1. May, Brandon

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In 1939, the first human bone marrow transplant was performed on a patient with aplastic anemia (Ann Intern Med 1939;13(2):357-367). Since then, allogeneic marrow transplantation has grown to become a prevalent-and often dominant-treatment approach for patients with leukemia. The curative potential of allogeneic hematopoietic stem transplantation for patients with hematological malignancies has encouraged its use in the clinical setting. However, careful patient selection and long-term monitoring is imperative for preventing substantial morbidity and mortality risks (Haematologica 2010;95(6):857-859, N Engl J Med 2006;354(17):1813-1826).

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The Fred Hutch Bone Marrow Transplant Program at Seattle Cancer Care Alliance (SCCA) is involved in researching the prevention, early identification, and treatment options associated with several different carcinoma types, including brain, breast, cervical, colorectal, leukemia, liver, lung, melanoma, myeloma, and prostate cancers. Although the Fred Hutch investigators are actively involved in researching and using immunotherapy for cancers like melanoma, bone marrow transplantation represents the program's main treatment focus for blood cancers.


"Over the last decade, patient survival rates following allogeneic transplantation have greatly improved among many centers across the nation, and there are many reasons to explain these improvements," said Marco Mielcarek, MD, Professor of the Department of Medicine at the University of Washington and the Medical Director of the Adult Blood and Marrow Transplantation program at Fred Hutch and SCCA. "Over time, smaller incremental improvements and different aspects of transplant care have contributed in higher survival rates, including better support during and after care, improved control of infections, and better donor matching."


At the end of 2017, the Center for International Blood and Marrow Transplant Research announced that the Fred Hutch program at SCCA had exceeded 1-year survival rates among bone marrow transplant patients presenting at their center (particularly transplants consisting of blood-forming stem cells). In addition, the Fred Hutch center was one of six centers across the nation that had exceeded U.S. expectations for 1-year bone marrow transplant survival up to 5 years in a row. According to a report issued by the Center for International Blood and Marrow Transplant Research (CIBMTR), a total of 795 allogeneic transplants were performed at Fred Hutch/SCCA during this 5-year period.


The SCCA brings together cancer experts and oncology research teams from Seattle Children's, UW Medicine, and Fred Hutch and features a total of six clinical care sites across the Seattle area. These cities include a hospital-based medical oncology clinic, academic medical and radiation oncology clinics, and Proton Therapy Center. In addition, the SCCA operates network hospital affiliations in five different states.


Investigators at Fred Hutch were pioneers in bone marrow transplantation development for the treatment of leukemia, in addition to other blood cancers. During the organization's initial stages in 1963, Fred Hutch investigators utilized chemotherapy and radiation to destroy diseased bone marrow, followed by replacing this marrow with healthy marrow from a non-cancer patient. During this process, malignant stem cells are destroyed by the stem cells of the donor's immune system, consisting of T and natural killer lymphocytes (Blood 1990;75(3):555-562, Curr Opin Hematol 2012;19(4):319-323). Simply put, the use of donor-derived stem cells in allogeneic transplantation allow alloimmunity, facilitating the eradication of residual disease via the "graft-vs-tumor" effect.


Transplantation & Mortality

Approximately 18,000 new leukemia cases are diagnosed each year in the U.S., of which 12,000 cases are considered acute (CA Cancer J Clin 2007;57(1):43-66, Blood 2012;119(17):3890-3899). Currently, acute myeloid leukemia (AML) is the most common indication for blood marrow transplantation, primarily due to the fact that the accumulated cells in AML are resistant to chemotherapy and drive relapse (Nat Rev Cancer 2005;5(4):275-284, Bone Marrow Transplant 2011;46(4):485-501).


The mechanisms driving mortality following transplantation are complex and likely the result of non-linear correlations. Research by Roni Shouval, MD, and colleagues demonstrate that disease stage, donor type, and conditioning regimen represent the three primary predictive components associated with non-relapse mortality in leukemia patients undergoing allogeneic hematopoietic stem transplantation (PLoS One 2016;11(3):e0150637). For patients with AML undergoing allogeneic transplantation with a myeloablative regimen, the 5-year survival for early, intermediate, and advanced (refractory or relapsed) stages has rates of approximately 53 percent, 44 percent, and 20 percent, respectively (Rev Bras Hematol Hemoter 2013;35(1):56-61).


"In individual clinical decision-making, both the disease risk (cytogenetic and molecular profile) and the risk associated with the transplant itself as assessed by comorbidity and other transplant-related risk-indices, should be taken into account," according to Jacopo Peccatori, MD, and Fabio Ciceri, MD, of the San Raffaele Scientific Institute in Milano, Italy. Early intervention is still heralded, however, and searching for a donor as soon as the patient receives a diagnosis is perhaps the best strategy for improving timely transplantation and improved outcomes.


Patients with AML who undergo transplantation and survive the first 2 years without relapsing appear to have better prognosis compared with patients who experience events following myeloablative conditioning and reduced-intensity conditioning approaches for allogeneic stem cell transplantation (J Hematol Oncol 2016;9(1):118).


Survival Outcomes

According to Mielcarek, the varying rates of survival across centers are not only attributable to care prior to and after transplant, but also depend on patient-specific factors. "When you look at transplant survival, you don't want to compare apples and oranges," he commented. "The types of patients transplanted at certain centers can be quite variable. Things such as disease type, disease stages, burden of comorbidities, types of donors, and matching and mismatching of donors can all affect survival outcomes." The report by the CIBMTR, however, has adjusted for the differences in patient-specific risk factors, demonstrating the high level of impact Fred Hutch/SCCA has on patient care.


Researchers of Fred Hutch conduct several clinical trials for cancer patients who require transplants, and the center has worked for more than 50 years to provide patients with transplants that feature lower toxicity and fewer risks for post-transplant complications (e.g., graft-vs-host disease). In fact, clinical trials from Fred Hutch/SCCA are currently underway that study immunosuppressive regimens, particularly the regimens' ability to minimize the risk and/or severity of post-transplant graft-vs-host disease. "There's also a program here focusing on immunotherapy," reported Mielcarek. "Frequently, this type of treatment has to be combined with transplantation, and we'll have to see how these two treatment modalities will synergize in the future."


Additionally, one of the research projects Fred Hutch/SCCA are involved in is improving conditioning prior to transplantation, according Mielcarek. "We're a research institution that's trying to improve outcomes by making incremental improvements to existing transplants," he said. "Like most other research centers, we're trying to make the conditioning regimen less toxic, subsequently reducing the likelihood for relapse."


In addition, Mielcarek believes a number of seemingly unconnected aspects of care play an undeniably interconnected role in the exceedingly high survival outcomes observed with the program. "We have a long track record doing what we're doing here," he said. "And we have very committed members of a multidisciplinary team who work very closely with advanced clinical care practice providers to support patients." In addition, the program features experienced consultation services and specialized physicians that are called upon to handle each individual case. "We have to talk to all of our specialists, including subspecialists," he added. "I think taking all these things together contributes to our improved outcomes."


Fred Hutch/SCCA also believe in the importance of long-term follow-up, particularly in regard to improving patient survival. In fact, Mielcarek believes the program's willingness to follow-up with patients either at 1 year or 30 years following transplantation has played a strong role in survival outcomes. "Patients are typically discharged 3 months following transplant, but this is not long enough to determine whether patients will experience a good long-term prognosis," he said. "We make sure patients are followed up to with community physicians to monitor progress and for potential management of complications that requires additional medical care." The Fred Hutch/SCCA center invites patients to come back to the center at 1 year following transplantation, but follow-up can be indefinite depending upon the patient.


"This group of people, including physicians, nurses, pharmacists, and advanced practice providers, are looking to develop further treatment options," said Mielcarek. The commitment by these health care professionals, according to the investigators at Fred Hutch/SCCA, represent one of the primary reasons why transplantation patients experience consistently greater survival following treatment.


Brandon May is a contributing writer.


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