the HIT population was 39 days; after the e-consult shift, it fell to 17 days. “And the range was on the shorter side, which we’re quite excited about,” May said.
More changes are afoot. UAB is working with a new assay to replace the SRA and provide a faster, more accurate result. May offered advice for taking on quality initiatives. “One key thing for us was starting small and manageable. In an ideal world, perhaps we would be able to review every EIA order and make sure that only those that were productive were actually performed,” she said. “But we were a small team, and we didn’t think that that was feasible for us.
“At the same time, even though you’re starting small, I encourage you to think big,” she continued. “If you are able to make improvements, thinking forward to how you might expand those improvements is also important.”
Reducing Excess Aspirin Among Patients Anticoagulated for VTE
Jordan K. Schaefer, MD, a clinical professor of hematology at Rogel Cancer Center at University of Michigan Health in Ann Arbor, presented a project that involved 6 clinical sites. The project was launched between October 2017 and June 2018 and has sustained meaningful change over 5 years, involving more than 4000 patients.3
The effort to reduce excess aspirin use among patients being treated for anticoagulation for venous thromboembolic disease (VTE) was a project of the Michigan Anticoagulation Quality Improvement (MAQI) Initiative, which combined the efforts of 5 urban sites and 1 rural site. It began with a simple idea: Look for patients who have no obvious reason to be on aspirin alongside warfarin or a DOAC—no recent myocardial infarction, no heart valve replacement—but are nonetheless taking it despite recent guideline updates that recommend against taking aspirin this way, because of the risk of bleeding.
The first step, Schaefer said, was to evaluate the results of adding aspirin to anticoagulant therapy. “Among our warfarin-treated patients,” he said, “we found the number needed to harm was about 36. So for every 36 patients treated with combination therapy, we saw it led to an increased major bleeding event compared [with] patients on warfarin monotherapy.”
And adding aspirin didn’t seem to provide any benefit. The same pattern was found among patients taking combination therapy with DOACs, Schaefer said.
He noted that the 2020 guideline specifically recommends suspending aspirin therapy—not merely not starting it—if patients with deep vein thrombosis or pulmonary embolism had been taking it for cardiovascular risk modification. “For about a third of our patients with guideline discordant therapy, our goal is to try to develop an intervention to bring these patients’ treatment more in line with ASH guidelines,” Schaefer said.
Staff at the 6 centers went to work. One unique element of the MAQI effort is that it allowed centers to customize approaches to identifying patients based on size and resources—some used pharmacists to help, some used electronic medical records. “We evaluated outcomes of the intervention based on the percent of patients with inappropriate aspirin use per month,” Schaefer said, and they also tracked site specific barriers to identification.
The fact that aspirin is an OTC medication was acknowledged as an issue to tracking it. So was the fact that it’s not always clear which specialist—if any—ordered the aspirin in the first place. Finally, so many patients see aspirin as not very harmful that this could be a barrier to taking it out of regimens, Schaefer noted.
“We kind of started with the low-hanging fruit,” Schaefer said. Patients at anticoagulation clinics with no history of vascular disease, no history of heart valve replacement, or no heart transplant were identified, and some were simply asked to complete forms on aspirin use. Shared decision-making between patients and providers was encouraged, as was coordination among multiple providers, he said.
Between the start of the initiative and the time of data cutoff in October 2022, there had been quite a shift. The mean level of aspirin use in the 24 months prior to the intervention was 19.1%, and just prior to the intervention it was 22.1%. Four years later, it was 12.1%, and the most recent data showed the rate had fallen to 8%. (The cohort had 4017 patients: 43.7% were men, average age was 58 years, 49.1% were obese, and 21.5% had cancer.)
Prior to the intervention, the centers had a mean of 2.4 bleeding events per month, compared with 1.7 events per month post intervention. There was also a statistically significant reduction in major bleeding, with 0.34% of patients experiencing major bleeding events preintervention, compared with 0.25% of patients post intervention. Emergency department visits and admissions for bleeding also fell post intervention, Schaefer said.
“The magnitude of the change is small, but considering the thousands of patients, this is significant,” he said. “Also, with the associated with health care costs and complications for patients experiencing bleed, we see some significant impact,” he said.
Reducing Time to Delivering Analgesic Dose in Pediatric SCD
Andres Vasconez Samaniego, MD, now a fellow with Johns Hopkins University and the National Cancer Institute in Baltimore, Maryland, outlined how he and his former colleagues at Jackson Memorial Hospital and University of Miami in Florida, where Vasconez Samaniego was a resident, implemented a plan to dramatically reduce the time to give pain medication to pediatric patients with sickle cell disease (SCD) when they presented with vaso-occlusive episodes.4
Despite guidelines from both ASH and the National Heart, Lung, and Blood Institute that call for rapid assessment and administration of the first opioid-based pain medication within 60 minutes of arrival at the emergency department, Vasconez Samaniego and his fellow residents found that these young patients were waiting 90 minutes on average, well in excess of guidelines.
Besides the need to trim 30 minutes off the time until the first analgesic was delivered, the residents needed a system to ensure frequent reassessments—every 30 to 60 minutes—to stabilize these patients until they were ready to go home. Despite the fact that they are specifically exempt from CDC guidelines on opioids, many patients with SCD deal with medical providers who do not fully understand their need to manage acute and chronic pain, Vasconez Samaniego said.
In surveys, Vasconez Samaniego said, patients voiced that “there was lack of trust of their pain severity, and there were fears of drug-seeking behaviors” from the staff.
The team solved these challenges in a multipronged way. From the guidelines, they noted that pain medication should be delivered in a nonintravenous method, so they advocated for nurses to administer an initial dose of fentanyl via intranasal delivery to offer rapid relief. Second, they developed an SCD vaso-occlusive clinical pathway, which was uploaded on a mobile app and made available to all residents and staff. Residents were also given an orientation in its use.
At all times, the team aimed to trim the time for logistics. There was a need to balance better patient care with increased workload for nurses who would have to assess patients more frequently. Following the initial dose, a prescriber’s order sheet and an SCD power plan embedded in the electronic health record would let the physician take ownership from there. Patients would have to be checked for excessive sedation, and naloxone might be needed if too much opioid medication was used.
Between December 2019 and December 2020, the intervention drove tremendous change: the mean time until the first analgesic dose fell from 90 minutes to 45 minutes. Between September 2020 and February 2021, there were 64 patient encounters in which the patient with SCD was clinically qualified to receive intranasal fentanyl; of these 49 received it and 5 refused it; 10 did not receive it for another reason.
The effort shaved almost a full hour off time in the hospital for preintervention. Previously, the average length of stay was 5 hours, 21 minutes; after the introduction of intranasal fentanyl, the average length of stay was 4 hours, 29 minutes. The sickle cell occlusive pain episodes clinical has been applied in 90% of encounters.
There were some barriers. The nursing staff was concerned about opioid administration due to fears of respiratory depression, and patient refusal of medications was fueled by misconceptions about the drugs, Vasconez Samaniego said.
He noted the importance of this intervention as a health equity issue, since 88% of the patients were Black and 12% were Hispanic. Given the early success, this model is being repeated at other hospitals in the Miami area with pediatric emergency department, Vasconez Samaniego said.
“I have to give a shout-out to the nursing team who took ownership and appropriation of this project,” he said. Residents may move on, but nurses stay. Despite some initial fears, “they are taking care of these patients,” he said.
1. American Society of Hematology Clinical Practice Guidelines. Accessed December 29, 2022. https://www.hematology.org/education/clinicians/guidelines-and-quality-care/clinical-practice-guidelines
2. May JE, Irelan PC, Boedeker K, et al. Systems-based hematology: highlighting successes and next steps. Blood Adv. 2020;4(18):4574-4583. doi:10.1182/bloodadvances.2020002947
3. Schaefer JK, Errickson J, Gu X, et al. Assessment of an intervention to reduce aspirin prescribing for patients receiving warfarin for anticoagulation. JAMA Netw Open. 2022;5(9):e2231973. doi:10.1001/jamanetworkopen.2022.31973
4. Samaniego WAV, Matheus C, Aguilar-Velez C, et al. A resident-led quality improvement initiative to optimize care for children and young adults with sickle cell disease vaso-occlusive pain with intranasal fentanyl in the emergency department. Blood. 2021;138(suppl 1):1892. doi:10.1182/blood-2021-152849