Population preference values for health states in relapsed or refractory B-precursor acute lymphoblastic leukemia in the United Kingdom

Health state descriptions. (DOCX 41 kb

Outcomes for patients with EBV-positive PTLD post-allogeneic HCT after failure of rituximab-containing therapy

Enfermedad linfoproliferativa; Virus de Epstein-BarrMalaltia limfoproliferativa; Virus d'Epstein-BarrLymphoproliferative disease; Epstein-Barr virusEpstein–Barr virus-positive (EBV+) post-transplant lymphoproliferative disease (PTLD) is an ultra-rare and aggressive condition that may occur following allogeneic hematopoietic cell transplant (HCT) due to immunosuppression. Approximately half of EBV+ PTLD cases are relapsed or refractory (R/R) to initial rituximab-containing therapy. There are limited treatment options and no standard of care for patients with R/R EBV+ PTLD, and little is known about their treatment history and outcomes. We performed a multinational, multicenter, retrospective chart review of patients with R/R EBV+ PTLD following HCT to describe patients’ demographic and disease characteristics, treatment history, and overall survival (OS) from rituximab failure. Among 81 patients who received initial treatment with rituximab as monotherapy (84.0%) or in combination with chemotherapy (16.0%), median time from HCT to PTLD diagnosis was 3.0 months and median OS was 0.7 months. Thirty-six patients received a subsequent line of treatment. The most frequent causes of death were PTLD (56.8%), graft-versus-host disease (13.5%) and treatment-related mortality (10.8%). In multivariate analysis, early PTLD onset and lack of response to initial treatment were associated with mortality. This real-world study demonstrates that the prognosis of patients with R/R EBV+ PTLD following HCT remains poor, highlighting the urgent unmet medical need in this population

Cost burden of post-transplant lymphoproliferative disease following kidney transplants in Medicare-eligible patients by survival status

AIMS AND OBJECTIVES: Patients diagnosed with post-transplant lymphoproliferative disease (PTLD) experience high mortality within the first 2 years of diagnosis; however, few data exist on the economic burden of PTLD in these patients. We determined the healthcare resource utilization (HRU) and cost burden of post-kidney transplant PTLD and evaluated how these differ by survival status. MATERIALS AND METHODS: Utilizing data from the United States Renal Data System and the Scientific Registry of Transplant Recipients, we identified 83,818 Medicare-covered kidney transplant recipients between 2007 and 2016, of which 347 had at least one Medicare claim during the first year after diagnosis of PTLD. We tabulated Medicare Part A and Part B and calculated per patient-year (PPY) costs. RESULTS: Patients diagnosed with PTLD in the first year post-transplant had Part A + B costs of $222,336 PPY, in contrast with$83,546 PPY in all kidney transplants. Post-transplant costs in the first year of PTLD diagnosis were similar regardless of the year of diagnosis. Cost burden for PTLD patients who died within 2 years of diagnosis was \u3e3.3 times higher than PTLD patients still alive after 2 years. Of those who died within 2 years, the majority died within 6 months and costs were highest for these patients, with almost 7 times higher costs than PTLD patients who were still alive after 2 years. LIMITATIONS: Medicare costs were the only costs examined in this study and may not be representative of other costs incurred, nor be generalizable to other insured populations. Patients were only Medicare eligible for 3 years after transplant unless aged ≥62 years, therefore any costs after this cut-off were not included. CONCLUSIONS: PTLD represents a considerable HRU and cost burden following kidney transplant, and the burden is most pronounced in patients who die within 6 months

Outcomes for patients with EBV-positive PTLD post-allogeneic HCT after failure of rituximab-containing therapy

Epstein-Barr virus-positive (EBV+) post-transplant lymphoproliferative disease (PTLD) is an ultra-rare and aggressive condition that may occur following allogeneic hematopoietic cell transplant (HCT) due to immunosuppression. Approximately half of EBV+ PTLD cases are relapsed or refractory (R/R) to initial rituximab-containing therapy. There are limited treatment options and no standard of care for patients with R/R EBV+ PTLD, and little is known about their treatment history and outcomes. We performed a multinational, multicenter, retrospective chart review of patients with R/R EBV+ PTLD following HCT to describe patients' demographic and disease characteristics, treatment history, and overall survival (OS) from rituximab failure. Among 81 patients who received initial treatment with rituximab as monotherapy (84.0%) or in combination with chemotherapy (16.0%), median time from HCT to PTLD diagnosis was 3.0 months and median OS was 0.7 months. Thirty-six patients received a subsequent line of treatment. The most frequent causes of death were PTLD (56.8%), graft-versus-host disease (13.5%) and treatment-related mortality (10.8%). In multivariate analysis, early PTLD onset and lack of response to initial treatment were associated with mortality. This real-world study demonstrates that the prognosis of patients with R/R EBV+ PTLD following HCT remains poor, highlighting the urgent unmet medical need in this population.ACKNOWLEDGEMENTS. The authors gratefully acknowledge Benedetto Bruno, Federica Cavallo, Paul Chauvet, Sylvain Choquet, Vikas Dharnidharka, Daan Dierickx, Ulrich Jaeger, Charles Herbaux, Howard Huang, Periana Minga, Pietro Merli, Anthea Peters, Loretta Nastoupil, Josea Pérez Simón, John Reitan, Guillermo Rodríguez, Montserrat Rovira, Ahmed Sawas, Francesca Sismondi, Erin Sundaram, Ralph Ulrich Trappe, Jamie Wenke, and Heiner Zimmermann for their assistance with manuscript development. This study was funded by Atara Biotherapeutics. Medical writing assistance was provided by Folabomi Oladosu PhD, and Lee Blackburn MSc, from AMICULUM USA, funded by Atara Biotherapeutics

Estimating Long-Term Survival in a Cohort of Allogeneic Hematopoietic Stem Cell Transplant Patients

Abstract Introduction: Allogeneic hematopoietic cell transplantation (HCT) is a common treatment for many hematologic diseases. Most deaths occur in the first 2 years after HCT due to relapse, graft-versus-host disease, infections, malignancies, or other toxicities. Among patients who are alive and recurrence free at 2 years after HCT, survival at 10 years is between 80% and 92%. Advances in transplantation practices have led to improved outcomes and more long-term HCT survivors. As survival outcomes continue to improve and new treatments emerge, understanding and quantifying the full lifetime benefit of HCT in terms of mean overall survival (OS) is clinically relevant. In this analysis, we estimate the mean OS of a cohort of HCT patients. Methods: A systematic literature review of all studies reporting OS post-HCT was conducted. Extracted data were incorporated into a long-term survival model using a step-wise approach: short-term survival (up to 2 years post-HCT) using data reported by Uhlin et al (Haematologica. 2014;99:346-52), and longer-term survival (more than 2 years post-HCT) using data reported by Wingard et al (J Clin Oncol. 2011;29:2230-9) and the age-adjusted life tables for the general UK population. Available published data provided OS estimates up to 15 years post-HCT, and beyond this time, OS estimates are uncertain. To estimate mean OS and address this uncertainty, three different survival scenarios were modeled: best-case, worst-case, and base-case. For the best-case, it was assumed that HCT patients were cured and had the same OS as the age-adjusted general population. For the worst-case, it was assumed that HCT patients carried excess mortality for the rest of their lives. The excess mortality was calculated from Wingard et al 2011, which showed 20% mortality from year 2-15 post-HCT; this is an order of magnitude greater than the general population (2%). For the base-case, a Weibull parametric function was fit to the data published by Wingard et al 2011 to estimate the survival curve from year 2 post-HCT until death. To incorporate the excess mortality, the lowest survival was chosen cycle over cycle between the parametric estimate and the age-adjusted life tables. Sensitivity analysis for the mean survival estimate was performed by fitting several different parametric functions using exponential, Gompertz, log-logistic, and log-normal. A lifetime analysis was undertaken for a cohort of patients starting at the weighted mean age at the time of HCT, calculated from Wingard et al 2011. Results: Only two published articles were found that provided OS in patients without complications after HCT (Uhlin et al 2014 and Wingard et al 2011). Data from Uhlin et al 2014 was used to estimate the percent alive at 2 years post-HCT, which was 65%. For a cohort of HCT patients that received their transplant at age 23.5, the estimated mean OS for the base-case was 25.9 years post-HCT, with parametric models ranging between 25.9 and 29.5 years. The best-case and worst-case estimates were 31.7 and 23.9 years, respectively. Conclusions: The mean OS for a cohort of HCT patients was estimated to be 25.9 years. This estimate helps to understand and quantify the full lifetime survival benefit to HCT patients, including the tail end of the survival curve, and the potential added benefits of future treatments post-HCT. The sensitivity analysis revealed a narrow range for the estimated mean OS, minimizing the uncertainty of the results. Our estimates are based on data published by Wingard et al 2011, which incorporates excess mortality after 2 years post-HCT. This is consistent with the clinical assumption that HCT patients continue to have excess mortality throughout their lifetime. Since the first 2 years post-HCT has the highest mortality rate, new treatments that can improve survival during this time may change the impact on the lifetime benefit of the therapy. Disclosures Palmer: PRMA Consulting, Ltd: Consultancy. Watson:Atara Biotherapeutics, Inc: Employment, Equity Ownership. Barlev:Atara Biotherapeutics, Inc: Employment, Equity Ownership. </jats:sec

An Evidence Review of the Long-Term Consequences Associated with Components of the CHOP Chemotherapy Regimen in Transplant Recipients

Abstract Introduction: Epstein-Barr virus-driven post-transplant lymphoproliferative disease (EBV + PTLD) can be an aggressive, often deadly disease without any approved treatments. Current available treatments for EBV + PTLD may include cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). However, the long-term consequences of CHOP are poorly understood in immunocompromised transplant patients with cancer who may have different outcomes than immunocompetent cancer patients. This study reviewed and described the evidence for the long-term consequences associated with components of CHOP in transplant recipients. Methods: Potential long-term consequences of the components of CHOP were identified from the Children's Oncology Group Long-Term Follow-Up (COG LTFU) Guidelines. Abstracts were screened and eligibility was based on reporting data for the identified COG LTFU long-term consequences along with pre-specified criteria (English, systematic review, randomized controlled trial n&amp;gt;100, observation study n&amp;gt;100, case series n&amp;gt;20). Relevant studies that met the criteria were extracted and synthesized; of these, studies were selected if they evaluated patients who received any type of transplantation as part of their primary cancer treatment. Results: A total of 7 studies met the pre-specified selection criteria, all of which evaluated patients with hematopoietic stem cell transplantation (HCT) and none assessed solid organ transplant (SOT). None of the studies focused specifically on the CHOP regimen or EBV + PTLD. Long-term consequences of alkylating agents (eg, cyclophosphamide) and corticosteroids as primary treatment reported in these HCT studies included: hormone deficiencies and infertility (n=4 studies), osteonecrosis (n=2), and health status and quality of life (QoL; n=1). Results from three studies suggested that cancer survivors who received alkylating agents experienced hormone deficiencies and those with a HCT had a high risk. One quantified this by showing that, compared with cancer survivors without a history of HCT (CS), cancer survivors with a history of HCT (CS-HCT) and a history of total body irradiation had significantly impaired follicle stimulating hormone (40.42 vs 9.39 mIU/ml, P&amp;lt;0.001), Estradiol (15.09 vs 25.13 pg/ml, P=0.04), Inhibin B (10.61 vs 32.92 pg/ml, P=0.003), anti-Müllerian hormone (0.01 vs 1.28 ng/ml, P&amp;lt;0.001), antral follicle count (0.71 vs 17.78, P&amp;lt;0.001) and ovarian volume (1.82 vs 8.21 ml, P&amp;lt;0.001). In one study on the risk of osteonecrosis, the CS-HCT group had a significantly increased risk of developing osteonecrosis compared to the CS group treated with chemotherapy (6.8% vs 1.4%, respectively); cumulative incidence of osteonecrosis was 3.8% in the CS group for a steroid dose &amp;gt;5,835 mg/m 2 and 23.8% in the CS-HCT group for a post-transplant steroid dose &amp;gt;2,055 mg/m 2; and patients developed symptomatic osteonecrosis within a median of 2.4 years in the CS group with chemotherapy and 0.9 years after the first transplant in the CS-HCT group. A second study showed the rate ratio (RR) of osteonecrosis compared with a sibling comparison group was highest among the CS-HCT for acute lymphoblastic leukemia, acute myelogenous leukemia, and chronic myelogenous leukemia (RR = 26.9, 66.5, and 93.1, respectively; P&amp;lt;0.001 for all). One study reported that childhood acute leukemia survivors treated with HCT with preparative regimen with either busulfan-cyclophosphamide or total body irradiation/cyclophosphamide had a significantly lower QoL short-form (SF)-36 mental and physical composite scores in both treatment groups compared with norms. Conclusions: Since only a small number of studies (7) of long-term consequences in transplant recipients were identified and none were seen in patients with EBV + PTLD or in SOT recipients, more research is needed to evaluate adverse consequences of CHOP or its components in EBV + PTLD, especially in SOT patients where no studies were found. Results from this review suggest that immunocompromised HCT recipients who were cancer survivors are significantly more impaired by long-term consequences (hormone deficiencies and infertility, osteonecrosis, and QoL) of alkylating agents (eg, cyclophosphamide) and corticosteroids as primary treatment compared with other cancer survivors without HCT. Disclosures Watson: Atara Biotherapeutics: Current Employment, Current holder of individual stocks in a privately-held company. Gadikota: Maple Health Group: Current Employment. Barlev: Atara Biotherapeutics: Current Employment. Beckerman: Maple Health Group: Current Employment. </jats:sec