Antifungal Prophylaxis in Hematology Patients – Use Posaconazole

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Invasive mold infections tend to arise in patients who are profoundly immunosuppressed. Recently, those with COVID and severe influenza have been found to have a significant risk for these infections, but I will not focus on these. Instead, I will focus on those who lack that “first line of defense” i.e those who are neutropenic due to hematological malignancy and chemotherapy. One of the unavoidable things in life (including death and taxes) is our inhalation of molds and fungi. For most of us with functional “front lines” (aka neutrophils) this is not an issue. But for those who have either no neutrophils or crappy neutrophils, these molds pose a problem. With more hematological patients receiving bone marrow transplants and chemotherapy, neutropenia is becoming a more common occurrence. As a result, there has been interest in attempting to prophylax against these moulds

I have written about the mould-active triazoles before in the context of treatment, but to summarize, there are 3 general ones that have broad spectrum activity:

  • Posaconazole – 
  • Voriconazole – first-line therapy for aspergillus, no activity against mucorales and can cause nightmares 
  • Isavuconazole – the newer agent, active against aspergillus and several mucorales species. No issues with QTc (it actually shortens it). 

Fluconazole has been used for this purpose, which covers most Candida well (except for Krusei and Glabrata) but not invasive aspergillosis. Whenever the topic of antifungal prophylaxis pops up in this context, we usually think about covering aspergillosis. As a result, other drugs have been tried, including low dose amphotericin B and the mould-active triazoles. Prior to moving to the data, let’s look at the guidelines. The 2016 IDSA guidelines (1)  recommend either posaconazole or voriconazole for primary prophylaxis in those who are neutropenic and are at high risk for invasive aspergillosis. They also recommend micafungin, although this is a weak recommendation based on a 2004 randomized trial comparing micafungin and fluconazole prophylaxis in which micafungin did better for composite endpoints. They also recommend posaconazole for GVHD as well as voriconazole. ASCO guidelines (2) also mention a similar recommendation, but do not commit to any mold-active triazole nor echinocandin (they mention the use of a mold-active triazole). The German guidelines (3) endorse posaconazole over voriconazole for prophylaxis, while having luke-warm recommendations for inhaled liposomal amphotericin B and IV liposomal amphotericin B. 

Low Dose Amphotericin B

This is not something that is typically used, given the availability of posaconazole and isavuconazole, but it has been used in the past. 3 large trials evaluated its use. One multicenter, double-blind, placebo-controlled study compared low dose liposomal amphotericin B (2mg/kg, three times per week) with a placebo (4). Primary endpoint was the number of suspected fungal infections. 170 patients were randomized and 161 were evaluated. 40 patients in the placebo group (46%) and 31 patients in the AmBisome group (42%) developed suspected fungal infections, which did not reach statistical significance:

Of note, 28% of patients in the AmBisome group developed deep infections compared to 35.6% of those in the placebo group. There were no differences between groups in terms of nephrotoxicity or electrolyte disturbances. Another prospective, randomized, non-blinded study evaluated fluconazole vs amphotericin B (5). Primary endpoint was incidence of proven fungal infections. Amphotericin B was dosed at 0.2mg/kg daily, with max of 20mg per day while fluconazole was dosed at 400mg daily. 355 patients were randomized, with 2.6% of patients in the fluconazole group and 1.9% of patients in the AmB group having documented fungal infection during the prophylaxis period, while 4.1% and 7.5% of patients in each group, respectively, had a documented fungal infection overall (p-value >0.05 in both instances). Despite this, a higher proportion of patients in the amphotericin B group stopped their prophylaxis compared to fluconazole (57.9% vs 47.4%), with a significant proportion of having some sort of toxicity in the AmB group (12.6% vs 0.5%, p-value <0.05). Another prospective, randomized non blinded study evaluated low dose amphotericin (0.2mg/kg daily with max of 10mg daily) and fluconazole 200mg daily (6). Primary endpoint was incidence of proven invasive fungal infection through the first 100 days after HSCT. 186 patients were randomized, with 17% of patients in the fluconazole group and 19.8% of patients in the AmB group developing documented fungal infections during and after prophylaxis:

13% of patients in the fluconazole arm and 21% of patients in the AmB group developed renal toxicity, and mortality was not statistically different between groups. 

While theoretically it would be reasonable to think that ampho B would be better to prevent overall IFI, it does not seem to be the case here. It should be noted, however, that doses throughout these 3 trials were not standardized, as one trial only gave ampho B three times per week. Having said that, giving an IV drug as prophylaxis may not be terribly convenient, especially when all your lines are used for chemotherapy.

Inhaled Amphotericin B

This is something I tend to see in the lung transplant population. The idea here is that by giving it via aerosols, you circumvent the systemic toxicity of amphotericin B (i.e. nephrotoxicity).  A single center, randomized, double-blind study compared inhaled amphotericin B with placebo (. Patients who were anticipated to be neutropenic for over 10 days were enrolled, and inhalation of 2.5cc of a 5mg/mL solution was performed for 30 min per day on 2 consecutive days per week until neutrophil recovery or 12 inhalations per neutropenic episode. Primary endpoint was incidence of IPA per EORTC-MSG criteria with follow up until 28 days after the end of neutropenic episode (defined here as >300 cells/mm3). 339 episodes were evaluated, with 6 of the 139 patients treated with inhaled amphotericin B developing IPA (4%) compared to 18 patients (14%) of the 132 treated in the placebo group (OR 0.26, 95% CI 0.09-0.72) in the ITT analysis. The difference held true in the on-treatment population, with an OR of 0.14 (95% CI 0.02-0.66). 

It should be noted that more patients in the liposomal inhalation therapy discontinued prophylaxis compared to the placebo group by week 1 (45% vs 30%, p-value 0.01), mostly due to weakness of the patient to do the treatment or a technical problem. A larger, multicenter placebo controlled trial also evaluated prophylactic amphotericin B inhalations (8). In this study, however, 10mg of AmB were used twice per day until one of the study endpoints was reached (recovery of neutropenia for 2 consecutive days of >1000, day +50 after randomization, stable neutrophils for a week if >500, death). Primary endpoint was cumulative of proven, probable, or possible IPA on an ITT basis. 227 were randomized to the AmB arm while 155 were randomized to placebo. Notably, a significant proportion of patients in the AmB arm got G-CSF (48% vs 35%). There were no statistical differences in the cumulative incidence of IPA between groups, 4% in the AmB vs 7% in the placebo group (p-value 0.37). 

There was no difference in mortality between either group (13% vs 10%) nor was there any difference in several secondary outcomes, though there was a trend towards favoring the AmB group:

So inhaled abelcet is a reasonable option here. Of course, several adverse events, including irritation and coughing, may not make this such an attractive option for prophylaxis. 

Triazoles 

The major trials involve the use of posaconazole in comparison to fluconazole for prophylaxis, which is why this triazole is used in favor of others. For instance, an RCT comparing posaconazole to fluconazole/itraconazole (9). Patients who were neutropenic or were anticipated to be neutropenic for more than 7 days (defined as <500 neutrophils) were evaluated in A prospective, randomized control trial. Patients were randomized in a 1:1 ratio to either posaconazole or fluconazole/itraconazole. Prophylaxis was continued until remission, recovery from neutropenia, or occurrence of IFI up to 12 weeks after randomization. Primary endpoint was incidence of proven or probable IFI per EORTC/MSG guidelines. 602 patients were randomized. During the first 100 days, 14 patients in the posaconazole group had proven or probable fungal infection (5%) compared to 33 in the fluconazole or itraconazole group (11%, p-value 0.0003). 49 patients in the posaconazole group died (6%) compared to 67 in the fluconazole/itraconazole group (22%, p-value 0.048). Relative reduction in mortality in the posaconazole group as compared to the fluconazole/itraconazole group (33%) with an estimated NNT of 14.

In another randomized, multicenter, double blind study (10), posaconazole was compared with fluconazole in patients with GVHD (where people usually get lots of steroids). Patients were evaluated with primary endpoint being incidence of proven or probable invasive fungal infection up until day 112. 600 patients were randomized across 90 centers worldwide, with 5.3% of patients in the posazonale group having IFI vs 9% in the fluconazole group (OR 0.56, 95% CI 0.30 to 1.07). In terms of invasive aspergillosis, the posaconazole group did significantly better (OR 0.31, 95% CI 0.13-0.75). In this study, non-inferiority was established but not superiority. Mortality was similar in both groups, but was longer in the posaconazole group when it came to invasive fungal infections (1% vs 4%, p value 0.046). 

While a mortality benefit was not established in the GVHD study, in both instances, invasive moulds were better prevented in the posaconazole group. Voriconazole has also been compared with fluconazole in this setting. In a randomized, double-blind, multicenter trial (11), voriconazole and fluconazole were evaluated in HSCT patients. Primary end-point was fungal-free survival at 180 days. 600 patients were randomized, with the cumulative incidence rates of IFI of 11.2% in the fluconazole vs 7.34% in the voriconazole group (p-value 0.12) at 180 days. FFS rates were similar at 180 days between groups. Notably, these patients underwent GM testing twice per week until day 60 and beyond that, once weekly.

While not statistically different, there was a trend towards favoring voriconazole. The strength of triazoles in preventing fungal infections was established in 2 meta-analysis. One meta-analysis (12) evaluated 20 studies including 5725 patients. the primary outcome was proven or probable IFI comparing fluconazole with amphotericin B/voriconazole/posaconazole/itraconazole. The mold-active antifungals showed decreased problem or probable IFI, including invasive aspergillosis and IFI-related mortality, though no difference in overall mortality:

Of course, this pooled the mould-active antifungals into one large group, so you cannot tease out which one is better. A larger meta-analysis (13) of 54 studies evaluated nearly 13000 cases and 13 arms. Posaconazole was the best in preventing invasive fungal infections (RR 0.19, 95% CI 0.11 to 0.36), as well as being superior in preventing invasive aspergillosis (RR 0.13, 95% CI 0.03 to 0.65) in comparison to other antifungals. 

This pattern also held true for proven invasive fungal infections, with posaconazole being the best in preventing these:

So posaconazole seems to be the king here in terms of preventing IFI. Having said that, itraconazole seems to do better for invasive candida and posaconazole did not show any difference here:

Given all this, posaconazole is the go-to for fungal prophylaxis in hematological patients. Voriconazole seems to be ok as well, though data is scant here. Isavuconazole can theoretically be used, and guidelines seem to be ok with it, but there is little data in its use thus far (I do not know of any RCTs in this setting). The only study I was able to find was a retrospective study evaluating isavuconazole in HSCT and active heme patients (15). 

145 patients received 197 courses of isavuconazole as primary prophylaxis, with 12 breakthrough IFI being recorded, representing 8.3% of patients and 6.1% of courses of prophylaxis. When comparing isavuconazole prophylaxis in patients who received induction therapy for de novo AML and reinduction or salvage chemo for AML with posaconazole and isavuconazole, breakthrough IFI occurred in 7.9% of courses of isavuconazole compared to 2.7% of course of posaconazole and 0 of voriconazole prophylaxis. While the difference between posaconazole and isavuconazole did not reach statistical significance, there was nevertheless a trend favoring posaconazole. 

While it is difficult to fully evaluate the efficacy of isavuconazole based on a single-center retrospective study, it seems that based on the data at hand, posaconazole reigns supreme in terms of prophylaxis for this population.

TL;DR
–  Just use posaconazole for prophylaxis in heme patients. It has more data (2 large, well-designed RCTs) comparing it to fluconazole

  • You can also use voriconazole but data is not great. And there is little data for isavuconazole but theoretically you can use it as well
  • Micafungin and caspofungin can also be used if you don’t have isavuconazole available and have contraindications for the other 2
  • While you can use inhaled amphotericin, there is no defined dose for prophylaxis and adverse events lead to lots of discontinuation. 

References:

  1. Patterson TF, Thompson GR 3rd, 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 JA, Bennett JE. Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016 Aug 15;63(4):e1-e60. doi: 10.1093/cid/ciw326. Epub 2016 Jun 29. PMID: 27365388; PMCID: PMC4967602.
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  7. Rijnders BJ, Cornelissen JJ, Slobbe L, Becker MJ, Doorduijn JK, Hop WC, Ruijgrok EJ, Löwenberg B, Vulto A, Lugtenburg PJ, de Marie S. Aerosolized liposomal amphotericin B for the prevention of invasive pulmonary aspergillosis during prolonged neutropenia: a randomized, placebo-controlled trial. Clin Infect Dis. 2008 May 1;46(9):1401-8. doi: 10.1086/586739. PMID: 18419443.
  8. Schwartz S, Behre G, Heinemann V, Wandt H, Schilling E, Arning M, Trittin A, Kern WV, Boenisch O, Bosse D, Lenz K, Ludwig WD, Hiddemann W, Siegert W, Beyer J. Aerosolized amphotericin B inhalations as prophylaxis of invasive aspergillus infections during prolonged neutropenia: results of a prospective randomized multicenter trial. Blood. 1999 Jun 1;93(11):3654-61. PMID: 10339471.
  9. Cornely OA, Maertens J, Winston DJ, Perfect J, Ullmann AJ, Walsh TJ, Helfgott D, Holowiecki J, Stockelberg D, Goh YT, Petrini M, Hardalo C, Suresh R, Angulo-Gonzalez D. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med. 2007 Jan 25;356(4):348-59. doi: 10.1056/NEJMoa061094. PMID: 17251531.
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  11. Wingard JR, Carter SL, Walsh TJ, Kurtzberg J, Small TN, Baden LR, Gersten ID, Mendizabal AM, Leather HL, Confer DL, Maziarz RT, Stadtmauer EA, Bolaños-Meade J, Brown J, Dipersio JF, Boeckh M, Marr KA; Blood and Marrow Transplant Clinical Trials Network. Randomized, double-blind trial of fluconazole versus voriconazole for prevention of invasive fungal infection after allogeneic hematopoietic cell transplantation. Blood. 2010 Dec 9;116(24):5111-8. doi: 10.1182/blood-2010-02-268151. Epub 2010 Sep 8. PMID: 20826719; PMCID: PMC3012532.
  12. Ethier MC, Science M, Beyene J, Briel M, Lehrnbecher T, Sung L. Mould-active compared with fluconazole prophylaxis to prevent invasive fungal diseases in cancer patients receiving chemotherapy or haematopoietic stem-cell transplantation: a systematic review and meta-analysis of randomised controlled trials. Br J Cancer. 2012 May 8;106(10):1626-37. doi: 10.1038/bjc.2012.147. PMID: 22568999; PMCID: PMC3349180.
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  15. Fontana L, Perlin DS, Zhao Y, Noble BN, Lewis JS, Strasfeld L, Hakki M. Isavuconazole Prophylaxis in Patients With Hematologic Malignancies and Hematopoietic Cell Transplant Recipients. Clin Infect Dis. 2020 Feb 14;70(5):723-730. doi: 10.1093/cid/ciz282. PMID: 30958538.

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