ABSTRACT
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
Stem cell survival versus death is a developmentally programmed process essential for morphogenesis, sizing, and quality control of genome integrity and cell fates. Cell death is pervasive during development, but its programming is little known. Here, we report that Smad nuclear interacting protein 1 (SNIP1) promotes neural progenitor cell survival and neurogenesis and is, therefore, integral to brain development. The SNIP1-depleted brain exhibits dysplasia with robust induction of caspase 9-dependent apoptosis. Mechanistically, SNIP1 regulates target genes that promote cell survival and neurogenesis, and its activities are influenced by TGFß and NFκB signaling pathways. Further, SNIP1 facilitates the genomic occupancy of Polycomb complex PRC2 and instructs H3K27me3 turnover at target genes. Depletion of PRC2 is sufficient to reduce apoptosis and brain dysplasia and to partially restore genetic programs in the SNIP1-depleted brain in vivo. These findings suggest a loci-specific regulation of PRC2 and H3K27 marks to toggle cell survival and death in the developing brain.
Subject(s)
Intracellular Signaling Peptides and Proteins , RNA-Binding Proteins , Humans , Signal Transduction/physiology , NF-kappa B , Hyperplasia , BrainABSTRACT
Simultaneous multi-parametric acquisition and reconstruction techniques (SMART) are gaining attention for their potential to overcome some of cardiovascular magnetic resonance imaging's (CMR) clinical limitations. The major advantages of SMART lie within their ability to simultaneously capture multiple "features" such as cardiac motion, respiratory motion, T1/T2 relaxation. This review aims to summarize the overarching theory of SMART, describing key concepts that many of these techniques share to produce co-registered, high quality CMR images in less time and with less requirements for specialized personnel. Further, this review provides an overview of the recent developments in the field of SMART by describing how they work, the parameters they can acquire, their status of clinical testing and validation, and by providing examples for how their use can improve the current state of clinical CMR workflows. Many of the SMART are in early phases of development and testing, thus larger scale, controlled trials are needed to evaluate their use in clinical setting and with different cardiac pathologies.
