Invasive Candida Infections in Pediatric Patients Treated on the Pilot Study of Decitabine and Vorinostat with Chemotherapy for Relapsed ALL: A Report from the Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) Consortium
Authors: Burke Michael J. , Brown Patrick , Gore Lia , Sposto Richard , Bhojwani Deepa , Chang Bill H , Dubois Steven G. , Gaynon Paul S , Glade-Bender Julia , Heym Kenneth Matthew , Sulis Maria Luisa , Pollard Jessica A. , Verma Anupam , Huynh Van 
Published: November 2019

Abstract

Introduction Children and young adults with relapsed acute lymphoblastic leukemia (ALL) are at high risk for infectious complications, particularly invasive fungal infections, during their intensive re-induction therapy. We report results of a Pilot study investigating decitabine and vorinostat in combination with intensive re-induction chemotherapy for children and young adults with relapsed or refractory ALL. This study is currently open through the TACL Consortium [NCT01483690] and all patients and/or their parents or guardians signed informed consent to participate in this institutional review board approved therapeutic trial in accordance to the Declaration of Helsinki.
Methods Patients 1-25 years of age with 2nd or greater relapse or refractory ALL are eligible. Seventeen patients have enrolled with a median age of 12 years (range, 19 months - 21 years). Patients received one course of therapy which included decitabine (15mg/m2 days 1-7; 15-21), vorinostat (180mg/m2 days 3-10; 17-24), vincristine (1.5mg/m2 days 10, 17, 24, 31), dexamethasone (10mg/m2/dose BID days 8-12; 22-26), mitoxantrone (10mg/m2 days 8, 9), PEG-asparaginase (2500 IU/m2 days 10, 24) and intrathecal methotrexate (dosed according to age and CNS status). Nine patients (53%) relapsed after a prior allogeneic hematopoietic cell transplant and 5 patients had refractory disease (29%) prior to enrolling on this study. Initial infection prophylaxis guidelines did not require anti-bacterial or anti-fungal therapy.
Results The study was suspended after 5 patients enrolled due to 2 patients reporting a DLT [Grade 3 cholestasis/steatosis, Grade 4 bilirubin (n=1); Grade 3 delirium, Grade 4 seizure, Grade 4 somnolence (n=1)] and 4 of the 5 patients (80%) reporting non-albicans Candidemia [C. kruseii (n=2), C. lusitaniae (n=1), C. guillermondii (n=1)]. Based on this significant rate of fungal infection, despite all patients receiving prophylactic anti-fungal therapy (micafungin n=2, fluconazole n=1, amphotericin n=1), the study was amended to decrease the decitabine dose (15mg/m2 to 10mg/m2) and duration of decitabine (days 1-7; 15-21 to 1-5; 15-19) as well as require treatment dose non-azole class anti-fungal therapy (echinocandin or amphotericin) to be given to all patients on study. Twelve patients enrolled post-amendment; only 1 of 12 (8.3%) experienced a fungal infection (C. guillermondii). Of note, this infection occurred in a patient using fluconazole for prophylaxis in place of a protocol-specified agent. There have been no fungal infections reported to date for the 11 patients on study who have received echinocandin or amphotericin therapy at treatment doses. Treatment responses include 9 patients achieving a complete remission (CR) (53%), 5 with stable disease (29%), two treatment related deaths and 1 patient removed from protocol therapy on day 6 based on the physician’s decision. The median minimal residual disease (MRD) response in patients who achieved a CR and submitted bone marrow samples for end of therapy testing (n=5) was 0.056% (range, 0.00%-5%).
Conclusions We report a substantial initial incidence of invasive Candida infections in patients treated with decitabine and vorinostat in combination with intensive chemotherapy despite anti-fungal prophylaxis which appears to be abrogated once the fungal prophylaxis was required at treatment doses using either an echinocandin or amphotericin class agent. As well, the lower dose and duration of decitabine may have contributed to this improvement, resulting in potentially shorter periods of neutropenia which may contribute to the risk of fungal disease. The mechanism for the unique propensity for non-albicans Candida infections in this study remains unclear. The initial response to this regimen incorporating epigenetic therapy is promising with correlative biology studies investigating methylation, acetylation and gene expression changes pending study completion. The study continues to accrue at a dose expansion cohort.

Disclosures
Off Label Use: Decitabine in relapse ALL Vorinostat in relapse ALL.