A 16-year-old, spayed female domestic shorthair cat was referred to the Schwarzman Animal Medical Center for evaluation of chronic, progressive eosinophilia accompanied by vomiting and weight loss despite normal appetite. Blood smear evaluation revealed immature eosinophils with dysplastic features and occasional giant forms. Abdominal ultrasound identified small-intestinal thickening, a hepatopathy and splenomegaly. Screening for feline leukemia virus, feline immunodeficiency virus and heartworm infection were negative. Chronic eosinophilic leukemia was suspected, although hypereosinophilic syndrome could not be ruled out. At the time of referral, the cat was receiving prednisolone and chlorambucil for suspected small cell gastrointestinal lymphoma, but showed persistent clinical signs and progressive eosinophilia. Chlorambucil was discontinued and toceranib was initiated alongside prednisolone. No adverse effects attributable to toceranib were observed. A partial response, defined as resolution of clinical signs and a 30% reduction in circulating eosinophils, was observed on day 39. A subsequent progression-free survival interval of 4 weeks was achieved. Progressive disease developed on day 75, and given declining quality of life, euthanasia was thereby elected on day 89. This case report is the first to describe the use of toceranib to treat suspected chronic eosinophilic leukemia, a rare and poorly documented disease process in cats. This novel therapeutic approach is the first publication of a partial response and stable disease in the treatment of suspected chronic eosinophilic leukemia in a cat. Suspected Chronic Eosinophilic Leukemia in a Cat Treated with Toceranib A 16-year-old spayed female cat was referred for chronic progressive vomiting, weight loss, and high eosinophil counts. Bloodwork showed abnormal and immature eosinophils, suggesting chronic eosinophilic leukemia. Ultrasound revealed thickened intestines, along with changes in the liver and spleen. Common infectious causes were ruled out. Chronic eosinophilic leukemia was suspected, although hypereosinophilic syndrome could not be excluded. The cat had previously been treated with prednisolone and chlorambucil for suspected intestinal small cell lymphoma, but showed no improvement. Chlorambucil was stopped, and treatment with toceranib was started alongside prednisolone. The medication was well tolerated. After four weeks, the cat showed a partial response, with improvement in clinical signs and a decrease in eosinophil levels. This response lasted for about one month. By week nine, the disease progressed again. Due to declining quality of life, the cat was euthanized at week ten. This is the first reported case of using this specific drug (toceranib) to treat suspected chronic eosinophilic leukemia in a cat. This is the first publication to document a partial response to treatment and a progression free survival interval in a cat with suspected chronic eosinophilic leukemia.
Acute leukemias of the myeloid lineage most commonly show myeloid and/or monocytic differentiation. Leukemias with erythroid, megakaryoblastic, and basophilic differentiation are more rare but are well documented. In contrast, acute leukemia showing marked morphologic and immunophenotypic features of eosinophilic differentiation is not a defined entity. When acute leukemias do show a prominent population of cells with eosinophilic differentiation, the eosinophil populations typically show morphologic features of mature eosinophils and the eosinophilic population may be clonally related to the neoplastic cells or may be reactive. In this case report, we describe an unusual case of acute myeloid leukemia evolving from a myelodysplastic neoplasm with low blasts in which the predominant cell population in the peripheral blood and bone marrow were cells with round nuclei and immature chromatin with prominent eosinophilic granules and immunophenotypic features suggestive of maturation arrest at an eosinophilic promyelocyte-like stage. At the time of leukemic transformation, molecular studies showed acquisition of NRAS G13R, NRAS Q61K, and KRAS G12R mutations in addition to the TET2 variants (N582fs and E1357X), del(20q), and 7q- abnormalities detected in the antecedent myelodysplastic neoplasm. No PDGFRA, PDGFRB, FGFR1, JAK2, or FLT3 rearrangements were detected by FISH or in sequencing assays. BCR::ABL1 testing was also negative. Whole-genome sequencing did not detect additional abnormalities to explain the differentiation block. In summary, this is, to our knowledge, the only reported case of an acute leukemia in which the immature cells themselves demonstrate morphologic and immunophenotypic features of eosinophilic promyelocytes.
The Danish Lymphoid Cancer Research (DALY-CARE) Genetic Cohort was established to support research into how genetic factors influence clinical outcomes in lymphoid cancers (LCs), including disease progression, treatment response, toxicity, and survival. Individual-level genetic data were combined with detailed clinical information from national health registers, hospital-based electronic health records (EHR), laboratory data, and pathology reports. The cohort enables large-scale studies of genetic susceptibility, disease course, and therapy-related outcomes in LCs and provides a platform for genetic epidemiology and future multi-omics research within a unified data infrastructure. The genetic cohort includes 8675 genotyped individuals drawn from the broader DALY-CARE population (n=74,251, as of April 2025), including individuals diagnosed with LCs such as diffuse large B-cell lymphoma (DLBCL, n=1349), chronic lymphocytic leukemia (CLL, n=1245), multiple myeloma (MM, n=1209), follicular lymphoma (FL, n=704), Hodgkin lymphoma (HL, n=407), Waldenström macroglobulinemia and lymphoplasmacytic lymphoma (WM/LPL, n=368), marginal zone lymphoma (MZL, n=287), and precursor states such as monoclonal gammopathy of undetermined significance (MGUS, n=1299). Hematologic malignancy was the most frequent cause of death (30%), followed by infections (27%) and other cancers (15%). Polypharmacy, as a more sensitive proxy for comorbidity than hospital diagnosis codes, was substantial (median 7-8 drugs pre-diagnosis). Frequently observed comorbidities were hypertension (47%), cardiovascular disease (16%), cerebrovascular disease (11%) and type 2 diabetes (10%). Kinship analysis identified limited relatedness (41 parent-offspring, 51 siblings), while ancestry inference confirmed predominantly Northwestern European descent (97%). The DALY-CARE Genetic Cohort provides a foundation for studying genetic and clinical determinants of LC outcomes. Integration of genotype data with EHR and national health registers enables exploration of germline risk and protective variants. Future expansions will integrate additional omics data types, such as whole-genome sequencing, transcriptomics, proteomics, and immunophenotyping, positioning the cohort as a national platform for multi-omics research in LC.
Children with leukemia frequently experience chemotherapy-related symptoms that persist beyond hospitalization and require ongoing management at home. Parents assume primary responsibility for symptom monitoring and management during this period; however, limited evidence exists regarding how parents experience, respond to, and manage these symptoms within home settings. This study explored parents' experiences of managing chemotherapy-related symptoms in children with leukemia at home, including symptom experiences, their impact on children and caregiving, and parents' symptom management strategies. A qualitative exploratory study using focus group discussions (FGDs) was conducted among parents of children with leukemia receiving chemotherapy in Bandung, Indonesia. Twenty parents participated in four FGDs, with 4-6 participants per group. Discussions were audio-recorded, transcribed verbatim, and analyzed using Braun and Clarke's thematic analysis. Three themes were identified. First, children experienced a wide range of chemotherapy-related symptoms, including nausea and vomiting, diarrhea, oral mucositis, pain, fever, poor appetite, fatigue, itching, and hair loss. Symptoms varied in severity, frequently persisted after hospital discharge, and were perceived to be influenced by factors such as chemotherapy agents, fatigue, fever, post-transfusion conditions, and decreased hemoglobin levels. Second, symptoms affected children's comfort, eating ability, and sleep, while also disrupting daily caregiving routines, creating emotional strain and family burden, and occasionally resulting in unplanned emergency department visits or intensive care admissions. Third, parents employed multiple home-based symptom management strategies, combining prescribed medications, complementary therapies, comfort practices, and adaptations to daily hygiene practices. Parents play a central role in managing chemotherapy-related symptoms in children with leukemia at home. Home-based symptom management involves ongoing adaptation to children's symptoms and substantial caregiving demands. These findings highlight the importance of family-centered supportive care, structured discharge preparation, practical symptom management guidance, and ongoing professional support to strengthen parents' capacity in managing symptoms during the transition from hospital to home.
Dasatinib 100 mg once daily is effective for chronic-phase chronic myeloid leukemia (CP-CML), but dose-related toxicity may limit long-term tolerability. We therefore evaluated whether dasatinib 50 mg once daily as an initial dose strategy preserves efficacy while improving safety compared with 100 mg once daily. We performed a systematic review and meta-analysis of adults with CP-CML treated with initial dasatinib 50 mg once daily. MEDLINE via PubMed, Embase, Cochrane CENTRAL, and Web of Science were searched from inception to March 15, 2026. Direct comparative studies of dasatinib 50 mg versus 100 mg were included in the primary analysis; whereas single-arm 50 mg cohorts were summarized as supportive evidence. Risk ratios (RRs) with 95% confidence intervals (CIs) were pooled using random-effects models. Among 613 records identified, 10 reports met eligibility criteria and 7 nonoverlapping analytic reports were retained. Two studies directly compared frontline dasatinib 50 mg versus 100 mg. Twelve-month major molecular response was similar between doses (RR 1.07, 95% CI, 0.92-1.24), while complete cytogenetic response favored 50 mg in unadjusted analysis (RR 1.09, 95% CI, 1.02-1.16). Dasatinib 50 mg reduced pleural effusion (RR 0.20, 95% CI, 0.08-0.50) and thrombocytopenia (RR 0.71, 95% CI, 0.52-0.96). Supportive frontline single-arm data showed pooled 12-month MMR and CCyR proportions of 70.6% and 95.0%, respectively.Overall, initial dasatinib 50 mg once daily may preserve key efficacy outcomes while improving tolerability in CP-CML. Prospective controlled studies are needed.
Arsenic trioxide (ATO) is effective against FLT3-mutant acute promyelocytic leukemia (APL), but its role in non-APL FLT3-ITD-mutant acute myeloid leukemia (AML) remains unclear. This study aims to investigate the mechanistic impact of ATO on FLT3-ITD-mutated AML cells. This study utilized the CCK-8 assay, Wright-Giemsa staining, flow cytometry, Western blotting, and colorimetric assays to assess the effects of ATO on cell viability, cell morphology, apoptosis, Ki67 expression, reactive oxygen species (ROS), IL-2 levels, expression of apoptosis-related proteins, and LDH release in MV4-11 and HL-60 cells. Further validation was performed using NAC, PD98059 and LM22B-10. Following T-cell co-culture experiments, interferon-γ (IFN-γ) and granzyme B (GZMB) levels were measured. Differences in IL-2 expression were validated in primary cells from patients with AML. Compared to HL-60 cells, ATO-treated FLT3-ITD-mutated MV4-11 cells exhibited lower IC50, reduced Ki67 expression, and elevated LDH levels. ATO induced dose- and time-dependent apoptosis in MV4-11 cells, accompanied by increased Cleaved Caspase-3 expression and Bax/Bcl-2 ratio. NAC attenuated ATO-induced ROS accumulation and apoptosis. ATO suppressed extracellular signal-regulated kinase (ERK) phosphorylation in a concentration-dependent manner, which was reversed by LM22B-10 but exacerbated by PD98059. Additionally, ATO enhanced IL-2 secretion in MV4-11 cells, and their conditioned medium elevated IFN-γ and GZMB levels in CD4+ and CD8+ T cells. Similar IL-2 upregulation was observed in primary cells from FLT3-ITD+ AML patients. ATO triggers apoptosis in FLT3-ITD-mutated AML cells via ROS/ERK signaling and modulates T-cell activity through IL-2 secretion, suggesting a dual role in tumor suppression and immune regulation. This study confirms that ATO is a potential candidate drug for the treatment of FLT3-ITD-mutant AML and provides mechanistic insights into its cytotoxic and immunomodulatory functions.
B-cell malignancies comprise a biologically diverse group of neoplasms, with only rare reports describing the co-occurrence of two distinct lymphoid entities. While concurrent presentation of mature B-cell neoplasms has been documented, the simultaneous occurrence of B-cell acute lymphoblastic leukemia (B-ALL) and plasma cell neoplasm (PCN) has previously been reported rarely. Such cases may provide insight into the clonal architecture and evolutionary pathways underlying lymphoid malignancies. We report a 76-year-old man presenting with cytopenias and leukocytosis, in whom initial bone marrow evaluation and immunophenotyping established a diagnosis of B-ALL with a pre-B phenotype. At the time of diagnosis, flow cytometry also identified a distinct population of aberrant plasma cells, raising the possibility of a concurrent plasma cell neoplasm. Follow-up bone marrow analysis confirmed the coexistence of two immunophenotypically and morphologically distinct malignant populations: immature lymphoblasts consistent with B-ALL and clonal plasma cells. Initial ALL-directed therapy induced remission of both components. However, subsequent disease evolution demonstrated a clear phenotypic shift, with relapse characterized by expansion of a plasmablastic/plasma cell population consistent with PCN, while the B-ALL component remained undetectable by minimal residual disease assessment. Treatment was therefore redirected toward a myeloma-based regimen, which was limited by toxicity and failed to achieve disease control. Genomic analysis supported the presence of two clonally related but distinct malignancies. These findings support a model of early clonal divergence from a common progenitor rather than independent malignancies or linear differentiation. This case highlights the complexity of clonal evolution in B-cell malignancies and underscores the importance of integrated genomic and immunophenotypic analysis in understanding disease biology.
Management and prevention of thromboembolism (TE) in pediatric acute myeloid leukemia (AML) are challenging because of prolonged periods of thrombocytopenia and associated bleeding. There are no guidelines for prophylactic or therapeutic anticoagulation for children with AML. This study aimed to understand the use of anticoagulation and its association with bleeding events (BEs) during index hospitalization in children with AML, both with and without thromboses. A retrospective cohort study was performed using the Pediatric Health Information System administrative database of index hospitalizations for patients aged 1 to 21 years from 2016 to 2024 with the diagnosis of AML across 49 children's hospitals. Demographic data, diagnosis of TE, anticoagulation use, and BE were extracted. A total of 3768 patients with AML were included, with 167 (4.4%) experiencing a TE. A total of 171 patients (4.5%) received anticoagulation, with almost half receiving anticoagulation in the absence of a TE diagnosis (presumed prophylaxis). Of patients with a TE, 88 (52.3%) received anticoagulation, with the remainder receiving no anticoagulation. Enoxaparin was the most frequently used anticoagulant, followed by rivaroxaban, but wide institutional variation was observed in the choice of anticoagulant. A total of 750 patients (20%) experienced ≥1 BE. Most patients (705/750 [94%]) with BE received no anticoagulation. Prospective research is needed to determine the safest and most effective use of prophylactic and therapeutic anticoagulation in this patient population.
In this study, we modeled gene expression profile data from Acute Myeloid Leukemia (AML) and healthy cases. At first, the GEO-GSE9476 dataset was processed, and a total of 341 genes were identified as differentially expressed genes (DEGs) in patients, and 599 DEGs in healthy individuals. Gene Ontology and pathway analysis on DEGs led to the identification of 5 Transcription Factors for patients and 3 for healthy cases. Analysis of the respective metabolic pathways revealed a common region in the metabolic pathway between AML and Tuberculosis (TB) that confirmed the validity of our procedure due to the consistency with similar reports. Upon PPI network analysis, Hub genes and three modules containing 41 up-regulated and down-regulated genes in AML patients were identified. Survival analysis on these genes results in reducing the number of identified effective genes into 3 upregulated (ITGAM, ITGAL and CD163) and 5 downregulated genes (MCM2, MCM3, RFC4, RFC5 and FEN1). Finally, drug sensitivity analysis was performed on these genes demonstrating complexity in drug-resistance due to the pattern of gene expression. This knowledge could potentially enable personalized treatment approaches based on individual patient responses due to the epigenetics and life style which affect gene expression pattern.
Interferon (IFN)-resistant cell clones 3Cl8 and 3γR8, isolated from wild-type Friend erythroleukemia cells 745A were characterized to identify the resistance defect. The 3Cl8 cell clone is resistant to type I IFNs and sensitive to type II IFN, whereas 3γR8, derived from 3Cl8, is resistant to both type I and II IFNs. Here, we report that no activation of the JAK-STAT pathway is detected after IFN treatment of resistant cells. Interestingly, the absence of major transcripts of the IFNAR2 receptor chain has been observed in type I IFN-resistant cells, and a point mutation relative to the IFNGR2 receptor chain (β chain) has been identified in type II IFN-resistant cells, inducing a frameshift leading to premature termination of translation. In addition, we have identified a new polymorphism of the murine IFNAR1 chain and possibly the presence of a murine IFNAR2b transmembrane, non-transducing chain in 745A cells, similar to that observed in humans and differing from previous reports on other murine systems.
Chimeric antigen receptor T-cell (CAR-T) therapies targeting CD19 have demonstrated effectiveness in the treatment of relapsed/refractory B-cell malignancies. Several CAR-T therapies have been approved in the United States, including axicabtagene ciloleucel (axi-cel), for relapsed/refractory diffuse large B-cell lymphoma (DLBCL), and brexucabtagene autoleucel (brexu-cel), for B-cell precursor acute lymphoblastic leukemia and mantle cell lymphoma (MCL). However, use of CAR-T therapies can result in potentially severe adverse effects such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). This analysis of real-world data evaluated the incidence and management of CRS and ICANS in patients with B-cell malignancies following treatment with axi-cel or brexu-cel therapy. This retrospective observational cohort study analyzed data from the Center for International Blood and Marrow Transplant Research (CIBMTR). Adult patients in the United States who received axi-cel or brexu-cel for any indication from October 2020 to December 2021 with ≥1 follow-up visit were included. The main outcome of interest was incidence of CRS and ICANS following CAR-T therapy, graded according to the American Society for Transplantation and Cellular Therapy (ASTCT) guidelines. Management of CRS and ICANS with preventive therapies and treatments administered following development of CRS and ICANS was also investigated. Overall, 927 patients across 87 US centers were included (axi-cel, n=707 [76.3%]; brexu-cel, n=220 [23.7%]). Median (range) age was 63 (19-89) years, and 65.3% (605/927) were male. Most patients (83.3% [n=589]) received axi-cel for diffuse large B-cell lymphoma or transformed follicular lymphoma. All patients who received brexu-cel had mantle cell lymphoma. Overall, 766 (82.6%) patients developed CRS (grade ≥2, 47.0%; 360/766). Of patients with available data, 12.4% (89/715) received CRS preventive therapy, most commonly with tocilizumab alone (79.8%; 71/89). Of patients who developed CRS, 76.6% (587/766) received CRS treatment, including 63.5% (258/406) of patients with grade 1 and 91.4% (329/360) with grade ≥2. The most common treatment was tocilizumab (97.3%; 571/587), alone or in combination. Of patients with available data, 49.8% (356/715) received ICANS prevention, mostly anti-epileptics alone (93.3%; 332/356). Of 876 evaluable patients, 424 (48.4%) developed ICANS (grade ≥2, 71.5%; 303/424). Of these, 85.6% (363/424) received treatment for ICANS, most commonly corticosteroids (92.3%; 335/363). Rates of CRS (82.6%) and ICANS (48.4%) were consistent with incidences expected based on prescribing information for axi-cel and brexu-cel, highlighting potential burdens of CAR-T therapy. These results also stress the importance of continuous patient monitoring and management during CAR-T therapy and demonstrate an evolving treatment landscape, including more aggressive management of CRS and interest in preventive therapies for CRS and ICANS.
Anti-CD20 monoclonal antibodies (mAbs) are effective but not curative treatment for chronic lymphocytic leukemia (CLL). To study rituximab efficacy, we examined serial blood samples from CLL patients receiving initial monotherapy with high-frequency low-dose (HFLD) rituximab for 1 week followed by the addition of acalabrutinib. Low-dose rituximab (intravenous infusion of 25 mg over 1 h) decreased the circulating CLL cell count by 85% with no additional changes during infusion of the next 25 mg of rituximab. Limited clearance of CLL cells was not attributable to low concentrations of rituximab or complement and was most likely caused by exhaustion of innate immune cytotoxicity as previously described for larger rituximab doses. Circulating CLL counts and CD20 levels rebounded by 48 h when subcutaneous administration of 50 mg of rituximab caused a small but significant decrease in CLL cell counts. Administration of 100 mg of rituximab in the first week of therapy decreased palpable lymphadenopathy by 66%. Addition of acalabrutinib, a second-generation Bruton tyrosine kinase inhibitor (BTKi), on Day 8 of treatment was followed by decreases in CLL cell expression of MS4A1 coding for CD20, CD20 levels, and CLL cell sensitivity to rituximab-induced antibody-dependent cellular phagocytosis. Based on these data and previous reports, we propose that rituximab therapy in CLL patients is optimized by HFLD regimens, which achieve maximum CLL cell clearance at dosing intervals sufficient for recovery of immune cytotoxicity. Our data also suggest that the efficacy of rituximab, and possibly other CD20-targeting mAbs, could be decreased by the addition of acalabrutinib or other BTKi.
Friedreich Ataxia (FRDA) is a neurodegenerative disorder of children and young adults associated with cardiomyopathy and other systemic complications. We report a 10-year-old girl who presented simultaneously with Acute Myelogenous Leukemia and FRDA who was successfully treated for her leukemia with allogeneic hematopoietic stem cell transplant. She experienced no major complications. After the transplant, her neurologic disease progressed similarly to other patients, but her blood frataxin levels returned to normal and cardiac hypertrophy decreased. This shows that FRDA patients can be treated with bone marrow transplantation, but such treatment alone has no direct effect on progression of neurologic disease.
Second malignant neoplasms (SMNs) are rare but serious late effects in childhood acute lymphoblastic leukemia (ALL) survivors. Mature peripheral T-cell lymphomas involving both the breast and ovary are exceedingly rare, and their relationship with germline predisposition variants remains poorly understood. We report a 17-year-old female, previously treated for high-risk B-cell ALL and in sustained remission, who developed bilateral breast and ovarian masses in 2024. Histopathology and immunohistochemistry confirmed a mature T-cell lymphoma (CD7+, CD99+, weak CD5/CD3, Ki-67 >90%, TdT-). Whole-exome sequencing revealed a germline pathogenic BRCA2 variant (c.1910-2A>T) along with additional likely pathogenic variants (CUX1, MED12L, POLR3B, PIK3CA). The disease progressed rapidly despite CHOP chemotherapy, and the patient died shortly after diagnosis. This report describes an exceptionally rare SMN of peripheral T-cell lymphoma with breast and ovarian involvement in a pediatric leukemia survivor. The coexistence of a germline BRCA2 mutation and additional genomic alterations suggests a multigenic predisposition hypothesis. Early incorporation of next-generation sequencing may uncover molecular vulnerabilities and inform alternative therapeutic strategies in refractory hematologic malignancies.
Acute myeloid leukemia (AML) harboring a FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutation is characterized by a more aggressive clinical course, a higher likelihood of disease recurrence, and inferior survival outcomes. The introduction of targeted agents such as gilteritinib has expanded therapeutic options for patients with FLT3-mutated AML; however, the spectrum of rare treatment-related toxicities remains incompletely defined. We describe a case of profound hypertriglyceridemia that developed during treatment with a combination of azacitidine, venetoclax, and gilteritinib. A 52-year-old man presented with constitutional symptoms, marked leukocytosis, splenomegaly, and bone marrow findings consistent with AML exhibiting monocytic differentiation. Molecular analysis identified coexisting FLT3-ITD, nucleophosmin 1 (NPM1), and DNA methyltransferase 3A (DNMT3A) mutations. Owing to concomitant fungal pneumonia and unsuitability for intensive induction chemotherapy, he was treated with a modified regimen comprising azacitidine, venetoclax, and gilteritinib. The patient's baseline lipid profile was within normal limits. Following two cycles of induction therapy, a bone marrow aspirate was done. Serum triglyceride levels were found to be severely elevated at 6,964 mg/dL. Given the patient's prior episode of pancreatitis, this abnormality was considered clinically significant. Gilteritinib, venetoclax, and isavuconazole were discontinued, and lipid-lowering therapy with rosuvastatin and fenofibrate was commenced. Triglyceride concentrations progressively declined and returned to near-normal levels within one month. This report draws attention to a potentially serious and insufficiently recognized metabolic complication associated with FLT3 inhibitor-based combination therapy. It also underscores the importance of routine lipid surveillance, particularly in patients receiving concomitant azole antifungal agents.
Children with Down syndrome (DS) experience excessive treatment-related mortality (TRM), primarily due to infectious complications, during treatment for acute lymphoblastic leukemia (ALL). This risk further increases during the intensive chemotherapy required to treat a relapse of ALL, limiting the feasibility of conventional intensive relapse chemotherapy. Anti-cluster of differentiation 19 (CD19) chimeric antigen receptor (CAR) T-cell therapy is an emerging treatment option for children with DS and relapsed B-ALL, including those in first relapse. This approach has demonstrated promising efficacy while potentially reducing the TRM associated with intensive salvage chemotherapy. Access to this form of immunotherapy for patients with DS and relapsed B-ALL is strongly encouraged.
Juvenile myelomonocytic leukemia (JMML) rarely manifests with extramedullary involvement beyond spleen, liver, or skin; testicular infiltration at diagnosis is unreported. We describe a Novel Case of bilateral testicular leukemic infiltration as the initial presentation of NRAS-mutant JMML in a toddler, with rapid remission following azacitidine bridging and haploidentical HSCT. A 2-year-old boy presented with pallor, abdominal distension, and bilateral scrotal swelling. Labs: leukocytosis (58 × 10⁹/L, monocytes 12.8 × 10⁹/L), anemia (Hb 8.2 g/dL), HbF 22%. BM confirmed JMML with NRAS p.G12D (VAF 42%). No pathogenic variants were detected in KRAS, PTPN11, CBL, or NF1. Conventional cytogenetic analysis demonstrated a normal male karyotype (46,XY). US: testes enlarged (18.8/18.2 mL) with hypoechoic infiltration. Azacitidine (75 mg/m²/d × 5, 2 cycles) reduced counts and size. Paternal haplo-HSCT (Flu-Treo-TT conditioning, PTCy) engrafted D + 18; testes normal at 6 weeks, molecular remission (NRAS-) at 3 months. This novel case underscores the efficacy of azacitidine and haploidentical HSCT for NRAS-mutant JMML with testicular involvement. Routine genital examination and ultrasound are recommended for male patients.
Bosutinib, an orally administered dual Src and Bcr-Abl tyrosine kinase inhibitor (TKI), is approved for the treatment of chronic phase Philadelphia chromosome-positive chronic myelogenous leukemia, newly diagnosed or resistant/intolerant to previous treatment of one or more TKIs in adults and children ≥ 1 years (by the US Food and Drug Administration) and ≥ 6 years (by the European Medicines Agency). Owing to the limitations of non-compartmental analysis in pharmacokinetic (PK) characterization, this study applies a prior population PK modeling approach to describe the pediatric PK of bosutinib on the basis of its phase I dose-finding trial and the available bosutinib adult PK knowledge. From 26 pediatric patients in the phase I part of the ITCC-054/COG AAML1921 trial, 235 plasma bosutinib concentration samples were analyzed. A published adult bosutinib population PK (popPK) model was used as the reference model; the frequentist prior modeling approach was used during model development to integrate adult PK information, especially for parameters with poor identifiability. Bosutinib pediatric PK was well characterized by a two-compartment model with first-order absorption, an absorption lag time of 0.467 h, and allometric scaling with fixed exponents. The typical clearance was 74.9 L/h (normalized to 70 kg), higher than the reported adult value (56.3 L/h). Model-based simulations validated that the bosutinib recommended phase II dose (RP2D) could achieve the target exposure observed in adults and demonstrated the influence of higher clearance in pediatric patients. This study presents the first pediatric bosutinib popPK model, integrating prior adult PK knowledge to enable robust PK characterization using a small pediatric dataset from an early trial stage. In addition, the model confirms a higher clearance in children and supports the RP2D concluded in the phase I dose-finding part of the ITCC-054/COG AAML1921 trial.
No large, randomized trials have compared three or more tyrosine kinase inhibitors (TKIs) in a single chronic myeloid leukemia (CML) cohort. Most studies are two-arm comparisons versus imatinib, or rely on indirect methods. A retrospective cohort study was conducted of 349 patients with chronic- and accelerated-phase CML treated between 2007 and 2023 at Cleveland Clinic centers in Northeast Ohio. Overall survival (OS), event-free survival (EFS), 12-month therapeutic milestone achievement, and BCR-ABL1 transcript decline velocity across first-, second-, and third-line TKIs were compared. Baseline demographics, comorbidities, cytogenetics, and hematologic parameters were collected. Multivariable regression and time-dependent Cox models were adjusted for confounders and varying therapy initiation times. First-line TKIs included imatinib (53%), dasatinib (30%), nilotinib (15%), and bosutinib (2%). Median age ranged from 52 to 60 years, most patients were White, and high-risk cytogenetics were rare. Five-year OS ranged from 78% for dasatinib to 90% for nilotinib, with nilotinib associated with improved OS (hazard ratio [HR], 0.43) and EFS (HR, 0.48) and the fastest BCR-ABL1 decline (β = -8.3%) versus imatinib. In second- (n = 181) and third-line therapy (n = 91), no significant differences in outcomes were observed. Across all lines, time-dependent modeling showed improved EFS only for nilotinib (HR, 0.61). Unadjusted OS was higher in patients starting treatment in 2007-2010 versus later periods but differences disappeared after adjustment. Real-world data indicate that imatinib achieves comparable response rates to newer TKIs, with durable survival. Nilotinib consistently shows faster BCR-ABL1 decline and improved EFS overall, consistent with prior network meta-analyses. Lack of improvement in OS over time suggests the need to investigate factors influencing long-term outcomes in CML.
In the World Health Organization (WHO) 2022 classification of chronic myelomonocytic leukemia (CMML), the cutoff for absolute monocyte values was lowered from 1.0 × G/L (2016) to 0.5 × G/L to incorporate cases formerly referred to as oligomonocytic CMML. The prevalence of this criterion in the general population and its potential association with demographic parameters and comorbidities is unclear. In order to answer these questions, we used the previously published LEAD (lung, heart, social, body) cohort (ClinicalTrials.gov; NCT01727518), which is a longitudinal, observational, population-based Austrian cohort aiming to investigate the impact of genetic, environmental, social, developmental, and ageing factors on respiratory health and associated comorbidities through life. The prevalence of the 2022 criterion was 11.976% in the general population, as compared to 0.747% of the 2016 criterion. In the descriptive analysis, individuals with the 2022 criterion as compared to those without this criterion were more often males, had a greater height and bodyweight, more frequently suffered from cardiovascular (CVD) and chronic obstructive pulmonary disease (COPD), and had higher C‑reactive protein (CRP) values. In the multivariable logistic regression, higher CRP, COPD, and CVD were significantly associated with the 2022 criterion. Our results show that in the general population, the 2022 CMML blood diagnostic criterion is 16 times more common than the 2016 criterion. The 2022 criterion is associated with CVD, COPD, and inflammation, which should be considered in the interpretation of this criterion in clinical practice. In der Klassifikation der Weltgesundheitsorganisation (WHO) von 2022 für myeloische Neoplasien wurde der Grenzwert der absoluten Monozytenzahl für die Diagnose der chronischen myelomonozytären Leukämie (CMML) von 1,0 G/l (2016) auf 0,5 G/l herabgesetzt, um die Fälle der früheren oligomonozytären CMML mit zu erfassen. Die Prävalenz dieses Kriteriums in der Allgemeinbevölkerung und seine potenzielle Assoziation mit demografischen Parametern und Komorbiditäten ist unklar. Um diese Fragen zu beantworten, haben wir die LEAD-Kohorte („lung, heart, social, body“; ClinicalTrials.gov; NCT01727518) herangezogen, die als eine longitudinale, populationsbasierte österreichische Beobachtungsstudie publiziert und konzipiert wurde mit dem Ziel, den Einfluss genetischer, umweltbezogener, sozialer, entwicklungsabhängiger und altersabhängiger Faktoren auf Lungengesundheit und assoziierte Komorbiditäten im Laufe des Lebens zu untersuchen. Die Prävalenz des Kriteriums von 2022 in der Allgemeinbevölkerung war 11,976 % verglichen mit 0,747 % des Kriteriums von 2016. In der deskriptiven Analyse war dieses neue Kriterium bei Männern, bei Menschen mit vermehrter Körpergröße und höherem Körpergewicht häufiger nachweisbar sowie bei Personen mit kardiovaskulären Erkrankungen (CVD), chronisch obstruktiver Lungenerkrankung (COPD) und erhöhtem Wert für C‑reaktives Protein (CRP). Auch in der multivariablen logistischen Regression waren höhere CRP-Werte, CVD und COPD mit diesem Kriterium assoziiert. Die Assoziation dieser Faktoren mit dem 2022 eingeführten Monozytengrenzwert bei CMML sollte bei der Interpretation dieses neuen Kriteriums berücksichtigt werden.