European Society Of Blood And Marrow Transplantation Research Articles

Allogeneic Stem Cell Transplantation for Elderly Patients with Intermediate-Risk Cytogenetic Acute Myeloid Leukemia and Internal Tandem Duplication of FLT3 (FLT3-ITD); A Study from the Acute Leukemia Working Party (ALWP) of the European Society of Blood and Marrow Transplantation (EBMT)

Introduction: The presence of an internal tandem duplication of FLT3 (FLT3-ITD) confers a higher risk of relapse and is now a current indication of allogeneic stem cell transplantation (SCT) in patients with intermediate-risk cytogenetic acute myeloid leukemia (IRC-AML) in first complete remission (CR1). Most studies encouraging this strategy have been performed in patients below 60 year-old, after a myeloablative conditioning (MAC) and using a sibling donor. Because age remains associated with a worse outcome after SCT, we decided to analyse outcomes of SCT in patients aged 60 year-old or older with intermediate-risk AML and FLT3-ITD.Methods: Using the EBMT registry, we selected de novo acute myeloid leukemia (AML) harboring IRC-AML and FLT3-ITD in patients transplanted from a related or matched unrelated donor (9/10 or 10/10) between January 2000 and July 2014.Results: Two hundred and five patients have been allocated. Median age at the time of SCT was 64 (range, 60-75) year-old and median follow-up was 20 (range, 2-139) months. Ninety-four percent of the patients had a good performance status (Karnofsky at SCT ≥ 80%). Most patients had a normal karyotype at diagnosis (90% versus 10% with other intermediate-risk karyotype) and NPM1 status was reported in 131 patients out of which 100 (76%) were mutated. Thirty-four patients received a MAC, 142 had a reduced-intensity conditioning (RIC) and 29 a non-myeloablative conditioning (NMA). One hundred forty-six patients received their SCT in first remission (CR1), 24 in second remission (CR2) and 35 in more advanced stage of the disease, respectively. The 2-year leukemia-free survival (LFS) was 52% in patients in CR1, 17% in those in CR2 and 11% in patients with advanced disease, respectively (p<0.005). Similarly, the 2-year overall survival (OS) was 54% in CR1, 24% in CR2 and 11% in advanced disease, respectively (p<0.005). The 2-year non-relapse mortality (NRM) for the all cohort was 20%. The cumulative incidence of grade II to IV acute graft-versus-host disease (GvHD) was 24% and that of chronic GvHD was 30%.In multivariate analysis, disease status at SCT was the most powerful predictor of worse LFS and OS. Age, as a continuous variable, was not significantly associated with outcomes. Donor type (unrelated versus sibling donor) and donor CMV positivity correlated with worse OS and higher NRM. Next, we performed a second analysis focusing on patients transplanted in CR1. A multivariate analysis performed in this subgroup showed that age, as a continuous variable, did not translate into worse LFS, OS or NRM. Interval from diagnosis to CR1 was significantly associated with LFS, being 63% in patients achieving CR1 in less than 43 days and 45% in patients achieving CR1 in more than 43 days, respectively (p<0.005). NMA conditioning was associated with a trend to a worse OS.Conclusion: Allogeneic SCT in elderly (≥60 up to 75 year-old) patients with IRC-AML harboring the FLT3-ITD mutation, similar to current strategy in younger patients, appears as a good treatment strategy if performed in CR1, independently of age, with somewhat inferior outcome in transplants from unrelated donors. Nevertheless, indication for transplantation should still be evaluated taking into account donor type, co-morbidities and performance status. DisclosuresCraddock:Celgene: Consultancy, Honoraria, Research Funding; Pfizer: Speakers Bureau; Sunesis: Honoraria; Johnson and Johnson: Consultancy. Russell:Therakos: Other: shares.

Beyond Biology: Impact of Center- and Country-specific Economic Factors on Outcomes After Hematopoietic Cell Transplantation

Ever since the first hematopoietic cell transplantation (HCT) was performed in 1960s, thousands of studies have elucidated the impact of patient and donor factors (sociodemographic, disease and transplant characteristics) on outcomes after the procedure. Fewer studies have looked at the role of center specific factors such as procedure volume, center experience or accreditation status in influencing the outcomes (Loberiza et al., 2005, Horowitz et al., 1992, Gratwohl et al., 2014). Macroeconomic factors such as gross national income per capita or health care expenditure per capita have been shown to impact the diffusion and utilization of HCT, because it is an expensive and resource intensive technology (Gratwohl et al., 2013, Gratwohl et al., 2002). However, the impact of these factors on outcomes hasn't been well studied especially in the context of individual patient-level and center-specific factors. In this issue of EBioMedicine, Baldomero et al. present a retrospective population level analysis that examines the interplay of patient-, center- and country level factors on outcomes of allogeneic and autologous HCT using data from the European Society of Blood and Marrow Transplantation (EBMT) database (Baldomero et al., 2015). The authors use a large patient cohort with a long follow-up of 8 years from 404 HCT centers in 25 European countries and incorporate center- and country specific economic data into a detailed multi-level analysis. They describe the association of program accreditation and duration, patient volume, human development index, gross national income/capita, and health care expenditures/capita with clinical outcomes (overall survival (OS), non-relapse mortality (NRM) and relapse) after HCT while adjusting for patient related factors. They report accreditation, higher patient volumes and longer program duration as center properties associated with better overall outcomes. These favorable center characteristics are more common in affluent countries and may explain in part the better survival, decreased NRM and relapse risk after allogeneic HCT in countries with higher economic indices. However, the authors rightly note that this relationship cannot be determined as causal because of the nature of the study and analysis. The relationship between outcomes and center- and country-specific factors is less definitive in the case of autologous HCT. The findings about the differential impact of macroeconomic factors on survival after autologous and allogeneic HCT are novel, but not surprising as these are two different types of procedures with different degree of medical complexity, risk and resource requirement. Even though the study is about HCT in Europe, it has wider implications. An important question it raises is ‘if one size fits all?’ for worldwide practice of HCT or for that matter, any expensive medical technology. Should the benchmarks for assessing the success of an expensive technology be different amongst different countries at diverse stages of socioeconomic development with different resource capacity (knowledge base, human resources and institutional infrastructure)? The authors suggest streamlining and consolidation of the transplant activity to help maintain the quality of care and strengthening the overall health infrastructure to provide optimal pre- and post-HCT care. This proposition and a long term vision for the growth and sustainability of a transplant program may be more important for the poorer countries than the richer countries to help optimize the best utilization of the scarce resources. This is because the spending on health care especially on high cost medical technology is more likely to strain the government as well as individual household budgets in poorer countries as opposed to affluent countries. The bigger question is if the poorer countries should spend their limited resources to improve outcomes of expensive procedures that benefit only a few or focus on providing basic necessities and preventive care for a larger population? The authors highlight the role of professional medical societies worldwide in improving the quality of care and scaling up transplant systems through education and training that fit within the economic framework of individual countries across the globe. This will need to be supplemented with other measures such as international aid, advocacy efforts, partnerships and investment in research in the affluent countries to develop affordable technologies. Bidirectional knowledge transfer is important because the evolution of a technology developed in a richer country may follow a more cost-effective route when implemented in developing countries. This may provide an opportunity for the affluent countries to learn a less expensive way to do things as long as it doesn't impact short- and long-term outcomes (Ruiz-Delgado, 2012). Finally, the policy makers need to realize the importance of bridging the divide between macroeconomic policy and health policy to commit to building the necessary scientific and research capacity that can optimally address the medical needs of the country through careful resource allocation. We have crossed the one million mark for HCT across the world, now we need to strive to achieve a compromise between equity and efficiency.