The efficacy of BCR-ABL tyrosine kinase inhibitors (TKIs) in treating chronic myelogenous leukemia and other malignancies is well-documented. However, concerns about potential nephrotoxicity have raised questions. This study, conducted at Tikur Anbesa Specialized Hospital (TASH) in Addis Ababa, Ethiopia, aimed to investigate the association between TKIs and renal toxicities.
A hospital-based cross-sectional design was used to enroll 260 TASH patients actively receiving BCR-ABL TKIs. Demographic information, diagnoses, treatment details, and laboratory test results were collected for each participant's Electronic Medical Record. The primary goal was to assess adverse renal events, a combination of events of a decrease in estimated glomerular filtration rate (eGFR) exceeding 30% from baseline, significant proteinuria, and a diagnosis of acute kidney injury (AKI) or chronic kidney disease (CKD). A logistic regression model was used to analyze the data and identify factors associated with developing adverse renal events.
Our analysis revealed a statistically significant decrease in eGFR following treatment with TKIs. However, the observed rate of adverse renal events (13.1%) was lower than reported in some previous studies. Factors significantly associated with adverse renal events included longer TKI duration, male sex (protective), hypertension, HIV infection, and achieving complete molecular remission and/or a complete hematologic response. No significant associations were found with diabetes mellitus, age, angiotensin-converting enzyme inhibitors use, or baseline creatinine level.
While this study found that BCR-ABL TKIs can lead to a decline in eGFR, AKI, and CKD, it also demonstrated that they were relatively safer in our study population.
IDH2 mutation is an unfavorable prognostic factor in patients with primary myelofibrosis (PMF) but its effect on myelofibrosis (MF) remains largely unclear.
In this study, we aimed to elucidate the roles of IDH2 mutation in the development and progression of MF by transcriptomic and molecular techniques using the Idh2R172K transgenic mice.
We found that thrombopoietin (TPO)-overexpressed Idh2R172K (Idh2R172K + TPO) mice had accelerated progression to MF, compared with TPO-overexpressed Idh2-wild (WT + TPO) mice, showing activation of multiple inflammatory pathways, among which nuclear factor κB (NFκB) was the most significantly enhanced. Single-cell transcriptomes of the marrow cells in early MF showed that S100a8/a9 expression was mainly confined to neutrophil progenitors in the WT + TPO mice, but highly expressed in several types of myeloid precursor cells, including the megakaryocyte progenitors in the Idh2R172K + TPO group. Furthermore, Idh2R172K mice at age of 18 months had larger spleens, increased S100a8/a9-Tlr4 expression, and elevated serum S100a8/a9 levels compared with WT mice. PMF patients with IDH2 mutations had higher bone marrow plasma S100A8/A9 levels than those without IDH2 mutations.
Overall, our findings showed that IDH2 mutation induced proinflammatory effects, which further exacerbated MF, as evidenced by the increase in S100a8/a9 levels and NFκB hyperactivation in Idh2R172K + TPO mice.
Core-binding factor acute myeloid leukemia (CBF-AML) is characterized by the presence of inv(16)/t(16;16) or t(8;21) and is classified as a favorable risk by the 2022 European LeukemiaNet (ELN) guidelines. The CD33-targeting antibody-drug conjugate, gemtuzumab ozogamicin (GO), is commonly added to intensive chemotherapy (IC) in CBF-AML. We sought to compare outcomes in patients treated with IC with or without GO in CBF-AML. We included 200 patients with CBF-AML treated with IC across seven academic centers. Induction treatment regimens were categorized as IC alone, IC with GO, or IC with KIT inhibitor (dasatinib or midostaurin). Median follow-up for the whole cohort was 2.5 years. Three-year overall survival (OS) was 70% and 3-year event-free survival (EFS) was 51%. Patients treated with IC with GO experienced a 3-year EFS of 50% compared to those treated with IC alone who experienced a 3-year EFS of 47%, with no statistically significant difference (p = 0.62). Similarly, those treated with IC with GO did not experience an improved OS compared to those treated with IC alone (p = 0.67). Patients treated with IC with KIT inhibitor experienced a significantly improved 3-year EFS of 85% compared to those with IC with or without GO (p = 0.04). We find in our study that there is no survival benefit in patients treated with IC with the addition of GO; improved EFS was seen in patients with CBF-AML treated with IC plus KIT inhibitors, consistent with outcomes noted in prospective studies utilizing this approach.
Carfilzomib is a proteasome inhibitor that has been shown to improve progression-free survival and overall survival (OS) in patients with relapsed/refractory multiple myeloma (RRMM) [1-3]. In Europe, carfilzomib is approved for the treatment of patients with RRMM in combination with dexamethasone (Kd); lenalidomide and dexamethasone (KRd); and, since 2020, daratumumab and dexamethasone (D-Kd) [4-6]. A recent observational cohort study described the use of KRd and Kd across Europe and Israel [7, 8], but survival data in the real-world setting have not been reported for carfilzomib-treated patients in Europe. Using and expanding on a previous study of patients with RRMM from the Système Nationale des Données de Santé (SNDS) national claims database [9], this comprehensive real-world analysis describes the treatment patterns and outcomes of patients receiving carfilzomib (KRd and Kd) in France between 2016 and 2019.
Briefly, adults who were diagnosed with multiple myeloma and had received at least one dose of carfilzomib between 2014 and 2019 were included. The study design has previously been published [9]; this study extension had an end date of December 31, 2019. Carfilzomib became available in France in 2016 under an Authorization for Temporary Use, and then became fully available in July 2018. For each patient, data were collected on clinical characteristics and were analysed as a primary objective. Data on treatment patterns were also analysed. OS and time-to-next treatment (TTNT) were estimated in an exploratory analysis. OS was defined as the time from the start of carfilzomib treatment until death or the end of follow-up. TTNT was defined as the start of carfilzomib treatment until the initiation of the next line of treatment or death.
The database included 2471 patients treated with carfilzomib-based regimens. Clinical characteristics are presented by treatment group (KRd or Kd) and treatment line (second line [2L], third line [3L], and fourth or later lines [4L+]) in Table 1. Overall, 40% (n = 993) of patients received KRd. Half of patients (n = 497; 50%) receiving KRd initiated it as a 2L treatment, and 44%–60% had autologous stem cell transplantation (ASCT) at first line (1L). Most patients (n = 1478; 60%) received the Kd regimen, which was generally initiated as 4L+ (n = 1133; 77%). Among patients receiving Kd at 4L+, 40% had ASCT at 1L and most had previous exposure to bortezomib (98%), lenalidomide (91%), or daratumumab (60%) (Table 1).
Patients receiving KRd were followed up for a mean of 11–15 months. The median OS estimates for patients receiving KRd were 40, 39, and 16 months at 2L (n = 497), 3L (n = 203), and 4L+ (n = 293), respectively. For patients initiating KRd in 2018, the median TTNT was longer when carfilzomib was received at earlier lines than later lines (2L, 14 months; 3L, 11 months; 4L
A 31-year-old woman presented with progressive left arm, and neck swelling 2 weeks after a blood transfusion via a cannula in her left antecubital fossa, for severe menorrhagia. Imaging (Figure 1) demonstrated extensive deep vein thrombosis of the left arm extending to the skull base (top left image), extensive bilateral pulmonary emboli, and prominent, subcentimeter para-aortic and bilateral pelvic lymph nodes. The D-dimer level was significantly elevated at 46,212 ng/mL (0‒230). She was immediately started on apixaban.
Two weeks later, she presented with progressive headache and visual loss and was diagnosed with a left sigmoid sinus thrombus, a short segment occlusion of the left middle cerebral artery (bottom left image) and bilateral parieto-occipital infarction (middle left image). The strokes manifested as cortical blindness and aphasia. There were no concerns regarding the patient's compliance with apixaban; an anti-Xa apixaban level confirmed that she had taken a recent dose. The patient was switched to twice daily enoxaparin, aiming for a peak anti-Xa level of 1.0‒1.2 U/mL. Aspirin 75 mg daily was also initiated.
She was urgently investigated for possible causes of this severe prothrombotic state, including catastrophic anti-phospholipid syndrome, thrombotic thrombocytopenic purpura, myeloproliferative neoplasms, paroxysmal nocturnal hemoglobinuria, and auto-immune heparin-induced thrombocytopenia, all of which were negative. A further total body computed tomography demonstrated no change in the lymph node features but revealed new splenic and renal infarcts. On transthoracic echocardiogram, a thrombus was visible on both the tricuspid and mitral valves. In the absence of an identifiable cause, positron emission tomography was performed, demonstrating uptake in the cervix (right-sided image), para-aortic lymph nodes and peritoneal deposits. A cervical biopsy confirmed a diagnosis of metastatic cervical adenocarcinoma that was positive for high-risk human papillomavirus (HPV)45. Interestingly, cervical screening was HPV negative 20 months prior to this presentation. The patient unfortunately died shortly after commencing palliative chemotherapy.
Cancer is a hypercoagulable state associated with a sevenfold increase in venous thromboembolism; however, the association with arterial thromboembolism is less well-established [1]. Mucin-producing adenocarcinomas are one of the most common tumours associated with venous thromboembolism (VTE) [2] since mucin directly stimulates platelet activation [3]. Patients with cervical cancer have a higher cumulative risk of VTE as compared to the general population [4]. The incidence of thromboembolism has been demonstrated to be highest during chemotherapy [5].
Jordan Burgess wrote the paper. Fraser Hendry supplied images and performed interpretation of radiological findings. Catherine Bagot helped in writing the
Hydroxyurea is the preferred first-line cytoreductive treatment for high-risk essential thrombocythaemia (ET), but many patients are intolerant or refractory to hydroxyurea. Ruxolitinib has been shown to improve symptoms in patients with ET. This post hoc analysis compared the clinical outcomes of patients with ET who received hydroxyurea only with those who switched from hydroxyurea to ruxolitinib due to intolerance/resistance to hydroxyurea. Patients with ET refractory/intolerant to hydroxyurea treated with ruxolitinib in a completed phase 2 study (HU-RUX) were propensity score matched with patients who received hydroxyurea only in an observational study (HU). Changes in leukocyte and platelet counts were reported at 6-month intervals during the 48-month follow-up. Following propensity score matching, 37 patients were included for analysis in each cohort. Mean (standard deviation [SD]) leukocyte and platelet counts at index were higher for HU-RUX versus HU (leukocyte: 9.3 [5.1] vs. 6.8 [3.1] × 109/L; platelet: 1027.4 [497.8] vs. 513.9 [154.7] × 109/L), both of which decreased significantly from index to 6 months through to 48 months in HU-RUX (mean [SD] change from index at 6 months—leukocyte: −1.8 [4.6] × 109/L; platelet: −391.7 [472.9] × 109/L; at 48 months—leukocyte: −3.8 [5.3] × 109/L; platelet: −539.0 [521.8] × 109/L), but remained relatively stable in HU (mean [SD] change from index at 6 months—leukocyte: 0 [1.8] × 109/L; platelet: −5.7 [175.3] × 109/L; at 48 months—leukocyte: −0.1 [2.7] × 109/L; platelet: −6.9 [105.1] × 109/L). In conclusion, these results demonstrate that switching from hydroxyurea to ruxolitinib in patients with ET who are intolerant or refractory to hydroxyurea could improve abnormal haematologic values similar to those who receive first-line hydroxyurea.
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