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Hairy Cell Leukemia

Leukemia is a condition where the bone marrow makes too many immature white blood cells. In Hairy Cell Leukemia (HCL) is a specific kind of leukemia affecting B­-lymphocytes, a type of white blood cell. In HCL fine, hair-like strands develop around the outside of abnormal B­-lymphocytes, visible under a microscope. HCL accounts for about 2% of all cases of leukemia, it is a chronic leukemia (tending to develop slowly) and occurs most frequently in people aged 40-60.

(UK spelling: Leukaemia)

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Molecular Genetics of Hairy Cell Leukemia
Chronic Lymphocytic Leukemia - CLL

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  • PubMed search for publications about Hairy Cell Leukemia - Limit search to: [Reviews]

    PubMed Central search for free-access publications about Hairy Cell Leukemia
    MeSH term: Leukemia, Hairy Cell
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Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Furundarena JR, Sainz M, Uranga A, et al.
Comparison of abnormal cell flagging of the hematology analyzers Sysmex XN and Sysmex XE-5000 in oncohematologic patients.
Int J Lab Hematol. 2017; 39(1):58-67 [PubMed] Related Publications
INTRODUCTION: Hematology analyzers should optimize flagging while minimizing false-negative results and unnecessary microscopic reviews.
METHODS: We compared flagging performance of Sysmex XE-5000 and XN analyzers in oncohematologic patients. Differential counts were performed by Cellavision digital system (100 cells) and a hematologist (another 100 cells).
RESULTS: First, we included 292 samples (86 with blasts): 28 acute lymphoblastic leukemia, 88 acute myeloid leukemia, 91 myelodysplastic syndromes, 45 chronic myeloproliferative neoplasms, and 40 chronic myelomonocytic leukemia. Sensitivity, specificity and efficiency to detect blasts were 59.3%, 88.3%, and 79.8% for XE-5000 analyzer and 70.9%, 91.3%, and 85.2% for the XN analyzer. Then, we included 111 lymphoid malignancies. In 55 CLL XE-5000 flagged for Abn Lympho/L_Blasts?, XN flagged for Abn Lympho?. In one-third of 19 samples with splenic marginal lymphoma, none of the analyzers flagged. In 5 Sézary syndrome cases, XE-5000 triggered the Abn Lympho/L_Blasts? flag while the flagging in XN was less consistent: Abn Lympho? Blasts? and Atypical Lympho?. In 5 hairy cell leukemias, both analyzers only flagged one sample. In 13 myelomas, XE-5000 generated Atypical Lympho? flag; XN triggered more variable flags. In other lymphoid malignancies, flags were variable. XN analyzer generates less samples with false basophilia.
CONCLUSION: XN analyzer has improved blast detection in oncohematologic patients. Operators cannot rely on the blast flag alone but have to consider other flags and hemogram data. In lymphoproliferative disorders, XN analyzer yields less samples with pseudobasophilia. Both analyzers must improve flagging for hairy cell leukemia.

Ikebe T, Sasaki H, Takata H, et al.
Toxoplasmic Encephalitis with Untreated Hairy Cell Leukemia Variant.
Intern Med. 2016; 55(21):3175-3180 [PubMed] Free Access to Full Article Related Publications
Toxoplasmic encephalitis is a rare infectious complication in patients with hematological malignancy except for allogeneic hematopoietic stem cell transplantation (HSCT). We herein report a case of possible toxoplasmic encephalitis with untreated hairy cell leukemia variant. Magnetic resonance imaging showed multiple nodules with surrounding edema in the entire cerebrum. A polymerase chain reaction analysis for Toxoplasma gondii was negative. Her signs and symptoms fully recovered by empirical therapy with sulfadiazine and pyrimethamine. Toxoplasmic encephalitis may occur in patients who undergo non-allogeneic HSCT for hematological malignancies, even in those who have not been treated.

Broccoli A, Gandolfi L, Pellegrini C, et al.
Leukocytoclastic vasculitis associated with hairy cell leukemia at diagnosis: a case report and review of the literature.
Tumori. 2016; 102(Suppl. 2) [PubMed] Related Publications
BACKGROUND: Autoimmune manifestations may occur in patients with hairy cell leukemia (HCL), and some rare cases of polyarteritis nodosa and leukocytoclastic vasculitis have been reported. However, data regarding the treatment of these cutaneous manifestations are lacking, given the rarity of the concomitance of HCL and vasculitic syndromes.
CASE PRESENTATION: We present a 37-year-old man with paraneoplastic leukocytoclastic vasculitis complicating newly diagnosed HCL. The vasculitis completely resolved after the first 3 weekly administrations of cladribine, which is regarded as the gold-standard treatment for this disease. The underlying leukemia showed refractoriness to the same agent, thus requiring a second line of treatment.
CONCLUSIONS: The clinical picture we have observed is of interest for the following reasons: i) it confirms an existing pathogenetic relationship between this lymphoproliferative disorder and its cutaneous manifestations, as suggested by the prompt resolution of the purpuric lesions upon cladribine administration; ii) it indicates that cladribine is an effective treatment for HCL-related paraneoplastic syndromes, including leukocytoclastic vasculitis; iii) the evolution and the outcomes of the paraneoplastic manifestations may be independent of those of the underlying leukemia, which showed less than a partial response to its initial treatment.

Bouroncle BA, Wiseman BK, Doan CA. Leukemic reticuloendotheliosis. Blood. 1958;13(7):609-630.
Blood. 2016; 127(12):1519 [PubMed] Related Publications
In this paper, Bertha A. Bouroncle and colleagues describe for the first time the clinical and pathologic features of hairy cell leukemia. The term "leukemic reticuloendotheliosis" proposed a cell of origin that was misplaced, but the remainder of scientific work described is completely consistent with our current understanding of the disease. Specifically, this paper describes the frequency of hairy cell leukemia among all adult leukemias and characterizes the pathology using several techniques still applied today. Furthermore, examining the clinical features of these patients, the authors describe the signs and symptoms of the disease, complications that arise, and expected outcome without modern therapy available today.

Weston-Bell NJ, Tapper W, Gibson J, et al.
Exome Sequencing in Classic Hairy Cell Leukaemia Reveals Widespread Variation in Acquired Somatic Mutations between Individual Tumours Apart from the Signature BRAF V(600)E Lesion.
PLoS One. 2016; 11(2):e0149162 [PubMed] Free Access to Full Article Related Publications
In classic Hairy cell leukaemia (HCLc), a single case has thus far been interrogated by whole exome sequencing (WES) in a treatment naive patient, in which BRAF V(600)E was identified as an acquired somatic mutation and confirmed as occurring near-universally in this form of disease by conventional PCR-based cohort screens. It left open however the question whether other genome-wide mutations may also commonly occur at high frequency in presentation HCLc disease. To address this, we have carried out WES of 5 such typical HCLc cases, using highly purified splenic tumour cells paired with autologous T cells for germline. Apart from BRAF V(600)E, no other recurrent somatic mutation was identified in these HCLc exomes, thereby excluding additional acquired mutations as also prevalent at a near-universal frequency in this form of the disease. These data then place mutant BRAF at the centre of the neoplastic drive in HCLc. A comparison of our exome data with emerging genetic findings in HCL indicates that additional somatic mutations may however occur recurrently in smaller subsets of disease. As mutant BRAF alone is insufficient to drive malignant transformation in other histological cancers, it suggests that individual tumours utilise largely differing patterns of genetic somatic mutations to coalesce with BRAF V(600)E to drive pathogenesis of malignant HCLc disease.

Tabata R, Tabata C, Iwama H, et al.
CD27-positive hairy cell leukemia-Japanese variant.
Virchows Arch. 2016; 468(3):375-9 [PubMed] Related Publications
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.

Streu E
Hairy Cell Leukemia and Bone Pain.
Oncol Nurs Forum. 2016; 43(1):18-21 [PubMed] Related Publications
Hairy cell leukemia is a relatively rare but distinct B-cell lympho-proliferative disorder of the blood, bone marrow, and spleen that accounts for only 2% of all adult leukemia cases. The median age at presentation is 50-55 years, with a 4:1 male to female predominance. Although considered uncommon, a number of unusual clinical presentations have been noted in the literature, including the presence of peripheral lymphadenopathy, lytic bone lesions, skin involvement, organ involvement, and central nervous system involvement. Unlike the clinical management of other hematologic malignancies, no current system is used to stage hairy cell leukemia.

Getta BM, Park JH, Tallman MS
Hairy cell leukemia: Past, present and future.
Best Pract Res Clin Haematol. 2015; 28(4):269-72 [PubMed] Free Access to Full Article Related Publications
This brief review highlights the sequence of therapeutic milestones and advances in our understanding of the biology of hairy cell leukemia (HCL) with a focus on recent molecular findings and how these may be applied to improve disease outcomes in the future. Targeted therapy is discussed in the context of the recently identified BRAF mutation and other genetic findings.

Stone EJ, Margolin M
What your hairy cell leukemia patients want you to know.
Best Pract Res Clin Haematol. 2015; 28(4):264-8 [PubMed] Related Publications
Hairy cell leukemia is different from most other hematologic malignancies because it is so rare. Patient concerns include finding a knowledgeable physician, confirming the diagnosis at the initial presentation, coping with treatment side effects and monitoring for potential relapse of this chronic disease.

Matutes E, Martínez-Trillos A, Campo E
Hairy cell leukaemia-variant: Disease features and treatment.
Best Pract Res Clin Haematol. 2015; 28(4):253-63 [PubMed] Related Publications
Hairy cell leukaemia-variant (HCL-V) is a rare B-cell malignancy that affects elderly males and manifests with splenomegaly, lymphocytosis and cytopenias without monocytopenia. The neoplastic cells have morphological features of prolymphocytes and hairy cells. The immunophenotype is that of a clonal B-cell CD11c and CD103 positive but, unlike classical HCL, CD25, CD123 and CD200 negative. The spleen histology is similar to classical HCL and the pattern of bone marrow infiltration is interstitial and/or intrasinusoidal. Mutations of the immunoglobulin heavy chain (IGVH) are seen in two thirds of cases with a preferential VH4-34 family usage. There is no distinct chromosomal abnormality but del17p13 and mutations of the TP53 gene are frequent. Mutations in the MAP2K1 gene have been documented in half of the cases. The course is chronic with median survivals of 7-9 years. Patients are refractory to purine analogues and the most effective therapy is the combination of 2-chlorodeoxyadenosine and Rituximab.

Dietrich S, Zenz T
BRAF inhibitor therapy in HCL.
Best Pract Res Clin Haematol. 2015; 28(4):246-52 [PubMed] Related Publications
Targeted treatment approaches are transforming the therapeutic landscape of cancer care. The discovery of the BRAF V600E mutation in most cases of classical hairy cell leukemia opens up unique opportunities for tumor specific treatment of HCL targeting the MEK/ERK signaling pathway. The discovery and biological implications of BRAF V600E in HCL are summarized to form a basis for our current understanding of the potential for clinical exploitation. There is overwhelming clinical evidence for activity of inhibitors of BRAF in the disease. The review will review current trial activity as well as discuss novel trial concepts exploiting targeted treatment focusing on BRAF inhibition in HCL.

Kreitman RJ, Pastan I
Immunoconjugates in the management of hairy cell leukemia.
Best Pract Res Clin Haematol. 2015; 28(4):236-45 [PubMed] Free Access to Full Article Related Publications
Hairy cell leukemia (HCL) is an indolent B-cell malignancy effectively treated but not often cured by purine analog therapy; after multiple courses of purine analogs, patients can become purine analog resistant and in need of alternative therapies. Complete remission to single-agent purine analog is often accompanied by minimal residual disease (MRD), residual HCL cells detectable by immunologic methods, considered a risk factor for eventual relapse. Several different non-chemotherapy approaches are being used to target relapsed and refractory HCL, including inhibitors of BRAF, but so far only monoclonal antibody (MAb)-based approaches have been reported to eliminate MRD in a high percentage of patients. One of the MAb-based options for HCL currently under clinical investigation involves recombinant immunotoxins, containing a fragment of a MAb and a bacterial toxin. The bacterial toxin, a highly potent fragment from Pseudomonas exotoxin, catalytically ADP-ribosylates elongation factor 2 (EF2), resulting in protein synthesis inhibition and apoptotic cell death. Recombinant immunotoxins tested in HCL patients include LMB-2, targeting CD25, and BL22, targeting CD22. An affinity matured version of BL22, termed moxetumomab pasudotox (formerly HA22 or CAT-8015) achieved high CR rates in phase I, and is currently undergoing multicenter Phase 3 testing. Phase I testing was without dose-limiting toxicity, although 2 patients had grade 2 hemolytic uremic syndrome (HUS) with transient grade 1 abnormalities in platelets and creatinine. Preclinical work is underway to identify residues on moxetumomab pasudotox leading to immunogenicity. Moxetumomab pasudotox is undergoing pivotal testing for relapsed and refractory HCL.

Ravandi F
Chemoimmunotherapy for hairy cell leukemia.
Best Pract Res Clin Haematol. 2015; 28(4):230-5 [PubMed] Related Publications
Success in the treatment of patients with hairy cell leukemia (HCL) over the last several decades is largely due to the high efficacy of the nucleoside analogs, cladribine and pentostatin. However, the relapse-free survival curves have not shown a plateau and many patients treated with these agents will eventually relapse. Although better understanding of the pathogenic mechanisms in HCL have led to effective and novel options for the treatment of relapse, long term durability of the responses obtained with these agents still remains unclear. Combination of nucleoside analogs with monoclonal antibodies such as rituximab has been shown to be safe and effective and has the potential to supersede the nucleoside analogs as the frontline strategy. Such chemo-immunotherapy approaches are under further investigation and will have to be assessed with socioeconomic considerations in mind. Other novel monoclonal antibodies, approved for the treatment of other lymphoid neoplasms, may also be considered for future studies of chemo-immunotherapy.

Else M, Dearden CE, Catovsky D
Long-term follow-up after purine analogue therapy in hairy cell leukaemia.
Best Pract Res Clin Haematol. 2015; 28(4):217-29 [PubMed] Related Publications
Since 2006 when we last reviewed the literature concerning the use of purine analogues in hairy cell leukaemia (HCL), results from several new and updated series have been published. Here we examine these reports and consider their implications for patient management. The two purine analogues pentostatin and cladribine remain the first-line treatments of choice for all patients with HCL. Although they have not been compared in randomised trials, they appear to be equally effective. A complete response is important for the long-term outcome and we look at how best this can be achieved. Evidence is emerging which supports the use of either purine analogue plus an anti-CD20 monoclonal antibody after relapse, though questions remain concerning the scheduling of the monoclonal antibody. Patients refractory to the purine analogues may require alternative agents.

Sivina M, Burger JA
The importance of the tissue microenvironment in hairy cell leukemia.
Best Pract Res Clin Haematol. 2015; 28(4):208-16 [PubMed] Related Publications
Hairy cell leukemia (HCL) cells engage in complex cellular and molecular interactions with accessory cells, matrix proteins, and various cytokines in the bone marrow and spleen, collectively referred to as the tissue microenvironment. Chemokine receptors and adhesion molecules are critical players for homing and retention within these microenvironments. Engagement of B cell antigen receptors and CD40 on HCL cells promote survival and proliferation. In this chapter, we summarize the current knowledge about the cellular and molecular interactions between HCL cells and their supportive tissue microenvironment, and provide insight into new therapeutic approaches targeting B cell receptor signaling in HCL.

Wotherspoon A, Attygalle A, Mendes LS
Bone marrow and splenic histology in hairy cell leukaemia.
Best Pract Res Clin Haematol. 2015; 28(4):200-7 [PubMed] Related Publications
Hairy cell leukaemia is a rare chronic neoplastic B-cell lymphoproliferation that characteristically involves blood, bone marrow and spleen with liver, lymph node and skin less commonly involved. Histologically, the cells have a characteristic appearance with pale/clear cytoplasm and round or reniform nuclei. In the spleen, the infiltrate involves the red pulp and is frequently associated with areas of haemorrhage (blood lakes). The cells stain for B-cell related antigens as well as with antibodies against tartrate-resistant acid phosphatase, DBA44 (CD72), CD11c, CD25, CD103, CD123, cyclin D1 and annexin A1. Mutation of BRAF -V600E is present and antibody to the mutant protein can be used as a specific marker. Bone marrow biopsy is essential in the initial assessment of disease as the bone marrow may be inaspirable or unrepresentative of degree of marrow infiltration as a result of the tumour associated fibrosis preventing aspiration of the tumour cell component. Bone marrow biopsy is important in the assessment of therapy response but in this context staining for CD11c and Annexin A1 is not helpful as they are also markers of myeloid lineage and identification of low level infiltration may be obscured. In this context staining for CD20 may be used in conjunction with morphological assessment and staining of serial sections for cyclin D1 and DBA44 to identify subtle residual infiltration. Staining for CD79a and CD19 is not recommended as these antibodies will identify plasma cells and can lead to over-estimation of disease. Staining for CD20 should not be used in patients following with anti-CD20 based treatments. Down regulation of cyclin D1 and CD25 has been reported in patients following BRAF inhibitor therapy and assessment of these antigens should not be used in this context. Histologically, hairy cell leukaemia needs to be distinguished from other B-cell lymphoproliferations associated with splenomegaly including splenic marginal zone lymphoma, splenic diffuse red pulp small B-cell lymphoma and hairy cell leukaemia variant. This can be done by assessment of the spleen but as this is now rarely performed in this disorder distinction is almost always possible by a combination of morphological and immunophenotypic studies on bone marrow trephine biopsy, which can be supplemented by assessment of BRAF-V600E mutation assessment in borderline cases.

Tadmor T, Polliack A
Hairy cell leukemia: Uncommon clinical features, unusual sites of involvement and some rare associations.
Best Pract Res Clin Haematol. 2015; 28(4):193-9 [PubMed] Related Publications
Unusual clinical manifestations and associations with auto-immunity or other systemic disorders are uncommon clinical features of hairy cell leukemia (HCL). The exact prevalence of these rare associations is difficult to determine as they are mostly published as anecdotal case reports and generally not included in larger published series. This chapter deals with uncommon clinical manifestations and rare sites of involvement in HCL. It also summarizes the association with systemic hemato-oncological disorders as well as second malignancies, based on review of the relevant literature and from personal experience.

Quest GR, Johnston JB
Clinical features and diagnosis of hairy cell leukemia.
Best Pract Res Clin Haematol. 2015; 28(4):180-92 [PubMed] Related Publications
Significant advances in the diagnosis and treatment of hairy cell leukemia (HCL) have recently been made. Improved distinction of HCL from its mimics though clinical presentations, morphologic and immunophenotypic features, and more recently molecular biology, has highlighted marked differences in treatment response and overall prognosis between these disorders. As our understanding of the unique pathobiology of HCL has grown, exciting new avenues of treatment as well as insight into immune function have been obtained. This review provides an overview of the clinical features and diagnostic attributes of HCL, with contrast to other mature B cell lymphoproliferative disorders with overlapping features.

Tadmor T, Polliack A
Epidemiology and environmental risk in hairy cell leukemia.
Best Pract Res Clin Haematol. 2015; 28(4):175-9 [PubMed] Related Publications
Hairy cell leukaemia (HCL) is an orphan subtype of leukaemia which constitutes less than 2% of all leukaemia's, with an incidence of less than 1 per 100,000 persons per annum. Median age at presentation is 55 years and it is 3-4 times more frequent in males. It is also more frequently encountered in whites and less in Asians, Africans and Arabs. The epidemiologic data are multi-factorial and influenced by ethnicity and geographical factors. Other reported associations relate to some environmental exposures and possible occupational factors. Smoking appears to have an inverse correlation with the development of hairy cell leukaemia, while farming and exposure to pesticides, petroleum products, diesel and ionizing radiation have also been reported to be associated with an increased risk. National and international collaborative efforts are needed in order to undertake more extensive studies involving larger patient cohorts, aiming to determine the role of occupational and environmental risk factors in the development of this rare form of chronic leukaemia.

Andritsos LA, Grever MR
Historical overview of hairy cell leukemia.
Best Pract Res Clin Haematol. 2015; 28(4):166-74 [PubMed] Related Publications
Since its discovery in 1923 and further characterization in 1958, hairy cell leukemia (HCL) has undergone enormous advances in the understanding of the biology and treatment of the disease. Initially a uniformly fatal disease, new therapies in rapid succession transformed HCL into a chronic disease with a normal life expectancy in many cases. More recently, the identification of BRAFV600E mutations in the majority of patients with classic HCL have enabled targeted therapies as a therapeutic option. Additional discoveries into the biology of the disease have identified new subtypes of HCL. Modern approaches to the evaluation and treatment of HCL include detailed molecular analysis which informs therapeutic options, which may consist of traditional therapies such as purine nucleoside analogs, or targeted therapies with antibodies, BTK inhibitors, or BRAF inhibitors, or combination therapy. Because HCL is a rare disease, continued progress depends on patients being enrolled on clinical trials whenever possible.

Gupta AK, Sachdeva MU, Ahluwalia J, et al.
Haematological profile of 21 patients with hairy cell leukaemia in a tertiary care centre of north India.
Indian J Med Res. 2015; 142(4):426-9 [PubMed] Free Access to Full Article Related Publications
BACKGROUND & OBJECTIVES: Hairy cell leukaemia (HCL) is a B cell neoplasm which constitutes around 2 per cent of all the lymphoid leukaemias. It has a characteristic morphology and immunophenotypic profile. It is important to distinguish HCL from other B cell lymphoproliferative disorders due to availability of different chemotherapeutic agents. This study presents clinical, haematological and immunophenotypic profile of patients with HCL seen over a period of four years in a tertiary care hospital in north India.
METHODS: Twenty one cases of hairy cell leukaemia were analyzed for their clinical details, haemogram, bone marrow examination and immunophenotypic findings.
RESULTS: Age of the patients ranged from 28-76 yr with male predominance. Weakness and fever were commonest presentations. Splenomegaly, hepatomegaly, lymphadenopathy were seen in decreasing order of frequency. Anaemia was noted in all 21 patients, leukopenia in 15 and thrombocytopenia in 19 cases. Fourteen patients were pancytopenic. Bone marrow examination showed typical hairy cells in all cases. Immunophenotyping showed expression of CD19, CD20, CD103, CD25 and CD11c in all cases, while positivity was seen for CD79b in 93.7 per cent, kappa light chain restriction in 60 per cent and lambda in 40 per cent cases. Notably, 20 per cent showed CD10 and 12 per cent showed CD23 expression.
INTERPRETATION & CONCLUSIONS: This study reveals some unusual findings in otherwise classical disease entity, like absence of palpable spleen, presence of lymphadenopathy, normal or elevated leukocyte counts, expression of CD10, which at times could be diagnostically challenging.

Arons E, Zhou H, Edelman DC, et al.
Impact of telomere length on survival in classic and variant hairy cell leukemia.
Leuk Res. 2015; 39(12):1360-6 [PubMed] Free Access to Full Article Related Publications
Telomeres, which protect the ends of chromosomes, are shortened in several hematologic malignancies, often with adverse prognostic implications, but their effect on prognosis of classic and variant hairy cell leukemia (HCL and HCLv) has not been reported. HCL/HCLv genomic DNA from 46 patients was studied by PCR to determine the ratio of telomere to single copy gene number (T/S). T/S was unrelated to diagnosis of HCL or HCLv (p=0.27), but shorter T/S was associated with unmutated immunoglobulin rearrangements (p=0.033) and age above the median at diagnosis (p=0.017). Low T/S was associated with shorter overall survival from diagnosis (OS), particularly T/S <0.655 (p=0.0064, adjusted p=0.019). Shorter OS was also associated with presence of unmutated (p<0.0001) or IGHV4-34+ (p<0.0001) rearrangements, or increasing age (p=0.0002). Multivariable analysis with Cox modeling showed that short T/S along with either unmutated or IGHV4-34+ rearrangements remained associated with reduced OS (p=0.0071, p=0.0024, respectively) after age adjustment. While T/S is relatively long in HCL and the disease usually indolent with excellent survival, shortened telomeres in HCL/HCLv are associated with decreased survival. Shortened T/S could represent a risk factor needing further investigation/intervention to determine if non-chemotherapy treatment options, in addition to or instead of chemotherapy, might be particularly useful.

Sarvaria A, Topp Z, Saven A
Current Therapy and New Directions in the Treatment of Hairy Cell Leukemia: A Review.
JAMA Oncol. 2016; 2(1):123-9 [PubMed] Related Publications
Hairy cell leukemia (HCL) is a chronic B-cell leukemia noted for an indolent course that ultimately results in cytopenias and massive splenomegaly. Whereas treatment with the nucleoside purine analogues cladribine and pentostatin results in lengthy remissions in nearly all patients with HCL, most patients will experience relapse while a small percentage of patients' disease fails to respond to therapy in the first place. Retreatment with a purine nucleoside analogue often leads to an effective but limited response. For decades, few other viable therapeutic options were available to these patients who required retreatment. Recently, new insights into the mechanism of disease of HCL have led to research in new potential treatment agents, either alone or with a purine nucleoside analogue. Clinical trials with rituximab, bendamustine, and conjugate immunotoxins will reveal what role these therapies will have in HCL treatment. A better understanding of the BRAF/MEK/ERK pathway and the B-cell signaling pathway has allowed further exploration into the novel drugs vemurafenib, dabrafenib, trametinib, and ibrutinib.

Sarid N, Ahmad HN, Wotherspoon A, et al.
An unusual indication for splenectomy in hairy cell leukaemia: a report of three cases with persistent splenomegaly after chemoimmunotherapy.
Br J Haematol. 2015; 171(5):784-7 [PubMed] Free Access to Full Article Related Publications
We describe three cases of relapsed hairy cell leukaemia (HCL) treated with pentostatin plus rituximab. All three achieved bone marrow complete remission but had persistent splenomegaly and hypersplenism. Because of the clinical uncertainty of its significance, they were all splenectomized. The spleen histology showed no evidence of HCL, but a five-fold thickening of the splenic capsule and areas of fibrosis in the red pulp. This process may have contributed to the lack of elasticity and caused the persistent splenomegaly. We discuss the clinical implications for future patient management. The three patients remain in remission at 1 + , 5 + and 9 + years.

Tiacci E, Park JH, De Carolis L, et al.
Targeting Mutant BRAF in Relapsed or Refractory Hairy-Cell Leukemia.
N Engl J Med. 2015; 373(18):1733-47 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: BRAF V600E is the genetic lesion underlying hairy-cell leukemia. We assessed the safety and activity of the oral BRAF inhibitor vemurafenib in patients with hairy-cell leukemia that had relapsed after treatment with a purine analogue or who had disease that was refractory to purine analogues.
METHODS: We conducted two phase 2, single-group, multicenter studies of vemurafenib (at a dose of 960 mg twice daily)--one in Italy and one in the United States. The therapy was administered for a median of 16 weeks in the Italian study and 18 weeks in the U.S. study. Primary end points were the complete response rate (in the Italian trial) and the overall response rate (in the U.S. trial). Enrollment was completed (28 patients) in the Italian trial in April 2013 and is still open (26 of 36 planned patients) in the U.S. trial.
RESULTS: The overall response rates were 96% (25 of 26 patients who could be evaluated) after a median of 8 weeks in the Italian study and 100% (24 of 24) after a median of 12 weeks in the U.S. study. The rates of complete response were 35% (9 of 26 patients) and 42% (10 of 24) in the two trials, respectively. In the Italian trial, after a median follow-up of 23 months, the median relapse-free survival was 19 months among patients with a complete response and 6 months among those with a partial response; the median treatment-free survival was 25 months and 18 months, respectively. In the U.S. trial, at 1 year, the progression-free survival rate was 73% and the overall survival rate was 91%. Drug-related adverse events were usually of grade 1 or 2, and the events most frequently leading to dose reductions were rash and arthralgia or arthritis. Secondary cutaneous tumors (treated with simple excision) developed in 7 of 50 patients. The frequent persistence of phosphorylated ERK-positive leukemic cells in bone marrow at the end of treatment suggests bypass reactivation of MEK and ERK as a resistance mechanism.
CONCLUSIONS: A short oral course of vemurafenib was highly effective in patients with relapsed or refractory hairy-cell leukemia. (Funded by the Associazione Italiana per la Ricerca sul Cancro and others; EudraCT number, 2011-005487-13; ClinicalTrials.gov number NCT01711632.).

Robak T, Wolska A, Robak P
Potential breakthroughs with investigational drugs for hairy cell leukemia.
Expert Opin Investig Drugs. 2015; 24(11):1419-31 [PubMed] Related Publications
INTRODUCTION: Hairy cell leukemia (HCL) is a rare subtype of B-cell chronic lymphoid leukemia. It is characterized by progressive pancytopenia, splenomegaly and infiltrations of the bone marrow, liver and spleen. Over the last few years, several new immunological drugs, particularly immunotoxins, BRAF inhibitors and B-cell receptor (BCR) pathway inhibitors have been developed and investigated as potential treatment options.
AREAS COVERED: This article summarizes recent investigational therapies of HCL, looking at their: mechanism of action, pharmacological properties, clinical activity and toxicity, as well as their emerging role in its treatment. The authors conducted a literature review of the MEDLINE database for articles in English concerning immunotoxins, BRAF inhibitors and BCR pathway inhibitors via PubMed. Publications from 2000 through to June 2015 were scrutinized. The search terms used were: BRAF, vemurafenib, dabrafenib, ibrutinib, monoclonal antibodies, immunotoxins, moxetumomab pasudotox, and rituximab in conjunction with HCL. The authors also searched manually the conference proceedings from the previous 5 years of the American Society of Hematology, European Hematology Association, American Society of Clinical Oncology, and ACR/ARHP Annual Scientific Meetings were searched manually. Additional relevant publications were obtained by reviewing the references from the chosen articles.
EXPERT OPINION: The use of vemurafenib and moxetumomab pasudotox is a promising new strategy for the treatment of HCL. Data from ongoing and future clinical trials will aid in better defining the status of new drugs in the treatment of HCL.

Robak T, Smolewski P
New mutation in hairy cell leukemia.
Blood. 2015; 126(8):930-1 [PubMed] Related Publications
In this issue of Blood, Dietrich et al make the first observation of the presence of deleterious CDKN1B mutation in 16% of patients with hairy cell leukemia (HCL). Furthermore, in the majority of patients, the CDKN1B mutation was clonal, suggesting that this mutation plays a role in the pathogenesis of HCL.

Trousil S, Zheng B
Addicted to AA (Acetoacetate): A Point of Convergence between Metabolism and BRAF Signaling.
Mol Cell. 2015; 59(3):333-4 [PubMed] Related Publications
In this issue Kang et al. (2015) show that oncogenic BRAF(V600E) stimulates expression of ketogenic enzyme 3-hydroxy-3-methylglutaryl-CoA lyase and promotes the formation of the ketone body acetoacetate, which subsequently enhances BRAF(V600E)/MEK/ERK signaling.

Găman AM, Dobrea CM, Găman MA
A case of hairy cell leukemia variant.
Rom J Morphol Embryol. 2015; 56(2):553-6 [PubMed] Related Publications
Hairy cell leukemia variant (HCLv) is a rare B-cell chronic lymphoproliferative disorder with features of the classic HCL but presenting some particularities, a poor response to conventional therapy of classic HCL and a more aggressive course of disease with shorter survival than classic HCL. We present a case of a 52-year-old man hospitalized in July 2012 in the Clinic of Hematology of Craiova, Romania, having splenomegaly, leukocytosis with lymphocytosis, anemia and thrombocytopenia, without monocytopenia, which exposed, in the peripheral blood and bone marrow cells, intermediate morphology between hairy cells and prolymphocytes and immunophenotype of mature B-cell phenotype CD19, CD20, CD22, CD11c, CD103, low positive for CD25 and negative for CD3, diagnosed with HCL variant, with no response to conventional chemotherapy and interferon-alpha, an aggressive course of disease and a survival of less than a year from diagnosis.

Poret N, Fu Q, Guihard S, et al.
CD38 in Hairy Cell Leukemia Is a Marker of Poor Prognosis and a New Target for Therapy.
Cancer Res. 2015; 75(18):3902-11 [PubMed] Related Publications
Hairy cell leukemia (HCL) is characterized by underexpression of the intracellular signaling molecule RhoH. Reconstitution of RhoH expression limits HCL pathogenesis in a mouse model, indicating this could represent a new therapeutic strategy. However, while RhoH reconstitution is theoretically possible as a therapy, it is technically immensely challenging as an appropriately functional RhoH protein needs to be specifically targeted. Because of this problem, we sought to identify druggable proteins on the HCL surface that were dependent upon RhoH underexpression. One such protein was identified as CD38. Analysis of 51 HCL patients demonstrated that 18 were CD38-positive. Interrogation of the clinical record of 23 relapsed HCL patients demonstrated those that were CD38-positive had a mean time to salvage therapy 71 months shorter than patients who were CD38-negative. Knockout of the CD38 gene in HCL cells increased apoptosis, inhibited adherence to endothelial monolayers, and compromised ability to produce tumors in vivo. Furthermore, an anti-CD38 antibody proved effective against pre-existing HCL tumors. Taken together, our data indicate that CD38 expression in HCL drives poor prognosis by promoting survival and heterotypic adhesion. Our data also indicate that CD38-positive HCL patients might benefit from treatments based on CD38 targeting.

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