Hairy cell leukemia

Hairy cell leukemia is a malignancy with a variable course that can be relatively indolent or rapidly fatal. Alterations in the immune system are responsible for much of the morbidity and mortality from hairy cell leukemia. More than 60% of patients die from infection, and infections are both pyogenic and nonpyogenic. Many patients have transfusion requirements, and bleeding complications can also occur. Treatment strategies for hairy cell leukemia have evolved and are being modified as more is learned about the disease. Splenectomy is the initial treatment when patients become symptomatic, and if the disease progresses after splenectomy, chlorambucil offers good control in many patients. Radiation can be used for local palliation, as when complications such as bulky adenopathy or bone lesions occur. Initial studies using interferon in the treatment of hairy cell leukemia look encouraging, but more investigation is necessary before the role of interferon in treatment of hairy cell leukemia is determined.     

Hairy cell leukemia

Hairy cell leukemia is a rare B-cell neoplasm. When treated with either pentostatin or cladribine, complete and durable remissions can be secured and life expectancy for most patients is normal. A small minority of patients require alternative treatment with monoclonal antibodies or immunotoxins. Patients who attain a complete response to first-line treatment have the best prognosis.     

Hairy cell leukemia

The diagnosis of 131 patients with hairy cell leukemia was based on the demonstration of characteristic cells in the blood and bone marrow in 105 males and 26 females between 23 and 87 years (mean 52) of age. Enlargement of the spleen was found in 71% of cases. Anemia was present in 78% of the patients, neutropenia below 1000/mm³ in 63%, thrombocytopenia below 100,000/mm³ in 73%.The median survival (m.s.) was 42 months. Of 41 documented causes of death, 33 were related to infection. Prognosis is the worst for patients with neutropenia below 500/mm³ or leukocytosis over 10,000/mm³.The patients without palpable spleen have the best survival. The 14 patients who received chemotherapy had a 20 months m.s. Eighty-four patients (with and without splenomegaly) received only supportive therapy: their m.s. was 50 months. In splenomegalic patients, survival was better when splenectomy was performed (m.s. 42 months) than when it was not (m.s. 34 months).     

Hairy cell leukemia

Opinion statement The standard therapy for hairy cell leukemia (HCL) is with the nucleoside analogs, 2’-deoxycoformycin (dCF) or 2-chlorodeoxyadenosine (CdA), which produce morphologic complete remissions (CRs) in the majority of patients, although residual hairy cells can frequently be detected by molecular or immunologic techniques. Relapses continue to occur over time, but most patients respond well to retreatment withthe same agent. The longest follow-up is for patients treated with dCF, where the 5- and 10-year relapse-free survival rates are 80% to 85% and 67% to 76%, respectively. dCF is usually administered as 4 mg/m2 intravenously every second week until CR followed by two additional treatments for consolidation. CdA is administered as 0.09 mg/kg/d × 7, by continuous intravenous infusion, although it may be equally effective when given as daily boluses or subcutaneously. More recent studies have suggested that CdA, 0.15 mg/kg intravenously weekly × 6, produces equivalent response rates, while reducing the risk of febrile neutropenia (which occurs in approximately 50% of patients using the standard regimen). We have found this to be a very simple, safe, and effective regimen. Both dCF and CdA should be used with caution in the presence of renal or hepatic dysfunction, and both are contraindicated in the presence of active infection. Interferon-alfa (3 × 10⁶ U subcutaneously three times per week for 12 months) produces inferior response rates but is less likely to cause febrile neutropenia. It can be considered for initial treatment for patients with active infection, patients at high risk of febrile neutropenia, and patients who cannot tolerate or are resistant to the nucleoside analogs. Splenectomy is now rarely performed in HCL, but it is required for splenic rupture and may be of value in “splenic” HCL or those with massive splenomegaly and hypersplenism. In preliminary studies, monoclonal antibodies directed against CD20 or CD25 also show activity in HCL, but their roles in this disease require further study.     

Hairy cell leukemia

Hairy cell leukemia (HCL) is a chronic B-cell lymphoproliferative disorder characterized by pancytopenia and variable infiltration of the reticuloendothelial system with "hairy" lymphocytes. HCL is more common in men than women and has a median age of diagnosis of 52 yr. Typically, patients with HCL respond well to purine analog-based therapy. The purpose of this review will be to establish the current status of HCL with respect to its pathophysiology, diagnosis, management, and future directions.     

Hairy cell leukemia

Six patients of 'Hairy cell leukemia' (HCL) were seen by us between 1982 and 1987. Five patients had anaemia and two had leukopaenia. None of the patients had thrombocytopaenia at presentation. All the patients were positive for tartarate resistant acid phosphatase. Two had B and one had T cell surface markers. Characteristic cytoplasmic projections and ribosomal lamellar complexes were seen on electron microscopy in four patients. Three patients were treated with splenectomy with satisfactory results.     

Hairy cell leukemia

BACKGROUND:

Historically, the first treatment choices for hairy cell leukemia (HCL) were splenectomy and alpha‐interferon. Recently, purine analogues (pentostatin and cladribine) changed radically the treatment modality, inducing complete and durable responses in the majority of patients.

METHODS:

The authors analyzed the outcome of different lines of therapy in 121 HCL patients followed in their institute from 1986 to 2008, with a median follow‐up of 105 months. Patients were divided into subgroups according to the number of treatments; Group A included 121 patients who underwent a front‐line therapy, Group B patients (n =53) were treated with 2 lines, Group C patients (n = 34) with 3 lines, Group D patients (n = 17) with 4 lines, and Group E patients (n = 8) with 5 lines.

RESULTS:

In Group A, 92 (77%) patients obtained a complete response (CR), 23 (18%) a partial response, and the remaining 6 (5%) a minor or no response; median duration of response was 2.7 years. In Group B, 53 relapsed patients achieved a second CR rate of 73.5%; median duration of response was 2.5 years. Group C contained 34 patients in a second relapse, with a CR rate after the third line of treatment of 70.5% (median duration of response, 2.2 years). In Group D, 11 (64.7%) patients obtained a CR (median duration of response, 1.6 years), and in Group E 4 (50%) of 8 patients achieved a CR (median duration of response, 1.3 years).

CONCLUSIONS:

This study confirms the high risk (>40% of all patients) of retreatment of HCL patients and the need to maximize primary response. Cancer 2010. © 2010 American Cancer Society.     

Hairy cell leukemia: towards a curative strategy

Although not all patients who have HCL require therapy at diagnosis, most eventually need treatment. Historically, splenectomy and interferon-alpha resulted in hematologic responses; however, responses tend to be short. The introduction of purine analogs dramatically changed the prognosis for most patients who hae HCL. It is now considered standard of care to use a purine analog, such as 2-CdA or 2'-DCF, as first-line therapy. This approach results in a high CR rate and prolong DFS. Although both agents yield the same rates of CR and survival, 2-CdA seems easier to administer and my be associated with less toxicity. Despite the excellent results with purine analogs, most patients have MRD detected by sensitive techniques; 30% to 40% of patients eventually relapse and most require further therapy. A repeat course of 2-CdA (or 2'-DCF) will result in CR in approximately 70% of patients. For patients who have relapsed or refractory disease, monoclonal antibody-based therapies are emerging options. Rituximab and BL22 are highly active in this setting. Until BL22 becomes widely available, rituximab is a reasonable choice for salvage therapy; however, the dosing schedule needs to be denied further. The roles of rituximab and BL22 as initial therapy for patients who have previously untreated HCL have not been investigated. Fig. 1 is a suggested algorithm for the treatment of HCL. With the introduction of effective new agents, further studies will determine whether the now achievable prolonged survival will translate into cure.     

Hairy cell leukemia: its place among the chronic B cell leukemias

Hairy cell leukemia is a chronic B cell leukemia. The presence of surface Ig (SIg) of gamma or multiple isotypes on the cells locates HCL at a rather mature stage of B cell differentiation. The reactivity of HC with McAb is in accordance with this concept (T65-, OKM1+, FMC7+, BA-1-). To relate HCL to other chronic B cell leukemias, a morphologic classification was developed that distinguishes, besides HCL, five subtypes of chronic B cell leukemia. CLL showed weak staining for SIg of mu +/- delta class. The phenotype with McAb was T65+, OKM1-, FMC7-, BA-1+. Prolymphocytic transformation of CLL had essentially the same membrane phenotype. LPL often had brighter SIg of mu +/- delta class with gamma or multiple isotypes in about half of the cases. McAb gave a T65-or+, OKM1-or+, FMC7-or+, BA-1+ phenotype. The same surface-marker profile was found in CL. Finally, PLL showed bright SIg of gamma or multiple isotypes in the majority of cases and reactivity with McAb according to a T65-or+, OKM1+, FMC7+, BA-1+ pattern. The various immunologic phenotypes of the morphologic subtypes showed a considerable overlap. The various chronic B cell leukemias should be located in the scheme of B cell differentiation in the sequence CLL-LPL/CL-PLL-HCL.     

Hairy cell leukemia: treatment prospects

The recent advances in the management of hairy cell leukemia, a chronic and indolent B-cell lymphoproliferative disorder are reviewed. The introduction of α-interferon, purine analogs and recombinant monoclonal antibodies/immunotoxins has dramatically improved the outcome in a disease that once had a dismal prognosis. The underlying genetic defect remains unknown.     

Hairy cell leukemia: current concepts

Hairy cell Leukemia (HCL) is a chronic lymphoproliferative disorder that was characterized in the late 1950s. HCL is defined, according to the WHO classification, as a mature (peripheral) B-cell neoplasm (1). HCL accounts for between 2-3% of all leukemia cases, with about 600 new cases diagnosed in the U.S. each year (1). HCL occurs more commonly in males, with an overall male to female ratio of approximately 4:1. The median age of onset is 52 years. This disease is seen more commonly in Caucasians and appears to be especially frequent in Ashkenazi Jewish males, with rare occurrence in persons of Asian and African descents (1). Hairy cells are distinct, clonal B cells arrested at a late stage of maturation. They are small B lymphoid cells that possess oval nuclei and abundant cytoplasm with characteristic micro-filamentous ("hairy") projections. They strongly express CD103, CD22, and CD11c (2). These cells typically infiltrate the bone marrow, the spleen, and to a lesser extent the liver, lymph nodes, and skin. Many patients present with splenomegaly and pancytopenia. Other clinical manifestations include recurrent opportunistic infections and vasculitis. Historically, HCL was considered uniformly fatal (2). However, recent treatment advances, using purine analogues such as Cladribine and Pentostatin, led to a significant improvement in prognosis with achievement of high response rates and durable remissions (2).     

Hairy cell leukemia: treatment prospects

The recent advances in the management of hairy cell leukemia, a chronic and indolent B-cell lymphoproliferative disorder are reviewed. The introduction of alpha-interferon, purine analogs and recombinant monoclonal antibodies/immunotoxins has dramatically improved the outcome in a disease that once had a dismal prognosis. The underlying genetic defect remains unknown.     

Hairy cell leukemia: diagnostic pathology

The pathology of HCL has been reviewed with a focus on the diagnostic hematopathology of this rare, but fascinating, disease. The discrimination of HCL from other B-cell lymphoproliferations, particularly HCL-V and SMZL, has been emphasized. The unique responsiveness of HCL to 2-CdA and other chemotherapeutic agents makes this distinction critical. Fortunately, HCL has consistent cytologic, histologic, cytochemical, and immunologic features that make classification reliable and reproducible. Less straightforward is the differential diagnosis of SMZL and HCL-V, problematic because of the rarity of both disorders, lack of discriminating evidence-based criteria, and perhaps a biologic kinship between these two disorders that share many clinical and pathologic features. Fortunately, this is not a clinically critical distinction.     

Hairy cell leukemia and human T cell leukemia virus

HCL is a lymphoproliferative disorder, primarily of B cells. T cell variant HCL is a rare clinical entity, which has a clinical picture similar to that of the common B cell HCL disease. HTLV-II has been isolated from a case of T cell variant HCL. This subtype of HTLV-II-associated disease is indolent in character in comparison to the very aggressive HTLV-I-associated disease. Investigation of the biology and molecular genetics of HTLV is in progress. It is hoped that better understanding of HTLV and the comparative differences between HTLV-I and HTLV-II will provide specific insights into the mechanisms of human leukemogenesis.     

Hairy cell leukemia has a B-cell genotype

The phenotype and, by inference, the cell of origin of some lymphocytic neoplasms has been defined by surface marker studies; however, the precise cellular origin of other neoplasms of the lymphoid system is still unknown. For example, with reference to hairy cell leukemia (HCL), cell marker data has been used in support of a monocytic, a T cell, or a B cell origin. If hairy cell leukemia is a B cell-derived neoplasm, the controversy may be resolved by genotyping the cells, using the rearrangement of immunoglobulin genes as a marker of the B cell nature of the process. Rearrangement of these genes is detected using the Southern blot technique and cloned probes specific for the JH segment of the immunoglobulin genes. In this study, the arrangement of the immunoglobulin genes was analysed in normal tissue, in two accepted B cell lymphomas and in nine cases of hairy cell leukemia. DNA from peripheral blood leukocytes (two patients) and from the spleen (seven patients) revealed a discrete new JH restriction fragment length in the leukocytes of hairy cell leukemia cases. The presence of rearranged restriction fragments is interpreted as evidence of the existence of clonal B cell populations. Three of six samples had rearranged kappa light chain fragments. We conclude that most cases of hairy cell leukemia have a B cell genotype. The use of genotyping has wider application in the analysis of hematological malignancies.     

Hairy cell leukemia and sarcoid.

A 45-year-old female simultaneously developed both hairy cell leukemia and acute sarcoid. A defect in suppressor T lymphocytes which allowed an unrestrained B-cell proliferation manifested as both hairy cell leukemia and sarcoid is proposed.     

Hairy cell leukemia: in-vitro proliferation and pseudo-colony formation

In an established double layer clonogenic assay, the PHA-leukocyte feeder colony assay, hairy cell leukemia (HCL) cells formed strong aggregates simulating colonies. After irradiation with 50 Gy, colony formation persisted. Even in a modified colony assay consisting of agar 0.5% overlayered by methylcellulose 0.9%, cell aggregation was still possible due to increasing fluidity of the methylcellulose during the culture period. Time-lapse video recordings confirmed prominent cell motility leading to pseudo-colony formation. Studies with bromodeoxyuridine incorporation showed a low proliferation index (up to 13%) of hairy cells. In conclusion, any assay that facilitates cell motility is unsuitable to study HCL colony growth.     

Hairy cell leukemia: clinical features and therapeutic advances

Hairy cell leukemia (HCL) is a rare chronic lymphoproliferative disorder which has been extensively studied over the past decade. Much has been learned regarding the diagnosis, natural history, biology, and treatment of this unique neoplasm. The disease most commonly affects middle aged men and characteristic clinical features include splenomegaly, cytopenias, and usually the presence in the peripheral blood of distinctive thairy cells with irregular cytoplasmic projections. Diagnosis can usually be confirmed by bone marrow biopsy. Although the natural history can be extremely variable among patients, complications are usually referable to the cytopenias, with anemia and infection being most frequent. In addition to pyogenic infections, patients are susceptible to unusual organisms including atypical mycobacterium, legionella, and fungi. The requirement of red blood cell transfusion, severe granulocytopenia or thrombocytopenia, frequent infections, or painful splenomegaly are all indications for treatment. Splenectomy is the standard initial treatment of choice. However, in the past few years there have been exciting major advances in the therapeutic modalities for HCL. Recombinant alfa-interferon is highly effective, with beneficial responses occurring in close to 90% of patients. The Food and Drug Administration has recently approved the use the interferon for HCL. This represents the first time a biological response modifier has been approved for the treatment of human disease. In addition, preliminary results with the adenosine deaminase inhibitor, 2 deoxycoformycin (def), have been encouraging. Further clinical trials are required in order to determine the optimal sequential treatment strategy for HCL. The exact mechanisms of action of both interferon and def in HCL remain to be elucidated. A better understanding of the unusual features of the hairy cell and the underlying biological effect of these two agents in HCL may have important applications in other hamatologic and non-hematologic malignancies.     

Hairy cell leukemia: an autopsy study.

Autopsy material from 5 patients with hairy cell leukemia was examined. In addition to the expected widespread involvement of the hematopoietic system and of the liver, all of the patients had various amounts of pulmonary infiltration by leukemic cells. This infiltration was so severe in one instance that the resulting pulmonary insufficiency was the cause of death. Other areas of hairy cell infiltration included the peripancreatic connective tissue in all cases, kidneys in 3 cases, pericardium in 2 cases, and skin in 1 case. Association of plasma cells with the infiltrating neoplastic cells was prominent. In one patient, foci of large, bizarre cells were found in several lymph nodes and in the pericardium. Whether these cells represent transformation of the hairy cells into a larger, less differentiated cell type, or the emergence of a second hematopoietic neoplasm, is unknown.