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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]

Purpose of Review: This article summarizes the current state of knowledge of hairy cell leukemia (HCL) regarding presentation, diagnosis, therapy, and monitoring, including perspectives on emergent therapies. Recent Findings: Over the past decade, there has been enormous progress in the understanding of the biology of HCL which has led to the development of novel therapeutic strategies. The maturation of data regarding existing management strategies has also lent considerable insight into therapeutic outcomes and prognosis of patients treated with chemo- or chemoimmunotherapy. Purine nucleoside analogs remain the cornerstone of treatment, and the addition of rituximab has deepened and prolonged responses in the upfront and relapsed setting. Targeted therapies now have a more defined role in the management of HCL, with BRAF inhibitors now having a potential in the first-line setting in selected cases as well as in relapse. Next-generation sequencing for the identification of targetable mutations, evaluation of measurable residual disease, and risk stratification continue to be areas of active investigation. Summary: Recent advances in HCL have led to more effective therapeutics in the upfront and relapsed setting. Future efforts will focus on identifying patients with high-risk disease who require intensified regimens. Multicenter collaborations are the key to improving overall survival and quality of life in this rare disease. [ABSTRACT FROM AUTHOR]

Purpose of Review: This article aims to bring an update on the recent discoveries in hairy cell leukemia (HCL), especially findings in pathophysiology and therapeutic advances. Recent Findings: Major discoveries have been made in genetics and epigenetics of HCL. Moreover, the importance of several signaling pathways and tumor microenvironment has been recently highlighted. These findings led to the development of new targeted therapies which have shown interesting results in recent clinical trials. Summary: HCL is a chronic B-cell lymphoproliferative disorder. Most patients respond to purine nucleoside analogs (PNA) like cladribine or pentostatin. However, relapses are frequent and the disease often becomes less sensitive to chemotherapy. Recent discoveries in pathophysiology, like the presence of the V600E mutation of the B-raf proto-oncogene (BRAF) gene and the importance of the B-cell receptor (BCR) pathway, led to the development of new drugs for relapsed/refractory (R/R) HCL patients. The variant-type of HCL (HCL-V) is usually less sensitive to PNA. Chemo-immunotherapy using PNA and rituximab (R), BRAF, MEK, or Bruton Tyrosine Kinase (BTK) inhibitors may be used. Good results were recently published and achieved with moxetumomab pasudotox (Moxe), an anti-CD22 immunoconjugate. In this review, we will present an update on HCL and HCL-V, focusing on pathophysiology and recent therapeutic advances. [ABSTRACT FROM AUTHOR]

Background: Hairy cell leukemia (HCL) is a rare chronic B cell malignancy, characterized by infiltration of bone marrow, blood and spleen by typical "hairy cells" that bear the BRAFV600E mutation. However, in addition to the intrinsic activation of the MAP kinase pathway as a consequence of the BRAFV600E mutation, the potential participation of other signaling pathways to the pathophysiology of the disease remains unclear as the precise origin of the malignant hairy B cells. Materials and methods: Using mRNA gene expression profiling based on the Nanostring technology and the analysis of 290 genes with crucial roles in B cell lymphomas, we defined a 17 gene expression signature specific for HCL. Results: Separate analysis of samples from classical and variant forms of hairy cell leukemia showed almost similar mRNA expression profiles apart from overexpression in vHCL of the immune checkpoints CD274 and PDCD1LG2 and underexpression of FAS. Our results point to a post-germinal memory B cell origin and in some samples to the activation of the non-canonical NF-κB pathway. Conclusions: This study provides a better understanding of the pathogenesis of HCL and describes new and potential targets for treatment approaches and guidance for studies in the molecular mechanisms of HCL. [ABSTRACT FROM AUTHOR]

Hairy cell leukemia (HCL) is a rare hematologic disorder characterized by pancytopenia and splenomegaly for which a single course of cladribine is highly effective in inducing complete remissions. However, there is limited real-world data on outcomes and complications among geriatric patients with HCL treated with cladribine. We conducted a retrospective review of all patients 70 years or older within the Scripps Clinic HCL Database at the time of first treatment with cladribine. Of the 45 patients meeting inclusion criteria, 32 (71%) achieved CR and 4 (9%) achieved PR. Of the 9 remaining patients, 7 achieved normalization of peripheral blood counts after a single course of cladribine (complete hematologic response, CHR) and 2 had no response. The median duration of response for all responders was 119 months. Nine (20%) patients relapsed with a median time to first relapse of 28 months. Ten patients subsequently developed 12 primary malignancies with an excess frequency (observed-to-expected ratio) of 0.85 (95% confidence interval, 0.48–1.49). Median overall survival for the entire cohort was 166 months from time of HCL diagnosis and 119 months from time of first cladribine administration. Forty patient deaths were observed; the standardized mortality ratio (observed-to-expected ratio) was 1.42 (95% confidence interval, 1.03–1.96), representing a statistically significant increase in the risk of death (P =.03). This study supports the high rate of complete and durable responses following a single course of cladribine in geriatric patients. [ABSTRACT FROM AUTHOR]

Opinion statement: Hairy cell leukemia variant (HCL-V) is a rare B cell lymphoproliferative disorder with a clinical-pathological distinction from the classic form of hairy cell leukemia (HCL-C). HCL-V is more aggressive in nature, has a higher tendency to be refractory to conventional purine analog pharmacotherapies, and leads to a poorer prognosis. Hence, these differing features bring paramount importance to the diagnosis and management of HCL-V. While there is no genetic mutation diagnostic of HCL-V, genetic profiling efforts have identified potential therapeutic targets (i.e., MAP2K1, KDM6A, CREBBP, ARID1A, CCND3, U2AF1, KMT2C) and yielded prognostic markers (i.e., IGHV4-34 rearrangements). To date, combination chemoimmunotherapies, such as cladribine and rituximab, have shown the best results in HCL-V. Future directions include targeted therapies such as moxetumomab pasudotox, ibrutinib, trametinib, and binimetinib and potentially anti-CD22 chimeric antigen receptor T cell therapy. The purpose of this review is to provide an outline of the diagnostic approach and an update on the therapeutic advancements in HCL-V. [ABSTRACT FROM AUTHOR]

Dear Editor, Hairy cell leukemia (HCL) is a rare and indolent form of small mature B cell leukemias, which constitutes 2-3% of all leukemias [[1]]. Before the SP 18 sp F-FDG PET/CT imaging era, CT and MRI were used for evaluating skeletal lesions and defining treatment response [[3]]. Our report indicates that SP 18 sp F-FDG PET/CT can be a useful imaging method for staging and treatment evaluation in HCL. [Extracted from the article]

Skin lesions have been reported in about 10–12% of hairy cell leukemia (HCL) patients. Most are etiologically related to autoimmune or infectious processes, although secondary cutaneous neoplasms and drug-induced lesions are also reported. However, leukemia cutis with the direct infiltration of the skin by leukemic cells is extremely rare in HCL patients. This paper reviews the epidemiology, pathogenesis, clinical symptoms, diagnosis, and approach to treating skin lesions in HCL. A literature review of the MEDLINE database for articles in English concerning hairy cell leukemia, skin lesions, leukemia cutis, adverse events, infectious, cutaneous, drug reactions, neutrophilic dermatoses, secondary neoplasms, and vasculitis was conducted via PubMed. Publications from January 1980 to September 2020 were scrutinized. Additional relevant publications were obtained by reviewing the references from the chosen articles. [ABSTRACT FROM AUTHOR]

Opinion Statement: Despite its rarity, hairy cell leukemia (HCL) remains a fascinating disease and the physiopathology is becoming more and more understood. The accurate diagnosis of HCL relies on the recognition of hairy cells by morphology and flow cytometry (FCM) in the blood and/or bone marrow (BM). The BRAF V600E mutation, an HCL-defining mutation, represents a novel diagnostic parameter and a potential therapeutic target. The precise cellular origin of HCL is a late-activated postgerminal center memory B cell. BRAF mutations were detected in hematopoietic stem cells (HSCs) of patients with HCL, suggesting that this is an early HCL-defining event. Watch-and-wait strategy is necessary in approximately 10% of asymptomatic HCL patients, sometimes for several years. Purine analogs (PNAs) are the established first-line options for symptomatic HCL patients. In second-line treatment, chemoimmunotherapy combining PNA plus rituximab should be considered in high-risk HCL patients. The three options for relapsed/refractory HCL patients include recombinant immunoconjugates targeting CD22, BRAF inhibitors, and BCR inhibitors. The clinical interest to investigate blood minimal residual disease (MRD) was recently demonstrated, with a high risk of relapse in patients with positive testing for MRD and a low risk in patients with negative testing. However, efforts must be made to standardize MRD analyses in the near future. Patients with HCL are at risk of second malignancies. The increased risk could be related to the disease and/or the treatment, and the respective role of PNAs in the development of secondary malignancies remains a topic of debate. [ABSTRACT FROM AUTHOR]

BRAF V600E is a disease defining mutation for hairy cell leukemia (HCL), which helps in its diagnosis and differentiation from morphologically similar splenic marginal zone lymphoma (SMZL) and HCL-variant (HCL-v). Forty eight cases:HCL(n = 34), SMZL(n = 11) and HCL-v(n = 3) were included. Of these, 32 were retrospective and 16 were prospective. DNA was extracted, in retrospective cases from cells obtained by smears from bone marrow aspirate/trephine imprint (BMA/BMTx) slides, and in prospective cases from peripheral blood (PB)/BMA samples. BRAF V600E mutation testing was done using ARMS-PCR. BRAF V600E mutation was positive in all HCL and negative in all SMZL and HCL-v cases. DNA extracted from BMA/BMTx slides gave results comparable to DNA extracted from PB/BMA samples. Median age of presentation for HCL (53 years) and SMZL (56 years) were quite similar, however, HCL-v (71 years) cases presented at an older age. Statistically significant differences between the three groups were seen for total leucocyte, platelet, absolute lymphocyte and monocyte counts, bone marrow-infiltration pattern, reticulin fibrosis, and an expression of CD11c, CD25, CD103, CD123, and CD200. The use of BMA/BMTx smears for DNA extraction was found to be a useful alternative to DNA extraction from formalin-fixed paraffin-embedded biopsy sections. ARMS-PCR is an efficient and specific technique to detect BRAF V600E mutation in HCL patients. [ABSTRACT FROM AUTHOR]

HCL is an uncommon B cell lympho-proliferative disorder with high remission rates. There is paucity of data on the long-term outcome of HCL from India. We retrospectively collected data from individual case records of patients with HCL who were treated in Cancer Institute, Chennai from January 2001 until January 2018. Sixteen patients were diagnosed with HCL and were treated with cladribine (81%), interferon (13%) and one patient received only best supportive care (6%). All the treated patients achieved complete response. More than half of the patients developed febrile neutropenia but there were no treatment related mortality. The 5-year DFS was 77% and 5-year OS was 80%. Relapse of disease was seen in 27%. HCL is a curable malignancy with high remission rates and survival comparable to patient treated in west. [ABSTRACT FROM AUTHOR]

We aimed to analyze the characteristics and response rates of different treatment modalities in hairy cell leukemia patients over 20 diagnosed as hairy cell leukemia (HCL). Clinical data, response rates and survival outcome of the patients who were diagnosed with HCL were retrospectively analyzed. Fifty-two patients with a median age of 50 (28–87) years were enrolled in the study. 38 patients (73%) were male and male to female ratio was 2.7. First line therapy was cladrabine in 36 patients (69.2%). The overall response rate was 97%. CR and PR rates were 86.1% and 11.1%, respectively. Interferon was used in 10(19.2%) patients who were diagnosed before 2000s years. CR and PR rates were 70% and 30%, respectively. Although the CR rates were lower in IFN group, this difference could not be reached statistically significance (p = 0.24). The median follow up was 48 months (12–252). The median OS was not reached and median PFS was 150 months (95% CI, 116–214). The OS at 36 and 48 months were 95.9% and 92.3%, respectively and the PFS at 36 and 48 months were 90.2% and 83.4%, respectively. After the introduction of purine analogues, the fate of the HCL patients have been changed. Cladrabin achieved very high response rates in both young and older patients, in our study. Although relapse still constitutes a problem, another single dose of cladrabine results in good response rates. [ABSTRACT FROM AUTHOR]

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Purpose: Hairy cell leukemia (HCL) is a rare mature B cell leukemia. Purine analogs are the mainstay of treatment of HCL, but relapse after purine analog therapy is common. Outcomes of treatment of relapsed/refractory HCL typically diminish with each successive line of therapy. Moxetumomab pasudotox-tdfk is a novel recombinant immunotoxin approved for the treatment of patients with relapsed/refractory HCL who have received at least two prior therapies, including a purine analog. This article reviews HCL treatment, focusing on moxetumomab pasudotox-tdfk, its place in therapy, considerations for preparation and administration, and strategies for prevention and management of toxicities.Methods: A literature search was conducted in the PubMed database from inception to January 2019, using the following terms: moxetumomab, hairy cell leukemia, relapsed/refractory hairy cell leukemia, immunotoxin, and CD22. The package insert and available posters and abstracts were also reviewed.Results: FDA approval of moxetumomab pasudotox-tdfk was based on a phase III single-arm, open-label trial in 80 patients. Treatment with moxetumomab pasudotox-tdfk yielded a durable complete response rate of 30% with a median duration of response that had not yet been reached at a median follow-up of 16.7 months. The objective response rate was 75% based on blinded independent central review. The most common adverse reactions were infusion-related reactions, edema, nausea, fatigue, headache, pyrexia and anemia. Serious adverse events include capillary leak syndrome and hemolytic uremic syndrome.Conclusions: Clinicians providing care for patients receiving moxetumomab pasudotox-tdfk should be aware of the strategies required for safe administration, including the management of serious adverse events. [ABSTRACT FROM AUTHOR]

Bioactive phospholipids, including sphingosine-1-phosphate (S1P), ceramide-1-phosphate (C1P), lysophosphatidylcholine (LPC), and its derivative lysophosphatidic acid (LPA), have emerged as important mediators regulating the trafficking of normal and cancer cells. While the role of S1P in regulating migration of hematopoietic cells is well established, in this work we compared its biological effects to the effects of C1P, LPC, and LPA. We employed 10 human myeloid and lymphoid cell lines as well as blasts from AML patients. We observed that human leukemic cells express functional receptors for phospholipids and respond to stimulation by phosphorylation of p42/44 MAPK and AKT. We also found that bioactive phospholipids enhanced cell migration and adhesion of leukemic cells by downregulating expression of HO-1 and iNOS in a p38 MAPK-dependent manner but did not affect cell proliferation. By contrast, downregulation of p38 MAPK by SB203580 enhanced expression of HO-1 and iNOS and decreased migration of leukemic cells in vitro and their seeding efficiency to vital organs in vivo after injection into immunodeficient mice. Based on these findings, we demonstrate that, besides S1P, human leukemic cells also respond to C1P, LPC, and LPA. Since the prometastatic effects of bioactive phospholipids in vivo were mediated, at least in part, by downregulating HO-1 and iNOS expression in a p38 MAPK-dependent manner, we propose that inhibitors of p38 MAPK or stimulators of HO-1 activity will find application in inhibiting the spread of leukemic cells in response to bioactive phospholipids. [ABSTRACT FROM AUTHOR]

Hairy cell leukemia (HCL) is a rare B-cell lymphoid malignancy that is difficult to distinguish from other morphological variants. The frequency of HCL has not been determined accurately in Japan. Recent studies revealed that the BRAF V600E mutation is the causal genetic event in HCL. We assessed the BRAF mutation in Japanese patients with HCL and related diseases using the quenching probe (QP) method, a single-nucleotide polymorphism detection system, and evaluated the incidence rate of HCL among Japanese patients with chronic lymphocytic leukemia, and related diseases. We identified 18 cases (33.3%) harboring the BRAF mutation among 54 patients diagnosed with, or suspected of having HCL. Of BRAF V600E-positive patients, 7 were only detected using the QP method, not by direct sequencing, whereas 11 were positive using both tests. In a larger cohort of Japanese patients diagnosed with chronic lymphoid leukemia or related diseases, the frequency of HCL was 4%. Patients with the BRAF V600E mutation had a significantly higher frequency of neutropenia, thrombocytopenia, and elevated soluble interleukin-2 receptor and common B-cell surface markers than patients without the mutation. Our results confirm that BRAF V600E-positive HCL is a relatively rare disorder in the Japanese leukemia patient population. [ABSTRACT FROM AUTHOR]

Introduction: Pentostatin (20-deoxycoformycin) and cladribine (2-chlorodeoxyadenosine) are adenosine analogues widely used to treat lymphoid malignancies, mainly hairy cell leukemia (HCL). Oral or parenteral adenosine analogues have been also used as immunomodulatory agents in multiple sclerosis and in acute graft-versus-host disease. Case Report: Here, we report the case of a 43-year-old patient with a history of extensive psoriasis who later developed HCL. Results: The patient had achieved complete remission of both psoriasis and HCL after receiving intravenous infusions of pentostatin. It is worth noting that cladribine has already been reported to treat plaque psoriasis lesions in two patients with HCL and in a third patient with gastric marginal zone B cell lymphoma [1]. Conclusion: We believe that adenosine analogues constitute a promising therapeutic option for moderate to severe psoriasis, especially for severe and refractory psoriasis, as well as for patients with adjacent lymphoid malignancies. [ABSTRACT FROM AUTHOR]

Hairy cell leukemia (HCL) is a rare and indolent mature B cell neoplasm. Most patients with HCL have excellent response to purine analogs and BRAF inhibitors. Therefore, it is clinically important to identify and differentiate HCL from other B cell neoplasms. HCL is predominantly found in the peripheral blood, bone marrow, or spleen. HCL presenting initially or solely in unusual sites is extremely rare (approximately ten or fewer). We hereby report a unique case of HCL presenting as vertebral osteolytic and epidural mass lesions without bone marrow, spleen, or peripheral blood involvement. The patient was a 53-year-old male with acute and chronic radicular pain down the posterior aspect of bilateral thighs. Imaging study with MRI demonstrated a L4 posterior vertebral osteolytic mass lesion, extending into the spinal canal, and a second right sacral S1 lesion extending into the sacral iliac joint. These two noncontiguous lesions were thought to be consistent with metastatic cancer or sarcoma, and the specimen was submitted to non-hematopoietic pathologist for diagnosis without flow cytometry. Initial immunohistochemical stains were ordered for solid tumor markers, which were all negative. As part of the workup, immunostain for BRAF V600E (VE1) was ordered for melanoma, and CD138 and cyclin D1 for myeloma, which returned positive and suggested the possibility of hairy cell leukemia. Additional workup for hairy cell leukemia confirmed the diagnosis. HCL typically presents with peripheral blood, bone marrow, or spleen involvement, while mass lesions in other sites are rare. High index of suspicion is essential for the correct diagnosis of HCL in mass lesions at unusual sites. In the absence of initial hematopathological workup and flow cytometry, HCL presenting as solid mass in unusual locations is misdiagnosed most likely as marginal zone B cell lymphoma (mucosa-associated lymphoid tissue (MALT) lymphoma). The expression of cyclin D1, TRAP, annexin A1, and BRAF V600E mutation would confirm the diagnosis of HCL. The main differentials include MALT lymphoma, mantle cell lymphoma (MCL), and hairy cell leukemia variant (HCLv). This case report will be interesting for the clinicians and pathologists alike and broaden the spectrum of clinical presentation of lymphomatous HCL. [ABSTRACT FROM AUTHOR]

The MinION is a miniaturized high-throughput next generation sequencing platform of novel conception. The use of nucleic acids derived from formalin-fixed paraffin-embedded samples is highly desirable, but their adoption for molecular assays is hurdled by the high degree of fragmentation and by the chemical-induced mutations stemming from the fixation protocols. In order to investigate the suitability of MinION sequencing on formalin-fixed paraffin-embedded samples, the presence and frequency of BRAF c.1799T > A mutation was investigated in two archival tissue specimens of Hairy cell leukemia and Hairy cell leukemia Variant. Despite the poor quality of the starting DNA, BRAF mutation was successfully detected in the Hairy cell leukemia sample with around 50% of the reads obtained within 2 h of the sequencing start. Notably, the mutational burden of the Hairy cell leukemia sample as derived from nanopore sequencing proved to be comparable to a sensitive method for the detection of point mutations, namely the Digital PCR, using a validated assay. Nanopore sequencing can be adopted for targeted sequencing of genetic lesions on critical DNA samples such as those extracted from archival routine formalin-fixed paraffin-embedded samples. This result let speculating about the possibility that the nanopore sequencing could be trustably adopted for the real-time targeted sequencing of genetic lesions. Our report opens the window for the adoption of nanopore sequencing in molecular pathology for research and diagnostics. [ABSTRACT FROM AUTHOR]

We report a unique case of composite hairy cell leukemia (HCL) and monoclonal B-cell lymphocytosis with chronic lymphocytic leukemia (CLL) phenotype evaluated comprehensively through cell sorting and deep sequencing. The patient presented with decreased exercise tolerance and complete blood count revealed neutropenia, monocytopenia, and thrombocytopenia. The peripheral blood film was suggestive of HCL. However, a bone marrow evaluation was suspicious for composite HCL and CLL. Flow cytometry not only confirmed monoclonal kappa light chain restricted HCL and CLL populations, but also identified a kappa restricted population with co-expression of bright CD20, bright CD22, and CD11c without CD25 or CD103. Each population was isolated by cell sorting and subsequent B-cell receptor gene rearrangement analysis showed distinct rearrangements in each population. Likewise, next-generation sequencing (NGS) showed distinct mutation patterns in each of the monoclonal B-cell populations. The HCL clone harbored the signature BRAF V600E mutation, the CLL clone harbored an RB1 (L343fs*6) mutation, and the third clone was essentially negative for either mutation. In HCL, the BRAF V600E has been found in hematopoietic stem cells, raising the possibility of a common stem cell origin for composite HCL/CLL. However, our findings suggest a process of independent clonal development of multiple neoplastic B-cell populations in composite lymphoma, likely occurring somewhere after the common lymphoid progenitor stage. [ABSTRACT FROM AUTHOR]

Interferon-α (IFNα) was the first effective drug therapy for hairy cell leukemia (HCL). Nowadays, it is used as an alternative treatment in selected patients. Due to unlimited treatment time, monitoring and early prediction of response are important. Moreover, IFNα is used in the therapy of chronic hepatitis C, where a single nucleotide polymorphism of interleukin-28B gene (IL28B) correlates with therapy response. The role of this polymorphism in therapy response of IFNα-treated patients with HCL is unknown. Thirty-seven HCL patients treated between 1978 and 2014 were included in this study. Treatment strategy and response parameters (blood cell counts, soluble interleukin-2 receptor (sIL2R), and bone marrow examination) have been assessed. Relative decrease of sIL2R was correlated with outcome parameters. Response parameters of IFNα-treated patients were correlated with IL28B polymorphism. Twenty-one patients were analyzed for the correlation of sIL2R ratio and outcome. After 1 and 3 months of therapy (IFNα or cladribine (CDA)), the median sIL2R level showed a relative decrease of 79 and 91%. These decreases significantly correlate with time to complete remission (CR, p = 0.029 and p = 0.018). Correlation analyses of IL28B genotype with outcome parameters are not significant. Six patients (16%) were diagnosed with secondary malignancies, and one death was registered (median follow-up time 14 years). IFNα is a safe, effective, and well-tolerated long-term treatment in HCL. Relative decreases of sIL2R levels correlate with time to CR and are useful as early predictor for response. There is no significant correlation between IL28B polymorphism and treatment response to IFNα. Graphical abstract. [ABSTRACT FROM AUTHOR]

Hairy cell leukemia (HCL) is a rare, indolent B cell malignancy characterized by bone marrow infiltration, splenomegaly, pancytopenia, and neoplastic cells morphologically with cytoplasmic "hair-like" projections [[1]]. Analogous to other B cell disorders, autoimmune diseases have been reported in HCL; however, autoimmune hemolytic anemia (AIHA) has seldom been reported [[2]]. Initial 2-CdA course (0.09 mg/kg) administered after diagnosis in August 1997. b HCL involvement in bone marrow, assessed by hematoxylin and eosin (H&E) stain with mutant allele frequencies reported via hematologic malignancy sequencing panel. [Extracted from the article]

We report a very rare case of a 45-year-old Japanese male patient with hairy cell leukemia-Japanese variant (HCL-JV) expressing CD27. The patient showed a high number of abnormal peripheral lymphocytes, thrombocytopenia, and severe splenomegaly but no lymphadenopathy. Histology of the resected spleen showed small-sized lymphoma cells diffusely infiltrating the red pulp without follicle formation. By immunohistochemistry, lymphoma cells were negative for CD3, CD5, CD8, CD10, CD34, cyclin-D1, and annexin A1 but positive for CD20 and BCL2. BRAF V600E mutation was not observed. Bone marrow aspirate showed preserved normal hematopoietic cells with invasion of lymphoma cells in an interstitial pattern without obvious nodules. The cells had abundant pale cytoplasm and round nuclei with inconspicuous nucleoli. After natural drying, the cells had unevenly distributed microvilli. Flow cytometric analysis demonstrated positivity for CD11a, CD11c, CD19, CD20, CD22, CD27, surface IgG, and λ but not for CD2, CD3, CD4, CD5, CD7, CD8, CD10, CD21, CD23, CD25, CD30, CD34, CD38, CD43, CD56, CD57, CD103, IgD, IgM, and κ. Monoclonal expansion of B cells was confirmed by an immunoglobulin heavy chain (IgH) rearrangement band as demonstrated by Southern blot hybridization. The lymphoma cells had unevenly distributed long, large, and broad-based microvilli, which resembled splenic diffuse red pulp small B cell lymphoma (SDRPL) cells. CD27 expression is extremely rare in HCL-JV, but the young age of the patient and high peripheral WBC counts were similar to HCL-JV, which suggests, in this case, an intermediate disease between SDRPL and HCL-JV. [ABSTRACT FROM AUTHOR]

Copyright of Der Onkologe is the property of Springer Nature 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.)

Mutations in ASXL1 are frequent in patients with myelodysplastic syndrome (MDS) and are associated with adverse survival, yet the molecular pathogenesis of ASXL1 mutations (ASXL1-MT) is not fully understood. Recently, it has been found that deletion of Asxl1 or expression of C-terminal-truncating ASXL1-MTs inhibit myeloid differentiation and induce MDS-like disease in mice. Here, we find that SET-binding protein 1 (SETBP1) mutations (SETBP1-MT) are enriched among ASXL1-mutated MDS patients and associated with increased incidence of leukemic transformation, as well as shorter survival, suggesting that SETBP1-MT play a critical role in leukemic transformation of MDS. We identify that SETBP1-MT inhibit ubiquitination and subsequent degradation of SETBP1, resulting in increased expression. Expression of SETBP1-MT, in turn, inhibited protein phosphatase 2A activity, leading to Akt activation and enhanced expression of posterior Hoxa genes in ASXL1-mutant cells. Biologically, SETBP1-MT augmented ASXL1-MT-induced differentiation block, inhibited apoptosis and enhanced myeloid colony output. SETBP1-MT collaborated with ASXL1-MT in inducing acute myeloid leukemia in vivo. The combination of ASXL1-MT and SETBP1-MT activated a stem cell signature and repressed the tumor growth factor-β signaling pathway, in contrast to the ASXL1-MT-induced MDS model. These data reveal that SETBP1-MT are critical drivers of ASXL1-mutated MDS and identify several deregulated pathways as potential therapeutic targets in high-risk MDS. [ABSTRACT FROM AUTHOR]

The purine analogs (PAs) cladribine and pentostatin have transformed the prognosis of hairy cell leukemia (HCL). However, some patients still relapse after PAs, or fail to reach an optimal response, and new agents are needed to further improve treatment outcome. We retrospectively studied 41 HCL patients from 10 centers in France and Belgium, who received 49 treatment courses with the anti-CD20 monoclonal antibody rituximab. Most of the patients were treated at relapse (84 % of cases) and rituximab was combined to a PA in 41 % of cases. Overall, response rate is 90 % including 71 % complete hematologic responses (CHRs). Frontline treatment, combination therapy, and absolute neutrophil count were associated with response in multivariate analysis. Three-year relapse-free and overall survivals are 68 and 90 %, respectively. When combined to a PA, rituximab yields a 100 % response rate, even beyond frontline therapy. In contrast, response rate is only 82 % (59 % CHR) when rituximab is used alone. In this latter setting, relapse rate is 56 % and median time to relapse is 17.5 months. All eight patients who were treated two times with the antibody responded again to re-treatment. We confirm the high efficacy of the combination rituximab + PA. However, when rituximab is used as monotherapy, response rate is lower and the high relapse rate is a concern. Prospective clinical trials are needed to confirm the superiority of the combination rituximab + PA over PA alone, both as frontline therapy and at relapse. [ABSTRACT FROM AUTHOR]

Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis seen in association with systemic disorders including hematologic malignancies. Hairy cell leukemia (HCL) however, is an unusual association of PG. We describe a 49-year old lady who presented to our hematology clinic with easy fatiguability and ulcerative skin lesions of 6 months duration. Examination revealed pallor and massive splenomegaly. Indurated, ulcerated lesion with undermined edges and necrotic base was observed on left thigh. Investigations revealed pancytopenia and bone marrow examination identified typical hairy cells. Flow cytometry of marrow aspirate was suggestive of classical HCL. BRAF V600E mutation was detected in peripheral blood by reverse transcriptase polymerase chain reaction. Skin biopsy revealed neutrophilic dermatosis and findings classical of bullous PG. Cladribine therapy (0.09 mg/kg/day by continuous intravenous infusion for 7 days) led to remission of both HCL and PG after a duration of 4 weeks. Cladribine monotherapy in a case of PG with HCL may avoid the additional immunosuppresion risk imposed by treating PG separately with corticosteroids. Immunosuppressive role of cladribine might be helpful in treating PG concurrent with HCL. [ABSTRACT FROM AUTHOR]

Introduction: Hairy cell leukemia (HCL) is an uncommon B cell lymphoproliferative disorder. The object of the present audit was to assess whether the investigation and management of HCL in University College Hospital Galway (UCHG) complies with the British Committee for Standards in Haematology (BCSH) guidelines. Methods: Following a review of the records in our Haematology Department, 18 cases of HCL were identified between January 2006 and October 2014. Results: Blood film examination had been performed in all cases. Flow cytometry of liquid material had been undertaken in 89 % ( n = 16) of cases, of which only 31 % ( n = 5) included all four hairy cell panel markers (CD11c, CD25, CD103, CD123). Although all initial trephine biopsies included CD20, none analyzed DBA44. Only 65 % ( n = 11) of treated patients had a post-treatment bone marrow biopsy preformed. Conclusion: This audit highlights areas of improvement in the diagnosis and management of HCL in UCHG, which do not currently adhere to the BCSH recommendations. [ABSTRACT FROM AUTHOR]

Hairy cell leukaemia (HCL) is a rare haematological malignancy, with approximately 175 new incident cases in France. Diagnosis is based on a careful examination of the blood smear and immunophenotyping of the tumour cells, with a panel of four markers being used specifically to screen for hairy cells (CD11c, CD25, CD103 and CD123). In 2011, the V600E mutation of the BRAF gene in exon 15 was identified in HCL; being present in HCL, it is absent in the variant form of HCL (HCL-v) and in splenic red pulp lymphoma (SRPL), two entities related to HCL. The management of patients with HCL has changed in recent years. A poorer response to purine nucleoside analogues (PNAs) is observed in patients with more marked leukocytosis, bulky splenomegaly, an unmutated immunoglobulin variable heavy chain ( IgVH) gene profile, use of VH4-34 or with TP53 mutations. We present the recommendations of a group of 11 experts belonging to a number of French hospitals. This group met in November 2013 to examine the criteria for managing patients with HCL. The ideas and proposals of the group are based on a critical analysis of the recommendations already published in the literature and on an analysis of the practices of clinical haematology departments with experience in managing these patients. The first-line treatment uses purine analogues: cladribine or pentostatin. The role of BRAF inhibitors, whether or not combined with MEK inhibitors, is discussed. The panel of French experts proposed recommendations to manage patients with HCL, which can be used in a daily practice. [ABSTRACT FROM AUTHOR]

Hairy cell leukemia (HCL) is a rare mature B cell malignancy that typically involves the bone marrow, peripheral blood, and spleen. Clinically detectable lymph node infiltration occurs in a minority of patients, and extranodal tissue involvement of sites such as the central nervous system, gastrointestinal tract, and skin is uncommon. Consequently, the vast majority of patients with HCL present with pancytopenia and splenomegaly but without lymphadenopathy or soft tissue masses. Herein we present a unique case of HCL presenting as a palpable breast mass without concomitant marrow or peripheral blood involvement and without radiologic evidence of other sites of disease. Several features of the tumor cell infiltrate (ample pale cytoplasm, nested appearance) evoked other entities that would more typically involve breast tissue such as the alveolar or solid variants of invasive lobular carcinoma. However, the immunophenotypic and molecular characteristics of the tumor cells were indistinguishable from classic HCL. The significant challenge in this case was recognizing this entity outside of its usual clinical and anatomic context. Although rare, HCL should be a diagnostic consideration in tumors arising at extramedullary/extranodal sites including the breast. [ABSTRACT FROM AUTHOR]

Castleman disease is a rare lymphoproliferative disorder of unknown etiology that most commonly presents as a mediastinal nodal mass or, in the extranodal form of the disease, a mass located in the mediastinum or retroperitoneum. It is exceptionally uncommon for Castleman disease to present in the extremities. We report a rare case of extranodal Castleman disease presenting as a muscular forearm mass. We compare our case with the seven other reported cases in which Castleman disease presented as an isolated soft tissue mass in the extremities. [ABSTRACT FROM AUTHOR]

Hairy cell leukemia (HCL) is characterized by pancytopenia and usually associated with massive splenomegaly, however the same may not be true in the clinical settings. Here we report four cases of HCL and all of them were without the classical clinical feature of splenomegaly. This is an observational study conducted between January 2013 to March 2014 where we could diagnose ten cases of HCL in Department of Hematology, All India Institute of Medical Sciences, New Delhi. Of these, four cases attracted attention because of absence of classical clinical features of HCL. Of the four cases, three presented with weakness/fatigability while fourth patient presented with recurrent respiratory tract infection. Surprising finding in these cases was absence of splenomegaly, both clinically and on imaging which demerit the suspicion of HCL clinically. All four had bi/pancytopenia and bone marrow examination coupled with immunophenotypic analysis confirmed the diagnosis of HCL. Three patients received chemotherapy with cladribine and achieved complete hematological remission. One patient did not receive chemotherapy due to poor general condition and was subsequently lost to follow up. To conclude, HCL can and do present without splenomegaly and this should not restrain one from suspecting HCL based on histomorphology which needs to be further confirmed by ancillary techniques. This finding in our series could be because these cases were picked early in their natural course of the disease. A high index of suspicion is essential for diagnosing and appropriately managing such cases. [ABSTRACT FROM AUTHOR]