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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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Information for Patients and the Public
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Latest Research Publications
Molecular Genetics of Hairy Cell Leukemia
Chronic Lymphocytic Leukemia - CLL

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Latest Research Publications

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

Falini B, Tiacci E
New treatment options in hairy cell leukemia with focus on BRAF inhibitors.
Hematol Oncol. 2019; 37 Suppl 1:30-37 [PubMed] Related Publications
Hairy cell leukemia (HCL) responds initially very well to chemotherapy with purine analogues. However, up to 50% of patients relapse, often multiple times, and become progressively less sensitive to these myelotoxic and immune-suppressive drugs. At progression, viable therapeutic strategies include addition of rituximab to purine analogues, and treatment with the anti-CD22 immunotoxin moxetumomab pasudotox, which has been recently approved by the FDA in HCL patients after at least two prior therapies. Identification of the BRAF-V600E kinase mutation as the genetic cause of HCL has opened the way, in the relapsed/refractory experimental setting, to targeted and non-myelotoxic effective strategies that are based on inhibition of BRAF with vemurafenib, co-inhibition of BRAF and its target MEK with dabrafenib and trametinib, and BRAF inhibition with vemurafenib combined with anti-CD20 immunotherapy. In particular, vemurafenib plus rituximab is emerging as a short, safe, chemotherapy-free regimen able to induce deep complete remissions in most HCL patients refractory to, or relapsed multiple times, after chemo(immuno)therapy.

Doma A, Škerget M, Žagar I
18F-FDG PET/CT for Staging and Evaluation of Therapy in a Patient With Unusual Hairy Cell Leukemia Presentation.
Clin Nucl Med. 2019; 44(7):e458-e460 [PubMed] Related Publications
Hairy cell leukemia is a rare hematologic malignancy characterized by splenomegaly, pancytopenia, and susceptibility to infections. We report a case of a 66-year-old man, diagnosed with hairy cell leukemia, without severe cytopenias and splenomegaly, but with an extensive pathological retroperitoneal mass and infiltration of the spleen and skeletal involvement. All findings were highly avid on pretreatment F-FDG PET/CT scan. Treatment response evaluation F-FDG PET/CT scan showed normalization of FDG uptake on all previously pathological sites.

Cardus B, Colling R, Hamblin A, Soilleux E
Comparison of methodologies for the detection of
J Clin Pathol. 2019; 72(6):406-411 [PubMed] Related Publications

Bourhis A, Le Flahec G, Uguen A
Decalcification can cause the failure of BRAF molecular analyses and anti-BRAFV600E VE1 immunohistochemistry.
Pathol Int. 2019; 69(4):219-223 [PubMed] Related Publications
BRAF mutation detection is worthwhile for the management of patients with some advanced cancers. The tumor samples are sometimes difficult to analyze using DNA-based molecular methods because of poor tumor DNA quality or quantity. Anti-BRAFV600E VE1 immunohistochemistry (IHC) has been proposed as a valuable ancillary tool to analyze some "molecularly challenging" tumor samples. In this technical study, we focused on its application in the field of decalcified tumor samples. We selected four patients with known BRAFV600E-mutated cancer (3 metastatic melanomas and 1 hairy cell leukemia) and paired non-decalcified/decalcified tumor samples. Molecular analyses failed in the four decalcified samples (3 bone metastases and 1 osteo-medullar biopsy) with non-contributive mutation status. Whereas non-decalcified tumor samples were all positive using anti-BRAFV600E VE1 IHC, the four decalcified samples were concluded negative. Because decalcified tumor samples are difficult to analyze from a molecular point of view, it is tempting to use IHC instead of DNA-based methods searching for BRAFV600E mutations in these samples. Nevertheless, the decalcification process may also cause false-negative results using VE1 IHC. Decalcified samples require specific and optimized IHC and molecular protocols and quality controls.

Sluga R, Tersmette M, Sohne M
Hairy cell leukemia presenting with Ecthyma Gangrenosum- a case report.
BMC Infect Dis. 2019; 19(1):85 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Ecthyma gangrenosum is a cutaneous infectious usually associated with P. aeruginosa. It usually develops In patients with an underlying immunodeficiency.
CASE PRESENTATION: A 50-year old mentally disabled white male with a history of epilepsy presented with fever and a painless red macule on his right arm which rapidly progressed to a painful ulcer. Blood and lesion cultures revealed P.aeruginosa, confirming our clinical diagnosis of ecthyma gangrenosum. Subsequently an underlying immune deficit was found, namely patient was diagnosed with hairy-cell leukemia. Despite adequate antibiotics no infection control could be achieved. After treating the underlying immune deficit as well, the infection and hairy-cell leukemia resolved completely.
CONCLUSION: Ecthyma gangrenosum is an important cutaneous infection to recognize, because it is it is typically associated with P.aeruginosa bacteremia. Recognizing this skin leasion should prompt empiric antimicrobial therapy including an agent with antipseudomonal activity. Furthermore, just like in our case, the presence of ecthyma gangrenosum can signal the presence of an occult immune deficit, warranting further investigation.

Inbar M, Herishanu Y, Goldschmidt N, et al.
Hairy Cell Leukemia: Retrospective Analysis of Demographic Data and Outcome of 203 Patients from 12 Medical Centers in Israel.
Anticancer Res. 2018; 38(11):6423-6429 [PubMed] Related Publications
BACKGROUND/AIM: In this retrospective study, we summarized the national Israeli experience with hairy cell leukemia (HCL) in a large cohort of patients with a long follow-up.
PATIENTS AND METHODS: Demographic data, and relevant laboratory and clinical parameters were analyzed, emphasizing the outcome after first-line treatment with cladribine.
RESULTS: Data on 203 patients was collected from 12 medical centers during 1985-2015. Mean and median follow-up were 7.5 years and 5.18 years (interquartile range=0.1-40 years), and 5- and 10-year survival were 96% and 90.62%, respectively. The median age of diagnosis was 55.5 years for Jews and 49 years for Arabs (p=0.021), and most patients were males (81.77%); 52.2% were Ashkenazi Jews, 36.1% Sephardic Jews and 11.7% were Arab, Druze or other ethnicity. Cladribine was given to 159 patients (80.7%%) and most (62%) received intravenous (i.v.) and 38% received subcutaneous (s.c.) therapy. Overall survival and time to next treatment were not significantly different between the two schedules (i.v., s.c.). In univariate analysis of a variety of factors, only age >65 years had a negative impact on outcome, with shorter overall survival. It is of interest that Arab patients with HCL were diagnosed at an earlier age, but had a similar clinical course and outcome to both Ashkenazi and Sephardic Jews.

Bibi A, Java S, Chaudhary S, et al.
Indian J Pathol Microbiol. 2018 Oct-Dec; 61(4):532-536 [PubMed] Related Publications
Background: BRAFV600E mutation has been reported as a unique genetic lesion of hairy cell leukemia (HCL), a subset of which lacks this lesion and shows adverse outcomes.
Aims: To determine the prevalence of BRAFV600E in HCL from our center and derive clinicopathological correlation, if any.
Materials and Methods: A 9-year retrospective analysis of 46 consecutive cases of HCL diagnosed on morphology and immunophenotyping was done. Stained smears were used as samples for amplification refractory mutation system polymerase-chain reaction using fluorescent primers for mutation detection.
Results: BRAFV600E mutation was detected in 41/46 patients (89.1%) while absent in control samples of chronic lymphocytic leukemia. Cases mimicking HCL-variant clinically or immunophenotypically too showed the presence of this mutation. HCL with mutated BRAF presented at a younger age. No statistical difference in blood counts, tumor load, and immunophenotype patterns existed among BRAF mutated and unmutated group. Nine patients (45%) with mutated BRAF had residual disease following treatment with cladribine.
Conclusion: BRAFV600E mutation analysis has a definitive role in the diagnosis of HCL.

Rahman K, Kumari S, Singh MK, et al.
Atypical presentation of hairy cell leukemia: Significance of CD200 on flow cytometry.
J Cancer Res Ther. 2018 Jul-Sep; 14(5):1130-1134 [PubMed] Related Publications
Hairy cell leukemia (HCL) is a rare, low-grade mature B-cell neoplasm with a characteristic clinical, morphological, immunophenotypic, and more recently described molecular (BRAF p.V600E mutation) profile. It typically affects middle-aged to elderly male who present with pancytopenia and massive splenomegaly. Lymphadenopathy is usually not seen. Atypical presentations such as absence of splenomegaly and presence of lymphadenopathy and leukocytosis, a hypoplastic marrow masquerading as aplastic anemia, pose a diagnostic challenge to both clinician and pathologist. A diligent morphological examination to look for the presence of hairy cells along with flow cytometric immunophenotyping showing consistent bright expression of CD200, in addition to well-described characteristic immunophenotype, helps in correctly diagnosing the case. This can be further confirmed by the consistent presence of V600E point mutation in BRAF gene. The correct identification of HCL in these unusual clinical presentations is of utmost importance owing to a different treatment approach in these cases. We present here four such cases with atypical presentation.

Itamura H, Ide M, Sato A, et al.
Identification of the BRAF V600E mutation in Japanese patients with hairy cell leukemia and related diseases using a quenching probe method.
Int J Hematol. 2018; 108(4):416-422 [PubMed] Related Publications
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.

Kreitman RJ, Dearden C, Zinzani PL, et al.
Moxetumomab pasudotox in relapsed/refractory hairy cell leukemia.
Leukemia. 2018; 32(8):1768-1777 [PubMed] Free Access to Full Article Related Publications
This is a pivotal, multicenter, open-label study of moxetumomab pasudotox, a recombinant CD22-targeting immunotoxin, in hairy cell leukemia (HCL), a rare B cell malignancy with high CD22 expression. The study enrolled patients with relapsed/refractory HCL who had ≥2 prior systemic therapies, including ≥1 purine nucleoside analog. Patients received moxetumomab pasudotox 40 µg/kg intravenously on days 1, 3, and 5 every 28 days for ≤6 cycles. Blinded independent central review determined disease response and minimal residual disease (MRD) status. Among 80 patients (79% males; median age, 60.0 years), durable complete response (CR) rate was 30%, CR rate was 41%, and objective response rate (CR and partial response) was 75%; 64 patients (80%) achieved hematologic remission. Among complete responders, 27 (85%) achieved MRD negativity by immunohistochemistry. The most frequent adverse events (AEs) were peripheral edema (39%), nausea (35%), fatigue (34%), and headache (33%). Treatment-related serious AEs of hemolytic uremic syndrome (7.5%) and capillary leak syndrome (5%) were reversible and generally manageable with supportive care and treatment discontinuation (6 patients; 7.5%). Moxetumomab pasudotox treatment achieved a high rate of independently assessed durable response and MRD eradication in heavily pretreated patients with HCL, with acceptable tolerability.

Angelova EA, Medeiros LJ, Wang W, et al.
Clinicopathologic and molecular features in hairy cell leukemia-variant: single institutional experience.
Mod Pathol. 2018; 31(11):1717-1732 [PubMed] Related Publications
Hairy cell leukemia-variant is rare. Only a small number of cases have been reported in the literature with little cytogenetic or molecular data available. In this study, we describe the clinicopathologic and genetic features of 23 patients with hairy cell leukemia-variant (16 men and 7 women) with a median age of 70 years. Most patients had splenomegaly (90%), leukocytosis (77%), and lymphocytosis (82%); no patients had monocytopenia. Histologically, the bone marrow biopsy specimens showed a mixed pattern of predominantly interstitial and lesser intrasinusoidal infiltration by leukemic cells. In bone marrow aspirate smears most cells had villous cytoplasmic features and a small nucleolus. We describe unusual sites of hairy cell leukemia-variant involvement in 4 patients, including brain, omentum, terminal ileum, and skin at the time of initial presentation. Immunophenotyping showed monotypic B-cells positive for pan B-cell antigens, CD11c, and CD103, and negative for CD25 and annexin A1. Conventional cytogenetic or fluorescence in situ hybridization analysis showed deletions of 17p13/TP53 and 11q22/ATM gene in 5/12 (42%) and 2/9 (22%) cases, respectively. Sequencing of the variable region of IGVH showed mutations (>2% deviation from germline) in 40% of the cases assessed. MAP2K1 mutation (p.C121S) was seen in 1 of 14 (7%) patients tested. No BRAF V600E mutations were detected. The patients were treated in a heterogeneous manner, but most often with therapies designed for classical hairy cell leukemia and the 5-year overall survival was 84%. In summary, hairy cell leukemia-variant exhibits a heterogeneous spectrum of clinical, morphologic, immunophenotypic, and genetic features that may overlap with classic hairy cell leukemia and other hairy cell-like B-cell neoplasms. A subset of patients can have an aggressive clinical course. In our experience MAP2K1 mutations are uncommon in this disease.

Kreitman RJ, Arons E
Update on hairy cell leukemia.
Clin Adv Hematol Oncol. 2018; 16(3):205-215 [PubMed] Free Access to Full Article Related Publications
Hairy cell leukemia (HCL) is a chronic B-cell malignancy with multiple treatment options, including several that are investigational. Patients present with pancytopenia and splenomegaly, owing to the infiltration of leukemic cells expressing CD22, CD25, CD20, CD103, tartrate-resistant acid phosphatase (TRAP), annexin A1 (ANXA1), and the BRAF V600E mutation. A variant lacking CD25, ANXA1, TRAP, and the BRAF V600E mutation, called HCLv, is more aggressive and is classified as a separate disease. A molecularly defined variant expressing unmutated immunoglobulin heavy variable 4-34 (IGHV4-34) is also aggressive, lacks the BRAF V600E mutation, and has a phenotype of HCL or HCLv. The standard first-line treatment, which has remained unchanged for the past 25 to 30 years, is single-agent therapy with a purine analogue, either cladribine or pentostatin. This approach produces a high rate of complete remission. Residual traces of HCL cells, referred to as minimal residual disease, are present in most patients and cause frequent relapse. Repeated treatment with a purine analogue can restore remission, but at decreasing rates and with increasing cumulative toxicity. Rituximab has limited activity as a single agent but achieves high complete remission rates without minimal residual disease when combined with purine analogues, albeit with chemotherapy-associated toxicity. Investigational nonchemotherapy options include moxetumomab pasudotox, which targets CD22; vemurafenib or dabrafenib, each of which targets the BRAF V600E protein; trametinib, which targets mitogen-activated protein kinase enzyme (MEK); and ibrutinib, which targets Bruton tyrosine kinase (BTK).

Andrasiak I, Rybka J, Wrobel T
Response to the Therapy in Hairy Cell Leukemia: Systematic Review and Meta-Analysis.
Clin Lymphoma Myeloma Leuk. 2018; 18(6):392-399.e3 [PubMed] Related Publications
Hairy cell leukemia is an uncommon chronic B-cell lymphoproliferative disorder. Various treatment options are available. The objective of the study was to evaluate through meta-analysis the pooled proportions of patients responding to each therapeutic agent. We conducted a systematic review and meta-analysis to estimate the pooled response rate to modern hairy cell leukemia therapies. Articles published between January 1992 and August 2017 were identified by searching PubMed, Web of Science, and the Cochrane Library. Weighted meta-analysis of proportion using a random-effects model was performed for each treatment option. Of 3287 articles viewed, 20 articles describing 21 studies were included in the meta-analysis. The pooled random effect of the response rate was up to 99% in both cladribine with rituximab at 0.99 (95% confidence interval [CI], 0.98-1.0) and vemurafenib treatment at 0.99 (95% CI, 0.95-1.0). The pooled random effect of the complete response rate was up to 97% (0.97; 95% CI, 0.88-1.0) in cladribine followed by rituximab. The most effective therapy in patients treatment naïve and in first relapse was cladribine with rituximab maintenance.

Habberstad AH, Tran HTT, Randen U, et al.
Neutropenia caused by hairy cell leukemia in a patient with myelofibrosis secondary to polycythemia vera: a case report.
J Med Case Rep. 2018; 12(1):105 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Polycythemia vera is a myeloproliferative disease that sometimes evolves to myelofibrosis, causing splenomegaly and neutropenia. In this case report, we describe a patient with polycythemia vera and unexplained neutropenia who later turned out to also have hairy cell leukemia.
CASE PRESENTATION: A middle-aged Caucasian man with polycythemia vera presented to our hospital with chronic mouth ulcers. Later he developed leukopenia and pancytopenia. Bone marrow biopsies showed fibrosis. Further morphological analyses of bone marrow and blood smears revealed probable transformation into acute myeloid leukemia. However, there were also cells indicating hairy cell leukemia. Morphological and immunohistochemical analyses later confirmed the presence of hairy cell leukemia in biopsies that had been present for 3 years. Treatment with cladribine temporarily reversed the patient's neutropenia.
CONCLUSIONS: Hairy cell leukemia may mimic development to myelofibrosis in patients with polycythemia vera.

Kreitman RJ, Tallman MS, Robak T, et al.
Minimal residual hairy cell leukemia eradication with moxetumomab pasudotox: phase 1 results and long-term follow-up.
Blood. 2018; 131(21):2331-2334 [PubMed] Free Access to Full Article Related Publications
Anti-CD22 moxetumomab pasudotox achieved 46% complete remissions (CRs) in previously reported phase 1 testing in relapsed/refractory hairy cell leukemia (HCL; n = 28). The importance of minimal residual disease (MRD) after CR in HCL is unknown. A 21-patient extension cohort received 50 µg/kg every other day for 3 doses in 4-week cycles. These patients plus 12 previously reported at this upper dose level received 143 cycles without dose-limiting toxicity. The combined 33-patient cohort achieved 64% CR and 88% overall response rates, with median CR duration of 42.4 months. Of 32 50-µg/kg patients evaluable for MRD by bone marrow aspirate flow cytometry (most stringent assessment), median CR duration was 13.5 (4.9-42.4) months in 9 MRD-positive CRs vs 42.1 (24.0-69.2) months in 11 MRD-negative CRs (

Wiernik PH
Androgen Therapy for Acute Myeloid and Hairy Cell Leukemia.
Curr Treat Options Oncol. 2018; 19(1):4 [PubMed] Related Publications
OPINION STATEMENT: The purpose of this paper is to review the preclinical and clinical rationale for androgen therapy of acute myeloid (AML) and hairy cell leukemia (HCL). A major recent positive study should renew interest in this therapy, which has been reported to be effective in these leukemias for more than 50 years. Hopefully, renewed interest in this approach, which seems promising, will lead to well-designed modern studies that will precisely define a role for androgens in these leukemias. A recent large prospective, randomized study has demonstrated enhanced survival for elderly AML patients who present with WBC counts < 30,000/μL have improved overall survival when androgens are given post-remission, and numerous case reports suggest that androgens frequently restore normal peripheral blood counts in severely pancytopenic patients with HCL. Well-designed prospective studies are needed to precisely define which patients are most likely to benefit from androgen therapy and where in the treatment plan they should be incorporated.

Vacca D, Cancila V, Gulino A, et al.
Real-time detection of BRAF V600E mutation from archival hairy cell leukemia FFPE tissue by nanopore sequencing.
Mol Biol Rep. 2018; 45(1):1-7 [PubMed] Related Publications
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.

Öngören Ş, Eşkazan AE, Berk S, et al.
Retrospective Evaluation of Hairy Cell Leukemia Patients Treated with Three Different First-Line Treatment Modalities in the Last Two Decades: A Single-Center Experience.
Turk J Haematol. 2017; 34(4):291-299 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: In this study, we retrospectively analyzed the clinical outcome, treatment responses, infectious complications, and survival rates of 71 hairy cell leukemia (HCL) cases.
MATERIALS AND METHODS: Sixty-seven patients received a first-line treatment and 2-chlorodeoxyadenosine (cladribine-2-CdA) was administered in 31 cases, 19 patients received interferon-alpha (INF-α), splenectomy was performed in 16 cases, and rituximab was used in one.
RESULTS: Although the highest overall response rate (ORR) was observed in patients receiving 2-CdA upfront, ORRs were comparable in the 2-CdA, INF-α, and splenectomy subgroups. Relapse rates were significantly lower in patients who received first-line 2-CdA. The progression-free survival (PFS) rate with 2-CdA was significantly higher than in patients with INF-α and splenectomy, but we found similar overall survival rates with all three upfront treatment modalities. Infections including tuberculosis were a major problem.
CONCLUSION: Although purine analogues have improved the ORRs and PFS, there is still much progress to make with regard to overall survival and relapsed/refractory disease in patients with HCL.

Wierda WG, Byrd JC, Abramson JS, et al.
Hairy Cell Leukemia, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology.
J Natl Compr Canc Netw. 2017; 15(11):1414-1427 [PubMed] Related Publications
Hairy cell leukemia (HCL) is a rare type of indolent B-cell leukemia, characterized by symptoms of fatigue and weakness, organomegaly, pancytopenia, and recurrent opportunistic infections. Classic HCL should be considered a distinct clinical entity separate from HCLvariant (HCLv), which is associated with a more aggressive disease course and may not respond to standard HCL therapies. Somatic hypermutation in the

Troussard X, Cornet E
Hairy cell leukemia 2018: Update on diagnosis, risk-stratification, and treatment.
Am J Hematol. 2017; 92(12):1382-1390 [PubMed] Free Access to Full Article Related Publications
DISEASE OVERVIEW: Hairy cell leukemia (HCL) and HCL-like disorders, including HCL variant (HCL-V) and splenic diffuse red pulp lymphoma (SDRPL), are a very heterogeneous group of mature lymphoid B-cell disorders, characterized by the identification of hairy cells, a specific genetic profile, a different clinical course and the need for appropriate treatment.
DIAGNOSIS: Diagnosis of HCL is based on morphological evidence of hairy cells, an HCL immunologic score of 3 or 4 based on the CD11C, CD103, CD123, and CD25 expression, the trephine biopsy which makes it possible to specify the degree of tumoral medullary infiltration and the presence of BRAF V600E somatic mutation.
RISK STRATIFICATION: Progression of patients with HCL is based on a large splenomegaly, leukocytosis, a high number of hairy cells in the peripheral blood and the immunoglobulin heavy chain variable region gene mutational status. VH4-34 positive HCL cases are associated with poor prognosis RISK ADAPTED THERAPY: Purine analogs (PNA) are indicated in symptomatic first line HCL patients. The use of PNA followed by rituximab represents an alternative option.
MANAGEMENT OF PROGRESSIVE OR REFRACTORY DISEASE: It is based on the use of BRAF inhibitors associated or not with MEK inhibitors, recombinant immunoconjugates targeting CD22 or BCR inhibitors.

Durham BH, Getta B, Dietrich S, et al.
Genomic analysis of hairy cell leukemia identifies novel recurrent genetic alterations.
Blood. 2017; 130(14):1644-1648 [PubMed] Free Access to Full Article Related Publications
Classical hairy cell leukemia (cHCL) is characterized by a near 100% frequency of the

Madanat YF, Rybicki L, Radivoyevitch T, et al.
Long-Term Outcomes of Hairy Cell Leukemia Treated With Purine Analogs: A Comparison With the General Population.
Clin Lymphoma Myeloma Leuk. 2017; 17(12):857-862 [PubMed] Related Publications
Hairy cell leukemia (HCL) is a rare hematologic malignancy with high response rates and long progression-free survival (PFS) after treatment with purine nucleoside analogs (PNAs; Pentostatin/Cladribine). However, treatment is not curative, and subsequent treatment at relapse is often required. Rechallenge with a purine analog is commonly implemented despite limited data regarding the efficacy of this approach. We retrospectively analyzed 61 consecutive patients with HCL diagnosed between 1995 and 2013 at Cleveland Clinic. Median follow-up was 72 months (3-193). Cladribine as first-line therapy was administered to 59 patients (97%). Overall response rate (ORR) was 97%, with 78% of patients achieving complete remission (CR). PFS after response was significantly improved for patients who achieved CR compared with those with a partial remission (PR) (5-year PFS 71% vs. 39%, respectively [P = .004]). Of the 19 patients who relapsed, 12 received PNAs as second-line treatment with an ORR (83%) comparable to what these patients had with first-line treatment (ORR 92%). Overall survival of all 61 patients was excellent and superior to that of age-, sex-, and race-matched controls from the general population, possibly due to selection bias. In an analysis of a larger cohort of unselected patients in the Surveillance, Epidemiology, and End Results (SEER) database, we found that mortality rates for patients with HCL were similar to those of the general population approximately 5 years after diagnosis. These data confirm the excellent prognosis for patients with HCL after first- and second-line PNA therapy.

Divino V, Karve S, Gaughan A, et al.
Characteristics and treatment patterns among US patients with hairy cell leukemia: a retrospective claims analysis.
J Comp Eff Res. 2017; 6(6):497-508 [PubMed] Related Publications
AIM: Describe hairy cell leukemia (HCL) treatment patterns using a large, nationally representative US database.
PATIENTS & METHODS: Adults newly diagnosed with HCL (1 January 2006 to 30 June 2014) with continuous health plan enrollment ≥180 days pre- and 90 days post-diagnosis were identified from the QuintilesIMS PharMetrics Plus Health Plan Claims Database. Treatment patterns by line of therapy were assessed over the variable follow-up.
RESULTS: Among 749 HCL patients (77.4% male; mean age 55.6; mean 32.3 months follow-up), only 37.7% initiated first-line therapy during the available follow-up in a mean of 4.4 months following diagnosis; the majority (75.5%) received cladribine (mean duration 7.3 days). Thirty-eight patients (5.1%) received second-line treatment.
CONCLUSION: Over 2.7 years follow-up, more than a third of patients initiated first-line therapy which appeared to provide a long-lasting response.

Rozenvald IB, Richardson MD, Brock L, Maiese RL
Immunohistochemical Detection of Hairy Cell Leukemia in Paraffin Sections: The Role of Pax5 and CD103 Double Staining to Improve Specificity and Sensitivity.
Arch Pathol Lab Med. 2017; 141(6):837-840 [PubMed] Related Publications
CONTEXT: - In hematopathology practice, abnormal expression of CD103 on B cells is detected by flow cytometry in hairy cell leukemia (HCL) and, in combination with other phenotypic and morphologic findings, provides diagnostic specificity and sensitivity. Immunostaining on paraffin sections makes it possible to perform immunophenotyping in situ. However, normal bone marrow contains CD103-positive cells, which are not B cells, making it difficult to be certain about low-level involvement by HCL.
OBJECTIVE: - To develop dual immunostaining for confirmation that CD103 is expressed in B cells, which may be highly desirable in assessing low-level involvement by HCL.
DESIGN: - We developed a dual immunostaining approach using a B-cell marker, Pax5, expressed in the nucleus, in combination with a membrane marker, CD103.
RESULTS: - We analyzed 6 HCLs, 7 marginal zone lymphomas, 12 lymphoplasmacytic lymphomas, 7 follicular lymphomas, 5 chronic lymphocytic leukemias, 5 mantle cell lymphomas, 1 multiple myeloma (lymphocytic variant), and 3 bone marrows not involved by any B-cell neoplasm. Our dual staining approach confirmed that only the neoplastic cells of HCL were positive for both CD103 and Pax5.
CONCLUSIONS: - This dual-staining method is particularly helpful in cases with low-level involvement by HCL and can be used for determining minimal residual disease after treatment.

Davis G, Perks A, Liyanage P, Staines K
Oral hairy leukoplakia arising in a patient with hairy cell leukaemia: the first reported case.
BMJ Case Rep. 2017; 2017 [PubMed] Free Access to Full Article Related Publications
Oral hairy leukoplakia (OHL) is an oral mucosal lesion that is associated with Epstein-Barr virus infection. It commonly presents as an asymptomatic, non-removable white patch on the lateral borders of the tongue in individuals who are immunocompromised. Historically, OHL was thought to be pathognomonic of HIV infection; however, it is now an established phenomenon in a range of conditions affecting immune competence. Hairy cell leukaemia (HCL) is a rare chronic B cell lymphoproliferative disease named after the distinctive cytology of the atypical cells. We report the first case of OHL arising in an individual with HCL that resolved following remission of the haematological malignancy.

Tiacci E, Pettirossi V, Schiavoni G, Falini B
Genomics of Hairy Cell Leukemia.
J Clin Oncol. 2017; 35(9):1002-1010 [PubMed] Free Access to Full Article Related Publications
Hairy cell leukemia (HCL) is a chronic mature B-cell neoplasm with unique clinicopathologic features and an initial exquisite sensitivity to chemotherapy with purine analogs; however, the disease relapses, often repeatedly. The enigmatic pathogenesis of HCL was recently clarified by the discovery of its underlying genetic cause, the BRAF-V600E kinase-activating mutation, which is somatically and clonally present in almost all patients through the entire disease spectrum and clinical course. By aberrantly activating the RAF-MEK-ERK signaling pathway, BRAF-V600E shapes key biologic features of HCL, including its specific expression signature, hairy morphology, and antiapoptotic behavior. Accompanying mutations of the KLF2 transcription factor or the CDKN1B/p27 cell cycle inhibitor are recurrent in 16% of patients with HCL and likely cooperate with BRAF-V600E in HCL pathogenesis. Conversely, BRAF-V600E is absent in other B-cell neoplasms, including mimickers of HCL that require different treatments (eg, HCL-variant and splenic marginal zone lymphoma). Thus, testing for BRAF-V600E allows for a genetics-based differential diagnosis between HCL and HCL-like tumors, even noninvasively in routine blood samples. BRAF-V600E also represents a new therapeutic target. Patients' leukemic cells exposed ex vivo to BRAF inhibitors are spoiled of their HCL identity and then undergo apoptosis. In clinical trials of patients with HCL who have experienced multiple relapses after purine analogs or who are refractory to purine analogs, a short course of the oral BRAF inhibitor vemurafenib produced an almost 100% response rate, including complete remission rates of 35% to 42%, without myelotoxicity. To further improve on these results, it will be important to clarify the mechanisms of incomplete leukemic cell eradication by vemurafenib and to explore chemotherapy-free combinations of a BRAF inhibitor with other targeted agents (eg, a MEK inhibitor and/or an anti-CD20 monoclonal antibody).

Cortazar JM, DeAngelo DJ, Pinkus GS, Morgan EA
Morphological and immunophenotypical features of hairy cell leukaemia involving lymph nodes and extranodal tissues.
Histopathology. 2017; 71(1):112-124 [PubMed] Related Publications
AIMS: Hairy cell leukaemia (HCL) is a rare B cell neoplasm that mainly affects bone marrow (BM), peripheral blood (PB) and spleen. Involvement of lymph nodes and extranodal structures is considered infrequent. Herein we describe our institutional experience of nodal (n = 10) and extranodal (n = 3) HCL during a 30-year period.
METHODS AND RESULTS: Ten patients had prior evidence of HCL within the BM or PB at a median 35.8 months before nodal/extranodal diagnosis (range: <1-175 months), and HCL was diagnosed concurrently within the bone marrow of one additional patient. Nodal involvement showed distinct architectural patterns, including diffuse (62% of cases), sinusoidal (25%) and nodular (13%). Extranodal involvement was characterized as diffuse infiltration through underlying structures in all cases. Morphological features ranged from classic 'fried-egg' cytology to a plasmacytoid appearance. Nodal/extranodal disease showed an overlapping immunophenotypical profile with other small B cell lymphomas, including expression of cyclin D1 (70%), CD43 (55%), CD10 (38%) and CD5 (8%). Rates of both CD43 and CD10 reactivity were higher than described previously in leukaemic HCL, suggesting that expression may be enriched in cases with extramedullary extension.
CONCLUSIONS: Although uncommon, HCL should be considered in the differential diagnosis of small B cell neoplasms involving nodal/extranodal sites, given the therapeutic implications. In particular, recent discoveries including detection of the BRAF

Jud S, Goede JS, Senn O, et al.
sIL2R ratio as early marker for response in hairy cell leukemia and the prognostic relevance of IL28B genotype to interferon-α therapy.
Ann Hematol. 2017; 96(5):757-763 [PubMed] Related Publications
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.

Thompson PA, Ravandi F
How I manage patients with hairy cell leukaemia.
Br J Haematol. 2017; 177(4):543-556 [PubMed] Related Publications
Patients with hairy cell leukaemia (HCL) have highly favourable outcomes after purine analogue therapy. However, most patients subsequently relapse and require re-treatment. A minority of patients develop purine analogue-refractory disease. Targeted therapies have improved outcomes for such patients. Recently, the BRAF V600E mutation was identified in most patients with classical HCL, resulting in constitutive mitogen-activated protein kinase pathway activation; impressive responses are achieved in heavily pre-treated patients with BRAF inhibition. The CD22-targeted immunoconjugate moxetumomab pasudotox and BTK inhibitor ibrutinib also achieve responses in relapsed and refractory patients. HCL variant and the IGHV4-34 molecular variant of HCL lack BRAF mutation and have inferior outcomes with standard purine analogue therapy. The addition of rituximab to purine analogues achieves very high rates of minimal residual disease-negative complete remission and improves outcomes for patients with HCL variant. Given the rarity of HCL, optimal integration of novel therapies into treatment algorithms will require well-designed, collaborative studies.

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.

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