Antifungal prophylaxis and novel drugs in acute myeloid leukemia: the midostaurin and posaconazole dilemma

Abstract

With the advent of new targeted drugs in hematology and oncology patient prognosis is improved. Combination with antifungal prophylaxis challenges clinicians due to pharmacological profiles prone to drug–drug interactions (DDI). Midostaurin is a novel agent for FLT3-TKD/-ITDmut-acute myeloid leukemia (AML) and metabolized via cytochrome P450 3A4 (CYP3A4). Posaconazole is a standard of care antifungal agent used for prophylaxis during induction treatment of AML and a strong CYP3A4 inhibitor. Concomitant administration of both drugs leads to elevated midostaurin exposure. Both drugs improve overall survival at low numbers needed to treat. The impact of CYP3A4-related DDI remains to be determined. Severe adverse events have been observed; however, it remains unclear if they can be directly linked to DDI. The lack of prospective clinical studies assessing incidence of invasive fungal infections and clinical impact of DDI contributes to neglecting live-saving antifungal prophylaxis. Management strategies to combine both drugs have been proposed, but evidence on which approach to use is scarce. In this review, we discuss several approaches in the specific clinical setting of concomitant administration of midostaurin and posaconazole and give examples from everyday clinical practice. Therapeutic drug monitoring will become increasingly important to individualize and personalize antineoplastic concomitant and antifungal treatment in the context of DDI. Pharmaceutical companies addressing the issue in clinical trials may take a pioneer role in this field. Other recently developed and approved drugs for the treatment of AML likely inhere potential of DDI marking a foreseeable issue in future treatment of this life-threatening disease.

Background

Acute myeloid leukemia (AML) is the most common acute leukemia type in adults [1, 2]. Until recently, treatment of AML relied on intensive chemotherapy regimens associated with high treatment-related mortality. Over the last decade, several new drugs have been developed representing a major change in the management of AML. Among them, especially inhibitors targeting a mutation of the fms-like tyrosine kinase 3 (FLT3), present in 20–30% of AML patients, are of interest [3,4,5]. The FLT3-mutation is associated with a shorter overall survival and decreased disease-free survival as compared to patients with wild type (FLT3WT), thus being a major target to improve prognosis in this population [6].

AML patients can have disease-associated impaired neutrophil function, and intensive chemotherapy regularly induces prolonged neutropenia exposing them at highest risk for developing invasive fungal disease (IFD) [7, 8]. Several clinical trials have established antifungal prophylaxis with triazoles as standard of care in patients with AML, allogeneic stem cell transplantation (HSCT), and graft-versus-host disease (GvHD) [9,10,11,12]. Posaconazole is a second-generation triazole with activity against a broad-spectrum of yeasts and molds, and it is a strong cytochrome p450 (CYP) 3A4 inhibitor [13, 14].

Midostaurin, previously known as PKC412, is a first-generation tyrosine kinase inhibitor (TKI) for the treatment of FLT3-TKD/-ITDmut AML. It is also approved for aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN), and mast cell leukemia (MCL). The introduction of midostaurin as a targeted drug represents a paradigm shift in treating patients with FLT3-mutated AML.

However, concerns have come up that drug–drug interactions (DDI) with posaconazole threaten the use of each of the two substances and data to support the decision is currently lacking. This review aims to summarize available evidence of potential DDI with these two drugs and to offer solutions for their concomitant use in clinical routine to maximize patient benefit.

The case of midostaurin and posaconazole

Midostaurin: development, dosage, and adverse events

Midostaurin was approved for treatment of FLT3-TKD/-ITDmut AML in the USA in 2017 and in the European Union in 2018 after the RATIFY trial proved that the addition of midostaurin to standard induction treatment significantly increased overall and event-free survival of patients with AML [15].

According to the prescribing information, midostaurin should be administered from day 8 to 21 of each 21-day induction (7 + 3 cytarabine and anthracycline) and consolidation chemotherapy cycle in a dosage of 50 mg twice daily. In patients with complete remission (CR), continuous daily midostaurin intake is recommended for 1 year or until relapse and in case of allogeneic HSCT the drug is to be stopped 48 h prior to conditioning chemotherapy [16]. Midostaurin is a substrate to CYP3A4, which converts the drug into further active metabolites, CPG6221 and CGP52421. All three substances were shown to inhere multi-kinase inhibition activity especially in clonal heterogenous AML [17, 18]. The metabolites provide additional antileukemic activity by targeting peripheral blasts non-selectively [19]. The described effects apparently add up for midostaurin effectiveness.

Midostaurin demonstrated a low toxicity profile in early clinical trials in solid tumor entities [20]. The relatively safe profile paved the way for evaluation among other populations, including AML. Adverse events (AEs) are mostly low-grade gastrointestinal toxicities such as nausea, vomiting, and diarrhea, but also QTc prolongation and interstitial lung disease can occur (Table 1) [16, 21]. Early clinical trials also observed two fatal pulmonary AEs of unclear etiology despite thorough workup [22]. In the extension of the trial, two more cases of severe pulmonary edema occurred. Affected patients had excessive midostaurin levels while being administered azole compounds. Thereafter, enrollment of patients receiving azoles was suspended and a clear chest X-ray was made an inclusion criterion. Subsequently, no other pulmonary AEs were observed [23]. Strong interpatient variability of plasma concentrations was noted [22].

Table 1 Selected adverse events of midostaurin and management [16]

A retrospective sub-analysis of the RATIFY trial showed no significant increase in midostaurin- or midostaurin-metabolite-related AEs in patients receiving strong CYP3A4 inhibitors. These were defined as fluconazole, ciprofloxacin, voriconazole, and posaconazole with the latter being administered in less than 40% of patients, even during induction treatment. This exposure-safety-matched control analysis revealed earlier onset of first clinically noted adverse events (CNAE) in patients with higher midostaurin and CPG6221 exposure [24]. Of note, a 1.44-fold increase in midostaurin exposure was observed in patients who had strong CYP3A4 inhibitors administered concomitantly compared to those who had not. CYP3A4 inducing medications, such as rifampin, showed even a 10-fold decrease of midostaurin levels, leading to the clear recommendation to avoid concomitant administration of such agents [25]. Interestingly, administered daily doses of midostaurin varied broadly between early clinical trials with a maximum dose up to 225 mg [23, 26].

Current Food and Drug Administration and European Commission package inserts on midostaurin underline the risk of pulmonary toxicity and recommend withdrawal of the drug upon observation of severe pulmonary events [27, 28].

Posaconazole-based antifungal prophylaxis

Azole-based prophylaxis has proven effective in prevention of IFD in long-term neutropenic patients, allogeneic HSCT, or patients with GvHD and is strongly recommended by numerous international guidelines [29,30,31,32]. In particular posaconazole was successfully investigated in AML patients during induction remission chemotherapy and reduced incidence of IFD from 8 to 2%, now being a worldwide life-saving standard in this population [9]. Administration of posaconazole begins during the first days of administration of chemotherapy and ends upon recovery of neutropenia in a standard dosage of once daily 300 mg tablets [33]. It has an enhanced spectrum of activity, also covering Fusarium spp. and Zygomycetes [34, 35]. Triazoles are inhibitors of the cytochrome p450 enzyme, especially CYP3A4, with posaconazole belonging to the group of strong inhibitors [14]. The drug is available as oral tablet, oral suspension, and intravenous (i.v.) formulation of which the tablet and i.v. are proven to be safe and effective in risk populations [11, 12].

Especially the tablet formulation of the drug inheres this effect being of more reliable pharmacokinetics than the oral suspension formulation. Its distinctly higher peroral bioavailability is associated with higher serum concentrations [36].

Several factors influencing posaconazole exposure in patients with AML/MDS have been identified, among them concomitant use of proton-pump inhibitors, diarrhea or otherwise altered gastrointestinal function, high weight, and co-administration of chemotherapy [37, 38]. Therapeutic drug monitoring (TDM) is advised by current guidelines to optimize exposure and clinical efficacy and for cases of clinical failure [29, 30]. Other antifungals are frequently used for prophylaxis in different patient populations, some of them despite being proved inferior compared to posaconazole (Table 2) [33, 39,40,41,42].

Table 2 Selected antifungals, CYP3A4 impact, and clinical considerations [33, 39,40,41,42]

Drug–drug interactions and therapeutic drug monitoring

Over the years, numerous orally available anti-neoplastic drugs have become available. However, the medical team is confronted with new challenges while treating patients with these agents, in particular with potential DDI linked to the high number of CYP3A4-metabolized drugs [43, 44]. A retrospective study found potential DDI in 46% (total n = 900) of patients treated with oral anti-neoplastic therapy, of which 16% were classified as severe defined as requiring further interventions or being of harmful nature [45]. The high amount of suspected DDI underlines the clinical impact. It should alert clinicians not to indulge the promising results of novel anti-tumor therapies but also consider their side effects. DDI have constantly played a role in medical therapy also affecting hematology patients in the context of immunosuppressive agents, anti-infective drugs, and proton-pump inhibitors [46, 47].

In the case of midostaurin and posaconazole, both drugs are indispensable in the specific clinical setting. Each has been shown to improve overall survival, and numbers needed to treat (NNT) to save a life are low at fifteen and fourteen, respectively [9, 15, 48]. Inhibition of CYP3A4 increases midostaurin in vivo exposure. In pharmacological studies on healthy subjects receiving ketoconazole with concomitant midostaurin, a tenfold increase in area under the curve (AUC) and doubled plasma concentration (Cmax) were observed [25]. With midostaurin being the drug targeting the principal underlying disease and posaconazole considered part of supportive care, co-administration of triazoles with midostaurin could be discouraged. On the other side, it has been suggested to withhold midostaurin only during induction chemotherapy when risk for IFI is the highest [49]. However, this strategy deprives patients of the survival benefit of midostaurin as assessed in the RATIFY trial. Currently, non-evidence-based practice has become routine in this specific case and is displayed in Table 3. Triazoles have been a clear-cut standard for antifungal prophylaxis in hematology, but recommendations and subsequently clinical practice seem to drift apart due to fear of DDI. Standardized approaches are missing, and the lack of clear guidance in this specific setting has been pointed out previously [49]. This leads to a change in behavior of clinicians and leaves the decision of choice of antifungal agent to the treating team.

Table 3 Strategies for clinical use of antifungal prophylaxis in AML patients treated with midostaurin

To assess DDI, a rating and classification system has been developed [50]. Midostaurin-posaconazole DDI were stratified in the third of five categories defined as “monitor therapy” with clinical impact being unclear, but not requiring major therapy alteration [16, 44]. Additionally, several tools have been proposed including multidisciplinary interaction checks, computerized order entry systems, software-based guidance, clinical monitoring, and therapeutic drug monitoring (TDM) [50]. TDM seems to be the most exact and efficient tool in order to assess optimal dosing of drugs with a narrow therapeutic window and DDI. TDM of posaconazole and other antifungals is already established and clinically indicated [51]. In this setting, it should aim to determine a sufficient exposure of the drug. Subsequently, TDM of midostaurin is flattering to adapt and personalize dose depending on the individual inhibitory CYP effect by the antifungal. The large interpatient variability in a drug with a probably narrow therapeutic window like midostaurin supports the use of TDM [52].

Individualization of dosage by means of TDM has been highly recommended in transplant patients on immunosuppressants with antifungals [50]. TDM contributes to patient safety and optimal management with targeted agents in hematology and might be a new option for administration of midostaurin and posaconazole. The lack of a prospective sub-study, which specifically assesses interactions of antifungal prophylaxis and midostaurin by comparing drug levels, questions the reliability of retrospective data [24]. Since the described CNAEs were not clearly defined, and potential AEs as pulmonary edema and QTc-prolongation can be life-threatening or even fatal, this topic requires urgent further evaluation. Given that future approval procedures for novel agents, especially in oncology, might require interaction studies, any study assessing potential DDI in detail as primary objective constitutes to a pioneer position. Additionally, the understanding of pharmacological mechanisms underlying the DDI of midostaurin and posaconazole has to be increased and shall be subject to further pharmacological investigations.

Strategies for antifungal prophylaxis in AML patients treated with midostaurin

Multidisciplinary approaches are essential in current management of hematology patients at risk for potential DDI. Recommendations are given for some novel hematologic drugs despite midostaurin. For example, the use of combination treatment of venetoclax with hypomethylating agents becomes more frequent since it showed promising results in patients with newly diagnosed or relapsed/refractory AML not eligible for intensive chemotherapy [53]. This treatment results in prolonged cytopenia exposing patient to IFD and therefore indicates the use of antifungal prophylaxis in this population [54]. With venetoclax being a CYP3A4 metabolized drug, a dose reduction of 75% is recommended while concomitant posaconazole prophylaxis is administered [55]. An AUC increase up to 8.8-fold was observed, and consistency with CYP3A4-mediated inhibition of venetoclax metabolism was concluded. Of note, this recommendation is based on a prospective sub-study, which included only twelve patients [56]. Nonetheless, this kind of DDI study marks a pioneer role in clinical trials aiming to license novel targeted treatments—especially in hematology. The retrieved evidence paved the way for modified clinical practice considerations in the specific setting, but is lacking for midostaurin [57]. Hence, strategies on how to handle patients on concomitant midostaurin and posaconazole are subject of paper arguments and expert opinion while clear guidance is lacking [49].

Several approaches have been proposed to best prevent potential DDI in concomitant administration of midostaurin and antifungals.

Continue as recommended by manufacturer and closely monitor adverse effects

Administration of posaconazole concomitant to 50 mg twice daily of midostaurin represents the current approved standard for both drugs. These dosages have been investigated under trial conditions and should provide the necessary antileukemic activity [16, 33]. Midostaurin administration at approved dose requires close monitoring on AEs, especially cardiac and pulmonary, but no strict measures are advised by the manufacturer at the moment [16]. Upon occurrence of severe AEs, withdrawal of the drug is recommended. This approach comprises the increased probability to detect midostaurin-related severe AEs too late and expose patients to unpredictable risks. Several publications have recommended this approach assuming the risk of DDI not to be significantly increased [44, 58]. Other authors have raised awareness for the issue considering the risk of DDI clinically important. Thus, this approach remains to be investigated in a robust clinical trial and tested for validity.

Dose reduction of midostaurin during induction remission treatment and concomitant posaconazole administration

Another approach consists in decreasing the dose of midostaurin to 50% (i.e., 25 mg b.i.d) during induction treatment, a strategy which has been proposed and implemented by leading hematologists [59]. On the one hand, this seems reasonable in reducing risk of dose excess of midostaurin and consecutive adverse effects and posaconazole remains as prophylactic agent. However, without local availability of midostaurin blood level monitoring or response in FLT3-expression, this strategy seems questionable considering the decreased antileukemic activity of potentially underdosed midostaurin. Monitoring FLT3 expression has been evaluated but underlies polymerase chain reaction bias and requires bone marrow samples not being feasible on a very regular basis [60, 61]. Furthermore, non-adherence to prophylactic regimen or pharmacokinetic alterations can lead to decreased posaconazole blood levels and subsequently to lower midostaurin levels. Additionally, posaconazole is usually administered only during induction treatment while midostaurin is continued during consolidation until allogeneic HSCT or 1 year of maintenance or even further [16]. Therefore, once posaconazole prophylaxis is stopped, dose increase of midostaurin must be guaranteed in order to avoid underdosing and depriving AML patients of effective therapy.

Switch antifungal prophylaxis to other antifungal agents

A third option in management is a change of class in antifungal prophylaxis. Hematology centers may decide to use echinocandins (EC) in patients receiving midostaurin. Micafungin is broadly used in children, in patients not eligible for posaconazole due to intolerability, and in patients undergoing allogeneic stem cell transplantation for Candida-directed prophylaxis [62, 63]. Micafungin prophylaxis has shown similar results compared to fluconazole in efficacy studies in similar patient populations [64, 65]. It has even been suggested as alternative prophylactic agent in AML [64, 66]. However, this recommendation is derived from studies with limited statistical power. Caspofungin has also been used as prophylactic agent in AML patients with mixed results [67, 68]. EC are the drugs of choice for invasive candidiasis; caspofungin is also approved for salvage treatment of invasive aspergillosis [42]. Nevertheless, they are commonly known to provide poor CNS penetration [69, 70]. Additionally, they lack of coverage against some Mucorales and Fusarium species, which are discovered with increasing frequency in patients with hematological malignancies [71,72,73,74]. Ultimately, they are only available intravenously.

Another appealing choice for primary antifungal prophylaxis is isavuconazole with only moderate CYP3A4 inhibition. It has been proven safe and effective at a 200 mg or 400 mg daily dose in AML and MDS patients [75, 76]. Isavuconazole is an extended spectrum triazole agent approved for treatment of invasive aspergillosis and mucormycosis [39, 77]. Pharmacological features seem to be favorable with very reliable absorption and 98% oral bioavailability. The additional effect of QTc-interval shortening makes this drug a serious alternative for concomitant administration with novel hematological therapies [78, 79]. However, the efficacy data for primary prophylaxis use are contradictory, especially because of a higher rate of breakthrough fungal infections than compared to voriconazole or posaconazole [80,81,82]. This observation seems to be the case especially for breakthrough invasive pulmonary aspergillosis [82]. Voriconazole seems to be a negligible option in this context since it is not considered superior to posaconazole as prophylactic agent and has similar CYP3A4 inhibitory effects [83].

Continue as recommended by manufacturer and implement therapeutic drug monitoring

Finally, the fourth approach foresees implementing TDM for both midostaurin and posaconazole in patients receiving these drugs concomitantly and dose adaption according to measured drug levels.

In a first step, standard-of-care utilization of TDM needs to be implemented for patients receiving midostaurin. Highly sensitive methods for TDM of the drug are available, including UPLC-MS/MS (ultra performance liquid chromatography–tandem mass spectrometry) for simultaneous determination of midostaurin in serum and plasma matrix, but not broadly implemented in TDM units of hematology centers [84,85,86]. To date, reference ranges for novel drugs remain to be determined. In fact, this currently impedes the second step—a standardized dose adaption according to measured midostaurin level. However, obtained results may lead the way to optimized dosing. On the other side, TDM of midostaurin for individual dose adaptation is questionable, if metabolites cannot be measured at the same time. Given the potential anti-leukemic activity, a CYP3A4-mediated inhibition of the metabolization of midostaurin would also decrease the amount of metabolites and therefore their anti-leukemic effect [87].

This fourth strategy displays the “Cologne approach.” At our hospital, patients on midostaurin treatment undergo twice weekly TDM for both drugs simultaneously with the second step of dose adaption being under consideration. In the future, the availability and standardized use of TDM methods in the respective patient population may allow individualized dosing of oncological and anti-infective drugs. Overall, this last approach contributes to a personalized management of AML patients receiving midostaurin and posaconazole concomitantly and may provide the safest and most efficient way to avoid adverse events and outcomes.

Further approaches and additional measures to each strategy are conceivable. A pharmacodynamic assay to measure FLT3-inhibiting effects in plasma in vivo has been proposed. This approach can complement pharmacokinetic data by focusing on the target of a drug and not on a drug itself as conventional pharmacokinetic methods like TDM do [87]. Some hematology centers may consider avoiding triazole prophylaxis completely and instead use diagnostic-driven counteractions including galactomannan monitoring and chest CT in the initial workup for febrile neutropenia. At least during induction remission chemotherapy, triazole antifungal prophylaxis seems to be of higher importance than FLT3-inhibitor administration. A survival benefit has been shown for posaconazole during this highest-risk period to develop IFD, whereas midostaurin seems to not play a role in CR attainment during initial treatment and might be more beneficial on a long-term perspective [88]. Reduction of antifungal dose cannot be recommended generally since their efficacy has been linked strongly to sufficient plasma concentrations [89].

Future developments

Antifungal prophylaxis becomes more complex in modern AML therapy as with any hematological malignancy. On the one hand, this is due to emerging fungal pathogens with resistance to antifungal agents used for prophylaxis [90, 91] and breakthrough fungal infections [92]. On the other hand, novel drugs for AML treatment comprising increased interaction potential with triazoles will be more frequently administered. Antifungal prophylaxis might be individualized according to the given anti-leukemic agent [44].

The use of CYP3A4 metabolized drugs will expand in the future. The clinical efficacy and safety of midostaurin in FLT3WT AML are currently investigated in an ongoing Phase III trial (NCT03512197) as well as the prolonged treatment and application in other populations [59, 93, 94]. New-generation FLT3 inhibitors are already approved or currently in trial, such as gilteritinib, quizartinib, or lestaurtinib [95,96,97]. Further multikinase inhibitors might become available with expanded approval for second- or third-line treatment, relapsed/refractory AML, and other indications. Recently, other drugs, which underlie a CYP3A4-mediated metabolism, have been approved, like the isocitrate dehydrogenase (IDH) inhibitors ivosidenib and enasidenib or the sonic hedgehog inhibitor glasdegib [98,99,100,101] and more agents are under development [102]. Unfortunately, potential DDI are frequently not assessed in clinical trials. Enrolled patient populations do not necessarily represent a real-world population complicating routine use upon approval [103]. Expected approval of these drugs and expanded use of midostaurin will increase clinical use and has to raise awareness in the treating medical team as potential DDI other than with antifungals while on concomitant midostaurin treatment have been identified [104]. In the specific case of midostaurin and posaconazole, it remains important to emphasize that clinicians should be reassured that posaconazole prophylaxis does neither represent a contraindication to administer midostaurin nor the other way around.

A personalized-medicine approach includes standard of care therapeutic drug monitoring for antifungal agents and antileukemic drugs simultaneously and following dose adaptions according to drug levels [52]. TDM already plays a role in oncology in drugs with a narrow therapeutic window to increase efficacy and reduce toxicity. However, determination of the optimal management and routine use of TDM for dose adaptation remains to be investigated in real-life clinical trials. TDM methods have not been established broadly at hematology centers. This is also of high importance in orally available drugs and other drugs undergoing CYP3A4 metabolization. CYP3A4 interactions are a subject to clinical practice in nearly all medical specialties and being investigated broadly. Future monitoring of CYP3A4 could be standardized by routinely determining 4-ß-hydroxycholesterol (4βHC), a marker measuring the activity of this CYP enzyme. It has been proposed for that purpose mostly for patients treated with strong CYP-inducers, but also inhibitors [105, 106]. Another recent discovery of CYP3A4 inhibitors preventing FLT3-TKI resistance by inhibiting CYP-expressing bone marrow stromal cells in vivo seems of interest to rather promote CYP3A4 inhibitors in patients on FLT3 inhibitors in the future [19]. Novel antifungal agents are upcoming and might also represent future options for antifungal prophylaxis. However, until this point optimal management of patients receiving drugs which inheres potential of DDI must be warranted.

Novel targeted drugs improve patient prognosis in hematology and oncology. Combination with antifungal prophylaxis challenges clinicians due to pharmacological profiles favoring drug–drug interactions. Severe AEs have been observed; however, in current evidence it remains unclear if they can be directly linked to DDI. Especially FLT3 inhibitors are promising in the present and future treatment of AML. It appears timely to evaluate their clinical impact on DDI and their outcome. Several management strategies have been proposed, but evidence on which approach to use is scarce and the lack of robust clinical studies assessing incidence of IFD and clinical impact of DDI pave the way to neglecting a life-saving standard. Pharmaceutical companies addressing this issue in phase III and IV trials may take a pioneer role in this field. TDM will become increasingly important to individualize and personalize combination antineoplastic and antifungal treatment.

References

  1. 1.

    Estey EH (2018) Acute myeloid leukemia: 2019 update on risk-stratification and management. Am J Hematol 93(10):1267–1291. https://doi.org/10.1002/ajh.25214

    Article  PubMed  Google Scholar 

  2. 2.

    SEER Cancer Stat Facts: Leukemia—acute myeloid leukemia. (2020) National Cancer Institute. https://seer.cancer.gov/statfacts/html/amyl.html. Accessed 04-01-2020

  3. 3.

    Gilliland DG, Griffin JD (2002) The roles of FLT3 in hematopoiesis and leukemia. Blood 100(5):1532–1542. https://doi.org/10.1182/blood-2002-02-0492

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Yamamoto Y, Kiyoi H, Nakano Y, Suzuki R, Kodera Y, Miyawaki S, Asou N, Kuriyama K, Yagasaki F, Shimazaki C, Akiyama H, Saito K, Nishimura M, Motoji T, Shinagawa K, Takeshita A, Saito H, Ueda R, Ohno R, Naoe T (2001) Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood 97(8):2434–2439. https://doi.org/10.1182/blood.v97.8.2434

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Levis M (2013) FLT3 mutations in acute myeloid leukemia: what is the best approach in 2013? Hematology Am Soc Hematol Educ Program 2013:220–226. https://doi.org/10.1182/asheducation-2013.1.220

  6. 6.

    Frohling S, Schlenk RF, Breitruck J, Benner A, Kreitmeier S, Tobis K, Dohner H, Dohner K (2002) Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm. Blood 100(13):4372–4380. https://doi.org/10.1182/blood-2002-05-1440

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Pagano L, Akova M, Dimopoulos G, Herbrecht R, Drgona L, Blijlevens N (2011) Risk assessment and prognostic factors for mould-related diseases in immunocompromised patients. J Antimicrob Chemother 66(Suppl 1):i5–i14. https://doi.org/10.1093/jac/dkq437

  8. 8.

    Bodey GP (1966) Infectious complications of acute leukemia. Med Times 94(9):1076–1085

    CAS  PubMed  Google Scholar 

  9. 9.

    Cornely OA, Maertens J, Winston DJ, Perfect J, Ullmann AJ, Walsh TJ, Helfgott D, Holowiecki J, Stockelberg D, Goh Y-T, Petrini M, Hardalo C, Suresh R, Angulo-Gonzalez D (2007) Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med 356(4):348–359. https://doi.org/10.1056/NEJMoa061094

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Ullmann AJ, Lipton JH, Vesole DH, Chandrasekar P, Langston A, Tarantolo SR, Greinix H, Morais de Azevedo W, Reddy V, Boparai N, Pedicone L, Patino H, Durrant S (2007) Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. N Engl J Med 356(4):335–347. https://doi.org/10.1056/NEJMoa061098

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Cornely OA, Robertson MN, Haider S, Grigg A, Geddes M, Aoun M, Heinz WJ, Raad I, Schanz U, Meyer RG, Hammond SP, Mullane KM, Ostermann H, Ullmann AJ, Zimmerli S, Van Iersel M, Hepler DA, Waskin H, Kartsonis NA, Maertens J (2017) Pharmacokinetics and safety results from the Phase 3 randomized, open-label, study of intravenous posaconazole in patients at risk of invasive fungal disease. J Antimicrob Chemother 72(12):3406–3413. https://doi.org/10.1093/jac/dkx263

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Cornely OA, Duarte RF, Haider S, Chandrasekar P, Helfgott D, Jimenez JL, Candoni A, Raad I, Laverdiere M, Langston A, Kartsonis N, Van Iersel M, Connelly N, Waskin H (2016) Phase 3 pharmacokinetics and safety study of a posaconazole tablet formulation in patients at risk for invasive fungal disease. J Antimicrob Chemother 71(3):718–726. https://doi.org/10.1093/jac/dkv380

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Farowski F, Vehreschild JJ, Cornely OA (2007) Posaconazole: a next-generation triazole antifungal. Future Microbiol 2(3):231–243. https://doi.org/10.2217/17460913.2.3.231

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Wexler D, Courtney R, Richards W, Banfield C, Lim J, Laughlin M (2004) Effect of posaconazole on cytochrome P450 enzymes: a randomized, open-label, two-way crossover study. Eur J Pharm Sci 21(5):645–653. https://doi.org/10.1016/j.ejps.2004.01.005

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, Thiede C, Prior TW, Dohner K, Marcucci G, Lo-Coco F, Klisovic RB, Wei A, Sierra J, Sanz MA, Brandwein JM, de Witte T, Niederwieser D, Appelbaum FR, Medeiros BC, Tallman MS, Krauter J, Schlenk RF, Ganser A, Serve H, Ehninger G, Amadori S, Larson RA, Dohner H (2017) Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med 377(5):454–464. https://doi.org/10.1056/NEJMoa1614359

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    RYDAPT® (midostaurin)—package insert and label information (December 2019). Novartis Pharmaceuticals Corporation, East Hanover

  17. 17.

    Daver N, Schlenk RF, Russell NH, Levis MJ (2019) Targeting FLT3 mutations in AML: review of current knowledge and evidence. Leukemia 33(2):299–312. https://doi.org/10.1038/s41375-018-0357-9

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Stone RM, Manley PW, Larson RA, Capdeville R (2018) Midostaurin: its odyssey from discovery to approval for treating acute myeloid leukemia and advanced systemic mastocytosis. Blood Adv 2(4):444–453. https://doi.org/10.1182/bloodadvances.2017011080

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Chang YT, Hernandez D, Alonso S, Gao M, Su M, Ghiaur G, Levis MJ, Jones RJ (2019) Role of CYP3A4 in bone marrow microenvironment-mediated protection of FLT3/ITD AML from tyrosine kinase inhibitors. Blood Adv 3(6):908–916. https://doi.org/10.1182/bloodadvances.2018022921

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Propper DJ, McDonald AC, Man A, Thavasu P, Balkwill F, Braybrooke JP, Caponigro F, Graf P, Dutreix C, Blackie R, Kaye SB, Ganesan TS, Talbot DC, Harris AL, Twelves C (2001) Phase I and pharmacokinetic study of PKC412, an inhibitor of protein kinase C. J Clin Oncol 19(5):1485–1492. https://doi.org/10.1200/jco.2001.19.5.1485

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Abbas HA, Alfayez M, Kadia T, Ravandi-Kashani F, Daver N (2019) Midostaurin in acute myeloid leukemia: an evidence-based review and patient selection. Cancer Manag Res 11:8817–8828. https://doi.org/10.2147/CMAR.S177894

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Stone RM, DeAngelo DJ, Klimek V, Galinsky I, Estey E, Nimer SD, Grandin W, Lebwohl D, Wang Y, Cohen P, Fox EA, Neuberg D, Clark J, Gilliland DG, Griffin JD (2005) Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412. Blood 105(1):54–60. https://doi.org/10.1182/blood-2004-03-0891

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Stone RM (2007) A phase III randomized, double-blind study of induction (Daunorubicin/Cytarabin) and consolidation (high-dose Cytarabine) chemotherapy + Midostaurin (PKC412) (IND # TBD) or placebo in newly diagnosed patients < 60 years of age with FLT3 mutated acute myeloid leukemia (AML). Study Protocol

  24. 24.

    Ouatas T, Duval V, Sinclair K, Berkowitz N (2017) Concomitant use of Midostaurin with strong CYP3A4 inhibitors: an analysis from the Ratify trial. Blood 130(Suppl 1):3814–3814

    Google Scholar 

  25. 25.

    Dutreix C, Munarini F, Lorenzo S, Roesel J, Wang Y (2013) Investigation into CYP3A4-mediated drug-drug interactions on midostaurin in healthy volunteers. Cancer Chemother Pharmacol 72(6):1223–1234. https://doi.org/10.1007/s00280-013-2287-6

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Fischer T, Stone RM, Deangelo DJ, Galinsky I, Estey E, Lanza C, Fox E, Ehninger G, Feldman EJ, Schiller GJ, Klimek VM, Nimer SD, Gilliland DG, Dutreix C, Huntsman-Labed A, Virkus J, Giles FJ (2010) Phase IIB trial of oral Midostaurin (PKC412), the FMS-like tyrosine kinase 3 receptor (FLT3) and multi-targeted kinase inhibitor, in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome with either wild-type or mutated FLT3. J Clin Oncol 28(28):4339–4345. https://doi.org/10.1200/jco.2010.28.9678

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Food and Drug Aadministration (2017) https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/207997s000lbl.pdf. Accessed 05-15-2020

  28. 28.

    European Commission (2017) https://ec.europa.eu/health/documents/community-register/2017/20170918138684/anx_138684_de.pdf. Accessed 05-15-2020

  29. 29.

    Mellinghoff SC, Panse J, Alakel N, Behre G, Buchheidt D, Christopeit M, Hasenkamp J, Kiehl M, Koldehoff M, Krause SW, Lehners N, von Lilienfeld-Toal M, Lohnert AY, Maschmeyer G, Teschner D, Ullmann AJ, Penack O, Ruhnke M, Mayer K, Ostermann H, Wolf HH, Cornely OA (2018) 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). Ann Hematol 97(2):197–207. https://doi.org/10.1007/s00277-017-3196-2

    Article  PubMed  Google Scholar 

  30. 30.

    Patterson TF, Thompson GR III, Denning DW, Fishman JA, Hadley S, Herbrecht R, Kontoyiannis DP, Marr KA, Morrison VA, Nguyen MH, Segal BH, Steinbach WJ, Stevens DA, Walsh TJ, Wingard JR, Young J-AH, Bennett JE (2016) Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis 63(4):e1–e60. https://doi.org/10.1093/cid/ciw326

    Article  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Maertens JA, Girmenia C, Bruggemann RJ, Duarte RF, Kibbler CC, Ljungman P, Racil Z, Ribaud P, Slavin MA, Cornely OA, Peter Donnelly J, Cordonnier C (2018) European guidelines for primary antifungal prophylaxis in adult haematology patients: summary of the updated recommendations from the European Conference on Infections in Leukaemia. J Antimicrob Chemother 73(12):3221–3230. https://doi.org/10.1093/jac/dky286

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Taplitz RA, Kennedy EB, Bow EJ, Crews J, Gleason C, Hawley DK, Langston AA, Nastoupil LJ, Rajotte M, Rolston KV, Strasfeld L, Flowers CR (2018) Antimicrobial prophylaxis for adult patients with Cancer-related immunosuppression: ASCO and IDSA clinical practice guideline update. J Clin Oncol 36(30):3043–3054. https://doi.org/10.1200/jco.18.00374

    Article  PubMed  Google Scholar 

  33. 33.

    Noxafil® (posaconazole)—prescribing information (2019). Merck & Co Inc., Whitehouse Station,

  34. 34.

    Cornely OA (2008) Aspergillus to Zygomycetes: causes, risk factors, prevention, and treatment of invasive fungal infections. Infection 36(4):296–313. https://doi.org/10.1007/s15010-008-7357-z

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Cornely OA, Vehreschild JJ, Ruping MJ (2009) Current experience in treating invasive zygomycosis with posaconazole. Clin Microbiol Infect 15(Suppl 5):77–81. https://doi.org/10.1111/j.1469-0691.2009.02985.x

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Petitcollin A, Crochette R, Tron C, Verdier MC, Boglione-Kerrien C, Vigneau C, Bellissant E, Lemaitre F (2016) Increased inhibition of cytochrome P450 3A4 with the tablet formulation of posaconazole. Drug Metab Pharmacokinet 31(5):389–393. https://doi.org/10.1016/j.dmpk.2016.05.001

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Vehreschild JJ, Muller C, Farowski F, Vehreschild MJ, Cornely OA, Fuhr U, Kreuzer KA, Hallek M, Kohl V (2012) Factors influencing the pharmacokinetics of prophylactic posaconazole oral suspension in patients with acute myeloid leukemia or myelodysplastic syndrome. Eur J Clin Pharmacol 68(6):987–995. https://doi.org/10.1007/s00228-012-1212-y

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Cornely OA, Helfgott D, Langston A, Heinz W, Vehreschild JJ, Vehreschild MJ, Krishna G, Ma L, Huyck S, McCarthy MC (2012) Pharmacokinetics of different dosing strategies of oral posaconazole in patients with compromised gastrointestinal function and who are at high risk for invasive fungal infection. Antimicrob Agents Chemother 56(5):2652–2658. https://doi.org/10.1128/aac.05937-11

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. 39.

    CRESEMBA® (Isavuconazoium)—prescribing information (2019). Astellas Pharma US Inc., Northbrook.

  40. 40.

    Vfend® (voriconazole)—precribing information (2019). Pfizer Inc., New York

  41. 41.

    Mycamine® (micafungin)—precribing information (2019). Astellas Pharma Inc., Northbrook.

  42. 42.

    CANCIDAS® (caspofungin acetate)—prescribing information (2019). Merck & Co Inc., Whitehouse Station.

  43. 43.

    Petri H (2018) Arzneimitteltherapiesicherheit: Metabolische Interaktionen der Proteinkinase-Inhibitoren. Dtsch Arztebl International 115 (7):[32]

  44. 44.

    Lindsay J, Teh BW, Micklethwaite K, Slavin M (2019) Azole antifungals and new targeted therapies for hematological malignancy. Curr Opin Infect Dis 32(6):538–545. https://doi.org/10.1097/qco.0000000000000611

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    van Leeuwen RWF, Brundel DHS, Neef C, van Gelder T, Mathijssen RHJ, Burger DM, Jansman FGA (2013) Prevalence of potential drug-drug interactions in cancer patients treated with oral anticancer drugs. Br J Cancer 108(5):1071–1078. https://doi.org/10.1038/bjc.2013.48

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Groll AH, Townsend R, Desai A, Azie N, Jones M, Engelhardt M, Schmitt-Hoffman AH, Bruggemann RJM (2017) Drug-drug interactions between triazole antifungal agents used to treat invasive aspergillosis and immunosuppressants metabolized by cytochrome P450 3A4. Transpl Infect Dis 19(5). https://doi.org/10.1111/tid.12751

  47. 47.

    Pejcic A, Jankovic SM, Opancina V, Babic G, Milosavljevic M (2019) Drug-drug interactions in patients receiving hematopoietic stem cell transplantation. Expert Opin Drug Metab Toxicol 15(1):49–59. https://doi.org/10.1080/17425255.2019.1552256

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Cornely OA, Ullmann AJ (2008) Numbers needed to treat with posaconazole prophylaxis to prevent invasive fungal infection and death. Clin Infect Dis 46(10):1626–1627; author reply 1627-1628. https://doi.org/10.1086/587177

    Article  PubMed  Google Scholar 

  49. 49.

    Weis TM, Marini BL, Bixby DL, Perissinotti AJ (2019) Clinical considerations for the use of FLT3 inhibitors in acute myeloid leukemia. Crit Rev Oncol Hematol 141:125–138. https://doi.org/10.1016/j.critrevonc.2019.06.011

    Article  PubMed  Google Scholar 

  50. 50.

    Lempers VJ, Martial LC, Schreuder MF, Blijlevens NM, Burger DM, Aarnoutse RE, Bruggemann RJ (2015) Drug-interactions of azole antifungals with selected immunosuppressants in transplant patients: strategies for optimal management in clinical practice. Curr Opin Pharmacol 24:38–44. https://doi.org/10.1016/j.coph.2015.07.002

    CAS  Article  PubMed  Google Scholar 

  51. 51.

    Brüggemann RJM, Aarnoutse RE (2015) Fundament and prerequisites for the application of an antifungal TDM service. Current Fungal Infection Reports 9(2):122–129. https://doi.org/10.1007/s12281-015-0224-3

    Article  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Oellerich M, Kanzow P, Walson PD (2017) Therapeutic drug monitoring—key to personalized pharmacotherapy. Clin Biochem 50(7–8):375–379. https://doi.org/10.1016/j.clinbiochem.2017.01.007

    Article  PubMed  Google Scholar 

  53. 53.

    DiNardo CD, Pratz KW, Letai A, Jonas BA, Wei AH, Thirman M, Arellano M, Frattini MG, Kantarjian H, Popovic R, Chyla B, Xu T, Dunbar M, Agarwal SK, Humerickhouse R, Mabry M, Potluri J, Konopleva M, Pollyea DA (2018) Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study. Lancet Oncol 19(2):216–228. https://doi.org/10.1016/s1470-2045(18)30010-x

    CAS  Article  PubMed  Google Scholar 

  54. 54.

    Aldoss I, Dadwal S, Zhang J, Tegtmeier B, Mei M, Arslan S, Al Malki MM, Salhotra A, Ali H, Aribi A, Sandhu K, Khaled S, Snyder D, Nakamura R, Stein AS, Forman SJ, Marcucci G, Pullarkat V (2019) Invasive fungal infections in acute myeloid leukemia treated with venetoclax and hypomethylating agents. Blood Adv 3(23):4043–4049. https://doi.org/10.1182/bloodadvances.2019000930

    Article  PubMed  PubMed Central  Google Scholar 

  55. 55.

    VENCLEXTA® (venetoclax)—prescribing information (2019). AbbVie Inc., North Chicago

  56. 56.

    Agarwal SK, DiNardo CD, Potluri J, Dunbar M, Kantarjian HM, Humerickhouse RA, Wong SL, Menon RM, Konopleva MY, Salem AH (2017) Management of Venetoclax-Posaconazole Interaction in acute myeloid leukemia patients: evaluation of dose adjustments. Clin Ther 39(2):359–367. https://doi.org/10.1016/j.clinthera.2017.01.003

    CAS  Article  PubMed  Google Scholar 

  57. 57.

    Mei M, Aldoss I, Marcucci G, Pullarkat V (2019) Hypomethylating agents in combination with venetoclax for acute myeloid leukemia: update on clinical trial data and practical considerations for use. Am J Hematol 94(3):358–362. https://doi.org/10.1002/ajh.25369

    Article  PubMed  Google Scholar 

  58. 58.

    Schlafer D (2019) Management of Midostaurin-CYP3A4 drug-drug interactions in patients with acute myeloid leukemia. Oncology (Williston Park) 33(7)

  59. 59.

    Schlenk RF, Weber D, Fiedler W, Salih HR, Wulf G, Salwender H, Schroeder T, Kindler T, Lubbert M, Wolf D, Westermann J, Kraemer D, Gotze KS, Horst HA, Krauter J, Girschikofsky M, Ringhoffer M, Sudhoff T, Held G, Derigs HG, Schroers R, Greil R, Griesshammer M, Lange E, Burchardt A, Martens U, Hertenstein B, Marretta L, Heuser M, Thol F, Gaidzik VI, Herr W, Krzykalla J, Benner A, Dohner K, Ganser A, Paschka P, Dohner H (2019) Midostaurin added to chemotherapy and continued single-agent maintenance therapy in acute myeloid leukemia with FLT3-ITD. Blood 133(8):840–851. https://doi.org/10.1182/blood-2018-08-869453

    CAS  Article  PubMed  Google Scholar 

  60. 60.

    De Marchi F, Candoni A, Zannier ME, Haley L, Lau BW, Fanin R (2017) Concomitant monitoring of WT1 and FLT3-ITD expression in FLT3-ITD acute myeloid leukemia patients: which should we trust as a minimal residual disease marker? Am J Hematol 92(5):E72–e74. https://doi.org/10.1002/ajh.24686

    Article  PubMed  Google Scholar 

  61. 61.

    Levis M (2017) FLT3 as a marker of minimal residual disease: time to re-think? Am J Hematol 92(4):329–330. https://doi.org/10.1002/ajh.24667

    Article  PubMed  Google Scholar 

  62. 62.

    Rothe A, Classen A, Carney J, Hallek M, Mellinghoff SC, Scheid C, Holtick U, von Bergwelt-Baildon M (2019) Bridging antifungal prophylaxis with 50 mg or 100 mg micafungin in allogeneic stem cell transplantation: a retrospective analysis. Eur J Haematol 104:291–298. https://doi.org/10.1111/ejh.13372

    CAS  Article  Google Scholar 

  63. 63.

    van Burik JA, Ratanatharathorn V, Stepan DE, Miller CB, Lipton JH, Vesole DH, Bunin N, Wall DA, Hiemenz JW, Satoi Y, Lee JM, Walsh TJ (2004) Micafungin versus fluconazole for prophylaxis against invasive fungal infections during neutropenia in patients undergoing hematopoietic stem cell transplantation. Clin Infect Dis 39(10):1407–1416. https://doi.org/10.1086/422312

    Article  PubMed  Google Scholar 

  64. 64.

    Park H, Youk J, Shin DY, Hong J, Kim I, Kim NJ, Lee JO, Bang SM, Yoon SS, Park WB, Koh Y (2019) Micafungin prophylaxis for acute leukemia patients undergoing induction chemotherapy. BMC Cancer 19(1):358. https://doi.org/10.1186/s12885-019-5557-9

    Article  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Park S, Kim K, Jang JH, Kim SJ, Kim WS, Chung DR, Kang CI, Peck KR, Jung CW (2016) Randomized trial of micafungin versus fluconazole as prophylaxis against invasive fungal infections in hematopoietic stem cell transplant recipients. J Inf Secur 73(5):496–505. https://doi.org/10.1016/j.jinf.2016.06.011

    Article  Google Scholar 

  66. 66.

    Epstein DJ, Seo SK, Huang YT, Park JH, Klimek VM, Berman E, Tallman MS, Frattini MG, Papanicolaou GA (2018) Micafungin versus posaconazole prophylaxis in acute leukemia or myelodysplastic syndrome: a randomized study. J Inf Secur 77(3):227–234. https://doi.org/10.1016/j.jinf.2018.03.015

    Article  Google Scholar 

  67. 67.

    Fisher BT, Zaoutis T, Dvorak CC, Nieder M, Zerr D, Wingard JR, Callahan C, Villaluna D, Chen L, Dang H, Esbenshade AJ, Alexander S, Wiley JM, Sung L (2019) Effect of caspofungin vs fluconazole prophylaxis on invasive fungal disease among children and Young adults with acute myeloid leukemia: a randomized clinical trial. Jama 322(17):1673–1681. https://doi.org/10.1001/jama.2019.15702

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Mattiuzzi GN, Alvarado G, Giles FJ, Ostrosky-Zeichner L, Cortes J, O'Brien S, Verstovsek S, Faderl S, Zhou X, Raad II, Bekele BN, Leitz GJ, Lopez-Roman I, Estey EH (2006) Open-label, randomized comparison of itraconazole versus caspofungin for prophylaxis in patients with hematologic malignancies. Antimicrob Agents Chemother 50(1):143–147. https://doi.org/10.1128/aac.50.1.143-147.2006

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Traunmuller F, Popovic M, Konz KH, Smolle-Juttner FM, Joukhadar C (2011) Efficacy and safety of current drug therapies for invasive aspergillosis. Pharmacology 88(3–4):213–224. https://doi.org/10.1159/000331860

    CAS  Article  PubMed  Google Scholar 

  70. 70.

    Patil A, Majumdar S (2017) Echinocandins in antifungal pharmacotherapy. J Pharm Pharmacol 69(12):1635–1660. https://doi.org/10.1111/jphp.12780

    CAS  Article  PubMed  Google Scholar 

  71. 71.

    Groll AH, Stergiopoulou T, Roilides E, Walsh TJ (2005) Micafungin: pharmacology, experimental therapeutics and clinical applications. Expert Opin Investig Drugs 14(4):489–509. https://doi.org/10.1517/13543784.14.4.489

    CAS  Article  PubMed  Google Scholar 

  72. 72.

    Rosa PDD, Ramirez-Castrillon M, Borges R, Aquino V, Meneghello Fuentefria A, Zubaran Goldani L (2019) Epidemiological aspects and characterization of the resistance profile of Fusarium spp. in patients with invasive fusariosis. J Med Microbiol 68(10):1489–1496. https://doi.org/10.1099/jmm.0.001059

    CAS  Article  PubMed  Google Scholar 

  73. 73.

    Pagano L, Busca A, Candoni A, Cattaneo C, Cesaro S, Fanci R, Nadali G, Potenza L, Russo D, Tumbarello M, Nosari A, Aversa F (2017) Risk stratification for invasive fungal infections in patients with hematological malignancies: SEIFEM recommendations. Blood Rev 31(2):17–29. https://doi.org/10.1016/j.blre.2016.09.002

    Article  PubMed  Google Scholar 

  74. 74.

    Cornely OA, Alastruey-Izquierdo A, Arenz D, Chen SCA, Dannaoui E, Hochhegger B, Hoenigl M, Jensen HE, Lagrou K, Lewis RE, Mellinghoff SC, Mer M, Pana ZD, Seidel D, Sheppard DC, Wahba R, Akova M, Alanio A, Al-Hatmi AMS, Arikan-Akdagli S, Badali H, Ben-Ami R, Bonifaz A, Bretagne S, Castagnola E, Chayakulkeeree M, Colombo AL, Corzo-Leon DE, Drgona L, Groll AH, Guinea J, Heussel CP, Ibrahim AS, Kanj SS, Klimko N, Lackner M, Lamoth F, Lanternier F, Lass-Floerl C, Lee DG, Lehrnbecher T, Lmimouni BE, Mares M, Maschmeyer G, Meis JF, Meletiadis J, Morrissey CO, Nucci M, Oladele R, Pagano L, Pasqualotto A, Patel A, Racil Z, Richardson M, Roilides E, Ruhnke M, Seyedmousavi S, Sidharthan N, Singh N, Sinko J, Skiada A, Slavin M, Soman R, Spellberg B, Steinbach W, Tan BH, Ullmann AJ, Vehreschild JJ, Vehreschild M, Walsh TJ, White PL, Wiederhold NP, Zaoutis T, Chakrabarti A (2019) Global guideline for the diagnosis and management of mucormycosis: an initiative of the European Confederation of Medical Mycology in cooperation with the Mycoses Study Group Education and Research Consortium. Lancet Infect Dis 19(12):e405–e421. https://doi.org/10.1016/s1473-3099(19)30312-3

    CAS  Article  PubMed  Google Scholar 

  75. 75.

    Cornely OA, Bohme A, Schmitt-Hoffmann A, Ullmann AJ (2015) Safety and pharmacokinetics of isavuconazole as antifungal prophylaxis in acute myeloid leukemia patients with neutropenia: results of a phase 2, dose escalation study. Antimicrob Agents Chemother 59(4):2078–2085. https://doi.org/10.1128/aac.04569-14

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Bose P, McCue D, Wurster S, Wiederhold NP, Konopleva M, Kadia TM, Borthakur G, Ravandi F, Masarova L, Takahashi K, Zeev E, Yilmaz M, Daver N, Pemmaraju N, Naqvi K, Rausch CR, Marx KR, Qiao W, Huang X, Bivins CA, Pierce SA, Kantarjian HM, Kontoyiannis DP (2020) Isavuconazole as primary anti-fungal prophylaxis in patients with acute myeloid leukemia or myelodysplastic syndrome: an open-label, prospective. Phase II Study Clin Infect Dis. https://doi.org/10.1093/cid/ciaa358

  77. 77.

    Marty FM, Ostrosky-Zeichner L, Cornely OA, Mullane KM, Perfect JR, Thompson GR 3rd, Alangaden GJ, Brown JM, Fredricks DN, Heinz WJ, Herbrecht R, Klimko N, Klyasova G, Maertens JA, Melinkeri SR, Oren I, Pappas PG, Racil Z, Rahav G, Santos R, Schwartz S, Vehreschild JJ, Young JH, Chetchotisakd P, Jaruratanasirikul S, Kanj SS, Engelhardt M, Kaufhold A, Ito M, Lee M, Sasse C, Maher RM, Zeiher B, Vehreschild M (2016) Isavuconazole treatment for mucormycosis: a single-arm open-label trial and case-control analysis. Lancet Infect Dis 16(7):828–837. https://doi.org/10.1016/s1473-3099(16)00071-2

    CAS  Article  PubMed  Google Scholar 

  78. 78.

    Mellinghoff SC, Bassetti M, Dorfel D, Hagel S, Lehners N, Plis A, Schalk E, Vena A, Cornely OA (2018) Isavuconazole shortens the QTc interval. Mycoses 61(4):256–260. https://doi.org/10.1111/myc.12731

    CAS  Article  PubMed  Google Scholar 

  79. 79.

    Townsend R, Dietz A, Hale C, Akhtar S, Kowalski D, Lademacher C, Lasseter K, Pearlman H, Rammelsberg D, Schmitt-Hoffmann A, Yamazaki T, Desai A (2017) Pharmacokinetic evaluation of CYP3A4-mediated drug-drug interactions of Isavuconazole with rifampin, ketoconazole, midazolam, and ethinyl estradiol/norethindrone in healthy adults. Clin Pharmacol Drug Dev 6(1):44–53. https://doi.org/10.1002/cpdd.285

    CAS  Article  PubMed  Google Scholar 

  80. 80.

    Fung M, Schwartz BS, Doernberg SB, Langelier C, Lo M, Graff L, Tan M, Logan AC, Chin-Hong P, Babik JM (2018) Breakthrough invasive fungal infections on Isavuconazole prophylaxis and treatment: what is happening in the real-world setting? Clin Infect Dis 67(7):1142–1143. https://doi.org/10.1093/cid/ciy260

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  81. 81.

    Rausch CR, DiPippo AJ, Bose P, Kontoyiannis DP (2018) Breakthrough fungal infections in patients with leukemia receiving Isavuconazole. Clin Infect Dis 67(10):1610–1613. https://doi.org/10.1093/cid/ciy406

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Fontana L, Perlin DS, Zhao Y, Noble BN, Lewis JS, Strasfeld L, Hakki M (2020) Isavuconazole prophylaxis in patients with hematologic malignancies and hematopoietic cell transplant recipients. Clin Infect Dis 70(5):723–730. https://doi.org/10.1093/cid/ciz282

    CAS  Article  PubMed  Google Scholar 

  83. 83.

    Mattiuzzi GN, Cortes J, Alvarado G, Verstovsek S, Koller C, Pierce S, Blamble D, Faderl S, Xiao L, Hernandez M, Kantarjian H (2011) Efficacy and safety of intravenous voriconazole and intravenous itraconazole for antifungal prophylaxis in patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome. Support Care Cancer 19(1):19–26. https://doi.org/10.1007/s00520-009-0783-3

    Article  PubMed  Google Scholar 

  84. 84.

    Müller C, FIetz C, Streichert T, Cornely OA, Stemler J, Wiesen M (2019) LC-MS/MS-method for the determination of midostaurin—a multitargeted tyrosine kinase inhibitor for the treatment of for acute myeloid leukemia. Paper presented at the 16. Jahrestagung der Deutschen Gesellschaft für Klinische Chemie und Laboratoriumsmedizin e.V., Magdeburg,

  85. 85.

    Illmer T, Thiede HM, Thiede C, Bornhauser M, Schaich M, Schleyer E, Ehninger G (2007) A highly sensitive method for the detection of PKC412 (CGP41251) and its metabolites by high-performance liquid chromatography. J Pharmacol Toxicol Methods 56(1):23–27. https://doi.org/10.1016/j.vascn.2006.11.005

    CAS  Article  PubMed  Google Scholar 

  86. 86.

    Bourget P, Amin A, Chandesris MO, Vidal F, Merlette C, Hirsch I, Cabaret L, Carvalhosa A, Mogenet A, Frenzel L, Damaj G, Lortholary O, Hermine O (2014) Liquid chromatography-tandem mass spectrometry assay for therapeutic drug monitoring of the tyrosine kinase inhibitor, midostaurin, in plasma from patients with advanced systemic mastocytosis. J Chromatogr B Anal Technol Biomed Life Sci 944:175–181. https://doi.org/10.1016/j.jchromb.2013.11.003

    CAS  Article  Google Scholar 

  87. 87.

    Levis M, Brown P, Smith BD, Stine A, Pham R, Stone R, Deangelo D, Galinsky I, Giles F, Estey E, Kantarjian H, Cohen P, Wang Y, Roesel J, Karp JE, Small D (2006) Plasma inhibitory activity (PIA): a pharmacodynamic assay reveals insights into the basis for cytotoxic response to FLT3 inhibitors. Blood 108(10):3477–3483. https://doi.org/10.1182/blood-2006-04-015743

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  88. 88.

    Lewis RE AML - In the era of FLT3 inhibitors. In: 9th Trends in Medical Mycology (TIMM-9), Nice, France, 2019. Nice,

  89. 89.

    Andes D (2006) Pharmacokinetics and pharmacodynamics of antifungals. Infect Dis Clin N Am 20(3):679–697. https://doi.org/10.1016/j.idc.2006.06.007

    Article  Google Scholar 

  90. 90.

    Verweij PE, Chowdhary A, Melchers WJ, Meis JF (2016) Azole resistance in Aspergillus fumigatus: can we retain the clinical use of mold-active antifungal azoles? Clin Infect Dis 62(3):362–368. https://doi.org/10.1093/cid/civ885

    CAS  Article  PubMed  Google Scholar 

  91. 91.

    Delliere S, Rivero-Menendez O, Gautier C, Garcia-Hermoso D, Alastruey-Izquierdo A, Alanio A (2020) Emerging mould infections: get prepared to meet unexpected fungi in your patient. Med Mycol 58(2):156–162. https://doi.org/10.1093/mmy/myz039

    Article  PubMed  Google Scholar 

  92. 92.

    Cornely OA, Hoenigl M, Lass-Florl C, Chen SC, Kontoyiannis DP, Morrissey CO, Thompson GR 3rd (2019) Defining breakthrough invasive fungal infection—position paper of the mycoses study group education and research consortium and the European Confederation of Medical Mycology. Mycoses 62(9):716–729. https://doi.org/10.1111/myc.12960

    Article  PubMed  Google Scholar 

  93. 93.

    Cooper BW, Kindwall-Keller TL, Craig MD, Creger RJ, Hamadani M, Tse WW, Lazarus HM (2015) A phase I study of midostaurin and azacitidine in relapsed and elderly AML patients. Clin Lymphoma Myeloma Leuk 15(7):428–432.e422. https://doi.org/10.1016/j.clml.2015.02.017

    Article  PubMed  PubMed Central  Google Scholar 

  94. 94.

    Maziarz RTT, Patnaik MM, Scott BL, Mohan SR, Deol A, Rowley SD, Kim D, Haines K, Bonifacio GJ, Rine P, Purkayastha D, Fernandez HF (2018) Radius: a phase 2 randomized trial investigating standard of care ± midostaurin after allogeneic stem cell transplant in FLT3-ITD-mutated AML. Blood 132(supplement 1):662–662. https://doi.org/10.1182/blood-2018-99-113582

    Article  Google Scholar 

  95. 95.

    Perl AE, Martinelli G, Cortes JE, Neubauer A, Berman E, Paolini S, Montesinos P, Baer MR, Larson RA, Ustun C, Fabbiano F, Erba HP, Di Stasi A, Stuart R, Olin R, Kasner M, Ciceri F, Chou WC, Podoltsev N, Recher C, Yokoyama H, Hosono N, Yoon SS, Lee JH, Pardee T, Fathi AT, Liu C, Hasabou N, Liu X, Bahceci E, Levis MJ (2019) Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. N Engl J Med 381(18):1728–1740. https://doi.org/10.1056/NEJMoa1902688

    CAS  Article  PubMed  Google Scholar 

  96. 96.

    Wander SA, Levis MJ, Fathi AT (2014) The evolving role of FLT3 inhibitors in acute myeloid leukemia: quizartinib and beyond. Ther Adv Hematol 5(3):65–77. https://doi.org/10.1177/2040620714532123

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  97. 97.

    Knapper S, Russell N, Gilkes A, Hills RK, Gale RE, Cavenagh JD, Jones G, Kjeldsen L, Grunwald MR, Thomas I, Konig H, Levis MJ, Burnett AK (2017) A randomized assessment of adding the kinase inhibitor lestaurtinib to first-line chemotherapy for FLT3-mutated AML. Blood 129(9):1143–1154. https://doi.org/10.1182/blood-2016-07-730648

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Lin S, Shaik N, Martinelli G, Wagner AJ, Cortes J, Ruiz-Garcia A (2019) Population pharmacokinetics of Glasdegib in patients with advanced hematologic malignancies and solid tumors. J Clin Pharmacol. https://doi.org/10.1002/jcph.1556

  99. 99.

    Dhillon S (2018) Ivosidenib: first global approval. Drugs 78(14):1509–1516. https://doi.org/10.1007/s40265-018-0978-3

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  100. 100.

    Stein EM, DiNardo CD, Pollyea DA, Fathi AT, Roboz GJ, Altman JK, Stone RM, DeAngelo DJ, Levine RL, Flinn IW, Kantarjian HM, Collins R, Patel MR, Frankel AE, Stein A, Sekeres MA, Swords RT, Medeiros BC, Willekens C, Vyas P, Tosolini A, Xu Q, Knight RD, Yen KE, Agresta S, de Botton S, Tallman MS (2017) Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood 130(6):722–731. https://doi.org/10.1182/blood-2017-04-779405

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  101. 101.

    DiNardo CD, Stein EM, de Botton S, Roboz GJ, Altman JK, Mims AS, Swords R, Collins RH, Mannis GN, Pollyea DA, Donnellan W, Fathi AT, Pigneux A, Erba HP, Prince GT, Stein AS, Uy GL, Foran JM, Traer E, Stuart RK, Arellano ML, Slack JL, Sekeres MA, Willekens C, Choe S, Wang H, Zhang V, Yen KE, Kapsalis SM, Yang H, Dai D, Fan B, Goldwasser M, Liu H, Agresta S, Wu B, Attar EC, Tallman MS, Stone RM, Kantarjian HM (2018) Durable remissions with Ivosidenib in IDH1-mutated relapsed or refractory AML. N Engl J Med 378(25):2386–2398. https://doi.org/10.1056/NEJMoa1716984

    CAS  Article  PubMed  Google Scholar 

  102. 102.

    Castelli G, Pelosi E, Testa U (2016) Targeted therapies in the treatment of adult acute myeloid leukemias: current status and future perspectives. Int J Hematol Oncol 5(4):143–164. https://doi.org/10.2217/ijh-2016-0011

    CAS  Article  PubMed  Google Scholar 

  103. 103.

    Naci H, Davis C, Savović J, Higgins JPT, Sterne JAC, Gyawali B, Romo-Sandoval X, Handley N, Booth CM (2019) Design characteristics, risk of bias, and reporting of randomised controlled trials supporting approvals of cancer drugs by European Medicines Agency, 2014-16: cross sectional analysis. BMJ 366:l5221. https://doi.org/10.1136/bmj.l5221

    Article  PubMed  PubMed Central  Google Scholar 

  104. 104.

    Mancini R, LaMontagne L, Williams T, Kreisle W, Petersen F (2019) Midostaurin and cyclosporine drug interaction: a case report. J Clin Pharm Ther 00:1–4. https://doi.org/10.1111/jcpt.13077

    Article  Google Scholar 

  105. 105.

    Diczfalusy U, Nylén H, Elander P, Bertilsson L (2011) 4β-Hydroxycholesterol, an endogenous marker of CYP3A4/5 activity in humans. Br J Clin Pharmacol 71(2):183–189. https://doi.org/10.1111/j.1365-2125.2010.03773.x

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  106. 106.

    Bergman PW, Bjorkhem-Bergman L (2013) Is there a role for statins in fungal infections? Expert Rev Anti-Infect Ther 11(12):1391–1400. https://doi.org/10.1586/14787210.2014.856755

    CAS  Article  PubMed  Google Scholar 

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Contributions

Jannik Stemler and Oliver A. Cornely conceived the idea for this review. Jannik Stemler and Philipp Koehler performed comprehensive literature research. All authors contributed literature content from their individual area of expertise. Jannik Stemler drafted the initial manuscript. All authors critically revised and approved the final manuscript.

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Correspondence to Oliver A. Cornely.

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Conflict of interest

JS reports research grants from Basilea Pharmaceutica International Ltd. and travel grants from Meta-Alexander Foundation and from the German Society for Infectious Diseases (DGI) outside of the submitted work.

PK has received non-financial scientific grants from Miltenyi Biotec GmbH, Bergisch Gladbach, Germany, and the Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany, and received lecture honoraria from Akademie für Infektionsmedizin e.V., Astellas Pharma, Gilead Sciences, GPR Academy Ruesselsheim, MSD Sharp & Dohme GmbH, and University Hospital, LMU Munich outside the submitted work.

ChM reports travel grants from Munipharma, Amgen, Servier Deutschland GmbH.

CaM reports no conflict of interest.

OAC has received research grants from Actelion, Amplyx, Astellas, Basilea, Cidara, Da Volterra, F2G, Gilead, Janssen Pharmaceuticals, Medicines Company, MedPace, Melinta Therapeutics, Merck/MSD, Pfizer, and Scynexis; is a consultant to Actelion, Allecra Therapeutics, Amplyx, Astellas, Basilea, Biosys UK Limited, Cidara, Da Volterra, Entasis, F2G, Gilead, Matinas, MedPace, Menarini Ricerche, Roche Diagnostics, Merck/MSD, Nabriva Therapeutics, Octapharma, Paratek Pharmaceuticals, Pfizer, PSI, Rempex, Scynexis, Seres Therapeutics, Tetraphase, and Vical; and received lecture honoraria from Astellas, Basilea, Gilead, Grupo Biotoscana, Merck/MSD, and Pfizer.

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Stemler, J., Koehler, P., Maurer, C. et al. Antifungal prophylaxis and novel drugs in acute myeloid leukemia: the midostaurin and posaconazole dilemma. Ann Hematol 99, 1429–1440 (2020). https://doi.org/10.1007/s00277-020-04107-1

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Keywords

  • Targeted therapy
  • Therapeutic drug monitoring
  • Blood levels
  • Personalized medicine
  • Protein kinase inhibitor