The UK ALLR3 Chemotherapy Regimen for Relapsed/Refractory Acute Lymphoblastic Leukemia of Childhood: A Multi-Institutional Retrospective Study of Treatment Related Adverse Events
Authors: Sun Weili , Smith Alison Marie , Etan Orgal , Sposto Richard , Wilkes Jennifer J. , Gardner Rebecca A , Minjun Hur , Pineros Vanessa , Olson Emily , Tan Yijuin , Rheingold Susan R. , Burke Michael J. , Wayne Alan S. 
Published: November 2019

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 1st 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 1st 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.

Table 1. Patient Characteristics and Response All Patients 1st Relapse > 2nd Relapse N 59 43 16 Median Age (yrs) 7 (0.4 – 19) 7 (0.4 – 19) 6.5 (2 – 15) Gender Male 41 (69%) 30 (70%) 11 (69%) Female 18 (31%) 13 (30%) 5 (31%) Site of Relapse Isolated BM 32 (54%) 22 (51%) 10 (63%) Isolated EM 15 (25%) 11 (26%) 4 (25%) Combined 12 (20%) 10 (23%) 2 (13%) Induction Death 1 (2%) 1 (2%) 0 Response Data CR/CRi 53 (90%) 41 (95%) 12 (75%) MRD - 30 (59%)* 23 (59%)* 7 (58%) MRD + 21 (41%) 16 (41%) 5 (42%) Refractory Disease 5 (8%) 1 (2%) 4 (25%) Subsequent HSCT Yes 24 (41%) 14 (33%) 10 (63%) No 35 (59%) 29 (67%) 6 (38%)

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.

Table 2. Organism identified Biopsy/Culture confirmed or Suspected Infection by Imaging* 65 Bacterial Infection 44 (68%) Gram + 18 Gram - 19 Other 7 Fungal Infection 11 (17%) Biopsy/Culture confirmed 7 Suspected by CT/MRI 4 Viral Infection 10 (15%) Parasite 1

*Eighteen patients had > 1 organism identified

Disclosures

No relevant conflicts of interest to declare.