The authors have declared that no competing interests exist.
Theobjective of reviewing Hairy Cell Leukaemia may be achieved by emphasising the condition as a category of chronic lymphocytic leukaemia with hair like protrusions of the cytoplasm situated on the aberrant B cell surface. An infrequent disorder, hairy cell leukaemia contributes an estimated 2% of lymphoid malignancies with a male predominance ( M:F ::4-5:1). A majority (90%) of instances depict a mutant immunoglobulin heavy chain variable region (IGHV). The haematopoietic stem cells (HSCs) elucidate a B raf proto-oncogene( BRAF V600E gene- 7q34). An enlarged spleen may be discerned along with pancytopenia as a presenting symptom. The morphology of specific hairy cell leukaemia may be on account of an in vitro interaction of primary hairy cells with BRAF genes and MEK inhibitors, which incite a prominent MEK - ERK dephosphorylation, thereby curtailing transcriptional outpourings of the RAS- RAF- MEK-ERK pathway. Bone marrow aspiration or bone marrow trephine biopsy may be inadequate for diagnosis in 30%-50% individuals on account of extensive fibrosis and the bone marrow sections depict a characteristic interstitial infiltration of leukaemia cells.. Reticulin stains exhibit broad, dense reticulum fibres surrounding the individual or aggregates of leukaemia cells with fibrotic extensions into the abutting bone marrow. The immune reactivity of classic hairy cell leukaemia is concurrent CD19+ CD20+,CD 11c+, CD25+, CD103+ and CD123+. Immune staining for CD20+, annexin 1 and VE1 (a BRAF V600E stain) validates the diagnosis and analyses the extent of malignant bone marrow infiltration. Application of inhibitors of BRAF V600E gene is efficacious in patients resistant to standard therapy. An enlarged spleen beyond 3 centimetres of the left costal margin, a white blood cell count greater than 10000 cells/µL , circulating hairy cells in the peripheral blood greater than 5000 cells/µL and a β 2 micro-globulin level exceeding twice the normal range of 3 µg/ml delineate an inferior outcome with resistance to purine analogues (PNAs). CD38+ elucidation ensures a worse prognosis as does the lack of an IGHV mutation with a reduced overall survival,. A lack of BRAF genetic mutation in 10% -20% of hairy cell leukaemia comprises of inferior prognosis.
Originally delineated in 1958 by Bouroncle and colleagues, hairy cell leukaemia (HCL) is a category of chronic lymphocytic leukaemia with the terminology based on the hair like protrusions of cytoplasm situated on the surface of aberrant B cell
The delayed activation of post germinal centre memory B cells probably along with marginal zone B cells of the spleen may constitute a cellular origin of hairy cell leukaemia. A majority (90%) of instances may depict a mutant genetic profile of immunoglobulin heavy chain variable region (IGHV). The haematopoietic stem cells (HSCs)and the cellular component of Langerhans Cell Histiocytosis(LCH) and Erdheim Chester Disease (ECD) may elucidate a B raf proto-oncogene( BRAF V600E gene- 7q34). Majority of the mutant alleles accompanying these disorders may be situated in the CD14+ classical monocytes, the CD 16+ non classical monocytes and CD1c+ myeloid dendritic cells, located in the peripheral blood
The patients may display systemic symptoms such as fatigue , infection, splenomegaly besides a constitutional depiction of pancytopenia. An enlarged spleen may be discovered in a majority (90%) of the instances, although the feature may be infrequent in recent times, on account of the earlier discernment of the disorder. Pancytopenia may be the presenting symptom
The morphology of hairy cell leukaemia may be specific , in contrast to the variants, on account of an in vitro interaction of the primary hairy cells with BRAF genes and MEK inhibitors, which may incite a prominent MEK - ERK dephosphorylation, thereby curtailing transcriptional outpourings of the RAS- RAF- MEK-ERK pathway. The particular occurrence may induce a deficit in hairy cell leukaemia specific genetic profile signature that may convert the morphology of hairy cells into smooth cells with ultimate apoptosis
The classic hairy cell is medium sized with a magnitude of 10-14µm. The moderately abundant or variable cytoplasm may be transparent or mildly basophilic. The cellular surface with the characteristic serrated perimeter depicts innumerable fragile or stout extensions of cytoplasm ,particularly discernible on the phase contrast and electron microscopy. The cytoplasm may exhibit vacuoles with occasional azurophilic granules
The leukaemia cells may enunciate a characteristic immune phenotype, crucial for a confirmatory diagnosis. The peripheral blood mononuclear B cell population may display a kappa or lambda light chain restriction. The phenotype of classic hairy cell leukaemia may be delineated by concurrent, immune reactive CD19+ CD20+,CD 11c+, CD25+, CD103+ and CD123+. An intensely immune reactive CD200+ and a non reactive CD27- antigen may be present
A complete blood count with an assiduous peripheral smear may assist the detection of hairy cells. Characteristic immune phenotype of the B cell leukaemia clone may depict an augmented, intense staining of CD19 +, CD20+, CD22+ with CD200+. Malignant hairy cells may be non reactive or weakly reactive for CD5-,CD23-,CD10-, CD79b-, and CD27- though reactive for CD11C+, CD103+, CD123+ and CD25+
Hairy cell leukaemia necessitates a distinction from adjunctive disorders such as the hairy cell leukaemia –variant ( HCL –V) and splenic diffuse red pulp lymphoma (SDRPL)
An enlarged spleen beyond 3 centimetres of the left costal margin, leucocytosis with a white blood cell count greater than 10000 cells/µL , circulating hairy cells in the peripheral blood greater than 5000 cells/µL and a β 2 micro-globulin level exceeding twice the normal range of 3 µg/ml may be accompanied by an inferior therapeutic outcome and an emerging resistance to purine analogues (PNAs)
The employment of whole exome sequencing (WES) for the detection of a BRAF V600E somatic mutation may be advocated. The B raf proto-oncogene( BRAF gene- 7q34) comprises of 18 exons and a genetic mutation of exon 15 in position 1799 may interchange the thymine and adenine nucleobases, thus engendering a replacement of valine ( v) by glutamate(E) at codon 600 (V 600 E) of the BRAF protein. The mutation may be detected in 80% to 90% of hairy cell leukaemia
Refractory hairy cell leukaemia may delineate a repetitive neutralization of the cell cycle inhibitor CDKN1B / p27 in a minority (16 %) of the instances. Supplementary mutations of KLF2 genes may be exemplified in an estimated one third (30%) of marginal zone lymphoma ( MZL) and diffuse lymphomas( DLBCL). KLF2 is a transcription factor which regulates the maturation and differentiation of numerous B cell subpopulations, especially marginal zone B cells
Recommendations | Specialized procedures |
Diagnosis and initial assessment | |
Complete blood count | |
Peripheral blood smear review | A Wright’s stain for white blood cell differential count to identify leukaemia cells |
Immuno-phenotypic analysis by flow cytometry | Immune reactive for CD19+, CD20+, CD11c+,CD25+, CD103+,CD123+ CD200+ & immunoglobulin light chain restriction for circulating mononuclear cells. |
Bone marrow aspiration and trephine biopsy | A haematoxylin and eosin stain, reticulin stain and immune reactivity for CD20+, annexin-1, DBA44 & VE-1( BRAF V600E), identification of the genetic or BRAF V600E mutation by allele specific PCR , a sequence analysis or an immune stain to confirm diagnosis & the degree of bone marrow infiltration |
Complete history and physical examination | Including renal function tests for patients requiring nucleoside analogue therapy |
Optional imaging studies | Chest X-ray to evaluate infection, CT or abdominal ultrasound to assess organomegaly and/or lymphadenopathy, particularly with patients on clinical trials or with concordant systemic symptoms. |
Hepatitis serology for employing the anti CD20 monoclonal antibody | |
Differential Diagnosis | Consider hairy cell leukaemia, hairy cell leukaemia variant, splenic marginal zone lymphoma, splenic diffuse red pulp small B cell lymphoma( with specific immune phenotype) |
Indications for treatment | |
Haematological parameters consistent with commencement of treatment | A minimal of one parameter : haemoglobin<11gm/dl, platelets<100,000/µL or absolute neutrophil count < 1000/µL. |
Clinical features or systemic symptoms appropriate for therapy | Symptomatic organomegaly, progressive lymphocytosis, lymphadenopathy, unexplained weight loss(>10% body weight in the preceding six months), excessive fatigue( grade >2) |
Specific Mutation | Percentage Alterations |
MAPK pathway | |
BRAF V600E | 70%-100% |
MAPK 2K1 | 0.0%- 22% |
Cell Cycle | |
CDKN1B( p27) | 11%-16% |
CCND3 | 0% |
NOTCH pathway | |
NOTCH 1 | 4%-13% |
NOTCH 2 | 0.0% - 4% |
Epigenetic regulators | |
KMT2C( histone methyltransferase ) | 15% |
ARID 1A( SWI/SNF family) | 4% |
Transcription factors | |
TTN | 4% |
KLF2 | 13%-16% |
NF ₭B pathway (MYD88,TNFAIP3),Spliceosome (U2 AF1,TP53),TF repressor (BCOR) | 0% |
Preliminary Treatment |
Cladarabine administered subcutaneously or as a continuous, intravenous infusion. |
Pentostatin administered intravenously with a deliberation upon the renal function |
Treatment at Relapse |
Following confirmation of the preliminary diagnosis, a review of previously employed therapeutic protocols with the identification of patients with poor risk ( severe anaemia, spleen > 10 cm below the left costal margin, atypical immune phenotype, absence of BRAFV600E mutation) |
Indications of repetitive therapy simulating the initial criterion for therapeutic commencement particularly symptomatic disease (splenomegaly) or progressive anaemia, thrombocytopenia or neutropenia. |
If previous remission was > 24 months , a retreatment with a purine analogue with a concurrent anti CD 20 monoclonal antibody or a clinical trial |
If previous remission was > 60 months, consider initiating the preliminary therapy. |
If previous remission was < 24 months, alternative therapy with investigational agents( such as vemurafenib) may be employed following the ascertainment of a precise diagnosis. |
Previously approved therapeutic modalities may be beneficial( such as interferon ᾳ, splenectomy ,rituximab) |
Category of response | Approved criterion for response |
Complete Remission(CR) | Near normalization of peripheral blood counts( haemoglobin > 11gm/dl without transfusion, platelets > 100,000/µL, absolute neutrophil count > 1500/µL. Regression of palpable splenomegaly, absence of morphological evidence of hairy cell leukaemia on peripheral smear and bone marrow. |
Timing of response assessment | Response evaluation on the bone marrow treated with cladarabine should be done after 4-6 months following discontinuation of therapy. Patients on pentostatin may require a bone marrow evaluation after near normalization of the peripheral blood counts and regression of palpable splenomegaly. |
Complete Remission with/ without Minimal Residual Disease(CR with/without MRD) | In patients who have achieved a CR, an immune-histochemical evaluation of the percentage of MRD will demarcate betwixt individuals on CR with or without evidence of MRD |
Partial Response(PR) | A near normalization of the peripheral blood counts( as in CR) with a minimal 50% improvement of organomegaly and a bone marrow biopsy infiltrated with hairy cells. |
Stable Disease(SD) | Patients who do not meet the criteria of objective remission following therapy may be considered to have SD. As the patients are treated for specific reasons such as constitutional symptoms or a decline in the haematological parameters, the category of stable disease may not be an acceptable response |
Progressive Disease(PD) | Amplifying disease related systemic symptoms, augmented organomegaly by 25% or a 25% decline in the haematological parameters may qualify as PD. A distinction from reduced haematolo gical parameters due to therapeutic myelo-suppression may be mandated |
Hairy Cell Leukaemia in relapse | Morphological relapse is defined as the reappearance of hairy cell leukaemia in the peripheral blood, the bone marrow biopsy or both by appropriate stains in the absence of a haematological relapse. Haematological relapse is defined as a reappearance of cytopenia(s) or parameters below the threshold as defined for complete response and partial response. Whereas no treatment is required for morphologic relapse , therapeutic decisions for a haematological relapse may be obtained by evaluating benchmarks such as haematological values necessitating intervention or reoccurrence of disease related symptoms. |