No abstract

Persisting clones in compartments other than bone marrow may not be covered by MRD quantification but could still be responsive to blinatumomab therapy. The responses detected in this TCF3-HLF-positive ALL cohort are encouraging and suggest that the application of immunotherapy prior to extensive clonal selection secondary to intensive chemotherapy may be beneficial. As data are updated, the true value of this approach can be assessed. The benefit of adding blinatumomab to frontline ALL chemotherapy will be addressed in an international prospective clinical trial (clinicaltrials.gov identifier: 03643276). Taken together, our results indicate that immunotherapy may improve the outcome of TCF3-HLF-positive ALL.

This Phase I study investigated the recommended Phase II dose (RP2D) of inotuzumab ozogamicin (InO), a CD22-directed antibody-drug conjugate, in pediatric patients with multiple-relapsed/refractory (R/R) CD22-positive acute lymphoblastic leukemia (ALL). Patients (≥1-<18 years) received three InO doses (Days 1, 8, 15) per course. Dose-escalation was based on dose-limiting toxicities (DLT) during Course 1 . Dose level 1 (DL1)=1.4 mg/m2 (0.6-0.4-0.4 mg/m2); DL2=1.8 mg/m2 (0.8-0.5-0.5 mg/m2). Secondary endpoints included safety, anti-leukemic activity, and pharmacokinetics. Twenty-five patients (23 evaluable for DLT) were enrolled. In Course 1, first cohort, 1/6 (DL1) and 2/5 (DL2) patients experienced DLTs; subsequent review considered DL2 DLTs to be non-dose-limiting. Dose was de-escalated to DL1 while awaiting protocol amendment to re-evaluate DL2 in a second cohort, where 0/6 (DL1) and 1/6 (DL2) patients had a DLT. Twenty-three patients experienced Grade 3-4 adverse events; hepatic sinusoidal obstruction syndrome was reported in two patients after subsequent chemotherapy. Overall response rate after Course 1 was 80% [95% CI: 59-93%] (20/25 patients; DL1=75% [43-95%], DL2=85% [55-98%]); 84% [60-97%] of responders obtained minimal residual disease-negative CR; 12-month overall survival was 40% [95% CI: 25-66%]. Nine patients received hematopoietic stem cell transplant or chimeric-antigen receptor T-cells after InO. InO median maximum concentrations were comparable to simulated adult concentrations. InO was well tolerated, demonstrating anti-leukemic activity in heavily pre-treated children with CD22-positive R/R ALL. RP2D was established as 1.8 mg/m2/course, as in adults.

Aim: Outcomes of children with high-risk (HR) relapsed acute lymphoblastic leukaemia (ALL) (N Z 393), recruited to ALLR3 and ALL-REZ BFM 2002 trials, were analysed. Minimal residual disease (MRD) was assessed after induction and at predetermined time points until haematopoietic stem cell transplantation (SCT). Methods: Genetic analyses included karyotype, copy-number alterations and mutation analyses. Ten-year survivals were analysed using Kaplan-Meier and Cox models for multivariable analyses. Results: Outcomes of patients were comparable in ALLR3 and ALL-REZ BFM 2002. The eventfree survival of B-cell precursor (BCP) and T-cell ALL (T-ALL) was 22.6% and 26.2% (P Z 0.94), respectively, and the overall survival (OS) was 32.6% and 28.2% (P Z 0.11), respectively. Induction failures (38%) were associated with deletions of NR3C1 (P Z 0.002) and BTG1 (P Z 0.03) in BCP-ALL. The disease-free survival (DFS) and OS in patients with good vs poor MRD responses were 57.4% vs 22.6% (P < 0.0001) and 57.8% vs 32.0% (P Z 0.0004), respectively. For BCP-and T-ALL, the post-SCT DFS and OS were 42.1% and 56.8% (P Z 0.26) and 51.6% and 55.4% (P Z 0.67), respectively. The cumulative incidences of post-SCT relapse for BCP-and T-ALL were 36.9% and 17.8% (P Z 0.012) and of death were 10.7% and 25.5% (P Z 0.013), respectively. Determinants of outcomes after SCT were acute graft versus host disease, pre-SCT MRD (!10 À3 ), HR cytogenetics and TP53 alterations in BCP-ALL. Conclusion: Improvements in outcomes for HR ALL relapses require novel compounds in induction therapy to improve remission rates and immune targeted therapy after induction to maintain remission after SCT.