Primary prophylaxis of invasive fungal infections in patients with haematological malignancies: 2017 update of the recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society for Haematology and Medical Oncology (DGHO)

Abstract

Immunocompromised patients are at high risk of invasive fungal infections (IFI), in particular those with haematological malignancies undergoing remission-induction chemotherapy for acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS) and recipients of allogeneic haematopoietic stem cell transplants (HSCT). Despite the development of new treatment options in the past decades, IFI remains a concern due to substantial morbidity and mortality in these patient populations. In addition, the increasing use of new immune modulating drugs in cancer therapy has opened an entirely new spectrum of at risk periods. Since the last edition of antifungal prophylaxis recommendations of the German Society for Haematology and Medical Oncology in 2014, seven clinical trials regarding antifungal prophylaxis in patients with haematological malignancies have been published, comprising 1227 patients. This update assesses the impact of this additional evidence and effective revisions. Our key recommendations are the following: prophylaxis should be performed with posaconazole delayed release tablets during remission induction chemotherapy for AML and MDS (AI). Posaconazole iv can be used when the oral route is contraindicated or not feasible. Intravenous liposomal amphotericin B did not significantly decrease IFI rates in acute lymphoblastic leukaemia (ALL) patients during induction chemotherapy, and there is poor evidence to recommend it for prophylaxis in these patients (CI). Despite substantial risk of IFI, we cannot provide a stronger recommendation for these patients. There is poor evidence regarding voriconazole prophylaxis in patients with neutropenia (CII). Therapeutic drug monitoring TDM should be performed within 2 to 5 days of initiating voriconazole prophylaxis and should be repeated in case of suspicious adverse events or of dose changes of interacting drugs (BIItu). General TDM during posaconazole prophylaxis is not recommended (CIItu), but may be helpful in cases of clinical failure such as breakthrough IFI for verification of compliance or absorption.Electronic supplementary materialThe online version of this article (10.1007/s00277-017-3196-2) contains supplementary material, which is available to authorized users.

Itraconazole Increases Ibrutinib Exposure 10‐Fold and Reduces Interindividual Variation—A Potentially Beneficial Drug‐Drug Interaction

“…However, antifungal prophylaxis in patients using ibrutinib is considered problematic because many antifungal agents interact strongly with ibrutinib . Voriconazole is effective in the treatment of invasive fungal infections but it is generally not recommended for primary prophylaxis . Itraconazole and fluconazole can be used to reduce the incidence of invasive fungal infections, although in high‐risk hematologic patients their efficacy is weaker than that of posaconazole .…”

EQUAL Aspergillosis Score 2018: An ECMM score derived from current guidelines to measure QUALity of the clinical management of invasive pulmonary aspergillosis

“…In a population of patients with (expected) neutropenia >10 days or patients undergoing allogeneic stem cell transplantation use of mould active prophylaxis or galactomannan screening 2‐3x/week in those not receiving prophylaxis is indicated (three points). In patients with 72‐96 hours of persistent fever despite broad‐spectrum antibacterial treatment chest computed tomography (CT) is the imaging modality of choice (three points) .…”

“…Voriconazole use without TDM leads to reduced scoring (−1 point) . In patients receiving mould prophylaxis, who develop breakthrough aspergillosis, liposomal amphotericin B, or caspofungin is indicated (five points) …”

How to prophylax against invasive fungal infections in adult ALL? An unmet need

“…For example, a major concern regarding the role of azoles, the preferred drug for antifungal prophylaxis in high risk haematology patients, is the fact they have significant drug interactions with vincristine, which is a vital component of commonly used chemotherapy regimens for ALL . Although influenced to some degree by pharmacogenetics, the major dose‐limiting toxicity of vincristine is peripheral neuropathy, which causes significant morbidity and may attenuate or even postpone the administration of curative ALL therapy . Vincristine exhibits highly variable pharmacokinetics and is metabolized primarily through the CYP3A4/5 system, leading to the potential for significant drug‐drug interactions .…”

“…Furthermore support for this mechanism is provided by the differences in toxicity among azoles, with relatively small increases in toxicity seen with fluconazole, a weaker CYP3A inhibitor than the other azoles. Fluconazole 200 mg QD is used often, although doses lower than 400 mg QD have not successfully reduced IFI incidence during neutropenia in randomized controlled trials . Another approach is intermittent prophylaxis with mold active azoles, but given the long vincristine half live (85 hours) and its extensive tissue distribution this is not a reliable prophylactic option either .…”