The diagnosis and treatment of hairy-cell leukaemia

The diagnosis of HCL is usually straightforward and is based on the identification of typical HCs in the blood and bone marrow. The suspected diagnosis is confirmed by a combination of TRAP cytochemistry, a distinctive immunophenotype and characteristic BM trephine appearances. Nucleoside treatment is highly effective in inducing prolonged remissions; relapsing patients can usually be successfully retreated with nucleoside. Monoclonal antibody therapy is a promising novel approach to the treatment of resistant disease.     

Alpha interferon treatment of patients with hairy-cell leukaemia

We have treated 10 patients with hairy-cell, or hairy-cell-like leukaemia, for more than 6 months, with alpha interferon 3 X 10(6) IV/day I.M. or subcutaneously. All patients were severely pancytopenic before treatment. 7 patients had a typical hairy-cell leukaemia, whereas 3 lacked hairy cells but had the characteristic bone-marrow infiltration. The peripheral blood counts improved in all patients during treatment and the lymphoid infiltration of the bone-marrow was shown to decrease. 1 patient obtained complete remission, 6 partial remission and 3 had a minor response. It is concluded that alpha interferon is effective in the treatment of patients suffering from hairy-cell leukaemia.     

Cladribine in the treatment of hairy-cell leukaemia

Cladribine, a purine nucleoside analogue, is a safe and effective treatment for patients with hairy-cell leukaemia. It is administered at a dose of 0.09 mg/kg daily as a continuous intravenous infusion over 7 days. This chapter discusses the history, rationale, chemical structure and mechanism of action of cladribine. The indications for therapy and guidelines for clinical usage are reviewed. The response of hairy-cell leukaemia to cladribine, the acute and chronic complications and the risk for second malignancies are summarized. The chapter concludes with a section on salvage therapy.     

Successful treatment of aplastic variant of hairy-cell leukaemia with deoxycoformycin

The case of a patient with the aplastic variant of hairy cell leukaemia, successfully treated with the drug Deoxycoformycin(Pentostatin), is presented. It is very important to be aware of this rare variant of a rare disease so that the right treatment can be offered.     

The variant form of hairy-cell leukaemia

Hairy-cell leukaemia-variant (HCL-variant) is a rare B-cell disorder which accounts for 10% of HCL cases. It affects elderly or middle-aged males. The main features are splenomegaly, lymphocytosis and cytopenias without monocytopenia. The circulating cells have a morphology intermediate between prolymphocytes and hairy cells. The immunophenotype shows a mature B-cell phenotype with expression of the B-cell antigens CD11c and CD103-but unlike typical HCL the cells are CD25- and HC2-negative. The histology of bone marrow and spleen shows a pattern of infiltration similar to that in HCL. There is no recurrent chromosomal abnormality but complex karyotypes and monoallelic p53 deletion by fluorescence in situ hybridization are common. Patients are resistant to alkylating agents and interferon-alpha (IFN-alpha) and only half achieve partial responses to pentostatin and/or cladribine. Splenectomy results in long-lasting partial responses in over two-thirds of the patients and is a good palliative treatment. Despite the lack of response to most therapies, the clinical course of HCL-variant is chronic. The median survival is 9 years and 42% of patients die of unrelated causes. Transformation to large cell is seen in 6% of patients. The inferior survival in HCL-variant compared with typical HCL cases may reflect the chemotherapy resistance.     

Recombinant interferon-alpha-2b treatment of hairy-cell leukaemia: experience with a low-dose schedule

50 patients with hairy cell leukaemia (HCL) were treated with recombinant interferon (IFN) alpha-2b 2.0 x 10(6) IU/m2 subcutaneously three times weekly to evaluate the efficacy of low-dose IFN therapy in inducing and maintaining remission of the disease. At the time of this report 48 patients, of whom 22 were splenectomized, had been treated for at least 3 months and were considered evaluable for response. The median observation time on IFN-alpha-2b was 11 months (range 3 to 20). 4 cases with atypical disease (spongy lymphoid myelofibrosis) were also included. All patients responded to IFN. After 3 months 11/48 patients (23%) had achieved a partial remission (PR) with normalization of peripheral blood values. After 6 months 27/43 patients (63%) had achieved a favourable response; complete remission (CR) was recorded in 4 and PR in 23 patients. The proportion of patients with favourable responses (CR + PR) increased with the duration of therapy and after 12 months of therapy 23/28 (82%) patients showed CR or PR, 9 patients (32%) being in CR. Splenectomized patients disclosed a trend towards a more rapid response. It is concluded that IFN-alpha-2b is a highly effective first-line therapy for HCL.     

Pathology of hairy-cell leukaemia

Hairy-cell leukaemia (HCL) is a low grade B-cell lymphoproliferative process that presents either with lymphocytosis or neutropenia/monocytopenia. It is a disease predominantly of bone marrow and spleen, although it can also involve other organs and sites. Recent advances including multi-parameter flow cytometry and the development of antibodies with high specificity for HCL have permitted precise distinction of typical HCL from other lymphoproliferative diseases that can morphologically mimic the appearance of HCL. Although there is a commonly held belief that HCL is associated with a significant increase in second neoplasms, several recent studies have not supported this notion. The development of extremely effective therapy for HCL results in a high incidence of complete remission. However, a significant percentage of patients continue to harbour minimal residual disease that can be revealed with immunohistochemical and flow cytometric studies.     

The place of myeloid growth factors in the treatment of hairy-cell leukaemia

A patient with hairy-cell leukaemia was treated with granulocyte colony stimulating factor lenograstim (Granocyte) 300 μg daily by subcutaneous injections. His pre-existing neutropenia remitted and the therapy was continued for a total of 4 months. When the therapy was discontinued the neutropenia returned. There was no evidence that the growth factor itself had any disease modifying activity.     

Toxoplasmosis in hairy-cell leukaemia

Toxoplasma serology was performed in 28 patients with hairy-cell leukaemia and was positive in eight patients (29%). In two patients (7%) reactivated toxoplasmosis was proven by either isolation of Toxoplasma gondii or by significant antibody titre rise with generation of specific IgM-antibodies. In four patients (14%), a clinical diagnosis of active toxoplasmosis was based on signs and symptoms, serologic tests, and response to specific treatment. The high proportion of patients in which active toxoplasmosis was proven or probable (six; 21%) may be related to the presence of severe monocytopenia. In patients with hairy-cell leukaemia developing fever of unknown origin and myositis, toxoplasma serology should be performed, particularly because treatment of active toxoplasmosis usually is successful.     

Chemotherapy of progressive hairy-cell leukaemia

5 patients with hairy-cell leukaemia were treated with chemotherapy. 3 of them received multiple courses of CHOP (cyclophosphamide-doxorubicin-vincristine-prednisolone); 1 patient received cyclophosphamide monotherapy for 6 months. The 5th patient developed a Mikulicz's syndrome after splenectomy and was initially treated with cyclophosphamide monotherapy, then received 1 course of CHOP, and finally 9 courses of intermediate-dose methotrexate. 1 complete remission (45 months+) and 3 partial remissions (75+, 68, 32+ months) were observed, while 1 patient had progressive disease. Our results indicate that chemotherapy may be a valuable alternative to alpha-interferon in the treatment of hairy-cell leukaemia progressing after splenectomy.     

Immunobiological treatments of hairy-cell leukaemia

Hairy cell leukaemia (HCL) is extremely responsive to purine analogue theropy developed during the early 1990s, but some patients have emerged with resistance to purine analogues. For these patients, as well as for those with primarily refractory HCL, new treatments are necessary. Several new therapeutic options have been developed for the salvage treatment of HCL. These include recombinant immunotoxins and unlabelled monoclonal antibodies (mAbs). Recombinant immunotoxins are chimeric proteins in which the Fv portion of a mAb is fused to a 38 kDa fragment of Pseudomonas exotoxin A. Two recombinant immunotoxins, BL22 and LMB-2, targeting CD22 and CD25, respectively, have demonstrated efficacy in patients with HCL resistant to purine analogues. BL22 was reported to induce complete remissions (CRs) in the majority of patients with cladribine-resistant HCL; its clinical efficacy and safety profile are currently being further defined. The unlabelled mAb rituximab has also been reported to induce responses in the majority of HCL patients treated, and several CRs have been observed.     

Phenotypic conversion of acute leukaemia from T-lymphoblastic to myeloblastic induced by therapy with 2''-deoxycoformycin

A 6-year-old boy with T-cell acute lymphoblastic leukaemia (ALL) in relapse was treated with the adenosine deaminase inhibitor, 2'-deoxycoformycin (DCF). Remarkably, his residual leukaemia underwent an abrupt phenotypic shift, coincident with a massive anti-leukaemic effect of DCF. Both at diagnosis and prior to therapy with DCF, blast cells had typical lymphoblastic morphology and T-cell characteristics (terminal transferase +, T-antigen +, Ia -, cALLa -, myeloperoxidase -, and high in adenosine deaminase content). After four courses of DCF by constant infusion, the blast cells were myeloid in appearance and reactivity to a variety of tests (terminal transferase -, myeloperoxidase +, Sudan black B +, esterase +, My-1 +). We hypothesize that DCF therapy created a selection pressure, blocking pathways of T-cell differentiation and proliferation, permitting the emergence of a newly dominant myeloid subclone of a multipotential leukaemic cell progenitor with the innate capacity for both T-lymphocytic and myeloid differentiation.     

Autoimmune disease in hairy-cell leukaemia: clinical syndromes and treatment

Thirty-seven patients with hairy-cell leukaemia were retrospectively reviewed for the presence of autoimmune disease. Ten definite and two probable cases were identified; these patients had positive serologies (immune complexes, antinuclear antibodies or rheumatoid factor) or biopsy-proven vasculitis. Clinically, two distinct syndromes were recognized. Six patients had joint symptoms, usually associated with nodular skin lesions; all responded promptly to therapy. Four additional cases had a more severe disease consisting of fevers, malaise, weight loss, skin rash, and variable visceral involvement; there was one death in this group. There appeared to be no relationship between presence of vasculitis and the severity or progression of the underlying malignant disease. We conclude that autoimmune disease is much more frequent in hairy-cell leukaemia than has previously been recognized, and that the outcome in these syndromes is usually good. Although the autoimmune syndrome generally responds promptly to splenectomy, corticosteroids, or cytotoxic therapy, failure to recognize this complication may lead to increased morbidity and occasional mortality.     

Interferon is effective in hairy-cell leukaemia

Seventeen patients with hairy-cell leukaemia (HCL) and peripheral cytopenias were given human lymphoblastoid interferon (Wellferon), 3 megaunits daily or 6 megaunits on alternate days intramuscularly, for 4-24 weeks. Twelve of the patients had undergone splenectomy, three had no palpable spleen and had therefore not been offered surgery, and two patients with substantial splenomegaly were given interferon (IFN) as treatment of first choice. Toxic effects were minor except in one patient who experienced a severe form of somnolence syndrome. In all patients hairy cells (HCs) were cleared from the blood and platelet and Hb levels improved in 2-14 weeks. Neutrophils were improved in 14/17 of the patients. In the two patients with splenomegaly, the spleen became impalpable after 5-8 weeks therapy, and haematological improvement occurred at 12-14 weeks. HC infiltration of the marrow was reduced in all patients, but was complete (less than 5%) in only two, both of whom had impalpable spleens. Immunological surface-marker studies confirmed that light-chain-restricted B cells disappeared from the blood in parallel with the clearance of morphological HCs. There was no evidence of HC maturation and no increase in phenotypic NK cells. T cells were moderately reduced and the relatively greater reduction of Leu 2a+ suppressor cells resulted in increased Leu 3a+/2a+ helper/suppressor ratios in 11/17 of the patients. Early experience in the six patients who have stopped IFN suggests that, after an initial further increase in Hb and neutrophil levels, HCs gradually return with slow deterioration of haematological parameters. Interferon is now the treatment of choice for patients becoming cytopenic post-splenectomy or for patients without splenomegaly. IFN is effective first-line therapy in patients with splenomegaly, but further work is needed to establish whether the agent should replace splenectomy in such patients. Some form of maintenance or re-treatment therapy will probably be necessary.     

Clinical differential diagnosis of hairy-cell leukaemia

The data on hairy-cell leukaemia (HCL) and resembling disorders in the literature and in our patients were analyzed to determine which clinical features and laboratory data are important for the recognition of HCL in an early stage. In pancytopenic patients the typical pattern of bone marrow involvement in HCL and the low number of monocytes in the peripheral blood appear to be essential for the differential diagnosis. In patients with many neoplastic cells in the peripheral blood, the presence of neutropenia and monocytopenia as well as tartrate-resistant acid phosphatase activity in the neoplastic cells, appears to be crucial for early diagnosis. Thus, the clinical features and routine laboratory data alone are sufficient in the majority of cases to suggest the diagnosis HCL. The monocytopenia proved to be most helpful in this respect. Nevertheless, in all patients, and certainly in patients presenting with atypical features, a bone marrow biopsy is indispensable for the correct diagnosis.     

Monoclonal antibody-defined T-cell subsets in hairy-cell leukaemia

In 17 tests in 14 patients with hairy-cell leukaemia (HCL), peripheral blood Leu 2a+ and 3a+ suppressor and helper cells were present in normal mean percentage (3a+ 63 +/- 15%, normal 64 +/- 8%; 2a+ 39 +/- 16%, normal 34 +/- 8%), absolute (3a+ 0.8 +/- 0.4 x 10(9)/1, normal 0.6-1.4 x 10(9)/1; 2a+ 0.5 +/- 0.4 x 10(9)/1, normal 0.2-0.6 x 10(9)/1), and relative (3a+/2a+) (2.2 +/- 1.3, normal 1.9 +/- 0.7) numbers. In all the 9 untreated patients, 3a+ helper cells were normal or increased in percentage numbers, while 2a+ suppressor cells were normal or slightly reduced. It is suggested that these data explain, at least in part, the lack of immuneparesis of HCL as compared with chronic lymphocytic leukaemia (CLL) which is consistently associated with immuneparesis and an excess of Leu 2a+ suppressor cells. In individual splenectomised patients, some variations in Leu 2a+ and 3a+ numbers were observed, and it is suggested that the spleen, known to be important in the natural history of HCL, may have an influence on peripheral T-cell subsets. Although HCL is clearly shown to differ from CLL and myeloma regarding T-cell subset numbers, the fundamental mechanism underlying this difference remains unknown.     

Clinical manifestations and infectious complications of hairy-cell leukaemia

Hairy-cell leukaemia is an indolent lymphoproliferative malignancy characterized by infiltration of the bone marrow, liver, spleen, and occasionally lymph nodes with a malignant B cell with hair-like cytoplasmic projections. This involvement leads to splenomegaly with secondary consumption of red cells, platelets and neutrophils as well as other complications of an enlarged spleen, including infarction-or-rarely rupture. The common haematological complications of anaemia, neutropenia and thrombocytopenia are due not only to the enlarged spleen but probably also to hairy cells in the bone marrow inducing cytokine-mediated suppression of haematopoiesis. Hepatic involvement, although frequent, only occasionally leads to liver dysfunction. Infections are a major cause of morbidity and mortality in patients with hairy-cell leukaemia, presumably owing to neutropenia and monocytopenia in these patients. The infections seen may be due to unusual pathogens, including Mycobacterium and Listeria.Autoimmune disease, including polyarthitis and vasculitis, occurs frequently and does not correlate with the severity of the disease. Other rare complications include bone involvement, meningitis and ascites. A wide range of secondary malignancies have been reported in patients with hairy-cell leukaemia, but it is still unclear whether the incidence is increased and whether they are related to the disease or treatment.     

Paraproteinaemia plus osteolytic lesions in typical hairy-cell leukaemia

Most cases of hairy-cell leukaemia (HCL) involve proliferations of neoplastic B lymphocytes. In rare cases, M-proteins or osteolytic lesions have been documented in patients with HCL. In this study two patients with typical HCL are reported in whom both paraproteinaemia and osteolytic lesions of the femoral neck developed. In one of the patients the production of the M-protein by hairy cells could be established. In the other patient, at autopsy no signs of myeloma were found. The hairy cells from inside the osteolytic lesion had the same immunological phenotype as hairy cells from the peripheral blood, the spleen, and other parts of the bone marrow. These cases once more confirm the B-cell nature of many cases of HCL, and show that hairy cells can have functional capacities usually attributed to much more mature B lymphocytes, i.e. plasma cells.     

New rearrangement pattern after treatment of hairy-cell leukemia with 2-chlorodeoxyadenosine

Leukemic hairy cells are clonally proliferating B-lymphoid cells with clonal rearrangements of genes for immunoglobulin chains. We describe a patient with a new hairy-cell clone after treatment with 2-chlorodeoxyadenosine (2-CdA). In this patient, a single course of 2-CdA resulted in good partial remission of hairy-cell leukemia, but Southern blot analysis of bone marrow biopsies and polymerase chain reaction using seminested amplifications with consensus primers revealed a new rearranged band 4 months after therapy with 2-CdA. Four years after therapy, the patient is in complete clinical remission and both bands disappeared during follow-up. The new rearranged band might have been related to prior treatment of hairy-cell leukemia with 2-CdA.