Brentuximab vedotin with dacarbazine or nivolumab as frontline cHL therapy for older patients ineligible for chemotherapy.

ABSTRACT: Older patients with advanced-stage classical Hodgkin lymphoma (cHL) have inferior outcomes compared with younger patients, potentially due to comorbidities and frailty. This noncomparative phase 2 study enrolled patients aged ≥60 years with cHL unfit for conventional chemotherapy to receive frontline brentuximab vedotin (BV; 1.8 mg/kg) with dacarbazine (DTIC; 375 mg/m2) (part B) or nivolumab (part D; 3 mg/kg). In parts B and D, 50% and 38% of patients, respectively, had ≥3 general comorbidities or ≥1 significant comorbidity. Of the 22 patients treated with BV-DTIC, 95% achieved objective response, and 64% achieved complete response (CR). With a median follow-up of 63.6 months, median duration of response (mDOR) was 46.0 months. Median progression-free survival (mPFS) was 47.2 months; median overall survival (mOS) was not reached. Of 21 patients treated with BV-nivolumab, 86% achieved objective response, and 67% achieved CR. With 51.6 months of median follow-up, mDOR, mPFS, and mOS were not reached. Ten patients (45%) with BV-DTIC and 16 patients (76%) with BV-nivolumab experienced grade ≥3 treatment-emergent adverse events; sensory peripheral neuropathy (PN; 27%) and neutropenia (9%) were most common with BV-DTIC, and increased lipase (24%), motor PN (19%), and sensory PN (19%) were most common with BV-nivolumab. Despite high median age, inclusion of patients aged ≤88 years, and frailty, these results demonstrate safety and promising durable efficacy of BV-DTIC and BV-nivolumab combinations as frontline treatment, suggesting potential alternatives for older patients with cHL unfit for initial conventional chemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT01716806.

An open-label phase 2 trial of entospletinib in indolent non-Hodgkin lymphoma and mantle cell lymphoma.

Spleen tyrosine kinase (Syk) mediates B-cell receptor signalling in normal and malignant B cells. Entospletinib is an oral, selective Syk inhibitor. Entospletinib monotherapy was evaluated in a multicentre, phase 2 study of patients with relapsed or refractory indolent non-Hodgkin lymphoma or mantle cell lymphoma (MCL). Subjects received 800 mg entospletinib twice daily. Forty-one follicular lymphoma (FL), 17 lymphoplasmacytoid lymphoma/Waldenström macroglobulinaemia (LPL/WM), 17 marginal zone lymphoma (MZL) and 39 MCL patients were evaluated. The primary endpoint was a progression-free survival (PFS) rate (defined as not experiencing progression or death) at 16 weeks for patients with MCL and at 24 weeks for patients with FL, LPL/WM and MZL. The most common treatment-emergent adverse events were fatigue, nausea, diarrhoea, vomiting, headache and cough. Common laboratory abnormalities were anaemia, neutropenia and thrombocytopenia; aspartate transaminase, alanine transaminase, total bilirubin and serum creatinine were all increased. PFS at 16 weeks in the MCL cohort was 63·9% [95% confidence interval (CI) 45-77·8%]; PFS at 24 weeks in the FL, LPL/WM, MCL and MZL cohorts was 51·5% (95% CI 32·8-67·4%), 69·8% (95% CI 31·8-89·4%), 56·6% (95% CI 37·5-71·8%) and 46·2% (95% CI 18·5-70·2%), respectively. Entospletinib had limited single-agent activity with manageable toxicity in these patient populations.

Frontline brentuximab vedotin in combination with dacarbazine or bendamustine in patients aged ≥60 years with HL.

Patients aged ≥60 years with treatment-naive Hodgkin lymphoma (HL) have few treatment options and inferior survival due to treatment-related toxicities and comorbidities. This phase 2, nonrandomized, open-label study evaluated brentuximab vedotin (BV) monotherapy (results previously reported), BV plus dacarbazine (DTIC), and BV plus bendamustine. Patients had classical HL and were ineligible for or declined frontline chemotherapy. Twenty-two patients received 1.8 mg/kg BV and 375 mg/m2 DTIC for up to 12 cycles, and 20 more patients received 1.8 mg/kg BV plus 90 or 70 mg/m2 bendamustine for up to 6 cycles (dose reduced due to toxicity). Subsequent BV monotherapy was allowed. Approximately 30 patients were to receive BV plus bendamustine; however, the incidence of serious adverse events (65%) and 2 deaths on study led to discontinuation of bendamustine and cessation of enrollment. Most patients had stage III/IV disease, and approximately half had ≥3 comorbidities or were impaired in ≥1 aspect that significantly interfered with quality of life. For BV plus DTIC, the objective response rate (ORR) was 100% and the complete remission (CR) rate was 62%. To date, the median progression-free survival (PFS) is 17.9 months. For BV plus bendamustine, the ORR was 100% and the CR rate was 88%. Neither the median PFS nor overall survival was reached. For elderly patients with HL, BV plus DTIC may be a frontline option based on tolerability and response duration. Despite activity, BV plus bendamustine is not a tolerable regimen in these patients. This trial was registered at www.clinicaltrials.gov as #NCT01716806.

Phase 2 study of frontline brentuximab vedotin monotherapy in Hodgkin lymphoma patients aged 60 years and older.

Outcomes in older patients with Hodgkin lymphoma (HL) tend to be poor following conventional chemotherapy regimens. Treatment-related toxicity is significant and comorbidities often limit therapeutic options. This phase 2, open-label study evaluated the efficacy and safety of brentuximab vedotin, a CD30-directed antibody-drug conjugate, as frontline therapy in 27 HL patients aged ≥60 years. The objective response rate (ORR) was 92%, with 73% achieving complete remission. All patients achieved stable disease or better, and had decreased tumor volume following treatment. At the time of this analysis, the median duration of objective response for efficacy-evaluable patients (N = 26) was 9.1 months (range, 2.8 to 20.9+ months), median progression-free survival was 10.5 months (range, 2.6+ to 22.3+ months), and median overall survival had not been reached (range, 4.6+ to 24.9+ months). The observed adverse events (AEs) were generally consistent with the known safety profile of brentuximab vedotin. The most common AEs were peripheral sensory neuropathy (78%), fatigue (44%), and nausea (44%), and were ≤ grade 2 for most patients. The incidence of grade 3 peripheral neuropathy events was relatively high (30% overall), particularly among patients with the known risk factors of diabetes and/or hypothyroidism (46% vs 14% for those without). However, these risk factors were not associated with delayed time to resolution/improvement of peripheral neuropathy. Preliminary data showed no substantial age-related changes in brentuximab vedotin pharmacokinetics. Brentuximab vedotin monotherapy may provide a frontline treatment option for older patients who cannot tolerate conventional combination chemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT01716806.

Feasibility of Long-term Proteasome Inhibition in Multiple Myeloma by in-class Transition From Bortezomib to Ixazomib.

BACKGROUND: The ongoing US MM-6 study is investigating in-class transition (iCT) from parenteral bortezomib-based induction to all-oral IRd (ixazomib-lenalidomide-dexamethasone) with the aim of increasing proteasome inhibitor (PI)-based treatment adherence and duration while maintaining patients' health-related quality of life (HRQoL) and improving outcomes. PATIENTS AND METHODS: US community sites are enrolling non-transplant-eligible patients with newly diagnosed multiple myeloma (MM) with no evidence of progressive disease after 3 cycles of bortezomib-based therapy to receive IRd (up to 39 cycles or until progression or toxicity). The patients use mobile or wearable digital devices to collect actigraphy (activity and sleep) data and electronically complete HRQoL, treatment satisfaction and medication adherence questionnaires. The primary endpoint is progression-free survival. The key secondary endpoints include response rates and therapy duration. RESULTS: At the data cutoff, 84 patients had been treated (median age 73 years; 44% aged ≥ 75 years; 49% men; 15% Black or African American; and 10% Hispanic or Latino). Of the 84 patients, 62% were continuing therapy. The mean duration of total PI therapy was 10.1 months and for the IRd regimen was 7.3 months. With an 8-month median follow-up, the 12-month progression-free survival rate was 86% (95% confidence interval, 73%-93%) from both the start of bortezomib-based treatment and the start of IRd. The overall response rate was 62% (complete response, 4%; very good partial response, 25%; partial response, 33%) after bortezomib-based induction and 70% (complete response, 26%; very good partial response, 29%; partial response, 15%) after iCT. The IRd safety profile was consistent with previous clinical trial data, and HRQoL and treatment satisfaction were maintained. CONCLUSION: The patients included in the US MM-6 study are representative of the real-world US MM population. The use of iCT might permit prolonged PI-based therapy with promising efficacy, without impacting patients' HRQoL or treatment satisfaction.

Results of a Phase II Placebo-controlled Randomized Discontinuation Trial of Cabozantinib in Patients with Non-small-cell Lung Carcinoma.

INTRODUCTION: Cabozantinib, an orally bioavailable tyrosine kinase inhibitor with activity against MET, vascular endothelial growth factor receptor 2, AXL, ROS1, and RET was assessed in patients with non-small-cell lung carcinoma (NSCLC) as part of a phase II randomized discontinuation trial with cohorts from 9 tumor types. PATIENTS AND METHODS: Patients received cabozantinib 100 mg/day during a 12-week open-label lead-in stage. Those with stable disease per Response Evaluation Criteria in Solid Tumors version 1.0 at week 12 were randomized to cabozantinib or placebo. Primary endpoints were objective response rate (ORR) at week 12 and progression-free survival (PFS) after randomization. RESULTS: Sixty patients with NSCLC who had received a median of 2 prior lines of therapy were enrolled. ORR at week 12 was 10%; 6 patients had a confirmed partial response, and no patients had a complete response. Overall disease-control rate (ORR + stable disease) at week 12 was 38%. Tumor regression was observed in 30 (64%) of 47 patients with post-baseline radiographic tumor assessments, including 3 or 4 patients with KRAS or epidermal growth factor receptor mutations, respectively. Median PFS after randomization was 2.4 months for both the cabozantinib and placebo arms. Median PFS from first dose for the entire cohort was 4.2 months. The most common grade 3/4 adverse events were fatigue (13%), palmar-plantar erythrodysesthesia (10%), diarrhea (7%), hypertension (7%), and asthenia (5%); 1 treatment-related grade 5 adverse event (hemorrhage) was reported during the lead-in stage. CONCLUSION: Cabozantinib exhibited clinical activity based on ORR and regression of tumor lesions in pretreated patients with NSCLC, including in patients with KRAS mutations.

Response to rituximab in patients with type II cryoglobulinemia.

Type II cryoglobulinemia (CG) is a heterogeneous, generally indolent disorder caused by a monoclonal antibody with activity against polyclonal antibodies and is commonly associated with hepatitis C, lymphoproliferative disorders (LPDs), or autoimmune diseases. It can lead to substantial morbidity, including renal failure, cutaneous ulcers, or neuropathy. Medical records were reviewed for 8 patients with previously treated symptomatic CG who were part of a prospectively held dysproteinemia database. Patients subsequently received 14 total courses of rituximab treatment (standard infusion, 375 mg/m2 for 4 or 8 doses) between February 1999 and March 2005. One patient had essential CG, and 1 had Gaucher disease with hypersplenism. Six patients had an LPD, and 4 of them had concomitant disorders (2 with hepatitis C and 2 with Sjogren syndrome). Treatment indications included purpura, LPD, cutaneous ulcers, and renal failure. Clinical improvement was evaluated by improved cryocrit, total complement, C4, and rheumatoid factor. Six patients had some clinical improvement. Cutaneous manifestations were the most responsive; renal disease and lymphoma were more refractory. Laboratory values showed improvement after 7 of 12 available treatment courses. No adverse reactions were noted. Overall, rituximab appears to be a safe and effective therapy.

Economic impact of disease progression following front-line therapy in classical Hodgkin lymphoma.

The current study aimed to assess the economic burden of progressive disease among patients with Hodgkin lymphoma (HL) receiving second- or third-line therapy in a large US network of community-based practices. This retrospective, observational cohort analysis used electronic health records to examine adult patients with classical HL who received chemotherapy between 2007 and 2011. Of 291 observations, 112 had non-progressive disease (received only one line of therapy; LOT1), 114 received second-line therapy (LOT2), and 65 received third-line therapy (LOT3). In LOT2, 49 patients (43%) underwent transplant. In LOT3, 13 patients (20%) underwent transplant. The mean total cost per line of therapy was $21 956 in LOT1, $77 219 in LOT2, and $59 442 in LOT3. When transplant was required, the mean total cost per line of therapy increased 7- to 8-fold when compared with the cost of LOT1 (approximately $154 000 for LOT2 and $193 000 for LOT3). Future therapies that intervene as early as possible in the treatment algorithm to prevent or significantly delay relapse will likely result in significant cost savings.