EJHaem最新文献

The incidence of Richter transformation in relapsed/refractory chronic lymphocytic leukemia (CLL) is up to 15% and Richter transformation is a frequent cause of treatment failure on ibrutinib (IBR) [1]. IBR has been promising in CLL cell growth suppression by inhibiting Bruton tyrosine kinase (BTK) [2]. However, resistance can occur due to specific mutations in BTK or PLCG2 genes [3]. Another agent, venetoclax (VEN) has shown excellent efficacy in relapsed refractory CLL [4]. In Richter transformation, the effectiveness of VEN alone or in combination with conventional chemotherapy has been demonstrated, although research in this area is limited and based on only a few cases [5-7]. BTK/PLCG2 mutations play a role in IBR-resistant CLL progression. However, there is limited knowledge about BTK or PLCG2 gene mutation statuses in Richter transformation.

A 72-year-old male was diagnosed with CLL characterized by a deletion in chromosome 17p [del(17p)] and a complex karyotype. After 12 months of diagnosis, he started IBR treatment. He initially showed a partial response. Two years after starting IBR, CLL cells in the peripheral blood increased, and he developed bilateral cervical lymphadenopathy, along with elevated levels of lactate dehydrogenase (LDH) and soluble interleukin-2 receptor (sIL-2R). Fluorodeoxyglucose-positron emission tomography (FDG-PET) revealed systemic lymphadenopathy. Bone marrow examination showed increased atypical lymphocytes, displaying a CD5+CD10-19+sIgκ+ phenotype, with del(17p) present in 27% of all nucleated cells, as confirmed by fluorescence in situ hybridization. The pathological examination of the cervical lymph nodes showed a diffuse proliferation of large lymphocytes that tested positive for CD5, CD19, CD20, CD22, CD23, CD45, and BCL-2 and negative for MUM-1 and BCL-6, with a Ki-67 index of ∼50%. A biopsy confirmed the transformation into diffuse large B-cell lymphoma (Figure 1). Genetic testing was conducted on lymph nodes and bone marrow samples collected simultaneously; TP53 mutation (R283P) was found in lymph nodes [variant allele frequency (VAF): 0.85] and bone marrow specimens (VAF: 0.77). However, PLCG2 mutation (D1144G) was only detected in the lymph node specimens (VAF: 0.07). In this case, a targeted gene panel was used in Japan. The sensitivity of allele mutation detection was 0.05. A single polymerase chain reaction was not performed. Additionally, we could not measure the IGHV mutation.

The patient's treatment involved VEN usage for gradually increasing doses up to 200 mg (with fluconazole concomitant use) as per guidelines, while the use of IBR gradually reduced (Figure 2). The patient's clinical symptoms (fever and others) and lymphadenopathy showed no signs of improvement with VEN initiation and IBR dose reduction. The laboratory values indicated a worseni

Myeloproliferative neoplasms (MPNs) are associated with immune dysregulation and increased susceptibility to infection, emphasizing the importance of vaccination for patients. This pilot study evaluated immune responses to influenza vaccination in MPN patients compared with healthy donors using mass cytometry and serology. We observed diminished CXCR5+ B-cell, CXCR3+ T-cell, activated CD127+ memory T-cell subsets, and a trend toward lower hemagglutinin inhibition titer in MPN patients. These results indicate that patients with MPN exhibit distinct responses to influenza vaccination suggestive of impaired migration to lymphoid organs and T-cell maturation which may impact the development of protective immunity.

Numerous clinical studies speculated the association between multiple myeloma (MM) and inflammatory diseases; however, there is limited validation of these claims via establishing a causal relationship and revealing the underlying mechanism. This exploratory study employed bidirectional Mendelian randomization (MR) analysis to investigate the causal relationships between MM and inflammatory diseases, including atherosclerosis, asthma, ankylosing spondylitis, Alzheimer's disease (AD), Parkinson's disease (PD), sarcoidosis, inflammatory bowel disease, nonalcoholic fatty liver disease, type II diabetes, and schizophrenia (SZ). Transcriptomic and genome-wide Bayesian colocalization analyses were further applied to reveal the underlying mechanism. A significant and previously unrecognized positive association was identified between genetic predisposition to MM and the risk of SZ. Two independent case reports showed that treatment-resistant psychosis is due to underlying MM and is resolved by treating MM. From our MR analyses, various statistical methods confirmed this association without detecting heterogeneity or pleiotropy effects. Transcriptomic analysis revealed shared inflammation-relevant pathways in MM and SZ patients, suggesting inflammation as a potential pathophysiological mediator of MM's causal effect on SZ. Bayesian colocalization analysis identified rs9273086, which maps to the protein-coding region of HLA-DRB1, as a common risk variant for both MM and SZ. Polymorphism of the HLA-DRB1 allele has been implicated in AD and PD, further highlighting the impact of our results. Additionally, we confirmed that interleukin-6 (IL-6) is a risk factor for SZ through secondary MR, reinforcing the role of neuroinflammation in SZ etiology. Overall, our findings showed that genetic predisposition to MM, HLA-DRB1 polymorphism, and enhanced IL-6 signaling are associated with the increased risk of SZ, providing evidence for a causal role for neuroinflammation in SZ etiology.

Multiple myeloma (MM) is a disease, that at times poses diagnostic and monitoring challenges. Over the last decades laboratory methods have been expanded with serum free light chain (FLC) analysis. Alerted by two index cases with clinical impact due to failure of the FLC analysis to indicate a disease progression, we aimed to identify any clinical consequences due to known differences between FLC analysis methods. We applied two FLC analysis methods (Freelite Binding Site [FBS] and N-Latex Siemens [NLS]) on all patients with MM and monoclonal gammopathy of uncertain significance diagnosed/followed up at Södra Älvsborg Hematology Unit, from April to December 2022. From a total of 123 patients with malignant plasma cell disorder, we identified five cases (4.1%) where solely the FBS method, as opposed to NLS, urine and serum electrophoresis, could support diagnosis or detect progression. The consequences of this discrepancy included not only change of diagnosis or delayed therapy but also change of treatment. Our findings indicate that a stronger awareness of the potential weaknesses of different FLC methods is needed, which calls for a closer collaboration between clinical chemists and hematologists.

The FMS-like tyrosine kinase 3 (FLT3) domain is the most mutated gene in acute myeloid leukemia (AML), with FLT3 internal tandem duplication (ITD) mutations conferring adverse outcomes [1, 2]. Maintenance therapy after hematopoietic stem cell transplant (HSCT) may be essential, as FLT3 AML patients experience high rates of post-HSCT relapse and mortality [3]. Terao et al. found that relapsed/refractory (R/R) FLT3 AML patients who received post-HSCT maintenance gilteritinib had improved overall survival (OS) (1-year OS, 100% vs. 45.5%, p = 0.0075) and cumulative incidence of relapse (CIR, 1-year CIR 0% vs. 68.8%, p = 0.0028) [4]. However, the phase 3 MORPHO trial failed to reach the primary outcome of improved relapse-free survival (RFS) with post-HSCT maintenance gilteritinib compared to placebo in FLT3-ITD AML patients except in measurable residual disease (MRD) positive patients [5]. As prospective data on FLT3 inhibitor maintenance therapy are evolving, there is a need to investigate real-life data and outcomes to guide clinical decisions. 

We retrospectively studied adult patients with FLT3 AML treated at the University of Southern California (USC) Norris Cancer Center between May 2017 and July 2022. This study was approved by USC's Institutional Review Board, and data were retrieved from the Norris Comprehensive Cancer Center's electronic medical record system. 

We found post-HSCT maintenance therapy with FLT3 inhibitors improved OS, with a 2-year OS of 96.2% (93.3% for gilteritinib and 100% for midostaurin). The RADIUS trial reported a lower 2-year OS of 85% with midostaurin maintenance, while SORMAIN reported 90.5% OS with sorafenib maintenance [6, 7]. Our 2-year RFS with FLT3 maintenance was 89.7% (88.9% for gilteritinib and 90.9% for midostaurin), whereas both RADIUS and SORMAIN trials reported 2-year RFS of 85%. The RADIUS study exclusively included patients with FLT3-ITD mutations, which have poorer prognosis and may have contributed to worse outcomes than our study population (75% ITD and 25% TKD). However, our cohort included R/R AML patients and post-HSCT maintenance with both midostaurin and gilteritinib, while the RADIUS population was exclusively in CR1 and used only post-HSCT midostaurin. This is significant because neither our R/R patients nor our post-HSCT gilteritinib patients had statistically significant improved survival. Therefore, survival benefit was exclusively derived from patients in CR1 and who received midostaurin.

Terao et al. found a survival benefit of gilteritinib maintenance in the post-HSCT setting. The ADMIRAL trial also found a survival benefit for gilteritinib in R/R FLT3 AML, though less pronounced than Terao's, with only 40% achieving RFS [8, 9]. Contrastingly, our study found a survival benefit with post-HSCT midostaurin maintenance but no benefit with gilteritinib. Possibly explaining

Paroxysmal nocturnal hemoglobinuria (PNH) results from the loss of erythrocyte surface proteins, leading to complement activation and its spectrum of effects. We explore this case of a 57-year-old man with post-essential thrombocythemia (ET) myelofibrosis (MF) who developed symptomatic anemia with evidence of hemolysis on lab work. While hemolysis was localized to be intramedullary based on workup, the exact diagnosis was undetermined, leading to a prolonged course of steroid therapy to control anemia. The hemolysis was eventually attributed to PNH diagnosed on flow cytometry and the patient was treated with complement inhibitors with eventual failure of therapy. He ultimately underwent a successful hematopoietic cell transplant (HCT) with post-transplantation flow cytometry showing complete resolution of PNH. While PNH has been identified as a progression of myelodysplastic syndromes, the mechanisms of its rare development in myeloproliferative neoplasms are poorly elucidated. Furthermore, its rarity and often vague symptoms make diagnosis and treatment a challenge. This is the second reported case of a JAK2-negative, CALR-positive post-ET MF and the first reported case to be treated with HCT. This case probes for further insight into the clinical significance between MF and PNH, its impact on management, and further consideration for HCT as curative therapy in such patients who fail complement inhibitor therapy.

A 41-year-old female patient with a past medical history of cutaneous mastocytosis presented with musculoskeletal pain. A whole-body positron emission tomography-computed tomography scan showed diffuse bone marrow (BM) fluorodeoxyglucose uptake, most prominent in the humerus and femur. Her complete blood count showed hemoglobin, 7.2 g/dL; white blood cells, 9.8 × 10⁹/L with eosinophilia (2.79 × 10⁹/L); neutrophils, 4.4 × 10⁹/L; lymphocytes, 2.16 × 10⁹/L; monocytes, 0.37 × 10⁹/L; basophils, 0.03 × 10⁹/L and platelets, 179 × 10⁹/L. Her Wright-Giemsa (WG)-stained peripheral blood showed normal-appearing eosinophils without circulating blasts, atypical lymphocytes, or mast cells (MCs). Her WG-stained BM aspirate smears (Figure 1A and 1B) and Hematoxylin-eosin-stained BM biopsy sections (Figure 1C) revealed 80% of cytologically atypical MCs. These MCs exhibited distinct bilobed or multi-lobed nuclei and metachromatic intracytoplasmic granules, morphologically consistent with type II (immature) MCs (denoted with asterisks at 1000X magnification in Panels A–C). They expressed CD25, CD117, and tryptase by immunohistochemical stains and were positive for KIT D816V (variant allele frequency [VAF], 11%) and DNMT3A R899C (VAF, 46%) mutations by a next-generation sequencing study. The cytogenetic study result was normal. The residual trilineage hematopoiesis was markedly decreased with normal morphology. The patient was diagnosed with MC leukemia (MCL) and was refractory to multiple lines of therapy, including Avapritinib.

As shown in this case, it is essential to recognize the type II MCs for both diagnosis and prognostification of MCL. Although this case fulfilled the diagnostic criteria of MCL by both the International Consensus Classification (ICC) and the 5th World Health Organization Classification, the ICC specifically requires more than 20% type II (immature) MCs on the BM smear or biopsy. MCL patients with increased type II MCs often have much worse clinical outcomes.

Constance Chen drafted the manuscript and made the figure. Dong Chen drafted the manuscript and provided the pathology images of this case.

The authors declare no conflict of interest.

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Pharmacotherapy options for chronic lymphocytic leukaemia (CLL) have expanded significantly in recent years. These options include chemotherapy, chemoimmunotherapy and signalling pathway inhibitors. A notable shift in the treatment landscape began with the widespread adoption of ibrutinib in 2016. This analysis of claims data focuses on understanding how the use of novel therapies has evolved in clinical practice over the past decade in Germany. Anonymized claims data (2010–2022) from German statutory health insurance was used, covering patient demographics, treatments, and prescriptions. The study population included patients with two confirmed CLL diagnoses. Treatment patterns were analysed, and survival outcomes were compared using time-to-event analyses. In the analysed cohort of 2983 incident CLL patients, 1041 started first-line therapy between 2011 and 2022, with a median duration of 18 months from diagnosis to the first prescription. Chemoimmunotherapy, the predominant 1L therapy until 2019, decreased significantly, while targeted therapy usage increased from 3% in 2015 to 77% in 2022. Targeted therapies became dominant in patients receiving treatment for relapsed or refractory disease after 2016. Median treatment durations were: 122 days for chemo, 176 days for chemo-immuno, and 373 days for targeted therapy. The overall survival for patients diagnosed in or after 2016 was significantly better (hazard ratio 0.56, 95% confidence interval, 0.44–0.69)). The adoption of targeted therapies like ibrutinib and venetoclax has transformed CLL treatment in Germany, leading to improved patient outcomes. Additionally, we demonstrate successful adherence to evolving clinical guidelines.

A recent evidence gaps assessment of the clinical, health-related quality of life, and economic burden associated with α-thalassemia is lacking. We conducted a systematic literature review (SLR) following the methodological and reporting requirements of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and the Cochrane Handbook for Systematic Reviews, using available literature over the past decade. This SLR identified a considerable evidence gap with regard to understanding the current burden of α-thalassemia as evident from paucity of studies published in the past 10 years. The limited data available still indicate that patients with α-thalassemia experience substantial morbidity and quality of life/economic burden that is generally comparable to patients with β-thalassemia.