造血器腫瘍患者への化学療法支援に対する臨床薬学的研究

造血器腫瘍患者への化学療法は、強力で副作用の出現率も高い。副作用コントロールの善し悪しが治療の継続性、相対的治療強度（relative dose intensity： RDI）あるいはquality of life の低下に繋がる。まず筆者らは、非ホジキンリンパ腫患者に対する通常量化学療法後のステロイド離脱症状頻度とステロイド漸減療法による症状軽減効果の検討を行った。その結果、ステロイド漸減療法は安全で有効率も高く症状の改善が期待できた。特に高齢者の場合は、ステロイド離脱症状が強ければ積極的に早い段階から行う必要があると考えられた。次に、RDI に関与する重篤な感染症の1 つとして、非ホジキンリンパ腫患者における帯状疱疹の出現の解析を行った。帯状疱疹発症に関する有意な危険因子として、自己末梢血幹細胞移植後、再発患者、総治療回数10 回以上、使用レジメン2 種類以上が見出された。帯状疱疹発症の危険性がある患者へは、少量の抗ウイルス薬の予防投与を考慮すべきであり、他の感染同様に注意深く経過観察を行う必要があることを明らかにした。さらに、造血器腫瘍領域において真菌感染の第一選択薬に推奨され汎用されているLiposomal-Amphotericin B 投与による低カリウム血症と適正なカリウム補正に関する検討を行った。Grade3 以上の低カリウム血症は53.8%出現し、血清カリウム値が2.83 mEq/L を下回る前にカリウム補正を開始することが必要であり、血清カリウム値が低下しすぎない早期から補正を行うことが電解質異常の重篤化を予防するために重要であることを明らかにした。The chemotherapy treatment of hematological patients is associated with an increased risk of adverse events because of theintensity of the treatment. Adverse event management leads to continuous treatments, a relative dose intensity, and quality of life.Therefore, we evaluated the prevalence of steroid withdrawal syndrome (SWS) to assess the relevance of steroid tapering innon-Hodgkin lymphoma (NHL) patients who received general NHL chemotherapy. We conclude that steroid tapering is a safe andeffective treatment method. If the patient has serious symptoms of SWS, steroid tapering should be introduced aggressively and early,especially in elderly patients. We then examined the frequency of herpes zoster as a fatal infection in NHL patients. Significant riskfactors for the development of herpes zoster were post-autologous peripheral blood stem cell transplantation, relapse, 10 or more totaltreatments, and the use of two or more regimens. We recommend that it is necessary to consider the prophylactic use of low-doseanti-viral drugs in patients who have a higher risk of herpes zoster. We also recommend further observation of other opportunisticinfections associated with chemotherapy usage. In addition, we examined the appropriate potassium supplementation conditions totreat hypokalemia induced by liposomal-amphotericin B (L-AMB), which is recommended as a first-line anti-fungal drug forhematological patients. Hypokalemia greater than grade 3 was exhibited by 53.8% patients. It is necessary to begin potassiumsupplementation prior to the reduction of serum potassium levels to <2.83 mEq/l. Potassium supplementation at an early stage ofL-AMB treatment is important to prevent severe electrolyte abnormalities

Pituitary-Related Adverse Events and Onset Patterns Caused by Immune Checkpoint Inhibitors: Analysis Using the Japanese Adverse Drug Event Report Database

Background and Objectives: One type of immune-related adverse event caused by immune checkpoint inhibitors (ICIs) is pituitary-related adverse events. The management of pituitary-related adverse events is important because they can be fatal if not treated promptly. Therefore, this study was conducted to investigate the onset of pituitary-related adverse events using the Japanese Adverse Drug Report (JADER) database. Materials and Methods: Cases registered in the JADER database from 2004 to 2019 were used. The target drugs were ipilimumab, nivolumab, pembrolizumab, avelumab, atezolizumab, and durvalumab, and the target adverse events were the high-level terms “Anterior pituitary hypofunction,” “Anterior pituitary hyperfunction,” “Posterior pituitary disorder,” and “Pituitary neoplasm” in the Medical Dictionary for Regulatory Activities, Japanese version (MedDRA/J). The information component (IC) was used for signal detection and IC delta (ICΔ) was used for women-related signals. Onset timing and patterns were analyzed using the Weibull distribution. Results: Signals were detected with ipilimumab, nivolumab, pembrolizumab, and atezolizumab in “Anterior pituitary hypofunction,” with ICs and 95% credible intervals (95%CrI) of 5.53 (5.30–5.69), 4.96 (4.79–5.08), 4.04 (3.76–4.25), and 2.40 (1.53–3.00). Significant signals were detected in women, except for atezolizumab. Additionally, the time of onset was classified as the wear-out failure type. Inverse signals were detected with ipilimumab and nivolumab in “Posterior pituitary disorder,” with ICs (95%CrI) of −1.24 (−2.80–−0.26), and −0.89 (−1.64–−0.37). Conclusions: Anterior pituitary hypofunction is likely to occur with the long-term administration of ipilimumab, nivolumab, and pembrolizumab. Further investigation is needed to determine the differences in the tendencies to detect signals in the anterior and posterior pituitaries between ipilimumab and nivolumab