Emerging FLT3 inhibitors for the treatment of acute myeloid leukemia.

INTRODUCTION: The FMS-like tyrosine kinase 3 (FLT3) gene is mutated in one-third of patients with Acute Myeloid Leukemia (AML). Midostaurin, quizartinib, and gilteritinib have been approved in the last years for the treatment of AML, and more Tyrosine Kinase Inhibitors (TKIs) targeting FLT3 are being developed such as crenolanib. AREAS COVERED: In this systematic review, we will analyze the available clinical data on FLT3 inhibitors in development and describe the potential role that these FLT3-TKIs may play in the future management of FLT3-mutated (FLT3mut) AML. EXPERT OPINION: Although several aspects may challenge the use of FLT3 inhibitors in AML (resistance mechanisms, on- and off-target toxicities or drug-drug interactions), these drugs are generally well tolerated, particularly if we compare their safety profile with classical chemotherapy agents or even with newer immunotherapies, thus enabling their use in fit and unfit AML patients, alone or combined. As AML is a polyclonal disease and FLT3 mutations are a late leukemogenic event, combinations of these FLT3 inhibitors with other antileukemic agents (like venetoclax or hypomethylating agents) seem a necessary research pathway.

Influence of polymorphisms in anthracyclines metabolism genes in the standard induction chemotherapy of acute myeloid leukemia.

OBJECTIVES: Genetic variability in anthracycline metabolism could modify the response and safety of acute myeloid leukemia (AML) induction. METHODS: Polymorphisms in genes that encodes enzymes of anthracyclines metabolic pathway (CBR3: rs1056892, rs8133052, NQO1: rs1800566, NQO2: rs1143684, NOS3: rs1799983, rs2070744) were evaluated in 225 adult de novo AML patients. RESULTS: The variant CBR3 rs8133052 was associated with lower hepatotoxicity (P = 0.028). Wild-type genotype of NQO2 rs1143684 was related to higher complete remission (P = 0.014), and the variant allele with greater gastrointestinal toxicity (P = 0.024). However, the variant genotype of NQO1 rs1800566 was associated with mucositis (P = 0.018), but heterozygous genotype showed less gastrointestinal toxicity (P = 0.028) and thrombocytopenia (P = 0.009). Protective effects against nephrotoxicity and thrombocytopenia were reported with variant NOS3 rs1799983 (P = 0.006, P = 0.014), whereas carriers of NOS3 rs2070744 showed higher hepatotoxicity and thrombocytopenia (P = 0.017, P = 0.013). CONCLUSIONS: This study supports the influence of genetic variability of idarubicin metabolizing could be critical in predicting anthracycline-induced toxicities.

Healthcare resource utilization in adult patients with relapsed/refractory FLT3 mutated acute myeloid leukemia: A retrospective chart review from Spain.

BACKGROUND: Information regarding impact on healthcare systems of relapsed or refractory (R/R) FLT3 mutated (FLT3mut) acute myeloid leukemia (AML) is scarce. OBJECTIVE: To assess the time and reimbursement associated with hospitalizations of patients with R/R FLT3mut AML in a tertiary Spanish hospital. METHODS: Retrospective review of medical charts identified patients aged ≥ 18 years with R/R FLT3mut AML between 1998 and 2018. Data were collected from the date of first diagnosis of R/R FLT3mut AML (index) until death or loss to follow-up. The primary end point was duration and frequency of hospitalization, use of outpatient resources and transfusion burden. Reimbursement associated with hospitalizations (including associated chemotherapy) was also assessed. RESULTS: Thirty-eight patients were eligible for inclusion. Their median age was 52 years, and 30 (79%) received intensive salvage chemotherapy; FLAG-IDA-based regimens were the most frequent (24 patients, 63%). Overall, there were 150 hospitalizations (mean 3.9/patient; mean duration 21 days). Patients spent a mean of 24% of the study period in hospital. Total mean reimbursement was €108 293 per patient; the majority (€89 834) attributable to inpatient stays (€22 576 /hospitalization). During chemotherapy period (prior to first alloHSCT), there were 73 hospitalizations (mean duration 22 days); mean reimbursement was €19 776 per hospitalization and €49 819 per patient. AlloHSCT (n = 16) involved 77 hospitalizations (mean duration 21 days), mean reimbursement €25 231/hospitalization and €131 515 per patient. CONCLUSION: Data from this study suggest that there is a substantial healthcare resource utilization and cost burden on R/R FLT3mut AML patients in Spain receiving active treatments.

Gilteritinib use in the treatment of relapsed or refractory acute myeloid leukemia with a FLT3 mutation.

The prognosis of patients with relapsed or refractory acute myeloid leukemia (R/R AML) is dismal with salvage standard approaches, and mutations of FMS-like tyrosine kinase 3 (FLT3) gene, occurring in around 30% of AML patients may confer even poorer outcomes. Several targeted tyrosine kinase inhibitors have been developed to improve FLT3-mutated AML patient´s survival. Gilteritinib, a highly specific second-generation class I oral FLT3 inhibitor, has demonstrated superiority to salvage chemotherapy (SC) in R/R FLT3 mutated AML based on significantly longer OS in the gilteritinib arm than in the SC arm. Gilteritinib is generally well tolerated, but some clinically relevant adverse events should be monitored, especially myelosuppression, QTc prolongation and differentiation syndrome, usually manageable (dose reductions, interruption or discontinuation) and reversible. We discuss clinical development, efficacy, safety and mechanisms of resistance of gilteritinib in the treatment of R/R patients with FLT3 mutated AML.

Extracorporeal photopheresis vs standard therapies for steroid-refractory chronic graft-vs-host disease: Pharmacoeconomic assessment of hospital resource use in Spain.

BACKGROUND: This study assessed pharmacoeconomic costs associated with extracorporeal photopheresis (ECP) compared with other available second-line therapies for chronic graft-vs-host disease (cGvHD) in a tertiary Spanish institution. METHODS: Patients (≥18 years) diagnosed with steroid-refractory cGvHD were eligible. Data were collected retrospectively from index date until 1 year or relapse. Patients were distributed in two cohorts (ECP vs non-ECP), matched by age (≤ or > 40), hematopoietic stem cell transplant (HLA-identical sibling donor or other) and number of previous immunosuppressive lines (1, 2, or ≥ 3). Costs were assigned using the 2016 diagnosis-related group (DRG) system: DRG 579 (€22 383) overnight stay due to major complication (ie, sepsis, pneumonia, parenteral nutrition, or respiratory failure), and DRG 875 (€5154) if no major complication. The primary endpoint was healthcare resource utilization per patient. RESULTS: Forty patients (n = 20 per cohort) were included. Median age was 49, and 37.5% were female. Mean total cost per patient was €25 319 (95% CI: €17 049-€33 590) across the two cohorts, with a slightly lower mean cost per ECP-treated patient (€23 120) compared with the non-ECP cohort (€27 519; P = .597). Twenty-seven inpatient hospitalizations occurred among ECP-treated patients, vs 33 in the non-ECP cohort. Day hospital and external consultations were more frequent in the ECP cohort. However, fewer inpatient admissions included DRG 579 compared with the non-ECP cohort (44% vs 58%). Inpatient length of stay was slightly shorter in the ECP cohort (30 vs 49 days; P = .298). CONCLUSIONS: ECP treatment may yield economic savings in Spain through resource savings and moving costs toward outpatient care.

Adherence and adverse events of intraperitoneal chemotherapy in optimally debulked ovarian cancer patients: Real-life study.

PURPOSE: Intraperitoneal with intravenous chemotherapy (IP/IV) is the recommended option for patients with stage III cancer with optimally debulked (<1 cm residual) disease based on randomized controlled trials and showing important improvements in overall survival and progression free survival. However, its application has not been largely adopted due to its difficult administration that requires a trained nurse staff. The aim of this work was to study the completion and the toxicity of an IP outpatient chemotherapy regimen in optimally debulked stage III ovarian cancer patients. METHODS: A single-center, retrospective observational study in women with stage III ovarian cancer following optimal cytoreductive surgery (<1 cm) followed by IP/IV chemotherapy from 2009 to 2017. The IP/IV regimen was as it follows: IV paclitaxel 175 mg/m2 in 3 h, day 1; IP cisplatin (100 mg/m2-until December 2013-or 75 mg/m2), day 2; IP paclitaxel 60 mg/m2, day 8, each 21 days for six cycles. RESULTS: A total of 60 patients received IP/IV regimen. Of these, 41 patients (68.3%) completed the six IP chemotherapy cycles and 51 (84.9%) completed four or more cycles. Most of the adverse events reported were non-hematological and G1-2. There was no difference neither in adherence nor in the frequency of adverse events between both cisplatin groups. Despite a high rate of adverse events, IP chemotherapy can be delivered with a high completion rate and manageable toxicity to patients with optimally debulked ovarian cancer.

Drug-drug interactions of newly approved small molecule inhibitors for acute myeloid leukemia.

Several small molecule inhibitors (SMIs) have been recently approved for AML patients. These targeted therapies could be more tolerable than classical antineoplastics, but potential drug-drug interactions (DDI) are relatively frequent. Underestimation or lack of appropriate awareness and management of DDIs with SMIs can jeopardize therapeutic success in AML patients, which often require multiple concomitant medications in the context of prior comorbidities or for the prevention and treatment of infectious and other complications. In this systematic review, we analyze DDIs of glasdegib, venetoclax, midostaurin, quizartinib, gilteritinib, enasidenib, and ivosidenib. CYP3A4 is the main enzyme responsible for SMIs metabolism, and strong CYP3A4 inhibitors, such azoles, could increase drug exposure and toxicity; therefore dose adjustments (venetoclax, quizartinib, and ivosidenib) or alternative therapies or close monitoring (glasdegib, midostaurin, and gilteritinib) are recommended. Besides, coadministration of strong CYP3A4 inducers with SMIs should be avoided due to potential decrease of efficacy. Regarding tolerability, QTc prolongation is frequently observed for most of approved SMIs, and drugs with a potential to prolong the QTc interval and CYP3A4 inhibitors should be avoided and replaced by alternative treatments. In this study, we critically assess the DDIs of SMIs, and we summarize best management options for these new drugs and concomitant medications.

Drug-drug interactions associated with FLT3 inhibitors for acute myeloblastic leukemia: current landscape.

INTRODUCTION: FLT3 inhibitors (FLT3i) are drugs in which there is limited experience and not yet enough information on the mechanisms of absorption, transport, and elimination; but especially on the potential drug-drug interactions (DDIs). There are therefore risks in the management of FLT3i DDIs (i.e. sorafenib, ponatinib, crenolanib, midostaurin, quizartinib, and gilteritinib) and ignoring them can compromise therapeutic success in acute myeloid leukemia (AML) treatment, in complex patients and secondary pathologies. AREAS COVERED: This review summarizes the DDIs of FLT3i with P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting (OAT), organic cationic transporting (OCT), cytochrome P450 (CYP) subunits, and other minor metabolic/transport pathways. EMBASE, PubMed, the Cochrane Central Register and the Web of Science were searched. The last literature search was performed on the 14 February 2022. EXPERT OPINION: FLT3i will be combined with other therapeutic agents (supportive care, doublet, or triplet therapy) and in different clinical settings, which means a greater chance of controlling and even eradicating the disease effectively, but also an increased risk to patients due to potential DDIs. Healthcare professionals should be aware of the potential interactions that may occur and be vigilant in monitoring those patients who are receiving any potentially interacting drug.

Baricitinib against severe COVID-19: effectiveness and safety in hospitalised pretreated patients.

OBJECTIVES: To analyse the effectiveness and safety of baricitinib for severe COVID-19 in cytokine storm syndrome based on its potential role as an anti-inflammatory immunomodulator and inhibitor of viral endocytosis. METHODS: This was an observational retrospective study of hospitalised patients treated with baricitinib for severe COVID-19. Outcomes were clinical improvement on an ordinal scale of 1-8 on day 1 of baricitinib compared with day 14 (where 8=death and 1=not hospitalised with no limitations of activities), overall survival, time to recovery since baricitinib treatment started (days until hospital discharge) and laboratory parameters related to COVID-19 poor prognosis. Adverse events related to baricitinib during the admission period were also reported. RESULTS: Forty-three patients (70% men, mean age 70 years (IQR 54-79)) treated with baricitinib daily for 6 days (IQR 5-7) were included. Thirty-six patients were treated with corticosteroids (84%). Clinical improvement was 3 points (IQR 1-4) in patients on an ordinal scale of 4-6, overall survival was 100% at day 30 and day 60 with a mean time to recovery of 12 days (IQR 9-25) from start of baricitinib treatment. No adverse events of interest were found and all poor prognosis risk factors improved at day 14: interleukin-6, C-reactive protein, ferritin, lymphocytes, platelets and D-dimers. CONCLUSIONS: Patients treated with baricitinib for severe COVID-19 showed improvements in clinical and analytical values without relevant adverse events and 100% overall survival. Clinical randomised trials are needed to confirm the clinical benefit of baricitinib.

Healthcare Resource Utilization among Patients between 60-75 Years with Secondary Acute Myeloid Leukemia Receiving Intensive Chemotherapy Induction: A Spanish Retrospective Observational Study.

BACKGROUND: Information regarding the impact on healthcare systems of secondary acute myeloid leukemia (sAML) is scarce. METHODS: A retrospective review of medical charts identified patients aged 60-75 years with sAML between 2010 and 2019. Patient information was collected from diagnosis to death or last follow-up. Outpatient resource use, reimbursement, frequency and duration of hospitalization, and transfusion burden were assessed. Forty-six patients with a median age of 64 years were included. Anthracycline plus cytarabine regimens were the most common induction treatment (39 patients, 85%). The ratio of the total days hospitalized between the total follow-up was 29%, with a sum of 204 hospitalizations (average four/patient; average duration 21 days). The total average reimbursement was EUR 90,008 per patient, with the majority (EUR 77,827) related to hospital admissions (EUR 17,403/hospitalization). Most hospitalizations (163, mean 22 days) occurred in the period before the first allogeneic hematopoietic stem cell transplant (alloHSCT), costing EUR 59,698 per patient and EUR 15,857 per hospitalization. The period after alloHSCT (in only 10 patients) had 41 hospitalizations (mean 21 days), and a mean reimbursement cost of EUR 99,542 per patient and EUR 24,278 per hospitalization. In conclusion, there is a high consumption of economic and healthcare resources in elderly patients with sAML receiving active treatments in Spain.

Proactive therapeutic drug monitoring and pharmacogenetic analysis in inflammatory bowel disease: A systematic review.

OBJECTIVE: The rise in the development of monoclonal antibodies has brought  about a revolution in the pharmacotherapy of inflammatory bowel disease  (Crohn's disease and ulcerative colitis). Systematic plasma concentrations monitoring of these biological drugs in anticipation of potential  clinical failures of treatment is known as proactive therapeutic drug  monitoring. New pharmacogenetic analysis techniques have recently been  developed that can predict response to these treatments even before they are administered. The goal of this systematic review is to analyze the potential benefits of proactive therapeutic drug monitoring and of the  harmacogenetic analysis of biological drugs in inflammatory bowel disease  patients in terms of clinical remission. METHOD: A systematic search was performed in the MEDLINE/Pubmed, Embase and Cochrane Library databases using the  escriptors proactive drug monitoring, biological drugs, inflammatory bowel  disease and pharmacogenetics. Only randomized clinical trials published  between January 2015 and May 2021 were included; all articles whose main  topic was not related to the topic were excluded by hand. The quality of the  articles  was assessed using the Jadad scale and risk of bias was assessed  using the Cochrane Collaboration tool. RESULTS: After applying inclusion and exclusion criteria, seven of the 228  retrieved articles were selected for review. Almost all the studies measured the  same clinical variables (Harvey-Bradshaw index for Crohn's disease and  Mayo score for ulcerative colitis). Only in two of the included studies was  proactive therapeutic drug monitoring superior to reactive monitoring- or no  level-guided dose adjustments. No pharmacogenetic analyses were found that  met the criteria defined. Conclusions: This review shows that the data  supporting the use of proactive therapeutic drug monitoring in inflammatory  bowel disease is limited and of low quality. Although pharmacogenetic analysis  can be a useful tool for personalizing treatment, further and better designed  randomized clinical trials are needed to determine the role of proactive drug monitoring strategies in clinical practice.

OBJETIVO: El auge del desarrollo de los anticuerpos monoclonales supuso una  revolución en la farmacoterapia de la enfermedad inflamatoria intestinal,  principalmente enfermedad de Crohn y colitis ulcerosa. La monitorización de  niveles plasmáticos de estos fármacos biológicos de forma programada y  anticipada a un posible fracaso clínico del tratamiento se conoce como  monitorización farmacocinética proactiva. Además, recientemente se han  puesto a punto nuevas técnicas para el análisis farmacogenético que pueden  predecir la respuesta a estos tratamientos, incluso antes de ser administrados.  El objetivo de esta revisión sistemática es analizar los posibles beneficios de la  monitorización proactiva y del análisis farmacogenético de fármacos biológicos  en pacientes con enfermedad inflamatoria intestinal en términos de remisión  clínica.Método: Se buscó en las bases de datos Medline/PubMed, Embase y Cochrane  Library con los descriptores "Proactive drug monitoring",  biological drugs", "inflammatory bowel disease" y "pharmacogenetics". Se  incluyeron únicamente ensayos clínicos aleatorizados publicados entre enero de 2015 y mayo de 2021, y se excluyeron las publicaciones cuyo  tema principal no era el de la búsqueda. La calidad de los artículos se evaluó  mediante la escala de Jadad y además se evaluaron los riesgos de sesgo por la herramienta de la Colaboración Cochrane. RESULTADOS: Tras aplicar los criterios de inclusión y exclusión, se seleccionaron para la revisión 7 de las 228 referencias recuperadas. Casi todos  los estudios coincidían en las variables clínicas medidas (índice de Harvey- Bradshaw en enfermedad de Crohn e índice de Mayo en colitis ulcerosa). Sólo  en dos de los estudios incluidos la monitorización proactiva era superior a la  reactiva o al no realizar ajustes de dosis guiados por niveles. No se  encontraron ensayos clínicos con los criterios de búsqueda definidos acerca del  análisis farmacogenético. CONCLUSIONES: Esta revisión muestra que los datos que apoyan el uso de la  monitorización farmacocinética proactiva en enfermedad inflamatoria intestinal  son limitados y de baja calidad. El análisis  armacogenético puede ser una herramienta útil para ofrecer a los pacientes el  tratamiento más personalizado, pero son necesarios más ensayos clínicos  aleatorizados con mejor diseño para determinar el lugar de estas estrategias  en la práctica clínica.

Impact of combinations of single-nucleotide polymorphisms of anthracycline transporter genes upon the efficacy and toxicity of induction chemotherapy in acute myeloid leukemia.

Anthracycline uptake could be affected by influx and efflux transporters in acute myeloid leukemia (AML). Combinations of single-nucleotide polymorphisms (SNPs) of wild-type genotype of influx transporters (SLC22A16, SLCO1B1) and homozygous variant genotypes of ABC polymorphisms (ABCB1, ABCC1, ABCC2, ABCG2) were evaluated in 225 adult de novo AML patients. No differences in complete remission were reported, but higher induction death was observed with combinations of SLCO1B1 rs4149056 and ABCB1 (triple variant haplotype, rs1128503), previously associated with ABCB1 and SLCO1B1 SNPs. Several combinations of SLCO1B1 and SLC22A16 with ABCB1 SNPs were associated with higher toxicities, including nephrotoxicity and hepatotoxicity, neutropenia, previously related to ABCB1, and a novel correlation with mucositis. Combination of SLC22A16 rs714368 and ABCG2 rs2231142 was related to cardiac toxicity, reproducing previous correlations with ABCG2. This study shows the impact of transporter polymorphisms in AML chemotherapy safety. Further prospective studies with larger populations are needed to validate these associations.

Tyrosine kinase inhibitors for acute myeloid leukemia: A step toward disease control?

Dysregulation of tyrosine kinases (TKs) may play a role in leukemogenesis by promoting survival and proliferation of acute myeloid leukemia (AML) cells. In AML, the main TKs mutations are produced in Fms-like tyrosine kinase 3 (FLT3), KIT and Janus kinase (JAK) genes, and with less frequency in BCR-ABL. The striking results with TK Inhibitors (TKIs) therapy in BCR-ABL1 chronic myeloid leukemias has paved the way for its clinical development in AML. However, the AML biology complexity seems to prevent TKI therapy from being proposed as a strong shift in the treatment paradigm and prognosis. While some FLT3 inhibitors have shown efficacy in well-designed studies, an increasing number of AML patients are being treated with TKIs as a new standard of care, compassionate use, or in clinical trials. We will review the current clinical evidence concerning the use of TKIs in different subsets of AML (BCR-ABL1, Core Binding Factor, FLT3 mutated, and FLT3 wild-type) to address the main topics concerning these targeted therapies for AML: 1) optimal place (upfront, relapsed/refractory or maintenance); 2) monotherapy or combination; 3) efficacy in TK mutated versus wild-type patients; 4) differences between selective and multi-targeted TKIs. In the next years, clinical trials and real-world data will help answer these questions and establish the impact of TKIs on outcomes of AML patients.

IDH1-mutated relapsed or refractory AML: current challenges and future prospects.

The prognosis of patients with relapsed or refractory acute myeloid leukemia (R/R AML) is discouraging with salvage standard approaches. Mutations of isocitrate dehydrogenase 1 (IDH1 mut ), present in 7-14% of AML patients, have been discovered recently, opening the door to targeted agents aiming to improve the outcomes in this setting. Several oral selective IDH1 mut inhibitors are under investigation, ivosidenib being the first approved for R/R AML. We performed a systematic review to analyze the clinical outcomes and safety reported with IDH1 mut inhibitors and other agents in adult patients with IDH1 mut R/R AML. Ivosidenib in monotherapy achieved complete remission (CR) of 24%, overall response of 42%, and median overall survival of 9 months in R/R AML, and promising outcomes were reported with IDH305 and FT-2102. IDH1 mut inhibitors were generally well tolerated, but some therapy-related toxicities should be monitored, including IDH-differentiation syndrome, prolongation of the QT interval, and leukocytosis, all manageable and reversible. Also, venetoclax, CB-839, PARP inhibitors, and IDH1 peptide vaccine are being studied in IDH1mut AML. The results of the ongoing and upcoming clinical trials will bring new evidence to establish the role of IDH1 mut inhibitors in therapeutic strategies of AML.