No abstract

Invasive fungal infections in haematological and oncological patients have a major impact on morbidity, mortality and treatment costs. Therefore, rational use of antifungal agents is important for optimal patient care and resource use. The study's objective was to analyse antifungal usage in a German tertiary teaching hospital, department of haematology and oncology, to evaluate quality of antifungal treatment and to assess the need for an antifungal stewardship programme. This retrospective observational study included patients ≥18 years receiving systemic antifungals for prophylaxis or therapy of invasive fungal infection between January and June 2016. Appropriateness of antifungal prescriptions was evaluated in accordance with guidelines of the German Society of Haematology and Oncology (DGHO) and drug labelling. In total, 104/1278 (8.1%) patients received antifungals. One hundred seventy-one antifungals were prescribed: 48 for prophylaxis, 104 for empirical and 19 for targeted therapy. In 127 (74.3%) prescriptions, indication was appropriate, and in 132 (77.2%), choice of drug. Antifungals were correctly dosed in 131 prescriptions (76.6%). Thirty-four antifungals (20.0%) were co-administrated with interacting drugs (5 mild to moderate, 29 severe interactions). Results of this analysis demonstrate that use of systemic antifungals in routine care differs in a substantial number of patients from guideline and labelling recommendations. To optimise antifungal use, the implementation of antifungal stewardship programmes seems to be justified.

Antifungal posaconazole prophylaxis for AML patients receiving induction chemotherapy has been routine at our centre since 2009. This retrospective study examined the feasibility and practicability of our prophylaxis guidelines in clinical practice. Data sets of 90 patients undergoing induction-chemotherapy for AML between 2011 and 2014 were evaluated regarding adherence to local guidelines for the administration of antifungal prophylaxis with posaconazole. 75.5% of the 90 patients received posaconazole prophylaxis. All but eight patients received the recommended dosage. A total of 77.95% on prophylaxis had serum galactomannan measured twice weekly. Contradicting our guidelines, 89.70% of patients received concomitant therapy with PPI. Overall, 16.17% of patients had prophylaxis discontinued and started empirical antifungal treatment in the absence of diagnostic criteria for IFI. The breakthrough IFI rate was 36.76% (proven, probable and possible) with 7.35% of infections being classified as proven or probable. Although limited by a small sample size, our study demonstrates the feasibility of local guidelines in a real life setting and outlines areas for improvement in both guidelines and clinical practice. We also highlight the importance of ensuring awareness of guidelines and raise questions about a uniform approach to antifungal prophylaxis in AML patients.

Unmanipulated, T-cell-replete (TCR) HLA-haploidentical hematopoietic stem cell transplantation (haplo-HSCT) using post-transplantation cyclophosphamide (PTCY) for selective in vivo T-cell depletion of allo-reactive T-cells has become a valuable treatment alternative in patients with various hematologic disorders who lack a conventional donor or need timely transplant due to aggressive disease. However, as of yet few data are available for the treatment of ALL with this approach, particularly in relapsed and refractory disease. To evaluate the outcome of TCR haplo-HSCT utilizing PTCY in the context of intensified conditioning in patients with high-risk, relapsed and refractory ALL, we retrospectively analysed 29 patients (B-ALL n=27, T-ALL n=2; 12 male; median age 42 years: range 8-68) transplanted between 2010 and 2015 in five German transplant centers including one pediatric. Disease was active (relapsed/refractory) in 14 patients (48%) while others were in first (35%) or subsequent remission (17%). Eleven patients (38%) had relapsed after a previous allogeneic transplantation. Patients not in CR received cytoreductive chemotherapy prior to the conditioning regimen, according to the "sequential therapy" concept (Schmid C et al., JCO 2005; Tischer J et al, Ann Hematol 2013). Conditioning was TBI-based in 15 adults consisting of fludarabine and +/- cyclophosphamide plus either 12 Gy TBI or 8 Gy TBI applied in patients older than 55 years; children (n=3) received 10-12 Gy TBI plus etoposide. In adults with relapse after a first allogeneic transplantation conditioning was drug-based replacing TBI with treosulfan (3 x 10-12 g/m2) and etoposide. Post-grafting immunosuppression was high-dose cyclophosphamide, tacrolimus or cyclosporine A (n=4) and MMF in all patients. 27/29 patients engrafted, while 2 patients died early in aplasia. No primary graft rejection was observed. Acute GvHD grade II-IV occurred in 7 patients (24%); no patient developed grade IV acute GvHD. Mostly mild to moderate chronic GvHD was observed in 6 patients (21%), and CI of chronic GvHD at 2 years was 25%. No patient died due to GvHD. Severe toxicity (grade III-IV) was observed in 12 patients (41%), most commonly mucositis (n=34%), diarrhoea (31%), hyperbilirubinemia and transient elevation of transaminases (28%) and hemorrhagic cystitis (21%). CMV reactivated in 11/23 patients at risk and EBV in 3 while no patient developed CMV disease or PTLD. Proven invasive aspergillosis was diagnosed in 2, probable invasive aspergillosis in 5 patients. One-year non-relapse mortality (NRM) was 10%. Patients grafted with active disease experienced a one-year NRM of 14%. One-year relapse incidence was 35%. After a median follow up of 31 months (range 7.1-53.6), estimated one-year and three-year overall and relapse-free survival was 72/49% and 55/41%, respectively. In summary, intensification of the preparative regimen is well tolerated in the setting of TCR haplo-HSCT using PTCY as GvHD prophylaxis with low GVHD rates and NRM in patients with high-risk, relapsed and refractory ALL, while providing effective anti-leukemic activity. Results are at least comparable to HLA-matched transplantation. Thus, we suggest that the donor pool can be safely expanded in patients with high-risk and advanced ALL who lack a conventional donor, and that unrelated donor transplantation might be challenged in patients suffering from aggressive disease in the future. Disclosures Albert: GSK: Research Funding.