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Resume Un patient âge de 59 ans, porteur d’une leucemie a tricholeucocytes, se presente a l’officine dans le cadre du renouvellement d’un interferon alpha. Ce medicament est prescrit sur une ordonnance de medicaments ou de produits et prestations d’exception dont le pharmacien doit observer les regles d’archivage.

The adenosine deaminase inhibitor 2'-deoxycoformycin (DCF) has been used to treat 40 patients with hairy cell leukaemia (HCL) who have been followed up for a minimum of 6 months. 21 patients had previously undergone splenectomy. 33 had received treatment with alpha-interferon (IFN), half of whom had relapsed and the remainder had either been partially treated due to intolerance or had an incomplete response. Deoxycoformycin was administered by slow intravenous injection at a dose of 4 mg/m(2) weekly for 4 consecutive weeks and then 2-weekly for 4 doses followed by 4-weekly injections until a complete remission was achieved. No maintenance therapy was given. The overall response rate was 97yi, with 82% complete remission (CR) and 15% partial remission (PR). CR have lasted from 3+ to 30+ months (median 12 +) with no relapses recorded so far. Only one evaluable patient, suffering from a variant form of HCL, failed to respond to DCF, whilst two other HCL-variant cases who had been resistant to alpha-IFN have achieved a PR and are still on treatment. DCF was generally well tolerated, the major toxicity being related to cytopenia and associated infection. Four patients developed severe infections, one of whom died of septicaemia before it was possible to evaluate the response to DCF. A group of 12 patients who had received alpha-IFN immediately prior to treatment with DCF and had obtained clinical and haematological benefit had fewer infections with DCF than the group who had either not received IFN immediately before or who had failed to respond to it. In view of the infections associated with DCF, we would now recommend initial therapy for HCL patients with alpha-IFN for 2-4 months to obtain clinical and haematological improvement, followed by DCF given 2-weekly, to eradicate residual disease. This approach may achieve a higher proportion of sustained CR with a short treatment time and minimal toxicity.

Keywords: chronic lymphocytic leukaemia ; hairy cell leukaemia; IGH ; BRAF V600E; quantitative PCR

SUMMARY Hairy cell leukaemia (HCL) has distinct clinical, morphological and immunophenotypic features with no recurrent cytogenetic or molecular abnormalities reported until the recent description of the BRAF V600E mutation in patients with classical HCL. The incidence of this mutation was sought in 27 patients with either classical HCL or HCL variant by an allele-specific PCR approach and findings related to morphology, cytochemistry and immunophenotype. A high degree of correlation was noted between the presence of BRAF V600E and established diagnostic criteria in 26/27 patients with HCL/HCL variant. Detection of the BRAF V600E mutation is therefore a useful adjunct in the differential diagnosis of HCL and HCL variant and highlights the value of a multifaceted approach to the diagnosis of this malignancy.

The British Committee for Standards in Haematology first produced guidelines for the diagnosis and management of hairy cell leukaemia and hairy cell leukaemia variant in 2000. This revision updates those guidelines and covers the areas of diagnosis, treatment and assessment of response to therapy.

Little is known about the cytogenetic features and molecular mechanisms behind hairy cell leukaemia (HCL), despite the advances in diagnosis and treatment. Therefore, we used high-resolution genome-wide array-based comparative genomic hybridisation (array-CGH) and multiplex ligation-dependent probe amplification (MLPA) to characterise copy number alterations (CNAs) in DNA from 13 cases of HCL. We also summarise CNAs and cytogenetic features in 109 HCL cases comprising our 13 cases and 96 cases from the literature. Genomic array-CGH revealed imbalances in two out of 13 cases in addition to previously described copy number variants (CNVs) found in healthy individuals. In one case, a 700 kb deletion of 20q11.22 was detected encompassing ten characterised genes, among them the TP53INP2, DNCL2A and ITCH genes. In the second case, trisomy 5, and a deletion of 5p15.2 encompassing a non-characterised gene AY328033 was found. Altogether only 20/81 (25%) of all cases studied by CGH or gene dose array revealed CNAs. The most common recurrent deletions and breakpoints were 14q22-32 (33%), 6q25 (16%), 2p12 (10%), 22q11 (10%), 17p11-13 (10%), 7q32-36 (9%), 18q11-13 (7%), 1q32-44 (6%), 8p22-23 (6%) and 7q11 (6%). Trisomy 5 occurred in 15%. In addition, several other recurrent breakpoints were identified. Although a number of genomic imbalances were identified in the HCL samples, the genome appeared remarkably stable.

Hairy cell leukaemia affecting primarily the spleen is a very rare feature of this disease at presentation. Splenectomy in such cases would seem to provide a cure. We report a case of primary splenic hairy cell leukaemia in which clinical and haematological remission were achieved after splenectomy, and we review the literature.

In all 11 patients with hairy-cell leukaemia (HCL) tested, a high percentage of peripheral blood and splenic (3 cases) hairy cells (HCs) reacted with 2 B-cell-specific monoclonal antibodies (FMC1 and FMC7), but failed to stain with 5 monocyte/macrophage-specific (FMC17, UCHM1, SM1, SMø and OKM1) and with 4 T-cell-specific antibodies (UCHT1, Leu1, 2a and 3a). The data provide further evidence in support of the B-cell nature of the HCs of HCL.

Hairy-cell leukaemia (leukaemic reticuloendotheliosis) is a well-defined clinical entity. Most of the recent reports are almost entirely concerned with the pathological and functional aspects of the disease. In the present retrospective study the clinical features and laboratory data of 12 patients were analyzed together with a series of 123 adequately clinically documented cases from the literature. The Hb level and the sex of the patient proved to be the only parameters having some prognostic value for the survival time after diagnosis. The effect of splenectomy was assessed in two comparable groups of 24 splenectomized and 51 non-splenectomized patients. The operation seemed to be beneficial, but after 2 years the difference was not significant(.05 less than P less than .10). Analysis of subgroups showed that splenectomy was definitely beneficial in women, in patients with a Hb level over 8.0 g/dl or a platelet level above 50 X 10(9)/1, in patients with leucocytes below 3 X 10(9/1, , and also in patients with hepatomegaly (P less than .05 in all cases). These findings suggest that splenectomy is beneficial in cases where anaemia and thrombocytopenia are not very severe; in severe cytopenia the operation does not increase the life expectancy.

8 patients with clinical and haematological features suggestive of hairy cell leukaemia are described. During their initial illness morphologic and cytochemical evidence of hairy cell leukaemia were lacking in all but 2 patients. A common highly characteristic histopathologic finding was reticulin fibrosis in the bone marrow, present in all patients at first presentation. The term spongy lymphoid myelofibrosis is proposed for such cases, which may represent a variant type of hairy cell leukaemia or an early stage of the disease.

3 cases of hairy cell leukaemia were studied with ultrastructural immunocytochemical methods using an anti human Ig HRPO-Fab fragment. Ig were detected on the cell surface, in the perinuclear cisterna and endoplasmic reticulum of hairy cells. Evidence of Ig in these sites demonstrates a B-lymphoid differentiation of the leukaemic cells.

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 times 109/1, normal 0.6-1.4 times 109/1; 2a+ 0.5 + 0.4 times 109/1, normal 0.2-0.6 times 109/1), 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.

Hairy cell leukaemia (HCL) is a rare, clonal, chronic lymphoproliferative disorder commonly seen in males in the middle years of life. Pancytopaenia with moderate to massive splenomegaly is the most common clinical presentation. Diagnosis is made on detecting the lymphocytes with abundant cytoplasm which spread into hair-like processes on peripheral blood and bone marrow smears, thus giving the name, “hairy cell leukaemia”. The bone marrow aspirate is frequently a dry tap. The trephine biopsy has the characteristic features of a honey comb appearance and flow cytometry is typically CD103, CD25, FMC7, CD11c, gamma or kappa light chain positive with the classic B lymphocyte markers CD19, CD20, CD79a. Purine analogues followed by granulocyte-colony stimulating factor (G-CSF) to manage the febrile neutropenia is currently the treatment of choice. A 10 year disease free survival is recorded with these management strategies. Experimental use of anti CD20 and CD22 has also shown promising results in the treatment of this disease. We report four cases of HCL diagnosed in a span of two years at the Royal Hospital, Muscat, Oman.

Summary. 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.

Summary. We describe four patients with mixed lympho- and myeloproliferative disorders. One patient had hairy cell leukaemia and acute myelomonocytic leukaemia, another lymphocytic lymphoma in leukaemic phase and chronic myelomonocytic leukaemia and the third patient had chronic lymphocytic leukaemia and polycythaemia rubra vera; none of these patients had received any prior therapy, and in two the diagnosis of the two malignancies was simultaneous. The fourth patient developed acute monocytic leukaemia 4 years after the diagnosis of chronic lymphocytic leukaemia after only 2 weeks of therapy with chlorambucil. The number of cases with concurrent or sequential but spontaneous occurrence of lympho- and myeloproliferative disorders reported so far is now 38. The questions relating to the pathogenesis of the two malignancies are discussed.

Bei 27 Patienten mit Haarzell-Leukamie konnte der Krankheitsverlauf uber maximal 97 Monate beobachtet werden. Eine Splenektomie war bei 17 Patienten durchgefuhrt worden; sie besserte den hamatologischen Status zumeist eindrucksvoll. Von den splenektomierten Patienten leben zehn inzwischen 8 bis 88 Monate nach der Operation. Bei funf von ihnen konnte ein Krankheitsprogres, der sich entweder als isolierte Leukozytose, als Verschlechterung des gesamten hamatologischen Status oder als intraabdominelles Lymphomwachstum auserte, durch Leukapherese, niedrig dosierte Langzeitbehandlung mit Chlorambucil, Gabe von Doxorubicin (Adriamycin) bzw. einer Doxorubicin enthaltenden Zytostatikakombination sowie abdominelle Lokal- oder Ganzbestrahlung erfolgreich behandelt werden. The course of hairy cell leukaemia was observed in 27 patients for a maximum of 97 months. Splenectomy had been performed in 17 patients and improved the haematological situation impressively in most cases. Amongst patients with splenectomy ten are alive with 8 to 88 months postoperatively. In five of them disease manifesting as isolated leucocytosis, deterioration of the overall haematological situation or as intraabdominal lymphomatous growth could be treated successfully. Treatment consisted of leucapheresis, low-dose long-term therapy with chlorambucil, administration of doxorubicin (adriamycin) or a combination of cytostatics containing doxorubicin as well as abdominal localized or overall irradiation.

Hairy cell leukaemia (HCL) is an orphan subtype of leukaemia which constitutes less than 2% of all leukaemia's, with an incidence of less than 1 per 100,000 persons per annum. Median age at presentation is 55 years and it is 3–4 times more frequent in males. It is also more frequently encountered in whites and less in Asians, Africans and Arabs. The epidemiologic data are multi-factorial and influenced by ethnicity and geographical factors. Other reported associations relate to some environmental exposures and possible occupational factors. Smoking appears to have an inverse correlation with the development of hairy cell leukaemia, while farming and exposure to pesticides, petroleum products, diesel and ionizing radiation have also been reported to be associated with an increased risk. National and international collaborative efforts are needed in order to undertake more extensive studies involving larger patient cohorts, aiming to determine the role of occupational and environmental risk factors in the development of this rare form of chronic leukaemia.

Hairy-cell leukaemia (HCL) has long been recognized as distinct from other chronic B-cell malignancies, but several questions remain unanswered. What is the HCL cell of origin? Why does HCL lack the hallmarks of most mature B-cell tumours (for example, chromosomal translocations and consistent lymph node involvement) and show unique features like 'hairy' morphology and bone-marrow fibrosis? Gene-expression profiling and other studies have recently provided new insights into HCL biology and have the potential to affect clinical practice.

The WHO classification of lymphoma represents the latest in a series of schemes to subdivide lymphoma into clinically significant subtypes. This classification recognizes the important contribution of clinical, immunophenotypic and molecular data to the recognition of separate entities. Classifications, by their very nature, are dynamic processes with more detailed information constantly emerging about the characteristics of each lymphoma type and their relationship to clinical outcomes, particularly with the advent of newer therapies. In this review we shall not give an overview of all the different small B-cell lymphomas but will try to highlight some areas that may be less familiar to diagnostic histopathologists or that are considered to be controversial or confusing.

This review outlines an approach to the diagnosis of lymphoid infiltrates in the bone marrow trephine. It concentrates on the commonly encountered disorders, but also includes some less common conditions. Emphasis is placed on the practicalities of tackling a biopsy with this diagnostic problem, embracing the range of differential diagnoses, the morphological and immunohistochemical features and an appreciation of the limitations of the marrow trephine as a diagnostic medium.

To further characterise the genetic background of the two closely related B-lymphocytic malignancies hairy cell leukaemia (HCL), and splenic marginal zone lymphoma (SMZL) we have identified characteristic copy number imbalances by comparative genomic hybridisation (CGH). Based on these findings, areas of special interest were fine mapped, and relevant probes constructed for use in interphase-fluorescence in situ hybridisation (FISH) investigations. Thus, using the CGH data from 52 HCL and 61 SMZL patients, we identified the characteristic profiles of copy number imbalances for both diseases. These were a gain of 5q13-31 (19%) and loss of 7q22-q35 (6%) for HCL, and gain of 3q25 (28%), loss of 7q31 (16%), and gain of 12q15 (16%) for SMZL. A partial loss of 7q unusual for low-malignant B-cell diseases was found to be common to the two diseases. This loss was therefore fine mapped with BAC/PAC clones. Fine mapping revealed that in SMZL the minimal lost region covers 11.4 Mb spanning from 7q31.33 to 7q33 located between sequence tagged site (STS)-markers SHGC-3275 and D7S725. This area was distinct from the commonly deleted 7q region of myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML). A FISH probe specific for the 7q region was constructed. Using this probe in an interphase-FISH investigation we showed the minimal lost 7q-region of HCL and SMZL to be one and the same. In one HCL case, this investigation furthermore showed the extent of the deleted region to be below the detection limit of CGH, whereas interphase-FISH screening of 36 chronic lymphocytic leukaemia (CLL) cases showed no deletion of the 7q area. In conclusion, we have identified characteristic profiles of copy number imbalances in HCL and SMZL and fine mapped the minimal extent of a commonly lost 7q area of special interest. We hypothesise that this region may contain (a) gene(s) important for the pathology of HCL and SMZL.

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.