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The oral BCL2 inhibitor navitoclax has moderate single-agent efficacy in chronic lymphocytic leukaemia (CLL) and minor activity in lymphoma in Phase 1 trials. Navitoclax synergizes with rituximab in preclinical models of B-cell lymphoid cancers. We report the safety, pharmacokinetics and clinical activity of this combination. Patients received navitoclax (200-325 mg) daily and four standard weekly doses of rituximab. Twenty-nine patients were enrolled across three dose-escalation cohorts and a safety expansion cohort (250 mg/d navitoclax). The combination was well tolerated. Common toxicities were mild diarrhoea (79%) and nausea (72%). Grade 4 thrombocytopenia occurred in 17% of patients (dose limiting at 325 mg/d). CD19(+) counts were severely reduced, while CD3(+) cells (~ 20%) and serum immunoglobulin M levels (~ 33%) were also reduced during the first year. The maximum tolerated dose for navitoclax in combination was 250 mg/d. Pharmacokinetic analyses revealed no apparent interactions between the drugs. The response rate in patients with follicular lymphoma was 9/12, including five complete responses. All five patients with CLL/small lymphocytic leukaemia achieved partial responses. One of nine patients with aggressive lymphoma responded. The addition of rituximab to navitoclax 250 mg/d is safe; the combination demonstrates higher response rates for low-grade lymphoid cancers than observed for either agent alone in previous Phase 1 trials., (© 2015 John Wiley & Sons Ltd.)

Although multiple myeloma (MM) remains an incurable disease, considerable improvements in survival have been made with the introduction of autologous stem cell transplantation and new drugs. Central nervous system (CNS) MM is a rare complication associated with poor survival. Historically, CNS disease developed early in the course of MM; however recently, patients often present with CNS disease following multiple lines of therapy. It is hypothesized that exposure to novel agents (thalidomide, lenalidomide and bortezomib) changes the natural history of MM, increasing the lifetime risk of CNS disease. We analysed the baseline characteristics, treatment and outcome data of patients who presented with CNS MM at Peter MacCallum Cancer Centre between 2001 and 2010. Seven patients were identified, from 2005 onwards. All patients were Durie-Salmon stage IIIA or IIIB and International Staging System Scores I to III at baseline. All had received at least three lines of therapy, including high-dose chemotherapy with autologous stem cell transplantation and a novel agent, prior to developing CNS MM. Median time from diagnosis to CNS disease was 24 months (range 10-42). All patients died after developing CNS disease with median survival post-CNS disease of 2 months (range 1-23). The incidence of CNS MM is increasing, and time to development of CNS manifestations is prolonging, associated with increased use of high-dose chemotherapy and novel agents. Whether this is due to improved overall survival or specific characteristics of these therapies is not clear. Despite the availability of novel agents, survival after CNS MM remains poor., (Copyright © 2011 John Wiley & Sons, Ltd.)

Reported rates of central nervous system (CNS) involvement in mantle cell lymphoma (MCL) are highly variable but substantial (4-26%). Data is lacking regarding risk factors for CNS relapse, and for those patients in whom CNS prophylaxis could be beneficial. We present single institution retrospective analysis of data of baseline features, clinical course, rate of CNS disease and putative risk factors in 62 patients with MCL (18 female, 44 male). CNS disease (all cases were symptomatic) occurred in four patients at a median of 12 months (range 1-58) from diagnosis, with a crude incidence of 6.5% and 5-year actuarial incidence of 5 +/- 3%. Two cases had blastic MCL at diagnosis. Survival after CNS relapse ranged from 2-9 months. Patients who developed CNS disease had a significantly shorter survival from diagnosis than those who did not (P = 0.0024). Symptomatic CNS disease in patients with MCL either at presentation or relapse is an uncommon but devastating complication. In younger patients, more aggressive immuno-chemotherapy regimens containing CNS-penetrating agents may reduce the incidence of CNS disease. While not routinely justified for all patients, CNS prophylaxis may particularly benefit patients with blastic histology at diagnosis, or those with systemic relapse after first-line treatment.