1734. Antifungal Prophylaxis in Allogeneic Hematopoietic Stem Cell Transplantation: A Single-Center Experience in Colombia

Abstract Background Invasive fungal infections (IFI) are significant causes of morbidity and mortality among patients with hematopoietic stem cell transplantation (HSCT). Primary antifungal prophylaxis has lowered the IFI cases however there is no clear guidance regarding which mold active agent is most useful if mold-active prophylaxis. We aim to present the incidence of IFI in patients with allogeneic HSCT, and the impact of primary antifungal prophylaxis regimen. Methods Retrospective cohort study. We included patients older than 18 years, with allogeneic HSCT from Fundación Valle del Lili, between January 2008 and April 2017. The patients received antifungal prophylaxis with fluconazole, itraconazole, or posaconazole from conditioning day to +100 post-transplant day. The prophylactic antifungal agent was selected according to the initial diagnosis, transplant type, conditioning regimen and the risk of developing GVHD. All patients received myeloablative conditioning regimens and were hospitalized in laminar airflow rooms during their period with neutropenia. The cases were defined according to the EORTC/MSG Consensus Group. We analyzed patients with probable or confirmed IFI, in the first 120 post-transplant days. Results We enrolled a total of 101 patients who received HSCT over the course of the study. The median age was 32 (23–43). Posaconazole prophylaxis was used in 73%, fluconazole in 18% and itraconazole 10% of the patients. The IFI incidence was 3.9% (4 cases) and the median time from HSCT to the diagnosis of IFI was 60 days. The percentages of patients who experienced probable IFI in the itraconazole arm was 22% (2/9 patients) and in the fluconazole arm 11.1% (2/18), there was no infection in the posaconazole group (P = 0.001). Donor sources were HLA-matched sibling (42%), Haploidentical (48%), and cord blood (10%). The cumulative incidence of grade I–IV aGVHD was 63.4% and that of grade III–IV aGVHD was 37.5%. Conclusion In patients undergoing HSCT posaconazole prevented invasive fungal infections more effectively than did either fluconazole or itraconazole. Disclosures All authors: No reported disclosures.

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Primary or Secondary Prophylaxis with Voriconazole Compared with Posaconazole for Prevention of Invasive Fungal Infections After Hematopoietic Stem Cell Transplantation

Open Forum Infectious Diseases ◽

10.1093/ofid/ofx163.010 ◽

2017 ◽

Vol 4 (suppl_1) ◽

pp. S75-S75

Author(s):

Jeffrey W Jansen ◽

Anupam Pande ◽

Rizwan Romee ◽

Steven J Lawrence ◽

William Powderly

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Hematopoietic Stem Cell ◽

Fungal Infections ◽

Antifungal Prophylaxis ◽

Invasive Fungal Infections ◽

Hematopoietic Stem ◽

Research Grant

Abstract Background Invasive fungal infections (IFI) remain a serious complication in hematopoietic stem cell transplantation (HSCT) patients and are associated with increased costs, morbidity, and mortality. Posaconazole (PCZ) and voriconazole (VCZ) are frequently utilized as antifungal prophylaxis in this population. To date, no direct comparison between PCZ and VCZ exists for the prevention of IFI in adult HSCT patients. Methods A retrospective cohort analysis of HSCT patients aged ≥18 years who received ≥28 continuous days of primary (PPPx) or secondary (SPPx) antifungal prophylaxis with either VCZ or PCZ between February 26, 2003 and September 30, 2015 at Barnes-Jewish Hospital was conducted. Patients who received PPPx or SPPx with both VCZ and PCZ were analyzed following intention to treat of the initial agent received. Patients who received both PPPx and SPPx were included once for both PPPx and SPPx. The primary outcome of interest was development of possible, probable, or proven IFI as defined by EORTC/MSG guidelines. In the SPPx patients, development of IFI was confirmed as a distinct event from primary IFI based on manual chart review and radiographic evidence. Results Overall, there were 472 patients included; 402 in the VCZ group and 70 in the PCZ group. At baseline, patients in the PCZ group had more graft vs. host disease (GVHD) prior to prophylaxis (27.1% vs. 16.7%, P = 0.04) and were more likely to be on SPPx (60% vs. 41%, P < 0.01). There were 22 and 1 IFI events in the VCZ and PCZ groups, respectively, which corresponded to a crude incidence rate of 0.345 and 0.077 per 1000 person-days of prophylaxis. Figure 1 displays the Cox proportional hazard model which was completed in the backwards stepwise method accounting for gender, transplant type, GVHD prior to prophylaxis, disease remission, and PPPx or SPPX. The hazard ratio for development of IFI while on prophylaxis between VCZ and PCZ was 5.22 (95% CI: 0.69–39.4; P = 0.11) after controlling for PPPx or SPPx. Conclusion There was not a significant difference between rates of IFI in HSCT patients who received antifungal prophylaxis with VCZ compared with PCZ. Our data trends towards favoring PCZ but is limited by low rates of IFI. Larger, prospective analyses are necessary to confirm our findings. Disclosures W. Powderly, Merck: Grant Investigator and Scientific Advisor, Consulting fee and Research grant. Gilead: Scientific Advisor, Consulting fee. Astellas: Grant Investigator, Research grant

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Breakthrough Invasive Fungal Infections in Allogeneic Hematopoietic Stem Cell Transplantation

Journal of Fungi ◽

10.3390/jof7050347 ◽

2021 ◽

Vol 7 (5) ◽

pp. 347

Author(s):

Carmine Liberatore ◽

Francesca Farina ◽

Raffaella Greco ◽

Fabio Giglio ◽

Daniela Clerici ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Hematopoietic Stem Cell ◽

Fungal Infections ◽

Antifungal Prophylaxis ◽

Invasive Fungal Infections ◽

Preemptive Therapy ◽

Hematopoietic Stem

Despite the recent introduction of mold-active antifungal prophylaxis (MAP), breakthrough invasive fungal infections (b-IFI) still represent a possible complication and a cause of morbidity and mortality in hematological patients and allogeneic hematopoietic stem-cell transplantation recipients (HSCT). Data on incidence and type of b-IFI are limited, although they are mainly caused by non-fumigatus Aspergillus and non-Aspergillus molds and seem to depend on specific antifungal prophylaxis and patients’ characteristics. Herein, we described the clinical presentation and management of two cases of rare b-IFI which recently occurred at our institution in patients undergoing HSCT and receiving MAP. The management of b-IFI is challenging due to the lack of data from prospective trials and high mortality rates. A thorough analysis of risk factors, ongoing antifungal prophylaxis, predisposing conditions and local epidemiology should drive the choice of antifungal treatments. Early broad-spectrum preemptive therapy with a lipid formulation of amphotericin-B, in combination with a different mold-active azole plus/minus terbinafine, is advisable. The therapy would cover against rare azole-susceptible and -resistant fungal strains, as well as atypical sites of infections. An aggressive diagnostic work-up is recommended for species identification and subsequent targeted therapy.

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Incidence, Risks, and Outcomes of Relapse Following Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplantation for Non-Hodgkin's Lymphoma.

Blood ◽

10.1182/blood.v116.21.3451.3451 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3451-3451

Author(s):

Michael R. Bishop ◽

Seth Steinberg ◽

Nancy M. Hardy ◽

Steven Z. Pavletic ◽

Ronald E. Gress ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Hematopoietic Stem Cell ◽

Disease Status ◽

Hematopoietic Stem ◽

Allogeneic Hsct ◽

Post Transplant ◽

Reduced Intensity

Abstract Abstract 3451 Relapse is the major cause of treatment failure and death following reduced-intensity (RI) allogeneic hematopoietic stem cell transplantation (HSCT) for non-Hodgkin's lymphoma (NHL), yet there are no reports that focus specifically on the natural history of relapse in this patient population. We assessed relapse risks and outcomes on 120 consecutive patients (median age = 52 years; range, 28–71 years) with NHL (indolent = 43; aggressive = 77) who all received a T-cell replete allograft from HLA-matched siblings following a reduced-intensity conditioning regimen (fludarabine/cyclophosphamide). All patients were assessed for disease status at 1, 3, 6, 12, 18, 24 months post-transplant, and annually thereafter or as clinically indicated. Median event-free survival (EFS) from transplant date for all 120 patients was 11.3 months (range, 0.5–105.5+ months) with a 5-year EFS = 35%. Median EFS (months) was assessed for the following pre-transplant characteristics: chemo-resistant vs. chemo-sensitive = 3.3 vs. 39.1, p = 0.0001; pre-transplant disease status - CR vs. PR vs. SD vs. PD = not reached (NR) vs. NR vs. 11.2 vs. 1.7, p <0.0001; aggressive vs. indolent histology = 6.6 vs. 15.8, p = 0.13; number of disease sites: 0–1 vs. 2 vs. 3 vs. 4+ = 4.8 vs. 7.4 vs. 18.4 vs. 7.1, p = 0.85. Median overall survival (OS) from transplant date for all 120 patients was 71.1 months (range, 0.5–120+ months). We identified 55 patients (46%) who either relapsed or progressed post-transplant. Among those who have progressed/relapsed to date, median time to progression/relapse was 3 months (range, 0.5–46 months) with 72% of progressions/relapses occurring prior to 6 months post-transplant. The overall cumulative incidence (CI) probabilities for relapse/progression, adjusted for competing non-relapse mortality, at 3, 6, 12, 24 and 36 months were 0.169, 0.329, 0.394, 0.447, and 0.460, respectively. The association of 3-year relapse CI probabilities with pre-transplant characteristics were as follows: aggressive vs. indolent histology = 0.530 vs. 0.315; chemo-resistant vs. chemo-sensitive = 0.571 vs. 0.316; disease status prior to transplant – CR vs. PR vs. SD vs. PD = 0.210 vs. 0.217 vs. 0.597 and 0.627; number of prior treatments: 1–2 vs. 3 vs. 4 vs. 5+ = 0.375 vs. 0.418 vs. 0.613 vs. 0.450; sites of disease: 0–1 vs. 2 vs. 3 vs. 4+ = 0.458 vs. 0.516 vs. 0.331 vs. 0.579. Median OS from date of progression was 8.3 months (0.5 - 94+ months) with a 5-year OS = 32%. No patient who progressed/relapsed within 3 months post-transplant has survived beyond 12 months, with one patient still alive at 6 months. Median OS (months) from date of progression was assessed for the following characteristics: progression < 3 months vs. ≥ 3 months post-transplant = 2.6 vs. NR, p <0.0001; progression < 6 months vs. ≥ 6 months post-transplant = 5.3 vs. NR, p = 0.0002; aggressive vs. indolent histology = 7.8 vs. 18.3, p = 0.53; number of disease sites: 0–1 vs. 2 vs. 3 vs. 4+ = 5.8 vs. 13.8 vs. 4.9 vs. 12.9, p = 0.75; number of prior treatments: 1–2 vs. 3 vs. 4 vs. 5+ = 8.4 vs. NR vs. 11 vs. 5.6, p = 0.27; response vs. no response to relapse/progression treatment = NR vs. 4.7, p = 0.0087 (determined by a landmark method, beginning 30 days after progression to allow time for determination of response to relapse treatment). These data demonstrate that a significant minority of NHL patients, who relapse after RI allogeneic HSCT, can achieve long-term survival, including patients with aggressive histology. These analyses, which utilized standard clinical characteristics, identified NHL patients at higher risk for relapse and poorer outcomes once relapse occurred. In particular, disease progression/relapse occurring less than 3 months post-transplant was associated with an extremely poor prognosis; novel strategies and trials are needed for such patients. These results need to be confirmed by other groups, and these analyses need to be performed in other transplant settings (e.g. unrelated donors and myeloablative conditioning). The use of these patient characteristics, alone or in combination, may ultimately lead to a method of estimating the risk for relapse and the subsequent prognosis, if relapse should occur, in NHL patients undergoing RI allogeneic HSCT. Disclosures: No relevant conflicts of interest to declare.

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Allogeneic hematopoietic stem cell transplantation for cutaneous T-cell lymphoma (CTCL)

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.7540 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 7540-7540

Author(s):

C. Hosing ◽

M. Donato ◽

I. F. Khouri ◽

D. T. Chu ◽

D. L. Bethancourt ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Hematopoietic Stem Cell ◽

Conditioning Regimen ◽

Hematopoietic Stem ◽

Allogeneic Hsct ◽

Post Transplant ◽

Treatment Regimens

7540 Background: Patients (pts.) with advanced CTCL have a poor prognosis. There has been limited experience with the use of allogeneic hematopoietic stem cell transplantation (HSCT) in these pts. We report the results of 11 pts. with advanced CTCL/Sezary syndrome who underwent allogeneic HSCT at our institution. Patients and Methods: All pts. signed informed consent. Median age at the time of HSCT was 50.5 years (range, 22–63). There were 8 F/3M. All were diagnosed with stage IV disease. The median number of prior treatment regimens was 5.5 (range, 3–11). Treatment regimens included PUVA, TSEB, ECP, topical therapy, retinoids, bexarotene, denileukin diftitox, and multiagent chemotherapy. Seven pts. had a PR to treatment administered prior to transplantation, 2 pts. were in CRu and 2 pts. had SD. The conditioning regimen was fludarabine (125 mg/m2), melphalan 140 mg/m2 in 8 pts., fludarabine (125 mg/m2), cyclophosphamide (3 g/m2) ± rituximab in 2 pts., and fludarabine (120 mg/m2), busulfan (11.2 mg/m2) in 1 pt. Patients who received unrelated or mismatched related stem cells also received ATG. GVHD prophylaxis was with tacrolimus/methotrexate in all patients. Results: Ten of 11 pts. engrafted with a median time to ANC >500 mm3 of 12 days (range, 8–14). One pt. died at 17 days post transplant without engraftment due to sepsis. One pt. developed autologous reconstitution and underwent a 2nd allogeneic HSCT procedure and remains in CR at 3 years post transplant. Of the remaining 9 pts., 7 achieved full donor chimerism and 2 pts. were mixed chimera. At the time of this report 4 of 11 pts. have died. Cause of death was sepsis in 2, fungal pneumonia in 1, and PD in 1 pt. Three pts. relapsed post transplant, all 3 were induced back in to a CR by tapering of immunosuppression (2) or DLI (1). Overall 7 pts. continue to be alive and remission with a median follow up of 2.9 years (range, 3 months to 4.4 years). Four of 7 pts. have cGVHD requiring treatment (Table). Conclusions: Allogeneic HSCT is an effective therapy for refractory CTCL/SS and merits further evaluation. [Table: see text] No significant financial relationships to disclose.

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Pharmacokinetic Analysis during Antifungal Prophylaxis with Posaconazole Suspension in Pediatric and Adolescent Patients after Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽

10.1182/blood.v126.23.4338.4338 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4338-4338

Author(s):

Michaela Döring ◽

Karin Melanie Cabanillas Stanchi ◽

Manon Queudeville ◽

Judith Feucht ◽

Patrick Schlegel ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Pediatric Patients ◽

Fungal Infections ◽

Antifungal Prophylaxis ◽

Hematopoietic Stem ◽

Allogeneic Hsct ◽

Trough Levels

Abstract Background: Invasive Aspergillosis and Candidiasis are some of the major infectious complications after allogeneic hematopoietic stem cell transplantation (HSCT) with an incidence between 10 - 30% and an associated mortality rate between 50 - 90%. Posaconazole is an extended spectrum triazole with clinical activity against Aspergillus spp., Candida spp., Zygomycetes, Fusarium spp. and other rare causes of invasive fungal infections such as Cryptococcus neoformans and Histoplasma capulatum. Due to the excellent results regarding efficacy, safety and feasibility that were shown in prospective studies in adults, we have been using posaconazole for antifungal prophylaxis in pediatric patients for several years now. Bioavailability of posaconazole suspension is impaired by low gastrointestinal resorption due to its lipophilicity. Investigations on adult patients after HSCT have shown that posaconazole resorption depends strongly on the gastric conditions, e.g. intestinal graft-versus-host disease, fat uptake during drug administration, or concomitant medication such as proton pump inhibitors, However, there is insufficient data on the pharmacokinetics of posaconazole in pediatric patients. This single-center analysis evaluated the pharmacokinetic properties as well as efficacy, safety, and feasibility of posaconazole during the initial four weeks of oral antifungal prophylaxis in pediatric and adolescent patients after allogeneic HSCT. Methods: 31 patients with hemato-oncological malignancies with a median age of 6 years (range 6 months - 17.6 years) received posaconazole as antifungal prophylaxis after allogeneic HSCT during the post-transplant period. The posaconazole trough levels were measured for all patients included in this analysis on day 2, 3, 5, 7, 10, day 14±1, and day 28±3 after the first intake of posaconazole suspension. The median observation period was 109 days (range 39 - 206 days), and the median treatment period was 97 days (range 25 - 192 days). Results: No proven, probable or possible fungal infection according to the EORTC/MSG guidelines was observed in the analyzed patient group. A total of 158 posaconazole trough levels were evaluated. During the first five days after start with posaconazole oral prophylaxis, the posaconazole trough level increased continuously. Median posaconazole levels registered 70.5 ng/mL (mean 78.89±50.19 ng/mL) on day 2, 133 ng/mL (mean 156.2±80.5 ng/mL) on day 3, and 209 ng/ml (mean 259.2±184.2 ng/mL) on day 5. Four weeks after start with oral posaconazole prophylaxis, the posaconazole level was at median 633.5 ng/mL (mean 731.7±407.8 ng/mL; range 290 - 1664 ng/mL). These values were significantly higher in comparison to the posaconazole levels on day 10 (P=0.016) with median 324 ng/mL (mean 446.7±350.8 ng/mL; range 104- 1581 ng/mL), and on day 7 (P=0.007) with median 252 ng/mL (mean 390.1±459.7 ng/mL; range 54 - 2441 ng/mL). On day 14 after start of antifungal prophylaxis the posaconazole plasma concentrations reached a stable level with a median of 529 ng/mL (mean 643.3±493.3 ng/mL; range 115 - 2081 ng/mL), and revealed no significant difference (P=0.24) in comparison to values analyzed four weeks after the start with posaconazole. The rates of potentially clinical drug related adverse events were very low. There was a significant transient increase (P<0.001) of transaminases ALT and AST during prophylaxis. Conclusions: Posaconazole suspension is effective in preventing invasive fungal infections in pediatric patients. 58% of the samples showed a sufficient posaconazole concentration above 500 ng/mL on day 14. 72% showed a sufficient posaconazole concentration four weeks after start with posaconazole prophylaxis. Disclosures No relevant conflicts of interest to declare.

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