Emerging monoclonal antibody therapies in the treatment of metastatic urothelial carcinoma.

INTRODUCTION: The treatment landscape for advanced-stage, unresectable or metastatic urothelial carcinoma (mUC) has shifted dramatically over a short period of time, with new therapeutic agents available for clinical use. However, despite these recent advances in the field, mUC continues to be a disease with significant morbidity and mortality and remains generally incurable. While platinum-based therapy remains the backbone of therapy, many patients are ineligible for chemotherapy or have failed initial chemotherapy treatment. In post-platinum treated patients, immunotherapy and antibody drug conjugates have provided incremental advances, but agents with better therapeutic index guided by precision medicine are needed. AREAS COVERED: This article covers the available monoclonal antibody therapies in mUC excluding immunotherapy and antibody drug conjugates. Included are a review of data utilizing monoclonal antibodies targeting VEG-F, HER-2, FGFR, and KIR-2 in the setting of mUC. A literature search from 6/2022- 9/2022 was performed utilizing PubMed with key terms including urothelial carcinoma, monoclonal antibody, VEG-F, HER-2, FGFR. EXPERT OPINION: Often used in combination with immunotherapy or other therapeutic agents, monoclonal antibody therapies have exhibited efficacy in mUC in early trials. Upcoming clinical trials will further explore their full clinical utility in treating mUC patients.

Non-myeloablative human leukocyte antigen-matched related donor transplantation in sickle cell disease: outcomes from three independent centres.

Non-myeloablative haematopoietic progenitor cell transplantation (HPCT) from matched related donors (MRD) has been increasingly utilized in sickle cell disease (SCD). A total of 122 patients received 300 cGy of total body irradiation (TBI), alemtuzumab, unmanipulated filgrastim-mobilized peripheral blood HPC and sirolimus. The median follow-up was four years; median age at HPCT was 29 years. Median neutrophil and platelet engraftment occurred on day 22 and 19 respectively; 41 patients required no platelet transfusions. Overall and sickle-free survival at one and five years were 93% and 85% respectively. Age, sex, pre-HPCT sickle complications, ferritin and infused HPC numbers were similar between graft failure and engrafted patients. Mean donor myeloid chimaerism at one and five years post HPCT were 84% and 88%, and CD3 was 48% and 53% respectively. Two patients developed grade 1 and 2 skin graft-versus-host disease (GVHD) with no chronic GVHD. Median days of recipients taking immunosuppression were 489; 83% of engrafted patients have discontinued immunosuppression. Haemoglobin, haemolytic parameters and hepatic iron levels improved post HPCT. Pulmonary function testing, hepatic histology and neurovascular imaging remained stable, suggesting cessation of further sickle-related injury. Fourteen patients had children. In this largest group of adult SCD patients, this regimen was highly efficacious, well-tolerated despite compromised organ functions pre HPCT, and without clinically significant GVHD.

Sputum induction to aid diagnosis of smear-negative or sputum-scarce tuberculosis in adults in HIV-endemic settings.

Sputum induction can aid tuberculosis (TB) diagnosis, but adult data from HIV-endemic environments are limited, and it is unclear how performance varies depending on the clinical context (in-patient versus outpatient), HIV status and whether patients are smear-negative or sputum-scarce. 696 adults with suspected smear-negative or sputum-scarce TB from Cape Town (South Africa) were referred for routine sputum induction. Liquid culture for Mycobacterium tuberculosis served as the reference standard. 82% (573 out of 696) of patients provided a specimen ≥1 mL, 83% (231 out of 278) of which were of adequate quality. 15% (96 out of 652) of sputum induction specimens were culture-positive, and this yield was higher among inpatients versus outpatients (17% (71 out of 408) versus 10% (25 out of 244), p=0.01) and HIV-infected versus uninfected patients (17% (51 out of 294) versus 9% (16 out of 173), p=0.02), but similar for CD4 (>200 versus ≤200 cells·µL(-1)) and patient (smear-negative versus sputum-scarce) subcategories. Overall sensitivity (95% CI) of smear-microscopy was 49% (39-59%), higher among in-patients versus outpatients (55% (43-67%) versus 32% (14-50%), p=0.05), but unaffected by HIV co-infection, CD4 count or patient type. 29% (203 out of 696) of patients commenced anti-TB treatment and sputum induction offered microbiological confirmation and susceptibility testing in only 47% (96 out of 203). Under programmatic conditions in an HIV-endemic environment although the yield of culture was approximately two-fold higher amongst HIV-infected patients and inpatients, a fifth of all patients were unable to provide a specimen following sputum induction. Same-day microbiological diagnosis was only possible in ~50% of patients.

Severe Thrombocytopenia in a Patient With a History of Olfactory Neuroblastoma.

Olfactory neuroblastoma is a rare disease with no randomized clinical trials to guide treatment decision making. Surgery, radiation, and chemotherapy are all used for treatment, and prognosis is mostly determined by the histologic grade and clinical stage. While a neuroendocrine type of neoplasm is similar to small cell carcinoma, metastatic disease in olfactory neuroblastoma is rare. We present a case at our institution of an uncommon clinical course of relapsed olfactory neuroblastoma complicated by severe thrombocytopenia.

Antibody-Drug Conjugates in the Treatment of Urothelial Cancer.

Antibody-drug conjugates (ADCs) have transformed the treatment landscape in oncology and become an essential therapeutic modality. In urothelial carcinoma (UC), the two ADCs that have been especially successful in clinical practice are enfortumab vedotin and sacituzumab govitecan. These drugs are currently approved as monotherapy for later lines of treatment in locally advanced or metastatic UC and have had a significant impact for patients with limited treatment options. Combinational trials, as well as additional ADCs, are currently being investigated in the treatment of UC for subsequent lines of therapy as overall survival rates remain dismal.

Safety Monitoring Activity During EGFR or Anaplastic Lymphoma Kinase Inhibitor Therapy for Patients With Lung Cancer.

Epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are highly effective for treatment of EGFR- or ALK-mutated lung cancer. Nevertheless, they are associated with several unique toxicities. Although the available US Food and Drug Administration (FDA)-approved drug label can provide guidance for safety monitoring, its integration into clinical practice has not been previously described. We studied the conduct of safety monitoring activity (SMA) at a large academic institution. On the basis of FDA-approved drug labels, two drug-specific SMAs were identified for osimertinib, crizotinib, alectinib, or lorlatinib. Electronic medical records of patients initiated on these drugs from 2017 to 2021 were retrospectively reviewed. Each course of treatment was evaluated for the occurrence of SMAs and the corresponding adverse events. Analyses included 130 treatment courses from 111 unique patients. For each SMA evaluated, the prevalence of SMA conduct ranged from 10.0% to 84.6%. The most frequently conducted SMA was ECG for lorlatinib therapy and the least was creatine phosphokinase analysis for alectinib. We observed none of the assessed SMAs being conducted in 41 treatment courses (31.5%). EGFR inhibitor predicted a higher likelihood of both SMAs being conducted than ALK inhibitors (P = .02). Serious, grade 3 or 4 adverse events were observed in 21 treatment courses (16.2%), including one grade 4 transaminitis related to alectinib. On the basis of our experience, the conduct of SMA was more challenging to implement for ALK inhibitor than for EGFR inhibitor. Clinicians should be vigilant and review the FDA-approved drug label before prescribing.