The Changing Landscape of Hematological
Malignancy Treatment


Implications for antifungal therapy



Russell E. Lewis, Pharm.D., FCCP
Associate Professor of Medicine, Infectious Diseases
Department of Molecular Medicine, University of Padua




russelledward.lewis@unipd.it
https://github.com/Russlewisbo

Disclosures


  • Research funding: Merck & Co Inc., Gilead Sciences
  • Speaking: Avir, Gilead
  • Consultancy: F2G, Scynexis, Basilea, Gilead Sciences, Cidara Therapeutics

The cure of leukemia through the optimist’s prism


Disease Current/
Future therapies*		 Survival
(5 year)
Hairy cell leukemia Clofarabine + gemtuzumab ozogamicin (GO) 90%
Acute premyelocytic leukemia ATRA + arsenic ± GO 80-90%
AML
(core binding factor positive)		 FLAG-GO ± IDA, alloHSCT if MRD positive, if indicated, oral AZA/HMA with venetoclax or FLT3/IDH or menin inhibitors 80-90%+
AML
(younger fit)		 FLAG-IDA and venetoclax, CLIA and venetoclax 50-60%
AML
(older, unfit, complex karyotype, T-53 mutations, MECOM)		 Low-intensity triple nucleosides (cladarabine, cytarabine and HMAs + venetoclax; HMAs + venetoclax + targeted therapy 40-50%
ALL < 60 years HyperCVAD + CD19/CD20 targeted antibodies 60-70%
ALL > 60 years Mini-hyper CVAD+ inotuzumab; blinatumab + ponatinib 50%
Ph-positive ALL HyperCVAD + ponatinib; blinatumab + ponatinib 70-80%?

The cure of leukemia through the optimist’s prism


Disease Current/ future therapy* Survival
(5 year)
CML BCR-Abl1 tyrosine kinase inhibitors (imatinib, dasatinib, bosutinib, nilotunib, ponatinib), alloHSCT 85-90%
CLL Ibrutinib, other BTKIs (acalabrutinib, zanubrutinib, pirtobrutinib) 80-90% +
MDS Parenteral HMAs, oral HMAs, venetoclax, others 40% +

Advances in allogeneic HSCT


  • Improvements in HLA typing and matching
  • Expanded donor pools
  • GVHD prophylaxis and treatment (cyclophosphamide, JAK inhibitors)
  • Refinement of reduced-intensity regimens
  • Improved supportive care (antifungal and CMV prophylaxis)
  • Cellular therapies for relapse prevention and treatment (DLI, CAR-T)
  • Molecular and genomic monitoring for MRD detection
  • Personalized medicine (targeted therapies)

Infectious complications after haploidentical HSCT with post-transplant cyclophosphamide

How are newer targeted therapies…



  • Changing the epidemiology of invasive fungal diseases?
  • Changing the risk of drug interactions and toxicity with antifungal therapy?
  • Is there a unique role for isavuconazole?

Immune sequela of targeted therapies

Unexpected consequences?


Ibrutinib-associated aspergillosis




  • Retrospective French surveillance study identified 33 cases of aspergillosis in ibrutinib-treated patients with CLL
  • CNS aspergillosis in 11/27 (40%), most cases within 3 months of starting therapy
  • All patients had refractory/relapsed CLL and other predisposing risk factors

Fungal infections in patients receiving
ibrutinib for lymphoid cancers

Data from MSKCC, New York



  • In a second, retrospective study from MDACC (2014-2018):
    • 21 (2.5%) with proven/probable invasive mold infection
    • Primarily pneumonia
    • Mostly Aspergillus spp.
    • Risk factors: monocytopenia, ≥ 3 prior CLL therapies

BTK drives neutrophil activation for sterilizing antifungal immunity


  • After phagocytosis of A. fumgatus by macrophages, BTK activates calcineurin-NFAT pathways and potentiates TNF-α signalling →
    • Impaired chemokine response and neutrophil recruitment
  • Aberrant innate immune response via TREM-1 signalling pathways→ decreased respiratory burst
  • Ibrutinib also inhibits platelet activation, granule secretion, and platelet-mediated damage of Aspergillus

Novel targeted agents-Risk of fungal infections

Guideline recommendations

Managing fungal infection risks with
novel therapies for AML

EHA consensus recommendations


  • Systematic review of the literature, recommendations developed using GRADE framework (4977 publications evaluated)
  • Outcomes evaluated:
    • Incidence of invasive fungal disease (IFD)
    • Prolongation of hospitalization
    • Days spent in ICU/mortality associated with IFD
    • Potential DDIs
  • Evidence-based recommendations were developed for hypomethylating agents (HMAs), FLT-3 inhibitors, and venetoclax-HMA combinations

Summary of EHA recommendations-1


  • Hypomethylating agent monotherapy:
    • Standard use or prophylaxis not recommended
    • Risk of IFI increased in patients with neutropenia at onset of treatment, prior intensive chemotherapy → conditional recommendation for prophylaxis
  • FLT3 inhibitors (midostaurin, gilteritinib)
    • Antifungal prophylaxis recommended during induction chemotherapy
    • Conditional recommendation for prophylaxis during consolidation in patients with risk factors (prior IFI, prolonged neutropenia)
    • Lack of clear medical guidance for managing drug interactions
    • Close monitoring favoured over empiric FLT-3 inhibitor dose reduction

Summary of EHA recommendations-2


  • Venetoclax
    • Risk of IFI increased in patients with neutropenia at onset of treatment, prior intensive chemotherapy, or prolonged neutropenia with venetoclax
    • Conditional recommendation to administer prophylaxis
    • Careful management of drug interactions with triazoles

Venetoclax dose-adjustment with triazoles


Venetoclax + hypomethylating agents for AML;

Co-administration with posaconazole ↑ venetoclax AUC 8-fold


Day Full dose Moderate CYP3A4 inhibitor1 Strong CYP3A4 inhibitor2
Day 1 100 mg 50 mg 10 mg
Day 2 200 mg 100 mg 20 mg
Day 3 400 mg 200 mg 50 mg
Day 4-28 400 mg 200 mg 70 mg


Triazole prophylaxis increases duration of thrombocytopenia but not neutropenia or infections with dose-adjusted venetoclax


CYP450 Interactions: The achilles heel of triazoles

75-85% of patients receiving mold-active triazoles have serious drug interactions


PK/PD Properties of Small Molecule Kinase Inhibitors



Drug Venetoclax Midostraurin Gilteritinib Ivosidenib Enasidinib Glasdegib
Specificity (targets) BCL2 FLT3 FLT3 IDH1 IDH2 Hedgehog pathway
Hepatic CYP3A4 CYP3A4 CYP3A4/5 CYP3A4/5 Multiple CYP enzymes including CYP3A4 CYP3A4/5
Efflux Substrate of PgP, BCRP Not a substrate Substrate of PgP, not BCRP, OATP Substrate PgP, but not BRCP Not a substrate of BCRP pr PgP Substrate for PGP, BCRP

Toxicities of small-molecule kinase inhibitors

Just avoid triazoles?







Is their a unique role for isavuconazole
vs. other triazoles?

Strong opinions about voriconazole

Pharmacokinetic complexity of voriconazole


Triazole toxicities



Triazole safety


  • Multicenter registry of prophylaxis (n=1777) and treatment (n=816) courses
  • Adverse effects leading to treatment discontinuation:
    • voriconazole (n=494) 14.2%
    • posaconazole (n=547) 11.3%
    • isavuconazole (n=514) 3.9%
    • multiple/sequenced therapy (n=454) 11.7%
  • QTc prolongation was rare, but more frequent with voriconazole and posaconazole
  • Severe drug interactions occurred in 4% of all treated patients
  • IFI mortality rates were similar for all agents ranging between 1.1-1.8%

What makes isavuconazole
(isavuconazonium) unique?



  • Broad spectrum of activity
  • Prodrug IV/ oral formulations (> 90% bioav.)
  • Predictable linear PK, t1/2=130h
  • Less need for TDM
  • Better safety profile than voriconazole
    • Less potent CYP3A4/5 inhibition
    • Less cutaneous, CNS, hepatic toxicities
    • Does not prolong QT

QT prolongation risk with triazoles




  • Older triazoles inhibit human ether-a-go-go (hERG) channel, which underlies rapid K+ rectifier current
  • Isavuconazole shortens cardiac QT in a dose-related manner, with no associated cardiac risk
    • hCav1.2 L-type Ca++ channels
  • Recent analysis of FDA ERS databases confirmed lowest risk of cardiac side effects with isavuconazole

Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE)


Treatment-emergent adverse effects
in the SECURE trial


  • Overall drug-related AE (VOR-60% vs. ISA-42%, p<0.001)

    • Hepatobiliary disorders (VOR-16% vs. ISA-9%, p=0.016)

    • Visual disturbances (VOR-27% vs. ISA-15%, p=0.002)

    • Skin or subcutaneous tissue (VOR-42% vs. ISA-33%, p=0.037)

Isavuconazole treatment for mucormycosis:
a single-arm, open-label, case-control study (VITAL)

Isavuconazole drug interaction potential in HSCT


Drug Pharmacokinetic change Initial management
Tacrolimus

↑ AUC 1.8-3xfold

↑ Cmax 1.4-2.8xfold

 40-50% reduction in tacrolimus dose, TDM.
Some case series suggest no empiric dose reduction was required
Prednisone or Prednisolone ↑ AUC (8%) minimal No dose adjustments recommended
Ruxolitinib ↑AUC and Cmax by an average of 27% and 8% Although dose reduction is recommended for strong CYP3A4 inhibitors, no dose reduction recommended with moderate inhibitors such as isavuconazole

Isavuconazole drug interaction potential


Drug Pharmacokinetic change Initial management
Venetoclax ↑AUC 2-3.9xfold Dose reduction of venetoclax by 50%
Midostaurin ↑AUC 1.44xfold higher Avoid strong CYP3A4 inhibitors, no dose reduction recommended for moderate CYP3A4 inhibitors
Gilteritinib

↑AUC 1.4xfold;

↑Cmax 1.2-fold higher

 Avoid strong CYP3A4 inhibitors, no dose reduction recommended for moderate CYP3A4 inhibitors

Does TDM support claims of less potent
CYP3A4 inhibition?

Antifungal prophylaxis in the targeted therapy era

Study design

Demographics

Breakthrough infections

Isavuconazole tolerability



  • Posaconazole experience
    (previous study with tablet/IV)

    • Grade III/IV liver injury with tablet and IV formulations (9%)

    • Primarily presenting with hyperbilirubinemia

    • Higher frequency in patients with POS serum levels > 1,830 ng/mL

  • Isavuconazole

    • Grade 1 transaminitis (2.7%)

    • Grade 2 elevated T. bilirubin (1.3%)

    • No QTc elevation vs. baseline at 10 days

“Isavuconazole was well tolerated and facilitated use of the most potent molecular-targeted agents in remission-induction chemotherapy with excellent short term survival and high remission rates.”



(Young, 2021)

Jo-Anne H. Young, Clin Infect Dis 2021



“This is the first antifungal prophylaxis study in this select population of patients with leukemia, specifically, those patients being treated with the BCL-2 antagonist venetoclax and fms3-like tyrosine kinase 3 (FLT3) inhibitors.


“Clinicians should take away from these studies the fact that many of the advanced-generation azoles can be used interchangeably in times of prophylaxis when they are needed.”

Summary


  • Knowledge of fungal infection risk with targeted therapy is evolving, and depends heavily on the individual patient treatment scenario

  • Many small molecule inhibitors are metabolised by CYP3A4/5 and have potential for QTc prolongation, making concurrent use with broad-spectrum triazoles difficult

  • Isavuconazole has several unique pharmacokinetic and safety advantages over older triazoles, making it an useful alternative in patients receiving targeted therapies

Treviso, Italy


References


All figures created by R. Lewis using www.biorender.com

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