The activities and regulatory landscape of cellular therapies including hematopoietic cell transplantation in the world.

A variety of cellular therapies including hematopoietic cell transplantation (HCT) hold the promise to treat medical conditions and diseases that currently have limited or no effective therapeutic options. A number of cellular therapies other than HCT, such as CAR T-cell therapy, are currently in preclinical and clinical development and the field is rapidly growing. The current activity of cellular therapies, including HCT, in the clinical setting are summarized in this article. Collaborative efforts from all relevant professionals and organizations will be of great importance to overcome substantial challenges in clinical development and post-launch evidence collection of cellular therapies. Harmonization among decision-makers also plays a critical role in reinforcing consistency and improving efficiencies of the regulatory and health technology assessment process. For the long-term safety follow-up of patients undergoing cellular therapies, registries for HCT are able to manage the complexity of data and in the best position to introduce and monitor future innovative cellular therapies for a variety of hematological disorders.

Increasing access to allogeneic hematopoietic cell transplant: an international perspective.

Allogeneic hematopoietic cell transplantation (allo-HCT) is a highly complex, costly procedure for patients with oncologic, hematologic, genetic, and immunologic diseases. Demographics and socioeconomic status as well as donor availability and type of health care system are important factors that influence access to and outcomes following allo-HCT. The last decade has seen an increase in the numbers of allo-HCTs and teams all over the world, with no signs of saturation. More than 80 000 procedures are being performed annually, with 1 million allo-HCTs estimated to take place by the end of 2024. Many factors have contributed to this, including increased numbers of eligible patients (older adults with or without comorbidities) and available donors (unrelated and haploidentical), improved supportive care, and decreased early and late post-HCT mortalities. This increase is also directly linked to macro- and microeconomic indicators that affect health care both regionally and globally. Despite this global increase in the number of allo-HCTs and transplant centers, there is an enormous need for increased access to and improved outcomes following allo-HCT in resource-constrained countries. The reduction of poverty, global economic changes, greater access to information, exchange of technologies, and use of artificial intelligence, mobile health, and telehealth are certainly creating unprecedented opportunities to establish collaborations and share experiences and thus increase patient access to allo-HCT. A specific research agenda to address issues of allo-HCT in resource-constrained settings is urgently warranted.

The Global State of Hematopoietic Cell Transplantation for Multiple Myeloma: An Analysis of the Worldwide Network of Blood and Marrow Transplantation Database and the Global Burden of Disease Study.

Multiple myeloma (MM) is a plasma cell neoplasm characterized by destructive bony lesions, anemia, and renal impairment. Access to effective therapy is limited globally. We report the rates and utilization of hematopoietic cell transplantation (HCT) globally from 2006-2015 to better characterize access to HCT for patients with MM. This was an analysis of a retrospective survey of Worldwide Network of Blood and Marrow Transplant sites, conducted annually between 2006-2015. Incidence estimates were from the Global Burden of Disease study. Outcome measures included total number of autologous and allogeneic HCTs by world regions, and percentage of newly diagnosed MM patients who underwent HCT, calculated by the number of transplants per region in calendar year/gross annual incidence of MM per region. From 2006 to 2015, the number of autologous HCT performed worldwide for MM increased by 107%. Utilization of autologous HCT was highest in Northern America and European regions, increasing from 13% to 24% in Northern America, and an increase from 15% to 22% in Europe. In contrast, the utilization of autologous HCT was lower in the Africa/Mediterranean region, with utilization only changing from 1.8% in 2006 to 4% in 2015. The number of first allogeneic HCT performed globally for MM declined after a peak in 2012 by -3% since 2006. Autologous HCT utilization for MM has increased worldwide in high-income regions but remains poorly utilized in Africa and the East Mediterranean. More work is needed to improve access to HCT for MM patients, especially in low to middle income countries. © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Association of Country-Specific Socioeconomic Factors With Survival of Patients Who Experience Severe Classic Acute Graft-vs.-Host Disease After Allogeneic Hematopoietic Cell Transplantation. An Analysis From the Transplant Complications Working Party of the EBMT.

Acute graft-vs.-host disease (aGvHD) is one of the most frequent causes of transplant-related mortality (TRM) after allogeneic hematopoietic cell transplantation (alloHCT). Its treatment is complex and costly. The aim of this study was to retrospectively analyze the impact of country-specific socioeconomic factors on outcome of patients who experience severe aGvHD. Adults with hematological malignancies receiving alloHCT from either HLA-matched siblings (n = 1,328) or unrelated donors (n = 2,824) developing grade 3 or 4 aGvHD were included. In univariate analysis, the probability of TRM at 2 years was increased for countries with lower current Health Care Expenditure (HCE, p = 0.04), lower HCE as % of Gross Domestic Product per capita (p = 0.003) and lower values of the Human Development Index (p = 0.02). In a multivariate model, the risk of TRM was most strongly predicted by current HCE (HR = 0.76, p = 0.006). HCE >median was also associated with reduced risk of the overall mortality (HR 0.73, p = 0.0006) and reduced risk of treatment failure (either relapse or TRM; HR 0.77, p = 0.004). We conclude that country-specific socioeconomic factors, in particular current HCE, are strongly associated with survival of patients who experience severe aGvHD.

Worldwide Network for Blood and Marrow Transplantation Recommendations for Establishing a Hematopoietic Stem Cell Transplantation Program in Countries with Limited Resources, Part II: Clinical, Technical, and Socioeconomic Considerations.

The development of hematopoietic stem cell transplantation (HSCT) programs can face significant challenges in most developing countries because such endeavors must compete with other government health care priorities, including the delivery of basic services. Although this is may be a limiting factor, these countries should prioritize development of the needed expertise to offer state-of-the-art treatments, including transplantation, by providing financial, technological, legal, ethical, and other needed support. This would prove beneficial in providing successful programs customized to the needs of their population and potentially provide long-term cost savings by circumventing the need for their citizens to seek care abroad. The costs of establishing an HSCT program and the costs of the HSCT procedure itself can be substantial barriers in developing countries. In addition, socioeconomic factors intrinsic to specific countries can influence access to HSCT, patient eligibility for HSCT, and timely utilization of HSCT center capabilities. This report describes recommendations from the Worldwide Network for Blood and Marrow Transplantation for establishing HSCT programs, with a specific focus on developing countries, and identifies challenges and opportunities for providing this specialized procedure in resource-constrained settings.

The effects of multi-disciplinary psycho-social care on socio-economic problems in cancer patients: a cluster-randomized trial.

PURPOSE: We examined whether multi-disciplinary stepped psycho-social care decreases financial problems and improves return-to-work in cancer patients. METHODS: In a university hospital, wards were randomly allocated to either stepped or standard care. Stepped care comprised screening for financial problems, consultation between doctor and patient, and the provision of social service. Outcomes were financial problems at the time of discharge and return-to-work in patients < 65 years old half a year after baseline. The analysis employed mixed-effect multivariate regression modeling. RESULTS: Thirteen wards were randomized and 1012 patients participated (n = 570 in stepped care and n = 442 in standard care). Those who reported financial problems at baseline were less likely to have financial problems at discharge when they had received stepped care (odds ratio (OR) 0.2, 95% confidence interval (CI) 0.1, 0.7; p = 0.01). There was no evidence for an effect of stepped care on financial problems in patients without such problems at baseline (OR 1.1, CI 0.5, 2.6; p = 0.82). There were 399 patients < 65 years old who were not retired at baseline. In this group, there was no evidence for an effect of stepped care on being employed half a year after baseline (OR 0.7, CI 0.3, 2.0; p = 0.52). TRIAL REGISTRATION: NCT01859429 CONCLUSIONS: Financial problems can be avoided more effectively with multi-disciplinary stepped psycho-social care than with standard care in patients who have such problems.

Socio-economic disparities in long-term cancer survival-10 year follow-up with individual patient data.

PURPOSE: Reasons for the social gradient in cancer survival are not fully understood yet. Previous studies were often only able to determine the socio-economic status of the patients from the area they live in, not from their individual socio-economic characteristics. METHODS: In a multi-centre cohort study with 1633 cancer patients and 10-year follow-up, individual socio-economic position was measured using the indicators: education, job grade, job type, and equivalence income. The effect on survival was measured for each indicator individually, adjusting for age, gender, and medical characteristics. The mediating effect of health behaviour (alcohol and tobacco consumption) was analysed in separate models. RESULTS: Patients without vocational training were at increased risk of dying (rate ratio (RR) 1.5, 95% confidence interval (CI) 1.1-2.2) compared to patients with the highest vocational training; patients with blue collar jobs were at increased risk (RR 1.2; 95% CI 1.0-1.5) compared to patients with white collar jobs; income had a gradual effect (RR for the lowest income compared to highest was 2.7, 95% CI 1.9-3.8). Adding health behaviour to the models did not change the effect estimates considerably. There was no evidence for an effect of school education and job grade on cancer survival. CONCLUSIONS: Patients with higher income, better vocational training, and white collar jobs survived longer, regardless of disease stage at baseline and of tobacco and alcohol consumption.

Cost-effectiveness of Tyrosine Kinase Inhibitor Treatment Strategies for Chronic Myeloid Leukemia in Chronic Phase After Generic Entry of Imatinib in the United States.

BACKGROUND: We analyzed the cost-effectiveness of treating incident chronic myeloid leukemia in chronic phase (CML-CP) with generic imatinib when it becomes available in United States in 2016. In the year following generic entry, imatinib's price is expected to drop 70% to 90%. We hypothesized that initiating treatment with generic imatinib in these patients and then switching to the other tyrosine-kinase inhibitors (TKIs), dasatinib or nilotinib, because of intolerance or lack of effectiveness ("imatinib-first") would be cost-effective compared with the current standard of care: "physicians' choice" of initiating treatment with any one of the three TKIs. METHODS: We constructed Markov models to compare the five-year cost-effectiveness of imatinib-first vs physician's choice from a US commercial payer perspective, assuming 3% annual discounting ($US 2013). The models' clinical endpoint was five-year overall survival taken from a systematic review of clinical trial results. Per-person spending on incident CML-CP treatment overall care components was estimated using Truven's MarketScan claims data. The main outcome of the models was cost per quality-adjusted life-year (QALY). We interpreted outcomes based on a willingness-to-pay threshold of $100 000/QALY. A panel of European LeukemiaNet experts oversaw the study's conduct. RESULTS: Both strategies met the threshold. Imatinib-first ($277 401, 3.87 QALYs) offered patients a 0.10 decrement in QALYs at a savings of $88 343 over five years to payers compared with physician's choice ($365 744, 3.97 QALYs). The imatinib-first incremental cost-effectiveness ratio was approximately $883 730/QALY. The results were robust to multiple sensitivity analyses. CONCLUSION: When imatinib loses patent protection and its price declines, its use will be the cost-effective initial treatment strategy for CML-CP.

Economics and Outcome After Hematopoietic Stem Cell Transplantation: A Retrospective Cohort Study.

Hematopoietic stem cell transplantation (HSCT) is a lifesaving expensive medical procedure. Hence, more transplants are performed in more affluent countries. The impact of economic factors on patient outcome is less defined. We analyzed retrospectively a defined cohort of 102,549 patients treated with an allogeneic (N = 37,542; 37%) or autologous (N = 65,007; 63%) HSCT. They were transplanted by one of 404 HSCT centers in 25 European countries between 1999 and 2006. We searched for associations between center-specific microeconomic or country-specific macroeconomic factors and outcome. Center patient-volume and center program-duration were significantly and systematically associated with improved survival after allogeneic HSCT (HR 0·87; 0·84-0·91 per 10 patients; p < 0·0001; HR 0·90;0·85-0·90 per 10 years; p < 0·001) and autologous HSCT (HR 0·91;0·87-0·96 per 10 patients; p < 0·001; HR 0·93;0·87-0·99 per 10 years; p = 0·02). The product of Health Care Expenditures by Gross National Income/capita was significantly associated in multivariate analysis with all endpoints (R(2) = 18%; for relapse free survival) after allogeneic HSCT. Data indicate that country- and center-specific economic factors are associated with distinct, significant, systematic, and clinically relevant effects on survival after HSCT. They impact on center expertise in long-term disease and complication management. It is likely that these findings apply to other forms of complex treatments.

Quantitative and qualitative differences in use and trends of hematopoietic stem cell transplantation: a Global Observational Study.

Fifty-five years after publication of the first hematopoietic stem cell transplantation this technique has become an accepted treatment option for defined hematologic and non-hematologic disorders. There is considerable interest in understanding differences in its use and trends on a global level and the macro-economic factors associated with these differences. Data on the numbers of hematopoietic stem cell transplants performed in the 3-year period 2006-2008 were obtained from Worldwide Network for Blood and Marrow Transplantation member registries and from transplant centers in countries without registries. Population and macro-economic data were collected from the World Bank and from the International Monetary Fund. Transplant rates were analyzed by indication, donor type, country, and World Health Organization regional offices areas and related to selected health care indicators using single and multiple linear regression analyses. Data from a total of 146,808 patients were reported by 1,411 teams from 72 countries over five continents. The annual number of transplants increased worldwide with the highest relative increase in the Asia Pacific region. Transplant rates increased preferentially in high income countries (P=0.02), not in low or medium income countries. Allogeneic transplants increased for myelodysplasia, chronic lymphocytic leukemia, acute leukemias, and non-malignant diseases but decreased for chronic myelogenous leukemia. Autologous transplants increased for autoimmune and lymphoproliferative diseases but decreased for leukemias and solid tumors. Transplant rates (P<0.01), donor type (P<0.01) aand disease indications (P<0.01) differed significantly between countries and regions. Transplant rates were associated with Gross National Income/capita (P<0.01) but showed a wide variation of explanatory content by donor type, disease indication and World Health Organization region. Hematopoietic stem cell transplantation activity is increasing worldwide. The preferential increase in high income countries, the widening gap between low and high income countries and the significant regional differences suggest that different strategies are required in individual countries to foster hematopoietic stem cell transplantation as an efficient and cost-effective treatment modality.

Changes in the use of hematopoietic stem cell transplantation: a model for diffusion of medical technology.

BACKGROUND: Innovations in hematology spread rapidly. Factors affecting the speed of introduction, international diffusion, and durability of use of innovations are, however, poorly understood. DESIGN AND METHODS: We used data on 251,106 hematopoietic stem cell transplants from 591 teams in 36 European countries to analyze the increase and decrease in such transplants for breast cancer and chronic myeloid leukemia and the replacement of bone marrow by peripheral blood as the source of stem cells as processes of diffusion. Regression analyses were used to measure the quantitative impact of defined macro- and microeconomic factors, to look for significant associations (t-test), and to describe the coefficient of determination or explanatory content (R(2)). RESULTS: Gross national income per capita, World Bank category, team density, team distribution, team size, team experience and, team innovator status were all significantly associated with some or all of the changes. The analyses revealed different patterns of associations and a wide range of explanatory content. Macro- and micro-economic factors were sufficient to explain the increase of allogeneic hematopoietic stem cell transplants in general (R(2) = 78.41%) and for chronic myeloid leukemia in particular (R(2) = 79.39%). They were insufficient to explain the changes in stem cell source (R(2) =26.79% autologous hematopoietic stem cell transplants; R(2) = 9.67% allogeneic hematopoietic stem cell transplants) or the decreases in hematopoietic stem cell transplants (R(2) =10.22% breast cancer; R(2)=33.17% chronic myeloid leukemia). CONCLUSIONS: The diffusion of hematopoietic stem cell transplants is more complex than previously thought. Availability of resources, evidence, external regulations and, expectations were identified as key determinants. These data might serve as a model for diffusion of medical technology in general.

Hematopoietic stem cell transplantation: a global perspective.

CONTEXT: Hematopoietic stem cell transplantation (HSCT) requires significant infrastructure. Little is known about HSCT use and the factors associated with it on a global level. OBJECTIVES: To determine current use of HSCT to assess differences in its application and to explore associations of macroeconomic factors with transplant rates on a global level. DESIGN, SETTING, AND PATIENTS: Retrospective survey study of patients receiving allogeneic and autologous HSCTs for 2006 collected by 1327 centers in 71 participating countries of the Worldwide Network for Blood and Marrow Transplantation. The regional areas used herein are (1) the Americas (the corresponding World Health Organization regions are North and South America); (2) Asia (Southeast Asia and the Western Pacific Region, which includes Australia and New Zealand); (3) Europe (includes Turkey and Israel); and (4) the Eastern Mediterranean and Africa. MAIN OUTCOME MEASURES: Transplant rates (number of HSCTs per 10 million inhabitants) by indication, donor type, and country; description of main differences in HSCT use; and macroeconomic factors of reporting countries associated with HSCT rates. RESULTS: There were 50 417 first HSCTs; 21 516 allogeneic (43%) and 28 901 autologous (57%). The median HSCT rates varied between regions and countries from 48.5 (range, 2.5-505.4) in the Americas, 184 (range, 0.6-488.5) in Asia, 268.9 (range, 5.7-792.1) in Europe, and 47.7 (range, 2.8-95.3) in the Eastern Mediterranean and Africa. No HSCTs were performed in countries with less than 300,000 inhabitants, smaller than 960 km(2), or having less than US $680 gross national income per capita. Use of allogeneic or autologous HSCT, unrelated or family donors for allogeneic HSCT, and proportions of disease indications varied significantly between countries and regions. In linear regression analyses, government health care expenditures (r(2) = 77.33), HSCT team density (indicates the number of transplant teams per 1 million inhabitants; r(2) = 76.28), human development index (r(2) = 74.36), and gross national income per capita (r(2) = 74.04) showed the highest associations with HSCT rates. CONCLUSION: Hematopoietic stem cell transplantation is used for a broad spectrum of indications worldwide, but most frequently in countries with higher gross national incomes, higher governmental health care expenditures, and higher team densities.

Predictability of hematopoietic stem cell transplantation rates.

BACKGROUND AND OBJECTIVES: Hematopoietic stem cell transplantation (HSCT) is a complex and expensive procedure. Trends in the use of this procedure have appeared erratic in the past. Information on future needs is essential for health care administrators. DESIGN AND METHODS: We analyzed the evolution of transplant rates, e.g. numbers of transplants per 10 million inhabitants, in Europe from 1990 to 2004 for all major disease categories and used Gross National Income (GNI) per capita, team density (numbers of teams per 10 million inhabitants) and team distribution (numbers of teams per 10,000 km2) to measure the impact of economic factors in participating countries. Trends were compared by regression analyses, and countries were grouped by World Bank definitions into high, middle and low income categories. RESULTS: Transplant rates increased over time with nearly linear trends, in clear association with GNI per capita (R2=0.72), and distinct by World Bank category within a narrow window of variation for both autologous HSCT (R2=0.95, 0.98 and 0.94 for high, middle and low income categories, respectively) and allogeneic HSCT (R2=0.99, 0.96 and 0.95 for high, middle and low income categories, respectively) when breast cancer (autologous) and chronic myeloid leukemia (allogeneic) were excluded. Team density (R2=0.72) and team distribution (R2=0.51) were also associated with transplant rates. INTERPRETATION AND CONCLUSIONS: Transplant rates for HSCT in Europe are highly predictable. They are primarily influenced by GNI per capita. The absence of saturation and a nearly linear trend indicate that infrastructure lags behind medical needs. Isolated changes in single disease entities can easily be recognized.