Breakthrough Mucormycosis Developing on Mucorales-Active Antifungals Portrays a Poor Prognosis in Patients with Hematologic Cancer
Abstract
:1. Introduction
2. Patients and Methods
2.1. Study Design
2.2. Characteristics Assessed and Definitions
2.3. Outcomes and Statistical Analysis
3. Results
3.1. Patients and Clinical Characteristics
3.2. Outcomes
4. Discussion
5. Conclusions and Outlook
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Conflicts of Interest
References
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Characteristic | All Patients (n = 103) | Mucorales-Active Antifungals (n = 16) | Other Mold-Active Antifungals (n = 87) | p-Value | |
---|---|---|---|---|---|
Age (years), median (range) | 52 (18–76) | 57 (25–75) | 52 (18–76) | 0.26 | |
Gender, male | 67 (65) | 11 (69) | 56 (64) | 0.74 | |
Race | 0.45 | ||||
White | 86 (84) | 13 (81) | 73 (84) | ||
Black | 11 (11) | 3 (19) | 8 (9) | ||
Asian | 6 (6) | 0 (0) | 6 (7) | ||
Ethnicity | 0.12 | ||||
Hispanic | 14 (14) | 0 (0) | 14 (16) | ||
Non-Hispanic | 89 (86) | 16 (100) | 73 (84) | ||
Underlying malignancy | >0.99 | ||||
Leukemia/MDS | 92 (89) | 15 (94) | 77 (89) | ||
Lymphoma/myeloma | 11 (11) | 1 (6) | 10 (11) | ||
Status of primary disease | 0.51 | ||||
Active | 80 (78) | 14 (88) | 66 (76) | ||
In remission | 23 (22) | 2 (12) | 21 (24) | ||
Allogeneic HSCT recipients | 50 (49) | 5 (31) | 45 (52) | 0.13 | |
GvHD | 40/50 (80) | 5/5 (100) | 35/45 (78) | 0.57 | |
Active | 23/40 (58) | 3/5 (60) | 20/35 (57) | ||
Chronic | 17/40 (43) | 2/5 (40) | 15/35 (43) | ||
Neutropenia at diagnosis | 65 (63) | 12 (75) | 53 (61) | 0.28 | |
Neutrophil recovery after neutropenia | 41/65 (63) | 6/12 (50) | 35/53 (66) | 0.33 | |
Duration of neutropenia at diagnosis (days), median (IQR) | 21 (12–52) | 29 (20–49) | 18 (11–54) | 0.26 | |
Corticosteroid use | 36 (35) | 5 (31) | 31 (36) | 0.74 | |
History of diabetes mellitus | 42 (41) | 2 (13) | 40 (46) | 0.012 | |
Type of infection | 0.58 | ||||
Localized infection | 19 (18) | 2 (13) | 17 (20) | ||
Sinopulmonary infection | 65 (63) | 12 (75) | 53 (61) | ||
Disseminated infection | 19 (18) | 2 (13) | 17 (20) | ||
Genus isolated | 0.77 | ||||
Rhizopus spp. | 61 (59) | 10 (63) | 51 (59) | ||
Mucor spp. | 18 (17) | 3 (19) | 15 (17) | ||
Rhizomucor spp. | 1 (12) | 2 (13) | 10 (11) | ||
Cunninghamella spp. | 8 (8) | 0 | 8 (9) | ||
Absidia/Lichtheimia spp. | 4 (4) | 1 (6) | 3 (3) | ||
APACHE II score at diagnosis, median (IQR) | 14 (12–17) | 16 (13–18) | 14 (12–17) | 0.31 | |
ICU admission at diagnosis | 13 (13) | 2 (13) | 11 (13) | >0.99 | |
ICU/Hospice at any time during treatment | 79 (77) | 15 (94) | 64 (74) | 0.11 | |
Days from symptom onset to treatment initiation, median (IQR) | 6 (3–11) | 4 (2–10) | 7 (3–12) | 0.16 | |
Initial treatment strategy | 0.88 | ||||
AMB + POSA + CAS | 31 (30) | 5 (31) | 26 (30) | ||
AMB + POSA | 26 (25) | 6 (38) | 20 (23) | ||
AMB + CAS | 21 (20) | 2 (13) | 19 (22) | ||
AMB | 1 (15) | 2 (13) | 13 (15) | ||
AMB + ISA | 8 (8) | 1 (6) | 7 (8) | ||
POSA | 2 (2) | 0 (0) | 2 (2) | ||
Surgical treatment of mucormycosis | 47 (46) | 3 (19) | 44 (51) | 0.019 |
Anti-Fungal | Year | Daily Dose | Form | Serum Level | Age/Sex | Cancer | Days ANC <500 a | ANC <500 at Dx? | ANC Reco-Very b | Antifungal Indication | Days AntiFungal c | BT-MCR Location | Pathogen | Treatment Strategy | Day 42 Outcome d |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
AMB | 2004 | 5 mg/kg | IV | N/D | 29/M | Burkitt’s | 34 | yes | no | Treatment e | 7 | Localized | Rhizopus spp. | AMB | dead |
ISA | 2015 | 372 mg | tab | N/D | 61/F | R/R AML | 11 | yes | yes | 1º PPx (NP) | 34 | Pulmonary | Mucor spp. | AMB + PSOA | alive |
ISA | 2016 | 372 mg | tab | N/D | 75/M | act AML | 24 | yes | no | 1º PPx (NP) | 14 | Disseminated | Rhizopus spp. | AMB + POSA | dead |
ISA | 2016 | 372 mg | tab | N/D | 47/M | act ALL | 110 | yes | yes | 1º PPx | 37 | Sinusitis | Rhizopus spp. | AMB + POSA | dead |
ISA | 2016 | 372 mg | tab | N/D | 61/M | R/R CLL | 191 | yes | no | Treatment f | 243 | Pulmonary | Rhizomucor spp. | AMB + POSA | dead |
ISA | 2017 | 372 mg | tab | N/D | 60/F | R/R ALL | 47 | yes | no | Treatment g | 151 | Pulmonary | Rhizopus spp. | AMB + CAS + POSA | dead |
ISA | 2018 | 372 mg | tab | N/D | 45/M | R/R CLL | 0 | no | - | 1º PPx (GC) | 60 | Sinusitis | Rhizopus spp. | AMB + POSA | alive |
ISA | 2019 | 372 mg | tab | N/D | 54/M | act AML | 21 | yes | no | 1º PPx | 106 | Pulmonary | Mucor spp. | AMB + POSA | dead |
ISA | 2019 | 372 mg | tab | N/D | 49/F | R/R AML | 51 | yes | yes | Treatment h | 16 | Sinusitis | Rhizopus spp. | AMB + CAS + POSA | alive |
ISA | 2019 | 372 mg | tab | N/D | 65/F | act AML | 44 | yes | no | Treatment i | 27 | Sinusitis | Rhizopus spp. | AMB + CAS + POSA | dead |
POSA | 2000 | 800 mg | liquid | N/D | 29/F | AML (CR) | 0 | no | - | Treatment j | 211 | Disseminated | Rhizopus spp. | AMB | dead |
POSA | 2009 | 600 mg | liquid | N/D | 52/M | CLL (CR) | 0 | no | - | 1º PPx (GC) | 61 | Sinusitis | Rhizopus spp. | AMB + CAS | dead |
POSA | 2012 | 800 mg | liquid | 685 ng/dL | 70/M | R/R AML | 20 | yes | yes | 1º PPx (NP) k | 54 | Pulmonary | Rhizomucor spp. | AMB + CAS | dead |
POSA | 2016 | 300 mg | tab | 1750 ng/dL | 61/M | R/R AML | 14 | yes | yes | 1º PPx (NP) | 17 | Cutaneous | Rhizopus spp. | AMB + CAS + POSA | alive |
POSA | 2017 | 300 mg | tab | 2520 ng/dL | 25/M | R/R ALL | 20 | yes | yes | 1º PPx (NP) | 437 | Sinusitis | Absidia spp. | AMB + CAS + POSA | alive |
POSA | 2019 | 300 mg | tab | 2180 ng/dL | 68/M | act AML | 0 | no | - | 1º PPx (NP) | 63 | Pulmonary | Mucor spp. | AMB + ISA | dead |
Characteristic | All Patients (n = 103) | Mucorales-Active Antifungals (n = 16) | Other Mold-Active Antifungals (n = 87) | p-Value |
---|---|---|---|---|
42-Day mortality from treatment initiation | 45 (44) | 11 (69) | 34 (39) | 0.028 |
84-Day mortality from treatment initiation | 64 (62) | 16 (100) | 48 (55) | 0.0007 |
42-Day mortality from symptom onset | 32 (31) | 10 (63) | 22 (25) | 0.006 |
84-Day mortality from symptom onset | 61 (59) | 16 (100) | 45 (52) | 0.0003 |
Days from treatment initiation to death, median (IQR) | 44 (27–110) | 27 (12–50) | 49 (30–146) | 0.007 |
Days from symptom onset to death, median (IQR) | 55 (34–114) | 35 (22–59) | 61 (40–151) | 0.007 |
(A) Mortality within 42 Days of Treatment Initiation | ||||
Predictors | Hazard Ratio | 95% Confidence Interval | p-Value | |
ICU at diagnosis | 2.46 | 1.07 to 5.68 | 0.034 | |
APACHE II score at diagnosis | Every 1-unit increase | 1.21 | 1.12 to 1.30 | <0.0001 |
Neutropenia status | <0.001 | |||
No neutropenia at diagnosis | Reference | |||
Neutropenia, recovered | 0.83 | 0.37 to 1.84 | ||
Neutropenia, not recovered | 3.25 | 1.53 to 6.90 | ||
Antifungal prophylaxis | 0.015 | |||
Mucorales-active | 2.40 | 1.19 to 4.86 | ||
Other mold-active | Reference | |||
(B) Mortality within 42 Days of Symptom Onset | ||||
Predictors | Hazard Ratio | 95% Confidence Interval | p-Value | |
ICU at diagnosis | 4.71 | 2.05 to 10.85 | <0.001 | |
APACHE II score at diagnosis | Every 1-unit increase | 1.13 | 1.04 to 1.23 | 0.005 |
Neutropenia status | <0.0001 | |||
No neutropenia at diagnosis | Reference | |||
Neutropenia, recovered | 0.67 | 0.23 to 2.00 | ||
Neutropenia, not recovered | 9.63 | 3.57 to 25.99 | ||
Antifungal prophylaxis | <0.001 | |||
Mucorales-active | 4.63 | 1.91 to 11.23 | ||
Other mold-active | Reference | |||
Treatment * | <0.0001 | |||
Amphotericin B + caspofungin | 8.15 | 3.09 to 21.48 | ||
Others | Reference |
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Axell-House, D.B.; Wurster, S.; Jiang, Y.; Kyvernitakis, A.; Lewis, R.E.; Tarrand, J.J.; Raad, I.I.; Kontoyiannis, D.P. Breakthrough Mucormycosis Developing on Mucorales-Active Antifungals Portrays a Poor Prognosis in Patients with Hematologic Cancer. J. Fungi 2021, 7, 217. https://doi.org/10.3390/jof7030217
Axell-House DB, Wurster S, Jiang Y, Kyvernitakis A, Lewis RE, Tarrand JJ, Raad II, Kontoyiannis DP. Breakthrough Mucormycosis Developing on Mucorales-Active Antifungals Portrays a Poor Prognosis in Patients with Hematologic Cancer. Journal of Fungi. 2021; 7(3):217. https://doi.org/10.3390/jof7030217
Chicago/Turabian StyleAxell-House, Dierdre B., Sebastian Wurster, Ying Jiang, Andreas Kyvernitakis, Russell E. Lewis, Jeffrey J. Tarrand, Issam I. Raad, and Dimitrios P. Kontoyiannis. 2021. "Breakthrough Mucormycosis Developing on Mucorales-Active Antifungals Portrays a Poor Prognosis in Patients with Hematologic Cancer" Journal of Fungi 7, no. 3: 217. https://doi.org/10.3390/jof7030217