Faculty Bibliography

Acute lymphoblastic leukemia (ALL) is the most common and one of the most treatable cancers in children. Although the majority of children with ALL are now cured, 10%-20% of patients are predicted to relapse and outcomes with salvage therapy have been disappointing, with approximately only one-third of children surviving long-term after disease recurrence. Several prognostic factors have been identified, with timing of recurrence relative to diagnosis and site of relapse emerging as the most important variables. Despite heterogeneity in the elements of salvage therapy that are delivered in trials conducted internationally, outcomes have been remarkably similar and have remained static. Because most intensive salvage regimens have reached the limit of tolerability, current strategies are focusing on identifying new agents tailored to the unique biology of relapsed disease and identifying methods to develop these agents efficiently for clinical use. Recently, high-resolution genomic analyses of matched pairs of diagnostic and relapse bone marrow samples are emerging as a promising tool for identifying pathways that impart chemoresistance.

Outcomes for children with relapsed ALL remain poor, especially when relapses occur early (<36 months) following initial diagnosis. A factor contributing to poor outcomes is much lower rates of successful induction of second remission (CR2). CD22 is almost universally expressed in children with B-cell precursor (BCP) ALL and we previously demonstrated the safety of adding the anti-CD22 monoclonal antibody, epratuzumab, to reinduction chemotherapy in children with first marrow relapse (Raetz et al, JCO 2008 26:3756-62) (COG ADVL04P2). The primary aim of the second part of the COG ADVL04P2 study was to determine if addition of epratuzumab to an established chemotherapy platform improves rates of CR2 in individuals with BCP ALL and early bone marrow relapse. Children, adolescents and young adults, ages 2-30 years with first early marrow relapse of BCP ALL, with or without extramedullary disease, were eligible for this study. The primary study endpoint was CR2 rate at the end of the first block of chemotherapy plus epratuzumab as compared to the 67% CR2 rate for historical controls (COG AALL01P2; Raetz et al, JCO 2008 26:3971-8) treated with the same chemotherapy without epratuzumab. For addition of epratuzumab to be deemed effective, an improvement in CR2 rate of 13% (67% vs. 80%) was required. Because there is a significant difference in CR2 rate between patients with very early (<18 months from diagnosis) vs. early (18 to <36 months from diagnosis) relapse, the statistical design used a model to account for potential differences in time to relapse between these studies. ADVL04P2 had several stages. In part A, epratuzumab was given alone for 4 doses twice weekly in an upfront window to assess safety and response, followed by AALL01P2 chemotherapy plus epratuzumab weekly during the first block of therapy. In part B, patients received the AALL01P2 3-block platform chemotherapy plus epratuzumab (360 mg/m²/dose) during block 1. Initially during part B, epratuzumab was administered weekly for 4 doses starting on day 1 based on pharmacokinetic (PK) data from adults with lymphoma. However, ADVL04P2 PK data showed that the half-life of epratuzumab was much shorter in children with ALL. Thus, ADVL04P2 was amended to give epratuzumab twice weekly for 8 doses, starting on day 1. This report focuses on ADVL04P2 part B and includes results of both the weekly (B1) and twice weekly (B2) epratuzumab dosing schedules. Between 1/07 and 1/11, 116 patients (114 eligible) were enrolled; 54 on B1 and 60 on B2, including 23 (B1) and 19 (B2) very early relapses. Median age at relapse was 10.2 years for the B1 cohort and 8.4 years for the B2 cohort. Concomitant extramedullary disease was present in 3 and 9 of the B1 and B2 patients, respectively. At the end of block 1, 48 B1 patients and 50 B2 patients were evaluable for response with CR2 achieved in (31/48) 65% of B1 and (33/50) 66% of B2 patients. Minimal residual disease (MRD) was measured by flow cytometry in a COG reference laboratory at the end of block 1. Among the 62 pooled B1 and B2 patients who achieved CR2 and had MRD data available at the end of block 1, 26 (42%) (14/31 B1 and 12/31 B2) were MRD negative (< 0.01%), which was significantly higher than the 25% with chemotherapy alone on AALL01P2 (one-sided p=0.001). The addition of epratuzumab to reinduction chemotherapy was well tolerated with no significant increase in the baseline toxicity observed with the platform regimen alone with either schedule. Toxic deaths occurred in 3 patients (2.6%) during block 1 in part B (2 in B1, 1 in B2), compared to 2.4% with block 1 chemotherapy alone. PK analyses in a cohort of B2 patients showed that the epratuzumab trough serum concentration steadily increased to 501 +/- 149 mcg/mL before the final dose on day 25 (n=26). The mean serum half-life of epratuzumab was 17.0 +/- 4.9 days (n=17) and was shorter than the value of 23 days observed in adults treated with epratuzumab for indolent non-Hodgkin lymphoma. No patient developed human anti-human antibodies. Epratuzumab, as given on the B1 and B2 schedules was tolerable in combination with chemotherapy in pediatric and young adult patients with early relapsed CD22-positive BCP ALL, but did not improve CR2 rates when compared to historical controls treated with chemotherapy alone. However, among patients who attained a complete remission, those treated with epratuzumab were significantly more likely to become MRD negative as compared to those treated without epratuzumab

Despite an increase in survival for children with acute lymphoblastic leukemia (ALL), the outcome after relapse is poor. To understand the genetic events that contribute to relapse and chemoresistance, and identify novel targets of therapy, three high-throughput assays were used to identify genetic and epigenetic changes at relapse. Using matched diagnosis/relapse bone marrow samples from children with relapsed B-precursor ALL we evaluated gene expression, copy number abnormalities (CNA), and DNA methylation. Gene expression analysis revealed a signature of differentially expressed genes from diagnosis to relapse, that is different for early (<36 months) and late (>/=36 months) relapse. CNA analysis discovered CNAs that were shared at diagnosis and relapse, and others that were new lesions acquired at relapse. DNA methylation analysis found increased promoter methylation at relapse. There were many genetic alterations that evolved from diagnosis to relapse, and in some cases these genes had previously been associated with chemoresistance. Integration of the results from all three platforms identified genes of potential interest including CDKN2A, COL6A2, PTPRO and CSMD1. While our results indicate that a diversity of genetic changes are seen at relapse, integration of gene expression, CNA and methylation data suggest a possible convergence on the WNT and MAPK pathways

High-risk (HR) acute lymphoblastic leukemia (ALL) remains one of the greatest challenges in pediatric oncology. Relapsed ALL is a leading cause of death in young people, and further improvements in outcome will required the development of therapeutic approaches directed against rational therapeutic targets, as escalation of the intensity of existing therapies is limited by toxicity. This review summarizes advances in the biology and treatment of HR and relapsed ALL presented at a symposium at the 2010 American Society for Pediatric Hematology and Oncology Annual Meeting. Analysis of large patient cohorts has identified several factors associated with HR of relapse including older age, T-lineage disease, and persisting minimal residual disease (MRD) early in therapy. As the results of salvage therapy remain poor, new treatment approaches are needed. BCR-ABL1-positive (Ph+) ALL has historically had a very poor outcome, but recent studies have demonstrated the impressive improvements in treatment outcome with the use of tyrosine kinase inhibitors (TKIs). High-resolution genomic profiling of genetic alterations and gene expression has revolutionized our understanding of the genetic basis of ALL, and has identified several alterations associated with poor outcome, including mutations of the lymphoid transcription factor gene IKZF1 (IKAROS), activating mutations of Janus kinases, and rearrangement of the lymphoid cytokine receptor gene CRLF2. These data indicated that the genetic basis of HR-ALL is multifactorial, and have also provided a new potential therapeutic option directed at JAK inhibition