The UK ALLR3 Chemotherapy Regimen for Relapsed/Refractory Acute Lymphoblastic Leukemia of Childhood: A Multi-Institutional Retrospective Study of Treatment Related Adverse Events

Background: The Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) Consortium and Children's Oncology Group (COG) have recently adopted a modified UK ALLR3 (R3) re-induction regimen as a chemotherapy backbone to test novel agents in multiply relapsed pediatric acute lymphoblastic leukemia (ALL). A detailed toxicity profile of this platform has not previously been published, nor have data using this regimen beyond 1^st relapse. Such baseline data with this backbone would be helpful in the design, conduct and assessment of future clinical trials of R3 in combination with novel agents.

Methods: This was a multi-institutional, retrospective study to investigate adverse events (AEs) and outcome following R3 re-induction chemotherapy (vincristine, mitoxantrone, dexamethasone, and asparaginase) in pediatric relapsed/refractory (R/R) ALL. The objectives of the study were to: 1) establish baseline treatment related AEs during re-induction block 1; and 2) analyze the complete remission (CR) rate and minimal residual disease (MRD) status at the end of re-induction. Patients were identified using medical records from 5 pediatric oncology centers. The study was approved by IRBs at all sites. Data about diagnosis, relapse, prior therapy, AEs, and response to R3 block 1 were extracted from medical records and de-identified. AEs were graded according to the NCI CTCAE v4.0.

Results: 59 patients were included in the study (Table 1). The median number of prior treatment attempts in multiply relapsed patients was 2.5 (range 2-4). Grade ≥ 3 infection was reported in 54/59 patients (92%) and 41 (76%) of these had an infectious source identified by culture, biopsy, and/or imaging. Poly-microbial infection was detected in 18 patients. Bacterial infections occurred most frequently, followed by viral and fungal infections (Table 2). The only grade 5 event in re-induction was due to sepsis. 9 patients (15%) were admitted to the intensive care unit (ICU) due to infection. The most common site of infection was blood, followed by gastrointestinal (GI) and pulmonary. Other grade ≥ 3 non-hematologic toxicities were metabolic derangements (39%), GI (22%), and pain (8%). There was no difference in the grade > 3 toxicities between 1^st relapsed vs. multiply relapsed patients. 36 patients were discharged home prior to neutrophil count recovery. Among these patients, 92% (33/36) had hospital readmission, 7 (19%) required ICU care, and 10 (28%) required chemotherapy modification. In contrast, only 9% (2/23) of patients who remained hospitalized until count recovery received ICU care or had chemotherapy modifications. The median duration from the start of block 1 to block 2 was 39 days (range 28-115 days). 53 patients achieved CR after block 1; 5 had refractory disease; and 1 died of septic shock prior to disease evaluation.

Conclusion: Our study confirmed that R3 block 1 is a highly active re-induction chemotherapy regimen for children with R/R ALL. However, it was associated with very high risk of life-threatening infections. Toxicity reported from this study should be used as a reference for future combination clinical trials using R3 as a backbone in pediatric R/R ALL. Hospitalization until blood count recovery may reduce the need for ICU care and chemotherapy modification.

BM = bone marrow; EM = extra medullary; CRi = CR with incomplete blood count recovery;

HSCT = hematopoietic stem cell transplant *MRD was not performed in 2 patients.

*Eighteen patients had > 1 organism identified