Background: Inadequate depletion of asparaginase is associated with reduced survival in children diagnosed with acute lymphoblastic leukemia (ALL). Pegaspargase induces a severe hypersensitivity reaction in 7-25% of patients necessitating a change to alternative formulations of asparaginase. The administration of alternative asparaginase formulations can be challenging, as manufacturing issues have led to their reduced availability, and the shorter half-life of alternative formulations requires more frequent dosing. Methods: Since 2016, Children's Mercy Kansas City has utilized a 3-bag, 12-step desensitization protocol for patients that experience a hypersensitivity reaction to pegaspargase. Initially, patients were required to be monitored in the Pediatric Intensive Care Unit (PICU) for the first two desensitization infusions. Starting in 2020, due to an increase in the utilization and success of desensitization, we updated our protocol to allow for patients to undergo desensitization as an inpatient observation admission in the pediatric oncology inpatient unit. If patients tolerate desensitization twice without a reaction, further doses are administered in the outpatient oncology clinic. Results: Since 2016, we have performed 58 pegaspargase desensitizations in 21 patients with ALL or lymphoblastic lymphoma (LL) (median age: 8 years, range: 2-19). Patients were considered eligible for desensitization if they were suspected of having a hypersensitivity reaction to pegaspargase based on clinical symptoms. Seven patients received the first two desensitization infusions in the PICU and 14 patients received the first two desensitization infusions in the pediatric oncology inpatient unit. Seventeen patients (81.0%) tolerated desensitization without a reaction while four patients had a reaction necessitating a switch to an alternative asparaginase formulation. Of the four patients that experienced hypersensitivity, two experienced a grade 3 reaction >2 hours into the infusion and received IM epinephrine, one had a grade 2 reaction and was able to complete the infusion but had inadequate serum asparaginase activity (SAA) 5 days later and one patient had a grade 2 reaction, was able to complete the infusion but reacted again to a second infusion. All patients that experienced a reaction responded promptly to treatment with resolution of symptoms and no patient required transfer to the PICU or escalation of care. Twelve patients received subsequent scheduled pegaspargase desensitization doses after tolerating the first dose (median: 4 total doses, range 2-6) and all subsequent desensitizations were tolerated without a reaction. For patients that tolerated desensitization, SAA was obtained following 42 doses, four to 14 days from the infusion, with all but one level above the 0.1 IU/mL threshold considered to be appropriate for asparaginase depletion. The median SAA after pegaspargase desensitization was 0.614 IU/mL. One patient had an initial SAA activity <0.1 IU/mL after the first desensitization but subsequently received four additional pegaspargase doses using the desensitization protocol with adequate SAA levels after each infusion. The time between a hypersensitivity reaction and initial desensitization did not impact the chance of having a reaction. Among patients who had a reaction during desensitization, there was no difference in the incidence of a hypersensitivity reaction comparing patients who were desensitized ≤3 days following their baseline reaction (22.2%, 2 of 9 patients) compared to those treated >4 days from their baseline reaction (22.2%, 2 of 9 patients). Three patients treated with desensitization at relapse, >1 year from their initial reaction were excluded from this analysis. Conclusion: Pegaspargase desensitization is a safe and highly effective method for ensuring adequate asparaginase exposure for children with ALL and LL who experience a hypersensitivity reaction. The majority of patients tolerated desensitization without a reaction and were able to receive all protocol-directed pegaspargase doses with adequate asparaginase depletion based on SAA levels. The major advantage of desensitization, in comparison to switching to short-acting asparaginase products, is the ability to complete the course of asparagine therapy in a single day.

Introduction Acute lymphoblastic leukemia (ALL) with KMT2A-rearrangement (KMT2A-r) in infants <1 year is a high-risk childhood ALL subtype, with consistently poor event-free survival (EFS) of approximately 35% when treated with intensive chemotherapy with or without hematopoietic stem cell transplant. Infant ALL blasts are characterized by DNA hypermethylation, which is hypothesized to contribute to chemoresistance by altering transcriptional regulation of gene expression. In preclinical studies of KMT2A-r blasts, epigenetic priming with DNA methyltransferase inhibitors improved the in vitro cytotoxicity of chemotherapy. Azacitidine, a pyrimidine nucleoside analog of cytidine and hypomethylating agent, has been used in combination with chemotherapy in children with leukemia. We previously reported that azacitidine was safe and well tolerated in AALL15P1 (ASPHO 2021) and herein we report survival outcomes. Methods The Children's Oncology Group (COG) trial AALL15P1 (NCT02828358) was a single arm, open label, groupwide pilot trial. The primary aim of the trial was to evaluate the tolerability of azacitidine in addition to Interfant-06 standard chemotherapy in infants with newly diagnosed KMT2A-r ALL. Estimation of 5-year EFS was an exploratory aim, given the small sample size. Eligibility criteria included B-ALL or acute leukemia of ambiguous lineage with ≥50% B-lymphoblasts, <366 days of age at diagnosis, and >36 weeks gestational age at enrollment. Exclusions included Down syndrome, secondary ALL, and prior cytotoxic therapy (except intrathecal chemotherapy or corticosteroids). Following an Interfant-based induction, infants with KMT2A-r received 4 courses of azacitidine, 2.5 mg/kg/dose intravenously over 10-40 minutes daily for 5 consecutive days in each course, immediately preceding the start of a chemotherapy course on day 6. Infants without KMT2A-r were removed from protocol following induction and did not receive azacitidine. Treatment failure was defined as failure to achieve M1 marrow status (<5% blasts by morphology) with resolution of extramedullary leukemia by the end of consolidation. EFS and overall survival (OS) were measured from the time of enrollment. Results The study accrued from March 2017 to December 2019 and all protocol-directed treatment concluded in December 2021. Of the 78 infants enrolled, 56 had KMT2A-r (72%), and 53 completed induction therapy and received at least 1 course of azacitidine. No patients were ineligible. Diagnostic clinical characteristics of infants with KMT2A-r included four infants age <7 days (7%), 13 age <90 days (23%), 18 with white blood cell count ≥300,000/µL (32%), 32 CNS2 (57%), and four CNS3 (7%). As of the data cutoff (06/30/2022), the median follow-up is 3.8 years, and the 3-year EFS (SE) and OS (SE) rates are 34.2% (+/- 0.08) and 63.8% (+/-0.08), respectively, for infants with KMT2A-r. Six infants experienced treatment failure. Minimal residual disease (MRD) levels of marrow blasts by flow cytometry in COG-approved laboratories were submitted for 49 KMT2A-r patients at the end of induction. Of those, 32 were MRD negative <0.01% (65%), eight MRD positive 0.01%-<1% (16%) and nine MRD positive ≥1% (18%). Event-free survival was significantly associated with MRD; the 3-year EFS of patients with any positive MRD was 20.6% (+/-0.13) vs. 40.1% (+/-0.09) (p=0.0185) for those without MRD. As previously reported, at no time did the trial meet or exceed the pre-determined dose limiting toxicity boundaries, and the rates and types of toxicities observed were within the expected range for infants receiving standard chemotherapy alone. Conclusions Epigenetic priming with azacitidine prior to standard chemotherapy was well tolerated in infants with KMT2A-r ALL, but the EFS was consistent with the poor survival of historical outcomes. Positive flow MRD at the end of induction predicted a higher risk of treatment failure, relapse, or death, in comparison to negative MRD, but EFS was still unacceptably low for MRD-negative patients. There remains an urgent need for improved therapies for infants with KMT2A-r ALL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Hypersensitivity to pegaspargase is associated with inferior survival in pediatric patients with acute lymphoblastic leukemia and lymphoblastic lymphoma. In the past year, drug-supply shortages have led to the lack of an available alternative to pegaspargase. Rather than omit asparaginase from the treatment of acute lymphoblastic leukemia or lymphoblastic lymphoma patients with hypersensitivity to pegaspargase, we continued pegaspargase treatments for nine pediatric patients, utilizing a rapid desensitization protocol. There were no adverse events related to the pegaspargase during desensitization, and all patients who were checked had asparaginase serum levels above the threshold of 0.1 IU/mL at 7 to 14 days after pegaspargase therapy.

The primary objective was to determine whether topically administered Caphosol, rinsed orally four times daily at the initiation of conditioning, reduces the duration of severe oral mucositis (OM) compared with placebo among children and adolescents undergoing haematopoietic cell transplantation (HCT). This was a Children’s Oncology Group multicentre randomised double-blinded placebo-controlled clinical trial. Patients between the ages of 4 and 21 years who were scheduled to undergo myeloablative HCT for any indication were randomised to Caphosol or placebo saline rinses four times daily from initiation of conditioning through day +20. Subjects were assessed daily for OM using the World Health Organisation (WHO) Oral Toxicity Scale, Mouth Pain Categorical Scale (0–10) and the Oral Mucositis Daily Questionnaire (OMDQ). The primary end point was duration of severe OM (WHO ⩾3). The study enrolled 220 participants with a median age of 13.7 years (range 4.0–21.9); 163 (74%) received allogeneic HCT. The mean (±s.d.) duration of severe OM was not reduced among Caphosol (4.5±5.0 days) vs placebo (4.5±4.8; P=0.99) recipients. The incidence of severe OM in the Caphosol and placebo arms was 63% (57 out of 91) and 68% (62 out of 91), respectively (P=0.44). There were no significant differences in any of the secondary end points between the groups. Caphosol did not reduce severe OM when compared with placebo among children and adolescents undergoing myeloablative HCT. Studies to identify effective interventions for OM are needed in this population.