Comment on: Invasive fungal infections in children with acute lymphoblastic leukemia

Abstract Background In pediatric hematologic malignancy, the incidence of invasive fungal infections (IFI) is ~ 5-10% and leads to significant morbidity and mortality. Acute lymphoblastic leukemia (ALL) accounts for the largest group at risk and has the largest absolute number of IFI. Antifungal prophylaxis has the potential to mitigate risk of invasive infections in ALL but is not currently standard of care due to the paucity of data in ALL subgroups. A recent systematic review showed a significant reduction in proven/probable IFI and fungal infection-related mortality in pediatric patients when using a mold active agent compared with fluconazole, therefore an echinocandin was selected for systemic antifungal prophylaxis in our institution. In this study we investigate the incidence of IFI in patients with ALL in a highly endemic area (Ohio River Valley) and describe the impact of echinocandin prophylaxis in this population. Methods We conducted a retrospective cohort study of consecutive patients <25 years with ALL from 2015 to 2021 at Norton Children's Hospital, Louisville, KY. IFI was classified as possible, probable, or proven as defined by the 2020 European Organization for Research and Treatment of Cancer/ Mycoses Study Group Consensus Group. Patients were then analyzed in 2 subgroups based on prophylaxis with caspofungin. Inpatient administration of caspofungin was given to patients with high-risk B-ALL (HR B-ALL) and T-ALL as outlined in Table 1. Patient and IFI characteristics were collected, and cumulative incidence analyses used for subgroup comparisons. Results Demographics and patient characteristics are summarized in Table 2. Between 2015 to 2020 we identified 100 patients with ALL. Mean age at diagnosis was 7.2 years and 43% were female. We identified 14 unique cases of IFI in 13 patients with ALL who did not receive prophylaxis with caspofungin during 2015 to 2020 (14%). Prior to the implementation of prophylaxis, IFI occurred in 0% (0/43) of the SR B-ALL group, 18.2% (6/33) in HR B-ALL group and 35% (8/23) in T-ALL group. IFI incidence was highest in induction and consolidation phases (71.4%) and implicated species during these phases included Aspergillus, Candida, Fusarium, and Papulasopora. From April 2020 to July 2021, there were 22 newly diagnosed patients with ALL, 11 (50%) of whom received inpatient prophylaxis with caspofungin. There was 1 case (4.5%) of reported IFI during delayed intensification (no prophylaxis at the time of infection). As seen in Figure 1, patients with HR B-ALL and T-ALL who were hospitalized and received caspofungin during induction saw a notable decrease in the cumulative incidence of IFI, from 18.3% to 0% at 6 months into treatment before reaching similar levels in the patients who did not receive prophylaxis. Conclusion In our pediatric population, patients with T-ALL and HR B-ALL were more likely to develop IFI than those with SR B-ALL. Prophylaxis with caspofungin and inpatient hospitalization during induction were effective strategies for reducing the incidence of IFI in induction and consolidation for our high-risk leukemia population. This approach should be validated in larger studies with special consideration being given to patients in fungal endemic areas. Figure 1 Figure 1. Disclosures Raj: Terumo Medical Corporation: Honoraria, Speakers Bureau; Forma therapeutics: Consultancy; Global biotherapeutics: Speakers Bureau.

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Epidemiology of invasive fungal infections during induction therapy in adults with acute lymphoblastic leukemia: a GRAALL-2005 study

Leukemia & Lymphoma ◽

10.1080/10428194.2016.1204652 ◽

2016 ◽

Vol 58 (3) ◽

pp. 586-593 ◽

Cited By ~ 24

Author(s):

Clara Mariette ◽

Emmanuelle Tavernier ◽

Didier Hocquet ◽

Anne Huynh ◽

Françoise Isnard ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Induction Therapy ◽

Fungal Infections ◽

Lymphoblastic Leukemia ◽

Invasive Fungal Infections

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Clinical Experience of Antifungal Combination Therapy for Invasive Fungal Infections in Pediatric Hematological Malignancy Patients

10.22541/au.161116366.65011217/v1 ◽

2021 ◽

Author(s):

Saliha Kanık Yüksek ◽

Aslınur Özkaya Parlakay ◽

Belgin Gülhan ◽

Neşe Yaralı ◽

Namık Yaşar Özbek ◽

...

Keyword(s):

Mortality Rate ◽

Fungal Infections ◽

Lymphoblastic Leukemia ◽

Total Mortality ◽

Complete Response ◽

Hematologic Malignancies ◽

Invasive Fungal Infections ◽

Attributable Mortality ◽

Combination Regimen ◽

Pediatric Leukemia

Background: The role of combination regimens in the treatment of invasive fungal infections (IFI) in patients with hematologic malignancies remains unclear. This study was aimed to demonstrate experience data about combined antifungal therapy (CAT) in pediatric IFI patients with haematological malignancies. Methods: Between January 2014 and December 2017, a total of 33 IFI episodes in 28 patients with hematological malignancies were analyzed retrospectively. Results: Of the patients (19 with acute lymphoblastic leukemia, and 9 with acute myeloblastic leukemia), 21 (75%) had leukemia relapse and 7 (25%) had remission. IFI was classified as possible in 26 (78.8%) episodes, probable in 5 (15.1%) episodes, and proven in 2 (6.1%) episodes. LamB (%50) was the most preferred agent in monotherapy. Mean duration of monotherapy was 12.84 ± 4.28 (5-24) days. LamB plus voriconazole (54.5%) were the most common combination preference in CAT. Mean duration of CAT was 42.36 ± 36.4 days, and unchanged according to combination regimen type (p = 0.571). Total mortality rate and IFI attributable mortality rate were 60.7% vs 76.5%. Mortality rate was significantly higher in patients with relapse (p = 0.006). Complete response was obtained in 81.8% of surviving patients. Duration of neutropenia and CAT, and recovery time were not found statistically different in the episodes with/without death and according to relapse or remission status. Side effects due to CAT use were observed quite low level. Conclusion: CAT has been found to be safe in IFI episodes of pediatric leukemia. The result will contribute to the data about combined antifungal use in daily clinical practice in pediatric haematological patients with IFI.

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Efficacy and Safety of Fludarabine Combined with Cytarabine in the Treatment of Patients with Relapsed and Refractory Acute Lymphoblastic Leukemia (ALL).

Blood ◽

10.1182/blood.v106.11.4593.4593 ◽

2005 ◽

Vol 106 (11) ◽

pp. 4593-4593

Author(s):

Bin Jiang ◽

Wei Wang ◽

Li Bao ◽

Xiaojun Huang ◽

Jin Lu ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Bacterial Infections ◽

Overall Response Rate ◽

Fungal Infections ◽

Lymphoblastic Leukemia ◽

Gastrointestinal Symptoms ◽

Efficacy And Safety ◽

Who Grade ◽

Myeloid Antigens ◽

Nonhematologic Toxicity

Abstract Objective: The objective of this study was to evaluate the efficacy and safety of fludarabine (Flu) combined with cytarabine (Ara-c) in the treatment of relapsed and refractory ALL. Methods: From March 2003 to February 2005, 28 patients in our institution with adult relapsed and refractory acute lymphoblastic leukemia were treated with Flu and Ara-c chemotherapy. The median age of patients was 28 years (range, 11–64 years). Twenty-four patients were treated with Flu IV Ara-c: Flu (30 mg/m2/day as a 30 minute infusion IV dl-4) and Ara-c (1000 mg/m2 ql2h, 6–10 times IV). The Ara-c infusions commenced 4 hours after the fludarabine infusion. Four patients were treated with following regimen: Flu (30 mg/m2/day as a 30 minute infusion IV dl-4), Ara-c (100 mg/day q12h 6–10 times), and mitoxantrone (4 mg/d dl~4 IV). Results: Efficacy: The overall response rate was 48.1%. Ten of the 27 ALL patients achieved a CR (37%), and 3 patients achieved a PR (11.1%). Median CR duration was 8 months (ranges, 2–34 months). Among 14 Ph- ALL patients, 4 achieved a CR (28.6%); of 8 Ph+ ALL patients, 5 (62.5%) achieved a CR, 2 achieved a PR, and 1 was NR. Among 5 patients with T-ALL, only 1 achieved a CR. The patients with acute mixed lineage leukemia achieved a CR. Among 19 patients with full immunophenotyping data, there were 3 CRs, 1 PR in the 5 ALL patients with myeloid antigens (My+), and 3 CR and 2 PR in 14 ALL patients without myeloid antigens (My−). Four Ph+ My+ ALL patients achieved a CR. Safety: Flu combined with Ara-c resulted in myelosuppression in all patients, 27 patients had WBC <1′109/L, and the median time to WBC <1′109/L was 11 days (range, 5–27 days). The lowest PMN emerged 9 days (range, 3–18 days) after the regimen commenced. Twenty-five patients had PLT <20′109/L, and the median duration was 8 days (range, 1–30 days). The lowest PLT count occurred 11 days (range, 3–18 days) after the regimen commenced. Sixteen patients had pyrexia with 8 definite pathogenic bacterium, 3 bacterial infections, 1 CMV infection, 2 fungal infections, and 2 multiplicity of infection. The major nonhematologic toxicity was gastrointestinal symptoms (35.7%, 10/28), such as nausea, vomiting, diarrhea, anorexia (i.e. WHO grade 1 or 2), and the symptoms disappeared soon after the regimen completed. Conclusion: Favorable efficacy and safety were obtained in relapsed and refractory ALL patients treated with Flu and Ara-c, especially in Ph+ ALL and My+ ALL patients. In the future, larger studies are warranted to evaluate the efficacy and safety of Flu and Ara-c.

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Downs Syndrome Patients with Acute Lymphoblastic Leukemia; an Intermediate Outcome with a High Infectious Morbidity.

Blood ◽

10.1182/blood.v108.11.4521.4521 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4521-4521

Author(s):

Mahasen Saleh ◽

Ashraf R. Khairy ◽

Hassan El-Solh ◽

Mohammed Al-Mahr ◽

Abdulrahman Al-Musa ◽

...

Keyword(s):

Overall Survival ◽

Acute Lymphoblastic Leukemia ◽

Febrile Neutropenia ◽

Fungal Infections ◽

Lymphoblastic Leukemia ◽

Chromosome 21 ◽

Cell Phenotype ◽

Induction Phase ◽

Bleeding Tendency ◽

Infectious Morbidity

Abstract Unlike AML, children with Down syndrome and Acute Lymphoblastic Leukemia (DS-ALL) have been reported to achieve significantly lower rates of remission, with higher mortality and a poorer overall survival. To further study this, we conducted a retrospective review for all DS children who were diagnosed and treated for ALL at our institution from 1997 to 2006. 12 (1.8%) out of 645 children (age 0–14 years) diagnosed with ALL had DS. The median age at diagnosis was 55 months (range 23 – 108 months) and eight were male. The most frequent signs and symptoms were fever (n=11; 91.6%), bleeding tendency (n=8; 75%) and organomegaly (n=9; 83.3%). The median WBC count at diagnosis was 4.99×109/L (range 0.58–500×109/L). The median platelet count and hemoglobin were 255×109/L and 80.5g/L, respectively. None of the patients had CNS disease at diagnosis. Leukemia cell cytogenetics revealed only the additional chromosome 21 for all patients, except in one patient who had 48XY,+X,+21. All cases had a precursor B-cell phenotype, and a DNA index of 1.0. Patients received treatment according to the protocol utilized for intermediate risk ALL at our institution. A good early response to induction therapy by a day-14 bone marrow (BM) evaluation was seen in all patients, and complete remission (CR) was achieved by day 28 of induction for the 11 who completed induction chemotherapy. One patient died toward the end of induction due to severe sepsis. Infection was the most commonly encountered morbidity throughout the course of therapy. Six episodes of febrile neutropenia, two documented bacteremias and one disseminated invasive Aspergillosis were reported during the induction phase. In the post-induction period, 21 episodes of febrile neutropenia were reported, in addition to six documented bacteremias and two patients developed fungal infections, one with fungemia and the other with a nail bed infection. Four patients relapsed at a median time of 13 months from diagnosis. Relapses occurred in the BM for two, as isolated CNS in one, and as combined BM and CNS relapse in one. Seven patients continue in first CR. The overall survival and the relapse free survival at 3 years were 53.7% and 60% respectively. Conclusion: Although DS ALL children do not present with poor-risk features (infancy, T-cell phenotype, adverse cytogenetics, CNS involvement) they tend to have an intermediate treatment outcome even if treated on relatively intensive protocols. Delays in appropriate therapy due to infectious morbidity could contribute to this sub-optimal outcome.

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Eradication of Pulmonary Aspergillosis in an Adolescent Patient Undergoing Three Allogeneic Stem Cell Transplantations for Acute Lymphoblastic Leukemia

Case Reports in Transplantation ◽

10.1155/2012/672923 ◽

2012 ◽

Vol 2012 ◽

pp. 1-4

Author(s):

Michaela Döring ◽

Angelika Zierl ◽

Markus Mezger ◽

Peter Lang ◽

Rupert Handgretinger ◽

...

Keyword(s):

Stem Cell ◽

Acute Lymphoblastic Leukemia ◽

Combination Therapy ◽

Hematopoietic Stem Cell ◽

Fungal Infections ◽

Lymphoblastic Leukemia ◽

Antifungal Drugs ◽

Adolescent Patient ◽

Pulmonary Aspergillosis ◽

Hematopoietic Stem

Systemic fungal infections are a major cause of infection-related mortality in patients with hematologic malignancies. This report addresses the case of an adolescent patient with acute lymphoblastic leukemia who underwent three allogeneic hematopoietic stem cell transplantations and developed pulmonary aspergillosis. Combination therapy with liposomal amphotericin B (L-AmB, 3 mg/kg bw/day) and caspofungin (CAS, 50 mg/day) during the first allogeneic hematopoietic stem cell transplantation (HSCT) improved the pulmonary situation. After shifting the antifungal combination therapy to oral voriconazole (2 × 200 mg/day) and CAS, a new pulmonal lesion occurred alongside the improvements in the existing pulmonary aspergillosis. An antifungal combination during a second HSCT with L-AmB (3 mg/kg bw/day) and CAS showed an improvement in the pulmonary aspergillosis. A combination therapy with CAS and L-AmB (1 mg/kg bw/day) during the third HSCT led once again to progress the pulmonary aspergillosis, after increasing the L-AMB to 3 mg/kg bw/day for recovery. The presented case provides an example of how, despite severe immunosuppression, a combination of antifungal drugs administered intravenously at therapeutic dosages may be more efficient than either intravenous monotherapy or combinations of intravenous and oral antifungals in selecting pediatric and adolescent patients with proven fungal infections.

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Invasive fungal infections in a pediatric hematology-oncology department: A 16-year retrospective study

Current Medical Mycology ◽

10.18502/cmm.6.2.2840 ◽

2020 ◽

Author(s):

Nikoleta Kazakou ◽

Timoleon-Achilleas Vyzantiadis ◽

Anastasia Gambeta ◽

Eleni Vasileiou ◽

Eleni Tsotridou ◽

...

Keyword(s):

Mortality Rate ◽

Fungal Infections ◽

Lymphoblastic Leukemia ◽

Patient Characteristics ◽

Hematologic Malignancies ◽

Incidence Rates ◽

Invasive Fungal Infections ◽

Antifungal Treatment ◽

Pediatric Hematology ◽

Non Hodgkin Lymphoma

Background and Purpose: Invasive fungal infections (IFIs) are a major cause of morbidity and mortality in immunocompromised children. The purpose of our study was to evaluate the incidence of IFIs in pediatric patients with underlying hematologic malignancies and determine the patient characteristics, predisposing factors, diagnosis, treatment efficacy, and outcome of IFIs. Materials and Methods: For the purpose of the study, a retrospective analysis was performed on cases with proven and probable fungal infections from January 2001 to December 2016 (16 years). Results: During this period, 297 children with hematologic malignancies were admitted to the 2nd Pediatric Department of Aristotle University of Thessaloniki, Greece, and 24 cases of IFIs were registered. The most common underlying diseases were acute lymphoblastic leukemia (ALL; n=19, 79%), followed by acute myeloid leukemia (AML; n=4, 17%) and non-Hodgkin lymphoma (NHL; n=1, 4%). The crude incidence rates of IFIs in ALL, AML, and NHL were 10.5%, 18.2%, and 2.8% respectively. Based on the results, 25% (n=6) and 75% (n=18) of the patients were diagnosed as proven and probable IFI cases, respectively. The lung was the most common site of involvement in 16 (66.7%) cases. Furthermore, Aspergillus and Candida species represented 58.3% and 29.1% of the identified species, respectively. Regarding antifungal treatment, liposomal amphotericin B was the most commonly prescribed therapeutic agent (n=21), followed by voriconazole (n=9), caspofungin (n=3), posaconazole (n=3), micafungin (n=1), and fluconazole (n=1). In addition, 12 children received combined antifungal treatment. The crude mortality rate was obtained as 33.3%. Conclusion: As the findings of the present study indicated, despite the progress in the diagnosis and treatment of IFIs with the use of new antifungal agents, the mortality rate of these infections still remains high.

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Voriconazole prophylaxis in leukemic patients: A retrospective single-center study

Journal of Oncology Pharmacy Practice ◽

10.1177/1078155219876683 ◽

2019 ◽

Vol 26 (4) ◽

pp. 873-881

Author(s):

Vivian Bui ◽

Sandra AN Walker ◽

Marion Elligsen ◽

Anju Vyas ◽

Alex Kiss ◽

...

Keyword(s):

Acute Leukemia ◽

Fungal Infection ◽

Invasive Fungal Infection ◽

Fungal Infections ◽

Lymphoblastic Leukemia ◽

Retrospective Chart Review ◽

Liver Function Tests ◽

Antifungal Prophylaxis ◽

Invasive Fungal Infections ◽

Acute Myeloid

Background Invasive fungal infections commonly occur in acute myeloid and lymphoblastic leukemia patients receiving chemotherapy. In these patients with acute leukemia, posaconazole prophylaxis is recommended; however, voriconazole may be a less costly alternative. Objectives The objective of this study was to evaluate the efficacy and safety of voriconazole prophylaxis in acute leukemia patients. Methods A retrospective chart review of inpatients at Sunnybrook Health Sciences Centre between 2005 and 2017 was completed. Hospitalized adult acute leukemia patients who received voriconazole prophylaxis (cases) were compared to patients who received fluconazole or no prophylaxis during chemotherapy (controls). Statistical analyses comparing baseline characteristics, safety, and efficacy outcomes between the study cohorts were completed. A posaconazole literature-based weighted mean risk was compared to the voriconazole risk of invasive fungal infection identified in this study. Results Of 490 acute myeloid leukemia or acute lymphoblastic leukemia patients, 83 controls and 92 cases were eligible. Case patients received an average of 24.4 ± 10.8 days of voriconazole prophylaxis. The incidence of proven or probable invasive fungal infections with voriconazole was 3.3% (3/92) versus 7.2% (6/83) in the control cohort (p > 0.05) and was comparable to the literature reported weighted incidence of invasive fungal infection with posaconazole (2.4 ± 2.1%; 95% CI 1.3%–3.4%; p > 0.05). Voriconazole was well tolerated by patients (91%; 84/91; seven discontinued due to asymptomatic elevated liver function tests). Conclusions Voriconazole prophylaxis was found to be safe, effective, and comparable to literature-based efficacy data for risk of invasive fungal infection with posaconazole antifungal prophylaxis in patients with acute leukemia undergoing chemotherapy and could represent a significant cost advantage.

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