Myeloid cell leukemia sequence 1 (MCL-1) is an antiapoptotic protein that plays a key role in promoting cell survival in multiple myeloma (MM), acute myeloid leukemia (AML), and non-Hodgkin lymphoma ...(NHL). Overexpression of MCL-1 is associated with treatment resistance and poor prognosis; thus, MCL-1 inhibitors are rational therapeutic options for malignancies depending on MCL-1. Several MCL-1 inhibitors have entered clinical trials, including AZD5991, S64315, AMG 176, and AMG 397. A key area of investigation is whether MCL-1 inhibitors will complement the activity of BCL-2 inhibitors, such as venetoclax, and synergistically enhance anti-tumor efficacy when given in combination with other anti-cancer drugs. Another important question is whether a safe therapeutic window can be found for this new class of inhibitors. In summary, inhibition of MCL-1 shows potential as a treatment for hematologic malignancies and clinical evaluation of MCL-1 inhibitors is currently underway.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Purpose
Filgrastim (NEUPOGEN
®
) is the originator recombinant human granulocyte colony-stimulating factor widely used for preventing neutropenia-related infections and mobilizing hematopoietic stem ...cells. This report presents findings of a systematic literature review and meta-analysis of efficacy and safety of originator filgrastim to update previous reports.
Methods
A literature search of electronic databases, congress abstracts, and bibliographies of recent reviews was conducted to identify English-language reports of clinical trials and observational studies evaluating filgrastim in its US-approved indications up to February 2015. Two independent reviewers assessed titles/abstracts and full texts of publications, and extracted data from studies that compared originator filgrastim vs placebo or no treatment. For outcomes with sufficient homogeneous data reported across studies, meta-analysis was performed and relative risk (RR) determined. Data were summarized descriptively for all other evaluated outcomes.
Results
A total of 1194 unique articles evaluating originator filgrastim were identified, with 25 meeting eligibility criteria for data extraction: 18 randomized controlled trials, 2 nonrandomized clinical trials, and 5 observational studies. In chemotherapy-induced neutropenia (CIN), filgrastim vs placebo or no treatment significantly reduced febrile neutropenia incidence (RR 0.63, 95% CI 0.53–0.75) and grade 3 or 4 neutropenia incidence (RR 0.50, 95% CI 0.37–0.68). The most commonly reported adverse event (AE) with filgrastim was bone pain (RR 2.61, 95% CI 1.29–5.27 in CIN). Additional efficacy and safety outcomes are described within indications.
Conclusions
This systematic literature review and meta-analysis confirms and updates previous reports on the efficacy and safety of originator filgrastim. Bone pain was the commonly reported AE associated with filgrastim use.
Purpose
Mild-to-moderate bone pain is a commonly reported adverse event (AE) associated with pegfilgrastim. We evaluated the effect of prophylactic naproxen or loratadine vs no prophylactic treatment ...on pegfilgrastim-associated bone pain.
Methods
In this open-label study (NCT01712009), women ≥ 18 years of age with newly diagnosed stage I–III breast cancer and an ECOG performance status ≤ 2 who were planning ≥ 4 cycles of adjuvant or neoadjuvant chemotherapy with pegfilgrastim support starting in cycle 1 were randomized 1:1:1 to receive naproxen, loratadine, or no treatment to prevent pegfilgrastim-associated bone pain. The primary endpoint was all-grade bone pain in cycle 1 from AE reporting. Secondary endpoints included bone pain in cycles 2–4 and across all cycles from AE reporting and patient-reported bone pain by cycle and across all cycles.
Results
Six hundred patients were enrolled. Most patients (83.0%) were white, and mean (SD) age was 54.2 (11.1) years. The percentage of patients with all-grade bone pain in cycle 1 from AE reporting in the naproxen, loratadine, and no prophylaxis groups was 40.3, 42.5, and 46.6%, respectively; differences between the treatment groups were not statistically significant. Maximum, mean, and area under the curve for patient-reported bone pain were consistently lower in the naproxen and loratadine groups than in the no prophylaxis group; some of these differences were significant. Loratadine was associated with fewer treatment-related AEs and discontinuations than naproxen.
Conclusions
Given its tolerability, its ease of administration, and its potential benefit, treatment with loratadine should be considered to help prevent bone pain in patients receiving chemotherapy and pegfilgrastim.
Clinical trial registration
ClinicalTrials.gov
; NCT01712009
Purpose
For patients with clinically significant risk of febrile neutropenia, pegfilgrastim administration should occur the day after myelosuppressive chemotherapy; however, a variety of factors may ...preclude patients from returning to the clinic the next day for pegfilgrastim administration, necessitating other strategies. This study compared the pharmacokinetics and safety of pegfilgrastim administered via an on-body injector applied to the subject’s skin versus manual injection using a prefilled syringe.
Methods
Healthy subjects aged 18–50 years were randomized 1:1 to receive a single 6-mg subcutaneous pegfilgrastim dose from an on-body injector or a prefilled syringe. Blood for pharmacokinetic measurements was collected at baseline and prespecified time points after pegfilgrastim administration; safety was assessed throughout the 6-week study. Primary endpoints were maximum concentration (
C
max
) and area under the concentration curve from time 0 to infinity (AUC
0–inf
). Secondary endpoints included safety, tolerability, and immunogenicity.
Results
Pegfilgrastim mean AUC
0–inf
values for the on-body injector (
n
= 125) and manual injection (
n
= 128) were 10,900 and 11,100 h ng/mL, respectively; mean
C
max
values were 248 and 262 ng/mL, respectively. The least squares geometric mean ratios were 0.97 for
C
max
and 1.00 for AUC
0–inf
; the corresponding 90 % CIs were within the prespecified range (0.80–1.25), indicating comparable pegfilgrastim pharmacokinetics between delivery methods. Treatment-emergent adverse events (AEs) were similar between groups (injector, 86 %; manual, 85 %). Injector- or syringe-related AEs were more prevalent with the injector (13 %; manual, 4 %); none were serious. No pegfilgrastim-neutralizing antibodies were detected.
Conclusions
Pegfilgrastim pharmacokinetics and safety were comparable between the on-body injector and manual injection groups.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Of 35 patients with transfusion-dependent β-thalassemia treated with gene-edited autologous hematopoietic stem and progenitor cells, 32 had hemoglobin levels maintained without red-cell transfusions ...for at least 12 consecutive months.
Of 30 patients with severe sickle cell disease who were treated with gene-edited autologous hematopoietic stem and progenitor cells, 29 were free from vaso-occlusive crises for at least 12 ...consecutive months.
Many therapies are being studied for the treatment of hot flashes for individuals with cancer, yet few studies have demonstrated safe and effective clinical benefit for those who suffer from this ...distressing symptom. The purpose of this paper is to assess the current options for the management of hot flashes, examining key endpoints from recent clinical trials and reviewing future directions. Hot flashes are a common stressful symptom for individuals with cancer, particularly women with a history of breast cancer and men with prostate cancer. Lifestyle modifications are proposed as the first step in the management of less severe hot flashes. Several publications have addressed nonhormonal agents as a treatment option for hot flashes. Newer antidepressant and anticonvulsant agents have been studied and show potential in treating vasomotor symptoms. Although many complementary and alternative therapies, including herbal medications and phytoestrogens, have been studied for the treatment of hot flashes, none are clinically recommended at this time. Additionally, further evidence is needed for supportive exercise such as yoga and relaxation techniques. Acupuncture may warrant further investigation in the reduction and severity of hot flashes in both men and women. Hormonal therapies, including estrogens and progestogens, are the most well‐known and efficient agents in alleviating hot flashes; however, the safety of these agents is disputable.
摘要
目前许多治疗方法正在探索如何解决癌症患者的潮热问题，但少有研究表明该研究可为深受该症状困扰的患者带来兼具安全性与有效性的临床获益。本文旨在评估当前治疗潮热的各种方法，审视近期临床试验的主要治疗终点，复核未来的研究方向。潮热是令癌症患者苦恼不已的常见症状，尤其是对于患有乳腺癌的女性患者和患有前列腺癌的男性患者而言。一般认为调整生活方式是治疗不甚严重的潮热症状的第一步措施。一些已发表的文献对以非激素药物作为潮热的治疗选择进行了讨论。较新的抗抑郁与抗惊厥药物已在研究中显示出治疗血管舒缩症状的潜力。虽然已有包括中药药物与植物雌激素在内的很多互补与替代疗法用于潮热治疗的研究，但目前均不推荐在临床实践中予以应用。此外，诸如瑜伽和放松技巧等支持性运动锻炼还需要进一步的证据以证实其效果。针灸在缓解男性与女性潮热方面的作用以及所能缓解的程度或许也需要进一步的探讨。包括雌激素和孕激素在内的激素治疗是最广为人知且用于缓解潮热最为有效的药物；但对于这些药物的安全性仍有争议。
Current options for the management of hot flashes are addressed, key endpoints from recent clinical trials are examined, and future directions are reviewed.
This study assessed the efficacy of methylphenidate versus placebo for cancer-related fatigue reduction. Other objectives were to analyze cytokine levels and to determine the effects of ...methylphenidate on other symptoms, cognitive function, work yield, and patients' perceptions and preferences.
Patients were randomly assigned (1:1) to receive methylphenidate-placebo or placebo-methylphenidate for 4 weeks. Patients crossed over after 2 weeks. Wilcoxon signed rank tests and McNemar tests were used to assess continuous and categorical variables. The primary efficacy endpoint was change in the level of worst fatigue on the Brief Fatigue Inventory (BFI) at the end of each 2-week period.
The mean baseline BFI score was moderate (5.7). Methylphenidate treatment did not affect patients' worst level of fatigue or other symptoms. Results from the Wechsler Adult Intelligence Scale Digit Symbol Test and the Hopkins Verbal Learning Test with BFI interference questions and BFI activity questions showed significant improvement in the methylphenidate-treated patients' verbal learning, memory, visual perception, analysis, and scanning speed. Patients treated with methylphenidate missed significantly fewer work hours owing to health reasons and worked significantly more hours. After 4 weeks, 64% of patients reported that methylphenidate improved their cancer-related fatigue, and 58% wanted to continue treatment. Significant difference in interleukin 6R (positive), interleukin 10 (negative), and tumor necrosis factor α (positive) was noted between the methylphenidate and the placebo group.
Low-dose methylphenidate did not improve cancer-related fatigue. Patients taking methylphenidate had better cognition and were able to work more hours. Patients tolerated methylphenidate well, and the majority felt better and wanted to continue treatment.
Abstract Neuropathic pain (NP) is a debilitating symptom experienced by a number of patients with cancer. We evaluated the validity of ID Pain as a screening tool for NP in breast cancer survivors ...using the Self-Report Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS) and a reported diagnosis of NP as criterion measures. Two hundred forty breast cancer survivors with a mean age of 58 years (standard deviation = 16) participated in this survey. Forty-five percent of the sample reported having pain in the past week. Of those reporting pain, 33% reported that they had been diagnosed by their health care provider with NP, 39% had a positive ID Pain (≥2) score, and 19% had a positive S-LANSS score. The most commonly endorsed ID Pain item was “hot/burning” ( n = 48) followed by feeling “numb” ( n = 47) and “pins and needles” ( n = 45). Total ID Pain score was significantly associated with a clinical diagnosis of NP ( r = 0.41; P < 0.001) and the S-LANSS total score ( r = 0.54; P < 0.001). Receiver operating curve analysis demonstrated that ID Pain has a predictive validity of 0.72 and 0.70 for diagnosis of NP as made by clinicians and the S-LANSS, respectively. We also found that an ID Pain score greater than or equal to 2 corresponded with the likelihood of NP in this sample, consistent with the original ID Pain development study. This study provides evidence for ID Pain as a valid screening measure for NP in breast cancer survivors.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Human epidermal growth factor receptor (HER)2 over-expression is associated with a shortened disease-free interval and poor survival. Although the addition of trastuzumab to chemotherapy in the ...first-line setting has improved response rates, progression-free survival, and overall survival, response rates declined when trastuzumab was used beyond the first-line setting because of multiple mechanisms of resistance. Studies have demonstrated the clinical utility of continuing trastuzumab beyond progression, and further trials to explore this concept are ongoing. New tyrosine kinase inhibitors, monoclonal antibodies, PTEN (phosphatase and tensin homolog) pathway regulators, HER2 antibody-drug conjugates, and inhibitors of heat shock protein-90 are being evaluated to determine whether they may have a role to play in treating trastuzumab-resistant metastatic breast cancer.
PDF
