Cost-Effectiveness Analysis of Axicabtagene Ciloleucel vs. Tisagenlecleucel for the Management of Relapsed/Refractory Diffuse Large B-Cell Lymphoma in Spain

CAR T therapies axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) have been approved in Spain for patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), given their favourable outcomes for overall survival and progression-free survival. However, the cost of these treatments must be weighed within the context of the Spanish health system. In this study, we assessed the cost-effectiveness and cost-utility of axi-cel vs. tisa-cel from the Spanish National Health System perspective. Using commonly applied willingness-to-pay thresholds in Spain, our analysis shows that axi-cel is highly cost-effective when compared to tisa-cel in R/R DLBCL. These results could be used to support decision-making criteria for axi-cel financing. The study aimed to assess the cost-effectiveness of axicabtagene ciloleucel (axi-cel) vs. tisagenlecleucel (tisa-cel) for the treatment of relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) after >= 2 lines of systemic therapy in Spain. A lifetime partitioned survival mixture cure model, which comprises pre-progression, post-progression, and death health states, was used to estimate the accumulated costs and outcomes in terms of life years gained (LYG) and quality-adjusted life years (QALY). A matching-adjusted indirect comparison was used to reweight patient-level data from ZUMA-1, the pivotal clinical trial for axi-cel, to aggregate-level data from the pivotal tisa-cel trial, JULIET. The analysis was performed from the National Health System perspective, thus only direct costs were included. Sensitivity analyses (SA) were performed. Axi-cel yielded 2.74 incremental LYG and 2.31 additional QALY gained per patient compared to tisa-cel. Total incremental lifetime costs for axi-cel versus tisa-cel were euro30,135/patient. The incremental cost-effectiveness ratio of axi-cel versus tisa-cel resulted in euro10,999/LYG and the incremental cost-utility ratio in euro13,049/QALY gained. SA proved robustness of the results. Considering the frequently assumed willingness-to-pay thresholds in Spain (euro22,000/QALY and euro60,000/QALY), axi-cel is a cost-effective treatment vs. tisa-cel for adult patients with R/R DLBCL in Spain

Alloreactivity: the Janus-face of hematopoietic stem cell transplantation

Differences in major and minor histocompatibility antigens between donor and recipient trigger powerful graft-versus-host reactions after allogeneic hematopoietic stem cell transplantation (HSCT). The clinical effects of alloreactivity present a Janus-face: detrimental graft-versus-host disease increases non-relapse mortality, beneficial graft-versus-malignancy may cure the recipient. The ultimate consequences on long-term outcome remain a matter of debate. We hypothesized that increasing donor-recipient antigen matching would decrease the negative effects, while preserving antitumor alloreactivity. We analyzed retrospectively a predefined cohort of 32 838 such patients and compared it to 59 692 patients with autologous HSCT as reference group. We found a significant and systematic decrease in non-relapse mortality with decreasing phenotypic and genotypic antigen disparity, paralleled by a stepwise increase in overall and relapse-free survival (Spearman correlation coefficients of cumulative excess event rates at 5 years 0.964; P<0.00; respectively 0.976; P<0.00). We observed this systematic stepwise effect in all main disease and disease-stage categories. The results suggest that detrimental effects of alloreactivity are additive with each step of mismatching; the beneficial effects remain preserved. Hence, if there is a choice, the best match should be donor of choice. The data support an intensified search for predictive genomic and environmental factors of ‘no-graft-versus-host disease’.Leukemia advance online publication, 7 April 2017; doi:10.1038/leu.2017.79

Rituximab-containing reduced-intensity conditioning improves progression-free survival following allogeneic transplantation in B cell non-Hodgkin lymphoma

Background: In B cell non-Hodgkin lymphoma (B-NHL), rituximab-containing reduced-intensity conditioning regimens (R-RIC) have been shown to provide favorable outcomes in single-arm studies; however, large multicenter studies comparing R-RIC and non-rituximab-containing reduced-intensity conditioning regimens (nonR-RIC) have not been performed. Using the CIBMTR database, we report the outcomes of R-RIC versus nonR-RIC regimens in B-NHL. Methods: We evaluated 1401 adult B-NHL patients undergoing allogeneic hematopoietic cell transplantation (alloHCT) who received nonR-RIC (n = 1022) or R-RIC (n = 379) regimens. Graft-versus-host disease (GVHD) prophylaxis was limited to calcineurin inhibitor-based approaches. Results: Median follow-up of survivors in the R-RIC and nonR-RIC groups was 47 and 37 months, respectively. On multivariate analysis, no difference was seen between the R-RIC and nonR-RIC cohorts in terms of acute GVHD grade II-IV (RR = 1.14, 95% CI = 0.83-1.56, p = 0.43) or grade III-IV (RR = 1.16, 95% CI = 0.72-1.89, p = 0.54), chronic GVHD (RR = 1.15, 95% CI = 0.92-1.46, p = 0.22), non-relapse mortality (RR = 0.90; 95% CI = 0.67-1.22; p = 0.51), relapse/progression (RR = 0.79; 95% CI = 0.63-1.01; p = 0.055), and mortality (RR = 0.84, 95% CI = 0.69-1.02, p = 0.08) risk. However, R-RIC was associated with a significantly improved progression-free survival (RR = 0.76; 95% CI 0.62-0.92; p = 0.006). On subgroup analysis, mortality benefit was noted in the R-RIC group patients not receiving busulfanbased RIC (RR = 0.76; 95% CI = 0.60-0.96; p = 0.02) and with the use of a higher cumulative rituximab dose (RR = 0.43; 95% CI = 0.21-0.90; p = 0.02). Conclusion: Our analysis shows that inclusion of rituximab in RIC regimens improves progression-free survival in patients with B cell NHL. These data supports the use of R-RIC in B-NHL patients undergoing allo-HCT

The adjusted International Prognostic Index and beta-2-microglobulin predict the outcome after autologous stem cell transplantation in relapsing/refractory peripheral T-cell lymphoma

BACKGROUND AND OBJECTIVES: Preliminary data on the use of autologous stem cell transplantation (ASCT) as a salvage therapy for peripheral T-cell lymphoma (PTCL) indicate that the results are similar to those obtained in aggressive B-cell lymphomas. The aim of our study was to analyze outcomes of a large series of patients with PTCL with a prolonged follow-up who received ASCT as salvage therapy. DESIGN AND METHODS: Between 1990 and 2004, 123 patients in this situation were registered in the GELTAMO database. The median age at transplantation was 43.5 years; in 91% of patients the disease was chemosensitive. RESULTS: Seventy-three percent of the patients achieved complete remission, 11% partial remission and the procedure failed in 16%. At a median follow-up of 61 months, the 5-year overall and progression-free survival rates were 45% and 34%, respectively. The presence of more than one factor of the adjusted International Prognostic Index (a-IPI) and a high beta2-microglobulin at transplantation were identified as adverse prognostic factors for both overall and progression-free survival and allowed the population to be stratified into three distinct risk groups. INTERPRETATION AND CONCLUSIONS: Our data show that approximately one third of patients with PTCL in the salvage setting may enjoy prolonged survival following ASCT, provided they are transplanted in a chemosensitive disease state. The a-IPI and beta2-microglobulin level predict the outcome after ASCT in relapsing/refractory PTCL

Results of an early access treatment protocol of daratumumab monotherapy in spanish patients with relapsed or refractory multiple myeloma

Daratumumab is a human CD38-targeted monoclonal antibody approved as monotherapy for heavily pretreated relapsed and refractory multiple myeloma. We report findings for the Spanish cohort of an open-label treatment protocol that provided early access to daratumumab monotherapy and collected safety and patient-reported outcomes data for patients with relapsed or refractory multiple myeloma. At 15 centers across Spain, intravenous daratumumab (16mg/kg) was administered to 73 patients who had ≥3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory drug, or who were double refractory to both. The median duration of daratumumab treatment was 3.3 (range: 0.03–13.17) months, with a median number of 12 (range: 1–25) infusions. Grade 3/4 treatment-emergent adverse events were reported in 74% of patients and included lymphopenia (28.8%), thrombocytopenia (27.4%), neutropenia (21.9%), leukopenia (19.2%), and anemia (15.1%). Common (>5%) serious treatmentemergent adverse events included respiratory tract infection (9.6%), general physical health deterioration (6.8%), and back pain (5.5%). Infusion-related reactions occurred in 45% of patients. The median change from baseline in all domains of the EQ-5D-5L and EORTC QLQ-C30 was mostly 0. A total of 18 (24.7%) patients achieved a partial response or better, with 10 (13.7%) patients achieving a very good partial response or better. Median progression-free survival was 3.98 months. The results of this early access treatment protocol are consistent with previously reported trials of daratumumab monotherapy and confirm its safety and antitumoral efficacy in Spanish patients with heavily treated relapsed or refractory multiple myeloma

Prolonged survival of patients with angioimmunoblastic T-cell lymphoma after high-dose chemotherapy and autologous stem cell transplantation: the GELTAMO experience

Abstract OBJECTIVES: Angioimmunoblastic T-cell lymphoma (AIL) is a rare lymphoma with a poor prognosis and no standard treatment. Here, we report our experiences with 19 patients treated with high-dose chemotherapy and autologous stem cell transplantation (HDC/ASCT) within the GELTAMO co-operative group between 1992 and 2004. METHODS: The median age at transplantation was 46 yr. Fifteen patients underwent the procedure as front-line therapy and four patients as salvage therapy. Most patients received peripheral stem cells (90%) coupled with BEAM or BEAC as conditioning regimen (79%). RESULTS: A 79% of patients achieved complete response, 5% partial response and 16% failed the procedure. After a median follow-up of 25 months, eight patients died (seven of progressive disease and secondary neoplasia), while actuarial overall survival and progression-free survival at 3 yr was 60% and 55%. Prognostic factors associated with a poor outcome included bone marrow involvement, transplantation in refractory disease state, attributing more than one factor of the age-adjusted-International Prognostic Index, Pretransplant peripheral T-cell lymphoma (PTCL) Score or Prognostic Index for PTCL. CONCLUSIONS: More than half of the patients with AIL that display unfavourable prognostic factors at diagnosis or relapse would be expected to be alive and disease-free after 3 yr when treated with HDC/ASCT. Patients who are transplanted in a refractory disease state do not benefit from this procedure

Outcome of Allogeneic Transplantation for Mature T-cell Lymphomas: Impact of Donor Source and Disease Characteristics

Mature T-cell lymphomas constitute the most common indication for allogeneic hematopoietic cell transplantation (allo-HCT) of all lymphomas. Large studies evaluating contemporary outcomes of allo-HCT in mature T-cell lymphomas relative to commonly used donor sources are not available. Included in this registry study were adult patients who had undergone allo-HCT for anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma (AITL), or peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) between 2008 and 2018. Hematopoietic cell transplantation (HCT) platforms compared were posttransplant cyclophosphamidebased haploidentical (haplo-)HCT, matched sibling donor (MSD) HCT, matched unrelated donor HCT with in vivo T-cell depletion (MUD TCD+), and matched unrelated donor HCT without in vivo T-cell depletion (MUD TCD-). Coprimary end points were overall survival (OS) and progression-free survival (PFS); secondary end points included nonrelapse mortality (NRM), and relapse/progression incidence (RI). A total of 1942 patients were eligible (237 haplo-HCT; 911 MSD; 468 MUD TCD+; 326 MUD TCD-). Cohorts were comparable for baseline characteristics with the exception of higher proportions of patients with decreased performance status (PS) and marrow graft recipients in the haplo-HCT group. Using univariate and multivariate comparisons, OS, PFS, RI, and NRM were not significantly different among the haplo-HCT, MSD, MUD TCD+, and MUD TCD- cohorts, with 3-year OS and PFS of 60%, 63%, 59%, and 64%, respectively, and 50%, 50%, 48%, and 52%, respectively. Significant predictors of inferior OS and PFS on multivariate analysis were active disease status at HCT and decreased PS. AITL was associated with significantly reduced relapse risk and better PFS compared with PTCL-NOS. Allo-HCT can provide durable PFS in patients with mature T-cell lymphoma (TCL). Outcomes of haplo-HCT were comparable to those of matched donor allo-HCT

Safety and Efficacy of Axicabtagene Ciloleucel versus Standard of Care in Patients 65 Years of Age or Older with Relapsed/Refractory Large B-Cell Lymphoma

Purpose: Older patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) may be considered ineligible for curative-intent therapy including high-dose chemotherapy with autologous stem-cell transplantation (HDT-ASCT). Here, we report outcomes of a preplanned subgroup analysis of patients >= 65 years in ZUMA-7. Patients and Methods: Patients with LBCL refractory to or relapsed = 65 years were random-ized to axi-cel and SOC, respectively. Median EFS was greater with axi-cel versus SOC (21.5 vs. 2.5 months; median follow-up: 24.3 months; HR, 0.276; descriptive P = 3 adverse events occurred in 94% of axi-cel and 82% of SOC patients. No grade 5 cytokine release syndrome or neurologic events occurred. In the quality-of-life analysis, the mean change in PRO scores from baseline at days 100 and 150 favored axi-cel for EORTC QLQ-C30 Global Health, Physical Functioning, and EQ-5D-5L visual analog scale (descriptive P = 65 and = 65 years with R/R LBCL

Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: updated time-to-events results and prognostic factors for time to progression

New treatment options offering enhanced activity in elderly, newly diagnosed patients with multiple myeloma are required. One strategy is to combine melphalan and prednisone with novel agents. We previously reported an 89% response rate, including 32% complete responses and 11% near complete responses, in our phase 1/2 study of bortezomib plus melphalan and prednisone (VMP) in 60 newly diagnosed multiple myeloma patients with a median age of 75 years. Here, we report updated time-to-events data and the impact of poor prognosis factors on outcome

Allogeneic transplantation provides durable remission in a subset of DLBCL patients relapsing after autologous transplantation

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/133605/1/bjh14046.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/133605/2/bjh14046_am.pd