Invasive Fungal Infections in Children with Acute Lymphoblastic Leukemia: Experience from a Reference University Hospital in Cappadocia

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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Genomic Analisys of Notch Mutations in a Case of Alagille Syndrome with Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood.v124.21.5338.5338 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5338-5338

Author(s):

Simona Bernardi ◽

Paola Tononi ◽

Sergio Marin Vargas ◽

Giulio Bassi ◽

Paul Takam Kamga ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Philadelphia Chromosome ◽

Anterior Segment ◽

Alagille Syndrome ◽

University Hospital ◽

Pulmonary Artery Stenosis ◽

Notch 1 ◽

Germline Mosaicism ◽

Genetic Components

Abstract Alagille syndrome (ALGS), or arteriohepatic dysplasia, is a congenital multisystem disease due to Notch signalling pathway mutations, most commonly affecting JAGGED-1 (ALGS type 1), and more rarely NOTCH-2 (ALGS type 2), leading to hepatic, lung, renal and ocular dysfunction (chronic cholestasis, peripheral pulmonary artery stenosis, dysplastic kidneys pigmentary retinopathy), and skeletal abnormalies (minor vertebral segmentation, characteristic facies, posterior embryotoxon/anterior segment defects). ALGS is an autosomal dominant disease, but it is characterized also by variable penetrance and clinical expression and somatic/germline mosaicism. A 20-year-old man with ALGS was admitted to the University Hospital of Verona because of pancytopenia. Following analyses led to the diagnosis of Philadelphia chromosome/bcr-abl-negative, CD10-positive, B-lineage acute lymphoblastic leukemia (common B-ALL). In order to identify the genetic components involved in this complex phenotype, we sequenced the exome of a bone marrow sample collected from the patient. By genome interpretation with Knome pipeline applied to the reference genome UCSC hg19, we found missense variants both in NOTCH-2 (E38K) and JAGGED-1 (P871R) genes that are mainly involved in the syndrome, although their effect on protein function was predicted not to be deleterious. However, we detected putative damaging mutations in genes such as PAX5 (R38H) and NOTCH-1 (K1821N), which might be strongly related to the observed disease. In fact, PAX5 is a member of PAX protein family of transcription factors implicated into regulation of early development that binds NOTCH-2 and likely altering its functionality. On the other hand, NOTCH-1 is involved in cell growth and proliferation and thus the predicted alteration of function of the corresponding protein may have an important role in neoplastic transformation. Disclosures Martinelli: Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy; ARIAD: Consultancy.

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Association between Sociodemographic, Clinical and Immunophenotypic Variables with Disease Relapse and Survival at 12 Months, in Patients with B-Cell Acute Lymphoblastic Leukemia Treated at a Colombian University Hospital

Blood ◽

10.1182/blood-2021-148883 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4380-4380

Author(s):

Luis Antonio Salazar ◽

Sandra Vanesa Rios ◽

Angela María Peña ◽

Maria Luna-Gonzalez ◽

Mario Andrés Arenas ◽

...

Keyword(s):

Overall Survival ◽

Acute Lymphoblastic Leukemia ◽

B Cell ◽

Research Funding ◽

Lymphoblastic Leukemia ◽

Survival Function ◽

Advisory Board ◽

Overweight And Obesity ◽

University Hospital ◽

The Impact

Abstract INTRODUCTION Acute lymphoblastic leukemia (ALL) is a clonal hematopoietic disorder that originates from B or T lymphoid progenitors. It affects more frequently children, but prognosis is worse in adults. ALL has a high incidence in Hispanics (Swords R et al. Blood Cancer J. 2016) and is important to identify baseline clinical, sociodemographic, and cytogenetic characteristics in these patients that are relevant for relapse free and overall survival. Reports of Hispanic patients with ALL outsides of the U.S.A are scare but are important to further characterize the impact of this disease in minority populations. OBJETIVE To describe the association between sociodemographic, clinical and immunophenotypic variables with 12-month relapse free survival (RFS) and overall survival (OS) in patients diagnosed and treated for ALL in a Colombian university hospital (FOSCAL). MATERIALS AND METHODS This is a descriptive observational cohort study that included patients older than 18 years with a confirmed diagnosis of ALL treated in a tertiary university hospital between 2013-2020 and that had at least 12 months follow-up after starting treatment. Baseline sociodemographic, clinical, laboratory and immunophenotypic data were collected. Bivariate analyses of both relapse and mortality cumulative incidences at 12 months, with relative risks (RR) and their 95% Confidence intervals were performed, using either chi-square or Fischer exact test when needed. In a second term, bivariate survival analyses through Kaplan-Meier survival function and Hazard ratios were evaluated, using Cox proportional hazards as the main statistical test. RESULTS Among 128 of include patients, the median age at diagnosis was 34 years (range 0-89 years), 54% were men, 6.2% had type 2 Diabetes Mellitus (T2DM), most had an ECOG PS of 0 (72.7%), 31.8% had splenomegaly, 12% had hepatomegaly and 47% presented without organomegalies. The proportion of patients with overweight and obesity were 26.3% and 22.2% respectively. At diagnosis 80.5% and 8.8% of patients had high risk and standard risk ALL, respectively Forty-eight patients had a FAB classification with 58% being ALL-2 and most of the were unclassified. Most cases (81%) had B-cell immunophenotype, with 55% being pre-B-cell and 32% mature B-cell. Twelve percent of patients were Ph+ B-ALL. At 12 months, the proportion of mortality was 34.4%. Most of the patients (83%) did not have major co-morbidities, however patients with T2DM had a significantly inferior survival at 12 months, HR: 3.68 (95%CI 1.54-8.8 P=0.003), as patients older than 35 years (HR: 2.15, 95%CI: 1.14-4.0, P=0.017) (Table 1). CONCLUSIONS Colombian patients with B-cell ALL have similar clinical, immunophenotypic and cytogenetic (Ph+ prevalence) characteristics as seen in other international cohorts. In our cohort patients older than 35 years and subjects with T2DM had inferior survival at 1 year. Further analyses of socioeconomic factors, molecular features and response to specific regimens are needed to have a better understanding of Colombian B-ALL patients. Figure 1 Figure 1. Disclosures Salazar: Amgen: Research Funding. Peña: Amgen: Research Funding. Sandoval-Sus: BMS: Other: Advisory Board, Speakers Bureau; SeaGen, Janssen, MassiveBio, TG: Other: Advisory Board. Sossa: Amgen: Research Funding.

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Faculty Opinions recommendation of Trends in the postmortem epidemiology of invasive fungal infections at a university hospital.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718535023.793498840 ◽

2014 ◽

Author(s):

María Cecilia Dignani

Keyword(s):

Fungal Infections ◽

Invasive Fungal Infections ◽

University Hospital

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Proven and probable invasive fungal infections in children with acute lymphoblastic leukaemia: results from an university hospital, 2005-2013

Mycoses ◽

10.1111/myc.12303 ◽

2015 ◽

Vol 58 (4) ◽

pp. 225-232 ◽

Cited By ~ 12

Author(s):

Zumrut Sahbudak Bal ◽

Deniz Yilmaz Karapinar ◽

Nihal Karadas ◽

Semra Sen ◽

Zuhal Onder Sivis ◽

...

Keyword(s):

Acute Lymphoblastic Leukaemia ◽

Lymphoblastic Leukaemia ◽

Fungal Infections ◽

Invasive Fungal Infections ◽

University Hospital

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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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