Clofarabine-Based Chemotherapy for KMT2Ar Infantile Acute Lymphoblastic Leukemia

Rearrangements in KMT2A (KMT2Ar) are associated with pediatric, adult and therapy-induced acute leukemias. Infants with KMT2Ar acute lymphoblastic leukemia (ALL) have a poor prognosis, with an event-free-survival (EFS) of 33.6-36.9%. In the context of the remarkable improvements in the treatment of childhood ALL, the dismal outcome of infantile KMT2Ar ALL and the lack of any significant progress for more than two decades are striking . The St. Jude Total Therapy 16 study (the most recently reported study of a program for childhood ALL that begun in 1962) yielded a 5-year EFS of 88.2% overall. Total 16 enrolled all subtypes of newly diagnosed pediatric ALL patients including infants, with intensity of treatment adapted to presenting clinical and genomic features, and early treatment response as determined by minimal/measurable residual disease (MRD). KMT2Ar infants were treated on an intensified high-risk arm and received clofarabine in combination with cyclophosphamide and etoposide (CCE) at two points during treatment: Induction days 22-25 and Reinduction I. Infants who lacked KMT2Ar and KMT2Ar patients who were one year of age or older received the same risk-directed treatment plan given to all other patients enrolled on study. A total of 28 patients with KMT2Ar were enrolled on Total 16; the 19 patients > 1 year of age received standard-risk therapy, and the 9 patients < 1 year of age received high-risk therapy on the infant arm with CCE. The probabilities of 5-year EFS and overall survival in KMT2Ar patients > 1 year of age and those < 1 year of age were 73.3% vs. 44.4% (p=0.071) and 84.2% vs. 55.6% (p=0.060), respectively. Six of the nine infants were MRD-positive on Induction day 15 prior to CCE (MRD-positive range, 0.012% to 13.7%; median, 2.13%) with MRD negative status (<0.01%) achieved post CCE in six of the eight patients with data (MRD was 0.011% and 0.07% in the remaining two patients). The trend towards superior outcomes in older KMT2Ar patients was not due to a lower incidence of relapse, as the 5-year cumulative incidence of relapse was 26.7% in patients > 1 year of age and 12.5% for those < 1 year of age (p=0.454). Five infants remain alive (four in CR1, one in CR2), while four expired in CR1. Three deaths were secondary to infection, including a multi-drug resistant soft tissue bacterial infection during Induction days 1-21, a respiratory syncytial virus pneumonia during Reinduction II, and a chronic parainfluenza 3 infection during Continuation weeks 70-101 that led to chronic pneumonitis and interstitial fibrosis. The fourth patient developed grade 5 pulmonary hypertension following induction, a complication potentially compounded by their presenting WBC count of 905 x 10 ⁹/L and pulmonary leukostasis. A comparison of 3-year cumulative risk of selected major toxic effects of treatment revealed that high-risk infants had a lower incidence of asparaginase allergic reactions, osteonecrosis, hyperglycemia, and pancreatitis; in contrast, the incidence of fever and neutropenia, hepatic toxicity and seizures, was similar in high-risk patients regardless of age. Infants had a higher risk of thrombosis (46.7% vs. 23.1%, p<0.001) and of severe infection (70% vs. 19.7%, p<0.001). To further study the contribution of clofarabine to severe infections, we looked at the incidence in high-risk patients > 1 year of age that received one or more clofarabine-containing Reintensification chemotherapy cycles prior to hematopoietic stem cell transplant in first remission (CR1). This revealed a higher frequency of infections in infants, suggesting a greater susceptibility to this complication independent from clofarabine exposure (mean number of episodes, 2.39 vs. 1, p<0.001, Poisson regression modeling). In conclusion, treatment of infants with KMT2Ar ALL with chemotherapy including high-intensity clofarabine leads to a lower cumulative incidence of relapse but a higher risk of treatment-related mortality. Severe infections were a major cause of morbidity and mortality.