Posaconazole enteric-coated tablets on the efficacy and tolerability of secondary antifungal prophylaxis in haploidentical allogeneic stem cell transplantation

doi:10.21203/rs.3.rs-4695911/v1

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Posaconazole enteric-coated tablets on the efficacy and tolerability of secondary antifungal prophylaxis in haploidentical allogeneic stem cell transplantation

https://doi.org/10.21203/rs.3.rs-4695911/v1

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Background:

There are limited researches about posaconazole enteric-coated tablets on the efficacy and tolerability of secondary antifungal prophylaxis(SAP)for invasive fungal disease (IFD) in haploidentical allogeneic hematopoietic stem cell transplantation༈allo-HSCT༉.

Objective:

To investigate the plasma concentration of posaconazole enteric-coated tablets on the efficacy and tolerability of SAP and drug-drug interactions between posaconazole, cyclosporine A (CsA) and mycophenolate mofetil (MMF) in haploidentical allo-HSCT.

Methods:

We conducted a single-arm, open-label, prospective trial (ChiCTR2200059472, Date of Registration 30th April, 2022) to assess efficacy and tolerability of posaconazole enteric-coated tablets as SAP in haploidentical allo-HSCT patients. Plasma concentrations of posaconazole and mycophenolic acid (MPA,active metabolites of MMF) as well as CsA were monitored within 30 days post-transplantation. Additionally, the incidence of IFD was observed.

Results

Fourty-six patients previously with IFD were enrolled in the trial. The incidence of IFD was 4.35% at 100 days and 10.86% at 6 months. The primary cause of prophylaxis failure was gastrointestinal intolerance. The mean plasma concentrations of posaconazole were 0.48 ± 0.06ug/ml at week 1, 0.54 ± 0.07ug/ml at week 2, 0.75 ± 0.08ug/ml at week 3 and 0.90 ± 0.08ug/ml at week 4. The mean plasma concentrations of CsA were 133.04 ± 0.13ng/ml at week 1, 179.53 ± 11.19ng/ml at week 2, 225.02 ± 13.80ng/ml at week 3 and 278.61 ± 13.61ng/ml at week 4. The mean plasma concentrations of MPA during week 2, 3 and 4 were 0.41 ± 0.06mg/L, 0.84 ± 0.08mg/L and 1.08 ± 0.13mg/L, respectively. Posaconazole reached steady state concentrations by week 2 and MPA reached target concentrations at week 3.

Conclusion

Posaconazole enteric-coated tablets appears to be effective and tolerability for SAP of IFD after haploidentical allo-HSCT. When cyclosporine, MMF, and posaconazole are used in combination, the dosage of MMF does not need to be adjusted. The dosage of CsA needs to be personalized and adjusted based on therapeutic drug monitoring.

Posaconazole enteric-coated tablets

secondary antifungal prophylaxis

invasive fungal infection

haploidentical allogeneic hematopoietic stem cell transplantation

cyclosporine A

mycophenolate mofetil

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective therapeutic approach for the treatment of hematological malignancies. In China, haploidentical stem cell transplantation (HID-HSCT) accounted for 60%^[1]. The classic graft versus host disease(GVHD)prophylaxis regimen consists of cyclosporine A༈CsA༉, methotrexate༈MTX༉, and mycophenolate mofetil༈MMF༉in HID-HSCT.

Posaconazole enteric-coated tablet is the second-generation broad-spectrum antifungal drug.Its absorption is not affected by gastrointestinal conditions. Numerous guidelines^[2–4] recommend posaconazole for primary prevention of invasive fungal disease (IFD) in patients undergoing allo-HSCT. CsA and posaconazole have significant drug interactions. Similarly, CsA and MPA (mycophenolate mofetil is the pro-drug of mycophenolic acid) also have interactions with each other ^[5]. Additionally, posaconazole is metabolized by P-gp(P-glycoprotein) and a P-gp inhibitor, the study has shown that plasma concertrations of MPA may be affected by multiple membrane transporters and the MPA is also a substrate of P-gp^[6]. Currently, there is insufficient data to determine the presence of DDI between posaconazole and MMF or establish dosage adjustments for a more rational use of posaconazole enteric-coated tablets in combination with CsA and MMF.

This study aims to assess the effect of posaconazole enteric-coated tablets on the plasma concentration of immunosuppressants, the occurrence of acute GVHD, and the effectiveness and tolerability in the secondary antifungal prophylaxis (SAP) for IFD.

Study population

This was a prospective, open-labeled, single-center study (ChiCTR2200059472, Date of Registration 30th April, 2022 ). Patients meeting the following criteria were included:(1)Age > 13 and<60 years old, male and female are not limited. (2)Patients undergoing HID-HSCT.(3)GVHD prophylaxis regimen is CsA + MTX + MMF. (4)Patients with a history of proven or probable invasive pulmonary aspergillosis (IPA) before transplantation. Exclusion criteria were as follows: (1) liver dysfunction (bilirubin or transaminase level > the upper limit of normal) or renal impairment (creatinine > 97umol/L), or (2) possible IPA. (3) medications known to interact with azoles and possibly leading to life-threatening effects within 24 h (except astemizole, which could not have been taken within 10 days) or β-hydroxy-β-methylglutaryl- coenzyme A reductase inhibitors metabolized by cytochrome P450 enzyme 3A4 within 24 h of the start of the study. The study was performed in accordance with the modified Helsinki Declaration, and the protocol was approved by the ethical review boards of the first affiliated hospital of Xi’an jiaotong university. All adult patients or authorized client of minors provided written informed consent.

Conditioning regimen

For severe aplastic anemia patients received FAC regimen:Fludarabine 30mg/m² d-5~-2, anti-thymocyte globulin (ATG) (Thymoglobulin^®, Genzyme, Cambridge, MA)d-5~-2, Cyclophosphamide 30mg/kg d-5~-2.Other patients received myeloablative regimen conditioning of modified BuCy2 regimen, the regimen consists of: cytarabine 4g/m² d-9~-8, Busulfan 0.8mg/kg q6h d-7~-5, Cyclophosphamide 1.8g/m² d-4~-3, Semustine 250mg/m² d-3, anti-thymocyte globulin (ATG) (Thymoglobulin^Ⓡ, Genzyme, Cambridge, MA) were administered for 2.5mg/kg.d on day-4, -3,-2 and − 1.

Graft versus host disease prophylaxis

CsA in combination with MMF and a short course of MTX was administered for GVHD prophylaxis. CsA is administered intravenously at a dose of 3mg/kg/day starting from the conditioning regimen, then switched to oral on day + 14. The dose is gradually reduced starting from day + 50, the discontinuation depending on the presence of acute GVHD. MTX is administered intravenously at a dose of 15mg/m² on day + 1, followed by 10mg/m² on days + 3, +6, and + 11. MMF is started on day + 1, with a dosage of 0.5g bid. After one month, the dose is reduced to 0.5g qd, and discontinued 45 days after transplantation.

Secondary antifungal prophylaxis

Posaconazole enteric-coated tablets 300 mg/d (loading dose 300 mg twice daily for the first day)was administered as SAP. SAP was started from the first day of the conditioning regimen and continuing until 180 days after transplantation, unless a breakthrough IFD, an adverse event requiring discontinuation of the study medication, or death. Once failure of SAP, we would give the other broad-spectrum antifungal drugs.

Therapeutic drug monitoring

Posaconazole,MMF and CsA samples were analyzed using a validated ultra-performance liquid chromatography fluorescence assay and independent quality control center was employed for comprehensive quality control management throughout the entire process.Exposure metrics were defined as trough concentrations (Cmin; 24h ± 2h postdose (day7,14,21,28)) Samples were collected in the morning on days 7, 14, 21, and 28 after transplantation and collected in EDTA-containing anticoagulant tubes. The samples were centrifuged at 4°C, 3000 rpm for 10 minutes using a refrigerated centrifuge, and then subjected to sample processing and concentration determination following the standard steps of LC-MS/MS.

Definition and follow up

IFD was classified as proven, probable, or possible infection according to EORTC/MSG criteria^[7]. Invasive pulmonary aspergillosis (IPA) was defined as the presence of radiographic findings consistent with IFD on computed tomography scan and at least one of the following: (1) Aspergillus identified by biopsy, (2) Aspergillus identified from culture of bronchoalveolar lavage fluids, or (3) positive finding of serum galactomannan test (> 0.5 ng/mL).

Responses to treatment were categorized as complete response(CR), partial response (PR), stable responses, and failure of therapy. Stable IFD was defined as CR to prior IFD at transplantation while active IFD was defined as PR or stable responses to prior IFD treatment at transplantation. Failure of SAP was defined by any of following cases: persistent fever in an appropriate clinical conditions and failure to respond to empiric antibiotics during IFD prophylaxis, receipt of any other systemic antifungal agents for the occurrence of suspected IFD^[8]。

The grading criteria for aGVHD were referred to “Chinese consensus of allogeneic hematopoietic stem cell transplantation for hematological disease (Ⅲ)-acute graft-versus-host disease (2020)”^[9]

The follow-up assessments were conducted on weekly during the first 3 months, and biweekly intervals from months 3–6 after transplantation.All patients were followed up until April 30,2024.

IFD was routinely assessed including clinical symptoms, chest (monthly during the first 3 months and every 2–3 months between 3–6 months), sinuses, and/or abdomen computed tomography test, bronchoscopy and bronchoalveolar lavage serological testing for Aspergillus galactomannan, (1,3)-B-D-glucan, culture of related tissue or samples, and next-generation sequencing.

Statistical analysis

Continuous variables were represented in median, and categorical variables were represented in percentages. The proved and probable groups were compared using the chi-square test for categorical variables and Wilcoxon rank sum test for quantitative data. The survival curves for OS was plotted using the Kaplan–Meier method. SPSS16.0 (IBM, Chicago, IL, USA) was used for the statistical analysis. The R version 3.6.0 (http://www.r-project.org) software was used for competing risks analysis. P < 0.05 was considered as statistically significant.

Patient characteristics

Out of the 72 patients initially enrolled in the study, 46 patients were included for analysis (Fig. 1). As indicated in Table 1,17 (36.96%) patients had previous proven IFD and 29 (63.04%) patients had previous probable IFD. The median age was 37 years (range 15–63 years), with 25 (58.70%) males and 21 (41.30%) females. The underlying diseases were acute myeloid leukemia (AML) (n = 27), acute lymphoid leukemia(ALL) (n = 12), myelodysplastic syndrome (MDS) (n = 3) and aplastic anemia(AA) (n = 4). Additionally, one patient presented with diabetes as a comorbidity. 38(82.6%) patients achieved CR of primary disease before HSCT.

Table 1

Patients Characteristics
Characteristic	Number(%)
Previous IFD
Proven	17(36.96)
Probable	29(63.04)
IFD before HSCT
CR	36(78.26)
PR	8(17.39)
SD	2(4.35)
Age at transplantation (y)
Median (range)	37(15–63)
Gender, no. (%)
Male	27(58.70)
Female	19(41.30)
Underlying disease, no. (%)
AML	27(58.70)
ALL	12(26.09)
MDS	3(6.52)
AA	4(8.69)
Complication, no. (%)
Diabetes	1(2.17)
No Diabetes	15(97.83)
Stage of underlying disease, no. (%)
CR	38(82.61)
Non-CR	8(17.39)
IFD Invasive fungal diseases, AML acute myeloid leukemia, ALL acute lymphoid leukemia, MDS: myelodysplastic syndrome, AA:aplastic anemia. CR complete responses

The plasma concentrations of posaconazole, CsA and MPA

The mean plasma concentrations of posaconazole enteric-coated tablet at week1, 2, 3 and 4 after conditioning were 0.48 ± 0.06ug/ml, 0.54 ± 0.07ug/ml, 0.75 ± 0.08ug/ml and 0.90 ± 0.08ug/ml(Figure 2A). The mean plasma concentrations of MPA at week 2, 3 and 4 were 0.41 ± 0.06mg/L, 0.84 ± 0.08mg/L and 1.08 ± 0.13mg/L (Fig. 2B). The mean plasma concentrations of CsA at week1, 2, 3 and 4 were 133.04 ± 0.13ng/ml, 179.53 ± 11.19ng/ml, 225.02 ± 13.80ng/ml and 278.61 ± 13.61ng/ml༈Figure 2C༉.Following week 1, concentration of CsA of 26 cases was below 150ng/ml and the dosage was increased by 25% of the original dose, at week 4, concentration of CsA of 15 cases was above 250ng/ml and the dosage was decreased by 25%.

Once posaconazole enteric-coated tablet reached steady-state concentrations at week 2, leading to dose reduction of CsA in 4 patients. At week 2, MPA did not attain target concentrations. However, the concentrations of MPA significantly increased without altering the MMF dose and reached target concentrations at week 3 when combined with the three-drug combination. CsA concentrations increased significantly by week 4 while maintaining stable concentrations of MPA and posaconazole enteric-coated tablet.

Graft versus host disease

To the end of follow-up, twenty two cases developed acute GVHD (7 cases of grade IV, 3 cases of grade III), 10 cases developed chronic GVHD, and 3 patients died from intestinal steriod-resista nce acute GVHD.

Efficacy of secondary antifungal prophylaxis

The incidence of IFD was 4.35% at 100 days and 10.86% at 6 months. The primary reason for the failure of prophylaxis was gastrointestinal intolerance and persistent fever (Table 2). Four patients received L-AmB treatment, one patient reveived combination therapy of voriconazole and caspofungin. None of the patients died attributed to IFD.

Table 2

Reason for failure of antifungal prophylaxis with posaconazole tablet
	Proven IFD pre-HSCT (n = 17)	Probable IFD pre-HSCT(n = 29)	P
Breakthrough of IFD	3 (17.64)	2 (6.89)	0.258
Gastrointestinal intolerance	1 (5.88)	1 (3.44)	0.153
Persistent fever	1 (5.88)	1 (3.44)	0.153
Drug–drug interaction	1 (5.88)	0 (0)	1.744

Survival

During the median follow-up of 274 days (range 133–408 days), a total of 8 deaths, attributed to relapse (4 cases), GVHD (3 cases), and myocarditis (1 case). The 3-year expected overall survival (OS) and progression-free survival (PFS) rates were 79.5% and 69.4% respectively (Fig. 3).

The patients undergoing allo-HSCT with previous IFD can effectively reduce IFD recurrence and mortality by SAP ^[10].The reported incidence of IFD after SAP was 38.6% ^[11]. Broad-spectrum antifungal agents, including voriconazole, itraconazole, liposomal amphotericin B, and caspofungin, have shown efficacy in patients with previous IFD. Due to the limited availability of large prospective studies, in patients with previous IFD undergoing allo-HSCT, two retrospective studies have reported the incidence of IFD as follows: 42.9% with itraconazole as SAP, 31.3% with voriconazole, 0–55.5% with liposomal amphotericin B, and 13.8–16.7% with caspofungin^{[11, 12]}. There were limited data to assess the efficacy and tolerability of posaconazole enteric-coated tablet as SAP in patients undergoing allo-HSCT. Our study showed the incidence of IFD after SAP was 4.35% at 100 days and 10.86% at 6 months,which is lower than that reported in previous studies. This finding suggests that posaconazole enteric-coated tablet is relatively effective in IFD prophylaxis. The primary cause of prophylaxis failure, accounting for nearly half of the cases, was gastrointestinal intolerance. However, posaconazole enteric-coated tablet was discontinued in only two patients. In our study, the 3-year OS and PFS of the 46 patients with IFD history was 79.5% and 69.4% respectively. A prospective randomized trial ^[13] shown that the combination of CsA and MMF prophylactic regimens resulted in the incidence of II–IV acute GHVD and chronic GVHD were 48% and 63%. Our study showed the similar incidence of aGVHD and a lower cGVHD compared to the above study. Most deaths were attributed to primary disease relapse and grade III–IV GVHD. This indicates that posaconazole enteric-coated tabletprophylaxis can be safely utilized for allo-HSCT patients with previous IFD.

However, there are well-defined DDI between antifungal durgs and immunosuppressants. The secondary objective of this study is to explore the dosage adjustments when combining the CsA and MMF with posaconazole enteric-coated tablet. The systematic review indicate^[14] that the dosage of CsA should be reduced when initiating posaconazole suspension therapy, and plasma levels of the immunosuppressant should be monitored throughout the course of posaconazole suspension therapy so that dose adjustments appropriately. Other studies^{[15, 16]} found a significant elevation in CsA levels within one week of initiating posaconazole suspension therapy, and the highest C/D ratio was observed 9 to 12 days after posaconazole suspension initiation. Compared with posaconazole suspension, the absorption of posaconazole enteric-coated tablets is not affected by gastrointestinal conditions.Our study also found that after one week of administering posaconazole enteric-coated tablets, CsA concentration of 43.48% patients increased significantly, approximately 56.52% of patients required dose adjustment.

MMF is commonly used in combination with a calcineurin inhibitor, as a maintenance immunosuppressive regimen. HSCT patients has many factors may disturb the pharmacokinetics of MPA, leading to fluctuations in plasma MPA exposures ^[17]. During the early post-transplantation phase, HCT patients commonly experience diarrhea, which decreased the reabsorption of MPA in the gastrointestinal tract and consequently lower the MPA concentration ^[18]. CsA inhibits MRP2-mediated enterohepatic circulation of MPAG, and causes a decrease in plasma MPA exposures. Literature data^[19] has shown that the concomitant use of CsA and MMF in kidney transplant recipients, cyclosporine-induced inhibition of the enterohepatic recirculation of mycophenolate, the MPA area under the curve is significantly lower (40%).MPA AUC cotreated with cyclosporine is often below the therapeutic window, and that this results in a higher incidence of rejection. Another important clinical implication of the interaction is that, after discontinuation of cyclosporine, the MPA concentrations will increase and can cause MPA-related adverse effects, such as leukopenia, so the dosage of MMF needs to be readjusted and reduced.A Phase I/II Study ^[20] investigating MMF combination with CsA for GVHD had shown that dose escalation of MMF to achieve the target concentration. MPA is a substrate of P-glycoprotein (P-gp), posaconazole is also a P-gp substrate and inhibitor. MPA may accumulate when administered with Posaconazole^[21].For the first time, we conducted a more detailed analysis of the blood concentrations of these three drugs when used in combination. The combination of posaconazole and cyclosporine does not cause significantly decrease the concentration of MMF. Instead, it slightly increases the concentration indicating that there is no need to adjust the dose of MMF. This reduces the complexity of medication management and lower risk of adverse reactions associated with MMF, such as neutropenia. Therefore, the addition of posaconazole ensures relatively stable blood concentrations of all three drugs. This treatment regimen greatly benefits patients and improves medication safety.

Our study has several limitations. Firstly, our study is a single-center study with small a sample size, which limits the generalizability of our findings. Our study was non-controlled and did not include a comparison with other drugs utilized for SAP. Secondly, the monitoring of drug concentrations was limited to 1 month after transplantation, and further investigation is necessary to understand the subsequent DDI and their specific mechanisms.

Posaconazole enteric-coated tablets appears to be effective and tolerability for SAP of IFD after allo-HSCT. When cyclosporine, MMF, and posaconazole are used in combination, the dosage of MPA does not need to be adjusted. The dosage of cyclosporine needs to be personalized and adjusted based on TDM. In the triple combination, posaconazole reduces the impact of cyclosporine on the blood trough concentration of MMF, thereby reducing the need for adjustment of MMF dosage.

Allo-HSCT

allogeneic hematopoietic stem cell transplantation

HID-HSCT

haploidentical hematopoietic stem cell transplantation

GVHD

graft versus host disease

CsA

cyclosporine A

MTX

methotrexate

MMF

mycophenolate mofetil

IFD

invasive fungal disease

SAP

secondary antifungal prophylaxis

P- gp

Q- P-glycoprotein

ATG

anti-thymocyte globulin

complete response

partial response

AML

acute myeloid leukemia

ALL

acute lymphoid leukemia

MDS

myelodysplastic syndrome

aplastic anemia

MPA

mycophenolic acid

Ethics approval and consent to participate

The study was performed in accordance with the modified Helsinki Declaration, and the protocol was approved by the ethical review boards of the first affiliated hospital of Xi’an jiaotong university. All adult patients or authorized client of minors provided written informed consent.

Consent for publication

All authors and patients approved the publication of the article.

Availability of data and material

The datasets used and analysed during the current study may be made available by the corresponding author upon reasonable request.

Competing interests

There is no conflict of interests.

Funding

This study was funded by Medical Basic Clinical Integration Innovation Project of Xi'an Jiaotong Univeristy（YXJLRH2022007), the Key Research and National Key R&D Program of China（2022YFC2502700）

Authors' contributions

Xiaoning Wang has received funds for research and write the draft. Chunhong Sun,Yuqi Wang carried out the trial. Ruimin Liu,Juan Ren and Huahcao Zhu contributed to the analyze and detection of drug concentration. Pengcheng He designed the study and reviewed the draft. All authors approved the final version of the article, including the authorship list.

Acknowledgements

This study would not have been possible without the collaboration of all the patients, medical and nursery staff, and data managers who have taken part in the project. Supported in part by a research grant from Investigator-Initiated Studies Program of MSD. The opinions expressed in this paper are those of the authors and do not necessarily represent those of MSD.

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No competing interests reported.

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Posaconazole enteric-coated tablets on the efficacy and tolerability of secondary antifungal prophylaxis in haploidentical allogeneic stem cell transplantation

Status:

Version 1

Abstract

Background:

Objective:

Methods:

Results

Conclusion

Figures

Introduction

Patients and Methods

Study population

Conditioning regimen

Graft versus host disease prophylaxis

Secondary antifungal prophylaxis

Therapeutic drug monitoring

Definition and follow up

Statistical analysis

Results

Patient characteristics

The plasma concentrations of posaconazole, CsA and MPA

Graft versus host disease

Efficacy of secondary antifungal prophylaxis

Survival

Discusssion

Conclusion

Abbreviations

Declarations

References

Additional Declarations

Status:

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