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Hairy cell leukemia (HCL) is an uncommon mature B-cell malignancy characterized by a typical morphology, immunophenotype, and clinical profile. The vast majority of HCL patients harbor the canonical BRAF V600E mutation which has become a rationalized target of the subsequently deregulated RAS-RAF-MEK-MAPK signaling pathway in HCL patients who have relapsed or who are refractory to front-line therapy. However, several HCL patients with a classical phenotype display non-canonical BRAF mutations or rearrangements. These include sequence variants within alternative exons and an oncogenic fusion with the IGH gene. Care must be taken in the molecular diagnostic work-up of patients with typical HCL but without the BRAF V600E to include investigation of these uncommon mechanisms. Identification, functional characterization, and reporting of further such patients is likely to provide insights into the pathogenesis of HCL and enable rational selection of targeted inhibitors in such patients if required. [ABSTRACT FROM AUTHOR]

Background: Hairy cell leukemia (HCL) is rare leukemia of mature B cells, accounting for 2% of all lymphoid neoplasms. Although the association of venous thromboembolism (VTE) with cancer is well established, there is no systematic study describing VTE in HCL. Aim: To analyze prevalence and risk factors associated with VTE in HCL patients. Methods: We retrospectively reviewed data from the medical records of 56 consecutive HCL patients evaluated in our Hematology/Oncology clinic between 1998 and 2023. Results: The median age at diagnosis was 59 years (range, 37–94), and 49 patients (87%) were male. With a median follow-up of 122 months (1–291), we identified 11 episodes of VTE in 8 (14%) HCL patients: pulmonary embolism (PE) (5 cases) with or without concurrent deep venous thrombosis (DVT), and DVT alone (6 cases). All thrombotic episodes occurred after the diagnosis of HCL, or at the same time of it, as presenting clinical manifestation of the HCL. Risk factors for VTE other than cancer were identified in only 3 patients. Conclusion: Our study found a high incidence of VTE in patients with HCL, mostly in the absence of other provoking factors, suggesting that this hematologic malignancy is associated with an underlying thrombophilic state. [ABSTRACT FROM AUTHOR]

Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a tumour target currently used for the development of novel therapeutic modalities, such as antibody-drug conjugates, chimeric antigen receptor T-cell therapies, and others. Success of these new drugs depends on the selection of relevant indications based on ROR1 tumour prevalence, staining heterogeneity, and subcellular localization, among other parameters. We investigated ROR1 immunophenotype using validated antibody clones for immunohistochemistry (IHC) and flow cytometry (FC), analyzing 292 tumour specimens from 7 haematological malignancies and triple negative breast cancer (TNBC) as a reference solid tumour indication. ROR1 prevalence varied significantly across distinct tumour types, showing 100% of ROR1 positivity in all chronic lymphocytic leukaemia (n = 48) and hairy cell leukaemia (n = 14) specimens analyzed via FC with ranges between 1.1–99.8% and 0.8–62.1%, respectively. Samples analysed via IHC showed ROR1 membrane/cytoplasmic positivity in 44% of mantle cell lymphoma tumour samples (n = 27; H-score range: 10–285 in positive cases); 30% in TNBC (n = 46; H-score range: 1–200); 15% in diffuse large B-cell lymphoma (n = 45; H-score: 40–250); and 11% in follicular lymphoma (n = 34; H-score: 2–300). Finally, all acute myeloid leukaemia (n = 52) and most T-cell non-Hodgkin lymphoma (n = 31/32) tested samples were negative for ROR1 via IHC. In conclusion, ROR1 shows a heterogeneous tumour cell expression profile across multiple leukaemias and lymphomas, making it a tumour target that would require different patient selection strategies to develop novel therapeutic modalities. [ABSTRACT FROM AUTHOR]

Copyright of Medical Journal of Babylon is the property of Wolters Kluwer India Pvt Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Hairy cell leukemia (HCL) is a rare B-cell leukemia. This study aimed to investigate the clinical and demographic features and treatment responses of HCL patients diagnosed and treated at our center. Thirteen patients were diagnosed between March 2019 and February 2024. Morphology, immunohistochemistry, and flow cytometry were used for diagnosis. All patients received cladribine as first -line treatment. Patients with partial response or less and those who relapsed received salvage therapy. The median age of the patients was 53. Seven patients (53.8%) had pancytopenia. BRAF V600E mutation was positive in 9 patients (69%). Splenomegaly was present in 10 patients (76.9%) at diagnosi s. Cladribine treatment achieved complete response in 11 patients (84%), partial response in 1 patient (7%). One patient did not respond to treatment. Two patients relapsed and achieved complete remission with pentostatin or rituximab treatment. The 5 -year overall survival (OS) rate was 92.3% and progression-free survival (PFS) rate was 84.6%. The demographic and laboratory features and treatment outcomes of HCL patients followed at our center are consistent with the literature. Cladribine is highly effective as a first-line treatment in HCL and provides high response rates. Pentostatin and rituximab monotherapy were found to be effective in relapsed patients. [ABSTRACT FROM AUTHOR]

Abstract Hairy cell leukemia is an uncommon B‐cell malignancy with excellent response to purine analogs and to targeted therapies such as ibrutinib and vemurafenib. However, purine analogs are known to be highly immunosuppressive and the infection burden in this patient population with current therapies is unknown. We therefore conducted a retrospective cohort study following 149 patients. Median follow‐up time was 6.9 years. Thirty‐six percent developed an opportunistic or serious infection requiring hospitalization. Most cases were bacterial and most coincided with neutropenia and/or CD4 T‐lymphopenia. No single treatment agent was significantly associated with increased or decreased incidence of infection. Reassuringly, the cumulative incidence of infections plateaued 2 months after initial treatment suggesting clinically significant immune recovery. Only one patient in our cohort passed away due to infection. Estimated 10‐year overall survival was 99% suggesting that infections may not cause as much mortality as was seen prior to current therapies.

Aim: Sarcopenia may develop in patients with hairy cell leukemia (HCL). There is no study in the literature showing the prognostic importance of sarcopenia in patients with HCL. In this study, the effect of pretreatment sarcopenia on clinical outcomes in patients with HCL was investigated. Methods: This study included 34 patients with pre-treatment abdominal computed tomography (CT) images who received cladribine (purine nucleoside analog) treatment between April 2006 and April 2022 at Ondokuz Mayıs University Hospital. To ensure measurement standardization, measurements were performed using abdominal CT sections showing the L3 vertebra. The optimal cut-off value for the skeletal mass index to be used for the prediction of sarcopenia was determined by receiver operating characteristic analysis. Patients were divided into two groups according to whether they were sarcopenic or not, and their clinical results were compared. Results: Overall survival (OS) tended to be shorter in the sarcopenic group than in the non-sarcopenic group (p=0.046). Progression-free survival was significantly better in the non-sarcopenic group than in the sarcopenic group (p=0.009). In the multivariate analysis, sarcopenia (hazard ratio=0.154, p=0.043) was an effective variable for OS. Conclusion: Sarcopenia is a prognostic factor for prognosis and treatment parameters in patients with HCL.

Aim: Sarcopenia may develop in patients with hairy cell leukemia (HCL). There is no study in the literature showing the prognostic importance of sarcopenia in patients with HCL. In this study, the effect of pretreatment sarcopenia on clinical outcomes in patients with HCL was investigated. Methods: This study included 34 patients with pre-treatment abdominal computed tomography (CT) images who received cladribine (purine nucleoside analog) treatment between April 2006 and April 2022 at Ondokuz Mayis University Hospital. To ensure measurement standardization, measurements were performed using abdominal CT sections showing the L3 vertebra. The optimal cut-off value for the skeletal mass index to be used for the prediction of sarcopenia was determined by receiver operating characteristic analysis. Patients were divided into two groups according to whether they were sarcopenic or not, and their clinical results were compared. Results: Overall survival (OS) tended to be shorter in the sarcopenic group than in the non-sarcopenic group (p=0.046). Progressionfree survival was significantly better in the non-sarcopenic group than in the sarcopenic group (p=0.009). In the multivariate analysis, sarcopenia (hazard ratio=0.154, p=0.043) was an effective variable for OS. Conclusion: Sarcopenia is a prognostic factor for prognosis and treatment parameters in patients with HCL. [ABSTRACT FROM AUTHOR]

Simple Summary: Diagnosis of hairy cell leukemia is based on the presence of hairy cells in bone marrow and peripheral blood as well as the characteristic immunophenotype. Moreover, in classic HCL, most patients present with a BRAF V600E mutation. The typical symptoms of classic hairy cell leukemia include pancytopenia, massive splenomegaly and increased risk of infection. However, rarer manifestations of HCL are occasionally reported, including cutaneous symptoms, bone infiltration, arthritis and central nervous system symptoms, as well as gastrointestinal tracts, heart, lungs, ocular involvement and other symptoms. Background: Hairy cell leukemia (HCL) is a rare indolent B-cell lymphoid malignancy. The majority of patients are asymptomatic and HCL is usually diagnosed incidentally during a routine blood cell count. In symptomatic patients, typical symptoms are related to pancytopenia and splenomegaly. In this review, we present rare clinical symptoms in patients with HCL. Methods: A literature search was conducted of PubMed, Web of Science and Google Scholar for articles concerning hairy cell leukemia, leukemia cutis, bone lesions, neurological manifestations, pulmonary symptoms, ocular manifestations, cardiac manifestation and rare symptoms. Publications from January 1980 to August 2024 were scrutinized. Additional relevant publications were obtained by reviewing the references from the chosen articles. Results: Extramedullary and extranodal manifestations of classic HCL are rare. However, leukemic involvement in the skin, bone, central nervous system, gastrointestinal tract, heart, kidney, liver, lung, ocular system and other organs have been reported. [ABSTRACT FROM AUTHOR]

Background/Aim: Hairy cell leukemia (HCL) is a well-known lymphoproliferative disease with very effective treatment approaches primarily relying on purine analogues. However, these treatments are associated with profound and prolonged immunosuppression. Merkel cell carcinoma (MCC) is a rare and extremely aggressive skin tumor with an increased incidence in immunocompromised patients. Case Report: We report a case of a patient with HCL who was diagnosed with MCC, while in remission following retreatment with pentostatin, which induced a profound decrease in CD4 (+) T-cells. Conclusion: Our case provides further evidence supporting the hypothesis of a significant association between immunosuppression and MCC pathogenesis. [ABSTRACT FROM AUTHOR]

The article discusses Poland's first case of Erdheim-Chester Disease (ECD) with cerebellar manifestations, a rare inflammatory disorder with only about 1,500 documented cases worldwide. The case study highlights the diagnostic and therapeutic challenges faced by neurological specialists in treating ECD. The patient, a 39-year-old male, presented with speech difficulties, gait problems, weight loss, and other neurological symptoms, leading to the diagnosis of ECD confirmed through genetic testing. Treatment with vemurafenib was initiated, and the patient remained stable for two years under continuous medical follow-up. [Extracted from the article]

The article highlights the transformative impact of antibiotics introduced in the mid-20th century. Topics include the exploration of secondary metabolites from microorganisms as potential new antimicrobial drugs, the three approaches to antibiotic production—fermentation, semi-synthetic modification, and chemical synthesis—and a study on the metabolic potential of Arctic fungi, which revealed novel secondary metabolites and biosynthetic gene clusters.

Background: Hairy cell leukemia (HCL) is rare leukemia of mature B cells, accounting for 2% of all lymphoid neoplasms. Although the association of venous thromboembolism (VTE) with cancer is well established, there is no systematic study describing VTE in HCL.Aim: To analyze prevalence and risk factors associated with VTE in HCL patients.Methods: We retrospectively reviewed data from the medical records of 56 consecutive HCL patients evaluated in our Hematology/Oncology clinic between 1998 and 2023.Results: The median age at diagnosis was 59 years (range, 37–94), and 49 patients (87%) were male. With a median follow-up of 122 months (1–291), we identified 11 episodes of VTE in 8 (14%) HCL patients: pulmonary embolism (PE) (5 cases) with or without concurrent deep venous thrombosis (DVT), and DVT alone (6 cases). All thrombotic episodes occurred after the diagnosis of HCL, or at the same time of it, as presenting clinical manifestation of the HCL. Risk factors for VTE other than cancer were identified in only 3 patients.Conclusion: Our study found a high incidence of VTE in patients with HCL, mostly in the absence of other provoking factors, suggesting that this hematologic malignancy is associated with an underlying thrombophilic state.

A 62-year-old man diagnosed with acute myeloid leukemia (AML) showed limited responses to two courses of azacitidine (AZA) + Venetoclax (VEN) therapy. Twenty days after being transferred to our hospital, flow cytometry with broad antigen coverage and mutation analysis confirmed the presence of a second malignancy, hairy cell leukemia (HCL). Following haploidentical combined umbilical cord blood transplantation, the patient achieved complete remission (CR) for both AML and HCL. This CR has been maintained for the past 14 months. Patients with dual hematologic malignancies may not respond well to conventional therapy regimens. Early initiation of hematopoietic stem cell transplantation is beneficial for improving prognosis and extending overall survival. [ABSTRACT FROM AUTHOR]

BACKGROUND: Hairy cell leukemia (HCL) is a rare chronic B-cell lymphoproliferative disorder. Modern therapy with purine analogs and immunotherapy can provide long-term remission, but the risk of recurrence remains about 40%–50%. The aim of this study was to evaluate the outcome of patients with HCL who received treatment in Nanakali Hospital. PATIENTS AND METHODS: A retrospective cross-sectional study was carried out on 50 patients of HCL diagnosed from 2004 to 2022 in Nanakali Hospital in Erbil City, Kurdistan Region, Iraq. Demographics, clinical presentation, treatment data, complications, response, recurrence, and survival data were collected from medical records. The results were presented with descriptive statistics. Variables were compared by Chi-square analysis. RESULTS: The mean age was 52.64 ± 12.37 years, and 84% were male. The most common presenting symptoms were splenomegaly (18%) and fatigue (14%). The majority (69.6%) received cladribine; the response rate was 73.9%, with a complete remission (67.4%). 47.8% had recurrent disease. The most common adverse effects were febrile neutropenia (58.7%) and Grade III and IV hematologic toxicity (41.3%). The results were significantly associated with ANC pretreatment (P = 0.019), comorbidity (P = 0.001), and treatment response (P = 0.004). Cladribine–rituximab combination resulted in complete remission (100%). Ten-year overall survival was 70%. CONCLUSIONS: The results were broadly consistent with literature reports, demonstrating the efficacy and safety of cladribine with/without rituximab as first-line therapy for HCL but with a 30% mortality of concern. Further studies should identify modifiable factors that affect poor prognosis in subgroups to guide improvements in risk management of HCL.

Simple Summary: The diagnosis of hairy-cell leukemia (HCL) and HCL-like disorders including the variant form of HCL (HCL-V), splenic diffuse red pulp lymphoma (SDRPL) and splenic marginal zone lymphoma (SMZL) is a challenge in clinical practice. We discuss the major points for the diagnosis of HCL and HCL-like disorders and we propose recommendations for the diagnosis of HCL, treatment in first line and in relapsed/refractory patients. Introduction: Hairy-cell leukemia (HCL) is a rare B-cell chronic lymphoproliferative disorder (B-CLPD), whose favorable prognosis has changed with the use of purine nucleoside analogs (PNAs), such as cladribine (CDA) or pentostatin (P). However, some patients eventually relapse and over time HCL becomes resistant to chemotherapy. Many discoveries have been made in the pathophysiology of HCL during the last decade, especially in genomics, with the identification of the BRAFV600E mutation and cellular biology, including the importance of signaling pathways as well as tumor microenvironment. All of these new developments led to targeted treatments, especially BRAF inhibitors (BRAFis), MEK inhibitors (MEKis), Bruton's tyrosine kinase (BTK) inhibitors (BTKis) and recombinant anti-CD22 immunoconjugates. Results: The following major changes or additions were introduced in these updated guidelines: the clinical relevance of the changes in the classification of splenic B-cell lymphomas and leukemias; the increasingly important diagnostic role of BRAFV600E mutation; and the prognostic role of the immunoglobulin (IG) variable (V) heavy chain (H) (IGHV) mutational status and repertory. We also wish to insist on the specific involvement of bones, skin, brain and/or cerebrospinal fluid (CSF) of the disease at diagnosis or during the follow-up, the novel targeted drugs (BRAFi and MEKi) used for HCL treatment, and the increasing role of minimal residual disease (MRD) assessment. Conclusion: Here we present recommendations for the diagnosis of HCL, treatment in first line and in relapsed/refractory patients as well as for HCL-like disorders including HCL variant (HCL-V)/splenic B-cell lymphomas/leukemias with prominent nucleoli (SBLPN) and splenic diffuse red pulp lymphoma (SDRPL). [ABSTRACT FROM AUTHOR]

Background: Rare oncogenic driver events, particularly affecting the expression or splicing of driver genes, are suspected to substantially contribute to the large heterogeneity of hematologic malignancies. However, their identification remains challenging. Methods: To address this issue, we generated the largest dataset to date of matched whole genome sequencing and total RNA sequencing of hematologic malignancies from 3760 patients spanning 24 disease entities. Taking advantage of our dataset size, we focused on discovering rare regulatory aberrations. Therefore, we called expression and splicing outliers using an extension of the workflow DROP (Detection of RNA Outliers Pipeline) and AbSplice, a variant effect predictor that identifies genetic variants causing aberrant splicing. We next trained a machine learning model integrating these results to prioritize new candidate disease-specific driver genes. Results: We found a median of seven expression outlier genes, two splicing outlier genes, and two rare splice-affecting variants per sample. Each category showed significant enrichment for already well-characterized driver genes, with odds ratios exceeding three among genes called in more than five samples. On held-out data, our integrative modeling significantly outperformed modeling based solely on genomic data and revealed promising novel candidate driver genes. Remarkably, we found a truncated form of the low density lipoprotein receptor LRP1B transcript to be aberrantly overexpressed in about half of hairy cell leukemia variant (HCL-V) samples and, to a lesser extent, in closely related B-cell neoplasms. This observation, which was confirmed in an independent cohort, suggests LRP1B as a novel marker for a HCL-V subclass and a yet unreported functional role of LRP1B within these rare entities. Conclusions: Altogether, our census of expression and splicing outliers for 24 hematologic malignancy entities and the companion computational workflow constitute unique resources to deepen our understanding of rare oncogenic events in hematologic cancers. [ABSTRACT FROM AUTHOR]

The association between Hairy Cell Leukemia (HCL) and non-tuberculous mycobacterial infections (NTMs) is well described, most notably Mycobacterium kansasii. The exact pathophysiology is not known. We report a case of a 31-year-old male with concomitantly diagnosed HCL and disseminated M kansasii infection who presented with rash, pancytopenia, and bulky axillary lymphadenopathy. The M kansasii was initially diagnosed through use of cell-free DNA detection and confirmed by bone marrow and lymph node cultures. Hairy Cell Leukemia was diagnosed with peripheral flow cytometry and confirmed via the same bone marrow sample. His HCL was put into remission with a single course of cladribine and rituximab chemotherapy; however, his M kansasii infection persisted for 6 months despite aggressive antimicrobial and surgical therapy. It was finally controlled using high-dose rifampin in combination with azithromycin and ethambutol. This case highlights the known link between HCL and M kansasii. Furthermore, it hints at potential causes beyond chemotherapy-induced immunocompromise. Notable possibilities include HCL cells acting as sanctuary sites for M kansasii to evade the immune system, and subclinical M kansasii infections causing NLRP3 inflammasome overactivation to trigger the oncogenic transformation to HCL. More research into the pathophysiologic link between HCL and M kansasii infections would allow for more effective prevention, diagnosis, and treatment of these severe atypical infections which are the major cause of morbidity in the cladribine era of HCL treatment. [ABSTRACT FROM AUTHOR]

Hairy cell leukemia (HCL) represents 2% of all leukemia cases, with men aged above 55 years being the most affected. The most common symptoms of this type of leukemia include splenomegaly, monocytopenia, and neutropenia. In the basic blood count examination, leukopenia with monocytopenia and granulocytopenia, as well as aplastic anemia and/or thrombocytopenia occur. The mutation of β-rapidly accelerated fibrosarcoma (BRAF) proto-oncogene, which can be found in nearly 100% of patients, is an important feature of HCL. Immunophenotypic analysis of the HCL cells reveals high expression of B-lineage antigens, including CD19, CD20, and CD22. Additionally, CD11c, CD25, CD103, and CD123 belong to specific markers of HCL. Lactate dehydrogenase activity and β-2-microglobulin concentration are also important in the patient's assessment. The differential diagnosis between HCL, hairy cell leukemia variant (HCL-V) and splenic marginal zone lymphoma (SMZL) is of first importance. Currently, the main treatment for HCL involves the use of purine analogues, excluding pregnant women, individuals with severe infections, and those with relapsing HCL. [ABSTRACT FROM AUTHOR]

Copyright of Canadian Journal of Pathology is the property of Canadian Association of Pathologists and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Simple Summary: The prevalence of second neoplasms among patients with hairy cell leukemia (HCL) treated with cladribine is not negligible. Immunosuppression, high rate of cure, and aging may have a role in the pathogenesis of second cancers after HCL. We aimed to compare the risk of cancer between patients with HCL treated with cladribine and the general population. Concern has emerged about the prevalence of second cancers among patients with hairy cell leukemia (HCL) treated with purine analogs. We investigated 513 patients with HCL treated with cladribine over the last 30 years at 18 Italian centers and calculated their standardized incidence ratios (SIRs). We identified 24 patients with a second cancer diagnosed at a median time from treatment with cladribine of 59.9 months (range: 9.2–169.7 months). All patients with solid neoplasms presented with a limited-stage disease, except four cases of locally advanced cancer; multiple myeloma patients had a smoldering disease, while lymphoma patients had stage Ie and stage IV diseases. Response to therapy was complete in 19 cases; 1 patient is still receiving treatment for a relapsing bladder disease, while 2 patients progressed during treatment and died. These two patients died from unrelated causes: one from infection and one due to surgery complications. The median OS from HCL was 98.5 months (range: 38.4–409.2 months), while the median OS from second cancer was 27.6 months (range: 1–117.8 months). The SIR was 0.86 (95% CI: 0.54–1.30) for males and 1.13 (95% CI: 0.36–2.73) for females: no statistically significant differences were highlighted. We were not able to demonstrate an excess of second cancer or a significant association with the specific studied neoplasm. [ABSTRACT FROM AUTHOR]

Abstract Hairy cell leukemia (HCL) is a rare lymphoproliferative disorder classically presenting with cytopenia and recurrent infections but atypical manifestations such as bone lesions, skin lesions and effusion have been described. We report here an unusual meningeal localization in a 33 years old man who presented with headache, hand paresthesia and visual symptoms. Brain magnetic resonance imaging revealed an occipital meningeal lesion. Diagnostic explorations led to the diagnosis of classical HCL with meningeal localization. After treatment by cladribine and rituximab the patient rapidly improved and is still in complete remission 12 months after end of treatment. The literature review identified 9 other cases of HCL with central nervous system localization (CNS) presenting with brain parenchyma and/or meninges localization. Four out of 9 patients presented with hyperleukocytosis. Most patients experienced good responses with various treatments. Cladribine alone or with rituximab led to complete responses similar to our patient. In our patient, molecular biology revealed KLF2 mutations, which implication in the atypical localization could be suspected but would need dedicated studies. In conclusion, CNS localizations of HCL are rare but can be observed and treatment with cladribine alone or with rituximab appears as an effective strategy.

Atraumatic splenic rupture is a complex surgical pathology owing to its rarity, non-specificity of symptoms and gravity of possible outcomes. This case outlines the investigation and management of a patient with atraumatic splenic rupture secondary to undiagnosed hairy cell leukaemia. While the patient was initially managed conservatively, they went on to have a splenectomy owing to ongoing transfusion requirements. A review of the literature has also been performed and presented to highlight the potential causes of atraumatic splenic rupture and the various options for confirming diagnosis and definitive management. [ABSTRACT FROM AUTHOR]

Interferon alpha-2b (IFN- α 2b) is an essential cytokine widely used in the treatment of chronic hepatitis C and hairy cell leukemia, and serum albumin is the most abundant plasma protein with numerous physiological functions. Effective single-step aqueous biphasic system (ABS) extraction for the simultaneous purification of IFN- α 2b and BSA (serum albumin protein) was developed in this work. Effects of the ionic liquid (IL)-based ABS functionalization, fluorinated ILs (FILs; [C ​ 2 C ​ 1 Im][C ​ 4 F ​ 9 SO ​ 3 ] and [N ​ 1112 (OH) ][C ​ 4 F ​ 9 SO ​ 3 ]) vs. mere fluoro-containing IL ([C ​ 4 C ​ 1 Im][CF ​ 3 SO ​ 3 ]), in combination with sucrose or [N ​ 1112 (OH) ][H ​ 2 PO ​ 4 ] (well-known globular protein stabilizers), or high-charge-density salt K ​ 3 PO ​ 4 were investigated. The effects of phase pH, phase water content (%wt), phase composition (%wt), and phase volume ratio were investigated. The phase pH was found to have a significant effect on IFN- α 2b and BSA partition. Experimental results show that simultaneous single-step purification was achieved with a high yield (extraction efficiency up to 100%) for both proteins and a purification factor of IFN- α 2b high in the enriched IFN- α 2b phase (up to 23.22) and low in the BSA-enriched phase (down to 0.00). SDS-PAGE analysis confirmed the purity of both recovered proteins. The stability and structure of IFN- α 2b and BSA were preserved or even improved (FIL-rich phase) during the purification step, as evaluated by CD spectroscopy and DSC. Binding studies of IFN- α 2b and BSA with the ABS phase-forming components were assessed by MST, showing the strong interaction between FILs aggregates and both proteins. In view of their biocompatibility, customizable properties, and selectivity, FIL-based ABSs are suggested as an improved purification step that could facilitate the development of biologics. [ABSTRACT FROM AUTHOR]

Hairy cell leukemia (HCL) is an infrequent and persistent B-cell inert lymphoid leukemia. In this study, we present the case of a 71-year-old female patient with a previous diagnosis of variant HCL who experienced a severe herpes zoster infection leading to an extensive skin eruption. The patient's initial diagnosis of HCL occurred 7 years ago, and she underwent treatment with cladribine, interferon, COP (cyclophosphamide, vincristine, and prednisone), benztropine tablets + clarithromycin dispersible, and ibrutinib. Immune disorders resulting from repeated prior chemotherapy and targeted therapy may potentially precipitate herpes zoster infection. Despite an initial two-week period of unresponsiveness to antivirals and nerve nutrition treatments, the introduction of topical Coptis liquid to the treatment regimen yielded significant efficacy. This case report underscores the potential of Chinese medicine as an adjunct to conventional antiviral therapy in the management of herpes zoster infection in immunocompromised patients. This treatment protocol has the potential to enhance efficacy, enhance quality of life, and serve as a more robust foundation for clinical diagnosis and improved treatments. [ABSTRACT FROM AUTHOR]

The variant form of hairy cell leukaemia (HCL‐V) is a rare disease very different from hairy cell leukaemia (HCL), which is a very well‐defined entity. The 5th WHO edition (Leukemia, 36, 2022 and 1720) classification (WHO‐HAEM5) introduced splenic lymphomas/leukaemias including four different entities: (1) HCL, (2) splenic marginal zone lymphoma (SMZL) with circulating villous cells in the peripheral blood, (3) splenic lymphoma with prominent nucleolus (SLPN), which replaced HCL‐V and CD5 negative B‐prolymphocytic leukaemia (B‐PLL), and (4) splenic diffuse red pulp lymphoma (SDRPL). All these entities have to be distinguished because of a different clinical course and the need for a different treatment. The diagnosis can be challenging because of complex cases and overlap and/or grey zones between all the entities and needs integrating clinical, histologic, immunophenotypic, cytogenetic and molecular data. We review the diagnostic criteria including clinical, immunophenotypic and molecular characteristics of patients with HCL‐V and other HCL‐like disorders including HCL, SDRPL, SMZL, B‐PLL and the Japanese form of HCL. We also discuss the different criteria allowing us to separate these different entities and we will update the recent therapeutic options that have emerged, in particular the advances with chemoimmunotherapy and/or targeted therapies. [ABSTRACT FROM AUTHOR]

Context: Splenic B-cell lymphoma/leukemia with prominent nucleoli (SBLPN) aka hairy cell leukemia variant (HCL-v) is a rare B-cell chronic lymphoproliferative disorder. The main diagnostic challenge is to differentiate SBLPN from Classical hairy cell leukemia (HCL-c), as the former faces inferior responses to therapies and a poor prognosis. Aims: The aim is to discuss the clinic-hematological and immunophenotyping findings of three cases of SBLPN. Settings and Design: This is a retrospective observational study. Methods and Material: From the year 2011 to 2021, flow cytometry of all the cases with HCL diagnosis was reviewed, and three cases with negative or dim CD25 and hematological presentation matching with SBLPN were picked up. Statistical Analysis Used: Descriptive statistics is used. Results: All the cases were male. The age ranges from 43 to 64 years. Median hemoglobin concentration, total leucocyte count, and platelet count were 8.6 g/dL, 6.9 × 109/L, and 53 × 109/L, respectively. The atypical cells were medium to large. All three showed prominent nucleoli. Bone marrow biopsies showed an interstitial pattern of infiltration in all the cases. The hairy cells were positive for CD20, CD11c, and CD103. CD25 was dim positive in one case. Annexin A1 was negative in all three cases. BRAF V600E mutation analysis was done in one case and turned out negative for the mutation. Conclusions: SBLPN is a rare entity, usually on-flow cytometry CD25 negative. However, in dim CD25-positive cases, BRAFV600E mutational analysis helps in discerning SBLPN diagnosis and differentiating it from HCL-c. [ABSTRACT FROM AUTHOR]

Merkel cell carcinoma (MCC) is a rare cutaneous neoplasm that accounts for less than 1% of all primary cutaneous neoplasms. The majority of MCC cases (80%) are caused by Merkel cell polyomavirus (MCPyV) clonal integration into the host genome. In the remaining 20% of cases, UV mutations are responsible, and prolonged UV exposure is a factor. Herein, we present two cases of this rare tumor: a 48-year-old female with a diagnosis of hairy cell leukemia and an elderly male previously healthy. [ABSTRACT FROM AUTHOR]

This article discusses the development of a lentiviral vector-based gene therapy platform for the treatment of liver metastases (LMS). Liver metastases commonly arise from gastrointestinal tumors and are difficult to treat due to the immunosuppressive environment of the liver. The lentiviral vector delivers interferon-alpha (IFNα) to liver macrophages, which activates the immune system and reduces the growth of LMS. The study also found that combining gene-based IFNα delivery with monoclonal antibodies blocking CTLA-4 resulted in a strong therapeutic response. The use of lentiviral vectors in gene therapy has shown promise in various clinical applications and has the potential to be used in the treatment of LMS. [Extracted from the article]

Background. Hairy cell leukemia (HCL) is a rare indolent lymphoproliferative disease with an accumulation of mature B lymphocytes with fine reticular chromatin and cytoplasm with typical hairy-like cytoplasmic projections. Rarely, hairy cell leukemia manifests as a lung infiltration. The differential diagnosis between infection and malignant involvement with hairy cell leukemia is often challenging in such situations. Methods and Results. We present a 53-year-old female with an uncommon pulmonary involvement with hairy cell leukemia. In addition, we discuss the complicated differential diagnosis of pulmonary disease in patients with hairy cell leukemia and the treatment approach to these patients. Conclusion. This case report describes the successful therapy management of a patient with pulmonary involvement by hairy cell leukemia. Therapy with interferon-alfa and cladribine resulted in long-term remission of the underlying disease.

Key Clinical Message: This case of non‐nodal mantle cell lymphoma (MCL) showcases atypical hairy cell‐like features, distinguishing it via next‐generation sequencing. Despite a TP53 mutation indicating poor prognosis, our case followed an indolent course, highlighting the importance of genetic testing and phenotypical examination in MCL. [ABSTRACT FROM AUTHOR]

Abstract Hairy cell leukemia (HCL) is a B-lymphoma induced by BRAF(V600E) mutation. However, introducing BRAF(V600E) in B-lymphocytes fails to induce hematological malignancy, suggesting that BRAF(V600E) needs concurrent mutations to drive HCL ontogeny. To resolve this issue, here we surveyed human HCL genomic sequencing data. Together with previous reports, we speculated that the tumor suppressor TP53, P27, or PTEN restrict the oncogenicity of BRAF(V600E) in B-lymphocytes, and therefore that their loss-of-function facilitates BRAF(V600E)-driven HCL ontogeny. Using genetically modified mouse models, we demonstrate that indeed BRAF(V600E)KI together with Trp53KO or pTENKO in B-lymphocytes induces chronic lymphoma with pathological features of human HCL. To further understand the cellular programs essential for HCL ontogeny, we profiled the gene expression of leukemic cells isolated from BRAF(V600E)KI and Trp53KO or pTENKO mice, and found that they had similar but different gene expression signatures that resemble that of M2 or M1 macrophages. In addition, we examined the expression signature of transcription factors/regulators required for germinal center reaction and memory B cell versus plasma cell differentiation in these leukemic cells and found that most transcription factors/regulators essential for these programs were severely inhibited, illustrating why hairy cells are arrested at a transitional stage between activated B cells and memory B cells. Together, our study has uncovered concurrent mutations required for HCL ontogeny, revealed the B cell origin of hairy cells and investigated the molecular basis underlying the unique pathological features of the disease, with important implications for HCL research and treatment.

This case report discusses a 95-year-old man diagnosed with two types of lymphomas. He was hospitalized for erysipelas in September 2018. The lymph node revealed high-grade B-cell lymphoma with Myc and Bcl-2 rearrangement. Bone marrow biopsy revealed hairy cell leukemia, a rare type of indolent B-cell lymphoma. We found that the bone marrow and left inguinal lymph node were non-homologous. There are no known reports of super-aged patients with two types of lymphoma simultaneously. The toxicity of R-CHOP in elderly people limited its usage, so we first chose rituximab. However, this approach was not successful. We then considered the Bruton tyrosine kinase (BTK) inhibitor, but its use was limited due to high blood pressure. Finally, we administered venetoclax, which the patient took for 2 years. The results of the routine blood examination were close to normal and no enlarged superficial or abdominal lymph nodes were observed.This is the oldest reported patient with two types of malignant lymphatic diseases. Additionally, this rare case suggests that targeted therapy can be more effective and safe for super-aged individuals. To summarize, a 95-year-old man diagnosed with two types of lymphomas, high-grade B-cell lymphoma and hairy cell leukemia, was successfully treated with venetoclax after other treatments failed. This case suggests that targeted therapy can be effective and safe for super-aged patients with multiple malignant lymphatic system diseases.

Engineering immune cells to treat hematological malignancies has been a major focus of research since the first resounding successes of CAR-T-cell therapies in BALL. Several diseases can now be treated in highly therapy-refractory or relapsed conditions. Currently, a number of CD19- or BCMA-specific CAR-T-cell therapies are approved for acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), multiple myeloma (MM), and follicular lymphoma (FL). The implementation of these therapies has significantly improved patient outcome and survival even in cases with previously very poor prognosis. In this comprehensive review, we present the current state of research, recent innovations, and the applications of CAR-T-cell therapy in a selected group of hematologic malignancies. We focus on B- and T-cell malignancies, including the entities of cutaneous and peripheral T-cell lymphoma (T-ALL, PTCL, CTCL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), classical Hodgkin-Lymphoma (HL), Burkitt-Lymphoma (BL), hairy cell leukemia (HCL), and Waldenström’s macroglobulinemia (WM). While these diseases are highly heterogenous, we highlight several similarly used approaches (combination with established therapeutics, target depletion on healthy cells), targets used in multiple diseases (CD30, CD38, TRBC1/2), and unique features that require individualized approaches. Furthermore, we focus on current limitations of CAR-T-cell therapy in individual diseases and entities such as immunocompromising tumor microenvironment (TME), risk of on-target-off-tumor effects, and differences in the occurrence of adverse events. Finally, we present an outlook into novel innovations in CAR-T-cell engineering like the use of artificial intelligence and the future role of CAR-T cells in therapy regimens in everyday clinical practice. [ABSTRACT FROM AUTHOR]

Adenosine deaminase (ADA) is a Zn2+-containing enzyme that catalyzes the irreversible deamination of adenosine to inosine or deoxyadenosine to deoxyinosine. In addition to this enzymatic function, ADA mediates cell-to-cell interactions involved in lymphocyte co-stimulation or endothelial activation. ADA is implicated in cardiovascular pathologies such as atherosclerosis and certain types of cancers, including lymphoma and leukemia. To date, only two drugs (pentostatin and cladribine) have been approved for the treatment of hairy cell leukemia. In search of natural ADA inhibitors, we demonstrated the binding of selected phenolic compounds to the active site of ADA using molecular docking and molecular dynamics simulation. Our results show that phenolic compounds (chlorogenic acid, quercetin, and hyperoside) stabilized the ADA complex by forming persistent interactions with the catalytically essential Zn2+ ion. Furthermore, MM-GBSA ligand binding affinity calculations revealed that hyperoside had a comparable binding energy score (ΔG = − 46.56 ± 8.26 kcal/mol) to that of the cocrystal ligand in the ADA crystal structure (PDB ID: 1O5R) (ΔG = − 51.97 ± 4.70 kcal/mol). Similarly, chlorogenic acid exhibited a binding energy score (ΔG = − 18.76 ± 4.60 kcal/mol) comparable to those of the two approved ADA inhibitor drugs pentostatin (ΔG = − 14.54 ± 2.25 kcal/mol) and cladribine (ΔG = − 25.52 ± 4.10 kcal/mol) while quercetin was found to have modest binding affinity (ΔG = − 8.85 ± 7.32 kcal/mol). This study provides insights into the possible inhibitory potential of these phenolic compounds against ADA. [ABSTRACT FROM AUTHOR]

Background. Hairy cell leukemia (HCL) is a rare indolent lymphoproliferative disease with an accumulation of mature B lymphocytes with fine reticular chromatin and cytoplasm with typical hairy-like cytoplasmic projections. Rarely, hairy cell leukemia manifests as a lung infiltration. The differential diagnosis between infection and malignant involvement with hairy cell leukemia is often challenging in such situations. Methods and Results. We present a 53-year-old female with an uncommon pulmonary involvement with hairy cell leukemia. In addition, we discuss the complicated differential diagnosis of pulmonary disease in patients with hairy cell leukemia and the treatment approach to these patients. Conclusion. This case report describes the successful therapy management of a patient with pulmonary involvement by hairy cell leukemia. Therapy with interferon-alfa and cladribine resulted in long-term remission of the underlying disease. [ABSTRACT FROM AUTHOR]

Hairy cell leukemia (HCL) and HCL-like disorders, including HCL-variant, are disorders of heterogeneous mature lymphoid B-cells known for their hairy cell infiltration accompanied by a specific genetic profile, various clinical presentations, and, as they are uncommon hematological malignancies characterized by pancytopenia, the need for appropriate therapy. Sometimes HCL creates diagnostic challenges for clinicians, and its coincidence or association with mast cell and plasma cell infiltration is a rare condition. Herein, we report a case of HCL with confusing manifestations. A 44-year-old man was referred to the hospital for weakness, fatigue, and watery, non-bloody diarrhea. The laboratory tests showed pancytopenia, leading to a referral for bone marrow aspiration and biopsy. Medium to large cells exhibiting widespread cytoplasm, oval nuclei similar to monocyte nuclei (kidney-shaped) accompanied by an increased number of mast cells, and plasma cells were observed in the biopsy sample. In flow cytometry, the neoplastic cells were positive for CD19, FMC7, and the co-expression of the CD20/CD25, CD11C/CD22, and CD103 markers. In immunohistochemical staining, the mast cells were positive for CD117, the plasma cells were positive for CD138, and the hairy cells were positive for CD20. Overall, hematopathologists must be aware of various morphologic confounding factors such as lack of typical cell morphological features and increased plasma cell and mast cell infiltration in the diagnosis of patients with HCL.

COVID-19 is known to cause many hematological abnormalities, such as thrombocytopenia, leucopenia, and lymphopenia. Pancytopenia, a decrease in all peripheral blood cell lines, is a rare complication not commonly seen in patients with COVID-19. We report a case of a patient who experienced COVID-19 infection with mild clinical symptoms like fever, fatigue, and muscle and bone aches. The laboratory examinations revealed pancytopenia, mainly neutropenia, thrombocytopenia, mild anemia, and relative lymphocytosis, which persisted after infection resolution. The splenomegaly in abdominal echography and the characteristics of lymphocyte elements in peripheral blood smear examination raised suspicion of the presence of hairy cell leukemia (HCL); therefore, the patient was further examined with a bone marrow biopsy, which confirmed the diagnosis. The persistence of pancytopenia after recovery from COVID-19 infection, especially in patients with splenomegaly, should raise suspicion of another hematological coexistence diagnosis like HCL.

The article focuses on the importance of evidence-based disease classification for effective patient management and research, highlighting the WHO Classification of Tumours as a key system. Topics include the development of the Revised European–American Lymphoma (REAL) classification, the evolution of the WHO classification for haematolymphoid neoplasms, and the impact of genetic features on cancer diagnosis and treatment.

Introduction: Hairy cell leukemia (HCL) is an indolent B-cell lymphoproliferative disease. BRAF V600E mutation is detected in nearly all classical HCL cases which offers the possibility of targeted therapy.Objective: The aim of our study was to assess the efficacy of low-dose vemurafenib as well as to assess the long term outcome of HCL patients treated with this drug at the Department of Internal Medicine and Oncology at Semmelweis University.Methods: We report on 10 patients with classical HCL treated with low-dose vemurafenib at our Department between 2013 and 2022.Results: As a result of fixed time low-dose vemurafenib treatment, 5 of 10 patients (5/10) achieved partial remission, 4 (4/10) had stable disease, and 1 (1/10) had MRD positivity. No patients achieved complete remission. The median progression-free survival was 28.5 months while the overall survival was 82 months.Conclusion: We confirm that low dose of vemurafenib is effective and safe in the vast majority of patients with HCL. This small-molecule oral treatment allows to gain valuable time—months or even years—before further, usually parenteral treatment options have to be given or before previous treatment has to be repeated. There are also promising data supporting the combination of vemurafenib with other drugs for the treatment of HCL patients which could provide even further possibility to bridge treatment.

Background: The cluster of differentiation 200 (CD200) is a recently introduced marker, used to differentiate various lymphoproliferative disorders (LPDs) and is a potential target for chemotherapy. Objective: The objective is to study the utility of CD200 expression by flow cytometry (FC) in various LPDs and plasma cell disorders. Materials and Methods: This is a retrospective study done over a period of 2 years. The study group included 52 cases with a clinical suspicion of LPD (n = 40) or plasma cell disorder (n = 12). Clinical data, morphological data on peripheral blood, and/or bone marrow examination were analyzed and correlated with the final results on FC. Results: Out of 40 LPDs, chronic lymphocytic leukemia (CLL) accounted for a majority of the cases accounting for 57.5% (23 cases). Plasma cell myelomas (PCM) were the most common plasma cell disorders accounting for 75% (nine cases). All cases of CLL showed CD200 expression and the two cases of mantle cell lymphoma (MCL) were CD200 negative. Splenic marginal zone lymphomas (MZL) involving marrow showed dim CD200 expression. Bright CD200 expression was also observed in all cases of hairy cell leukemia (HCL) and 67% of cases diagnosed as PCM. Conclusion: CD200 is a very useful marker in the diagnosis of various LPDs especially CLL, HCL, and PCMs. It can be used as an additional marker particularly in distinguishing CLL/small lymphocytic lymphoma (SLL) from MCL and atypical CLL from other CD5+ B-cell neoplasms and extranodal MZL. [ABSTRACT FROM AUTHOR]

Hairy cell leukemia (HCL) is a B-lymphoma induced by BRAF(V600E) mutation. However, introducing BRAF(V600E) in B-lymphocytes fails to induce hematological malignancy, suggesting that BRAF(V600E) needs concurrent mutations to drive HCL ontogeny. To resolve this issue, here we surveyed human HCL genomic sequencing data. Together with previous reports, we speculated that the tumor suppressor TP53, P27, or PTEN restrict the oncogenicity of BRAF(V600E) in B-lymphocytes, and therefore that their loss-of-function facilitates BRAF(V600E)-driven HCL ontogeny. Using genetically modified mouse models, we demonstrate that indeed BRAF(V600E)KI together with Trp53KO or pTENKO in B-lymphocytes induces chronic lymphoma with pathological features of human HCL. To further understand the cellular programs essential for HCL ontogeny, we profiled the gene expression of leukemic cells isolated from BRAF(V600E)KI and Trp53KO or pTENKO mice, and found that they had similar but different gene expression signatures that resemble that of M2 or M1 macrophages. In addition, we examined the expression signature of transcription factors/regulators required for germinal center reaction and memory B cell versus plasma cell differentiation in these leukemic cells and found that most transcription factors/regulators essential for these programs were severely inhibited, illustrating why hairy cells are arrested at a transitional stage between activated B cells and memory B cells. Together, our study has uncovered concurrent mutations required for HCL ontogeny, revealed the B cell origin of hairy cells and investigated the molecular basis underlying the unique pathological features of the disease, with important implications for HCL research and treatment. Key Points: • Hairy cells originate from B-lymphocytes with BRAF(V600E) and TP53 or PTEN mutations. • Hairy cells exhibit a unique gene expression signature that underlies the pathological features of HCL. [ABSTRACT FROM AUTHOR]

Grover disease (GD) is an acquired, nonfamilial, nonimmune mediated, transient or persistent acantholytic dermatosis. Herein, we present a 72-year-old man who had clinical and histopathologic findings of GD following two weeks of treatment with vemurafenib without MEK inhibitor. The patient was successfully treated with topical emollients and a high-potency corticosteroid. Meanwhile, vemurafenib was temporarily discontinued. Drug-induced GD has increasingly been reported in patients on BRAF inhibitor monotherapy as an immune-related adverse event. The cutaneous side effects seem to arise secondary to a paradoxical activation of the mitogen-activated protein kinase signaling of BRAF inhibitor treatment, leading to keratinocyte proliferation. Although the pathogenesis of GD has not been delineated, there is suggestion of activation of T lymphocytes, particularly helper cells under the action of pro-inflammatory cytokines, resulting in proliferation of keratinocytes. Combination therapy with a MEK inhibitor appears to prevent BRAF-induced GD. Given that there is a higher prevalence of GD in patients with hematologic malignancy, a direct causal relationship between the initiation of vemurafenib therapy and development of GD in this case may be difficult to establish.

Hairy cell leukemia (HCL), an uncommon cancer affecting B-lymphocytes primarily in the bone marrow and spleen, is identified by abnormal projections on malignant B cells, which give the illness its name. This condition is less frequently observed in Asian populations compared with individuals from American and European backgrounds and tends to be diagnosed around the age of 55 years. The leading genetic association of this ailment is linked to the BRAFV600 mutation. Diagnosing HCL poses challenges due to its similarity to other conditions involving excessive lymphocyte growth. Here, we present a distinctive case of an aggressive disease course in a 46-year-old male.

Hairy cell leukemia (HCL) is a rare B-cell lymphoproliferative disorder. Patients typically present with cytopenia and splenomegaly. We describe the case of a 78-year-old patient with refractory HCL who acutely developed a cystic lesion on the back while receiving moxetumomab pasudotox therapy. Biopsy of the lesion revealed the presence of adenocarcinoma, which prompted a detailed evaluation resulting in a diagnosis of stage IV gastric cancer. Nevertheless, to establish any association between moxetumomab pasudotox therapy and secondary cancer development, a satisfactory number of studies need to be conducted.

Hairy Cell Leukemia is an infrequent leukemia that can be recognized both microscopically and flow cytometrically once the patient develops symptoms. We present a case where early diagnosis was achieved using flow cytometry long before the patient became symptomatic. This was achieved by focusing on a small percentage (0.9%) of total leukocytes that exhibited a higher side scatter and brighter CD19/CD20 than the remaining lymphocytes. A bone marrow aspirate three weeks later confirmed the presence of malignant B-cells. Shortly after, the patient presented splenomegaly and complained of fatigue. [ABSTRACT FROM AUTHOR]

Background: Rare oncogenic driver events, particularly affecting the expression or splicing of driver genes, are suspected to substantially contribute to the large heterogeneity of hematologic malignancies. However, their identification remains challenging. Methods: To address this issue, we generated the largest dataset to date of matched whole genome sequencing and total RNA sequencing of hematologic malignancies from 3760 patients spanning 24 disease entities. Taking advantage of our dataset size, we focused on discovering rare regulatory aberrations. Therefore, we called expression and splicing outliers using an extension of the workflow DROP (Detection of RNA Outliers Pipeline) and AbSplice, a variant effect predictor that identifies genetic variants causing aberrant splicing. We next trained a machine learning model integrating these results to prioritize new candidate disease-specific driver genes. Results: We found a median of seven expression outlier genes, two splicing outlier genes, and two rare splice-affecting variants per sample. Each category showed significant enrichment for already well-characterized driver genes, with odds ratios exceeding three among genes called in more than five samples. On held-out data, our integrative modeling significantly outperformed modeling based solely on genomic data and revealed promising novel candidate driver genes. Remarkably, we found a truncated form of the low density lipoprotein receptor LRP1B transcript to be aberrantly overexpressed in about half of hairy cell leukemia variant (HCL-V) samples and, to a lesser extent, in closely related B-cell neoplasms. This observation, which was confirmed in an independent cohort, suggests LRP1B as a novel marker for a HCL-V subclass and a yet unreported functional role of LRP1B within these rare entities. Conclusions: Altogether, our census of expression and splicing outliers for 24 hematologic malignancy entities and the companion computational workflow constitute unique resources to deepen our understanding of rare oncogenic events in hematologic cancers. [ABSTRACT FROM AUTHOR]

Key Clinical Message: 18F‐FDG PET/CT has clinical relevance in HCL at diagnosis and for the follow‐up of patients treated, especially in case of atypical presentations such as bone involvements (which are probably underestimated) and poor bone marrow infiltration. Bone lesions are rarely reported in Hairy Cell Leukemia (HCL). We report two BRAFV600E mutated HCL patients presented bone lesions at foreground, poor bone marrow involvement, and the important role 18F‐FDG PET/CT played in their management. We discuss the crucial role that 18F‐FDG PET/CT could play in HCL routine practice. [ABSTRACT FROM AUTHOR]