Brentuximab vedotin plus bendamustine in relapsed or refractory Hodgkin's lymphoma: an international, multicentre, single-arm, phase 1-2 trial.

BACKGROUND: Brentuximab vedotin is currently approved for patients with relapsed or refractory Hodgkin's lymphoma who previously received an autologous stem cell transplant or two previous multiagent chemotherapy regimens, and for patients with relapsed or refractory systemic anaplastic large-T-cell lymphoma who previously received at least one chemotherapy regimen. A high proportion of patients with CD30-expressing relapsed or refractory lymphomas have durable responses to single-agent brentuximab vedotin and show longer progression-free survival than do patients treated with chemotherapy. In patients with Hodgkin's lymphoma and peripheral T-cell lymphoma, treatment with bendamustine alone only achieves modest improvements in progression-free survival compared with that for chemotherapy. The objective of this study was to explore the safety and clinical activity of the combination of brentuximab vedotin plus bendamustine in heavily pretreated patients with relapsed or refractory Hodgkin's lymphoma and anaplastic large-T-cell lymphoma. METHODS: In this international, multicentre, single-arm, phase 1-2 trial, eligible patients were aged 18 years or older, had histologically confirmed relapsed or refractory Hodgkin's lymphoma or anaplastic large-T-cell lymphoma, had biopsy-proven CD30-positive tumours, had an Eastern Cooperative Oncology Group performance status of 2 or less, and received at least one previous multiagent chemotherapy regimen. In phase 1, patients were assigned following a 3+3 dose-escalation design to one of four cohorts to receive one dose of either 1·2 mg/kg or 1·8 mg/kg of brentuximab vedotin intravenously on day 1 of a 21 day cycle, plus one dose of bendamustine (70 mg/m2, 80 mg/m2, or 90 mg/m2) on days 1 and 2 of the treatment cycle. In phase 2, all patients were assigned to receive brentuximab vedotin plus bendamustine at the recommended phase 2 dose from phase 1. The primary endpoints were maximum tolerated dose and dose-limiting toxicity for phase 1, and the proportion of patients achieving an overall response in phase 2. For both phases 1 and 2, all patients receiving at least one dose of study drug were evaluable for toxicity and all patients completing at least one cycle of therapy were evaluable for response. The study is ongoing but no longer recruiting patients. This trial is registered with ClinicalTrials.gov, number NCT01657331. FINDINGS: Between July 26, 2012, and May 31, 2017, we enrolled and assigned 65 patients to treatment (64 [98%] with Hodgkin's lymphoma and one [2%] with anaplastic large-T-cell lymphoma; 28 [43%] during phase 1 and 37 [57%] during phase 2). In the phase 1 part, the maximum tolerated dose of the combination was not reached. Dose-limiting toxicities were observed in three (11%) of 28 patients, including grade 4 neutropenia at 1·8 mg/kg brentuximab vedotin plus 80 mg/m2 of bendamustine in two (7%) patients and diffuse rash at 1·2 mg/kg brentuximab vedotin plus 70 mg/m2 of bendamustine in one (4%) patient. The recommended phase 2 dose was deemed to be 1·8 mg/kg of brentuximab vedotin and 90 mg/m2 of bendamustine, which are the standard doses of the drugs when given as single agents. In the phase 2 part, an overall response was achieved in 29 (78% [95% CI 62-91]) of 37 patients. Serious adverse events included grade 3 lung infection in five (14%) of 37 patients in the phase 2, and grade 3-4 neutropenia in 16 (25%) of 65 patients across phases 1 and 2. There were no treatment-related deaths. INTERPRETATION: This study shows that brentuximab vedotin plus bendamustine, with a favourable safety profile, is an active salvage regimen for heavily pretreated patients with relapsed or refractory Hodgkin's lymphoma. This salvage regimen can potentially serve as an efficacious and safe alternative to platinum-based chemotherapy before autologous stem cell transplant. FUNDING: Seattle Genetics, Lymphoma Research Fund of Columbia University and National Center for Advancing Translational Sciences, and National Institutes of Health.

Rituximab and three dexamethasone cycles provide responses similar to splenectomy in women and those with immune thrombocytopenia of less than two years duration.

Adults with newly diagnosed or persistent immunothrombocytopenia frequently relapse upon tapering steroids; adults and children with chronic disease have an even lower likelihood of lasting response. In adults with newly-diagnosed immunothrombocytopenia, two studies showed that dexamethasone 40 mg/day × four days and 4 rituximab infusions were superior to dexamethasone alone. Studies have also shown three cycles of dexamethasone are better than one and patients with persistent/chronic immunothrombocytopenia respond less well to either dexamethasone or rituximab. Therefore, 375 mg/m(2) × 4 rituximab was combined with three 4-day cycles of 28 mg/m(2) (max. 40 mg) dexamethasone at 2-week intervals and explored in 67 ITP patients. Best long-term response was assessed as complete (platelet count ≥ 100 × 10(9)/L) or partial (50-99 × 10(9)/L). Only 5 patients had not been previously treated. Fifty achieved complete (n=43, 64%) or partial (n=7, 10%) responses. Thirty-five of 50 responders maintained treatment-free platelet counts over 50 × 10(9)/L at a median 17 months (range 4-67) projecting 44% event-free survival. Duration of immunothrombocytopenia less than 24 months, achieving complete responses, and being female were associated with better long-term response (P<0.01). Adverse events were generally mild-moderate, but 3 patients developed serum sickness and 2 colitis; there were no sequelae. Dexamethasone could be difficult to tolerate. Fourteen patients became hypogammaglobulinemic and half had increased frequency of minor infections; 9 of 12 evaluable patients recovered their IgG levels. Rituximab combined with three cycles of dexamethasone provides apparently better results to reported findings with rituximab alone, dexamethasone alone, or the combination with one cycle of dexamethasone. The results suggest medical cure may be achievable in immunothrombocytopenia, especially in women and in patients within two years of diagnosis. (clinicaltrials.gov identifier:02050581).

Gemcitabine-induced pulmonary toxicity.

BACKGROUND: Gemcitabine is the only approved cytotoxic agent for the treatment of pancreatic cancer by the Food and Drug Administration. In addition, gemcitabine is also commonly used for the management of breast, ovarian, and non-small cell lung cancer. Myelosuppression is the most common toxicity of gemcitabine therapy. Pulmonary toxicities due to gemcitabine have, however, been reported. Dyspnea occurs in approximately 25% of patients treated with gemcitabine, whereas serious pulmonary toxicities are much less common, approximately 0.3%. Here, we present a case of gemcitabine-induced pneumonitis, encountered during treatment of pancreatic cancer, and review the literature of this rare, but dangerous complication. CASE REPORT: A 56-year old male being treated for stage IV pancreatic cancer developed progressive dyspnea on exertion, chest tightness, and palpitations. Oxygen saturation was 82-84%. Computerized-tomography (CT) angiography of the chest demonstrated new diffuse groundglass opacities in the bilateral lower lobes when compared to the CT of the chest without intravenous contrast, 5 weeks prior. Mild to moderate emphysema was also seen, but no pulmonary emboli were detected. Myocardial infraction was ruled-out by normal electrocardiogram and normal cardiac biomarkers. CONCLUSION: We report another case of gemcitabine-induced pneumonitis. Physicians seeing such patients should be aware of this rare but real pulmonary toxicity. A delay in diagnosis and treatment can lead to potentially fatal outcomes.