Late-onset cardiotoxicity in patients with HER2-positive metastatic breast cancer receiving trastuzumab-based therapy.

INTRODUCTION: Patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) typically receive long-term trastuzumab treatment for several years. The aim of our study is to identify the incidence and characterize late-onset cardiotoxicity in patients with HER2-positive MBC receiving trastuzumab-based therapy. METHODS: We retrospectively reviewed charts of HER2-positive MBC patients who received >1 year of trastuzumab-based therapy at the Massachusetts General Hospital Cancer Center over three-year period. The primary endpoint was development of trastuzumab-induced cardiotoxicity (TIC). Secondary endpoints included time to TIC development, incidence/duration of trastuzumab interruption due to TIC, incidence of permanent discontinuation of trastuzumab due to TIC, clinic visit, or hospitalization due to TIC. RESULTS: Thirty-seven patients were included. Mean age was 56 years (range: 33-78 years, SD 9.5). Seven patients received prior doxorubicin and 14 patients received previous or concurrent breast irradiation. Mean duration of trastuzumab-based therapy was 57 months (range: 14-140 months, SD 39.3). Seven patients (18.9%) experienced TIC resulting in treatment interruption for two patients (28 and 78 days). The median time from starting trastuzumab therapy to TIC was 14 months (interquartile range: 11-29.5 months). The mean number of left ventricular ejection fraction (LVEF) assessment completed per year was 2.7 (range: 1.2-6.6, SD 1.1). CONCLUSION: Cardiotoxicity occurred in a minority of patients with HER2-positive MBC receiving trastuzumab-based therapy for more than one year. LVEF reductions to below the institutional lower limit of normal and therapy modifications were uncommon.

Letermovir and tacrolimus interaction effects in hematopoietic cell transplantation recipients receiving moderate cytochrome P450 3A4 inhibitors for antifungal prophylaxis.

INTRODUCTION: Letermovir inhibits cytomegalovirus replication and is approved for the prevention of cytomegalovirus infection in cytomegalovirus seropositive hematopoietic cell transplantation recipients. Studies have found that letermovir coadministration has minimal effect on tacrolimus levels prior to the start of voriconazole, a strong cytochrome P450 (CYP) 3A4 inhibitor. However, data are lacking for hematopoietic cell transplantation recipients receiving letermovir and tacrolimus with moderate CYP 3A4 inhibitors as antifungal prophylaxis. METHODS: In this retrospective single-center analysis, we reviewed the charts of 92 consecutive adult allogeneic hematopoietic cell transplantation recipients receiving letermovir, tacrolimus, and moderate CYP3A4 inhibitors for antifungal prophylaxis. RESULTS: Tacrolimus concentration/dose (C/D) ratios were evaluated for the first 7 days pre-letermovir and for the first and second 7-day periods after letermovir. The tacrolimus mean C/D ratios [(ng/mL)/(mg/kg/day)] increased significantly with the addition of letermovir: 172.99 (95% confidence interval (CI): 158.2-187.78) pre-letermovir, 268.66 (95% CI: 244.34-292.98) first-week letermovir, and 312.19 (95% CI: 279.39-344.99) second-week letermovir (P < 0.001). The average dosages (mg/kg) of tacrolimus also decreased significantly across the three-time intervals (P < 0.001). Only four patients experienced clinically significant cytomegalovirus reactivation which required systemic treatment. CONCLUSION: These results demonstrate a reduction in tacrolimus dosing requirements for patients receiving tacrolimus and letermovir with concomitant moderate CYP3A4 inhibitors. The results of this interaction suggest that frequent monitoring of tacrolimus trough levels is warranted when starting letermovir and that empiric reduction of tacrolimus dosing upon letermovir initiation should be considered.

Immediate reaction to ibrutinib amenable to oral desensitization.

INTRODUCTION: Although up to half of patients receiving chemotherapeutic agents develop hypersensitivity reactions to the same, desensitization protocols can induce temporary tolerance to allow patients to continue to receive first-line treatment. Approximately 25% of patients develop cutaneous hypersensitivity reactions to ibrutinib, but there are no published management guidelines. CASE REPORT: We describe the case of a 71-year-old woman with chronic lymphocytic leukemia who developed a delayed maculopapular rash with lip tingling and swelling following ibrutinib therapy. MANAGEMENT AND OUTCOME: We performed a novel 11-step desensitization procedure to ibrutinib allowing us to successfully induce tolerance against IgE-mediated symptoms in this patient. DISCUSSION: As indications for ibrutinib use expand and more patients present with IgE-mediated symptoms, we expect that this protocol will provide benefit for many such patients.

Outcomes with enoxaparin dose reductions during thrombocytopenia in patients with hematopoietic stem cell transplantation (HSCT).

INTRODUCTION: Appropriate dosing of therapeutic anticoagulation during periods of thrombocytopenia remains uncertain for patients undergoing hematopoietic stem cell transplants (HSCT). There is a paucity of literature on treatment outcomes for HSCT patients treated with non-prophylactic, but reduced doses of therapeutic anticoagulation during thrombocytopenia. The primary objective was to determine the incidence of major bleeding events during thrombocytopenia when reduced-dose enoxaparin was administered. METHODS: This is a retrospective review of patients with a venous thromboembolic event (VTE) who underwent HSCT and received reduced-dose enoxaparin during thrombocytopenia at the Massachusetts General Hospital (MGH) from April 1, 2016 to August 31, 2018. Incidence of recurrent VTE and bleeding events for up to one month were investigated. Rates of recurrent VTE and enoxaparin dose adjustments (0.5 mg/kg twice daily vs 1 mg/kg daily) were also reviewed. RESULTS: Out of 172 patients reviewed, 27 patients met inclusion criteria. There were no recurrent VTEs within one month of initial enoxaparin dose reduction. There was one major bleeding episode that occurred while a patient was on full-dose enoxaparin; believed to be related to cyclophosphamide cardiopulmonary toxicity and resulted in death. There were six non-major bleeding episodes, only one of which was clinically significant and resulted in the discontinuation of enoxaparin. CONCLUSION: Our evaluation of therapeutic enoxaparin dose reductions for thrombocytopenia in the HSCT patient population found this practice to be effective in reducing the recurrence of VTE with no major bleeding adverse events. However, the rate of non-significant minor bleeds should be monitored while on reduced-dose enoxaparin.

Effect of Levetiracetam on Time to High-Dose Methotrexate Clearance in Patients With Hematologic Malignancies.

High-dose methotrexate (HDMTX) is a commonly used treatment for hematologic malignancies involving the central nervous system. Two case reports described possible delayed methotrexate clearance in patients receiving concurrent levetiracetam, while a retrospective cohort study did not find this association. The objective of this single-center, retrospective case-control study of 121 patients who received their first cycle of HDMTX was to investigate the association between HDMTX clearance time and concomitant levetiracetam use. The most common diagnosis was primary central nervous system lymphoma (47.9%). The mean HDMTX dose was 4601 mg/m2 (standard deviation [SD], 2052.6 mg/m2 ). Concurrent levetiracetam was administered in 30 of 121 patients (24.8%), with a mean total daily levetiracetam dose of 1434.4 mg (SD, 622.9 mg; range, 900-3000 mg). Baseline characteristics were similar between patients who received concomitant levetiracetam and those who did not. The mean time to methotrexate clearance was 82.5 hours (SD, 51.2; 95% confidence interval, 69.4-95.7) in the concomitant levetiracetam group and 72.4 hours (SD, 31.2; 95% confidence interval, 61.7-83.0) in the nonlevetiracetam group, which was not significantly different (P > .05), even in the subgroup receiving methotrexate doses >3500 mg/m2 . Grade 3 or higher toxicity occurred in 33.3% of the concomitant levetiracetam group and in 34.1% of nonconcomitant levetiracetam patients. This study, which, to our knowledge, is the first examining levetiracetam effect on only the first dose of HDMTX, supports the larger retrospective study finding no significant effect of levetiracetam on HDMTX clearance time, and suggests that administering concomitant levetiracetam does not affect HDMTX toxicity.

Ephrin-B reverse signaling is required for formation of strictly contralateral auditory brainstem pathways.

Specificity in the projections from the mammalian ventral cochlear nucleus (VCN) is essential for sound localization. Globular bushy cells project from the VCN to the medial nucleus of the trapezoid body (MNTB) on the contralateral, but not the ipsilateral, side of the brainstem, terminating in large synaptic endings known as calyces of Held. The precision in this pathway is critical for the computation of interaural intensity differences, which are used in sound localization. The mechanisms underlying the development of this projection are not completely understood. In this study, we tested the role of Eph receptor tyrosine kinases and their ephrin ligands in limiting the VCN-MNTB projection to the contralateral side. We found that mice with null mutations in EphB2 and EphB3 had normal contralateral VCN-MNTB projections, yet these projections also had significant numbers of aberrant collateral branches in the ipsilateral MNTB. These aberrant branches ended in calyceal terminations in MNTB. Similar ipsilateral projections were seen in mice with mutations in ephrin-B2. In both of these mouse lines, ipsilateral projections formed concurrently with normal contralateral projections and were not eliminated later in development. However, mice with mutations that affected only the intracellular domain of EphB2 had normal, strictly contralateral VCN-MNTB projections. Expression studies showed that EphB2 is expressed in VCN axons and ephrin-B2 is expressed in MNTB. Together, these data suggest that EphB2-ephrin-B2 reverse signaling is required to prevent the formation of ipsilateral VCN-MNTB projections and that this signaling operates non-cell autonomously.