Clinical Practices and Institutional Protocols on Prophylaxis, Monitoring, and Management of Selected Adverse Events Associated with Trastuzumab Deruxtecan.

The treatment of metastatic breast cancer (mBC) has evolved significantly in the past several years with the approval of new targeted agents. Trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate with a topoisomerase I inhibitor payload, is a new addition to the class of therapies that target the human epidermal growth factor 2 (HER2) receptor. T-DXd was approved in the US in December 2019 for patients with HER2-positive metastatic or unresectable breast cancer who have received 2 or more prior anti-HER2-based regimens in the metastatic setting. In the DESTINY-Breast01 phase II trial (NCT03248492), T-DXd demonstrated high rates of durable responses in heavily pretreated patients with HER2-positive mBC, with a confirmed objective response rate of 62%, median duration of response of 18.2 months, and median progression-free survival of 19.4 months. In addition to efficacy, successful implementation of any new anticancer therapy includes learning how to prevent, monitor, and manage treatment-related adverse events. As T-DXd becomes more widely used, information can be gained from real-world clinical practices, institutional approaches, and the collaboration of multidisciplinary oncology teams who treat patients with T-DXd. This article reviews practical insights and management of nausea and vomiting, neutropenia, interstitial lung disease, risk of cardiotoxicity, and other adverse events associated with T-DXd administration from the perspective of health care providers who have experience utilizing T-DXd.

Management of Chemotherapy-Induced Nausea and Vomiting with Trastuzumab Deruxtecan: A Case Series.

INTRODUCTION: Trastuzumab deruxtecan is a monoclonal antibody linked to a chemotherapy moiety that was recently approved by the Food and Drug Administration (FDA) for the treatment of metastatic human epidermal growth factor receptor 2 (HER2) positive breast cancers. There are labeled black box warnings for interstitial lung disease (ILD)/pneumonitis and embryo-fetal toxicity. Additionally, chemotherapy-induced nausea and vomiting (CINV) was reported to be as high as 78% (∼8% grade 3 or higher) in phase I and II clinical trials. Clinical trial and package insert recommendations for the management of CINV are not available, making real-world management difficult. CASE PRESENTATION: We reviewed the first 10 patients who received trastuzumab deruxtecan at our hospital-based community cancer center to determine if CINV management was adequate. We found a rate of 28.9% CINV (all grade 1 and 2) despite treatment as a moderate emetic potential regimen. Interventions by the treatment team to manage trastuzumab deruxtecan as a high-risk emetic regimen resulted in reduced CINV and ongoing treatment for all patients. DISCUSSION AND CONCLUSION: This review indicates that management of CINV for patients receiving trastuzumab deruxtecan should follow recommendations for regimens with a high-risk emetic potential.

PCI-24781 induces caspase and reactive oxygen species-dependent apoptosis through NF-kappaB mechanisms and is synergistic with bortezomib in lymphoma cells.

PURPOSE: We investigated the cytotoxicity and mechanisms of cell death of the broad-spectrum histone deacetylase (HDAC) inhibitor PCI-24781, alone and combined with bortezomib in Hodgkin lymphoma and non-Hodgkin lymphoma cell lines and primary lymphoproliferative (CLL/SLL) cells. EXPERIMENTAL DESIGN: Apoptosis, mitochondrial membrane potential, cell cycle analysis, and reactive oxygen species (ROS) were measured by flow cytometry, whereas caspase activation was determined by Western blot. Nuclear factor kappaB (NF-kappaB)-related mRNAs were quantified by reverse transcription-PCR, NF-kappaB-related proteins by Western blotting, and NF-kappaB DNA-binding activity by electromobility shift assay. Finally, gene expression profiling was analyzed. RESULTS: PCI-24781 induced concentration-dependent apoptosis that was associated with prominent G(0)/G(1) arrest, decreased S-phase, increased p21 protein, and increased ROS in Hodgkin lymphoma and non-Hodgkin lymphoma cell lines. Dose-dependent apoptosis with PCI-24781 was also seen among primary CLL/SLL cells. PCI-24781-induced apoptosis was shown to be ROS- and caspase-dependent. Combined PCI-24781/bortezomib treatment resulted in strong synergistic apoptosis in all non-Hodgkin lymphoma lines (combination indices, 0.19-0.6) and was additive in Hodgkin lymphoma and primary CLL/SLL cells. Further, PCI-24781/bortezomib resulted in increased caspase cleavage, mitochondrial depolarization, and histone acetylation compared with either agent alone. Gene expression profiling showed that PCI-24781 alone significantly down-regulated several antioxidant genes, proteasome components, and NF-kappaB pathway genes, effects that were enhanced further with bortezomib. Reverse transcription-PCR confirmed down-regulation of NF-kappaB1 (p105), c-Myc, and IkappaB-kinase subunits, where NF-kappaB DNA binding activity was decreased. CONCLUSION: We show that PCI-24781 results in increased ROS and NF-kappaB inhibition, leading to caspase-dependent apoptosis. We also show that bortezomib is synergistic with PCI-24781. This combination or PCI-24781 alone has potential therapeutic value in lymphoma.

A Feasibility Study of Group-Delivered Behavioral Interventions for Insomnia Among Breast Cancer Survivors: Comparing Cognitive Behavioral Therapy for Insomnia and a Mind-Body Intervention.

Objectives: An estimated 30%-50% of breast cancer survivors (BCSs) report persistent insomnia, which may affect daytime functioning and quality of life, and lead to longer term health complications. Although the gold standard insomnia intervention, cognitive behavioral therapy for insomnia (CBT-I), has demonstrated efficacy, accessibility is limited due to a scarcity of trained providers, and adherence to therapy is variable. Group-delivered alternative therapies may offer an opportunity to reach and treat BCSs with insomnia. This pilot study was designed to assess feasibility of a group-delivered mind-body intervention compared with group-delivered CBT-I among BCSs. Design: The authors recruited n = 25 stages I - IV BCSs to a 9-week trial of group therapy for insomnia. Eligible women were assigned to the next upcoming group until it was full. Primary outcomes were to assess intervention feasibility measured by (1) qualitative focus group feedback and (2) attendance. The feasibility of using the Insomnia Severity Index (ISI) was also assessed in this population and ISI change scores were gathered to allow for power calculations in a future trial. Means and frequencies were used to describe participant demographics and attendance. Results: The authors found higher attendance (86% vs. 67% of sessions) and greater satisfaction with the intervention (84.6% vs. 57.1%) reported among mind-body participants than among CBT-I participants. Qualitative feedback suggested more group cohesion among the mind-body group and lower incentive to attend in-person among the CBT-I group. Conclusions: The results suggest that delivering a mind-body intervention for BCSs is feasible and acceptable, based on attendance and qualitative feedback.

Complications after uterine artery embolization for leiomyomas.

OBJECTIVE: To determine the frequency and severity of complications that occur as a result of uterine artery embolization for leiomyomas. METHODS: As part of an ongoing study of outcome after uterine embolization, prospective data regarding complications that occurred in 400 consecutive patients were gathered. Each patient had a minimum of a 3-month interval from the procedure at the time of analysis. Each complication was categorized and graded as to severity and outcome using the complication classification developed by the Society of Cardiovascular and Interventional Radiology (SCVIR) and a modified set of The American College of Obstetricians and Gynecologists (ACOG) criteria for complications of hysterectomy and myomectomy. All adverse events that occurred during the follow-up period were included, including those that occurred after the 3-month minimum interval. Confidence intervals (CIs) were calculated for each complication. RESULTS: There were no deaths and no major permanent injuries. One patient required hysterectomy as a result of a complication, and one patient had an undiagnosed leiomyosarcoma. There were ten in-hospital complications and an additional 27 complications within the first 30 days, with 34 patients experiencing a periprocedural complication for a rate of 8.5% (95% CI 6.0%, 11.7%). There were five serious complications (SCVIR class D), comprising 1.25% (95% CI 0.3%, 2.5%) of the study group. Using ACOG definitions for perioperative complications, the overall morbidity was 5% (95% CI 3.1%, 7.7%). CONCLUSION: The short-term complication rate was low in women undergoing uterine embolization.

Multicenter analysis of 80 solid organ transplantation recipients with post-transplantation lymphoproliferative disease: outcomes and prognostic factors in the modern era.

PURPOSE Adult post-transplantation lymphoproliferative disease (PTLD) has a reported 3-year overall survival (OS) of 35% to 40%. The impact of rituximab on the outcome of PTLD is not well defined. METHODS We examined the clinical features and outcomes among a large cohort of solid organ transplantation (SOT) -related patients with PTLD who were recently treated at four Chicago institutions (from January 1998 to January 2008). Results Eighty patients with PTLD were identified who had a median SOT-to-PTLD time of 48 months (range, 1 to 216 months). All patients had reduction of immunosuppression as part of initial therapy, whereas 59 (74%) of 80 patients received concurrent first-line rituximab with or without chemotherapy. During 40-month median follow-up, 3-year progression-free survival (PFS) for all patients was 57%, and the 3-year overall survival (OS) rate was 62%. Patients who received rituximab-based therapy as part of initial treatment had 3-year PFS of 70% and OS 73% compared with 21% (P < .0001) and 33% (P = .0001), respectively, without rituximab. Notably, of all relapses, only 9% (4 of 34 patients) occurred beyond 12 months from PTLD diagnosis. On multivariate regression analysis, three factors were associated with progression and survival: CNS involvement (PFS, 4.70; P = .01; OS, 3.61; P = .04), bone marrow involvement (PFS, 2.95; P = .03; OS, 3.14; P = .03), and hypoalbuminemia (PFS, 2.96; P = .05; OS, 3.64; P = .04). Furthermore, a survival model by multivariate CART analysis that was based on number of adverse factors present (ie, 0, 1, > or = 2) was formed: 3-year PFS rates were 84%, 66%, 7%, respectively, and 3-year OS rates were 93%, 68%, 11%, respectively (P < .0001). CONCLUSION This large, multicenter, retrospective analysis suggests significantly improved PFS and OS associated with early rituximab-based treatment in PTLD. In addition, clinical factors at diagnosis identified patients with markedly divergent outcomes.

Relapsed and refractory Hodgkin lymphoma: transplantation strategies and novel therapeutic options.

Many patients with Hodgkin lymphoma are cured with initial therapy, although a portion of patients will experience primary induction failure or disease relapse. Pathologic confirmation of refractory or relapsed Hodgkin lymphoma is important. Following two to four cycles of non-cross-resistant salvage chemotherapy, the standard of care is high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (HSCT), which is associated with long-term event-free survival rates of 45-68%. Of note, survival rates for studies integrating total lymphoid irradiation into the autologous HSCT-conditioning regimen are among the highest reported for relapsed/refractory Hodgkin lymphoma. Further treatment options are available for patients not fit to proceed to HSCT, for relapsed disease after autologous HSCT, and for 'high-risk' Hodgkin lymphoma including chemotherapy-resistant disease. Allogeneic HSCT is a valid treatment option, as a graft-vs.-Hodgkin-lymphoma effect has been demonstrated. In addition, novel targeted treatments are being investigated such as receptor-specific antibodies, radiolabeled antibodies, antiapoptotic agents including inhibitors of the nuclear factor-kappaB complex or X-linked inhibitor of apoptosis proteins, transcription pathway modulators such as histone deacetylase and mTOR inhibitors, and Epstein-Barr virus-directed therapy. Continued translational and collaborative prospective clinical research efforts are needed in order to continue to increase the survival rates for Hodgkin lymphoma and to lessen the toxicities associated with lymphoma-related therapy.