Echinocandin prophylaxis in patients undergoing haematopoietic cell transplantation and other treatments for haematological malignancies

Abstract

Antifungal prophylaxis is the standard of care for patients undergoing intensive chemotherapy for haematological malignancy or haematopoietic cell transplantation (HCT). Prophylaxis with azoles reduces invasive fungal infections and may reduce mortality. However, breakthrough infections still occur, and the use of azoles is sometimes complicated by pharmacokinetic variability, drug interactions, adverse events and other issues. Echinocandins are highly active against Candida species, including some organisms resistant to azoles, and have some clinical activity against Aspergillus species as well. Although currently approved echinocandins require daily intravenous administration, the drugs have a favourable safety profile and more predictable pharmacokinetics than mould-active azoles. Clinical data support the efficacy and safety of echinocandins for antifungal prophylaxis in haematology and HCT patients, though data are less robust than for azoles. Notably, sparse evidence exists supporting the use of echinocandins as antifungal prophylaxis for patients with significant graft-versus-host disease (GvHD) after HCT. Two drugs that target (1,3)-β-d-glucan are in development, including an oral glucan synthase inhibitor and an echinocandin with unique pharmacokinetics permitting subcutaneous and weekly administration. Echinocandins are a reasonable alternative to azoles and other agents for antifungal prophylaxis in patients undergoing intensive chemotherapy for haematological malignancy or those receiving HCT, excluding those with significant GvHD.

Introduction

Over the last decade, antifungal prophylaxis has become the standard of care for patients undergoing intensive chemotherapy for haematological malignancies or haematopoietic cell transplantation (HCT).^1–8 The impact of antifungal prophylaxis in reducing rates of invasive fungal infections (IFIs) and mortality has been summarized in meta-analyses in adult and paediatric patients.^9–11 Several studies have demonstrated the efficacy of azoles as primary antifungal prophylaxis.¹² However, IFIs remain a significant cause of morbidity and a leading cause of infection-related mortality.^13–16 Pharmacokinetic (PK) variability, drug interactions, adverse events (AEs) and cost may preclude consistent administration of azoles in an increasing number of patients.^17–20 Since their introduction 15 years ago, the echinocandins have become increasingly important in our antifungal armamentarium for prophylaxis and treatment (as monotherapy or part of combination therapy). Echinocandins have a relatively broad spectrum of activity and have demonstrated excellent safety and tolerability with few drug interactions.²¹ A novel echinocandin in development [rezafungin acetate (previously CD101); Cidara Therapeutics, Inc., San Diego, CA, USA] may alleviate the need for daily intravenous (iv) administration and expand the spectrum of coverage for targeted fungal pathogens. We review the currently unmet needs for antifungal prophylaxis in patients with haematological malignancies and HCT and the potential role of echinocandins for this indication.

Rationale for antifungal prophylaxis in haematological malignancies and haematopoietic cell transplantation

Patients with haematological malignancies and HCT are at risk for IFIs caused by opportunistic fungi. These patients have impaired immune defences against fungi owing to their underlying diseases and treatments. For example, patients with acute leukaemia have neutropenia due to marrow infiltration from leukaemia and due to chemotherapy. Lymphopenia, monocytopenia and qualitative defects in phagocytic function are common in patients with lymphoma owing to their underlying disease or treatments (such as corticosteroids and purine analogues). Similarly, cellular immunity is impaired in patients with graft-versus-host disease (GvHD) owing to the pathophysiology of their disease and immunosuppression used for treatment. Furthermore, host factors such as age, comorbidities, iron overload and genetic predisposition as well as exogenous factors such as environmental exposures and presence of iv catheters may increase the risk for IFIs.²² More than one predisposing factor may be present at any given time based on underlying disease and treatment and may affect the types of causative organisms and timing of IFI. Prior to the implementation of empirical antifungal therapy, up to 50% of patients treated for leukaemia were found to have an IFI at autopsy.²³ Empirical antifungal therapy reduced the incidence of IFIs during neutropenia.²⁴ The incidence of IFIs was further reduced after the adoption of antifungal prophylaxis.^9–11,25,26 However, even in the era of antifungal prophylaxis, IFIs affect quality of life, may delay or preclude potentially curative chemotherapy or HCT, pose a substantial burden for the healthcare system, and remain an important cause of morbidity and mortality.^{14–16,27,28}

Registry studies of IFI in HCT patients provide real-world data showing that: (i) IFIs are more common in allogeneic HCT, particularly recipients of mismatched or unrelated donor allografts; (ii) the majority of IFIs occur late (over 1 month after HCT) with incidence continuing to climb up to 1 year after HCT; (iii) Candida and Aspergillus account for over 85% of IFIs; and (iv) non-Aspergillus moulds (including Mucorales) and Pneumocystis remain rare [1% in a 30 month period after HCT and 1.51% in a 180 day period after the last dose of chemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine and corticosteroids (R-CHOP) in patients with B-cell lymphoma].^29–35 The incidence of IFI in multicentre clinical trials may reflect patient selection and controlled monitoring. In the randomized placebo-controlled trials of voriconazole or posaconazole prophylaxis compared with fluconazole, the rate of probable and proven IFIs was 8%–9% in the fluconazole arm and ∼5% in the voriconazole or posaconazole arm, the difference being driven largely by decreases in aspergillosis among those receiving mould-active azoles.^36,37

Similar to HCT, the majority of IFIs are caused by Candida and Aspergillus species in patients with haematological malignancies.^28,32,38,39 An increase in fluconazole-resistant Candida species, including C. glabrata and C. krusei, has been noted in several studies and has been attributed to azole prophylaxis.^40–42 Breakthrough or de novo IFIs by non-Aspergillus moulds also occur but remain relatively infrequent.^43,44 Select groups of patients with haematological malignancies and HCT recipients are at risk for pneumonia caused by Pneumocystis jirovecii and require prophylaxis directed against Pneumocystis in addition to traditional antifungal prophylaxis.

Patient-specific considerations in haematological malignancies and haematopoietic cell transplantation

Myeloid malignancies

AML is the most common leukaemia in adults, with an estimated 21 380 new cases (4.2 new cases per 100 000) diagnosed in the USA in 2017.⁴⁵ Patients with AML are at high risk for IFIs owing to multiple immune defects associated with the underlying malignancy and its treatment. Mucosal integrity is the first line of host defence against invasion by fungal pathogens. Oral and gastrointestinal mucositis due to chemotherapy facilitates translocation of endogenous flora into the bloodstream and is a risk factor for candidaemia and invasive candidiasis (IC). Profound, prolonged neutropenia is commonly caused by both AML and intensive chemotherapy used in its treatment. The duration and severity of neutropenia interact to increase the risk of IFI, particularly mould infections.⁴⁶ Intrinsic functional defects of neutrophils exist in patients with acute leukaemia, myelodysplastic syndrome (MDS) and pre-leukaemia states, but their clinical significance is poorly defined.⁴⁷ The risk of IFIs is higher during induction chemotherapy when the typical duration of neutropenia is over 2 weeks compared with consolidation, when the duration of neutropenia is ∼1 week.^39,48

MDS is a heterogeneous haematopoietic disease commonly associated with bone marrow failure, peripheral blood cytopenias and progression to AML. The incidence of MDS is similar to that of AML and is estimated at ∼5 per 100 000, representing the most commonly diagnosed myeloid neoplasm in the USA and Europe.⁴⁹ In comparison with AML patients receiving intensive chemotherapy, patients with MDS have a lower risk of IFIs, possibly because of a stationary neutrophil count and because they have been traditionally managed conservatively with supportive care and growth factors. Low incidence of IFIs has been reported in MDS patients treated with hypomethylating agents, including azacitidine and decitabine, though these populations are less well described and more data are needed.⁵⁰ A study evaluating over 800 cycles of azacitidine given mostly to patients with MDS without antifungal prophylaxis found that 0.8% were complicated by development of an IFI.⁵¹

Acute lymphoblastic leukaemia and other lymphoproliferative malignancies

Approximately 6000 new cases of ALL are diagnosed in the USA annually, of which 60% occur in children and adolescents, with cure rates approaching 90%.⁵² Adult ALL portends a poorer prognosis.⁵³ T cell function is required for macrophage activation and subsequent fungicidal activity. In the absence of functional T cells, selected fungal pathogens may survive and replicate inside macrophages. Patients with ALL, hairy cell leukaemia and mycosis fungoides have an intrinsic impairment in cellular immunity and are at increased risk for infections by P.jirovecii, Cryptococcus species and endemic fungi. In addition, therapies directed towards lymphoproliferative disorders often include corticosteroids, purine analogues (such as fludarabine and cladribine) and alemtuzumab, resulting in prolonged lymphopenia. Idelalisib, a PI3Kd inhibitor, is associated with a significantly increased risk for P. jirovecii pneumonia (PJP) through unclear mechanisms potentially unrelated to T cell lymphopenia.⁵⁴ The reported incidence of IFI among ALL patients ranges from 7% to 19% in single-centre studies without routine antifungal prophylaxis.^38,55

Patients with lymphoma and other lymphoproliferative disorders characterized by relatively short periods of mild neutropenia develop IFIs infrequently when compared with patients with acute leukaemia.⁵⁶ IFIs in this patient group are generally due to Candida species; mould infections are uncommon.⁵⁶ An increased incidence of IFIs is reported in patients with myeloma and chronic lymphocytic leukaemia owing to the cumulative immunosuppressive effects of an ever-expanding number of myeloma-specific therapies.⁵⁷

Haematopoietic cell transplantation

In 2012, ∼68 000 HCTs, including autologous and allogeneic transplants, were performed worldwide and represent a trend of consistent growth, particularly of allogeneic HCTs, since 2006.⁵⁸ The increased use of alternative donor sources and reduced-intensity conditioning enables an increasing number of older patients and those with comorbidities to undergo HCT. Furthermore, improved survival of patients with GvHD may further increase the number of individuals at risk for IFIs.⁵⁹ Periods of risk for IFIs after HCT have been traditionally divided into ‘early’ (pre-engraftment) and ‘late’ (post-engraftment) because of distinct predisposing factors.

Pre-engraftment

The main risk factors for IFIs in the early post-HCT period are neutropenia and mucositis. The duration and severity of neutropenia and mucositis depend on the type of conditioning and the stem cell source. Among HCT patients, IFIs occur less commonly in autologous HCT recipients than in their allogeneic counterparts, since neutropenia typically resolves within 7–10 days among autologous HCT recipients.^60,61 Myeloablative conditioning regimens used as part of autologous HCT, including high-dose melphalan and total body irradiation, can cause significant mucositis, which likely predisposes to IC in the absence of prophylaxis.⁶²

Patients undergoing allogeneic HCT have a higher risk for IFIs compared with those undergoing autologous HCT.^63–65 Allogeneic HCT recipients develop mucositis not only from conditioning regimens, but also from methotrexate, often used for preventing GvHD.⁶⁶ Allogeneic HCT patients whose graft is harvested from umbilical cord blood (UCB) and, to a lesser extent, bone marrow, experience delayed engraftment with likely increased short-term risk of IFIs.^67,68 Without prophylaxis, IC typically develops before mould infection occurs, likely reflecting the duration of neutropenia and mucositis occurring during the pre-engraftment phase.⁶⁴

Post-engraftment

The most important risk factors for IFIs after engraftment are receipt of an unrelated donor allograft, development of acute GvHD grades II–IV or extensive chronic GvHD, and treatment with high-dose corticosteroids.^31–33 The major effect of corticosteroids on neutrophils appears to be impairment of chemotaxis, which decreases localized inflammatory responses.^69,70 However, impairments of phagocytosis, microbicidal activity and antibody-dependent cytotoxicity have also been seen in vitro.⁷⁰

Acute and chronic GvHD predispose to IC and mould infections, particularly those caused by Aspergillus and agents of mucormycosis.^64,65,71 T cell depletion (TCD) of the graft greatly reduces the risk of GvHD, but the resulting prolonged and severe lymphopenia has been associated with late occurrence of mould infections.⁷² Impaired T cell immunity after HCT is also a risk factor for PJP.⁷³ The period of risk is longer for recipients of TCD allografts or patients who receive prolonged or cumulative high-dose corticosteroids, including patients with GvHD.^73–75

Novel therapies for refractory GvHD such as mesenchymal stem cells have been associated with increased risk of IFIs, although it is unclear whether this association reflects cumulative immunosuppression.⁷⁶

Novel targeted therapies and immunotherapies

Several novel targeted strategies are in development for haematological malignancies. Broadly characterized according to mechanism of action, these strategies employ monoclonal antibodies, bispecific antibodies, molecular targets such as tyrosine kinase inhibitors (TKIs) or checkpoint inhibitors, and adoptive or targeted cellular therapies such as chimeric antigen receptor (CAR)-T cells.^77,78 As our understanding of haematological malignancies expands at the genomic and molecular levels, it is likely that these agents will become more broadly applicable in the future. It is still too early to know the net impact of the new agents on IFI and antifungal prophylaxis. Some of the new agents are given in combination with traditional chemotherapies or sequentially, and may be administered long term, making it almost impossible to dissect their relative contribution to IFI risk. The new strategies intersect with IFI prophylaxis both in modulating IFI risk and in introducing new concerns for drug interactions with antifungal prophylaxis and AEs.

For AML, the potential applications of fms-like tyrosine kinase 3 (FLT3) inhibitors are expanding. Novel regimens incorporating FLT3 inhibitors, isocitrate dehydrogenase 1/2 inhibitors, epigenetic therapy and CD33-targeted agents are under intense evaluation.^79,80 Strategies for ALL include monoclonal antibodies, antibody–drug conjugates, mechanistic targeting of rapamycin inhibitors, proteasome inhibitors, histone deacetylase inhibitors, Bruton's tyrosine kinase inhibitors, Janus kinase and signal transducer and activator of transcription inhibitors, programmed cell death protein inhibitors and FLT3 inhibitors.⁸¹

Many of these agents have significant PK interactions with azoles. A detailed review of interactions is beyond the scope of this review. An illustrative example is the interaction of azoles with TKIs. Exposure to TKIs increases when taken in combination with a strong cytochrome P450 (CYP)3A inhibitor such as voriconazole; however, the appropriate dose adjustment of TKIs for concomitant administration with azoles is less clear.^19,82 In contrast, there are no identified interactions between TKI and echinocandins or polyenes.

Prolongation of the QT interval is another potential concern for many TKIs, especially in patients with multiple medications that affect the QT interval. Voriconazole and posaconazole are known to prolong the QT interval.^83,84 In contrast, isavuconazole is known to shorten the QT interval.⁸⁵

Transaminase elevation is common among patients receiving chemotherapy or immunomodulatory therapies and concomitant administration of azoles is often avoided in this setting by the clinicians.⁷⁸

Current unmet needs in antifungal prophylaxis

Fluconazole, posaconazole, and micafungin are approved by the US FDA for the prevention of IFIs among HCT patients (Table 1).^84,86,87 Posaconazole is additionally approved for antifungal prophylaxis in those with haematological malignancies at least 13 years of age with prolonged neutropenia from chemotherapy.⁸⁴ While the azoles are far more utilized for IFI prophylaxis and are better studied for this indication, these drugs are metabolized by cytochrome P450 isoenzymes, leading to the potential for serious drug interactions with concomitant administration of certain chemotherapeutic agents (including cyclophosphamide, vincristine and TKIs) or other immunosuppressants (including cyclosporine, tacrolimus and sirolimus).^19,88–90 QT prolongation may be a limiting factor for patients on multiple medications.

Table 1.

Antifungals approved for IFI prophylaxis

Parameter	Fluconazole	Posaconazole	Micafungin
FDA-approved indication	Prevention of candidiasis in patients undergoing HCT receiving cytotoxic chemotherapy and/or radiation therapy	Prevention of invasive Aspergillus and Candida infections in patients at high risk due to immunocompromise, such as HCT recipients with GvHD or those with haematological malignancies and prolonged chemotherapy-associated neutropenia	Prevention of Candida infections in patients undergoing HCT
Year approved for any indication	1992	2006 (suspension); 2013 (delayed-release tablet); 2014 (iv solution)	2006
Generic	Yes	No	No
Doses and formulations	Oral tablet: 50 mg, 100 mg, 150 mg, 200 mg	Oral suspension: 40 mg/mL (105 mL)	iv solution for reconstitution: 50 mg, 100 mg
	Oral suspension: 10 mg/mL (35 mL), 40 mg/mL (35 mL)	Delayed-release tablet: 100 mg
	iv solution: 100 mg (50 mL), 200 mg (100 mL), 400 mg (200 mL)	iv solution: 300 mg (16.7 mL)
Administration	Reliably absorbed orally with or without food	Delayed-release tablets must be given whole; tablets and suspension should be given with food for optimal absorption; iv should be given through central line	Only available iv
Dose adjustment for renal insufficiency	Yes	No (theoretical concerns about accumulation of cyclodextrin vehicle when iv formulation given to patients with severe renal insufficiency)	No
Dose adjustment for hepatic insufficiency	No	No	No
Drug interactions	Mediated by P450 system	Mediated by P450 system	None significant

Administration of oral posaconazole in particular can be challenging in the presence of mucositis that prevents administration of food or nutritional supplements required for optimal posaconazole absorption. Posaconazole levels <700 ng/mL have been associated with a higher rate of breakthrough IFIs compared with higher levels.⁹¹ Therapeutic drug monitoring is sometimes used owing to an association between low drug levels and breakthrough IFIs during prophylaxis, although this monitoring increases provider burden and treatment cost.⁹² Absorption and adherence have greatly improved with the availability of posaconazole delayed-release tablets; however, administration with food is still recommended for optimal absorption, and discontinuations due to mucositis and colitis limit the utility of posaconazole prophylaxis.⁹³ In a single-centre, prospective study of patients with AML or after HCT taking posaconazole tablets, 80.5% of samples showed a concentration of at least 700 ng/mL at steady state, but 16% of patients stopped posaconazole prematurely owing to colitis, transaminase elevations and mucositis.⁹⁴ The availability of iv posaconazole alleviates concerns related to absorption; however, cost is a factor limiting its use.

Voriconazole demonstrates wide inter-patient variability in serum concentrations that is due in part to variant CYP2C19 alleles.⁹⁵ Individuals who are CYP2C19 ultrarapid metabolizers have decreased voriconazole trough concentrations, whereas poor metabolizers have increased trough concentrations and are at increased risk of AEs. Up to one-third of HCT recipients develop biochemical hepatotoxicity while on voriconazole that often leads to discontinuation of voriconazole by the clinicians regardless of causality.¹⁷ A long-term safety concern is the association of prolonged exposure to voriconazole with the development of non-melanoma skin cancers in HCT recipients.⁹⁶ Notably, in randomized controlled trials (RCTs) of prophylaxis with voriconazole or posaconazole compared with fluconazole, the safety profiles of mould-active azoles were similar to those of fluconazole.^36,37 However, higher rates of discontinuation of voriconazole have been reported in clinical practice.¹⁷

Use of amphotericin B (AmB) and its lipid derivatives for prophylaxis is problematic due to infusional and renal toxicities, as well as insufficient evidence regarding their efficacy.^97,98

PJP prophylaxis has historically been considered separately from prevention of IFIs given the unique features of Pneumocystis and the challenges posed by this organism, including the lack of activity of commonly used antifungal agents. PJP prophylaxis is recommended for patients with ALL, HCT recipients and those under treatment with high-dose corticosteroids (generally considered to be at least 20 mg/day of prednisone or an equivalent dose of another corticosteroid for at least 4 weeks) or agents significantly affecting T cell immunity used for treatment of lymphoma and non-haematological malignancies.⁹⁹ Trimethoprim/sulfamethoxazole is recommended as first-line prophylaxis, but high rates of early withdrawal (31%–56%) have been reported for HCT recipients.⁹⁹ Mutations conferring resistance to sulfamethoxazole have been recently reported from certain geographic areas.¹⁰⁰ Inhaled pentamidine, an alternative to trimethoprim/sulfamethoxazole, frequently causes bronchospasm, needs to be given by a respiratory therapist and requires use of a private room during administration due to its teratogenicity. Dapsone, atovaquone and iv pentamidine are alternatives but may have inferior efficacy compared with trimethoprim/sulfamethoxazole and lack activity against other opportunistic infections (including, in the case of dapsone and pentamidine, Toxoplasma gondii). Atovaquone is associated with poor tolerability and is costly. Thus, there is a need for safer and better-tolerated PJP prophylaxis.

In summary, current prophylactic practices have significantly reduced the rates of IFIs and PJP. However, challenges with pill burden, adherence, safety, tolerability and drug interactions remain. It is thus worthwhile to reflect on the properties of echinocandins that may make them an attractive alternative to azoles or AmB products.

Rationale for echinocandins

Mechanism of action

Echinocandins, semisynthetic cyclic lipopeptides, emerged for clinical use with the approval of caspofungin in 2001, micafungin in 2005 and anidulafungin in 2006.²¹ These drugs inhibit fungal cell wall synthesis by binding to the (1,3)-β-d-glucan synthase enzyme complex, which is composed of at least two subunits (FKS1p and Rho1p).^21,101 This target is not found in mammalian cells and consequently enables this drug class to have a favourable safety profile.^21,101 However, echinocandin activity is predicated on the proportion of β-glucan composing the fungal cell wall, resulting in their inactivity against Mucormycetes, Fusarium species or Scedosporium species [owing to reduced (1,3)-β-d-glucan synthase activity] or against Trichosporon species and Cryptococcus species [owing to predominance of (1,6)-β-d-glucan instead].¹⁰² Echinocandins are not used to treat endemic fungi because of high MICs for the yeast forms, nor are they currently used to treat P. jirovecii, as previous studies showed limited activity against the trophic form of the biphasic (cyst/trophic) life cycle of Pneumocystis.^102–105 Echinocandins have been useful against Candida and Aspergillus species, which are the two primary targets for IFI prophylaxis.

All three echinocandins are fungicidal against Candida species, including those displaying resistance to the azoles, such as C. glabrata, or AmB, such as C. lusitaniae. For Aspergillus species, exposure to the echinocandins leads to lysis of the apical tips of expanding hyphae, alteration of hyphal morphology and modification of cell wall composition and organization.¹⁰⁶ Beyond the direct antifungal effect, the echinocandin-induced morphological changes may be able to amplify host immune responses, though this finding is of unclear clinical significance.¹⁰⁷ So although fungistatic and with less robust clinical activity in the treatment of invasive aspergillosis, this drug class exhibits excellent in vitro activity against many Aspergillus species, including A. fumigatus, A. flavus, A. niger and A. terreus.^108,109

By inhibiting production of glucans incorporated into the cell wall of Pneumocystis cyst forms, echinocandins likely have some activity against this organism.¹⁰⁴ While the currently available echinocandins have shown benefit in some pre-clinical studies in treatment of PJP, the utility of echinocandins for PJP prophylaxis has not been formally evaluated in clinical trials. The data on the efficacy of echinocandins as part of combination therapy for PJP in humans is limited and controversial.¹¹⁰

Pharmacokinetics

Owing to their high molecular weights, echinocandins are minimally absorbed after oral administration and are available only in iv formulations.¹⁰¹ These drugs are highly protein bound, display concentration-dependent activity against Candida and Aspergillus species, and distribute well into tissues such as the lung, liver and spleen but have minimal penetration into the CSF, eye and urine.^21,101,111 Where the drugs differ from one another is their metabolic pathways, leading to variations in half-lives, drug dosing strategies and drug interaction profiles, as detailed in previously published reviews.^21,111 Of the three, caspofungin displays triphasic non-linear PK, whereas both micafungin and anidulafungin exhibit linear PK.^21,111 Dose adjustments for any of the three echinocandins are not needed for renal insufficiency, including for patients receiving haemodialysis or continuous renal replacement therapy.^86,112,113 While caspofungin requires dose modification for moderate hepatic insufficiency, no data are available for adults with severe hepatic impairment or in paediatric patients with any degree of hepatic impairment.⁵¹ No dose adjustments for hepatic insufficiency are needed for micafungin or anidulafungin.^86,113 Some PK studies have suggested that echinocandin doses used in clinical practice may be subtherapeutic in some patients.^114,115 However, the clinical implications of these data are unclear and current adult dosing recommendations have not been modified based on these data.

In clinical practice, the echinocandins are dosed on a once-daily basis, which can be difficult to maintain in the outpatient setting given the requirement for iv administration. Based on their pharmacodynamic (PD) profile, the AUC/MIC ratio may be the best predictor of clinical outcome when these agents are used.¹¹⁶ Considering their concentration-dependent killing, linear PK, high tissue concentrations and a postulated prolonged post-antifungal effect, higher doses of echinocandins administered several times or once weekly may be a viable, if not better, alternative to daily dosing, though these strategies have not undergone rigorous clinical study and are rarely used as first-line dosing strategies.^116–119 Higher intermittent doses of micafungin have demonstrated efficacy against IC in animal models.^83,120 Limited clinical studies demonstrate safety and tolerability of higher doses of micafungin in humans, but data supporting the efficacy of alternative administration regimens for antifungal prophylaxis are extremely limited.¹²¹ It remains to be seen whether intermittent dosing is a viable strategy for prevention of IFIs. High concentrations of echinocandins can paradoxically lead to a reversal of growth inhibition in vitro, although the clinical relevance of this phenomenon remains unclear.¹²²

Safety profile

Echinocandins are well tolerated such that severe AEs requiring discontinuation occur less frequently when compared with the other antifungal classes.²¹ Modest elevations of aminotransferases and alkaline phosphatase are the most frequently reported laboratory abnormalities but generally are of little clinical consequence.^21,101 While histamine-associated infusion reactions have been reported, they are rare and can be prevented by slowing the infusion rate and providing supportive care as warranted.^21,111,123 Injection site pain, uncomplicated gastrointestinal symptoms (such as nausea, vomiting and diarrhoea) and haematological effects (such as anaemia, leukopenia and thrombocytopenia) account for fewer than 10% overall of AEs.^21,111

There have been rare case reports of decreased cardiac output, flash pulmonary oedema and haemodynamic instability occurring during echinocandin administration, though causality is difficult to determine.^124–126 Histamine release has been postulated as the underlying cause in some cases. Animal studies suggest that there may be a potential for direct mitochondrial injury to cardiac myocytes, particularly for anidulafungin and caspofungin, though only at blood levels rarely if ever seen in humans.^124,127 The clinical implications of this research are not understood, and documented cardiac toxicity attributed to echinocandins remains very rare.

A key advantage over the azoles is minimal potential for drug interactions since the echinocandins do not inhibit cytochrome P450 enzyme or P-glycoprotein transport systems.^111,123 On the other hand, several drugs (including carbamazepine, dexamethasone, efavirenz, phenytoin and rifampicin) appear to induce the metabolism of caspofungin, so an increased maintenance dose is recommended when any of these drugs is given concurrently with caspofungin.⁵¹

Echinocandin resistance

The mechanism of echinocandin resistance involves amino acid alterations in ‘hot spot’ regions of the FKS gene-encoded subunits of glucan synthase and is typically acquired.¹²⁸ Although the overall prevalence of echinocandin resistance among Candida species is low at 2%–3%, the exception may be C. glabrata, which can also be MDR.^128–130 One centre found an increase in echinocandin resistance among the C. glabrata bloodstream isolates from 4.9% in 2001 to 12.3% in 2010.¹²⁹ This same study found that clinical failure correlated with the presence of FKS mutations and elevated MICs. The increasing use of echinocandins in clinical practice, presence of gastrointestinal reservoirs and poor drug penetration into intra-abdominal infections have been postulated to be clinical factors driving development of echinocandin resistance.¹²⁸ National surveillance efforts as well as studies to better understand the echinocandin resistance mechanism are ongoing.

Published data on echinocandin prophylaxis

AmB products and azoles have demonstrated significant benefit in reducing rates of IFIs among patients with acute leukaemia and MDS and those undergoing HCT; some studies have also shown reductions in mortality.^2,7 Clinical trials and retrospective studies of echinocandin prophylaxis comprise heterogeneous populations and varying echinocandin doses, as well as different comparators and endpoints (Table 2). Studies directly comparing echinocandin prophylaxis with mould-active azoles (such as posaconazole) and data on specific groups, particularly HCT recipients with GvHD, are limited. Nonetheless, the data in aggregate support the safety and efficacy of echinocandins for antifungal prophylaxis in many clinical settings.²⁵

Table 2.

Studies on echinocandin prophylaxis in patients with haematological malignancies or undergoing HCT

Study citation	Methodology	Setting, population, dates	Arms	Qualitya	Primary endpoint
Echinocandin versus fluconazole
131	RCT, blinded	US; multicentre (72 centres); mostly adult; allogeneic or autologous HCT; assessed neutropenic phase; 1999–2000	Micafungin, (50 mg iv daily; N = 425) vs fluconazole (400 mg iv daily; N = 457) starting ≤48 h after conditioning through engraftment, D + 42, IFI or drug cessation	High	Absence of IFI: micafungin superior, NNT 15
132	retrospective, cohort (historical control)	Japan; single-centre; mostly adult; allogeneic HCT; assessed through D + 49; micafungin patients recruited from 2004–07; unknown dates of historical cases; assessed neutropenic phase	Micafungin (100 mg iv daily; N = 41) vs historical control fluconazole (400 mg iv/po daily; N = 29); both started D − 14; both groups changed to fluconazole 200 mg po daily after engraftment and tolerating po intake	Low	Absence of proven, probable, or possible IFI: micafungin superior, NNT 5
133	RCT, open label	Japan; multicentre (6 centres); mostly adult; allogeneic or autologous HCT; assessed neutropenic phase; 2004–06	Micafungin (150 mg iv daily; N = 50) vs fluconazole (400 mg iv daily; N = 50) starting ≤48 h after conditioning through engraftment, D + 42, IFI or drug cessation	Medium	Absence of IFI: no significant difference
134	RCT, open label	Korea; single-centre; adult; allogeneic or autologous HCT; assessed neutropenic phase; 2010–15	Micafungin (50 mg iv daily; N = 165) vs fluconazole (400 mg po/iv daily; N = 85) starting ≤24 h after HCT infusion through engraftment, D + 21, IFI or drug cessation	Medium	Incidence of proven or probable IFI: no significant difference
Echinocandin versus itraconazole
137	RCT, open label	US (TX); single-centre; mostly adult; AML or MDS undergoing induction chemotherapy; 2001–03	Caspofungin (50 mg iv daily; N = 107) vs itraconazole (200 mg iv bid ×2 days then daily; N = 90) starting with induction through resolution of neutropenia, CR, death, change in therapy, IFI, toxicity or through 25 days	Medium	Completion of prophylaxis without IFI: no significant difference
135	RCT, open label	China; multicentre (10 centres); adults; allogeneic or autologous HCT; assessed neutropenic phase; 2008–09	Micafungin (50 mg iv daily; N = 136) vs itraconazole (5 mg/kg/day po in 2 divided doses; N = 147) starting within 48 h of beginning of conditioning regimen ending with engraftment, IFI, toxicity, death, withdrawal or other discontinuation	Medium	Absence of IFI: no significant difference
Echinocandin versus posaconazole
158	Retrospective, cohort (historical control)	Austria; single-centre; adults; mixed population (induction and consolidation for acute leukaemia, allo- and auto-HCT, GvHD, some others); 2011–12 (historical control 2008–10); notable differences in baseline characteristics	Micafungin (50 mg iv daily; N = 100) vs posaconazole suspension (200 mg po q8h; N = 202) during neutropenia or other immunosuppression	Low	IFI incidence: no significant difference
Echinocandin versus mixed azoles
92	RCT, open label	Italy; multicentre; adults; mostly AML with some ALL; 2007–09	Caspofungin (70, 50 mg iv daily; N = 93) vs standard prophylaxis (mostly itraconazole; some posaconazole; unclear others; N = 82)	Medium	Incidence of proven or probable IFIs: no significant difference
138	Retrospective, cohort	USA (TX); single centre; adults; AML newly diagnosed undergoing induction chemotherapy; 2009–11	Echinocandin (N = 38) vs voriconazole or posaconazole (N = 42), minimally described	Low	Development of IFI: azole superior

NNT, number needed to treat; bid, twice daily; po, by mouth; D, day; CR, complete remission.

^aDouble-blinded RCTs were rated as high quality. Other RCTS were rated as medium quality. Non-interventional studies were rated as low quality.

Micafungin is currently FDA approved for the prevention of IFIs among neutropenic HCT patients in the pre-engraftment phase. The most robust data come from studies comparing micafungin and fluconazole. Three RCTs, one blinded and two open-label, along with a retrospective cohort study demonstrate that micafungin is either equivalent or superior to fluconazole in preventing IFIs among neutropenic HCT patients.^131–134 An open-label RCT comparing micafungin with itraconazole in the same patient population found similar rates of IFIs between the two arms.¹³⁵ In a cohort of neutropenic patients undergoing HCT, bridging posaconazole prophylaxis with micafungin improved exposure to antifungal prophylaxis and led to reduced incidence of IFIs compared with posaconazole alone.¹³⁶

Micafungin has also been studied for prophylaxis of IFIs among patients receiving induction chemotherapy for acute leukaemia and MDS. In two open-label RCTs in patients with acute leukaemia or MDS undergoing induction chemotherapy comparing caspofungin with itraconazole prophylaxis, the incidence of IFIs was similar in both arms.^92,137 In a retrospective study, echinocandin-based prophylaxis compared with prophylaxis with voriconazole or posaconazole was associated with a higher risk of IFIs during intensive chemotherapy for AML, although confounding variables could not be excluded.¹³⁸ Recently, micafungin was compared with posaconazole suspension in an open-label RCT in patients undergoing intensive chemotherapy for acute leukaemia or MDS at Memorial Sloan Kettering Cancer Center.¹³⁹ The incidence of IFIs was similar between the two arms, but the duration of prophylaxis was longer with micafungin, highlighting the improved safety and tolerability profile of micafungin in this population.

Overall these studies have consistently demonstrated the effectiveness of echinocandins in preventing IFIs among patients with neutropenia due to acute leukaemia and MDS and in the pre-engraftment phase after HCT. Efficacy and safety of micafungin in these patients were confirmed in a recently published meta-analysis of RCTs comparing micafungin with azoles in preventing IFIs among patients receiving chemotherapy, mostly for acute leukaemia, and those undergoing HCT.¹⁴⁰ This meta-analysis, in fact, found that micafungin use was associated with lower rates of IFIs and higher rates of treatment success (variably defined) with fewer AEs, and with no difference in mortality.¹⁴⁰ However, there is scant evidence for the use of echinocandins in preventing IFIs among patients with significant GvHD after HCT. These data are reflected in society guidelines. National Comprehensive Cancer Network guidelines endorse fluconazole and micafungin as first-line agents for preventing IFIs among patients with ALL and HCT with neutropenia in the pre-engraftment phase.⁸ Posaconazole is endorsed as first-line prophylaxis for patients with AML and MDS, and for those with significant GvHD, given its robust data in this patient group and its activity against moulds.⁸ These data are also reflected in the clinical practices of major cancer centres (Figure 1).

Figure 1.

Antifungal prophylaxis strategies at Memorial Sloan Kettering Cancer Center.

High doses of echinocandins

The safety and tolerability of higher doses of micafungin given at different dosing intervals have been explored in several uncontrolled studies with limited sample sizes.^141–144 These studies collectively support the safety and tolerability of doses of micafungin between 150 and 300 mg. A recent case series describing 104 patients (84 allogeneic HCT recipients, 20 patients with leukaemia) receiving intermittent administration of high-dose micafungin (at least five doses of 300 mg or more two to three times weekly) mostly for antifungal prophylaxis found few AEs and only a 6% breakthrough IFI rate though there was no comparator group.¹²¹

Novel agents in development

The drug development pipeline includes a number of antifungal agents, some of which may become part of future antifungal prophylaxis strategies. Two drugs in development that target (1,3)-β-d-glucan are summarized here, as part of our consideration of echinocandin prophylaxis for patients undergoing HCT and haematological malignancies.

Though not an echinocandin, SCY-078 (Scynexis, Inc., Jersey City, NJ, USA) is an oral glucan synthase inhibitor that, like echinocandins, targets synthesis of glucan.¹⁴⁵ The in vitro activity of SCY-078 is also similar to that of current echinocandins in terms of its activity against Candida species (including some isolates with FKS1 hot spot mutations) and Aspergillus species, and poor or absent activity against Mucormycetes and Fusarium species.^146–148 SCY-078 has also shown modest activity against Scedosporium prolificans but has not been studied against Pneumocystis species.¹⁴⁶In vivo data from a murine model of IC demonstrated SCY-078 efficacy against Candida species, and a Phase 3 trial of this oral glucan synthase inhibitor in patients with refractory or intolerant fungal diseases is under way.^145,149

Rezafungin acetate (CD101) (Cidara Therapeutics, Inc., San Diego, CA, USA) is a novel echinocandin in clinical development that is differentiated by its long half-life and a PK/PD profile that demonstrates high plasma drug exposure.^150,151 Once-weekly rezafungin achieved exposures well above the targeted AUC/MIC for various Candida species, theoretically predicting a potential to minimize emergence of resistance, though the drug has not yet been tested sufficiently in clinical studies.^150,151 Another novel property of rezafungin as an echinocandin is its stability, which enables subcutaneous formulation.¹⁵¹

The potency and spectrum of activity of rezafungin in vitro against common wild-type and antifungal-resistant species of Candida and Aspergillus are comparable to those of other echinocandins.^152,153 In neutropenic mouse models of azole-resistant candidiasis and aspergillosis, administration of rezafungin showed comparable efficacy to AmB.¹⁵⁴ Once-weekly subcutaneous administration was efficacious as prophylaxis against Candida and Aspergillus in neutropenic mouse models.¹⁵⁵ Of special interest are preliminary data in immunosuppressed mice supporting the efficacy of rezafungin in prevention of PJP.¹⁵⁶ Preliminary studies demonstrate safety in humans; clinical trials for the treatment of IC are ongoing.^150,157

Because of its spectrum of activity, PK and safety, rezafungin could be an attractive single agent for prophylaxis for Candida, Aspergillus and Pneumocystis if clinical trials ultimately support its safety and effectiveness. Well-designed clinical trials are warranted to formally evaluate the potential of rezafungin as prophylaxis in patients with haematological malignancies.

Conclusions

Diverse groups of patients with haematological and oncological disorders are at risk for IFIs, including PJP. Azole-based prophylaxis has reduced the rates of IFIs and mortality, but issues with tolerability, safety and drug interactions may limit its use. IFIs remain leading causes of infection-related mortality in these patients. The expanding clinical applications of molecular and immunomodulatory therapies pose new challenges with regard to drug interactions with azoles. Similarly, there is clearly an unmet need for better prophylaxis for PJP.

Compared with azoles, echinocandins have a more favourable safety profile, increased tolerability, minimal drug interactions and more predictable PK. Robust data support the use of echinocandins for prevention of IFIs among patients with prolonged neutropenia due to leukaemia or the neutropenic phase of HCT, although less data exist to warrant the routine use of echinocandins for prevention of IFIs in patients with GvHD after HCT. Novel antifungal drugs in early stages of development show potential as prophylaxis against Candida and Aspergillus, as well as possibly Pneumocystis in the case of rezafungin. If confirmed in clinical trials, newer antifungal agents might also help reduce pill burden and toxicities and improve adherence, allowing clinicians to provide effective and consistent antifungal prophylaxis to patients undergoing HCT and other treatments for haematological malignancies.