International comparison of the factors influencing reimbursement of targeted anti-cancer drugs

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background: Reimbursement policies for anti-cancer drugs vary among countries even though they rely on the same clinical evidence. We compared the pattern of publicly funded drug programs and analyzed major factors influencing the differences. Methods: We investigated reimbursement policies for 19 indications with targeted anti-cancer drugs that are used variably across ten countries. The available incremental cost-effectiveness ratio (ICER) data were retrieved for each indication. Based on the comparison between actual reimbursement decisions and the ICERs, we formulated a reimbursement adequacy index (RAI): calculating the proportion of cost-effective decisions, either reimbursement of cost-effective indications or non-reimbursement of cost-ineffective indications, out of the total number of indications for each country. The relationship between RAI and other indices were analyzed, including governmental dependency on health technology assessment, as well as other parameters for health expenditure. All the data used in this study were gathered from sources publicly available online. Results: Japan and France were the most likely to reimburse indications (16/19), whereas Sweden and the United Kingdom were the least likely to reimburse them (5/19 and 6/19, respectively). Indications with high cost-effectiveness values were more likely to be reimbursed (ρ = −0.68, P = 0.001). The three countries with high RAI scores each had a healthcare system that was financed by general taxation. Conclusions: Although reimbursement policies for anti-cancer drugs vary among countries, we found a strong correlation of reimbursements for those indications with lower ICERs. Countries with healthcare systems financed by general taxation demonstrated greater cost-effectiveness as evidenced by reimbursement decisions of anti-cancer drugs.Peer Reviewe

Increased Releasability of Skin Mast Cells after Exercise in Patients with Exercise-induced Asthma

The role of lung mast cells in exercise-induced asthma (EIA) is controversial. To investigate whether the skin mast cell releasability is increased after exercise in EIA, 49 young atopic men with or without asthma took part in a free-running test for 6 min and were given skin prick tests using morphine, a mast cell secretagogue, before and after the exercise. The mean diameters of the wheal induced by morphine in patients with EIA were not significantly different from those in patients without EIA before exercise, although the baseline lung function was significantly lower and the airway hyperresponsiveness, the peripheral blood eosinophil count, and the size of the wheal in response to Dermatophagoides pteronyssinus were significantly higher in patients with EIA. However, the differences of the morphine-induced wheal diameter between patients with EIA and those without EIA became significant at 120 min after exercise (p<0.05), while the responses to histamine were not significantly different. These results suggest that exercise increases the releasability of skin mast cells in EIA patients whose asthma/allergy are relatively severe

Effects of Cytokine Milieu Secreted by BCG-treated Dendritic Cells on Allergen-Specific Th Immune Response

Bacillus Calmette-Guérin (BCG) is reported to suppress Th2 response and asthmatic reaction. Dendritic cells (DCs), the major antigen-presenting cells, infections with BCG are known to result in inducing various cytokines. Thus, DCs are likely to play a role in the effects of BCG on asthma. This study aims at investigating that cytokine milieu secreted by BCG-treated DCs directly enhances allergen-specific Th1 response and/or suppresses Th2 response in allergic asthma. DCs and CD3+ T cells were generated from Dermatophagoides farinae-sensitive asthmatics. DCs were cultured with and without BCG and subjected to flow cytometric analysis. IL-12 and IL-10 were determined from the culture supernatants. Some DCs were cocultured with T cells in the presence of D. farinae extracts after adding the culture supernatants from BCG-treated DCs, and IL-5 and IFN-γ were determined. BCG-treated DCs enhanced significantly the expressions of CD80, CD86, and CD40, and the productions of IL-12 and IL-10. Addition of culture supernatants from BCG-treated DCs up-regulated production of IFN-γ by T cells stimulated by DCs and D. farinae extracts (p<0.05), but did not down-regulate production of IL-5 (p>0.05). The cytokine milieu secreted by BCG-treated DCs directly enhanced allergen-specific Th1 response, although did not suppress Th2 response

Polymorphisms in Genes That Regulate Cyclosporine Metabolism Affect Cyclosporine Blood Levels and Clinical Outcomes in Patients Who Receive Allogeneic Hematopoietic Stem Cell Transplantation

In patients who received allogeneic hematopoietic stem cell transplantation (HSCT), we investigated the correlations between single nucleotide polymorphisms (SNPs) in genes that regulate cyclosporine metabolism and clinical outcomes. All patients received sibling-matched HSCT. DNA samples of patients and donors were analyzed for 4 SNPs: MDR1 +1236C>T (rs1128503), +2677G>T>A (rs2032582), +3435C>T (rs1045642), and CYP3A5 +6986G>A (rs776746). A total of 156 patients (median age 40 years) were analyzed. Nineteen patients received HSCT for nonmalignant disease. The CYP3A5 +6986AA genotype was associated with a high cyclosporine blood level after transplantation. However, this genotype was not related to any particular clinical outcome. In contrast, the MDR1 +1236C>T SNP was correlated with specific clinical outcomes. When neither the donor nor the recipient had the CC genotype of MDR1 +1236, patients had lower creatinine levels (P < .001) and less transplantation-related mortality (TRM) (P = .012). These patients also showed longer overall survival (OS) in both univariate (P = .003) and multivariate (P = .003) analyses. Although the CYP3A5 +6986AA genotype was correlated with a high blood cyclosporine concentration, lack of the MDR1 +1236CC genotype in both the donor and recipient was correlated with less TRM and a longer OS in patients who received allogeneic HSCT

The molecular pathogenesis of Trichilemmal carcinoma

Background Trichilemmal carcinoma (TC) is an extremely rare hair follicle tumor. We aimed to explore the genetic abnormalities involved in TC to gain insight into its molecular pathogenesis. Methods Data from patients diagnosed with TC within a 12-year period were retrospectively reviewed. Genomic DNA isolated from a formalin-fixed paraffin-embedded (FFPE) tumor tissue block was sequenced and explored for a panel of cancer genes. Results DNA was extracted from the FFPE tissue of four patients (50% female; mean age, 51.5 years) diagnosed with TC for analysis. The tumor was located in the head and neck of three patients and in the shoulder of one patient. TP53 mutations (p.Arg213*, p.Arg249Trp, and p.Arg248Gln) were found in three patients. Fusions previously identified in melanoma were detected in two patients (TACC3-FGFR3 and ROS1-GOPC fusions). Other mutations found included NF1-truncating mutation (Arg1362*), NRAS mutation (p.Gln61Lys), TOP1 amplification, and PTEN deletion. Overall, genetic changes found in TC resemble that of other skin cancers, suggesting similar pathogenesis. All patients with TP53 mutations had aggressive clinical course, two who died (OS 93 and 36 months), and one who experienced recurrent relapse. Conclusions We reported the genomic variations found in TC, which may give insight into the molecular pathogenesis. Overall, genetic changes found in TC resembled that of other skin cancers, suggesting similar pathogenesis. TP53 mutations was were identified in patients who had an aggressive clinical course. Genetic alterations identified may further suggest the potential treatment options of TC.This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (Grant number NRF2018R1A4A1022513). FFPE Sample handling and next generation sequencing was performed using the below funding sourc

Isatuximab plus pomalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma according to prior lines of treatment and refractory status: ICARIA-MM subgroup analysis.

SB reports honoraria from Amgen, Bristol-Myers Squibb, Celgene, and Janssen; and reports a consultancy/advisory role for Celgene, Janssen, Karyopharm, and Takeda. VV reports a consultancy/advisory role for Astellas, Biocad, Bristol-Myers Squibb, Janssen, Roche, Sanofi, and Takeda. VM reports a consultancy/advisory role for Amgen, Bristol-Myers Squibb, Celgene, Janssen, and Takeda. LK reports honoraria from Amgen, Celgene, Janssen, and Takeda; a consultancy/advisory role for Amgen, Celgene, Janssen, and Takeda; and travel support from Amgen and Janssen. MP reports honoraria from Celgene, Pfizer, and Takeda; consultancy/advisory role for Amgen, Celgene, Janssen, Roche, and Takeda; and research funding from Amgen, Celgene, Janssen, Pfizer, Roche, and Takeda. PGR reports a consultancy/advisory role for Amgen, Janssen, Karyopharm, Oncopeptides, Sanofi, and Takeda; and research funding from Bristol-Myers Squibb, Celgene, Oncopeptides, and Takeda. LP, FV, KW, LB, and YK have no disclosures. FC, SLG, FM, and HvdV are employees of Sanofi

Transcriptional signatures of the BCL2 family for individualized acute myeloid leukaemia treatment

Abstract Background Although anti-apoptotic proteins of the B-cell lymphoma-2 (BCL2) family have been utilized as therapeutic targets in acute myeloid leukaemia (AML), their complicated regulatory networks make individualized therapy difficult. This study aimed to discover the transcriptional signatures of BCL2 family genes that reflect regulatory dynamics, which can guide individualized therapeutic strategies. Methods From three AML RNA-seq cohorts (BeatAML, LeuceGene, and TCGA; n = 451, 437, and 179, respectively), we constructed the BCL2 family signatures (BFSigs) by applying an innovative gene-set selection method reflecting biological knowledge followed by non-negative matrix factorization (NMF). To demonstrate the significance of the BFSigs, we conducted modelling to predict response to BCL2 family inhibitors, clustering, and functional enrichment analysis. Cross-platform validity of BFSigs was also confirmed using NanoString technology in a separate cohort of 47 patients. Results We established BFSigs labeled as the BCL2, MCL1/BCL2, and BFL1/MCL1 signatures that identify key anti-apoptotic proteins. Unsupervised clustering based on BFSig information consistently classified AML patients into three robust subtypes across different AML cohorts, implying the existence of biological entities revealed by the BFSig approach. Interestingly, each subtype has distinct enrichment patterns of major cancer pathways, including MAPK and mTORC1, which propose subtype-specific combination treatment with apoptosis modulating drugs. The BFSig-based classifier also predicted response to venetoclax with remarkable performance (area under the ROC curve, AUROC = 0.874), which was well-validated in an independent cohort (AUROC = 0.950). Lastly, we successfully confirmed the validity of BFSigs using NanoString technology. Conclusions This study proposes BFSigs as a biomarker for the effective selection of apoptosis targeting treatments and cancer pathways to co-target in AML

Phase II trial of daratumumab with DCEP in relapsed/refractory multiple myeloma patients with extramedullary disease

Extramedullary multiple myeloma (EMD) is an aggressive subentity of multiple myeloma (MM) with poor progno‑ sis. As more innovative therapeutic approaches are needed for the treatment of MM with EMD, we conducted this multicenter, non-randomized phase II trial of daratumumab in combination with dexamethasone, cyclophospha‑ mide, etoposide and cisplatin (DARA-DCEP). A total of 32 patients (median age 59, range 35–73) were treated with DARA-DCEP. Based on the best response during the study, the complete remission (CR) rate was 35.5% and overall response rate (ORR) 67.7%. During the median follow-up of 11 months, the median progression-free survival (PFS) was 5 months and median overall survival (OS) 10 months. There were 7 long-term responders whose median PFS was not reached. The most common grade≥3 hematologic AE was thrombocytopenia. The most common non-hematologic AE was nausea (22.6%), followed by dyspepsia, diarrhea and stomatitis (all 12.9%). Grade≥3 daratumumab infusionrelated reaction was noted in 9.7% of the patients. Except for the planned 30% dose adjustment in cycle 1, only 2 patients required DCEP dose reduction. This is one of the very few prospective trials focusing on EMD and we success‑ fully laid grounds for implementing immunochemotherapy in MM treatment.This work was supported by grants from the Korea Health Technolà ¢ ogy R&D Project through the Korea Health Industry Development Institute (KHIDI, HI14C1277)

Isatuximab, carfilzomib, and dexamethasone in patients with relapsed multiple myeloma: updated results from IKEMA, a randomized Phase 3 study

Longer-term outcomes with the anti-CD38 antibody isatuximab in combination with carfilzomib-dexamethasone (Isa-Kd) were evaluated in the randomized Phase 3 trial IKEMA (NCT03275285), in a prespecified, follow-up analysis of progression-free survival (PFS, primary study endpoint), final complete response (CR) using Hydrashift Isa immunofixation assay, minimal residual disease (MRD) negativity, and safety. Enrolled patients had relapsed/refractory multiple myeloma (1-3 prior treatment lines). Isa 10 mg/kg was administered intravenously weekly in cycle 1 then biweekly. Efficacy analyses were performed in the intent-to-treat population (Isa-Kd: n = 179, Kd: n = 123) and safety evaluated in treated patients (Isa-Kd: n = 177, Kd: n = 122). Consistent with the primary interim analysis, the addition of Isa to Kd prolonged PFS (HR 0.58, 95.4% CI: 0.42-0.79; median PFS 35.7 [95% CI: 25.8-44.0] vs 19.2 [95% CI: 15.8-25.0] months). PFS benefit was observed with Isa-Kd across subgroups, including patients with poor prognosis. The stringent CR/CR rate was 44.1% vs 28.5% (odds-ratio: 2.09, 95% CI: 1.26-3.48), the MRD negativity rate 33.5% vs 15.4% (odds-ratio: 2.78, 95% CI: 1.55-4.99) and the MRD negativity CR rate 26.3% vs 12.2%, with Isa-Kd vs Kd. The safety profile of Isa-Kd was similar to that reported in the prior interim analysis. These findings further support Isa-Kd as a standard-of-care treatment for relapsed multiple myeloma patients.Clinical trial information: ClinicalTrials.gov, NCT03275285