Posaconazole for secondary antifungal prophylaxis in allogeneic stem cell transplantation recipients: a retrospective study

doi:10.21203/rs.3.rs-1345686/v1

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Posaconazole for secondary antifungal prophylaxis in allogeneic stem cell transplantation recipients: a retrospective study

https://doi.org/10.21203/rs.3.rs-1345686/v1

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Background

There is no consensus on the optimal secondary antifungal prophylaxis (SAP) regimen in patients receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT). The purpose of this study was to evaluate the efficacy and safety of posaconazole in the secondary prophylaxis of invasive fungal disease (IFD) in patients with allo-HSCT.

Methods

We retrospectively reviewed clinical data from prior IFD patients who received posaconazole as systemic antifungal prophylaxis between June 2016 and January 2021, with a follow-up period of 1 year after HSCT. The clinical outcomes of patients with a history of IFD (n = 30) and those without IFD (n = 93) were compared.

Results

The 1-year cumulative incidence of prophylaxis failure was 44.1% in the group without prior IFD and 50.0% in the group with a past history of IFD (p = 0.470). The cumulative incidence of confirmed, probable or possible IFD within 1 year after allo-HSCT was 15.4% in the group without prior IFD and 25.9% in the group with a past history of IFD (p = 0.148). Two risk factors for the develop of post-transplantation IFD of posaconazole prophylaxis were found, namely, cytomegalovirus disease and steroid treatment for more than 90 days after transplantation. A similar overall survival can be achieved between patients with a prior IFD and those free from a history of IFD.

Conclusions

Posaconazole appears to be a viable alternative to SAP in appropriately selected patients for allo-HSCT.

secondary antifungal prophylaxis

invasive fungal diseases

posaconazole

allogeneic hematopoietic stem cell transplantation

Invasive fungal disease (IFD) is serious and prevalent in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT), causing considerable amount of morbidity and mortality [1]. Especially in China, the incidence of IFD after secondary antifungal prophylaxis (SAP) was 38.6% among patients receiving allo-HSCT, even with the adoption of novel prophylactic and therapeutic strategies [2]. In general, broad-spectrum antifungal agents such as voriconazole, itraconazole, liposomal amphotericin B, and caspofungin are recommended for patients with a history of fungal infection [3]. However, there is no optimal SAP strategy and no specific advice on the selection of SAP agents. In addition, the opportunistic molds and yeast-like fungi (e.g., Zygomycetes and Fusarium spp.) are more involved in HSCT recipients with the widespread use of new broad-spectrum antifungals [4, 5]. Therefore, the selection of SAP drugs should take into account the possible drug-resistant strains.

Posaconazole has become a widely accepted strategy for the prevention of IFD in recipients who undergo intensive chemotherapy such as acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) and allo-HSCT recipients with graft-versus-host disease (GVHD) [6, 7]. Compared with other azole antifungals, it has great characteristics of broad spectrum, potent activity, low cost and good long-term tolerance [6, 8–10]. However, it remains a question whether posaconazole is suitable for patients as SAP, considering the absorption issue.

In this retrospective study, the efficacy of posaconazole SAP therapy for IFD was assessed. In addition, we compared the clinical outcome of posaconazole as a systemic antifungal prophylaxis between allo-HSCT recipients with and without a history of IFD to confirm the feasibility of our approach.

Patients

In this single-center retrospective study, All hospitalized adult allo-HSCT patients adopting posaconazole as SAP at The Affiliated People's Hospital of Ningbo University from June 2016 to January 2021 were analyzed. During this period, 116 patients took posaconazole 200 mg orally three times daily, and 7 patients received posaconazole 400 mg twice daily. This study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of The Affiliated People's Hospital of Ningbo University. All patients have signed informed consent forms to participate in the study.

Transplant regimens and post-transplant immunosuppression

All patients undergoing allo-HSCT received conventional therapy including myeloablative/reduced-intensity conditionings, and were classified as previously described by Giralt et al [11]. Cyclosporine A (CsA) + mycophenolate mofetil (MMF) + a short course of methotrexate (MTX) were administered to the patients undergoing human leukocyte antigen (HLA)-matched sibling donor (MSD) transplant for GVHD prophylaxis. After January 2019, CsA + MMF + MTX + anti-thymocyte globulin (ATG) (Thymoglobulin®, Genzyme, Cambridge, MA) were administered for 1.5 mg/kg i.v. on day − 3, -2 and − 1 to the MSD transplant patients whose age ≥ 45 years, and CsA + MMF + MTX + ATG (2.5 mg/kg i.v. on day − 4, -3, -2 and − 1) with or without post-transplant cyclophosphamide (50 mg/kg day + 3) were administered to the patients undergoing haploidentical donor (HID) transplants for GVHD prophylaxis.

Administration of prophylactic antifungal agents

Antifungal prophylaxis was started on the first day of the conditioning regimen until 90 days after transplantation in patients without IFD before transplantation. SAP was given started on the first day of the conditioning regimen until 180 days after transplantation for patients with stable IFD. For patients with active IFD, SAP was started on the first day of the conditioning regimen until the eradication or stability of residual foci. The antifungal prophylaxis agent was given again if patients developed acute GVHD (aGVHD), chronic GVHD (cGVHD), or they were treated with long-term systemic corticosteroids. Posaconazole oral suspension (200 mg orally three times a day) was administered in the primary antifungal prophylaxis (PAP) and for the SAP patients who had a history of IFD and achieved complete response (CR) after antifungal treatment before HSCT. Posaconazole suspension was administered at 400 mg twice daily to the SAP patients who had active IFD and achieved partial response (PR) after antifungal treatment, then switched to 200 mg three times a day when the residual foci in the patients was eradicated or stable. In case of antifungal prophylaxis failure, we would switch prophylactic posaconazole to other broad-spectrum antifungal drugs such as voriconazole, caspofungin and amphotericin B.

Definition

The IFD was defined as proven, probable, or possible infection according to the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium (EORTC/MSG) [12]. Suspected IFD included these proven, probable, possible IFD. Responses to treatment were classified into CR, PR, stable responses, and failure of therapy [13]. Failure of antifungal prophylaxis was defined by any of following cases: changing to an alternative antifungal agent or dosing modification due to suspected IFD, gastrointestinal intolerance (GI) in patients with severe mucositis, colitis, diarrhea, nausea, or emesis, drug-drug interactions, persistent fever in an appropriate clinical context and failure to defervesce after administration of empiric antibiotics and deaths (any reason) during IFD prophylaxis. The absence of suspected IFD, as well as no emerging IFD (for SAP patients specifically) without antifungal agent or dosing modification, were defined as successful cases.

Efficacy evaluation

All the patients were followed up until at least 12 months after allo-HSCT. IFD was regularly monitored through clinical symptoms, chest, 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 PAP and SAP 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. A multivariate analysis was performed using Cox regression models for the incidence of IFD. The cumulative incidences of prophylaxis failure, IFD by 1 year after allo-HSCT were calculated using Fine and Gray’s model considering death as a competing event. As this retrospective analysis was designed as an exploratory investigation, statistical power calculation (sample size) was not conducted. The endpoint of the last follow-up for all of the surviving patients was December, 2021. 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

Among a total of 123 patients undergoing an allo-HSCT enrolled in the study, 93 (75.6%) patients received posaconazole as PAP and 30 (24.4%) had a past history of IFD received posaconazole as SAP. The patients had a median age of 39 years (range 14-72 years), with 70 (56.9%) males and 53 (43.1%) females. The underlying diseases were mainly AML (n = 41), acute lymphoid leukemia (n = 33), MDS (n = 22), and aplastic anemia (n = 19), and chronic myeloid leukemia (n = 4), lymphoblastic lymphoma (n = 3) as well as myelofibrosis (n = 1) were also included. Thirteen patients had diabetes as a complication. A hundred and three patients achieved CR and 20 patients were in non-CR at the time of transplantation. 37 patients received MSD transplantation and 86 received HID transplantation. Of the 30 patients who had a history of IFD pre-transplantation, 23 patients had stable IFD and 7 patients had active IFD at the time of transplantation. Among those 30 patients, 5 proven IFD patients was found, along with 13 probable IFD and 12 possible IFD patients. Out of all patients, 21 cases (17.1%) developed aGVHD (grade III-IV) while 32 (26.0%) developed extensive cGVHD. Based on the patient and transplant characteristics of PAP and SAP groups in Table 1, the similar demographic and transplantation characteristics could be seen.

Antifungal prophylaxis and efficacy

A documented reason for prophylaxis failure was identified in 43.1% (54/123) cases. There were no significant differences in the incidence of IFD, gastrointestinal intolerance, persistent fever, drug-drug interaction and death between the groups with and without a past history of IFD, respectively (data shown in Table 2). The median duration of antifungal prophylaxis with posaconazole was 90 days (range, 9-365 days) in PAP group and 180 days (range, 15-365 days) in SAP group. The 1-year cumulative incidence of prophylaxis failure was 50.0% (95% CI, 28.5-65.0%) in group with a past history of IFD and 44.1% (95% CI, 32.7-53.6%) in the group without a past history of IFD (p = 0.470) (Figure 1). The primary reason for prophylaxis failure of posaconazole intervention was GI, accounting for 46.3% (25/54) of failures. It is followed by the suspected IFD, accounting for 35.2% (19/54) of failures. Five (9.2%) patients had to discontinue posaconazole due to persistent fever. Three (5.6%) patients resulted in prophylaxis failure due to drug-drug interaction that developed hepatic toxicity, but two were later attributed to histologically proven GVHD. The two (3.7%) deaths were caused by relapse and hematencephalon, respectively.

IFD occurence post-transplantation

The 1-year cumulative incidence of IFD was 15.4% (95% CI, 7.0%-23.0%) in the patients without a history of IFD and 25.9% (95% CI, 7.4%-40.7%) in the group with a past history of IFD (p = 0.148, Figure 2). Among the 93 patients who used posaconazole as PAP, twelve (12.9%) cases developed IFD, including 8 during prophylaxis period and 4 after the period. The IFD occurred at a median time of day +107 after transplantation (range, day +8 to +262). Seven (23.3%) of the 30 patients with a history of IFD pre-transplantation after allo-HSCT developed breakthrough IFD, including six during the prophylaxis and one after the SAP. In these SAP patients, the IFD occurred at a median time of day +27 after transplantation (range, day +15 to +235). Among these proven IFD, the pathogens after the end of PAP were aspergillosis (2 cases), followed by Candida spp (1 case) and pneumocystis carnii (1 case) while the pathogen after the end of SAP were pneumocystis carnii (1 case).

Treatment and outcome of post-transplantation IFD

Nineteen patients who developed post-transplantation IFD received salvage therapy. Of these, eight (42.1%) patients were treated with voriconazole, the rest included 4 (21.1%) patients with caspofungin, 5 (26.3%) patients with combination therapy, 1 (5.3%) patient with L-AmB and 1 (5.3%) patient dose adjustment on posaconazole. After salvage therapy, besides 3 (15.8%) died of IFD, 12 (63.2%) patients achieved CR and 4 (21.0%) achieved PR. Among those 19 patients, twelve patients belonged to PAP group and 7 belongs to SAP group. One (8.3%) death happened in PAP group while 2 (28.5%) happened in the SAP group.

Risk factors for IFD

The potential risk factors for post-transplantation IFD are presented in Table 3. Two risk factors were found post-transplantation IFD from both univariate and multivariate analysis, Having cytomegalovirus (CMV) disease post-transplantation (HR, 14.369, 95% CI 2.302 to 89.699, p = 0.004) was identified as a serious risk factor, while steroid treatment longer than 90 days (HR, 6.059, 95% CI 1.854-19.803, p = 0.003) was the other risk factor.

Survival

With a median follow-up of 685 days (range 8-2005 days) post-transplantation, there were 26 deaths, the causes of which included relapse (10 cases), infections (6 cases including 3 fungal and 1 bacterial infection, 1 caused by CMV encephalitis and 1 by adenovirus encephalitis), GVHD (5 cases), thrombotic microangiopathy (4 cases) and hematencephalon (1 case). The 2-year OS after allo-HSCT was 74.9% ± 4.0%. No significant differences of 2-year OS were seen between PAP group and SAP group (76.9% ± 4.5% versus 68.1% ± 8.9%, p = 0.559, Figure 3). In the multivariable analysis, aGVHD III-IV [hazard ratio (HR), 5.817, 95% CI, 2.644 to 12.801, p = 0.001] and relapse of underlying primary diseases (HR, 4.068, 95% CI, 1.854 to 8.928, P = 0.001) were risk factors associated with worse OS (Table 4).

To our knowledge, this is the first report to evaluate the efficacy and safety of secondary prophylaxis with posaconazole in patients undergoing allo-HSCT. The number of observed prophylaxis failure during the study was high to rates reported in recent studies of posaconazole prophylaxis [9]. It was notable that previous report mainly focused on PAP in recipients of intensive chemotherapy with a short follow-up phase [9]. Our study had found some risk factors of prophylaxis failure, including more GI events during conditioning regimens, use of corticosteroid and immunosuppressants, GVHD, CMV infections, extended follow-up time and so on. Our results showed a relatively low rate of the 1-year incidence of IFD in allo-HSCT recipients who received posaconazole as second prophylactic, which was similar to rates reported in the literature [3, 14–16]. A major cause of prophylaxis failure, accounting for nearly half of cases, was GI intolerance. Posaconazole was stopped in only three patients with abnormal liver function tests, while two were subsequently found to be related to liver GVHD on biopsy, therefore, posaconazole is suggested to be safe without significant toxicity despite long-term use. Of note, the most common cause for posaconazole discontinuation was due to intolerance and clinician concern for absorption that occurred much earlier than discontinuations for suspected IFD, which was in line with recent reports [17]. Based on these results, posaconazole appears to be safe and effective in protecting such patients without severe mucositis, colitis, diarrhea, nausea, or emesis from recurring or new systemic fungal disease.

To identify the relevant risk factors of taking posaconazole orally as anti-fungal prophylaxis therapy in patients post allo-HSCT, further studies are required. We showed that the development of CMV organ disease, and duration of steroid treatment ≥ 90 days were associated with an increased risk of IFD in a multivariate analysis, consistent with previous studies [15, 18–20]. Therefore, intensification of antifungal prophylaxis and strict monitoring by radiological, serological method and molecular diagnostic should be strongly considered in these patients [21]. However, the result should be interpreted carefully because inconclusive result might be drawn due to low amount of events in the proportional hazard model.

It has been well demonstrated that prophylaxis with posaconazole is associated with an increased efficacy of IFD prevention and an improved survival comparing to fluconazole or itraconazole prophylaxis in acute leukemia or MDS patients undergoing intensive chemotherapy [6]. Furthermore, safety and efficacy were recently assessed on a phase 3, randomized controlled, non-inferiority trial, showing posaconazole had similar all-cause mortality and better tolerability than voriconazole for primary treatment in participants with invasive aspergillosis, including the patients undergoing allo-HSCT [22]. These results were similar to ours and confirmed that PAP of posaconazole was effective and safe in patients undergoing allo-HSCT. Generally, it is theoretically feasible to select the agent that has been proven effective, broad-spectrum and well tolerated in primary antifungal therapy for SAP. In our study, the 2-year overall survival rate of the 30 patients with known IFD history was 68.1% ± 8.9% which was not different between patients without a known history of IFD before transplantation. The majority of deaths were due to disease relapse and III-IV GVHD. This result indicated that IFD before transplantation does not have an adverse impact on transplant outcomes. This means that posaconazole prophylaxis can be used for allo-HSCT patients with a history of IFD. In addition, it is important to note that early diagnosis and prompt initiation of antifungal therapy are all critical to optimize treatment outcomes.

Our findings have several limitations. The most important one lies in the retrospective single-center study with small sample size, where most of the patients had a past history of IFD that were classified as probable or possible IFD. Therefore, the findings of our study may not be generalized. Second, posaconazole was switched to other antifungal agents in approximately one-fifth of patients long before discontinuations for suspected IFD. Therefore, our results did not reflect only the effect of posaconazole prophylaxis, but also multitude of challenges in clinical practice and in a real-world in this complex patient population. Therefore, for those patients more complexed variables should be considered. Finally, routine quantification of therapeutic drug monitoring for posaconazole is not carried out in clinical practice in this study. In the literature, the plasma concentration of posaconazole was related to the incidence of IFD [23]. This potential posaconazole serum concentration differences would make data analysis more difficult and complex.

In summary, our data support that allo-HSCT patients without impaired GI absorption and with a prior history of IFD can choose posaconazole as prophylactic option. Our study showed posaconazole is well-tolerated over a prolonged period of time. The availability of oral posaconazole makes the agent convenient for outpatient use, for example, in patients with cGVHD or taking long-term systemic immunosuppressant. Given several limitations we mentioned above, further investigation in prospective randomized large trials is required.

allo-HSCT

allogeneic hematopoietic stem cell transplantation

AML

acute myeloid leukemia

ATG

anti-thymocyte globulin

CMV

cytomegalovirus

complete response

CsA

Cyclosporine A

gastrointestinal intolerance

GVHD

graft-versus-host disease

HID

haploidentical donor

HLA

human leukocyte antigen

IFD

invasive fungal disease

MDS

myelodysplastic syndromes

MMF

mycophenolate mofetil

MSD

matched sibling donor

MTX

methotrexate

PAP

primary antifungal prophylaxis

partial response

SAP

secondary antifungal prophylaxis

Availability of data and materials

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

Acknowledgements

We would like to thank all authors of our department for their excellent work and all patients.

Funding: This work was supported by medical and health science and technology program of Zhejiang province (2020KY912) and Ningbo medical science and technology project (2020Y45).

Author information

Affiliations

Department of Hematology, The Affiliated People's Hospital of Ningbo University, Ningbo, China

Peipei Ye, Renzhi Pei, Youqian Hu, Dong Chen, Shuangyue Li, Junjie Cao, Fenglin Li, Mengjie Wu ,Ying Fang & Ying Lu*

Contributions

PY,YL conceived and designed the study, analyzed the data, interpreted the results, and wrote up the draft manuscript.YL, RP, YH, DC,SL,LC and FL, contributed to the analysis of the data, interpretation of the results and critically reviewing the manuscript. YL, MW and YF involved in the manuscript review and editing. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Ying Lu

Ethics declarations

Ethics approval and consent to participate

This study was approved by the local Ethic Committee (The Affiliated People's Hospital of Ningbo University, Ningbo, China ) in 2019. This study was conducted in accordance with the Declaration of Helsinki Written informed consent was provided by patients or by their legal representatives. All methods in this study were performed in accordance with the relevant guidelines and regulations.

Consent for publication

Written informed consent was obtained from the patient. All authors gave their consent for publication of this manuscript.

Competing interests

The authors declare that they have no competing interests.

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Table 1. Characteristics of patients who received posaconazole.

Characteristic	PAP (n=93)	SAP (n=30)	P value
Previous IFD
Proven		5 (16.7)
Probable		13 (10.6)
Possible		12 (9.8)
Age at transplantation (y)			0.821
Median (range)	38 (14-72)	40 (18-68)	0.258
Gender, no. (%)			0.975
Male	53（57.0）	17（56.7）
Female	40（43.0）	13（43.3）
Underlying disease, no. (%)			0.067
AML	30 (32.3)	11 (36.7)
ALL	21 (22.6)	12 (40.0)
Other^a	42 (45.2)	7 (23.3)
Complication, no. (%)			0.518
Diabetes	11 (11.8)	2 (6.7)
No diabetes	82 (88.2)	28 (93.3)
Stage of underlying disease, no. (%)			1.0
CR	78 (83.9)	25 (83.3)
Non-CR	15 (16.1)	5 (16.7)
Transplant type, no. (%)	10（33.3）	20（66.7）	0.655
MSD	27 (29.0)	10 (33.3)
HID	66 (71.0)	20 (66.7）
Conditioning regimen, no. (%)			1.0
Myeloablative	81（87.1）	26（86.7）
Reduced intensity	12（12.9）	4（13.3）
GVHD prophylaxis, no. (%)			0.394
ATG-based	75 (80.6)	22 (73.3)
Non-ATG based	18 (19.4)	8 (26.7)
Acute GVHD			0.624
Grades 0–II	78 (83.9)	24 (80)
Grades III–IV	15 (16.1)	6 (20)
Chronic GVHD			0.388
no/limited	67 (72)	24 (80)
extensive	26 (28)	6 (20)

PAP: primary antifungal prophylaxis; SAP: secondary antifungal prophylaxis; IFD: Invasive fungal diseases; AML: acute myeloid leukemia; ALL:acute lymphoid leukemia; Othera: myelodysplastic syndrome in 22 patients, aplastic anemia in 19 patients, chronic myeloid leukemia in 4 patients, lymphoblastic lymphoma in 3 patients and myelofibrosis in 1 patient. CR: complete responses; MSD: HLA-matched sibling donor; HID: haploidentcal donor; GVHD: graft-versus-host disease; ATG: antithymocyte globulin.

Table2. Reason for failure of antifungal prophylaxis with posaconazole.

	PAP (n=93)	SAP (n=30)	P
Suspected IFD	12 (12.9)	7 (23.3)	0.243
proven IFD	4 (4.3)	1 (3.3)
probable IFD	5 (5.4)	3 (10)
possible IFD	3 (3.2)	3 (10)
Gastrointestinal intolerance	20 (21.5)	5 (16.7)	0.567
persistent fever	3 (3.2)	2 (6.7)	0.595
drug-drug interaction	2 (2.2)	1 (3.3)	1.0
Death	2 (2.2)	0 (0.0)	1.0

PAP: primary antifungal prophylaxis; SAP: secondary antifungal prophylaxis; IFD: Invasive fungal diseases.

Table3. Univariate and multivariate analysis of risk factors for IFD.

Risk factor	Univariate analysis		Multivariate analysis
Risk factor	HR (95% CI)	P	HR (95% CI)	P
Patient age (years)
< 50 versus ≥ 50	0.838 (0.291-2.413)	0.743
Gender
Female versus male	0.417 (0.140-1.241)	0.116
Underlying disease, no. (%)
AML	1.0
ALL	0.917 (0.283-2.966)	0.885
Other^a	0.469 (0.140-1.564)	0.218
Stage of underlying disease
CR versus Non-CR	0.526 (0.112-2.473)	0.416
Diabetes
Yes versus no	2.815 (0.769-10.303)	0.118
Transplant type
MSD vs HID	0.463 (0.126-1.704)	0.246
Conditioning regimen
Reduced intensity vs Myeloablative	0.0 (0.0)	0.998
GVHD prophylaxis,
ATG-based vs no ATG-based	1.006 (0.303-3.337)	0.992
History of IFD pre-transplant
No versus yes	0.487 (0.172-1.378)	0.175
CMV DNA
Negative versus positive	0.765 (0.279-2.099)	0.603
CMV disease
Yes versus no	23.538 (4.295-129.005)	0.001	14.369 (2.302-89.699)	0.004
Acute GVHD
Grades III–IV versus Grades 0–II	3.750 (1.262-11.143)	0.003	2.140 (0.558-8.213)	0.267
chronic GVHD
extensive versus no/limited	1.843 (0.655-5.189)	0.247
Duration of steroid （days）
< 90 versus ≥ 90	8.519 (2.884-25.159)	0.001	6.059 (1.854-19.803)	0.003

IFD: Invasive fungal diseases; AML: acute myeloid leukemia; ALL:acute lymphoid leukemia; Othera: myelodysplastic syndrome in 22 patients, aplastic anemia in 19 patients, chronic myeloid leukemia in 4 patients, lymphoblastic lymphoma in 3 patients and myelofibrosis in 1 patient. CR: complete responses; MSD: HLA-matched sibling donor; HID: haploidentical donor; GVHD: graft-versus-host disease; ATG: antithymocyte globulin.

Table 4. Risk Factors for Overall Survival

Risk Factors	Univariate analysis		Multivariate analysis
	HR (95% CI)	P	HR (95% CI)	P
Patient age (years)
< 50 versus ≥ 50	0.687 (0.329-1.435)	0.318
Stage of underlying disease
NR versus CR	2.374 (1.090-5.167)	0.029	1.408 (0.605-3.278)	0.428
Transplant type
MSD vs HID	0.876 (0.392-1.959）	0.747
Conditioning regimen
Reduced intensity vs Myeloablative	1.441 (0.553-3.759）	0.455
History of IFD pre-transplant
No versus yes	0.794 (0.366-1.724)	0.560
CMV disease
Yes versus no	1.663 (0.505-5.481)	0.403
Acute GVHD
Grades III–IV versus Grades 0–II	7.851 (3.785-16.284)	0.001	5.817 (2.644-12.801)	0.001
chronic GVHD
extensive versus no/limited	0.347 (0.121-0.994)	0.049	0.432 (0.146-1.277)	0.129
Post -transplantation IFD
Yes versus no	2.182 (0.975-4.884)	0.671	1.248 (0.449-3.474)	0.671
Relapse of underlying primary diseases
Yes versus no	6.928 (3.391-14.157)	0.001	4.068 (1.854-8.928)	0.001

NR: no response; CR: complete responses; MSD: HLA-matched sibling donor; HID: haploidentcal donor; IFD: Invasive fungal diseases; GVHD: graft-versus-host disease.

No competing interests reported.

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Editorial decision: Major revision
08 Mar, 2022
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Editor invited by journal
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Posaconazole for secondary antifungal prophylaxis in allogeneic stem cell transplantation recipients: a retrospective study

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Transplant regimens and post-transplant immunosuppression

Administration of prophylactic antifungal agents

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