Overexposure to venetoclax is associated with prolonged-duration of neutropenia during venetoclax and azacitidine therapy in Japanese patients with acute myeloid leukemia.

PURPOSE: An observational study was conducted to evaluate the pharmacokinetics of venetoclax and its impact on the efficacy and safety for Japanese patients with acute myeloid leukemia (AML) treated with venetoclax and azacitidine therapy. METHODS: The association between the plasma concentration, after the first cycle of azacitidine and venetoclax therapy, and the efficacy and safety was evaluated in 33 patients with untreated or relapsed/refractory AML. RESULTS: Full dose of venetoclax was administered to all patients. Venetoclax treatment was 28 day long in 82% of patients; the relative dose intensity of azacitidine was 82%. Trough concentration was significantly higher among patients with complete remission (CR) and CR with incomplete hematologic recovery (CRi) than those with the morphologic leukemia-free state and partial remission, and no response groups (P = 0.01). Median duration of grade 3 neutropenia was 28 days (range 8-46 days). Area under the concentration-time curve (AUC0-24) was significantly higher among patients with protracted grade 3 neutropenia (≥ 28 days) than those with a shorter duration (< 28 days) (P = 0.03); multivariate analysis revealed that a higher AUC0-24 was a significant predictor of a longer duration of neutropenia (odds ratio 54.3, P = 0.007). CONCLUSION: Plasma concentrations of venetoclax were variable in Japanese patients with AML. Higher plasma concentrations were associated with CR/CRi and protracted grade 3 neutropenia. Therefore, it is essential to adjust the duration of venetoclax administration based on individual pharmacokinetic data to limit total drug exposure, reduce severe neutropenia, and achieve higher efficacy.

Abdominal aortic mural thrombus in association with active ulcerative colitis.

Aortic mural thrombus (AMT) in the absence of aneurysm or atherosclerosis is a rare clinical finding and an uncommon cause of peripheral arterial embolization. AMT in a normal artery is usually attributed to systemic hypercoagulability. We describe a case of subacute lower limb ischemia due to AMT associated with active ulcerative colitis (UC). A 46-year-old man with active UC was referred to our hospital for the evaluation and treatment of left leg pain. Ultrasound and contrast computed tomography showed occlusion of the left popliteal artery, and an AMT in the abdominal aorta between the inferior mesenteric artery and the aortic bifurcation. We started anticoagulant therapy, intravenous infliximab, and cytapheresis. Four weeks after initiating anticoagulation therapy, we were able to successfully treat the AMT with anticoagulation therapy without surgical thrombectomy. The inflammatory status of ulcerative colitis was also under control, and AMT had not recurred at 1 year after treatment. Invasive therapies are often selected to treat AMT. However, if a patient's hypercoagulable state is controlled, AMT can safely be treated with anticoagulation therapy alone without recurrence. Learning objective: Aortic mural thrombus (AMT) in the absence of aneurysm or atherosclerosis is a rare clinical finding and an uncommon cause of peripheral arterial embolization. AMT in a normal artery is usually attributed to systemic hypercoagulability. We describe a case of subacute lower limb ischemia due to AMT associated with active ulcerative colitis. We controlled the ulcerative colitis condition and successfully treated the AMT with anticoagulation therapy alone.

ctDNA improves prognostic prediction in relapsed/refractory MM receiving ixazomib, lenalidomide, and dexamethasone.

It remains elusive how driver mutations, including those detected in circulating tumor DNA (ctDNA), affect prognosis in relapsed/refractory multiple myeloma (RRMM). Here we performed targeted-capture sequencing using bone marrow plasma cells (BMPC) and ctDNA of 261 RRMM cases uniformly treated with ixazomib, lenalidomide, and dexamethasone in a multicenter, prospective, observational study. We detected 24 and 47 recurrently mutated genes in BMPC and ctDNA, respectively. In addition to clonal hematopoiesis-associated mutations, varying proportion of driver mutations, particularly TP53 mutations (59.2% of mutated cases), were present in only ctDNA, suggesting their subclonal origin. In univariable analyses, ctDNA mutations of KRAS, TP53, DIS3, BRAF, NRAS, and ATM were associated with worse progression-free survival (PFS). BMPC mutations of TP53 and KRAS were associated with inferior PFS, while KRAS mutations were prognostically relevant only when detected in both BMPC and ctDNA. A total number of ctDNA mutations in the six relevant genes was a strong prognostic predictor (2-year PFS rates: 57.3%, 22.7%, and 0% for 0, 1, and ≥ 2 mutations, respectively) and independent of clinical factors and plasma DNA concentration. Using the number of ctDNA mutations, plasma DNA concentration, and clinical factors, we developed a prognostic index (ctRRMM-PI), classifying patients into three categories with 2-year PFS rates of 57.9%, 28.6%, and 0%. Serial analysis of ctDNA mutations in 94 cases revealed that TP53 and KRAS mutations frequently emerge after therapy. Thus, we clarify the genetic characteristics and clonal architecture of ctDNA mutations and demonstrate their superiority over BMPC mutations for prognostic prediction in RRMM.

Prognostic impact of peripheral blood WT1 mRNA dynamics in patients with acute myeloid leukemia treated with venetoclax combination therapy.

BACKGROUND: Wilms' tumor gene 1 (WT1) mRNA quantification is a useful marker of measurable residual disease in acute myeloid leukemia (AML). However, whether monitoring the WT1 mRNA levels may predict the outcome of venetoclax (VEN) combination therapy in AML is not reported. This study aims to elucidate whether WT1 mRNA dynamics could predict long-term prognosis. METHODS: 33 patients with untreated or relapsed/refractory AML evaluated for peripheral blood WT1 dynamics in VEN combination therapy were analyzed. RESULTS: The median age was 73 years (range 39-87). Azacitidine was combined with VEN in 91% of patients. Overall, the median overall survival (OS) was 334 days (95% CI 210-482), and the complete remission (CR) plus CR with incomplete hematologic recovery rate was 59%. A 1-log reduction of WT1 mRNA values by the end of cycle 2 of treatment was associated with significantly better OS and event-free survival (EFS) (median OS 482 days vs. 237 days, p = 0.049; median EFS 270 days vs. 125 days, p = 0.02). The negativity of post-treatment WT1 mRNA value during the treatment was associated with significantly better OS and EFS (median OS 482 days vs. 256 days, p = 0.02; median EFS not reached vs. 150 days, p = 0.005). Multivariate analysis confirmed the significance of these two parameters as strong EFS predictors (HR 0.26, p = 0.024 and HR 0.15, p = 0.013, respectively). The increase in WT1 mRNA values was correlated with relapse. CONCLUSION: This study demonstrates that WT1 mRNA dynamics can be a useful marker for assessing long-term prognosis of VEN combination therapy for AML.

[Successful cord blood transplantation for refractory gamma-delta hepatosplenic T-cell lymphoma developed during treatment of Crohn's disease].

The patient was a 21-year-old man who had been diagnosed with Crohn's disease and received infliximab and azathioprine six years earlier. He was admitted with fever and fatigue. Peripheral blood examination showed LDH 2,473 U/l and thrombocytopenia, and contrast-enhanced computed tomography (CT) showed hepatosplenomegaly. Bone marrow biopsy and liver biopsy showed CD4+CD56+TCRγδ＋CD8- atypical cells, leading to a diagnosis of hepatosplenic T-cell lymphoma (HSTCL). The patient was refractory to CHOP and DA-EPOCH, and therefore received cord blood transplantation with myeloablative conditioning. CT showed reduced in hepatosplenomegaly and peripheral blood examination showed LDH 165 U/l and plt 180,000/µl, so the patient was discharged on day117. HSTCL is a tumor of immature γδT cells with a Vδ1 mutation in the spleen, and immunodeficiency has been implicated in its pathogenesis. Patients with inflammatory bowel disease treated with azathioprine are known to have an increased risk of lymphoproliferative disease. In this case, use of immunosuppressive drugs for Crohn's disease may have caused malignant transformation of γδ cells in the intestinal epithelium. Although the patient was refractory to chemotherapy, he was able to achieve remission with early cord blood transplantation and long-term survival is expected.

A prospective, multicenter, observational study of ixazomib plus lenalidomide-dexamethasone in patients with relapsed/refractory multiple myeloma in Japan.

Real-world studies permit inclusion of a more diverse patient population and provide more information on the effectiveness of treatments used in routine clinical practice. This prospective, multicenter, observational study investigated the effectiveness and safety of ixazomib plus lenalidomide and dexamethasone (IRd) in 295 patients with relapsed/refractory multiple myeloma (RRMM) in routine clinical practice in Japan. Patients had a median age of 74 years, 80.0% were aged ≥ 65 years, 42.0% had received ≥ 3 lines of prior treatment, and 28.5% were "frail" according to the International Myeloma Working Group frailty score. After a median follow-up of 25.0 months, median progression-free survival (PFS) was 15.3 (95% CI 12.4-19.5) months, while median overall survival was not reached. The overall response rate was 53.9%, and 31.5% of patients had a very good partial response or better. In the subgroup analysis, median PFS was better in patients with 1 versus 2 or ≥ 3 lines of prior treatment (29.0 vs 19.2 or 6.9 months) and paraprotein versus clinical relapse (16.0 vs 7.9 months), but median PFS was not notably affected by frailty score or age group. Dose adjustment was more frequent among patients aged > 75 years, especially early after IRd treatment initiation. Treatment-emergent adverse events (TEAEs) of any grade occurred in 84.4% of patients and 24.7% of patients discontinued treatment due to TEAEs; no new safety concerns were found. These findings suggest that oral IRd triplet regimen is an effective and tolerable treatment option for RRMM patients in real-world settings outside of clinical trials.ClinicalTrials.gov identifier: NCT03433001; Date of registration: 14 February 2018.

Occurrence of adult-onset Still's disease after coronavirus disease 2019 BNT162B2 vaccination in a patient with ulcerative colitis: A case report and review of literature.

Key Clinical Message: We report an extremely rare occurrence of adult-onset Still's disease (AOSD) in a patient with ulcerative colitis. The possibility of autoinflammatory conditions such as AOSD should be considered when evaluating or treating symptoms suspected as side effects of the severe acute respiratory syndrome coronavirus 2 vaccination, regardless of the associated comorbidities. Summary: A woman in her 50s with a history of stable ulcerative colitis (UC) for 20 years, managed using salazosulfapyridine, presented with migratory rashes, spiking fever, edema, and joint pain that started 1 week after receiving the BNT162B2 mRNA vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Laboratory tests revealed extremely high serum ferritin levels. The patient was diagnosed with adult-onset Still's disease (AOSD) based on the relevant classification criteria after ruling out other diseases. Detection of high levels of interleukin-18, an inflammatory cytokine related to AOSD, supported the diagnosis. Nonsteroidal anti-inflammatory drug monotherapy alone resulted in significant improvements in both the abovementioned symptoms and the elevated inflammatory marker levels. AOSD in a patient with UC is extremely rare. Only one case of AOSD with UC was reported before the coronavirus disease 2019 era. This case indicates that SARS-CoV-2 vaccination can trigger a hyperinflammatory response, classified as AOSD, in a patient with UC, which is extremely rare.

Soft x-ray photoelectron momentum microscope for multimodal valence band stereography.

The photoelectron momentum microscope (PMM) in operation at BL6U, an undulator-based soft x-ray beamline at the UVSOR Synchrotron Facility, offers a new approach for µm-scale momentum-resolved photoelectron spectroscopy (MRPES). A key feature of the PMM is that it can very effectively reduce radiation-induced damage by directly projecting a single photoelectron constant energy contour in reciprocal space with a radius of a few Å-1 or real space with a radius of a few 100 µm onto a two-dimensional detector. This approach was applied to three-dimensional valence band structure E(k) and E(r) measurements ("stereography") as functions of photon energy (hν), its polarization (e), detection position (r), and temperature (T). In this study, we described some examples of possible measurement techniques using a soft x-ray PMM. We successfully applied this stereography technique to µm-scale MRPES to selectively visualize the single-domain band structure of twinned face-centered-cubic Ir thin films grown on Al2O3(0001) substrates. The photon energy dependence of the photoelectron intensity on the Au(111) surface state was measured in detail within the bulk Fermi surface. By changing the temperature of 1T-TaS2, we clarified the variations in the valence band dispersion associated with chiral charge-density-wave phase transitions. Finally, PMMs for valence band stereography with various electron analyzers were compared, and the advantages of each were discussed.

Revealing the Hidden Spin-Polarized Bands in a Superconducting Tl Bilayer Crystal.

The interplay of spin-orbit coupling and crystal symmetry can generate spin-polarized bands in materials only a few atomic layers thick, potentially leading to unprecedented physical properties. In the case of bilayer materials with global inversion symmetry, locally broken inversion symmetry can generate degenerate spin-polarized bands, in which the spins in each layer are oppositely polarized. Here, we demonstrate that the hidden spins in a Tl bilayer crystal are revealed by growing it on Ag(111) of sizable lattice mismatch, together with the appearance of a remarkable phenomenon unique to centrosymmetric hidden-spin bilayer crystals: a novel band splitting in both spin and space. The key to success in observing this novel splitting is that the interaction at the interface has just the right strength: it does not destroy the original wave functions of the Tl bilayer but is strong enough to induce an energy separation.

Dual antithrombotic therapy with oral anticoagulant and P2Y12 inhibitors in patients with atrial fibrillation after percutaneous coronary intervention.

BACKGROUND: The efficacy and safety of dual antithrombotic therapy (DAT) with oral anticoagulant and P2Y12 inhibitors (P2Y12i) in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) have not been well investigated. The purpose of this study was first to evaluate clinical outcomes of DAT with P2Y12i compared with triple antithrombotic therapy (TAT), and then to compare DAT with low-dose prasugrel and DAT with clopidogrel, in patients with AF undergoing PCI. METHODS: This study was a multicenter, non-interventional, prospective and retrospective registry. A total of 710 patients with AF undergoing PCI between January 2015 and March 2021 at 15 institutions were analyzed. Clinical outcomes within 1 year, including major adverse cardiovascular events (MACE) and major bleeding events (BARC 3 or 5) were compared between patients receiving DAT (n = 239) and TAT (n = 471), and then, compared among prasugrel-DAT (n = 82), clopidogrel-DAT (n = 157), and TAT. RESULTS: The DAT group showed significantly lower incidence of MACE and major bleeding events compared with the TAT group (log-rank p = 0.013 and 0.047). In the multivariable Cox regression analyses, DAT (p = 0.028), acute coronary syndrome (p = 0.025), and anemia (p = 0.015) were independently associated with MACE. In addition, anemia (p = 0.022) was independently associated with, and DAT (p = 0.056) and thrombocytopenia (p = 0.051) tended to be associated with, major bleeding events. When analyzed among the prasugrel-DAT, clopidogrel-DAT, and TAT groups, there were no significant differences in clinical outcomes between the prasugrel-DAT and clopidogrel-DAT groups, and similar trends were observed for both 2 groups in comparison with the TAT group. CONCLUSIONS: In AF patients undergoing PCI, DAT was associated with lower incidence of MACE and major bleeding events compared with TAT. In comparison of P2Y12i, there might be no significant difference in the incidence of MACE and bleeding events between prasugrel-based DAT and clopidogrel-based DAT.

Inferior Pole Sleeve Fracture of the Patella in an Adolescent: A Case Report.

An 11-year-old boy was admitted to our hospital due to severe pain in his right knee when he landed after jumping over a vaulting box. A plain X-ray image and computed tomography scan showed an avulsion fracture of the lower pole of the patella and patella alta. Furthermore, magnetic resonance imaging (MRI) revealed an articular cartilage lesion and rupture between the inferior pole of the patella and the patella tendon. We diagnosed a sleeve fracture of the patella and performed surgical treatment. Open reduction and internal fixation were performed by the pull-out technique using transosseous no. 2 MaxBraid™â€‹â€‹â€‹â€‹â€‹â€‹ ​(Zimmer Biomet, Tokyo, Japan) sutures. While postoperative weight-bearing was permitted, the knee joint was immobilized in a brace for four weeks. Three months of postoperative assessment revealed excellent functional outcomes.