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Background: In the 21st century, the prevalence of tinnitus is increasing, impacting approximately one in five people. It is a very complicated condition that significantly affects quality of life. Despite the availability of hundreds of tinnitus treatment options, none are very successful. In light of this, there has been a steady increase in studies on tinnitus treatments in the recent past. To comprehend them better, this study used bibliometric approaches to analyze and summarize 21st century scientific research accomplishments in tinnitus treatment. Methods: The Web of Science Core Collection (WoSCC) was searched for papers that had been published and related to the treatment of tinnitus. VOSviewer, CiteSpace, R, and Tableau software programs were used to conduct bibliometric studies. To evaluate and visualize the results. Results: 2,933 publications on tinnitus treatment were found in 74 countries. Between 2000 and 2021, publications increased steadily. Otolaryngology-Head & Neck Surgery had the highest impact factor, whereas Otology & Neurotology had themostmagazines and the highest h, g, and m index. Langguth B was the most prolific author in terms of productivity during the past 21 years. Numerous eminent authors and organizations from multiple nations collaborated. With 626 papers, the United States of America (USA) contributed the most to this field, making them the leading contributor. Neuroplasticity, sound therapy, and cognitive behavioral therapy (CBT) have attracted the attention of researchers, leading to the development of innovative diagnostic and treatment strategies for tinnitus. Conclusion: This bibliometric study provides a comprehensive analysis of worldwide publications, cooperation, and research hotspots in tinnitus therapy, revealing the present status of research on this issue and guiding tinnitus treatment research in the coming years. [ABSTRACT FROM AUTHOR]

The term group A Streptococcus is considered synonymous for the species Streptococcus pyogenes. We describe an emergent invasive S. dysgalactiae subspecies equisimilis lineage that obtained the group A antigen through a single ancestral recombination event between a group C S. dysgalactiae subsp. equisimilis strain and a group A S. pyogenes strain. [ABSTRACT FROM AUTHOR]

On May 5, 2009, the U.S. Food and Drug Administration granted accelerated approval to bevacizumab injection (Avastin®; Genentech, Inc., South San Francisco, CA) as a single agent for patients with glioblastoma multiforme (GBM) with progressive disease following prior therapy. The approval was based on durable objective responses (independent radiologic review with stable or decreasing corticosteroid use). Two trials evaluating bevacizumab, 10 mg/kg by i.v. infusion every 2 weeks, were submitted. One trial also randomized patients to bevacizumab plus irinotecan treatment. All patients had received prior surgery, radiotherapy, and temozolomide. Patients with active brain hemorrhage were excluded. One trial enrolled 78 independently confirmed GBM patients. Partial responses were observed in 25.9% (95% confidence interval [CI], 17.0%-36.1%) of the patients. The median response duration was 4.2 months (95% CI, 3.0-5.7 months). The second trial enrolled 56GBMpatients. Partial responses were observed in 19.6% (95% CI, 10.9%-31.3%) of the patients. The median response duration was 3.9 months (95% CI, 2.4-17.4 months). Safety data were provided for the first study. The most frequently reported bevacizumab adverse events of any grade were infection, fatigue, headache, hypertension, epistaxis, and diarrhea. Grade 3-5 bevacizumab-related adverse events included bleeding/hemorrhage, central nervous system (CNS) hemorrhage, hypertension, venous and arterial thromboembolic events, wound-healing complications, proteinuria, gastrointestinal perforation, and reversible posterior leukoencephalopathy. The attribution of certain adverse events (e.g., CNS hemorrhage, wound-healing complications, and thromboembolic events) to either bevacizumab, underlying disease, or both could not be determined because of the single-arm, noncomparative study design. The Oncologist 2009;14:1131-1138 [ABSTRACT FROM AUTHOR]

The article discusses a study on the role of obesity in the development of the metabolic syndrome (MS) in the U.S. The analysis included a total of 3,596 whites aged 19 years and above who participated in the National Health and Nutrition Examination Survey (NHANES) 1992-2002. The metabolic profile in the NHANES group showed that obesity is associated with inflammation, insulin resistance and dyslipidemia.

It is believed by many people that going to the native country of a second language is the best way to learn this language well. Take English as an example. More and more people in China are willing to spend thousands and thousands of U.S. dollars sending their children to English-speaking countries for either a several days' trip or short-term study. They hope the experience abroad would help improve their children's English. Does this really help? As a Chinese student who started to learn English in primary school and completed her Masters Degree in Education at Harvard and are currently working in an institution of higher education in the U.S., the author will share with you her personal English-learning experience as well as the experiences of Chinese people she encountered in the U.S. A native country is not necessarily equal to a good language-learning environment. Many people who have been in the U.S. for more than ten years still cannot speak a complete English sentence; some students who completed their Ph.D.s in America could not express themselves verbally in English, though they might have achieved very high scores in English proficiency tests like TOFEL or GRE. How does this happen? What is the cause? Is there any solution to the problem? In the paper, the author will illustrate her views and share with you her thoughts. [ABSTRACT FROM AUTHOR]

This chapter seeks to unpack ethnicity through a close examination of ethnic language schools and the ethnic system of supplementary education in the immigrant Chinese community in the United States. It sheds light on the specific ways in which ethnic community organizations contribute to educational achievement. [ABSTRACT FROM AUTHOR]

Recent discussions in connection with U.S. President Harry S. Truman's Point IV program have made it abundantly clear that the general attitude of the United States towards the utilization of American capital in furthering the economic development of under-developed countries, apart from the question of technical assistance in the narrower sense, is based on the following convictions; namely, (1) that private enterprise and private funds should play the major role in foreign investment, (2) that public funds controlled by the government, outside the sphere of emergency measures for a transitional period only, should not enter into "direct and wasteful competition with private funds," and (3) that government guarantees should be given to private investors in order to eliminate the risks peculiar to investment activities overseas. Since the views of the United States in this field are of vital importance both to the investors and to the under-developed countries, an examination of some of the implications of these conceptions would appear to be timely, as well as advantageous. Of particular interest is the question of government guarantees for the encouragement of private foreign investment.

On August 25, 2021, the FDA approved ivosidenib for the treatment of adult patients with unresectable locally advanced or metastatic hepatocellular isocitrate dehydrogenase 1 (IDH1) mutated cholangiocarcinoma (CCA) as detected by an FDA-approved test with disease progression after 1 to 2 prior lines of systemic therapy for advanced disease. The approval was based on data from Study AG120-C-005 (ClarIDHy), a double-blind placebo-controlled trial that randomly allocated (2:1) patients to receive either ivosidenib or placebo. Independently assessed progression-free survival (PFS) was the primary endpoint. With a median follow-up of 6.9 months, the HR for PFS was 0.37 [95% confidence interval (CI), 0.25-0.54; P < 0.0001). Overall survival (OS) was the key secondary endpoint. At the final analysis of OS, with 70.5% of patients in the placebo arm receiving ivosidenib post disease progression, a non-statistically significant improvement in the ivosidenib arm with an HR = 0.79 (95% CI, 0.56-1.12) and median OS of 10.3 months (95% CI, 7.8-12.4) and 7.5 months (95% CI, 4.8-11.1) in the ivosidenib and placebo arms, respectively, were reported. Adverse reactions occurring in >20% of patients receiving ivosidenib were fatigue/asthenia, nausea, diarrhea, abdominal pain, ascites, vomiting, cough, and decreased appetite. Adverse reactions occurring in >20% of patients receiving placebo were fatigue/asthenia, nausea, abdominal pain, and vomiting. This is the first approval for the subset of patients with CCA harboring an IDH1 mutation., (©2022 American Association for Cancer Research.)

African Americans (AAs) have a higher incidence of multiple myeloma (MM) than White patients. Mortality is also higher in AAs compared with White patients. AAs more commonly have immunoglobulin H translocations t(11;14) and t(14;16) compared with White patients. We sought to characterize the demographic representation in MM clinical trials and evaluate outcomes based on race and ethnicity. We conducted a pooled analysis of all trials submitted to the US Food and Drug Administration (FDA) to support approval of a MM therapeutic between 2006 and 2019. Demographic characteristics were analyzed descriptively. An age-adjusted stratified Cox regression model was used to evaluate the relationship between time-to-event outcomes and race and ethnicity. Nineteen global trials comprising 10 157 patients were pooled. White, Asian, and Black patients comprised 84%, 7%, and 4% of the dataset, respectively; Hispanic patients comprised 4%. The age-adjusted overall survival hazard ratio (HR) for Black compared with White patients was 0.89 (95% confidence interval [CI], 0.75-1.05). The age-adjusted HR for US Black vs US White patients was 0.82 (95% CI, 0.66-1.02). For rest-of-world (RoW) Black vs RoW White patients, the HR was 1.31 (95% CI, 0.97-1.77). Black and Hispanic patients were underrepresented in the trials supporting FDA approval of MM drugs. Black patients were primarily enrolled in the United States. Outcomes in US patients were more favorable compared with those in patients in the RoW. Given the higher incidence of MM in AAs and the different disease characteristics, efforts should be made to improve representation of AAs in MM clinical trials.

Purpose: To explore trial-level and patient-level associations between response (complete remission [CR] and CR + CR with incomplete hematologic [CRi] or platelet [CRp] recovery), event-free survival (EFS), and overall survival (OS) in newly diagnosed acute myeloid leukemia (AML) trials of intensive chemotherapy., Methods: We identified data from eight randomized, active-controlled trials of intensive chemotherapy submitted to the US Food and Drug Administration for treatment of newly diagnosed AML (N = 4,482). Associations between trial-level odds ratios (ORs) for CR and CR + CRi or CRp, and hazard ratios (HRs) for EFS and OS were analyzed using weighted linear regression models. We performed patient-level responder analyses to compare OS by response using pooled data from all studies., Results: In trial-level analyses, association between HR for OS and OR for CR was moderate (R 2 = 0.49; 95% CI, 0.05 to 0.86), as was the association with OR for CR + CRi or CRp (R 2 = 0.48; 95% CI, 0.05 to 0.99). For OS versus EFS, a strong association was observed (R 2 = 0.87; 95% CI, 0.47 to 0.98) when EFS definitions were harmonized across trials using raw data. In the patient-level responder analyses, patients who achieved CR had better OS compared with CRi or CRp responders (0.73; 95% CI, 0.64 to 0.84) and nonresponders (HR, 0.33; 95% CI, 0.31 to 0.37)., Conclusion: On a trial level, there is a moderate association between OS and CR rate. A strong association between EFS and OS was observed. However, CIs were wide, and results became moderate using alternative definitions for EFS. Patient-level analyses showed CR responders have better OS compared with CRi or CRp responders and nonresponders. A therapy in newly diagnosed AML with benefit in EFS or substantial benefit in CR rate would be likely to have an OS effect., Competing Interests: Yutao GongEmployment: BeiGeneStock and Other Ownership Interests: BeiGene Jonathon VallejoEmployment: AstraZeneca (I) Gideon M. BlumenthalEmployment: MerckStock and Other Ownership Interests: MerckNo other potential conflicts of interest were reported.

Lessons Learned: The combination of anlotinib and S-1 exhibited good antitumor activity in third- or later-line treatment for stage IV non-small cell lung cancer (NSCLC). Combination therapy of anlotinib with S-1 has manageable toxicities in patients with NSCLC., Background: This study aimed to evaluate the efficacy and safety of anlotinib combined with S-1 as a third- or later-line treatment for patients with stage IV non-small cell lung cancer (NSCLC). Anlotinib was approved in 2018 by the Chinese Food and Drug Administration (FDA) as a third-line treatment for patients with refractory advanced NSCLC and is under study in the U.S. and Europe., Methods: Simon's phase II clinical trial design with an α error of 5% and a power β of 80% was used, anticipating a 10% objective response rate (ORR) of anlotinib and a 30% ORR of anlotinib combined with S-1; the required sample size was 29. A total of 29 patients were enrolled in the clinical trial. Patients were treated with anlotinib plus S-1 over a 21-day treatment course until disease progression or unacceptable toxic effects. If the efficacy was assessed as stable disease, partial response, or complete response after six cycles, anlotinib was maintained until disease progression or death. The primary endpoint was the objective response rate. Somatic mutations were not required for study enrollment., Results: The median follow-up time was 11.1 months. Objective responses were observed in 11 of 29 (37.9%) patients making up the intention-to-treat population, which reached the target primary endpoint of 30% ORR. The median overall and progression-free survival were 16.7 and 5.8 months, respectively. The most common grade 3 adverse events (AEs) were gastrointestinal, including nausea, vomiting and diarrhea, fatigue, and hypertension. No grade 4 treatment-related AEs or treatment-related deaths occurred., Conclusion: The combination of anlotinib with S-1 in the third- or later-line treatment of stage IV NSCLC shows promising antitumor activity and manageable toxicity in patients with NSCLC; phase III trials will be planned in the future., (© AlphaMed Press; the data published online to support this summary are the property of the authors.)

The FDA approved pembrolizumab on June 29, 2020, for the treatment of patients with unresectable or metastatic microsatellite instability-high (MSI-H) colorectal cancer with no prior systemic treatment for advanced disease. The approval was based on data from Study Keynote-177, which randomly allocated patients to receive either pembrolizumab or standard of care (SOC) with chemotherapy. Overall survival (OS) and independently assessed progression-free survival (PFS) were the primary endpoints. At the time of the final PFS analysis and second prespecified interim OS analysis, the estimated median PFS was 16.5 months (95% CI: 5.4-32.4) versus 8.2 months (95% CI: 6.1-10.2) in the pembrolizumab and SOC arms, respectively [HR: 0.60 (95% CI: 0.45-0.80); two-sided P = 0.0004]. FDA assessed unblinded OS data during the review of the application and identified no safety concerns that would preclude approval of this supplement. Adverse reactions occurring in >30% of patients receiving pembrolizumab were diarrhea, fatigue/asthenia, and nausea. Adverse reactions occurring in >30% of patients receiving SOC were diarrhea, nausea, fatigue/asthenia, neutropenia, decreased appetite, peripheral neuropathy (high-level term), vomiting, abdominal pain, constipation, and stomatitis. Duration of treatment in the pembrolizumab arm was almost double (median 11.1 months, range 0-30.6 months) than the duration of treatment in patients receiving SOC (median, 5.7 months). Approval of pembrolizumab is likely to change the treatment paradigm for first-line treatment with MSI-H advanced colorectal cancer given the study results and different safety profile., (©2021 American Association for Cancer Research.)

On April 10, 2020, the FDA approved selumetinib (KOSELUGO, AstraZeneca) for the treatment of pediatric patients 2 years of age and older with neurofibromatosis type 1 who have symptomatic, inoperable plexiform neurofibromas. Approval was based on demonstration of a durable overall response rate per Response Evaluation in Neurofibromatosis and Schwannomatosis criteria and supported by observed clinical improvements in plexiform neurofibroma-related symptoms and functional impairments in 50 pediatric patients with inoperable plexiform neurofibromas in a single-arm, multicenter trial. The overall reponse rate per NCI investigator assessment was 66% (95% confidence interval, 51-79) with at least 12 months of follow-up. The median duration of response was not reached, and 82% of responding patients experienced duration of response ≥12 months. Clinical outcome assessment endpoints provided supportive efficacy data. Risks of selumetinib are consistent with MAPK (MEK) inhibitor class effects, including ocular, cardiac, musculoskeletal, gastrointestinal, and dermatologic toxicities. Safety was assessed across a pooled database of 74 pediatric patients with plexiform neurofibromas and supported by adult and pediatric selumetinib clinical trial data in cancer indications. The benefit-risk assessment for selumetinib in patients with inoperable plexiform neurofibromas was considered favorable., (©2021 American Association for Cancer Research.)

Tagraxofusp-erzs (Elzonris, Stemline) is a cytotoxin that targets CD123-expressing cells. On December 21, 2018, FDA approved tagraxofusp-erzs for the treatment of blastic plasmacytoid dendritic cell neoplasms (BPDCN) in adult and pediatric patients 2 years and older. Approval was based on the response rate in a single-arm trial, Study STML-401-0114; the pivotal cohort included 13 patients with treatment-naïve BPDCN who received tagraxofusp-erzs monotherapy. The complete response or clinical complete response (CR/CRc) rate in the pivotal cohort was 54% (95% CI: 25%-81%), and the median duration of CR/CRc was not reached with a median follow-up of 11.5 months (range: 0.2-12.7). In a separate exploratory cohort, a CR/CRc was achieved by 2 (13%) patients with R/R BPDCN. Safety was assessed in 94 patients with myeloid neoplasms treated with tagraxofusp-erzs at the approved dose and schedule. The major toxicity was capillary leak syndrome (CLS), which occurred in 55% of patients and was fatal in 2%. Hepatotoxicity and hypersensitivity reactions were reported in 88% and 46% of patients, respectively. Other common (≥30%) adverse reactions were nausea, fatigue, peripheral edema, pyrexia, and weight increase. A high proportion of patients (85%) developed neutralizing antidrug antibodies. Tagraxofusp-erzs is the first FDA-approved treatment for BPDCN., (©2019 American Association for Cancer Research.)

On November 21, 2018, the FDA approved glasdegib (Daurismo; Pfizer), a small-molecule Hedgehog inhibitor, in combination with low-dose cytarabine (LDAC) for treatment of newly diagnosed acute myeloid leukemia (AML) in adults ≥ 75 years or with comorbidities that preclude use of intensive induction chemotherapy. Evidence of clinical benefit came from Study BRIGHT AML 1003, a randomized trial comparing glasdegib+LDAC with LDAC alone for treatment of newly diagnosed AML in 115 patients either ≥ 75 years old or ≥ 55 years old with preexisting comorbidities. Efficacy was established by improved overall survival (OS) with the combination compared with LDAC alone (HR, 0.46; 95% confidence interval, 0.30-0.71; one-sided stratified log-rank P = 0.0002). Median OS was 8.3 months with the combination and 4.3 months with LDAC alone. Common adverse reactions included cytopenias, fatigue, hemorrhage, febrile neutropenia, musculoskeletal pain, nausea, edema, dyspnea, decreased appetite, dysgeusia, mucositis, constipation, and rash. The label includes a boxed warning for embryo-fetal toxicity and a warning for QT interval prolongation. There is a limitation of use for patients with moderate-to-severe hepatic and severe renal impairment; trials studying glasdegib in these patient populations are required as a condition of this approval. See related commentary by Fathi, p. 6015 ., (©2019 American Association for Cancer Research.)

The FDA approved ivosidenib (Tibsovo; Agios), a small-molecule inhibitor of isocitrate dehydrogenase (IDH)1 on July 20, 2018, for treatment of adults with relapsed or refractory acute myeloid leukemia (R/R AML) with susceptible IDH1 mutation as detected by an FDA-approved test. The efficacy of ivosidenib was established on the basis of complete remission (CR) + CR with partial hematologic recovery (CRh) rate, duration of CR + CRh, and conversion from transfusion dependence (TD) to transfusion independence (TI) in Study AG120-C-001, a single-arm trial. With median follow-up of 8.3 months for 174 adults with IDH1-mutated R/R AML treated with 500 mg ivosidenib daily, the CR + CRh rate was 33% [95% confidence interval (CI), 26-40], median duration of response was 8.2 (95% CI, 5.6-12) months, and conversion from TD to TI occurred in 37% of patients. These endpoints reflect short-term benefit in patients with an unmet medical need; long-term efficacy outcomes were not assessed. Serious adverse reactions (AR) in ≥5% of patients were differentiation syndrome (10%), leukocytosis (10%), and QT interval prolongation (7%). Common (≥20%) ARs of any grade were fatigue, leukocytosis, arthralgia, diarrhea, dyspnea, edema, nausea, mucositis, QT interval prolongation, rash, pyrexia, cough, and constipation. Assessment of long-term safety of ivosidenib is a condition of this approval., (©2019 American Association for Cancer Research.)

On August 3, 2017, the FDA granted regular approval to Vyxeos (also known as CPX-351; Jazz Pharmaceuticals), a liposomal formulation of daunorubicin and cytarabine in a fixed combination, for the treatment of adults with newly diagnosed therapy-related acute myeloid leukemia (t-AML) or acute myeloid leukemia (AML) with myelodysplasia-related changes (AML-MRC). Approval was based on data from Study CLTR0310-301, a randomized, multicenter, open-label, active-controlled trial comparing Vyxeos with a standard combination of daunorubicin and cytarabine ("7+3") in 309 patients 60-75 years of age with newly diagnosed t-AML or AML-MRC. Because of elemental copper concerns with the Vyxeos formulation, patients with Wilson disease were excluded from the study. Vyxeos demonstrated an improvement in overall survival (HR 0.69; 95% confidence interval, 0.52-0.90; P = 0.005) with an estimated median overall survival of 9.6 months compared with 5.9 months for the "7+3" control arm. The toxicity profile of Vyxeos was similar to that seen with standard "7+3" with the exception of more prolonged neutropenia and thrombocytopenia on the Vyxeos arm. Because the pharmacology of Vyxeos differs from that of other formulations of daunorubicin and cytarabine, labeling includes a warning against interchanging formulations during treatment. This is the first FDA-approved treatment specifically for patients with t-AML or AML-MRC., (©2018 American Association for Cancer Research.)

On November 6, 2017, the U.S. Food and Drug Administration (FDA) granted regular approval to vemurafenib for the treatment of adult patients with Erdheim-Chester disease (ECD) with BRAF V600 mutation. ECD is a type of histiocytosis, a rare disorder characterized by an abnormal accumulation and behavior of cells of the mononuclear phagocytic system, which includes antigen-processing cells, dendritic cells, monocytes, or macrophages. Recently published data confirm a frequency of 54% of BRAF V600E mutations in patients with ECD.Approval was based on a cohort of 22 patients who received 960 mg of vemurafenib twice daily within the VE Basket Trial (MO28072), a single-arm, multicenter, multiple cohort study. Patients in the ECD cohort had histologically confirmed ECD with BRAF V600 mutations that were refractory to standard therapy. The ECD cohort achieved an overall response rate of 54.5% (95% confidence interval: 32.2-75.6), with a complete response rate of 4.5%. With a median duration of follow-up of 26.6 months, the median duration of response has not been reached. The most frequently reported adverse reactions (>50%) in the ECD cohort were arthralgia, rash maculo-papular, alopecia, fatigue, electrocardiogram QT interval prolonged, and skin papilloma. The median treatment duration for ECD patients in this study was 14.2 months. This article describes the FDA review of the vemurafenib efficacy supplement for patients with ECD with BRAF V600 mutations. IMPLICATIONS FOR PRACTICE: Vemurafenib, an oral monotherapy targeting a mutation in BRAF, is the first U.S. Food and Drug Administration approval for the treatment of Erdheim-Chester disease (ECD). ECD is an extremely rare hematopoietic neoplasm that represents clonal proliferation of myeloid progenitor cells. ECD may involve bone and one or more organ systems, primarily affecting adults in their 5th and 7th decades of life, with a slight male predominance. This approval provides an effective and reasonably safe therapy for patients with a serious and life-threatening condition for which no approved therapy exists., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (Published 2018. This article is a U.S. Government work and is in the public domain in the USA.)

On May 17, 2016, after an expedited priority review, the U.S. Food and Drug Administration granted accelerated approval to nivolumab for the treatment of patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and post-transplantation brentuximab vedotin (BV). Nivolumab in cHL had been granted breakthrough therapy designation. Accelerated approval was based on two single-arm, multicenter trials in adults with cHL. In 95 patients with relapsed or progressive cHL after autologous HSCT and post-transplantation BV, nivolumab, dosed at 3 mg/kg intravenously every 2 weeks, produced a 65% (95% confidence interval: 55%-75%) objective response rate (58% partial remission, 7% complete remission). The estimated median duration of response was 8.7 months, with 4.6-month median follow-up for response duration. The median time to response was 2.1 (range: 0.7-5.7) months. Among 263 patients with cHL treated with nivolumab, 21% reported serious adverse reactions (ARs). The most common all-grade ARs (reported in ≥20%) were fatigue, upper respiratory tract infection, cough, pyrexia, diarrhea, elevated transaminases, and cytopenias. Infusion-related reaction and hypothyroidism or thyroiditis occurred in >10% of patients; other immune-mediated ARs, occurring in 1%-5%, included rash, pneumonitis, hepatitis, hyperthyroidism, and colitis. A new Warning and Precaution was issued for complications of allogeneic HSCT after nivolumab, including severe or hyperacute graft-versus-host disease, other immune-mediated ARs, and transplant-related mortality. Continued approval for the cHL indication may be contingent upon verification of clinical benefit in a randomized trial. The Oncologist 2017;22:585-591 IMPLICATIONS FOR PRACTICE: Based on response rate and duration in single-arm studies, nivolumab is a new treatment option for patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed despite autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin. This was the first U.S. Food and Drug Administration marketing application for a programmed cell death 1 inhibitor in hematologic malignancies. The use of immune checkpoint blockade in cHL represents a new treatment paradigm. The safety of allogeneic HSCT after nivolumab requires further evaluation, as does the safety of nivolumab after allogeneic HSCT., (© AlphaMed Press 2017.)

Purpose: To describe the clinical studies that led to the FDA approval of rituximab in combination with fludarabine and cyclophosphamide (FC) for the treatment of patients with chronic lymphocytic leukemia (CLL)., Materials and Methods: The results of two multinational, randomized trials in CLL patients comparing rituximab combined with fludarabine and cyclophosphamide versus FC were reviewed. The primary endpoint of both studies was progression-free survival (PFS)., Results: The addition of rituximab to FC decreased the risk of a PFS event by 44% in 817 previously untreated patients and by 24% in 552 previously treated patients. Median survival times could not be estimated. Exploratory analysis in patients older than 70 suggested that there was no benefit to patients when rituximab was added to FC. The safety profile observed in both trials was consistent with the known toxicity profile of rituximab, FC, or CLL., Conclusions: On the basis of the demonstration of clinically meaningful prolongation of PFS, the FDA granted regular approval to rituximab in combination with FC for the treatment of patients with CLL. The magnitude of the treatment effect in patients 70 years and older is uncertain.