Outcomes after late bone marrow and very early central nervous system relapse of childhood B-acute lymphoblastic leukemia: a report from the Children's Oncology Group phase III study AALL0433

Abstract

Hunger. Outcomes after late bone marrow and very early central nervous system relapse of childhood B-Acute lymphoblastic leukemia: a report from the Children's Oncology Group phase III study AALL0433.(404) 785-3635 -Office (404) 553-9802 -FAX Glen.lew@choa.org RUNNING HEADOutcomes for relapsed B-ALL from Children's Oncology Group study AALL0433 PREVIOUS PRESENTATIONSThese results were presented in part in abstract form at the following meetings: American ABSTRACT Outcomes after relapse of childhood B-acute lymphoblastic leukemia (B-ALL) are poor, and optimal therapy is unclear. Children's Oncology Group study AALL0433 evaluated a new platform for relapsed ALL. Between enrolled 275 participants with late bone marrow or very early isolated central nervous system (iCNS) relapse of childhood B-ALL. Patients were randomized to receive standard versus intensive vincristine dosing; this randomization closed due to excess peripheral neuropathy in 2010. Patients with matched sibling donors received allogeneic hematopoietic cell transplantation (HCT) after the first three blocks of therapy. The prognostic value of minimal residual disease (MRD) was also evaluated in this study.The 3-year event free and overall survival (EFS/OS) for the 271 eligible patients were 63.6% + 3.0% and 72.3% + 2.8% respectively. MRD at the end of Induction-1 was highly predictive of outcome, with 3-year EFS/OS of 84.9 + 4.0% and 93.8 + 2.7% for patients with MRD <0.1%, vs. 53.7 + 7.8% and 60.6 + 7.8% for patients with MRD ≥ 0.1% (p<0.0001). Patients who received HCT vs. chemotherapy alone had an improved 3-year disease-free survival (77.5 + 6.2% vs. 66.9 + 4.5%, p=0.03) but not OS (81.5 + 5.8% for HCT vs. 85.8 + 3.4% for chemotherapy, p=0.46). Patients with early iCNS relapse fared poorly, with a 3-year EFS/OS of 41.4% + 9.2% and 51.7% + 9.3%, respectively. Infectious toxicities of the chemotherapy platform were significant. The AALL0433 chemotherapy platform is efficacious for late bone marrow relapse of B-ALL, but with significant toxicities. The MRD threshold of 0.1% at the end of Induction-1 was highly predictive of outcome. The optimal role for HCT for this patient population remains uncertain. This trial is registered at clinicaltrials.gov (NCT# 00381680).

Chimeric Antigen Receptor T Cell Therapy in Patients with Multiply Relapsed or Refractory Extramedullary Leukemia

“…Two patients did subsequently relapse; however, those relapses were isolated to the CNS. Although our sample is very small, this finding is interesting, because historically the majority of treatment failures for patients with EM relapse is subsequent BM relapse [13,14]. Three of the patients had no BM disease at time of infusion, indicating that CAR-T can traffic to the CNS effectively without ligand binding and expansion driven by BM lymphoblasts, consistent with previous data seen in a small cohort of adults with CNS lymphoma [15].…”

“…Patients with late (>18 months) isolated EM relapses are often treated by with intensive chemotherapy and radiation, with a 4-to 5-year EFS of 60% to 77.7% [13,24]. Earlier isolated EM relapses have poorer outcomes, with consolidative HSCT in remission providing suboptimal responses [14,25,26]. For example, a large collaborative international study comparing patients who underwent matched sibling HSCT for an isolated CNS relapse with those treated with chemotherapy showed an increased risk of treatment-related mortality (22% in HSCT versus 9% in chemotherapy) with overall no significant difference in leukemia-free survival [27].…”

How I treat relapsed acute lymphoblastic leukemia in the pediatric population

“…Relapsed ALL therapies differ significantly between cooperative groups, but attain similar outcomes (Table 2). 10,11,[13][14][15][16] We would administer the United Kingdom (UKALL) R3 reinduction regimen (dexamethasone, vincristine, mitoxantrone, pegaspargase, and intrathecal methotrexate) 15 used in the recent COG AALL1331 first relapse B-ALL trial (NCT02101853) or another 4-drug reinduction regimen. Because infectious risk is high, 17,18 we would hospitalize her until count recovery and provide antibacterial, antifungal, and Pneumocystis jirovecii prophylaxis.…”

“…Using illustrative cases, we describe our approach to these challenges, which is informed by our experience with Children's Oncology Group (COG) trials. [8][9][10][11][12] Patient 1: first bone marrow relapse of B-ALL A 12-year-old girl diagnosed with B-ALL 2 years ago has an isolated marrow relapse during maintenance therapy. What reinduction should be used and what postinduction therapy is optimal?…”

Immunotherapy in Pediatric B-Cell Acute Lymphoblastic Leukemia: Advances and Ongoing Challenges

“…Ultimately, the most significant prognostic factors are blast immunophenotype and the timing and site of relapse. The COG approach to risk stratification at relapse is summarized in Table 2, and other cooperative groups follow similar algorithms [42][43][44][45].…”