Subject(s)
Oncogene Proteins, Fusion , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma , Proto-Oncogene Proteins c-akt , Signal Transduction , Humans , Proto-Oncogene Proteins c-akt/metabolism , Proto-Oncogene Proteins c-akt/genetics , Oncogene Proteins, Fusion/genetics , Oncogene Proteins, Fusion/metabolism , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Class Ia Phosphatidylinositol 3-Kinase/metabolism , Class Ia Phosphatidylinositol 3-Kinase/genetics , Basic Helix-Loop-Helix Transcription Factors/genetics , Basic Helix-Loop-Helix Transcription Factors/metabolism , Child , Phosphatidylinositol 3-Kinases/metabolism , Phosphatidylinositol 3-Kinases/genetics , Male , Female , Child, PreschoolSubject(s)
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Child , Humans , Chromosomes, Human, Pair 21 , Chromosome Aberrations , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Prognosis , Risk Assessment , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/geneticsABSTRACT
PURPOSE: We tested whether blinatumomab (Blina) is effective as a toxicity-sparing alternative to first-line intensive chemotherapy in children and young persons (CYP) with B-ALL who were chemotherapy-intolerant or chemotherapy-resistant. METHODS: Data were collected for consecutive CYP (age 1-24 years) with Philadelphia chromosome-positive or Philadelphia chromosome-negative B-ALL who received Blina as first-line therapy. Blina was given as replacement for postremission intensive chemotherapy to patients with chemotherapy intolerance or resistance. Blina responders received further chemotherapy (Blin-CT) or first remission hematopoietic stem-cell transplant (Blin-HSCT) if indicated. Event-free survival (EFS) and overall survival (OS) of the Blin-CT group were compared with those of matched controls treated with standard chemotherapy in the UKALL 2003 trial. Events were defined as death, relapse, or secondary cancer. RESULTS: From February 2018 to February 2023, 105 patients were treated, of whom 85 were in the Blin-CT group and 20 were in the Blin-HSCT group. A majority of Blin-CT patients received Blina for chemotherapy intolerance (70 of 85, 82%), and the group had a higher-risk profile than unselected patients with B-ALL. Blina was well tolerated with only one patient having a grade 3/4-related toxicity event, and of the 60 patients who were minimal residual disease-positive pre-Blina, 58 of 60 (97%) responded. At a median follow-up of 22 months, the 2-year outcomes of the 80 matched Blin-CT group patients were similar to those of 192 controls (EFS, 95% [95% CI, 85 to 98] v 90% [95% CI, 65 to 93] and OS, 97% [95% CI, 86 to 99] v 94% [95% CI, 89 to 96]). Of the 20 in the HSCT group, three died because of transplant complications and two relapsed. CONCLUSION: Blina is safe and effective in first-line treatment of chemotherapy-intolerant CYP with ALL.
Subject(s)
Antibodies, Bispecific , Hematopoietic Stem Cell Transplantation , Leukemia, Myeloid, Acute , Child , Humans , Infant , Child, Preschool , Adolescent , Young Adult , Adult , Philadelphia Chromosome , Neoplasm Recurrence, Local/drug therapy , Antibodies, Bispecific/adverse effects , Leukemia, Myeloid, Acute/drug therapyABSTRACT
This phase 1 study investigated the recommended phase 2 dose (RP2D) of inotuzumab ozogamicin (InO), a CD22-directed antibody-drug conjugate, in pediatric patients with multiple relapsed/refractory (R/R) CD22+ acute lymphoblastic leukemia (ALL). Patients (age ≥1 year or <18 years) received 3 doses of InO (days 1, 8, and 15) per course. Dose escalation was based on dose-limiting toxicities (DLTs) during course 1. Dose level 1 (DL1) was 1.4 mg/m2 (0.6, 0.4, 0.4 mg/m2) and DL2 was 1.8 mg/m2 (0.8, 0.5, 0.5 mg/m2). Secondary end points included safety, antileukemic activity, and pharmacokinetics. Twenty-five patients (23 evaluable for DLTs) were enrolled. In course 1, the first cohort had 1 of 6 (DL1) and 2 of 5 (DL2) patients who 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, in which 0 of 6 (DL1) and 1 of 6 (DL2) patients had a DLT. Twenty-three patients experienced grade 3 to 4 adverse events; hepatic sinusoidal obstruction syndrome was reported in 2 patients after subsequent chemotherapy. Overall response rate after course 1 was 80% (95% confidence interval [CI], 59% to 93%) (20 of 25 patients; DL1: 75% [95% CI, 43% to 95%], DL2: 85% [95% CI, 55% to 98%]). Of the responders, 84% (95% CI, 60% to 97%) achieved minimal residual disease (MRD)-negative complete response, and 12-month overall survival was 40% (95% CI, 25% to 66%). Nine patients received hematopoietic stem cell transplantation or chimeric antigen receptor T cells after InO. InO median maximum concentrations were comparable to simulated adult concentrations. InO was well tolerated, demonstrating antileukemic activity in heavily pretreated children with CD22+ R/R ALL. RP2D was established as 1.8 mg/m2 per course, as in adults. This trial was registered at https://www.clinicaltrialsregister.eu as EUDRA-CT 2016-000227-71.
Subject(s)
Antineoplastic Agents, Immunological/therapeutic use , Inotuzumab Ozogamicin/therapeutic use , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Antineoplastic Agents, Immunological/adverse effects , Child , Child, Preschool , Female , Humans , Infant , Inotuzumab Ozogamicin/adverse effects , Male , Neoplasm Recurrence, Local/drug therapy , Treatment OutcomeABSTRACT
Patients diagnosed with Anaplastic Large Cell Lymphoma (ALCL) are still treated with toxic multi-agent chemotherapy and as many as 25-50% of patients relapse. To understand disease pathology and to uncover novel targets for therapy, Whole-Exome Sequencing (WES) of Anaplastic Lymphoma Kinase (ALK)+ ALCL was performed as well as Gene-Set Enrichment Analysis. This revealed that the T-cell receptor (TCR) and Notch pathways were the most enriched in mutations. In particular, variant T349P of NOTCH1, which confers a growth advantage to cells in which it is expressed, was detected in 12% of ALK+ and ALK- ALCL patient samples. Furthermore, we demonstrate that NPM-ALK promotes NOTCH1 expression through binding of STAT3 upstream of NOTCH1. Moreover, inhibition of NOTCH1 with γ-secretase inhibitors (GSIs) or silencing by shRNA leads to apoptosis; co-treatment in vitro with the ALK inhibitor Crizotinib led to additive/synergistic anti-tumour activity suggesting this may be an appropriate combination therapy for future use in the circumvention of ALK inhibitor resistance. Indeed, Crizotinib-resistant and sensitive ALCL were equally sensitive to GSIs. In conclusion, we show a variant in the extracellular domain of NOTCH1 that provides a growth advantage to cells and confirm the suitability of the Notch pathway as a second-line druggable target in ALK+ ALCL.
Subject(s)
Lymphoma, Large-Cell, Anaplastic , Cell Line, Tumor , Humans , Lymphoma, Large-Cell, Anaplastic/drug therapy , Lymphoma, Large-Cell, Anaplastic/genetics , Mutation , Neoplasm Recurrence, Local , Protein-Tyrosine Kinases/genetics , Receptor Protein-Tyrosine Kinases/genetics , Receptor, Notch1/genetics , Exome SequencingABSTRACT
BACKGROUND: Acute megakaryoblastic leukaemia (AMKL) is a subtype of myeloid leukaemia and is the most common leukaemia type in children with Down syndrome (DS) under 4 years of age. AMKL is often preceded by a transient neonatal pre-leukaemic syndrome, transient myeloproliferative disorder (TMD). Although TMD often spontaneously resolves, 20-30% of these patients subsequently develop AMKL within the first 4 years of life. AIMS: To perform a retrospective consecutive national audit of all documented cases of childhood TMD and AMKL-DS from 1990 to 2018 at Our Lady's Children's Hospital, Crumlin (OLCHC), Ireland. METHODS: All patients with a diagnosis of AMKL treated consecutively at (OLCHC) between 1990 and 2018 were reviewed. Kaplan-Meier survival curves were constructed. RESULTS: Twenty-seven patients with AMKL-DS were identified. A prior neonatal diagnosis of TMD was described in 10 patients (37%). Nineteen patients (70%) are alive and well, in complete remission, at a median follow-up of 11.4 years. Overall survival (OS) of this cohort has risen from 54% from those treated between the years 1990 and 2004 (n = 13) to 93% for those treated between the years 2005 and 2018 (n = 14). CONCLUSION: High cure rates are observed in AMKL-DS using current polychemotherapy protocols. The finding of a low platelet count at time of diagnosis is in keeping with the knowledge that AMKL-DS is a malignancy of platelet progenitor cells.
Subject(s)
Down Syndrome/complications , Leukemia, Myeloid/etiology , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Ireland , Male , Retrospective StudiesSubject(s)
Antibodies, Bispecific/therapeutic use , Antineoplastic Agents/therapeutic use , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Child, Preschool , Female , Follow-Up Studies , Humans , Infant , Infant, Newborn , Male , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Prognosis , Retrospective Studies , Survival RateABSTRACT
A 14-year-old boy with relapsed T cell acute lymphoblastic leukaemia received reinduction chemotherapy that included nelarabine, a purine nucleoside analogue known to cause dose-dependent neurotoxicity. Although he achieved aminimal residual disease negative remission after two cycles of chemotherapy he also developed severe, progressive peripheral and central neurotoxicities. Loss of grey-white differentiation was seen on a T2-weighted magnetic resonance imaging brain scan. This unusual clinical picture and previously unreported radiological findings are thought to be due to nelarabine toxicity. He was bridged with 6-mercaptopurine while transplant was deferred pending sustainable neurological improvement. This case posed clinical and ethical dilemmas while demonstrating previously unreported radiological features.