High Incidence of Invasive Fungal Diseases in Patients with FLT3-Mutated AML Treated with Midostaurin: Results of a Multicenter Observational SEIFEM Study

Abstract

The potential drug-drug interactions of midostaurin may impact the choice of antifungal (AF) prophylaxis in FLT3-positive acute myeloid leukemia (AML) patients. To evaluate the incidence of invasive fungal diseases (IFD) during the treatment of FLT3-mutated AML patients and to correlate it to the different AF prophylaxis strategies, we planned a multicenter observational study involving 15 SEIFEM centers. One hundred fourteen patients treated with chemotherapy + midostaurin as induction/reinduction, consolidation or both were enrolled. During induction, the incidence of probable/proven and possible IFD was 10.5% and 9.7%, respectively; no statistically significant difference was observed according to the different AF strategy adopted. The median duration of neutropenia was similar in patients with or without IFD. Proven/probable and possible IFD incidence was 2.4% and 1.8%, respectively, during consolidation. Age was the only risk factor for IFD (OR, 95% CI, 1.10 [1.03–1.19]) and complete remission achievement after first induction the only one for survival (OR, 95% CI, 5.12 [1.93–13.60]). The rate of midostaurin discontinuation was similar across different AF strategies. The IFD attributable mortality during induction was 8.3%. In conclusion, the 20.2% overall incidence of IFD occurring in FLT3-mutated AML during induction with chemotherapy + midostaurin, regardless of AF strategy type, was noteworthy, and merits further study, particularly in elderly patients.

Approach to diagnostic evaluation and prevention of invasive fungal disease in patients prior to allogeneic hematopoietic stem cell transplant

“…[1][2][3] Changes have been made to chemotherapy regimens, such as in the management of high grade myeloid neoplasms, involving the combination of cladribine and high-dose cytarabine. 4,5 An increase in use of immunotherapies and targeted oral therapies has also been seen, including bispecific antibodies (e.g., blinatumomab 6 ) and antibody-conjugated chemotherapy (e.g., gemtuzumab-ozogamicin 7 and inotuzumab-ozogamicin 8 ) while targets for novel oral therapies include Bruton's tyrosine kinase (e.g., ibrutinib 4 ), FMS-like tyrosine kinase (FLT3) (e.g., midostaurin and gilteritinib), 9,10 isocitrate dehydrogenase-2 (IDH-2) 11,12 and B-cell lymphoma 2 (BCL-2) (venetoclax 13 ). These therapies have improved treatment options, particularly in relapsed-refractory disease, and significantly improved disease prognosis and overall survival.…”

“…15 The FLT3 inhibitor midostaurin, whilst offering a new option for the treatment of AML, has demonstrated rates of IFD as high as 20.2% in one multicenter observational study. 9 Additionally, the drug-drug interactions (DDIs) encountered with the use of cytochrome-P (CYP) 450 substrate gilteritinib can prove challenging, given the indication for azole prophylaxis. 16 IFDs are opportunistic infections that disproportionately affect immunocompromised hosts.…”

“…(2023), many patients receiving targeted therapy did not meet European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium (EORTC/MSGERC) 14 criteria for IFD, with only 30% experiencing neutropenia 15 . The FLT3 inhibitor midostaurin, whilst offering a new option for the treatment of AML, has demonstrated rates of IFD as high as 20.2% in one multicenter observational study 9 . Additionally, the drug–drug interactions (DDIs) encountered with the use of cytochrome‐P (CYP) 450 substrate gilteritinib can prove challenging, given the indication for azole prophylaxis 16 …”

Posaconazole and midostaurin in patients with FLT3‐mutated acute myeloid leukemia: Pharmacokinetic interactions and clinical facts in a real life study

“…The incidence of probable/proven or possible IFIs is, respectively, 10.5% and 9.7% during remission induction chemotherapy, but decreases to 2.4% and 1.8% during consolidation chemotherapy. 2 Induction chemotherapy therefore represents the time window in which the burden of IFIs is of great concern, with mortality rates being as high as 8.3%. 2 Posaconazole (PCZ), a triazolic antifungal agent, is formally recommended for primary prophylaxis of IFIs during induction chemotherapy for AML 3,4 but its use is complicated by pharmacokinetic (PK) interactions with midostaurin.…”

“…2 Induction chemotherapy therefore represents the time window in which the burden of IFIs is of great concern, with mortality rates being as high as 8.3%. 2 Posaconazole (PCZ), a triazolic antifungal agent, is formally recommended for primary prophylaxis of IFIs during induction chemotherapy for AML 3,4 but its use is complicated by pharmacokinetic (PK) interactions with midostaurin. PCZ strongly inhibits CYP3A4, thereby diminishing midostaurin metabolism and exposing the patient to unnecessarily high and potentially toxic outcomes (complete remission and duration of severe neutropenia) and safety outcomes (midostaurin-related any grade or grade ≥3 AEs) were nonetheless similar for patients exposed to PCZ or micafungin, as was the number of breakthrough IFIs.…”