Upfront use of gemtuzumab ozogamicin in young children with CD33‐positive AML

Gemtuzumab ozogamicin (GO) is a humanized anti‐CD33 antibody used for treating patients with CD33+ acute myeloid leukemia (AML). We report three young children (two infants and one toddler) with AML treated with GO 9 mg/m². Two received two doses at diagnosis alone with conventional chemotherapy and one received one dose after relapse. GO was well tolerated and all three achieved remission. All were transplanted: one relapsed after 5 months and died of disease, one died a toxic death in remission due to pulmonary fibrosis, and one survived (41 months from diagnosis). In conclusion, GO was well tolerated in these young patients with evidence for efficacy. Pediatr Blood Cancer 2010;55:183–185. © 2010 Wiley‐Liss, Inc.     

Myeloid lineage switch following chimeric antigen receptor T‐cell therapy in a patient with TCF3‐ZNF384 fusion‐positive B‐lymphoblastic leukemia

A pediatric patient diagnosed initially with B‐lymphoblastic leukemia (B‐ALL) relapsed with lineage switch to acute myeloid leukemia (AML) after chimeric antigen receptor T‐cell (CAR‐T) therapy and hematopoietic stem cell transplant. A TCF3‐ZNF384 fusion was identified at diagnosis, persisted through B‐ALL relapse, and was also present in the AML relapse cell population. ZNF384‐rearrangements define a molecular subtype of B‐ALL characterized by a pro‐B‐cell immunophenotype; furthermore, ZNF384‐rearrangements are prevalent in mixed‐phenotype acute leukemias. Lineage switch following CAR‐T therapy has been described in patients with KMT2A (mixed lineage leukemia) rearrangements, but not previously in any patient with ZNF384 fusion.     

Glucocorticoid‐Induced Proliferation in Untreated Pediatric Acute Myeloid Leukemic Blasts

We evaluated the in vitro glucocorticoid (GC) responsiveness of 117 pediatric acute myeloid leukemia cells by considering GC resistance, GC‐induced proliferation, and GC‐induced differentiation. None of the samples was highly GC sensitive, and only 15% were intermediately sensitive. GC‐induced differentiation was not observed, while GC‐induced proliferation was observed in 27% of the samples. Samples with French‐American‐British classification (FAB) type M5 or activating Fms‐like tyrosine kinase 3 (FLT3) mutations were significantly more prone to this phenomenon. Although we could not confirm this in our study, if induced proliferation in vitro is paralleled in vivo, GCs during consolidation may have adverse effects on minimal residual leukemic cells, which might increase relapse risk.     

Early mixed T‐cell chimerism is predictive of pediatric AML or MDS relapse after hematopoietic stem cell transplant

Patients with acute myeloid leukemia (AML) who relapse after hematopoietic stem cell transplantation (HCT) have dismal outcomes. Our ability to predict those at risk for relapse is limited. We examined chimerism trends post‐HCT in 63 children who underwent HCT for AML or myelodysplastic syndrome (MDS). Mixed T‐cell chimerism at engraftment and absence of chronic graft versus host disease (cGVHD) were associated with relapse (P = 0.04 and P = 0.02, respectively). Mixed T‐cell chimerism at engraftment was predictive in patients without cGVHD (P = 0.03). Patients with engraftment mixed T‐cell chimerism may warrant closer disease monitoring and consideration for early intervention.     

Retrospective analysis of children with high‐risk acute myeloid leukemia who underwent allogeneic hematopoietic stem cell transplantation following complete remission with initial induction chemotherapy in the AML‐05 clinical trial

In the AML‐05 clinical trial conducted by the Japanese Pediatric Leukemia/Lymphoma Group from 2006 to 2010, children with high‐risk acute myeloid leukemia (HR AML) received allogeneic hematopoietic stem cell transplantation (allo‐HSCT) at first complete remission (CR1). The aim of this study was to investigate the impact of allo‐HSCT on the outcome of HR AML. Patients with either monosomy 7, 5q?, t(16;21), Ph1, FLT3‐ITD, or induction failure after the first course of chemotherapy were eligible for transplant. Of 53 children with HR AML, 51 received allo‐HSCT—45 in CR1, five in CR2, and one with non‐CR. t(8;21), t(9;11), and t(16;21) abnormalities were identified in eight, five, and four patients, respectively. The stem cell sources varied—bone marrow in 30 patients, peripheral blood in three, and cord blood in 18. The median follow‐up was 62 months. The overall survival (OS) rates at 3 years were 73% and 25% for patients who received transplant at CR1 and ≥CR2, respectively. Multivariable analysis showed that patients with chronic graft‐versus‐host disease (cGVHD) had better OS. This study supports that allo‐HSCT is a suitable treatment for HR AML in CR1. The favorable outcome associated with cGVHD indicates that a graft‐versus‐leukemia effect might be occurring.     

An overview of the potential strategies for NK cell‐based immunotherapy for acute myeloid leukemia

Patients with acute myeloid leukemia (AML) have relatively low survival rates compared to patients with other pediatric cancers. Relapse is frequent with conventional treatment and is a major cause of morbidity and mortality. Natural killer (NK) cells offer an alternative approach to chemotherapy that combats relapse by substantially eradicating AML blasts. New methods for enhancing NK cell activation and expression of the activating ligand on target malignant cells will increase the likelihood of success with this approach. We review these latest discoveries in NK cell‐based therapy for AML and delineate recent advances in sensitizing AML cells to NK cell‐mediated immunosurveillance.