ABSTRACT
Ponatinib is associated with cardiovascular adverse events (CAEs), and its frequency in the real world is limited. In this retrospective study, we examined the survival outcomes and associated toxicities in 78 consecutive ponatinib-treated patients with chronic myeloid leukemia (CML) at the Moffitt Cancer Center from January 2011 through December 2017. The most common non-CAE was thrombocytopenia (39.7%), occurring in a dose-dependent fashion. Eighteen patients (23.1%) experienced some form of CAE, with the most common being arrhythmia (9%) and hypertension (7.7%), whereas 3 patients experienced myocardial infarction (3.8%). Before 2014, most patients were started on ponatinib 45 mg daily. There was an inverse correlation between cardio-oncology referral and the number of CAEs (P = .0440); however, a lower ponatinib starting dose, more frequent dose reduction, and increased cardio-oncology referral all were likely to have contributed to the observed decrease in CAEs after 2014. The response rate and 5-year overall survival (OS) were higher than those observed in the Ponatinib Ph+ ALL and CML Evaluation (PACE) trial (major molecular response, 58.7% vs 40% and OS, 76% vs 73%; median follow-up of 32.5 months). Ponatinib-treated patients with chronic phase-CML did not show a significant improvement with allogeneic stem cell transplantation, whereas those with accelerated phase/blast phase-CML had a much better outcome (median OS of 32.9 months vs 9.2 months; P = .01). These results demonstrate that ponatinib is highly effective. Dose adjustments and increased awareness of the cardiotoxicities associated with ponatinib may help maximize its benefits.
Subject(s)
Antineoplastic Agents , Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Pyridazines , Antineoplastic Agents/adverse effects , Humans , Imidazoles , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Pyridazines/adverse effects , Retrospective StudiesSubject(s)
Nervous System Diseases/etiology , Scleromyxedema/complications , Biopsy , Female , Hematopoietic Stem Cell Transplantation , Humans , Middle Aged , Nervous System Diseases/diagnosis , Nervous System Diseases/drug therapy , Scleromyxedema/diagnosis , Scleromyxedema/therapy , Skin/pathology , Steroids/therapeutic use , Transplantation, Autologous , Treatment OutcomeABSTRACT
OBJECTIVES/HYPOTHESIS: The potential utility of direct injection of bioactive substances in the treatment of vocal fold tissue fibrosis is limited by rapid clearance from the injection site. The objective of this study is to evaluate the potential of a lipid-based microtube delivery system to preserve the biological activity of injected substances and prolong their duration of pharmacological effects in the larynx. STUDY DESIGN: Prospective in vitro and case-control in vivo murine study METHODS: Lipid-based microtubes were loaded with Texas red-dextran (MT-TR) and hepatocyte growth factor (MT-HGF). In vitro and in vivo (using a murine vocal fold injection model) release of MT-TR and MT-HGF were determined to assess duration of microtube-mediated delivery. The biologic effects of MT-HGF on fibroblasts were assessed after treatment in the presence of transforming growth factor (TGF)-ß. RESULTS: In vitro release kinetics demonstrated slow release of MT-TR and MT-HGF, correlating with in vivo results demonstrating persistence of MT-HGF at 4 weeks postinjection. Bioefficacy was maintained, as MT-HGF was shown to inhibit TGF-ß-mediated induction of procollagen mRNA levels in vitro 24 hours after treatment in fibroblast cells. Sustained release of HGF from microtubes at 6 days exacerbated the effects of TGF-ß and increased levels of procollagen mRNA. CONCLUSIONS: Microtubes have significant potential utility as an efficacious means of sustained-release delivery of bioactive agents to the larynx. Atthough the role of HGF as an antifibrotic agent is questioned, its sustained bioefficacy after microtube encapsulation distinguishes microtubes from other delivery vehicles.
Subject(s)
Drug Delivery Systems/methods , Microtubules , Animals , Fibrosis , Fluorescent Dyes , Hepatocyte Growth Factor , Larynx/drug effects , Mice , Mice, Inbred C57BL , Nanocapsules , Prospective Studies , Vocal Cords/pathology , XanthenesABSTRACT
OBJECTIVES/HYPOTHESIS: There is a need for a slow-release system for local delivery of therapeutics to the larynx. Most therapeutic substances, such as steroids or chemotherapeutic agents that are injected into the larynx are cleared rapidly. Repeated laryngeal injection of these substances at short intervals is impractical. Injectable encapsulated poly(lactide-co-glycolide) (PLGA) nanoparticles offer a potential slow-release delivery system for biologically active substances in the larynx. STUDY DESIGN: Controlled animal study. METHODS: PLGA nanoparticles were fabricated using a double emulsion method and were loaded with Texas Red-dextran (NPTR), hepatocyte growth factor (NPHGF), and bovine serum albumin (NPBSA). In vitro release of NPTR, NPBSA, and NPHGF was determined over approximately 2 weeks to assess potential duration of PLGA nanoparticle delivery. In vivo release of NPTR was assessed in a murine vocal fold injection model. The transcriptional effect of NPHGF on procollagen was measured in vitro to assess whether released growth factor retained functionality. RESULTS: In vitro release kinetics demonstrated slow release of NPTR, NPBSA, and NPHGF over 12 to 14 days. In vitro NPTR release correlated with in vivo results. In vivo presence of NPTR occurred up to 7 days compared to 1 day for Texas Red control. In addition, NPHGF ameliorated transforming growth factor-beta induced procollagen in vitro in 3T3 fibroblast cells. CONCLUSIONS: The results demonstrate the potential utility of nanoparticle encapsulation as an effective method for long-term delivery of specific drugs and biologically active substances to the larynx.