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A significant body of literature has been generated related to the detection of measurable residual disease (MRD) at the time of achieving complete remission (CR) in patients with hairy cell leukemia (HCL). However, due to the indolent nature of the disease as well as reports suggesting long-term survival in patients treated with a single course of a nucleoside analog albeit without evidence of cure, the merits of detection of MRD and attempts to eradicate it have been debated. Studies utilizing novel strategies in the relapse setting have demonstrated the utility of achieving CR with undetectable MRD (uMRD) in prolonging the duration of remission. Several assays including immunohistochemical analysis of bone marrow specimens, multi-parameter flow cytometry and molecular assays to detect the mutant BRAF V600E gene or the consensus primer for the immunoglobulin heavy chain gene (IGH) rearrangement have been utilized with few comparative studies. Here we provide a consensus report on the available data, the potential merits of MRD assessment in the front-line and relapse settings and recommendations on future role of MRD assessment in HCL., (© 2022. The Author(s).)

Hairy cell leukemia (HCL) is a rare lymphoproliferative disorder, comprising only 2% of all leukemias. The Hairy Cell Leukemia Foundation (HCLF) has developed a patient data registry to enable investigators to better study the clinical features, treatment outcomes, and complications of patients with HCL. This system utilizes a centralized registry architecture. Patients are enrolled at HCL Centers of Excellence (COE) or via a web-based portal. All data are de-identified, which reduces regulatory burden and increases opportunities for data access and re-use. To date, 579 patients have been enrolled in the registry. Efforts are underway to engage additional COE's to expand access to patients across the globe. This international PDR will enable researchers to study outcomes in HCL in ways not previously possible due to the rarity of the disease and will serve as a platform for future prospective research.

Standard treatment options in classic HCL (cHCL) result in high response rates and near normal life expectancy. However, the disease itself and the recommended standard treatment are associated with profound and prolonged immunosuppression, increasing susceptibility to infections and the risk for a severe course of COVID-19. The Hairy Cell Leukemia Foundation (HCLF) has recently convened experts and discussed different clinical strategies for the management of these patients. The new recommendations adapt the 2017 consensus for the diagnosis and management with cHCL to the current COVID-19 pandemic. They underline the option of active surveillance in patients with low but stable blood counts, consider the use of targeted and non-immunosuppressive agents as first-line treatment for cHCL, and give recommendations on preventive measures against COVID-19.

Classic hairy cell leukemia (HCL) is a tumor of mature clonal B cells with unique genetic, morphologic, and phenotypic features. DNA methylation profiling has provided a new tier of investigation to gain insight into the origin and behavior of B-cell malignancies; however, the methylation profile of HCL has not been specifically investigated. DNA methylation profiling was analyzed with the Infinium HumanMethylation27 array in 41 mature B-cell tumors, including 11 HCL, 7 splenic marginal zone lymphomas (SMZLs), and chronic lymphocytic leukemia with an unmutated (n = 7) or mutated (n = 6) immunoglobulin gene heavy chain variable (IGHV) region or using IGHV3-21 (n = 10). Methylation profiles of nontumor B-cell subsets and gene expression profiling data were obtained from public databases. HCL had a methylation signature distinct from each B-cell tumor entity, including the closest entity, SMZL. Comparison with normal B-cell subsets revealed the strongest similarity with postgerminal center (GC) B cells and a clear separation from pre-GC and GC cellular programs. Comparison of the integrated analysis with post-GC B cells revealed significant hypomethylation and overexpression of BCR-TLR-NF-κB and BRAF-MAPK signaling pathways and cell adhesion, as well as hypermethylation and underexpression of cell-differentiation markers and methylated genes in cancer, suggesting regulation of the transformed hairy cells through specific components of the B-cell receptor and the BRAF signaling pathways. Our data identify a specific methylation profile of HCL, which may help to distinguish it from other mature B-cell tumors., (© 2019 by The American Society of Hematology.)

Hairy cell leukemia is an uncommon hematologic malignancy characterized by pancytopenia and marked susceptibility to infection. Tremendous progress in the management of patients with this disease has resulted in high response rates and improved survival, yet relapse and an appropriate approach to re-treatment present continuing areas for research. The disease and its effective treatment are associated with immunosuppression. Because more patients are being treated with alternative programs, comparison of results will require general agreement on definitions of response, relapse, and methods of determining minimal residual disease. The development of internationally accepted, reproducible criteria is of paramount importance in evaluating and comparing clinical trials to provide optimal care. Despite the success achieved in managing these patients, continued participation in available clinical trials in the first-line and particularly in the relapse setting is highly recommended. The Hairy Cell Leukemia Foundation convened an international conference to provide common definitions and structure to guide current management. There is substantial opportunity for continued research in this disease. In addition to the importance of optimizing the prevention and management of the serious risk of infection, organized evaluations of minimal residual disease and treatment at relapse offer ample opportunities for clinical research. Finally, a scholarly evaluation of quality of life in the increasing number of survivors of this now manageable chronic illness merits further study. The development of consensus guidelines for this disease offers a framework for continued enhancement of the outcome for patients.

A functional B-cell receptor (BCR) is critical for survival of normal B-cells, but whether it plays a comparable role in B-cell malignancy is as yet not fully delineated. Typical Hairy Cell Leukemia (HCL) is a rare B-cell tumor, and unique in expressing multiple surface immunoglobulin (sIg) isotypes on individual tumor cells (mult-HCL), to raise questions as to their functional relevance. Typical mult-HCL also displays a mutated BRAF V(600)E lesion. Since wild type BRAF is a primary conduit for transducing normal BCR signals, as revealed by deletion modelling studies, it is as yet not apparent if mutated BRAF alters BCR signal transduction in mult-HCL. To address these questions, we examined BCR signalling in mult-HCL cases uniformly displaying mutated BRAF and IGHV genes. Two apparent functional sets were delineated by IgD co-expression. In sIgD(+ve) mult-HCL, IgD mediated persistent Ca(2+) flux, also evident via >1 sIgH isotype, linked to increased ERK activation and BCR endocytosis. In sIgD(-ve) mult-HCL however, BCR-mediated signals and downstream effects were restricted to a single sIgH isotype, with sIgM notably dysfunctional and remaining immobilised on the cell surface. These observations reveal discordance between expression and function of individual isotypes in mult-HCL. In dual sIgL expressing cases, only a single sIgL was fully functional. We examined effects of anti-BCR stimuli on mult-HCL survival ex-vivo. Significantly, all functional non-IgD isotypes increased ERK1/2 phosphorylation but triggered apoptosis of tumor cells, in both subsets. IgD stimuli, in marked contrast retained tumor viability. Despite mutant BRAF, BCR signals augment ERK1/2 phosphorylation, but isotype dictates functional downstream outcomes. In mult-HCL, sIgD retains a potential to transduce BCR signals for tumor survival in-vivo. The BCR in mult-HCL emerges as subject to complex regulation, with apparent conflicting signalling by individual isotypes when co-expressed with sIgD. This suggests the possibility that mutant BRAF by-passes BCR constraints in mult-HCL.

Hairy cell leukemia (HCL) is a distinct clinicopathologic entity that responds well to purine analogs but is sometimes difficult to differentiate from HCL-like disorders (e.g., splenic marginal zone lymphoma and HCL variant). We recently identified the BRAF-V600E mutation as the disease-defining genetic event in HCL. In this study, we describe a new, simple, and inexpensive test for genetics-based diagnosis of HCL in whole-blood samples that detects BRAF-V600E through a sensitive allele-specific PCR qualitative assay followed by agarose-gel electrophoresis. This approach detected BRAF-V600E in all 123 leukemic HCL samples investigated containing as few as 0.1% leukemic cells. BRAF-V600E was detected at different time points during the disease course, even after therapy, pointing to its pivotal role in HCL pathogenesis and maintenance of the leukemic clone. Conversely, 115 non-HCL chronic B-cell neoplasms, including 79 HCL-like disorders, were invariably negative for BRAF-V600E. This molecular assay is a powerful tool for improving the diagnostic accuracy in HCL.

Background: Hairy-cell leukemia (HCL) is a well-defined clinicopathological entity whose underlying genetic lesion is still obscure., Methods: We searched for HCL-associated mutations by performing massively parallel sequencing of the whole exome of leukemic and matched normal cells purified from the peripheral blood of an index patient with HCL. Findings were validated by Sanger sequencing in 47 additional patients with HCL., Results: Whole-exome sequencing identified five missense somatic clonal mutations that were confirmed on Sanger sequencing, including a heterozygous mutation in BRAF that results in the BRAF V600E variant protein. Since BRAF V600E is oncogenic in other tumors, further analyses were focused on this genetic lesion. The same BRAF mutation was noted in all the other 47 patients with HCL who were evaluated by means of Sanger sequencing. None of the 195 patients with other peripheral B-cell lymphomas or leukemias who were evaluated carried the BRAF V600E variant, including 38 patients with splenic marginal-zone lymphomas or unclassifiable splenic lymphomas or leukemias. In immunohistologic and Western blot studies, HCL cells expressed phosphorylated MEK and ERK (the downstream targets of the BRAF kinase), indicating a constitutive activation of the RAF-MEK-ERK mitogen-activated protein kinase pathway in HCL. In vitro incubation of BRAF-mutated primary leukemic hairy cells from 5 patients with PLX-4720, a specific inhibitor of active BRAF, led to a marked decrease in phosphorylated ERK and MEK. CONCLUSIONS; The BRAF V600E mutation was present in all patients with HCL who were evaluated. This finding may have implications for the pathogenesis, diagnosis, and targeted therapy of HCL. (Funded by Associazione Italiana per la Ricerca sul Cancro and others.).

The purine analogs pentostatin and cladribine are effective treatments for hairy cell leukemia (HCL). However, alternative treatments are needed for patients with recurrent disease. We reviewed retrospectively data from 18 patients who were retreated with either pentostatin (n = 12) or cladribine (n = 6) in combination with rituximab, after 1-6 (median 2) previous treatments with either purine analog as a single agent. All 18 patients responded to therapy, with a complete response (CR) rate of 89%. This compared favorably with CR rates of 68% after second-line therapy and 47% after third-line therapy in 88 patients retreated one or more times with a purine analog alone. Toxicity with the combination treatment was minimal. At a median follow-up of 36 months (range 5-83 months) all 16 complete responders remained in CR, while one partial responder developed recurrent disease at 10 months. The estimated recurrence rate at 3 years was 7%. This compares with 21% after second-line therapy and 42% after third-line therapy in the 88 patients retreated with a purine analog alone. Furthermore, it was a marked improvement on the 55% recurrence at 3 years previously seen in these same 18 patients after their own first-line treatment with single-agent pentostatin or cladribine (p = 0.006). The combination of a purine analog with rituximab was safe and effective for patients with recurrent HCL. The results suggest an added benefit compared with single-agent purine analog therapy.

Nucleoside derivative cladribine treatment in hairy cell leukemia (HCL) is a rare example of treatment success in cancer. In fact, HCL is generally responsive to single-agent cladribine and only a minority of patients are refractory. Cladribine was originally administered intravenously as a continuous infusion at a dose of 0.1 mg/kg/day for 7 consecutive days. Subsequently cladribine has been administered intravenously, as a 2 h infusion for 5 consecutive days or weekly for 7 weeks, or subcutaneously. These regimens are all very effective but often show relevant toxicity. The subcutaneous route is easier to administer and may increase compliance of the patient. We have had the opportunity to investigate the efficacy and toxicity of subcutaneous cladribine given at the dose of 0.1 mg/kg/day for 5 or 7 days as a single course in newly diagnosed HCL requiring treatment, in an ongoing Italian multicenter clinical trial. Overall responses have been no different in the two arms, while a much lower infection rate was observed when cladribine was given at the lowest dose. Subcutaneous administration may be deemed a very convenient route since it does not require hospitalization. A reduced dosage of cladribine may also be advantageous since it may be associated with reduced toxicity and may set the dose needed for combinations with antibody treatments.

The B cell receptor (BCR) is the functional distinguishing unit that defines any B cell. Immunoglobulin gene (IG) status is preserved in the neoplastic B cell clone and can provide an indicator of the maturation stage reached by the B cell prior to transformation. In hairy cell leukemia (HCL), several data from IG analysis provide clear hints regarding the cell of origin and the ongoing selective interactions of the tumor BCR with environmental stimuli: HCLs (i) have variable levels of IG somatic mutations, (ii) continue somatic mutations at low levels, (iii) have active processes of IG class switching after transformation, and (iv) have a relatively high frequency of selective events in the light chain of the BCR. It has recently emerged that an unmutated status of the HCL-derived IG can be associated with failure to respond to cladribine, genetic abnormalities indicative of poor outcome, and aggressive disease. These observations suggest that IG gene analysis may have biological and prognostic relevance in HCL and merits further characterization.

Hairy cell Leukaemia (HCL) is a rare neoplasm of peripheral B cells which represents a paradox in oncology. Despite its largely unknown origin and behaviour, HCL is one of the few example of dramatic success in the treatment of a malignancy. The recent steps forward to understanding the biology of HCL from immunogenetic and genomic studies have recently provided new insight into diagnosis and prognosis. Several data from immunoglobulin gene (IG) analysis have provided hints regarding the cell of origin and the ongoing selective interactions of the tumour BCR with environmental stimuli. It has also recently emerged that an unmutated status of the HCL IG can be associated with failure to respond to cladribine, genetic abnormalities indicative of poor outcome and aggressive disease. These observations suggest a central role of the tumour B-cell receptor in defining the outcome of HCL and that that IG gene analysis may have biological and prognostic relevance. Hopefully, IG analysis will help tailor treatment strategies for the most aggressive cases., (Copyright © 2010 John Wiley & Sons, Ltd.)

Analyses of the tumour immunoglobulin (Ig) gene (IG) heavy (H) and light chains show heterogeneity of mutational status, but reveal common features of ongoing IGH isotype-switching with multiple IGH isotype expression and preference of IG lambda (IGL) light chain with selective use of IGLJ3. Phenotypic and immunogenetic analyses were performed in a series of 105 HCL patients to estimate prevalence of multiple IG light chain expression by the tumour cells. By phenotype, 3/105 HCL (2.9%) expressed double tumour-related Ig kappa (K) and L light chain proteins. By immunogenetic analysis, functional mutated double IGK(I) /IGK(II) , IGK(I) /IGL(I) and IGL(I) /IGL(II) transcripts were cloned and sequenced in 3/71 (4.2%) HCL. These latter three HCL expressed multiple IGH isotypes with mutated IGHVDJ rearrangements at the time of AID transcript expression. Most interestingly, the three cases had reinduced RAG1 transcript. In the double IGL expresser, single-cell analysis documented co-expression of the tumour-related IGLs in 5/6 cells (83%). In the IGK/IGL co-expresser, evidence of surface IgK/IgL isotype proteins confirmed functionality of the tumour-derived transcripts. The evidence of double light chain expression in single HCs and the new observation of RAG re-induction suggest ongoing selective influences on the BCR that may promote or maintain the HCL clone in the periphery., (Copyright © 2010 John Wiley & Sons, Ltd.)

The B cell receptor (BCR) is the functional distinguishing unit that defines any B cell. Immunoglobulin gene (IG) status is preserved in the neoplastic B cell clone and can provide an indicator of the maturation stage reached by the B cell prior to transformation. In hairy cell leukemia (HCL), several pieces of data from IG analysis provide clear hints regarding the cell of origin and the ongoing selective interactions of the tumor BCR with environmental stimuli. HCLs have variable levels of IG somatic mutations, and continue somatic mutations at low levels as well as IG class switching after transformation. More recent data also show the occurrence of selective events in the light chain of the BCR, suggesting a dominant role for IG status in the pathogenesis of HCL. Moreover, it has recently emerged that an unmutated status of the HCL IG can be associated with failure to respond to cladribine, genetic abnormalities indicative of poor outcome, and aggressive disease. These observations suggest that IG analysis may have biological and prognostic relevance in HCL and merits further characterization.

Hairy cell leukemia (HCL) is generally responsive to single-agent cladribine, and only a minority of patients are refractory and with poor prognosis. HCLs generally express mutated (M) and, in a minority, unmutated (UM) IGHV. In a multicenter clinical trial in newly diagnosed HCL, we prospectively investigated clinical and molecular parameters predicting response and event-free survival after single-agent cladribine. Of 58 HCLs, 6 expressed UM-IGHV (UM-HCL) and 52 M-IGHV (M-HCL). Beneficial responses were obtained in 53 of 58 patients (91%), whereas treatment failures were observed in 5 of 58 patients (9%). Failures were associated significantly with UM-IGHV (5 of 5 failures vs 1 of 53 beneficial responses had UM-IGHV, P < .001), leukocytosis (3 of 5 vs 3 of 53, P = .006), and bulky spleen (4 of 5 vs 4 of 53, P < .001). The UM-HCL not benefiting from cladribine characteristically had bulky spleen (4 of 5, 80%), leukocytosis (3 of 5, 60%), and TP53 defects (2 of 5, 40%), and progressed rapidly after first treatment (median event-free survival, 7.5 months). Our data suggest that UM-HCLs identify the minor subgroup failing cladribine treatment and with more aggressive disease. High incidence of TP53 dysfunction indicates a potential mechanism of resistance to cladribine in the UM-HCL group. Overall, our data provide new molecular elements relevant for treatment concerns in HCL.

Since its first description in 1958, hairy cell leukemia (HCL) had a long period of different unsatisfactory treatments till the early 1980s, when interferon-alfa and subsequently purine analogs (PAs) pentostatin or cladribine, or pentostatin were described to determine durable responses. However, second lines of treatments are very often needed in the life span of patients with HCL and a small minority of patients are refractory and with poor prognosis. These disadvantages have led to test the efficacy of additional compounds, mainly monoclonal antibodies, combined with PAs. The objective of this presentation is to review the current knowledge of combination treatments in HCL. Combination treatments have been used or proposed for different purposes in HCL: to reduce acute toxicity, to improve complete remission (CR) rate, to overcome resistance/refractoriness, to prolong disease-free survival, or to prolong overall survival. The type of patients to be selected for the combinations and the perspectives of combinations of PAs with monoclonal antibodies will also be discussed.

Hairy cell leukaemia (HCL) was first described 50 years ago. Median survival was then 4 years. The purine analogues, introduced in the 1980s, transformed this prognosis. We reviewed data retrospectively from 233 patients, treated with pentostatin (n = 188) or cladribine (n = 45), to investigate the current long-term outlook. Median follow-up was 16 years. There were no significant differences in outcome between the two agents. Overall, the complete response (CR) rate was 80% and median relapse-free survival was 16 years. After relapse (n = 79) or non-response (n = 5), 26 patients received pentostatin and 58 cladribine; 69% achieved CR and median relapse-free survival was 11 years. After third-line therapy (n = 23), 50% achieved CR and median relapse-free survival was 6.5 years. However, CRs were equally durable, whether after first, second or third-line therapy. Complete responders and those with both haemoglobin >100 g/l and platelet count >100 x 10(9)/l before treatment had the longest relapse-free survival (P < 0.0001). Patients still in CR at 5 years had only a 25% risk of relapse by 15 years. Outcomes for patients with recurrent disease improved with the monoclonal antibody rituximab, combined with either purine analogue. Overall only eight patients died of HCL-related causes. Patients achieving a CR can expect a normal lifespan.

Hairy cell leukaemia (HCL) is a rare B-cell neoplasm for which the molecular mechanisms are largely unknown. High-density genome-wide DNA profiling was performed with Affymetrix 250K arrays to analyse copy number (CN) changes and loss of heterozygosity (LOH) in 16 cases of HCL. Four of 16 cases (25%) demonstrated gross non-recurrent CN deletions. Within the affected regions, we identified genes involved in bone marrow fibrosis (FGF12) and response to treatment (TP53) in individual cases. Large regions (> 5 Mb) of LOH without any concomitant DNA CN changes were identified in 5/16 (31%) HCL and were indicative of uniparental disomy UD. The germline origin of UD was demonstrated in one case for which a matched normal sample was available. Overall analysis of LOH showed that identical loci were recurrently targeted in chromosomes 1, 2 and 6. As a whole, however, HCL showed a remarkably stable genome. This finding adds to several other features that are unique to HCL among mature B-cell tumours.

Background: We previously reported ongoing mutational and isotype switch events in the immunoglobulin (Ig) heavy chain (H) locus in hairy cell leukemia. Those analyses raised questions on the incidence and type of selective influences occurring on the tumor B-cell receptor of hairy cell leukemia., Design and Methods: To further investigate this issue, we examined the full IGH and kappa and lambda light chains (IGkappa and IGlambda) variable and constant region transcripts expressed in a large cohort of patients with hairy cell leukemia (n=88)., Results: Multiple IgH isotypes were expressed in 46/56 (82%) cases of hairy cell leukemia. Comparison of tumor with normal B-cell repertoires revealed preferential usage of IGHV3-21, IGHV3-30 and IGHV3-33 in hairy cell leukemia (p=0.001, p=0.003 and p=0.001, respectively). Light chain analysis demonstrated preferential Igl use with an inverted IGk:IGl ratio (0.7:1) and universal usage of IGLJ3. Analysis of LCDR3 junctions revealed highly homologous motifs in 40% of IGL. Parallel analysis of IGH and IGL showed selective pairing of IGHV3-21/30/33 segments to specific LCDR3-J3 subsets (p=0.008). Of 40 cases of hairy cell leukemia, 38 had mutated IGHV and/or IGK/LV, with variations in 13/13 cloned cases, while two had 100% unmutated IGHV and IGK/LV., Conclusions: Overall, biased IGV usage, preference for Iglambda with universal IGLJ3 usage and a high incidence of LCDR3 homologous motifs suggest selective influences on the B-cell receptor of hairy cell leukemia. Ongoing mutations and isotype switching suggest that influences occur on the tumor B-cell receptor at ectopic sites.

Background: The purine analogs pentostatin and cladribine have revolutionized the treatment of hairy cell leukemia (HCL) with overall responses in greater than 85% of patients and a median progression-free survival of up to 15 years. They continue to be effective at second- and even third-line therapy; however, alternative treatments are needed for patients who are or have become refractory to these agents or whose remissions are shorter with each course of therapy., Methods: The authors conducted a retrospective review of 8 patients who received pentostatin or cladribine combined concurrently (n = 6 patients) or sequentially (n = 2 patients) with rituximab at second-line therapy (n = 3 patients) and at subsequent lines of therapy (n = 5 patients). Results from a previously reported database of 219 patients with HCL (73 patients who received second-line therapy and 20 patients who received third-line therapy) were used as a historic control group against which to measure benefit., Results: All 8 patients responded to therapy, with 7 complete responses (CRs) (87.5%) and minimal toxicity. All patients who had CRs were negative for minimal residual disease (MRD). At a median follow-up of 29 months (range, 5-39 months) 1 patient developed recurrent disease, and the estimated 2-year recurrence rate was 20% (0% after second-line therapy and 25% after subsequent lines of therapy). In the historic control group, the CR rates were 70% after second-line therapy and 45% after third-line therapy, and the recurrence rates at 2 years were 15% and 33%, respectively., Conclusions: The combination of purine analogs with rituximab was safe and effective for patients with recurrent and/or refractory HCL, and the current results suggested an added benefit compared with standard treatment., ((c) 2007 American Cancer Society.)

Hairy cell leukemia (HCL) commonly expresses multiple immunoglobulin isotypes, a feature rare in other B-cell malignancies or in normal B cells. In HCL, there is no phenotypic evidence for subpopulations, and single cells from one previous case contained transcripts for several isotypes. This raises the questions of the differentiation status of the cell of origin and of posttransformation events. We have investigated 9 cases, all expressing multiple immunoglobulin isotypes. Multiple tumor-derived variable-(diversity)-joining-constant mu delta, gamma, alpha (V(D)J-Cmu, delta, gamma, alpha) transcripts were confirmed in single cells of a further case. All cases were negative for germinal center (GC)-associated markers CD27 and CD38. Seven of 9 cases had mutated V(H) genes, with low levels of intraclonal heterogeneity, but 2 of 9 were unmutated, indicative of pre-GC origin. Eight of 9 cases expressed activation-induced cytidine deaminase (AID), a molecule essential for somatic mutation and isotype switch. All cases expressed germ line heavy-chain I exon (I(H))-C(H) transcripts which paralleled surface immunoglobulin (sIg) isotype. Significantly, no circle transcripts indicative of deletional recombination of switched isotypes were detectable in 9 of 9 cases. These data indicate heterogeneity in the cell of origin in terms of mutational status, but reveal common features of AID expression and isotype-switching events occurring prior to deletional recombination. Both mutational and switching events may be influenced by environmental factors at extrafollicular sites.

Hairy cell leukaemia (HCL) offers one of the few examples of rapid progress in the development of effective treatments for chronic lymphoproliferative disorders. After the first description of HCL as a separate disease in 1958, splenectomy was the treatment of choice, but rarely resulted in remission of disease and had scarce benefit on survival. In 1984, IFN-alpha became the first agent able to significantly modify the prognosis of HCL by inducing high response rates and long-term remissions. More recently, purine analogues have significantly further increased the percentages of remissions, with a reduced risk of relapse and are now generally used as first-line treatment. Monoclonal antibodies targeting CD20, CD22 and CD25 antigens, have also shown responses for resistant or relapsing disease. This article will review the current treatment strategies for HCL.