Here, we implemented WGS to characterize the genomic landscape of B-cell acute lymphoblastic leukemia (B-ALL), with emphasis on resistant/relapsed (R/R) cases. The study group contained 64 adult patients with B-ALL diagnosed and treated between 2008 and 2023, including 29 R/R cases. WGS-based mutation analysis was conducted in reference to the immunological and cytogenetic subtypes of the disease and response to therapy. In total, we identified 2,237 variants across 1,267 genes, including 248 pathogenic and 126 likely pathogenic genetic lesions. The numerous associations between the mutation profiles and B-ALL subtypes were found. Notably, 517 genes harbored variants exclusive to the R/R group. Mutated genes were significantly enriched in pathways related to DNA repair (e.g., BRCA2, FANCM), kinase signaling (JAK2, NF1), and chromatin remodeling (CREBBP, BARD1), as well as the gene ontology term “regulation of phosphorylation” (GO:0042325). The results of our study suggest an association between the presence of mutations in genes encoding proteins involved in phosphorylation processes and the R/R B-ALL. Furthermore, R/R patients also exhibited an increased mutational burden compared to those who responded to therapy. This highlights the need for precise evaluation of the nature of molecular changes in individual patients to determine the risk of therapy failure.

Allogeneic hematopoietic stem cell (allo-HSC) transplantation (allo-HSCT) is a therapy of choice for patients requiring total bone marrow replacement. One of the critical issues is optimizing the number of allo-HSCs for successful outcomes, measured by the engraftment time and the incidence/severity of graft versus host disease (GvHD). We evaluated engraftment time and GvHD in comparison to the composition of infused CD34+ immature HSCs and CD3+ T cells in all-HSCTs. The study evaluated 97 patients with allo-HSCT from matched related (group MRD; n = 40), matched unrelated (group MUD; n = 28), mismatched unrelated (group MMUD; n = 6), and haploidentical (group haplo; n = 23) donors. Overall, we did not observe any correlation between the total count of CD34+ allo-HSC and CD3+ T cells or the count of CD34+ and CD3+ calculated per kilogram of body weight (kg) on engraftment as well as GvHD symptoms in all studied groups. However, the CD34+/CD3+ ratio may provide valuable information in the process of a graft quality assessment in haploidentical allo-HCST for the choice of therapeutic options.

Talazoparib is a poly(ADP-ribose) polymerase inhibitor approved for the treatment of breast and prostate cancer. Commercialization of a soft gelatin capsule (SGC) formulation developed post-approval required a bioequivalence (BE) and food effect (FE) study to bridge SGC with the initial commercial hard capsule (HC) formulation. Study execution and meeting BE criteria are challenging due to high variability in Cmax, potentially higher Cmax for SGC based on dissolution data, and the need to perform BE/FE assessment at steady state in cancer patients. Model-informed drug development (MIDD) was used to facilitate an efficient/feasible study design. Semi-mechanistic pharmacokinetic (PK)/pharmacodynamic (PD) modeling and simulations showed that AUC, instead of Cmax, drove hematologic events, the main side effects of talazoparib. This supported a BE study powered for AUC equivalence only. Population PK simulation showed that following a 28-day treatment in the first period, 14 days in subsequent periods is sufficient for steady-state BE/FE assessments. Study results showed AUC met BE criteria while Cmax was 37% higher for SGC relative to HC, which was deemed not clinically significant based on the PK/PD model. FE on SGC formulation was consistent with FE on HC formulation reported previously. The safety profile of the two formulations was generally consistent with the known safety profile. The totality of data (AUC equivalence, lack of impact of Cmax on safety, observed safety data) supported bridging of the two formulations although Cmax failed to meet BE criteria. MIDD was critical in study design optimization and supported approval of the SGC formulation. Trial Registration: ClinicalTrials.gov Identifier: NCT04672460.

AIMS:To assess the effect of a potent cytochrome P450 (CYP) 3A inhibitor and CYP inducer on the pharmacokinetics of ritlecitinib, a JAK3/TEC family kinase inhibitor, and assess the effect of ritlecitinib on the pharmacokinetics of CYP substrates (midazolam, efavirenz, tolbutamide, caffeine and oral contraceptives [ethinyl oestradiol and levonorgestrel]) in healthy adults. METHODS:Seven clinical drug-drug interaction studies were analysed. Pharmacokinetic parameters for drugs as measured in blood plasma were used to estimate the drug interaction potential with ritlecitinib as a perpetrator or victim. RESULTS:Midazolam exposure (area under plasma concentration-time curve from time 0 to infinity [AUCinf]) and peak exposure (maximum concentration [Cmax]) were increased by ≈169% and ≈80.1%, respectively, in the presence of ritlecitinib. Efavirenz exposure (AUC0-72) and peak exposure (Cmax) were similar in the presence and absence of ritlecitinib coadministration. Tolbutamide pharmacokinetic parameters (AUCinf and Cmax) were not affected by multiple ritlecitinib doses. In the presence of ritlecitinib, AUCinf and Cmax of caffeine increased by ≈165% and ≈10%, respectively. AUCinf and Cmax of ethinyl oestradiol decreased by ≈18% and ≈12%, respectively, following coadministration of multiple ritlecitinib 200 mg once-daily doses, but no relevant change was observed following multiple 50 mg once-daily doses. Ritlecitinib doses did not affect the pharmacokinetics of levonorgestrel. Coadministration following multiple itraconazole doses increased ritlecitinib AUCinf by ≈15%. Coadministration following multiple rifampicin doses decreased AUCinf of ritlecitinib by ≈45%. CONCLUSIONS:Ritlecitinib is a moderate inhibitor of CYP3A and CYP1A2. Strong CYP inducers can reduce ritlecitinib concentrations, but not to clinically relevant levels leading to lack of benefit.

Background: Alopecia areata (AA) is an autoimmune disease characterized by hair loss that can negatively impact quality of life. AA has a significant pediatric prevalence; however, no systemic treatments are approved for AA in patients aged < 12 years. Ritlecitinib, a JAK3/TEC family kinase inhibitor, is approved to treat adults and adolescents with severe AA aged >= 12 years. This study evaluated ritlecitinib pharmacokinetic (PK) parameters and safety in pediatric patients with AA aged 6 to < 12 years. Methods: In this single-group, uncontrolled, open-label study, participants received ritlecitinib 20 mg once daily for 7 days. PK parameters of ritlecitinib on Day 7 were measured and summarized descriptively. Safety outcomes, including incidence of adverse events (AEs), were evaluated. Results: Fifteen participants were enrolled and 14 (93.3%) completed the study. The median time to maximum concentration (T-max) for plasma concentrations of ritlecitinib on Day 7 was similar to 0.5 h. The mean half-life of ritlecitinib was similar to 1.19 h. Geometric means (% coefficient of variation) for area under the curve from 0 to 24 h (AUC(24)) and maximum concentration (C-max) were 437.5 ng center dot h/mL (30%) and 208.7 ng/mL (38%), respectively. Four AEs were experienced by 3 participants, with 1 AE of urticaria resulting in permanent discontinuation. No severe AEs, serious AEs, or clinically meaningful laboratory abnormalities were reported. Conclusions: Ritlecitinib PK parameters in pediatric patients were successfully characterized in the present study. Ritlecitinib 20 mg once daily was generally well tolerated in pediatric patients with AA.

Ritlecitinib is an oral once-daily irreversible inhibitor of Janus kinase 3 and tyrosine-protein kinase family being developed for the treatment of moderate-to-severe alopecia areata. This study examined the disposition of ritlecitinib in male participants following oral and intravenous administration using accelerator mass spectroscopy methodology to estimate pharmacokinetic parameters and characterize metabolite profiles. The results indicated ritlecitinib had a systemic clearance of 43.7 L/h, a steady state volume of distribution of 73.8 L, extent of absorption of 89%, time to maximum plasma concentration of ∼0.5 hours, and absolute oral bioavailability of 64%. An observed long terminal half-life of total radioactivity was primarily attributed to ritlecitinib binding to plasma albumin. Ritlecitinib was the main circulating drug species in plasma (∼30%), with one major pharmacologically inactive cysteine conjugated metabolite (M2) at >10%. Oxidative metabolism (fractional clearance 0.47) and glutathione-related conjugation (fractional clearance 0.24) were the primary routes of elimination for ritlecitinib with the greatest disposition of radioactivity shown in the urine (∼71%). In vitro phenotyping indicated ritlecitinib cytochrome P450 (CYP) fraction of metabolism assignments of 0.29 for CYP3A, 0.09 for CYP2C8, 0.07 for CYP1A2, and 0.02 for CYP2C9. In vitro phenotyping in recombinant human glutathione S-transferases indicated ritlecitinib was turned over by a number of cytosolic and microsomal enzyme isoforms. SIGNIFICANCE STATEMENT: This study provides a detailed understanding of the disposition and metabolism of ritlecitinib, a JAK3 and TEC family kinase inhibitor for alopecia areata in humans, as well as characterization of clearance pathways and pharmacokinetics of ritlecitinib and its metabolites. As an AMS-based ADME study design, we have expanded on reporting the standard ADME endpoints, providing key pharmacokinetic parameters, such as clearance, volume of distribution, and bioavailability, allowing for a more comprehensive understanding of drug disposition.

BackgroundBCR::ABL1-like acute lymphoblastic leukaemia (BCR::ABL1-like ALL) is characterized by inferior outcomes. Current efforts concentrate on the identification of molecular targets to improve the therapy results. The accessibility to next generation sequencing, a recommended diagnostic method, is limited. We present our experience in the BCR::ABL1-like ALL diagnostics, using a simplified algorithm.ResultsOut of 102 B-ALL adult patients admitted to our Department in the years 2008-2022, 71 patients with available genetic material were included. The diagnostic algorithm comprised flow cytometry, fluorescent in-situ hybridization, karyotype analysis and molecular testing with high resolution melt analysis and Sanger Sequencing. We recognized recurring cytogenetic abnormalities in 32 patients. The remaining 39 patients were screened for BCR::ABL1-like features. Among them, we identified 6 patients with BCR::ABL1-like features (15.4%). Notably, we documented CRLF2-rearranged (CRLF2-r) BCR::ABL1-like ALL occurrence in a patient with long-term remission of previously CRLF2-r negative ALL.ConclusionsAn algorithm implementing widely available techniques enables the identification of BCR::ABL1-like ALL cases in settings with limited resources.

Out of BCR‐ABL negative myeloproliferative neoplasm (MPNPh − ) patients, 3%–14% display a concomitant monoclonal gammopathy of unknown significance (MGUS). In most cases, the diagnosis of plasma cell dyscrasia is either synchronous with that of MPNPh − or occurs later on. We present a 50‐year‐old patient with type 2 CALR Lys385Asnfs*47 mutation positive essential thrombocythemia (ET) who developed symptomatic multiple myeloma (MM) 13 years after the diagnosis of ET during PEG‐INF2α treatment. The NGS study performed at the time of the MM diagnosis revealed the HRAS Val14Gly/c.41T〉G mutation and the wild type CALR , JAK2 and MPL gene sequence. In the presented case, the complete molecular remission of ET was achieved after 16 months of PEG‐INF2α treatment. The origin of MM cells in MPNPh − patients remains unknown. Published data suggests that type 2 CALRins5 up‐regulate the ATF6 chaperone targets in hematopoietic cells and activate the inositol‐requiring enzyme 1α‐X‐box‐binding protein 1 pathway of the unfolded protein response (UPR) system to drive malignancy. It cannot be excluded that endoplasmic reticulum stress induced by the increased ATF6 resulted in an abnormal redox homeostasis and proteostasis, which are factors linked to MM. The presented case history and the proposed mechanism of mutant CALR interaction with UPR and/or ATF6 should initiate the discussion about the possible impact of the mutant CALR protein on the function and genomic stability of different types of myeloid cells, including progenitor cells.

Ritlecitinib, an inhibitor of Janus kinase 3 and hepatocellular carcinoma family kinases, is in development as potential treatment for several inflammatory diseases. In vitro studies presented ritlecitinib as an inhibitor of hepatic organic cation transporter (OCT) 1, renal transporters OCT2 and multidrug and toxin extrusion (MATE) proteins 1/2K using multiple substrates, and ritlecitinib's major inactive metabolite M2, as an inhibitor of OCT1. A clinical interaction study with an OCT1 drug probe (sumatriptan) and relevant probe biomarkers for OCT/MATE was conducted to assess the effect of ritlecitinib on these transporters in healthy adult participants. The selectivity of sumatriptan for OCT1 was confirmed through a series of in vitro uptake assays. A simple static model was used to help contextualize the observed changes in sumatriptan area under the plasma concentration-time curve (AUC). Coadministration of a single 400-mg dose of ritlecitinib increased sumatriptan AUC from time 0 to infinity (AUCinf ) by ≈30% relative to a single 25-mg sumatriptan administration alone. When administered 8 hours after a ritlecitinib dose, sumatriptan AUCinf increased by ≈50% relative to sumatriptan given alone. Consistent with OCT1 inhibition, the AUC from time 0 to 24 hours of isobutyryl-L-carnitine decreased by ≈15% after ritlecitinib. Based on the evaluation of the renal clearance of N1 -methylnicotinamide, ritlecitinib does not exert clinically meaningful inhibition on renal OCT2 or MATE1/2K. This study confirmed that ritlecitinib and M2 are inhibitors of OCT1 but not OCT2 or MATE1/2K in healthy adults.

Ritlecitinib, an inhibitor of Janus kinase 3 and tyrosine kinase expressed in hepatocellular carcinoma family kinases, is in development for inflammatory diseases. This study assessed the impact of ritlecitinib on drug transporters using a probe drug and endogenous biomarkers. In vitro transporter-mediated substrate uptake and inhibition by ritlecitinib and its major metabolite were evaluated. Subsequently, a clinical drug interaction study was conducted in 12 healthy adult participants to assess the effect of ritlecitinib on pharmacokinetics of rosuvastatin, a substrate of breast cancer resistance protein (BCRP), organic anion transporting polypeptide 1B1 (OATP1B1), and organic anion transporter 3 (OAT3). Plasma concentrations of coproporphyrin I (CP-I) and pyridoxic acid (PDA) were assessed as endogenous biomarkers for OATP1B1 and OAT1/3 function, respectively. In vitro studies suggested that ritlecitinib can potentially inhibit BCRP, OATP1B1 and OAT1/3 based on regulatory cutoffs. In the subsequent clinical study, coadministration of ritlecitinib decreased rosuvastatin plasma exposure area under the curve from time 0 to infinity (AUCinf) by 13

Ritlecitinib is a selective, covalent, irreversible inhibitor of Janus kinase 3 (JAK3) and the tyrosine kinase expressed in hepatocellular carcinoma (TEC) family kinases. Pharmacokinetics and safety of ritlecitinib in participants with hepatic (Study 1) or renal (Study 2) impairment were to be characterized from two phase I studies. Due to a study pause caused by the COVID-19 pandemic, the study 2 healthy participant (HP) cohort was not recruited; however, the demography of the severe renal impairment cohort closely matched the study 1 HP cohort. We present results from each study and two innovative approaches to utilizing available HP data as reference data for study 2: a statistical approach using analysis of variance and an in silico simulation of an HP cohort created using a population pharmacokinetics (POPPK) model derived from several ritlecitinib studies. For study 1, the observed area under the curve for 24-h dosing interval and maximum plasma concentration for HPs and their observed geometric mean ratios (participants with moderate hepatic impairment vs HPs) were within 90% prediction intervals from the POPPK simulation-based approach, thereby validating the latter approach. When applied to study 2, both the statistical and POPPK simulation approaches demonstrated that patients with renal impairment would not require ritlecitinib dose modification. In both phase I studies, ritlecitinib was generally safe and well tolerated. These analyses represent a new methodology for generating reference HP cohorts in special population studies for drugs in development with well-characterized pharmacokinetics in HPs and adequate POPPK models. Trial Registration ClinicalTrials.gov NCT04037865 , NCT04016077 , NCT02309827 , NCT02684760 , and NCT02969044 . Graphical Abstract

Introduction Acute lymphoblastic leukemia (ALL) and lymphomas affect both pediatric and adult populations, therefore, they might be treated by pediatric or adult centers.It has been proven that the prognosis among adolescents and young adults (AYA) is poorer than among children, which remains a subject of research. Many factors are suspected to affect the diagnostic and treatment processes in adolescents and young adults, one of them being the organization of the healthcare system.The aimof the studywas to compare the time intervals between different events on disease trajectory in pediatric and AYA groups suffering from ALL and lymphomas. Methods We collected data on 81 patients diagnosed with ALL (50 children and 31 AYAs) and 100 patients diagnosed with lymphomas (50 children and 50 AYAs). Statistical analysis was performed in order to compare the groups. Results The results confirmed the hypothesis that the duration of the diagnostic process differs significantly between groups. For patients with ALL, the analyzed time intervals were significantly shorter in the pediatric group than in the AYA group: first contact with a GP - admission to Hematology Department (2 vs. 5 days; pvalue= 0.004), first contact with a GP - treatment (6 vs. 12 days, p-value=0.001), diagnosis - treatment (1 vs. 3 days, p-value=0.003). In the case of patients suffering from lymphomas, the results were similar. The analyzed time intervals were significantly shorter in the pediatric group than in the AYA group: first contact with a GP- diagnosis (21 vs. 40.5 days, p-value<0.0001), first contact with a GP - treatment (27 vs. 65 days, p-value<0.0001). Trend analysis showed that the longer patients had presented symptoms before contacting the primary care physician, the longer they waited for the beginning of treatment both in ALL and lymphomas groups (p-values=0.0129 and 0.0038 respectively). Discussion As the diagnostic and treatment processes are longer for AYA patients, actions must be undertaken in order to ensure equality and improve the healthcare system in Poland and possibly other countries.

Objective: This clinical study was conducted to evaluate the impact of ritlecitinib on the pharmacokinetics (PK) of caffeine, a cytochrome P450 1A2 (CYP1A2) substrate. Methods: In this single-center, single-arm, open-label, fixed-sequence study, healthy participants received a single 100-mg dose of caffeine on two separate occasions: on Day 1 of Period 1 as monotherapy and on Day 8 of Period 2 after oral administration of ritlecitinib 200 mg once daily (QD) for 8 days. Serial blood samples were collected and analyzed using a validated LC/MS assay. PK parameters were estimated by using a non-compartmental method. Safety was monitored by physical examination, vital signs, electrocardiograms, and laboratory assessments. Results: Twelve participants were enrolled and completed the study. Co-administration of caffeine 100 mg in the presence of steady-state levels of ritlecitinib (200 mg QD) increased caffeine exposure compared with caffeine given alone. Area under the curve (AUCinf) and maximum concentration (Cmax) of caffeine increased by approximately 165% and 10%, respectively, when co-administered with ritlecitinib. The ratios of the adjusted geometric means (90% CI) for caffeine AUCinf and Cmax were 265.14% (234.12%-300.26%) and 109.74% (103.90%-15.91%), respectively, when caffeine was co-administered with steady-state ritlecitinib (test) compared with its administration alone (reference). Multiple doses of ritlecitinib when co-administered with a single dose of caffeine were generally safe and well tolerated in healthy participants. Conclusion: Ritlecitinib is a moderate inhibitor of CYP1A2 and can increase systemic exposures of CYP1A2 substrates.

BACKGROUND:BCR/ABL1-like acute lymphoblastic leukemia is a newly recognized high-risk subtype of ALL, characterized by the presence of genetic alterations activating kinase and cytokine receptor signaling. This subtype is associated with inferior outcomes, compared to other B-cell precursor ALL.SUMMARY:The recognition of BCR/ABL1-like ALL is challenging due to the complexity of underlying genetic alterations. Rearrangements of CRLF2 are the most frequent alteration in BCR/ABL1-like ALL and can be identified by flow cytometry. The identification of BCR/ABL1-like ALL can be achieved with stepwise algorithms or broad-based testing. The main goal of the diagnostic analysis is to detect the underlying genetic alterations, which are critical for the diagnosis and targeted therapy.KEY MESSAGES:The aim of the manuscript is to review the available data on BCR/ABL1-like ALL characteristics, diagnostic algorithms, and novel, molecularly targeted therapeutic options.

AIM:This phase I study investigated talazoparib pharmacokinetics (PK) and safety in patients with advanced solid tumours and varying degrees of hepatic function. METHODS:Patients with advanced solid tumours and normal hepatic function or varying degrees of hepatic impairment (mild, moderate or severe, based on National Cancer Institute Organ Dysfunction Working Group classification) received talazoparib 0.5 mg once daily for 22 calendar days. Plasma and urine samples after single and multiple doses were collected and analysed for talazoparib using validated assays. Plasma PK data from all patients were analysed using the population PK method. Plasma and urine PK parameters in PK-evaluable patients were calculated using noncompartmental analysis (NCA). Safety was monitored in all enrolled patients. RESULTS:Thirty-eight patients were enrolled; 37 had ≥1 PK concentration, among which 17 were evaluable for NCA. Population PK analysis (n = 37) indicated no significant impact of hepatic function on apparent clearance (CL/F) of talazoparib. Baseline creatinine clearance was the only significant covariate on CL/F (α = 0.05). NCA of data (n = 17) showed no clear trend for increase in exposure on day 22 with worsening hepatic function. Talazoparib protein binding was comparable in patients with varying hepatic function. Talazoparib was generally well tolerated, and the safety profile observed in this study was consistent with the known safety profile of the drug. CONCLUSIONS:Hepatic impairment (mild, moderate or severe) has no impact on the PK of talazoparib. No dose modification is recommended for patients with advanced solid tumours and various degrees of hepatic impairment, and this labelling language has been approved by the US Food and Drug Administration and the European Medicines Agency.

Purpose: The prevalence of psychosocial late effects and quality of life in adolescent and young adult (AYA)-aged survivors of pediatric cancer have been studied. Methods: The study was conducted in AYA survivors who had been diagnosed with leukemia, lymphoma, or brain tumor, had completed treatment at least 1 year before the study, and were 15-39 years old at study enrollment. The control group consisted of healthy volunteers. A questionnaire comprised a demographic form, eight questions concerning mental health and the disease, and survey The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30. Controls received a questionnaire without questions concerning an illness. Results: Most of survivors believed that cancer treatment might have a serious influence on their health. Survivors significantly more frequently declared using drugs: neuroleptics, tranquilizers, and antidepressants than controls. Survivors of leukemia demonstrated significantly more problems in cognitive functioning than lymphoma survivors. Females were significantly more disabled in emotional functioning than males. Young adults more often reported dysfunction in emotional functioning compared to adolescents. Survivors who were assessed ≥10 years since therapy reported significantly more disadvantage in social functioning than those assessed <10 years since treatment completion. Survivors reported significantly more disadvantages in social functioning than controls. Allogeneic hematopoietic stem cell transplantation survivors more often suffered cognitive limitations. Irradiated survivors more often attended psychological therapy. Conclusions: Survivors of pediatric cancer are vulnerable to consequences of oncological treatment, making their quality life significantly worse in comparison with healthy controls. They need to be monitored, supported, and educated.