Synergistic Effects of Venetoclax and Daratumumab on Antibody-Dependent Cell-Mediated Natural Killer Cytotoxicity in Multiple Myeloma.

The prognosis of multiple myeloma (MM) has drastically improved owing to the development of new drugs, such as proteasome inhibitors and immunomodulatory drugs. Nevertheless, MM is an extremely challenging disease, and many patients are still refractory to the existing therapies, thus requiring new treatment alternatives. Venetoclax is a selective, orally bioavailable inhibitor of BCL-2 that shows efficacy in MM not only as a single agent but also in combination therapy, especially for MM patients with translocation t(11;14). However, many patients are refractory to this drug. Here, we treated the MM cell lines KMS12PE and KMS27 with a combination treatment of venetoclax targeting BCL-2 and daratumumab targeting CD38 to evaluate the synergistic cytotoxicity of these drugs in vitro. MM cell lines were co-cultured with natural killer (NK) cells at an effector:target ratio of 0.3:1 in the presence of serial concentrations of daratumumab and venetoclax, and the resulting apoptotic MM cells were detected by flow cytometry using annexin V. These results indicated that the antibody-dependent cell-mediated NK cytotoxicity was enhanced in KMS12PE and KMS27 cells harboring t(11;14) with a high BCL-2 expression, suggesting that the combination treatment of venetoclax and daratumumab should be especially effective in patients with these characteristics.

CD52 is a novel target for the treatment of FLT3-ITD-mutated myeloid leukemia.

Internal tandem duplication (ITD) of FMS-like tyrosine kinase 3 (FLT3) confers poor prognosis and is found in approximately 25% of cases of acute myeloid leukemia (AML). Although FLT3 inhibitors have shown clinical benefit in patients with AML harboring FLT3-ITD, the therapeutic effect is limited. Here, to explore alternative therapeutics, we established a cellular model of monoallelic FLT3ITD/WT cells using the CRISPR-Cas9 system in a human myeloid leukemia cell line, K562. cDNA microarray analysis revealed elevated CD52 expression in K562-FLT3ITD/WT cells compared to K562-FLT3WT/WT cells, an observation that was further confirmed by quantitative real-time-PCR and flow cytometric analyses. The elevated expression of CD52 in K562-FLT3ITD/WT cells was decreased in wild-type FLT3 (FLT3-WT) knock-in K562-FLT3ITD/WT cells. In K562-FLT3ITD/WT cells, a STAT5 inhibitor, pimozide, downregulated CD52 protein expression while an AKT inhibitor, afuresertib, did not affect CD52 expression. Notably, an anti-CD52 antibody, alemtuzumab, induced significant antibody-dependent cell-mediated cytotoxicity (ADCC) in K562-FLT3ITD/WT cells compared to K562-FLT3WT/WT cells. Furthermore, alemtuzumab significantly suppressed the xenograft tumor growth of K562-FLT3ITD/WT cells in severe combined immunodeficiency (SCID) mice. Taken together, our data suggested that genetically modified FLT3-ITD knock-in human myeloid leukemia K562 cells upregulated CD52 expression via activation of STAT5, and alemtuzumab showed an antitumor effect via induction of ADCC in K562-FLT3ITD/WT cells. Our findings may allow establishment of a new therapeutic option, alemtuzumab, to treat leukemia with the FLT3-ITD mutation.

Effects of 5-mg dose of olanzapine for breakthrough nausea and vomiting in patients receiving carboplatin-based chemotherapy: a prospective trial.

BACKGROUND: Olanzapine 10 mg is recommended for breakthrough chemotherapy-induced nausea and vomiting. However, there is a possibility that 5 mg can be expected to be sufficiently effective. We aimed to investigate the efficacy and safety of olanzapine 5 mg for breakthrough chemotherapy-induced nausea and vomiting. METHODS: A single-arm prospective trial of olanzapine 5 mg every 24 h for 72 h was conducted to treat breakthrough chemotherapy-induced nausea and vomiting in patients receiving carboplatinbased chemotherapy. The primary endpoint was total control (i.e., no emesis, no nausea, and no rescue medications) over 72 h. The secondary endpoints were early efficacy using the nausea scores at 30, 60, and 120 min after taking olanzapine from baseline and adverse events. RESULTS: Among 84 potentially eligible patients, 19 patients who took olanzapine for breakthrough chemotherapy-induced nausea and vomiting were examined. The total control rate was 32% (95% CI: 13- 57%), 65% (95% CI: 38-89%), 65% (95% CI: 38-89%), and 29% (95% CI: 10-56%) during 2-24, 24-48, 48-72 h, and overall period, respectively. The nausea scale significantly reduced after 30 min (P=0.0078), and the scale had been reduced by 67% from the baseline after 60 min. The adverse event of somnolence of any grade was observed in 13 (68%) patients, 6 (32%) of whom had grade 2 and 1 (5%) grade 3 somnolence. CONCLUSIONS: Olanzapine 5 mg did not show the expected effect on the complete disappearance of breakthrough chemotherapy-induced nausea and vomiting within 24 h.

[A Study on the Status of End-of-Life Chemotherapy for Solid Cancer after the Introduction of New Anti-Cancer Drugs].

BACKGROUND: In recent years, the decision to discontinue chemotherapy has become more difficult, and there is a tendency for chemotherapy to continue until just before death. We investigated the current state of end-of-life(EOL)chemotherapy for solid cancer patients. METHODS: Patients who died of cancer during hospitalization between January and November 2018 were included. Patients were divided into 2 groups, those who received EOL chemotherapy within 30 days of death(Near group: NG)and those who did not receive it(Far group: FG). The contents of each treatment were compared retrospectively. RESULTS: The number of patients were 46(32%)in the NG and 96(68%)in the FG. As EOL chemotherapy, the number of patients received cytotoxic drugs were 27(59%)and 68(71%), molecular targeted drugs were 6(13%)and 16(16%), immune-checkpoint inhibitors were 8(18%)and 12(12%), and hormone drugs were 0(0%)and 5(5%)in patients with NG and FG respectively(p<0.05). DISCUSSION: Minimally invasive drugs were often selected for EOL chemotherapy. It was suggested that the advent of new drugs has expanded the options for EOL chemotherapy.

Cost-utility analysis of aprepitant for patients who truly need it in Japan.

PURPOSE: Neurokinin-1 receptor antagonist (NK1RA) is recommended to prevent chemotherapy-induced nausea and vomiting (CINV) in patients who receive highly or moderately emetogenic chemotherapy (HEC or MEC, respectively). We previously reported that aprepitant, an NK1RA, was needed to control CINV in 43% and 12% of patients who received HEC and MEC, respectively (Support Care Cancer 23:905-912, 2015). To elucidate the cost-effectiveness of aprepitant in these patients, a cost-utility analysis according to the necessity of aprepitant was performed. METHODS: A decision-analytic model was developed according to the necessity of aprepitant and CINV responses in both acute and delayed phases of chemotherapy. Probabilities of health states and medical costs were derived from the results of the abovementioned trial. RESULT: In patients who received HEC and needed aprepitant, the incremental cost-effectiveness ratio (ICER) with aprepitant, relative to the regimen with no aprepitant, was 7912 US dollars (USD) per quality-adjusted life year (QALY) gained, which was far below the commonly accepted threshold of 50,000 USD/QALY. The ICER was 27,457 USD/QALY in patients who received MEC and needed aprepitant. In contrast, in patients who received HEC or MEC but did not need aprepitant, the ICER was 175,959 or 478,844 USD/QALY, respectively. CONCLUSION: Regardless of whether a patient received HEC or MEC, aprepitant use was highly cost-effective for patients who truly needed it. These results warrant further research to predict the necessity of NK1RA treatment before initiating emetogenic chemotherapies.

Cost-effectiveness of aprepitant in Japanese patients treated with cisplatin-containing highly emetogenic chemotherapy.

Chemotherapy-induced nausea and vomiting (CINV) remains a major adverse event in cancer chemotherapy. Although aprepitant is effective in preventing CINV, an increment in financial burden for uniform use of aprepitant is a concern. The aim of the present study was to define the cost-effectiveness of aprepitant from the perspective of the Japanese National Health Insurance system. Based on the results of a randomized phase II trial comparing an aprepitant-containing regimen versus a nonaprepitant regimen in Japanese patients who received cisplatin-containing highly emetogenic chemotherapy, a decision analytic model was developed. The incremental cost-effectiveness ratio (ICER) was calculated both in the outpatient care setting (OCS) and in the inpatient care setting (ICS). The use of the aprepitant-containing regimen was associated with improved quality of life compared with the nonaprepitant regimen, with an increment in quality-adjusted life years (QALY) of 0.0016. The incremental total medical costs associated with the use of the aprepitant regimen were lower in the OCS than in the ICS, 6192 JPY (56.92 USD) and 9820 JPY (90.27 USD), respectively. The ICER was calculated as 3 906 698 JPY (35 910 USD) per QALY gained in the OCS and 6 195 781 JPY (56 952 USD) per QALY gained in the ICS. Cost-effectiveness of the aprepitant-containing antiemetic therapy was limited to the OCS, considering the threshold of willingness-to-pay commonly accepted (5 million JPY [45 960 USD] in Japan and 50 000 USD in the USA). The efficacy of aprepitant offsets the costs for revisiting clinics or rehospitalization added with rescue medications in the OCS.

A Cost-Effectiveness Analysis of Gemcitabine plus Cisplatin Versus Gemcitabine Alone for Treatment of Advanced Biliary Tract Cancer in Japan.

OBJECTIVES: This study assessed the cost-effectiveness of combination treatment with gemcitabine and cisplatin compared to treatment with gemcitabine alone for advanced biliary tract cancer (BTC) in Japan. METHODS: A monthly transmitted Markov model of three states was constructed based on the Japan BT-22 trial. Transition probabilities among the health states were derived from a trial conducted in Japan and converted to appropriate parameters for our model. The associated cost components, obtained from a receipt-based survey undertaken at the Aichi Medical University Hospital, were those related to inpatient care, outpatient care, and treatment for BTC. Costs for palliative care and treatment of adverse events were obtained from the National Health Insurance price list. We estimated cost-effectiveness per quality-adjusted life year (QALY) at a time horizon of 36 months. An annual discount of 3 % for both cost and outcome was considered. RESULTS: The base case outcomes indicated that combination therapy was less cost-effective than monotherapy when the incremental cost-effectiveness ratio (ICER) was approximately 14 million yen per QALY gained. The deterministic sensitivity analysis of the ICER revealed that the ICER of the base case was robust. A probabilistic analysis conducted with 10,000-time Monte Carlo simulations demonstrated efficacy at the willingness to pay threshold of 6 million yen per QALY gained for approximately 33 % of the population. CONCLUSION: In Japan, combination therapy is less cost-effective than monotherapy for treating advanced BTC, regardless of the statistical significance of the two therapies. Useful information on the cost-effectiveness of chemotherapy is much needed for the treatment of advanced BTC in Japan.

Carvedilol increases ciclosporin bioavailability by inhibiting P-glycoprotein-mediated transport.

Carvedilol is often used to treat hypertension and for prophylaxis in vascular sclerosis in renal transplant recipients, who require concomitant treatment with ciclosporin. However, there are few reports regarding the pharmacokinetic interactions between carvedilol and ciclosporin. We have investigated the potential effects of carvedilol on the pharmacokinetics of ciclosporin, and examined the inhibitory effects of carvedilol on P-glycoprotein-mediated transcellular transport using Caco2 cells. Ciclosporin alone or with carvedilol was orally or intravenously administered to rats. The oral administration of carvedilol (10 mg kg(-1)) with ciclosporin (10 mg kg(-1)) increased the whole blood concentration of ciclosporin. When ciclosporin (3 mg kg(-1)) was intravenously administered with carvedilol (3 mg kg(-1)), there was no difference in the whole blood ciclosporin concentration between administration with and without carvedilol. Co-administration with carvedilol increased ciclosporin bioavailability from 33% to 70%. In Caco2 cells, carvedilol caused a concentration-dependent increase in the intracellular accumulation of ciclosporin, and its effect was comparable with that of verapamil. Carvedilol considerably raised the concentration of ciclosporin in the blood and this interaction was associated with the absorption phase of ciclosporin. This interaction was caused by the inhibition of P-glycoprotein-mediated transport by carvedilol in the intestine.