Therapeutic options are limited for elderly patients with acute myeloid leukemia (AML). A phase Ib/II study was undertaken to evaluate the maximum-tolerated dose (MTD) and preliminary efficacy of the pan-histone deacetylase inhibitor panobinostat (LBH589) in combination with azacitidine in patients with AML or high-risk myelodysplastic syndrome (MDS) naïve to intensive chemotherapy. Thirty-nine patients (AML=29, MDS=10) received azacitidine 75 mg/m2 subcutaneously (days 1–5) and oral panobinostat (starting on day 5, thrice weekly for seven doses) in 28-day cycles until toxicity or disease progression. Dose-limiting toxicities during the phase Ib stage were observed in 0/4 patients receiving 10 mg panobinostat, in 1/7 patients (fatigue) receiving 20 mg, in 1/6 patients (fatigue) receiving 30 mg and in 4/5 patients (fatigue, syncope, hyponatremia and somnolence) receiving 40 mg. In phase II, an additional 17 patients received panobinostat at a MTD of 30 mg. The overall response rate (ORR=CR+CRi+PR) in patients with AML was 31% (9/29) and that in patients with MDS was 50% (5/10). After a median follow-up of 13 months, the median overall survival was 8 and 16 months in patients with AML and MDS, respectively. Increased histone H3 and H4 acetylation was a useful early biomarker of clinical response. Combining panobinostat with azacitidine was tolerable and clinically active in high-risk MDS/AML patients, warranting further exploration.

Invasive fungal disease (IFD) due to moulds other than Aspergillus is a significant cause of mortality in patients with malignancies or post haemopoietic stem cell transplantation. The current guidelines focus on the diagnosis and management of the common non‐Aspergillus moulds (NAM), such as Mucorales, Scedosporium species (spp.), Lomentospora prolificans and Fusarium spp. Rare but emerging NAM including Paecilomyces variotii, Purpureocillium lilacinum and Scopulariopsis spp. are also reviewed. Culture and histological examination of tissue biopsy specimens remain the mainstay of diagnosis, but molecular methods are increasingly being used. As NAM frequently disseminate, blood cultures and skin examination with biopsy of any suspicious lesions are critically important. Treatment requires a multidisciplinary approach with surgical debridement as a central component. Other management strategies include control of the underlying disease/predisposing factors, augmentation of the host response and the reduction of immunosuppression. Carefully selected antifungal therapy, guided by susceptibility testing, is critical to cure. We also outline novel antifungal agents still in clinical trial which offer substantial potential for improved outcomes in the future. Paediatric recommendations follow those of adults. Ongoing epidemiological research, improvement in diagnostics and the development of new antifungal agents will continue to improve the poor outcomes that have been traditionally associated with IFD due to NAM.

No abstract

Zanubrutinib (BGB-3111) is a next-generation Bruton tyrosine kinase inhibitor designed to be more selective with fewer off-target effects. We conducted a phase 1 study to assess the safety of its combination with obinutuzumab and evaluate early efficacy in 81 patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) or relapsed/refractory (R/R) follicular lymphoma (FL). In this phase 1b study, zanubrutinib was tolerable at 160 mg twice daily or 320 mg once daily combined with IV obinutuzumab in patients with CLL/SLL (n = 45) and FL (n = 36). Common adverse events (AEs) included upper respiratory tract infection (51%; n = 23), neutropenia (44%; n = 20), contusion (33%; n = 15), cough, diarrhea, or fatigue (27%; n = 12 each), and pyrexia (22%; n = 10) in CLL/SLL patients and upper respiratory tract infection (39%; n = 14), contusion (28%; n = 10), fatigue (25%; n = 9), and cough (22%; n = 8) in FL patients. Neutropenia was the most common grade 3/4 AE (CLL/SLL, 31% [n = 14]; FL, 14% [n = 5]). Five patients required temporary dose reductions, and 5 discontinued the study drug because of AEs. Overall response rate (ORR) was 100% (n = 20) in treatment-naïve CLL patients and 92% (n = 23) in R/R CLL patients. ORR in 36 R/R FL patients was 72% (n = 26), with 14 complete and 12 partial responses. Median follow-up was 29 months (range, 8-37) for CLL patients and 20 months (range, 2-37) for FL patients. Zanubrutinib and obinutuzumab combination therapy was generally well tolerated. This trial was registered at www.clinicaltrials.gov as #NCT02569476.

Tumour lysis syndrome (TLS) is a life-threatening oncological emergency characterized by hyperuricaemia, hyperkalaemia, hyperphosphataemia, and hypocalcaemia [1, 2] due to the rapid lysis of malignant cells, following the initiation of anticancer therapies [3].Traditionally, therapy for TLS involved intensive hydration, urinary alkalinization and administration of allopurinol [4][5][6]. Newer guidelines now include rasburicase, with monitoring of electrolytes, white blood cell counts (WCC) and lactate dehydrogenase (LDH) concentrations [1, 7,8].Rasburicase, a recombinant urate oxidase enzyme, effectively decreases existing serum uric acid (UA) by oxidizing it to allantoin which is readily soluble and excretable [3]. Although the recommended dose is 0.2 mg kg -1 day -1for 5-7 days [9], studies have shown the efficacious use of reduced doses for shorter periods of time and subsequent cost savings [5, 6,[10][11][12][13][14][15][16][17].Expert guidelines by Coieffer et al. [7] in 2008 and Cairo et al. in 2010 [1] on the management of TLS recommend a rasburicase dose of 0.1-0.2 mg kg -1 on the first day, then repeated for up to 7 days [1] or as necessary [7]. We present an analysis of a fixed 3 mg dose of rasburicase administered to adult patients, treated at a tertiary referral centre. The study was approved by the Alfred Health Human Research Ethics Committee and the Monash University Human Research Ethics Committee.Demographic data were collected. Biochemical parameters (serum creatinine, serum UA, phosphate and LDH concentrations), at baseline, 24 h and 72 h after initial administration of rasburicase were recorded and compared.The institution guideline indicates rasburicase to be given before the first dose of chemotherapy in patients considered high risk for TLS. This includes a diagnosis of Burkitt's lymphoma, acute lymhoblastic leukaemia, bulky non-Hodgkin's lymphoma, lymphoblastic lymphoma or acute myeloid leukaemia with one or more of the following: serum UA>0.46 mmol l -1 , white cell count (WCC) >50 ¥ 10 9 l -1 or LDH >two times normal. Patients who were at an ongoing risk of TLS (i.e. elevated UA or LDH or multiple days of aggressive cytoreductive chemotherapy) were allowed a repeat dose of rasburicase 3 mg. Adherence to the guideline was measured.Forty-one patients received 42 courses of rasburicase over a 40 month period ( Figure 1A). Diagnosis, demographic and baseline biochemical data are presented in Table 1.Rasburicase was administered as per institution guidelines in 40 (95%) of the patients. Median serum UA concentrations were within normal range at 72 h in all groups; in those who presented with hyperuricaemia, in those who presented with normal baseline serum UA concentrations and overall ( Figure 1B).The majority of patients received one dose of rasburicase 3 mg ( Figure 1A). In 34 patient episodes requiring one dose only, there was a decline in the median (range) UA concentration from 0.44 mmol l -1 (0.13-1.15) at baseline to 0.22 mmol l -1 (0.02-0.66) at 24 h. This decrease was maintained...