Association between drug tolerability and medical resource use in prophylaxis of invasive fungal infections after allogeneic hematopoietic stem cell transplant

Figures & data

Table 1. Patient baseline characteristics^a.

	Voriconazole (n = 224)	Traconazole (n = 241)	p-value
Randomization stratum, n (%)
Myeloablative & matched related	66 (29.5)	85 (35.3)	0.6174
Myeloablative & mismatched/unrelated	59 (26.3)	58 (24.1)
Non-myeloablative & matched related	58 (25.9)	57 (23.7)
Non-myeloablative & mismatched/unrelated	41 (18.3)	41 (17.0)
Primary diagnosis, n (%)^b	n = 221	n = 239
Acute lymphocytic leukemia	41 (18.3)	41 (17.0)	0.5755
Acute myeloid leukemia	98 (43.8)	109 (45.2)
Myelodysplastic syndrome	34 (15.2)	30 (12.4)
Failure of therapy for lymphoma	42 (18.8)	46 (19.1)
Transformation of chronic myeloid leukemia	6 (2.7)	13 (5.4)
Conditioning regimen, n (%)^c
Myeloablative	125 (55.8)	143 (59.3)	0.4411
Non-myeloablative	99 (44.2)	98 (40.7)
Gender, n (%)
Male	130 (58.0)	146 (60.6)	0.5766
Female	94 (42.0)	95 (39.4)
Age, year
Mean	43.3	42.3	0.5501
Range	11–70^d	13–70
Ethnicity, n (%)
White	207 (92.4)	219 (90.9)	0.7717
Black	0 (0.0)	2 (0.8)
Asian	2 (0.9)	3 (1.2)
Other	15 (6.7)	17 (7.1)
BMI, kg/m^2
Mean	25.5	25.8	0.5191
Range	15.7–41.8	14.9–49.5

^aBased on the modified-intent-to-treat population. No statistically significant difference was identified between voriconazole and itraconazle in all listed baseline characteristics at the 5% significance level.

^bFive patients with primary diagnoses ‘others’ were excluded due to per protocol violation.

^c34.4% of voriconazole patients and 33.6% of itraconazole patients underwent in vivo T-cell depletion, i.e., received antithymocyte immunoglobulin and/or alemtuzumab prior to screening (p = 0.86).

^dThe youngest subject was almost 12 years of age and was allowed to enter the study at the investigator and sponsor’s discretion.

Table 2. Treatment discontinuation/duration (MITT overall).

Parameters	Voriconazole (n = 224)	Itraconazole (n = 241)	p-value^a
Actual duration of exposure to study drugs (days) (up to 180 days)
Mean (SD)	86.89 (61.2)	69.59 (51.9)	0.0019
Median	96.00	68.00	<0.0001
Range	1.00–258.00	3.00–223.00
Duration of exposure to study drugs (days) (truncated to 100 days)
Mean (SD)	68.34 (36.9)	60.05 (37.2)	0.0044
Median^b	96.00	68.00	<0.0001
Range	1.00–100.00	3.00–100.00
Number of patients with non-missing discontinuation status, n (%)	164 (73.2)	198 (82.2)
Discontinued before day 100 due to the following reasons^c	113 (50.45)	153 (63.49)	0.0137
Breakthrough Fungal	1 (0.5)	4 (1.7)	0.1732^d
Infection	5 (2.2)	1 (0.4)	0.0797^d
Non-compliance	15 (6.7)	54 (22.4)	<0.0001
Intolerance of study medication
Adverse Event	72 (32.1)	64 (26.6)	0.1857
Death	5 (2.2)	3 (1.2)	0.2029^d
Other	15 (6.7)	27 (11.2)	0.0902

^ap-value based on two-sample Wilcoxon-Mann-Whitney test for continuous variables and Pearson chi-square test for categorical frequency variables unless specified otherwise.

^bThe 100-day results were actually ‘censored’ data (i.e., durations above 100 days were set to be 100 instead of being removed). The rank of duration did not change and the 96 vs 68 days happened to be the medians for both 100 and 180 days.

^cPercentage and p-value calculations were based on total population.

^dBased on Fisher’s exact test.

Table 3. Non-drug medical resource utilization.

Type of utilization	Voriconazole	Itraconazole	p-value^a
Number of hospitalizations
n	224	234
Mean (SD)	1.52 (0.76)	1.55 (0.80)	0.8319
Inpatient care^b
Total days of hospital stay
n (%)	209 (100)	217 (100)	0.9232
Mean (SD)	36.81 (21.13)	37.73 (22.45)
Intensive care unit (ICU) days
n (%)	16 (7.7)	14 (6.5)	0.6273
Mean (SD)	14.88 (14.56)	14.86 (11.82)	0.7866
Hem/Oncology unit or Transplant unit days
n (%)	207 (99.0)	216 (99.5)	0.3687
Mean (SD)	34.55 (18.02)	35.31 (19.36)	0.8707
Emergency Room/Day Hosp days
n (%)	41 (19.6)	41 (18.9)	0.8499
Mean (SD)	7.37 (4.04)	10.71 (12.10)	0.4045
Outpatient service
General Physician (GP) Visit
n (%)	1 (0.5)	1 (0.4)	–
Mean (SD)	2 (–)	17 (–)	–
Specialist Visit
n (%)	27 (12.1)	20 (8.3)	0.1795
Mean (SD)	9.30 (8.36)	6.90 (4.51)	0.6656
Homecare
n (%)	16 (7.1)	10 (4.2)	0.1604
Mean (SD)	27.50 (27.15)	25.60 (31.87)	0.3695
Concomitant treatment procedures^c
Patients who had at least one concomitant treatment procedure, n (%)	164 (73.2)	178 (73.9)	0.8749
Platelet/packed RBC/RBC transfusion/whole blood transfusion
n (%)	85 (38.0)	105 (43.6)	0.2176
Mean (SD)	3.33 (2.67)	3.90 (4.69)	0.9419
Chest X-ray
n (%)	65 (29.0)	74 (30.7)	0.6912
Mean (SD)	2.43 (2.11)	2.38 (1.82)	0.5782
Electrocardiogram
n (%)	33 (14.7)	25 (10.4)	0.1552
Mean (SD)	1.85 (1.35)	2.20 (1.41)	0.1939
Computerized tomogram thorax
n (%)	28 (12.5)	24 (10.0)	0.3849
Mean (SD)	1.61 (1.03)	1.63 (1.31)	0.6904
Ultrasound abdomen
n (%)	25 (11.2)	19 (7.9)	0.2277
Mean (SD)	1.52 (1.05)	1.21 (0.42)	0.4908
Parenteral nutrition
n (%)	29 (13.0)	40 (16.6)	0.2684
Mean (SD)	1.07 (0.26)	1.05 (0.22)	0.7525

^ap-value based on two-sample Wilcoxon-Mann-Whitney text for continuous variables and Pearson chi-square test for categorical frequency variables.

^bSubjects with missing discharge date were excluded for all inpatient analysis except the re-hospitalization rates and mean number of hospitalizations. Only ward types with more than five patients are listed.

^cOnly concomitant treatment procedures occurred with greater than 10% of patients are listed.

RBC, Red Blood Cell.

Table 4. Other concomitant antifungal use^a.

Type of utilization	Voriconazole (n = 224), n (%) Mean (SD)	Itraconazole (n = 241), n (%) Mean (SD)	p-value^b
Number of patients who had at least one concomitant AF use	55 (24.55)	93 (38.59)	0.0014
Duration of exposure to concomitant AFs (days)	28.91 (30.87)	41.47 (32.18)	0.0075
Caspofungin (IV)
Number of patients	23 (10.3)	44 (18.3)	0.0142
Duration (days)	14.43 (19.87)	16.89 (15.91)	0.1025
Liposomal amphotericin (AmBisome) (IV)
Number of patients	13 (5.8)	16 (6.6)	0.7097
Duration (days)	23.54 (25.20)	17.44 (21.39)	0.3652
Fluconazole (Oral)
Number of patients	11 (4.9)	31 (12.9)	0.0032
Duration (days)	40.73 (40.48)	43.68 (32.85)	0.7205
Voriconazole
Number of patients	5 (2.2)	29 (12.0)	<0.0001
Duration (days)	14.20 (13.29)	34.59 (32.38)	0.3065
Itraconazole
Number of patients	4 (1.8)	7 (2.9)	0.4276
Duration (days)	44.25 (32.12)	34.43 (24.47)	0.6366
Posaconazole (Oral)
Number of patients	4 (1.8)	7 (2.9)	0.4276
Duration (days)	62.00 (30.84)	42.71 (34.75)	0.3951
Amphotericin B (IV)
Number of patients	4 (1.8)	6 (2.5)	0.7529
Duration (days)	7.00 (1.15)	5.50 (2.95)	0.5872

^aNon-systemic concomitant antifungals were excluded.

^bp-values were based on Pearson chi-square test for patient frequency and two-sample Wilcoxon-Mann-Whitney test for treatment duration comparison.

Table 5. Impact of study drug prophylaxis and prophylaxis duration on other antifungal use (n = 460).

Parameters	Concomitant AF use (Logistic regression)
	Odds ratio estimate	95% Wald CI for OR estimate	p-value
Prophylaxis study drug, Itraconazole vs (Voriconazole)	1.783*	(1.140, 2.790)	0.011
Age	1.012	(0.992, 1.031)	0.237
Sex, Female vs (Male)	0.890	(0.531, 1.492)	0.658
Weight	1.002	(0.988, 1.018)	0.745
Regimen, Non-myeloablative vs (Myeloablative)	0.786	(0.454, 1.359)	0.389
Donor, MU vs MR	1.820*	(1.164, 2.846)	0.009
Primary diagnosis, AML vs ALL	0.891	(0.464, 1.709)	0.728
Primary diagnosis, Myelodysplastic syndrome vs ALL	0.733	(0.309, 1.737)	0.480
Primary diagnosis, No therapeutic response vs ALL	1.468	(0.682, 3.162)	0.326
Primary diagnosis, CML vs ALL	0.753	(0.237, 2.385)	0.629
Prophylaxis study drug exposure time (truncated)	0.976*	(0.970, 0.982)	<0.0001

*Coefficient significant at 5% level.

AML, Acute myeloid leukemia; ALL, Acute lymphatic leukemia; CML, Chronic myeloid leukemia; MU, Mismatched/unrelated; MR, Matched/related.

Figure 1. Association between Prophylaxis Treatment Duration and Resource Utilization (Total Hospital Days and Other Antifungal Days).

Table 6. Impact of study drug treatment duration on total hospital days and other antifungal duration, controlling for key baseline variables.

Parameters	Total hospital days (GLM gamma-identity link, n = 423)		Other AF duration (GLM gamma-identity link, n = 148)
	β estimate (days)	95% Wald CI for β estimate	β estimate (days)	95% Wald CI or β estimate
Intercept	44.771***	(33.195, 56.348)	49.034***	(34.192, 63.876)
Treatment, Itraconazole vs (Voriconazole)	1.333	(−2.193, 4.859)	10.991**	(5.192, 16.791)
Age	−0.015	(−0.166, 0.137)	−0.036	(−0.206, 0.133)
Sex, Female vs (Male)	2.363	(−1.611, 6.337)	7.111*	(0.683, 13.539)
Weight	−0.057	(−0.172, 0.058)	0.012	(−0.134, 0.159)
Regimen, Non-myeloablative vs (Myeloablative)	3.337	(−1.520, 8.193)	1.187	(−0.874, 3.248)
Donor, MU vs MR	11.071***	(7.256, 14.886)	4.694	(−0.618, 10.006)
Primary diagnosis, AML vs ALL	−2.897	(−7.777, 1.983)	−7.710	(−15.446, 0.025)
Primary diagnosis, Myelodysplastic syndrome vs ALL	−3.804	(−10.397, 2.790)	−6.375*	(−11.601, −1.149)
Primary diagnosis, No therapeutic response vs ALL	−1.175	(−8.245, 5.894)	−5.153	(−11.234, 0.928)
Primary diagnosis, CML vs ALL	−5.506	(−16.348, 5.335)	4.471	(−4.576, 13.519)
Study drug exposure (truncated)	−0.121***	(−0.177, −0.065)	−0.455***	(−0.553, −0.358)

*p < 0.05; **p < 0.001; ***p < 0.0001.

AML, Acute myeloid leukemia; ALL, Acute lymphatic leukemia; CML, Chronic myeloid leukemia; MU, Mismatched/unrelated; MR, Matched/related.