Long-Term Follow-Up in Patients With Chronic Myeloid Leukemia Treated With Ponatinib in a Real-World Cohort: Safety and Efficacy Analysis.

BACKGROUND: Ponatinib is a third-generation tyrosine-kinase inhibitor (TKI), indicated in patients with chronic phase (CP), accelerated phase (AP), or blast phase (BP) chronic myeloid leukemia (CML), who are resistant or intolerant to ≥2 prior TKIs, patients for whom subsequent treatment with imatinib is not appropriate, and patients who have a T315I mutation. PATIENTS AND METHODS: We aimed to evaluate outcomes of ponatinib treatment, including safety, with focus on cardiovascular toxicity, in real-world patients from Argentina. Data from patients with CP CML treated with ponatinib was retrospectively retrieved from 2013 to 2023 in 7 centers. RESULTS: Seventy-two patients were included (median age: 44 years; male: 55.5%; T315I mutation: 32%: median treatment duration: 36 months. At baseline, 57 patients (79%) had a breakpoint cluster region-Abelson (BCR::ABL1) transcript level >10% on the international reporting scale (BCR::ABL1 IS). A molecular response (MR, BCR::ABL1 (IS) <1%) was achieved at 12 months in 51.6% of evaluable patients; 57% maintained MR at last follow-up. Overall, 43% and 25% maintained major MR (MMR) or deep MR (DMR) (MR4.0-MR5.0), respectively at last follow-up. Twelve (16.6%) ponatinib-resistant patients were rescued with allogeneic hematopoietic stem cell transplantation. The estimated 2-year progression-free survival (PFS) was 84%. Ponatinib dose was reduced during treatment in 22 patients; nevertheless, MMR was maintained in 50% of these patients. Severe arterial occlusive events (AOE) were reported in 10.9% of patients after a median treatment of 5 months. CONCLUSION: CV toxicity was consistent with clinical trials and other real-world registries. Older age, hypercholesterolemia and a SCORE risk >2% were significantly associated with higher risk of AOEs. Controlling CV risk factors and reducing doses at optimal time points may help to optimize ponatinib use in daily practice.

Expression dynamics of the immune mediators ARG1, TBET, CIITA, IL10 and TGFB1 in chronic myeloid leukaemia patients during the first year of imatinib therapy.

The use of tyrosine kinase inhibitors seems to restore the broadly compromised immune system described in chronic myeloid leukaemia (CML) patients at diagnosis leading to a re-activation of the effector-mediated immune surveillance. Here, we describe the expression dynamics of immune factors during the first year on imatinib therapy. Gene expression was evaluated in 132 peripheral blood samples from 79 CML patients, including 34 who were serially followed. An aliquot of the stored sample used to monitor BCR-ABL1 levels was retro-transcribed to cDNA and gene expression was quantified by real-time PCR. An elevated expression of ARG1 was observed at diagnosis, while TBET, CIITA, IL10 and TGFB1 were significantly decreased. Once on therapy, each gene displayed a particular behaviour. ARG1 normalized to control levels at 3 months only in optimal molecular responders and was identified as the major contributor to the difference among patients. TBET reached normal levels after 12 months in optimal responders and non-responders, regardless the Th1-response previously associated, and CIITA continued downregulated. IL10 and TGFB1 achieved normal levels early at 3 months in both groups, afterwards IL10 was sustained while TGFB1 was slightly increased after 1 year in responders. Our findings are in agreement with an immune re-activation after imatinib initiation; however, some immune mediators may require a longer exposition. The follow-up of novel and reliable biomarkers, such as ARG1, one of the principal mechanisms of myeloid-derived-suppressor cells to inhibit immune system, may be useful to deepen the characterization of early responder patients.

miRNome profiling of LSC-enriched CD34+CD38-CD26+ fraction in Ph+ CML-CP samples from Argentinean patients: a potential new pharmacogenomic tool.

Chronic myeloid leukemia (CML) is a myeloid stem cell neoplasm characterized by an expansion of myeloid progenitor cells and the presence of BCR-ABL1 oncoprotein. Since the introduction of specific BCR-ABL1 tyrosine kinase inhibitors (TKI), overall survival has improved significantly. However, under long-term therapy patients may have residual disease that originates from TKI-resistant leukemic stem cells (LSC). In this work, we analyzed the miRNome of LSC-enriched CD34+CD38-CD26+ and normal hematopoietic stem cells (HSC) fractions obtained from the same chronic phase (CP) CML patients, and stem and progenitor cells obtained from healthy donors (HD) by next-generation sequencing. We detected a global decrease of microRNA levels in LSC-enriched CD34+CD38-CD26+ and HSC fractions from CML-CP patients, and decreased levels of microRNAs and snoRNAs from a genomic cluster in chromosome 14, suggesting a mechanism of silencing of multiple non-coding RNAs. Surprisingly, HSC from CML-CP patients, despite the absence of BCR-ABL1 expression, showed an altered miRNome. We confirmed by RT-qPCR that the levels of miR-196a-5p were increased more than nine-fold in CD26+ (BCR-ABL1 + ) vs. CD26- (BCR-ABL1 -) CD34+CD38- fractions from CML-CP patients at diagnosis, and in silico analysis revealed a significant association to lipid metabolism and hematopoiesis functions. In the light of recent descriptions of increased oxidative metabolism in CML LSC-enriched fractions, these results serve as a guide for future functional studies that evaluate the role of microRNAs in this process. Metabolic vulnerabilities in LSCs open the road for new therapeutic strategies. This is the first report of the miRNome of CML-CP CD34+CD38- fractions that distinguishes between CD26+ (BCR-ABL1 + ) and their CD26- (BCR-ABL1 - ) counterparts, providing valuable data for future studies.

Population pharmacokinetics of amikacin in patients with pediatric cystic fibrosis.

INTRODUCTION: Amikacin is commonly used in patients with pediatric cystic fibrosis (CF) for the treatment of pulmonary exacerbations. Amikacin efficacy is related to maximum plasma concentration/minimum inhibitory concentration (Cmax/MIC) ratio >8. Pharmacokinetic data in patients with pediatric CF are scarce. The aim of this study was to develop a population pharmacokinetic (PopPK) model describing amikacin disposition in patients with pediatric CF. METHODS: CF patients under 18 years of age with pulmonary exacerbation who received amikacin were enrolled. Patients received different amikacin regimens (30 mg-1 kg-1 day-1 every 8, 12, or 24 hours) depending on the patient's status and hospital protocols. Amikacin serum levels were obtained for therapeutic drug monitoring. PopPK model was developed using MONOLIX Suite-2018R1 (Lixoft). RESULTS: A total of 39 patients (114 amikacin concentrations) were included in this study. Population estimates for the elimination rate constant (k) and the volume of distribution (V) were 0.541 hours-1 and 0.451 L/kg, respectively. Between-subject and between-occasion variability were 53% and 16.5% for k and 31% and 22% for V, respectively. Bodyweight was a significant covariate associated with V. Based on simulations, almost 70% of the patients receiving 30 mg-1 kg-1 day-1 every 24 hours would achieve a Cmax/MIC ratio >8 which is an appropriate therapeutic goal while no patient in the other two groups (Q8 and Q12) would achieve that objective. CONCLUSIONS: The regimen of 30 mg-1 kg-1 day-1 every 24 hours more adequately fulfilled the therapeutic target for amikacin. Although all our patients had good clinical results and a good adverse-events profile, further studies are necessary to redefine the optimal treatment strategy.

Genetic diversity of the HLA system in human populations from the Sierra (Andean), Oriente (Amazonian) and Costa (Coastal) regions of Ecuador.

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in a total of 1101 Ecuadorian individuals from three regions of the country, the Coastal region, the Andean region, and the Amazonian region, to obtain information regarding allelic and haplotypic frequencies and their linkage disequilibrium. We find that the most frequent HLA haplotypes with significant linkage disequilibrium in those populations are HLA-A*24∼B*35∼DRB1*04∼DQB1*03:02, A*02∼B*35∼DRB1*04∼DQB1*03:02, A*24∼B*35∼DRB1*14∼DQB1*03:01, A*02∼B*35∼DRB1*14∼DQB1*03:01 and A*02∼B*40:02∼DRB1*04∼DQB1*03:02. The only non-Native American haplotype with frequency >1% shared by all groups was A*29∼B*44∼DRB1*07∼DQB1*02. Admixture estimates obtained by a maximum likelihood method using HLA-B as genetic estimator revealed that the main genetic components for this sample of mixed-ancestry Ecuadorians are Native American (ranging from 52.86% to 63.83%) and European (from 28.95% to 46.54%), while an African genetic component was only apparent in the Coastal region (18.19%). Our findings provide a starting point for the study of population immunogenetics of Ecuadorian populations.

Evaluation of the primitive fraction by functional in vitro assays at the RNA and DNA level represents a novel tool for complementing molecular monitoring in chronic myeloid leukemia.

Quantification of BCR-ABL1 mRNA levels in peripheral blood of chronic myeloid leukemia patients is a strong indicator of response to tyrosine-kinase inhibitors (TKI) treatment. However, additional prognostic markers are needed in order to better classify patients. The hypothesis of leukemic stem cells (LSCs) heterogeneity and persistence, suggests that their functional evaluation could be of clinical interest. In this work, we assessed the primitive and progenitor fractions in patients at diagnosis and during TKI treatment using functional in vitro assays, defining a "functional leukemic burden" (FLB). We observed that the FLB was reduced in vivo in both fractions upon treatment. However, different FLB levels were observed among patients according to their response to treatment, suggesting that quantification of the FLB could complement early molecular monitoring. Given that FLB assessment is limited by BCR-ABL1 mRNA expression levels, we developed a novel detection method of primitive cells at the DNA level, using patient-specific primers and direct nested PCR in colonies obtained from functional in vitro assays. We believe that this method could be useful in the context of discontinuation trials, given that it is unknown whether the persistent leukemic clone represents LSCs, able to resume the leukemia upon TKI removal.

Experiencia de tratamiento de la leucemia de células vellosas con clorodeoxiadenosina y con interferón alfa 2 / Treatment's experience of hairy cell leukemia with chlorodeoxyadenosine and alpha 2 interferon

Cinco pacientes con Leucemia de Células Vellosas fueron tratados con clorodeoxiadenosina (4291-63-8), análogo de las purinas, resistente a la adenosin deaminasa, a dosis 0,1 mg/kg/día, siete días, endovenoso continuo. Todos presentaban infiltración de médula ósea, esplenomegalia y pancitopenia. Media de neutrófilos 0.5 x 10 9/L; de plaquetas 53.8 x 10 9/L, y de hemoglobina 7,52 g/dL. Todos lograron remisión completa, seguimiento de 9 a 33 meses; dos fallecieron a los nueve y dieciséis meses debido a otras causas. La recuperación plaquetaria precedió a la de neutrófilos y hemoglobina. El tiempo medio de recuperación de neutrófilos fue 41 días. Todos recibieron G-CSF a 5 microg./kg. Toxicidad: mielosupresión y fiebre. Promedio de transfusiones de GRD: 7 unidades y de plaquetas 5 procedimientos. Dos pacientes fueron tratados con interferón alfa 2 a 4.5 MU/día por medio, subcutáneo, por un año. Ambos obtuvieron remisión hematológica completa a los doce y trece meses de tratamiento. El nivel de hematocrito y hemoglobina se normalizó a los tres y cuatro meses de tratamiento; el recuento leucocitario a los cuatro y siete meses, y las plaquetas a los dos meses. Sólo un paciente requirió transfusión de GRD: cuatro unidades. Toxicidad: prurito generalizado, síndrome pseudogripal, náuseas y cefalea. Ambos persisten en remisión hematológica completa luego de veintisiete y cinco meses de finalizado el tratamiento. El interferón alfa y la clorodeoxiadenosina ofrece ventajas por la alta probabilidad de remisiones completas a corto plazo y durables en la evolución.

Experiencia de tratamiento de la leucemia de células vellosas con clorodeoxiadenosina y con interferón alfa 2 / Treatments experience of hairy cell leukemia with chlorodeoxyadenosine and alpha 2 interferon

Cinco pacientes con Leucemia de Células Vellosas fueron tratados con clorodeoxiadenosina (4291-63-8), análogo de las purinas, resistente a la adenosin deaminasa, a dosis 0,1 mg/kg/día, siete días, endovenoso continuo. Todos presentaban infiltración de médula ósea, esplenomegalia y pancitopenia. Media de neutrófilos 0.5 x 10 9/L; de plaquetas 53.8 x 10 9/L, y de hemoglobina 7,52 g/dL. Todos lograron remisión completa, seguimiento de 9 a 33 meses; dos fallecieron a los nueve y dieciséis meses debido a otras causas. La recuperación plaquetaria precedió a la de neutrófilos y hemoglobina. El tiempo medio de recuperación de neutrófilos fue 41 días. Todos recibieron G-CSF a 5 microg./kg. Toxicidad: mielosupresión y fiebre. Promedio de transfusiones de GRD: 7 unidades y de plaquetas 5 procedimientos. Dos pacientes fueron tratados con interferón alfa 2 a 4.5 MU/día por medio, subcutáneo, por un año. Ambos obtuvieron remisión hematológica completa a los doce y trece meses de tratamiento. El nivel de hematocrito y hemoglobina se normalizó a los tres y cuatro meses de tratamiento; el recuento leucocitario a los cuatro y siete meses, y las plaquetas a los dos meses. Sólo un paciente requirió transfusión de GRD: cuatro unidades. Toxicidad: prurito generalizado, síndrome pseudogripal, náuseas y cefalea. Ambos persisten en remisión hematológica completa luego de veintisiete y cinco meses de finalizado el tratamiento. El interferón alfa y la clorodeoxiadenosina ofrece ventajas por la alta probabilidad de remisiones completas a corto plazo y durables en la evolución. (AU)