Patients with blastic plasmacytoid dendritic-cell neoplasm, an aggressive hematologic cancer, were treated with the cytotoxin tagraxofusp in a dose-escalation case series. Previously untreated ...patients had a 72% complete response rate, and 45% underwent stem-cell transplantation. Toxic effects included hepatic dysfunction, thrombocytopenia, and capillary leak syndrome.
Acquired thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are appropriately at the top of a clinician's differential when a patient presents with a clinical picture ...consistent with an acute thrombotic microangiopathy (TMA). However, there are several additional diagnoses that should be considered in patients presenting with an acute TMA, especially in patients with nondeficient ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity (>10%). An increased awareness of drug-induced TMA is also essential because the key to their diagnosis more often is an appropriately detailed medical history to inquire about potential exposures. Widespread inflammation and endothelial damage are central in the pathogenesis of the TMA, with the treatment directed at the underlying disease if possible. TMA presentations in the critically ill, drug-induced TMA, cancer-associated TMA, and hematopoietic transplant–associated TMA (TA-TMA) and their specific treatment, where applicable, will be discussed in this manuscript. A complete assessment of all the potential etiologies for the TMA findings including acquired TTP will allow for a more accurate diagnosis and prevent prolonged or inappropriate treatment with plasma exchange therapy when it is less likely to be successful.
Acute myelogenous leukemia (AML) is primarily a disease of the elderly, and as such, our approach to treatment needs to be tailored to address an aging population. Allogeneic hematopoietic stem cell ...transplantation (allo-HSCT) remains the only potentially curative treatment for intermediate and high risk AML, and until recently, its use had been limited to a younger population and dependent on availability of a donor. Advances in conditioning regimens, supportive care, and the use of alternative donor sources have greatly expanded access to this therapy. In this review, we summarize the challenges and unique biological aspects of treatment with allogeneic stem cell transplantation in this group of patients older than 60 years. We also highlight areas of ongoing research including measurement of residual disease prior to and following transplant, post-remission maintenance therapy, and natural killer cell immunotherapy. Finally, we propose future directions for AML treatment in an elderly and aging population.
Transplant-associated thrombotic microangiopathy (TA-TMA) is an increasingly recognized complication of allogeneic and autologous hematopoietic cellular therapy (HCT), associated with significant ...morbidity and mortality. Although the central drivers of the disease are thought to be endothelial damage and complement activation, no specific diagnostic biomarkers have been identified. TA-TMA is typically diagnosed using criteria comprised of non-specific clinical and laboratory features. Some patients will have a self-remitting course, but more than half develop multi-organ dysfunction or die, making prognostic biomarkers critical. Prevention of TA-TMA, an approach central to other HCT complications such as graft-versus-host disease, is largely untested in part due to a lack of identified early high-risk biomarkers. We conducted a systematic review to summarize the diagnostic, early risk, and prognostic biomarkers of TA-TMA. We screened the titles and abstracts of 1524 citations. After screening out duplications, we read the abstracts of 979 papers and fully reviewed 132 full-text publications. Thirty-one publications fulfilled the inclusion criteria of more than five patients with TA-TMA and a reported measure of association with diagnosis, prognosis, or risk of later development of the disease. Fourteen studies (45%) were with adults, 12 (39%) were with children <18 years old, three included both children and adults, and two did not report age. There were 53 biomarker or biomarker signature entries, and a total of 27 unique biomarkers. Only four biomarkers reported sensitivity and specificity. The single biomarker with the most robust data was sC5b-9, which conferred diagnostic, prognostic, and risk implications. Studies of combinations of biomarkers were rare. No meta-analyses were performed because of significant heterogeneity between studies. The limitations of studies included small sample size, study designs with a high risk of bias (i.e., case-control), the timing of sample collection, and the selection of controls. Furthermore, only two (6%) studies included a training and validation cohort. Cut-off points are needed to stratify groups, as most biomarkers do not have normal values, or normal values cannot be assumed in the HCT setting. In the future, multi-institutional, collaborative efforts are needed to perform rigorously designed, prospective studies with serially enrolled patients, with samples collected at the time of TA-TMA diagnosis, careful selection of controls, and validation of selected biomarkers and cut-off points in a separate cohort.
Summary
Activating
FLT3
internal tandem duplication (
FLT3
-ITD) mutations in acute myeloid leukemia (AML) associate with inferior outcomes. We determined that pacritinib, a JAK2/FLT3 inhibitor, has ...in vitro activity against
FLT3
-ITD and tyrosine kinase domain (TKD) mutations. Therefore, we conducted a phase I study of pacritinib in combination with chemotherapy in AML patients with
FLT3
mutations to determine the pharmacokinetics and preliminary toxicity and clinical activity. Pacritinib was administered at a dose of 100 mg or 200 mg twice daily following a 3 + 3 dose-escalation in combination with cytarabine and daunorubicin (cohort A) or with decitabine induction (cohort B). A total of thirteen patients were enrolled (five in cohort A; eight in cohort B). Dose limiting toxicities include hemolytic anemia and grade 3 QTc prolongation in two patients who received 100 mg. Complete remission was achieved in two patients in cohort A, one of whom had a minor D835Y clone at baseline. One patient in cohort B achieved morphologic leukemia free state. Seven patients (two in cohort A; five in cohort B) had stable disease. In conclusion, pacritinib, an inhibitor of
FLT3-
ITD and resistant-conferring TKD mutations, was well tolerated and demonstrated preliminary anti-leukemic activity in combination with chemotherapy in patients with
FLT3
mutations.
TLRs, a family of membrane-bound pattern recognition receptors found on innate immune cells, have been well studied in the context of cancer therapy. Activation of these receptors has been shown to ...induce inflammatory anticancer events, including differentiation and apoptosis, across a wide variety of malignancies. In contrast, intracellular pattern recognition receptors such as NOD-like receptors have been minimally studied. NOD2 is a member of the NOD-like receptor family that initiates inflammatory signaling in response to the bacterial motif muramyl dipeptide. In this study, we examined the influence of NOD2 in human acute myeloid leukemia (AML) cells, demonstrating that IFN-γ treatment upregulated the expression of NOD2 signaling pathway members SLC15A3 and SLC15A4, downstream signaling kinase RIPK2, and the NOD2 receptor itself. This priming allowed for effective induction of caspase-1-dependent cell death upon treatment with muramyl tripeptide phosphatidylethanolamine (MTP-PE), a synthetic ligand for NOD2. Furthermore, the combination of MTP-PE and IFN-γ on AML blasts generated an inflammatory cytokine profile and activated NK cells. In a murine model of AML, dual treatment with MTP-PE and IFN-γ led to a significant increase in mature CD27
CD11b
NK cells as well as a significant reduction in disease burden and extended survival. These results suggest that NOD2 activation, primed by IFN-γ, may provide a novel therapeutic option for AML.
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