Outcomes After Bone Marrow Transplants Continue to Improve

Pam Harrison

January 30, 2020

The downward trajectory in death rates among bone marrow transplant recipients that was first documented in the early 2000s is continuing, with the latest records showing a substantial drop in primarily nonrelapse mortality (NRM) out to 2017.

The improvement in survival and reduction in complications were substantial, say the authors of a retrospective analysis published online January 21 in the Annals of Internal Medicine.

"Each incremental change in our Standard Practice Manual is predicated on randomized trials and clinical observations in subsets of patients undergoing hematopoietic cell transplantation...and our standard practices are constantly evolving, based on [these] data," lead author George McDonald, MD, an emeritus member at the Fred Hutchinson Cancer Research Center in Seattle, Washington, told Medscape Medical News in an email.

"So we can reasonably speculate that the sum of numerous advances in the practice of allogeneic hematopoietic cell transplantation has led to better outcomes," he added.

Last Two Decades

In an earlier report, McDonald and colleagues noted that rates of NRM at 200 days dropped by 60% whereas overall mortality dropped by 41% between 1993 and 1997 vs a decade later in patients who received a transplant.

To assess what has happened since then, the research team compared outcomes among 1148 patients who received an allogeneic hematopoietic cell transplant between 2003 and 2007 and 1131 patients who received an allograft between 2013 and 2017.

They looked at death rates before day 200 after transplant (day-200 NRM), recurrent cancer, relapse-related mortality, and overall mortality.

Compared with the earlier 2003-2007 cohort, the risk of day-200 NRM was significantly reduced by 34% in the more recent 2013-2017 cohort (P = .008), the investigators report.

Relapse rates from cancer were also 24% lower in the more recent cohort than in the earlier cohort (P = .011) while relapse-related mortality rates were 31% lower in the latest cohort compared with their earlier counterparts (P = .002).

Importantly, overall mortality was also 34% lower in the 2013-2017 cohort compared with the 2003-2007 cohort (P < .001), the team reports.

"The degree of reduction in overall mortality was similar for patients who received myeloablative versus reduced-intensity conditioning, as well as for patients whose allograft came from a matched sibling versus an unrelated donor," the investigators observe.

"Even without adjustment for confounding factors, such as increased age and comorbid conditions, overall mortality and day-200 NRM still decreased in the more recent era," they emphasized.

Complication Rates

Reductions were also seen in complication rates frequently associated with NRM, including jaundice, renal insufficiency, mechanical ventilation, high-level cytomegalovirus viremia and other infections, and acute and chronic graft-versus-host disease (GVHD).

As investigators point out, extreme hyperbilirubinemia prior to day 100 post-transplant is an "ominous prognostic sign" in that its occurrence in this particular analysis dramatically increased the risk of day-200 NRM by almost 34-fold compared with patients who did not become deeply jaundiced.

So, too, was the need for renal replacement therapy (RRT), where patients who required RRT prior to day 100 had almost a 21-fold higher risk of day-200 NRM than patients who did not require RRT.

"We have known for decades that elevation in total serum bilirubin after transplant is an independent marker of mortality," McDonald explained — not necessarily because of liver failure but because several, potentially fatal complications cause liver damage and hyperbilirubinemia.

On the other hand, reducing the intensity of the conditioning regimen used prior to transplantation leads to a lower incidence of a syndrome referred to as "sinusoidal obstruction syndrome" which itself can lead to renal and lung complications.

McDonald pointed out that infections can also cause hyperbilirubinemia, which can be prevented by appropriate prophylaxis and pre-emptive treatment of infection along with lower doses of prednisone, both strategies that were more widely used in the later cohort.

"The marked reduction in hyperbilirubinemia [we saw] in our study likely resulted from a lower frequency of these sometimes fatal complications," McDonald noted, whereas fatal liver complications caused by hepatitis and herpes viruses after transplant have almost disappeared because of timely prophylactic interventions and the use of antiviral treatments.

Investigators cautioned that data showing improved survival after allogeneic transplant are "encouraging" but that the overall mortality rate even in the most recent era analyzed was still 40% — so "the more difficult path to further improvements in survival lies in prevention of posttransplant relapse or progression of hematologic cancers," researchers acknowledge.

Nevertheless, the reduction in nonrelapse mortality reported in this study provides transplant centers with a platform to implement different treatments that more specifically target blood cancers, McDonald suggested.

For example, novel pretransplant preparative regimens such as radioimmunotherapy may be used to deliver a radioactive "punch" to cancer cells without incurring much damage to healthy tissue.

These novel regimens are now being studied in order to reduce the cancer burden before patients undergo transplant, he noted.

Cellular therapies, including CAR T-cell therapy, might also be used to eliminate disease prior to transplantation.

"Now that we have significantly reduced nonrelapse mortality, we have a platform to implement different treatments to prevent relapse or treat early evidence of recurring disease," coauthor Brenda Sandmaier, MD, also at the Fred Hutchinson Cancer Research Center, said in a statement.

"In another 10 years, the relapse rate should and will go down," she predicted.

The study was supported by the National Institutes of Health, the American Cancer Society, and the Patient-Centered Outcomes Research Institute. McDonald reports data and safety monitoring for Sangamo Therapeutics and serving as a consultant for Soligenix Therapeutics, and Lucent Medical Systems. Sandmaier reports serving as a consultant for Actinium Pharmaceuticals, Bristol-Myers Squibb, and Kiadis Pharma.

Ann Intern Med. Published online January 21, 2020. Abstract

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