The Treatment of Hairy Cell Leukemia: A Review

Hairy cell leukemia is a chronic lymphoproliferative malignancy first described by Bouroncle et al. over 30 years ago¹. Representing less than 2% of adult leukemias, hairy cell leukemia has become the focus of intense interest over the past few years as a result of therapeutic advances. The malignant cell has characteristic irregular cytoplasmic projections visible on the peripheral blood smear and cytoplasmic vesicles staining positive for tartrate-resistant acid phosphatase. The origin of the hairy cell appears to be a preplasma cell B lymphocyte based on immunoglobulin gene rearrangements and B-cell-specific antigens, although very rare T-cell variants have been reported. While the diagnosis may be suspected from the clinical manifestations and examination of the peripheral smear, a bone-marrow biopsy is frequently necessary for definitive diagnosis. The typical patient is a middle-aged man with complaints of fatigue or weakness; symptoms of splenic pain, bleeding or bruising, or recurrent infections are less common at presentation². Splenomegaly without peripheral adenopathy occurs in 70-80 % of newly diagnosed patients². Pancytopenia is present in approximately two-thirds of patients, although 10% of patients present with a leukocytosis resulting from a high circulating hairy cell count.     

Survival Experience of 195 Patients with Hairy Cell Leukemia Treated in a Multi-Institutional Study with Interferon-Alfa 2B

One hundred ninety-five patients were entered into a multi-institutional study of interferon alfa 2b from 1983-1986; follow-up was completed through June 1989. A complete remission was documented in 7 patients, a partial remission in 152 patients, a minor response in 10 patients, and no response in 26 patients. One-hundred fifty-nine of the 195 patients treated (81%) had a normalization of their peripheral blood counts by the criteria used. To date, 17 patients have died. Only 3 of the 159 patients (2%) with a PR or CR have expired. Three of 10 MR patients have expired and 11 of 26 NR patients have expired. Of the 11 who expired, 7 did so before receiving an adequate duration of treatment. Three of the NR patients died within 1 week of starting interferon from intracranial hemorrhages secondary to severe thrombocytopenia (present prior to initiation of interferon) and 4 NR patients died of infectious deaths within 2 months of initiating interferon therapy secondary to severe neutropenia (present prior to initiation of interferon). Of the 17 NR's who remained alive and on-study for at least 6 months, only 2 eventually died, both after failing subsequent pentostatin therapy. Systemic therapy with agents that induce a more rapid response such as pentostatin or 2-chlorodeoxy-adenosine, or the combination of interferon plus growth factor are indicated in these severely cytopenic patients.     

Familial Hairy Cell Leukemia

Familial hairy cell leukemia (HCL) occurs rarely, and HCL occurring in association with other hematologic malignancies is even rarer. We describe two cases of familial HCL syndromes: a mother and son with HCL, and a HCL patient whose aunt developed Hodgkin's Disease (HD). This is the first reported familial association of HCL with HD.     

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).     

21例毛细胞白血病临床分析

 目的
探讨初诊毛细胞白血病(hairy cell leukemia,HCL)患者的临床特点和治疗疗效。方法 回顾性分析我院初诊的21例患者临床及相关
实验室检查资料。结果脾大是HCL最主要的症状体征,其次表现为全血细胞减少、骨髓增生活跃;少数患者电子显微镜可见核糖体－
板层复合物;典型的毛细胞表达CD11c、CD25、CD123、CD103,同时还表达CD20、CD22、CD52和Cyclin D1,尤其CD103是HCL较特异的
表型。核苷类似物治疗HCL疗效优于其他治疗,值得临床推荐。结论初诊的HCL临床特征与国外的基本相似;国内以氟达拉滨为主的联
合化疗方案,无明显的骨髓蓄积抑制作用,且疗效高于国外。     

Unusual Association of Hairy Cell Leukemia and Monoclonal Large Granular Lymphocyte Proliferation

The exceptional association of Hairy cell leukemia (HCL) and monoclonal large granular lymphocyte (LGL) proliferation is reported in the same patient. Immunophenotypic analysis, showed that most of the PBMC expressed CD3 and HNK-1 molecules, while in the bone marrow biopsy an infiltration by CD22 +/CD25 + lymphoid cells was detectable. The monoclonal rearrangement of βTTCR genes in the PBMC, suggests that the increased LGL is not reactive. Nevertheless, a possible interaction between the two entities is proposed. The high sIL-2R serum levels, related to proliferation of hairy cells, might account for the lack of NK activity observed in the LGL.     

Low Dose Interferon Alfa-2B for the Induction of Remission of Hairy Cell Leukemia: A Multi-institutional Study of 49 Patients

This multicenter study reports on 49 patients with hairy cell leukemia (HCL) who were treated subcutaneously with alfa-2b interferon (Intron A, Schering Corporation, Kenilworth, N.J.), three times a week at a reduced dosage of 200,000 units/m², one-tenth the dose of the standard 2 million units/m². The response rate (normalized blood counts) was 22% (11 of 49); an additional 12 patients had a minor response for an overall response rate of 47% (23 of 49). When response was assessed by prior IFN therapy, no significant difference was noted. Five of 21 (24%) with no prior IFN and 6 of 28 (21%) with prior IFN therapy achieved at least a normalization of blood counts (p = 0.07). The response rate with low-dose interferon is inferior to that with standard dose interferon and should not be used for remission induction, but should be evaluated for its role in long-term maintenance of response.     

Ultrastructural Characteristics of the Spleen in Hairy Cell Leukemia

Eighteen spleens derived from patients with hairy cell leukemia (HCL) were analyzed by correlative scanning and transmission electron microscopy. In 15 of the cases, the white pulp areas were markedly decreased or absent when compared to normal spleens, although few hairy cells were observed within this region. In only one case did the white pulp appear normal. In all HCL cases, hairy cells were observed within normal, dilated, and abnormal sinuses. The abnormal sinuses contained hairy cells of typical morphology attached to other hairy cells, to endothelial lining, and to erythrocytes. The degree of sinus filling by hairy cells varied from loosely- to tightly-packed. Endothelial cells exhibiting degenerative changes, such as swelling with smooth surfaces and dilated intercellular spaces, were frequently seen. These results indicate that in addition to the previously described overcrowding of the spleen by hairy cells, the splenic tissue itself is considerably altered and sometimes severely damaged in patients with HCL.     

High Serum Levels of Soluble Interleukin-2 Receptor and Absence of Detectable Levels of Soluble CD30 Molecule: A Specific Diagnostic Combination for Hairy Cell Leukemia

Hairy cell leukemia (HCL) is almost constantly characterized by the presence of very high levels of a soluble form of the interleukin-2 receptor (sIL-2R). Since several other hematologic neoplasias also display very high levels of sIL-2R, this feature cannot be considered specific for HCL. On the other hand, most of the above hematologic disorders are also characterized by the presence of detectable levels of the soluble CD30 molecule (sCD30). In the present study we investigated the sera from 22 patients with HCL for the presence of detectable circulating levels of sCD30 in combination with the detection of sIL-2R. In this report we demonstrate that the high serum levels of sIL-2R found in all HCL patients were never associated with the presence of sCD30. Since this pattern is unlikely to be found in neoplastic conditions other than HCL, we suggest that the combined serum determinations of sIL-2R and sCD30 be used as a reliable additional tool for the diagnosis of HCL.     

Inhibitor of BRAFV600E Mutation as a Treatment Option for Hairy Cell Leukemia With Deep Neutropenia and Infectious Complications

Standard therapy in hairy cell leukemia (HCL) is often impossible at the time of deep neutropenia/agranulocytosis with or without infectious complications; it is thus a complex therapeutic problem. Vemurafenib has been used to treat resistant HCL since 2012. Because vemurafenib does not have a myelotoxic effect, we thought that it could be used to treat HCL associated with deep neutropenia/agranulocytosis with or without the development of infectious complications as a preliminary stage before treatment with cladribine. We conducted a retrospective analysis of treatment with vemurafenib followed by a standard course of cladribine provided to 22 patients with deep neutropenia/agranulocytosis with or without infectious complications at diagnosis. Vemurafenib was provided to 22 patients with HCL. The response to therapy was evaluated by complete blood cell count (absolute neutrophil count [ANC], hemoglobin concentration, platelet count, absence of hairy cells), spleen size (assessed by ultrasound), and reduce infectious complications. After that, a standard course of cladribine was provided. Among the 22 patients, the male/female sex ratio was 2:1, and median (range) age was 52 (24-78) years. There were 7 patients with severe infectious manifestations admitted to the intensive care unit, including 1 patient during extracorporeal membrane oxygenation. The median (range) ANC at diagnosis was 0.3 (0.04-0.7) × 10⁹/L. Vemurafenib was provided at a dosage of 240 mg 1 or 2 times a day. In 20 patients, vemurafenib was provided for 3 months or more. In 1 case, the effect was not obtained during 1 month of treatment, and the patient died from severe infectious complications during prolonged agranulocytosis. In 21 patients treated with vemurafenib, an increase of ANC was observed and the infectious complications resolved, thus allowing the application of cladribine therapy. After a standard course (0.1 mg/kg per day for 7 days) of cladribine chemotherapy, 18 patients (90%) experienced complete clinical remission and 2 patients (10%) experienced partial remission with residual splenomegaly. In 1 patient, vemurafenib therapy was still ongoing 2 months after initiating therapy. In cases of proven BRAF^V600E mutation, vemurafenib can be successfully used as an effective preliminary therapy in patients with deep neutropenia/agranulocytosis with or without infectious complications before standard therapy with purine analogs.     

Demonstrated Benefit of Continuous Interferon-Alpha-2b Therapy in Hairy Cell Leukemia. A Two-Year Follow-Up

Interferon-alpha-2b (IFN) was given to a series of 50 patients with hairy cell leukemia (HCL). The IFN dose for both induction and maintenance was 2.0 × 10⁶ IU/m² s.c. three times weekly. At 24 months 38 patients remained in the study. The proportion of complete responders (CR) increased during the follow-up, and had at 24 months reached 58%, while 28% at the same time had a partial (PR) and 14% a minor response (MR). During the two years of continuous IFN treatment none of the 38 patients showed any signs of relapse. The response rate was similar between splenectomized (n = 15) and non-splenectomized (n = 23) patients, but the rise in platelets was much steeper and reached a significantly higher plateau in patients, who previously had undergone splenectomy. The IFN therapy was generally well tolerated, but when evaluated at 24 months at least some (mostly mild) toxicity was noted in 76% of the patients. None of the patients developed neutralizing antibodies to IFN.     

HDS: Establishment of a New Cell Line from a Hairy Cell Leukemia Patient with Resistance to Alpha-Interferon Therapy

A new cell line, designated “HDS”, was established in a suspension culture derived from the peripheral blood of a patient with hairy cell leukemia (HCL) who developed clinical resistance to alpha-interferon (aIFN) therapy. The patient exhibited a clinical picture characteristic of HCL, including splenomegaly, cytopenias, and tartrate-resistant acid phosphatase (TRAP)-positive “hairy” cells in blood and marrow. Chromosomal studies revealed that the cultured cells possess the chromosomal abnormality +12. Cytochemical and immunologic studies show the HDS cell line had the phenotype of a B-lymphocyte. HDS cells expressed the HLA-DR and CD19 surface antigens, but were negative for early B (CD10) and T (CD2, CD3) cell markers. The cells are also negative for other T-cell, granulocytic and monocytic markers and for typical HCL markers such as CD11c and CD22. However, the expression of these antigens was induced by in-vitro treatment of the cells with the differentiation-inducing agent tetradecanoyl phorbol acetate (TPA). Ultrastructural analyses of the cultured cells revealed a display of surface microvilli mixed with ruffles in a classical hairy cell pattern. It is therefore highly likely that the HDS cells represent HCL cells in an atypical stage of differentiation.     

Hairy Cell Leukemia, an Ultrastructural Study with Double Immunogold Labeling

Two cases of hairy cell leukemia were studied using a novel method of sequential double immunogold labeling for both scanning and transmission electron microscopy. Characteristic ribosome lamellae complexes were observed in one case only. The antigens expressed on the surface of hairy cells were those recognized by anti-CD 11c and anti-CD20 murine monoclonal antibodies. All hairy cells, in both cases, co-labeled for the corresponding antigens, as demonstrated by recognizing colloidal gold markers of distinct sizes (5 and 20 nm, or 15 and 40 nm) under SEM and TEM. The specificity of the double labeling method seems to be most satisfactory. Immuno-electron microscopy enables us to characterize the integrated ultrastructural and antigenic phenotype of hairy cells at the single cell level. This represents an unique analytical approach which may contribute significantly in further studies aimed at a better understanding of the pathogenesis of hairy cell leukemia.     

Prognostic Value of Baseline Serum Lactate Dehydrogenase Level in Patients With Hairy Cell Leukemia

BackgroundHairy cell leukemia is a rare B-cell lymphoproliferative disorder. It has an indolent course with relapse and remission periods. The aim of this study was to investigate the clinical characteristics and risk factors affecting the outcome of patients with hairy cell leukemia.Patients and MethodsThe retrospective data of 65 patients were evaluated according to initial hematologic and biochemical parameters, response rates, progression-free survival, and overall survival. Factors effecting response and survival rates were analyzed.ResultsThe median follow-up duration was 62.8 months (range, 5.7-229.3 months). The result of the analysis showed that the patients with relapse/progressive disease had higher lactate dehydrogenase (LDH) levels at the time of diagnosis than patients without relapse/progression (median [range], 243 [137-540] vs. 179 [99-334] U/L, P = .01). Patients with LDH ≥ 200.5 IU at the time of diagnosis were demonstrated to have a shorter progression-free survival than those with LDH < 200.5 IU (P = .010).ConclusionSerum LDH level is significantly associated with relapse/progression in hairy cell leukemia patients. Patients with higher LDH levels at diagnosis should be monitored closely even if they experience complete remission.     

Involvement of HLA Antigens, Interleukin 2 Receptor and B-Cell Growth Factor in Interferon Action in Hairy Cell Leukemia

Little is known about the mechanism(s) by which alpha-interferon (aIFN), when used as a biotherapeutic agent, suppresses the malignant cells and restores the normal phenotype of cells in patients with hairy cell leukemia (HCL). In previous studies using scanning electron microscopy (SEM) we found that alFN induced unique membrane alterations in target hairy cells in vitro. In addition, aIFN was shown to enhance the expression of HLA class II antigens on HCL cells, to induce the production of new proteins in such cells, and to lower the high levels of soluble IL-2 receptors in the serum of HCL patients. In the light of these results, and the fact that restoration of natural killer cell activity occurs in aIFN-treated patients well after the hematologic profile begins to improve, our studies have focused on the hypothesis that IFNs act directly on the target malignant cells, leading to the elimination of these cells either by inhibiting the proliferation of the malignant cells and/or triggering changes in the differentiation status of the malignant cells that lead to suppression (cytoconversion) of the malignant phenotype. We review the current hypotheses regarding alFN action on leukemic cells, with special reference to its potential antagonism with BCGF     

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--mediastinal involvement. A report of two cases and review of the literature

The clinical features of two patients with hairy cell leukemia involving the mediastinum are described. Both patients presented with acute chest pain 2-3 months prior to diagnosis being made. In one patient mediastinal disease was recorded only by computerized tomography of the thorax. There was good response of mediastinal disease to alpha-interferon in both patients, in spite of persisting bone marrow involvement with hairy cell leukemia.     

Autocrine and Paracrine Regulation of Neoplastic Cell Growth in Hairy Cell Leukemia

Hairy cell leukemia (HCL), a rare haematological disorder of B-cell origin, mainly presents with bone marrow infiltration, haematopoietic insufficiency, and splenomegaly. In some cases, osteolytic lesions can be observed. Many of these clinical features, especially haematopoietic insufficiency and osteolytic lesions are likely to be caused by soluble factors, such as cytokines. There is evidence that these factors are produced by the malignant hairy cells themselves, suggesting a paracrine pathway. The importance of autocrine as well as paracrine growth loops in growth regulation of HCL-cells is supported by a series of excellent studies, performed within the last few years. It could be clearly shown that cytokines are involved in this autocrine and paracrine regulatory process. The most important cytokines which should be mentioned in this respect are tumor necrosis factor alpha. (TNEa). Interleukin-2 (IL-2), Interleukin-4 (IL-4), Interleukin-6 (IL-6) and B-cell-growth factor (BCGF). The role of other factors such as viruses and oncogenes remains rather unclear. Nevertheless, recent data suggest that the c-fms, which encodes for the macrophage colony stimulating factor (M-CSF) may be involved in the pathophysiological control of HCL growth.     

Long-Term Outcomes of Hairy Cell Leukemia Treated With Purine Analogs: A Comparison With the General Population

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.     

Second Malignancy in Hairy Cell Leukaemia: No Evidence of Increased Incidence After Treatment with Interferon Alpha

The last decade has seen a dramatic improvement in prognosis of hairy cell leukaemia (HCL) but concern has emerged with regard to the incidence of second malgnancy. A recent report found an 18.8% incidence of second cancers and suggested a possible role for alpha-interferon (IFN) in their pathogenesis. We reviewed our larger series of 200 patients with HCL. We found second malignancies in 8 cases (4.0%), all but one of whom had received IFN. However, when compared to age- and sex-matched population data this represents no increase in relative risk of second cancer in patients with HCL and provides no evidence of a role for IFN in the pathogenesis of these second malignancies.