Background

Outline

Epidemiology
Pathogenesis
Laboratory/Radiologic/Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/Immunohistochemistry/Electron Microscopy
Differential Diagnosis
Prognosis and Treatment
Commonly Used Terms
Internet Links

EPIDEMIOLOGIC ASSOCIATIONS	CHARACTERIZATION
Epidemiology of hairy cell leukemia in Los Angeles County. Bernstein L, Newton P, Ross RK. Department of Preventive Medicine, University of Southern California School of Medicine, Los Angeles 90033.	Cancer Res 1990 Jun 15;50(12):3605-9 Abstract quote The descriptive epidemiological characteristics of hairy cell leukemia (HCL), a rare chronic lymphoproliferative disorder, were examined by using incidence data collected from 1972 to 1987 by the Cancer Surveillance Program, the population-based cancer registry for Los Angeles County. During the study period, 208 incident cases of histologically confirmed HCL were diagnosed. HCL comprised 2% of all leukemias diagnosed in Los Angeles County during the study period. HCL risk was concentrated in white males; there were few black and Asian patients for analysis. Overall, the age-adjusted incidence rate of HCL for men (2.9/million population) was 4.8 times greater than that for women (0.6/million population). Using data from all cancer patients diagnosed during the study period, Jewish men had significantly greater risk of HCL than Protestant men (odds ratio (OR) = 3.0, P less than 0.0001); there was no significant variation in risk of HCL by religion for women. For men, the OR was significantly elevated for professional and technical workers (OR = 2.1, P = 0.001); within this category of occupations, risk was significantly elevated for engineers (OR = 3.3, P less than 0.0001) and university faculty and school teachers (OR = 4.0, P = 0.0008). HCL patients were more than twice as likely to have multiple primary cancer diagnoses as other cancer patients. Since the majority of the other primary cancer diagnoses occurred prior to (greater than 1 year) or concurrent with (less than or equal to 1 year) the HCL diagnosis, this greater frequency of multiple primaries in HCL patients may be due to impaired immune function.
Hairy cell leukaemia: descriptive epidemiology and a case-control study. Staines A, Cartwright RA. Leukaemia Research Fund Centre for Clinical Epidemiology, University of Leeds.	Br J Haematol 1993 Dec;85(4):714-7 Abstract quote The descriptive epidemiology of hairy cell leukaemia is reported from a specialized register of haematological malignancies covering approximately one-third of England and Wales. The overall incidence of hairy cell leukaemia at 2.9 per million persons per year is similar to that recorded in America. There is a marked male preponderance (4.0 compared with 1.7 per million per year for females). A case-control study on hairy cell leukaemia was conducted in the Yorkshire and Trent Regional Health Authority areas. 50 cases and 95 controls were identified, and interviewed using a structured questionnaire. Previous results on the aetiology of hairy cell leukaemia were not supported by this study, with the exception of an association between hairy cell leukaemia and exposure to organic solvents, petrochemicals and related products.
Hairy cell leukemia is infrequent in Mexico and has a geographic distribution. Ruiz-Arguelles GJ, Cantu-Rodriquez OG, Gomez-Almaguer D, Cortes-Franco J, Gongora-Biachi RA, Pizzuto J, Rodriguez-Carrillo J, Romero-Garcia F, Torre-Lopez E, Apreza-Molina MG, Mercado-Diaz L. Centro de Hematologia y Medicina interna de Puebla, Mexico.	Am J Hematol 1996 Aug;52(4):316-8 Abstract quote Considering that the prevalence of some hematologic malignancies may have a geographic distribution that could be related with its etiology, a group of 2,387 patients with acute leukemia (1,968 adults and 419 children) was studied along a 5-year period in six different locations within Mexico. Twenty-seven patients (16 males and 11 females) with hairy cell leukemia (HCL) were identified. The adjusted overall proportion of HCL, after excluding data from centers reporting only adults, was 1.12% of all leukemia cases; this figure is lower than that reported in the United States or England. The proportion of adult leukemic patients with HCL was significantly higher in the northern region of the country-where there are more people devoted to farming and agricultural activities-as compared with the central or southeastern regions (3.07 vs. 1.03% vs. 0%; P < 0.05); possible explanations for these differences are briefly discussed.
Hairy cell leukemia in Hong Kong Chinese: a 12-year retrospective survey. Au WY, Kwong YL, Ma SK, Mak YK, Wong KF, Lei KI, Ng MH, Chan JC, Lin SY, Lee KK, Liang R. Department of Medicine, Queen Mary Hospital, Hong Kong.	Hematol Oncol 2000 Dec;18(4):155-159 Abstract quote BACKGROUND: Hairy cell leukemia (HCL) is a unique chronic B cell lymphoproliferative disease (B-LPD), with distinct clinical and pathological features, and excellent treatment response to 2-chlorodeoxyadenosine (2-CDA) and pentostatin. There have been few reports of HCL from oriental countries. PATIENTS AND METHODS: A retrospective survey of HCL in six major hematology units in Hong Kong over a 12-year period. RESULTS: There were 18 cases of HCL identified. Most patients presented with fever, splenomegaly and monocytopenia. Lymphadenopathy was present in three patients, and open biopsy revealed tuberculosis infection in two cases. Seven cases received interferon and 12 cases received 2-CDA. Four patients died from bronchogenic carcinoma, cerebral vascular accident, fulminant hepatitis B virus reactivation and malignant melanoma. The remaining 14 patients are in clinical remission at a median of 6 years' follow-up; two are also surviving from second malignancies (thyroid papillary carcinoma and renal cell carcinoma). CONCLUSIONS: Parallel to the low incidence of B-LPD in Chinese, the incidence of HCL (0.035/100000 population per year) is much lower than in Western series. Other clinical features such as male dominance, clinical presentation, response to 2-CDA treatment, and association with second malignancy are similar to Western reports. However, two common complications in the Chinese population are the fulminant reactivation of hepatitis B infection and disseminated tuberculosis infection.

 

DISEASE ASSOCIATIONS	CHARACTERIZATION
Second malignancies in patients with hairy cell leukemia in british columbia: a 20-year experience. Au WY, Klasa RJ, Gallagher R, Le N, Gascoyne RD, Connors JM. Division of Medical Oncology, British Columbia Cancer Agency and the University of British Columbia, Vancouver, Canada.	Blood 1998 Aug 15;92(4):1160-4 Abstract quote The purpose of this study was to compare the relative risk of second malignancies in a cohort of patients with hairy cell leukemia (HCL) against the normal population. Potential effects of type of treatment and duration of follow-up and the site distribution of cancer were also examined. Between 1976 and 1996, 117 patients were diagnosed with HCL in British Columbia who were referred to the British Columbia Cancer Agency (BCCA) for treatment. All additional malignancies were traced using a provincial population-based cancer registry and follow-up records from the BCCA. There were 90 men and 27 women. Median age at diagnosis was 53 years. The median follow-up time was 68 months. Twenty-three patients underwent primary splenectomy, 65 received interferon alpha, 24 deoxycoformycin, and 67 cladribine (2-chlorodeoxyadenosine). Thirty-six patients had an additional malignancy (30.7%) with a total of 44 tumors. Six patients (5.1%) had two or more malignancies. Twenty-five patients had malignancies diagnosed after HCL (21.3%), three concurrent with HCL (2.6%), and 12 preceding HCL (10.2%). Second tumors (n = 28 tumors) occurred at a median of 40 months after HCL (range, 3 to 167). The relative rate (RR) of second malignancy among men and women was 2.91 (P < .001) and 1.65 (P = .23), respectively, compared with age and secular trend-matched controls. There were eight prostate cancers, nine nonmelanoma skin cancers, two lung cancers, and four gastrointestinal adenocarcinomas. The RR (90% confidence interval [CI]) in the various treatment groups were: splenectomy (RR = 0.21 to 3.81), purine analogues (RR = 0.60 to 5.69), interferon then purine analogues (RR = 1.60 to 4.31), interferon alone (RR = 1. 57 to 8.40). Cancer risk peaked at 2 years after HCL (RR = 4.13) and fell steadily afterwards, reaching a RR of 1.82 at 6 years. Twenty patients died, six due to HCL, 10 due to second malignancies, and four of unrelated causes. HCL patients appear to be inherently prone to malignancies. This appears to be more related to HCL tumor burden than to genetic predisposition or treatment effect. RR tends to fall with time after effective treatment. However, close monitoring for and vigorous prevention of cancer in HCL patients is advisable.
Multiple myeloma and hairy cell leukemia: a rare association or coincidence? Saif MW, Greenberg BR. NCI, National Naval Medical Center, Bethesda, MD 20892, USA.	Leuk Lymphoma 2001 Sep-Oct;42(5):1043-8 Abstract quote Hairy cell leukemia (HCL) and multiple myeloma (MM) are well-defined entities with distinctive clinical and pathological features. Although most cases of HCL and MM fit their classic descriptions, more recent studies have revealed that their clinical and morphological boundaries may not only overlap but a transformation of HCL into MM could also occur. We report another case of HCL followed by the development of MM after 9 years. He also developed hemarthrosis of his right ankle at the time of diagnosis of MM. PCR analysis of DNA extracted from the bone marrow aspirate was negative for the presence of a monoclonally rearranged immunoglobulin heavy chain gene. Immunophenoytping revealed no evidence of HCL. There are several possible explanations for the development of MM in HCL patients, such as the coexistence of separate disease entities or different clinical and morphologic phases of a single disease entity. An accurate diagnosis of HCL or MM is critical because of differences in their treatment. Hemarthrosis in this patient may also have been the first manifestation of MM, a feature of MM which has rarely been reported.

 

PATHOGENESIS	CHARACTERIZATION
p53 mutations in hairy cell leukemia. Konig EA, Kusser WC, Day C, Porzsolt F, Glickman BW, Messer G, Schmid M, de Chatel R, Marcsek ZL, Demeter J. Department of Molecular Genetics, Semmelweis University, School of Medicine, Budapest, Hungary.	Leukemia 2000 Apr;14(4):706-11 Abstract quote We have studied the frequency of p53 mutations in genomic DNA extracted from peripheral blood or the spleen of 61 patients with hairy cell leukemia using PCR-SSCP and automated cycle sequencing. We identified exon 5-8 mutations in 17 cases, corresponding to a frequency of 28%. In four cases, mutations were localized in exon 5; one patient with atypical HCL had a mutation in exon 6 at the 3' boundary; five cases showed mutations in exon 7, while exon 8 was found to be mutated in seven cases. The mutations found could be divided into three major categories: structural (n=9), inactivating (n= 6), and neutral (n= 2) mutations. None of the three transitions found occurred at CpG dinucleotides. The rate of p53 mutations found in this large cohort of HCL patients is unexpectedly high as in other non-Hodgkin lymphomas p53 mutations predict for poor treatment outcome. The character of the mutations we have found is entirely different from that described in other hematologic malignancies.
Tumor cells of hairy cell leukemia express multiple clonally related immunoglobulin isotypes via RNA splicing. Forconi F, Sahota SS, Raspadori D, Mockridge CI, Lauria F, Stevenson FK. Molecular Immunology Group, Tenovus Laboratory, Southampton University Hospitals, Southampton, United Kingdom.	Blood 2001 Aug 15;98(4):1174-81 Abstract quote Hairy cell leukemia (HCL) derives from a mature B cell and expresses markers associated with activation. Analysis of immunoglobulin variable region genes has revealed somatic mutation in most cases, consistent with an origin from a cell that has encountered the germinal center. One unusual feature of hairy cells (HCs) is the frequent expression of multiple immunoglobulin heavy chain isotypes, with dominance of immunoglobulin (Ig)--G3, but only a single light chain type. The origin and clonal relationship of these isotype variants have been unclear. In order to probe the isotype switching status of HCL, RNA transcripts of V(H)DJ(H)--constant region sequences from 5 cases of typical HCL, all expressing multiple surface immunoglobulin isotypes, were analyzed. Tumor V(H)DJ(H)--C(mu) sequences were identified and found to be somatically mutated (range, 1.4% to 6.5%), with a low level of intraclonal heterogeneity. Additional immunoglobulin isotypes of identical V(H)DJ(H) sequence were also identified, including IgD (5 of 5), IgG3 (5 of 5), IgG1 (3 of 5), IgG2 (2 of 5), IgA1 (4 of 5), and IgA2 (1 of 5). Derivation of multiple isotypes from individual cells was demonstrated by analyzing transcripts in single sorted cells from one patient, with evidence for coexistence of isotype variants in 10 of 10 cells. These findings indicate that clonally related multiple isotypes coexist in single HCs, with individual isotypes presumably generated via RNA splicing. Production of IgG3 appears common, but IgG1, IgG2, IgA1, and IgA2 also arise, indicating a continuing influence of a directed process on the tumor clone. These HCs appear to be arrested at the point of isotype switch, where RNA processing may precede deletional recombination.

 

LABORATORY/RADIOLOGIC/ OTHER TESTS	CHARACTERIZATION
RADIOLOGIC
LABORATORY MARKERS
The diagnosis of hairy cell leukemia can be established by flow cytometric analysis of peripheral blood, even in patients with low levels of circulating malignant cells. Cornfield DB, Mitchell Nelson DM, Rimsza LM, Moller-Patti D, Braylan RC. Department of Pathology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida 32610, USA.	Am J Hematol 2001 Aug;67(4):223-6 Abstract quote The diagnosis of hairy cell leukemia (HCL) has traditionally been based on microscopic means. Immunophenotypic analysis of peripheral blood by flow cytometry is not widely recognized as a method for diagnosing HCL, perhaps due to the expectation of low yield of neoplastic cells in patients who are characteristically leukopenic. The abnormal coexpression of CD103, CD25, and intense CD11c and CD20 on monotypic, slightly large B-lymphocytes has previously been shown to be highly characteristic of HCL. We wished to determine if this pattern was valuable in the diagnosis of HCL in leukopenic patients with low levels of neoplastic cells in the peripheral blood. The abnormal immunophenotype above was observed in 25 peripheral blood specimens from patients with unexplained cytopenias or suspected lymphoproliferative processes. Ten of the 25 blood samples exhibited this abnormal phenotype in less than 5% of circulating leukocytes (ranging from <1% to 4%). All 10 patients had other manifestations of HCL, including cytopenias (mean white blood cell count, 1.8 x 10(3)/mm(3); hemoglobin, 11.0 gm/dl; platelets, 74 x 10(3)/mm(3)), splenomegaly, and typical bone marrow morphologic changes. Eight of the 10 patients achieved an excellent response to one course of 2-CDA, with significant improvement of cytopenias (mean white blood cell count: 5.3 x 10(3)/mm(3); hemoglobin: 14.4 g/dl; platelets: 181 x 10(3)/mm(3)) and regression of splenomegaly. One patient had a partial response to alpha interferon and a subsequent complete response to 2-CDA, and one died during treatment. In conclusion, flow cytometric immunophenotyping of peripheral blood is capable of detecting low levels of circulating malignant cells in HCL, even in leukopenic patients. As such, it can be a very useful, non-invasive tool in the diagnosis of this disorder.

 

GROSS APPEARANCE/ CLINICAL VARIANTS	CHARACTERIZATION
GENERAL
VARIANTS
Relapse in hairy cell leukemia due to isolated nodular skin infiltration. Yetgin S, Olcay L, Yenicesu I, Oner AF, Caglar M.	Pediatr Hematol Oncol 2001 Sep;18(6):415-7 Abstract quote Leukemic skin infiltration is quite uncommon in certain types of leukemia. Here, a child with hairy cell leukemia who developed isolated skin infiltration during remission is reported. The failure to diagnose the leukemic infiltration until the nodule reached a diameter of 2 cm is emphasized.

 

HISTOLOGICAL TYPES	CHARACTERIZATION
GENERAL
VARIANTS
Bone marrow morphology during alpha-interferon treatment in hairy cell leukemia. Hassan IB, Sundstrom C, Hagberg H. Department of Pathology, University Hospital, Uppsala, Sweden.	Eur J Haematol 1989 Aug;43(2):120-6 Abstract quote 14 patients with HCL were started on alpha-interferon (IFN) treatment. Bone marrow changes were followed in trephine biopsies every 3rd month. Differential counting was performed according to the point counting method and fiber content was evaluated. At the start of treatment all patients had 80% or more of tumor cells in the bone marrow. The reduction of granulopoiesis was more pronounced than for erythropoiesis. During treatment cellularity decreased in 6/13 patients already after 3 months; later, cellularity was normalized in most patients. Only 1 patient showed a complete remission. 12/14 patients showed a significant but slow reduction of tumor cells. Also, between 12 and 18 months an improvement was seen in some patients. The megakaryocytes improved rapidly and the erythropoiesis was normalized before the granulopoiesis. Only 1 patient did not show a bone marrow response. 5/14 patients showed a reduction of bone marrow fibers, first seen after 6 months of treatment. IFN was discontinued in 9/14 patients. 7 of these relapsed during the observation period (18 months).
Atypical hairy cell leukemia. Wu ML, Kwaan HC, Goolsby CL. Department of Pathology, Northwestern University Medical School, Chicago, IL, USA.	Arch Pathol Lab Med 2000 Nov;124(11):1710-3 Abstract quote The morphologic differential diagnosis of mature B-cell neoplasms with cytoplasmic projections includes splenic lymphoma with villous lymphocytes and hairy cell leukemia. Although the classification of hairy cell leukemia is not universally recognized, 3 variants have been described, namely, classic, variant, and Japanese variant, each of which has different clinical and immunophenotypic features. Classic hairy cell leukemia is virtually always CD11c(+), CD25(+), and CD103(+). Variant and Japanese variant hairy cell leukemias are usually CD11c(+), always CD25(-), and occasionally CD103(+). Each variant is characteristically CD10(-). We present a case of hairy cell leukemia with a unique immunoprofile in that the cells were CD10(+), CD25(+), and CD103(-), and we review the criteria helpful in differentiating "hairy" B-cell neoplasms. This case emphasizes the variability of hairy cell leukemia and the need to correlate all clinical and pathologic data in reaching a diagnosis.

 

SPECIAL STAINS/IMMUNOPEROXIDASE/ OTHER	CHARACTERIZATION
SPECIAL STAINS
IMMUNOPEROXIDASE
Immunohistochemical detection of cyclin D1 using optimized conditions is highly specific for mantle cell lymphoma and hairy cell leukemia. Miranda RN, Briggs RC, Kinney MC, Veno PA, Hammer RD, Cousar JB. Department of Pathology, Truman Medical Center and University of Missouri-Kansas City, 64108, USA.	Mod Pathol 2000 Dec;13(12):1308-14 Abstract quote Mantle cell lymphoma (MCL) is more aggressive when compared with other lymphomas composed of small, mature B lymphocytes. Cyclin D1 is overexpressed in MCL as a result of the translocation t(11;14)(q13;q32). Cyclin D1 immunohistochemistry in fixed, paraffin-embedded tissue contributes to the precise and reproducible diagnosis of MCL without the requirement of fresh tissue. However, its use in bone marrow biopsies is not well established. In addition, increased levels of cyclin D1 mRNA have been found in hairy cell leukemia but have not consistently been detected by immunohistochemistry. We used a polyclonal antibody and heat-induced antigen retrieval conditions to evaluate 73 fixed, paraffin-embedded bone marrow, spleen, and lymph node specimens with small B-cell infiltrates, obtained from 55 patients. Cyclin D1 was overexpressed in 13/13 specimens of MCL (usually strong, diffuse reactivity in most tumor cells) and in 14/14 specimens of hairy cell leukemia (usually weak, in a subpopulation of tumor cells). No reactivity was detected in five cases of B-chronic lymphocytic leukemia; five cases of splenic marginal zone lymphoma; six cases of nodal marginal zone cell lymphoma; two cases of gastric marginal zone cell lymphoma; or ten benign lymphoid infiltrates in bone marrow, spleen, or lymph nodes. In summary, although the total number of studied cases is small and a larger series of cases may be required to confirm our data, we present optimized immunohistochemical conditions for cyclin D1 in fixed, paraffin-embedded tissue that can be useful in distinguishing MCL and hairy cell leukemia from other small B-cell neoplasms and reactive lymphoid infiltrates.

 

DIFFERENTIAL DIAGNOSIS	KEY DIFFERENTIATING FEATURES
Chronic lymphocytic leukemia
Splenic lymphoma with villous lymphocytes

 

PROGNOSIS AND TREATMENT	CHARACTERIZATION
PROGNOSTIC FACTORS
Prognostic variables in hairy cell leukemia after splenectomy as initial therapy. Ratain MJ, Vardiman JW, Barker CM, Golomb HM. Department of Medicine, University of Chicago, Pritzker School of Medicine, Illinois.	Cancer 1988 Dec 1;62(11):2420-4 Abstract quote Splenectomy has been used as initial therapy in hairy cell leukemia (HCL) for many years and usually causes rapid improvement in peripheral blood counts. However, most patients eventually require further therapy. We have analyzed the case histories of 194 patients with HCL who had splenectomy as initial therapy. The median time to failure (second therapy or death) was 18.8 months. Univariate analysis of prognostic variables demonstrated that age, hemoglobin level, platelet count, bone marrow cellularity, bone marrow hairy cells, and hairy cell index (HCI) were statistically significant predictors of failure-free survival (FFS). However, only the bone marrow cellularity and platelet count were significant independent prognostic variables by Cox analysis. The patients were divided into the following three subsets by prognosis after splenectomy: (1) low risk of failure (cellularity less than 85% and platelet count greater than or equal to 60,000/microliters), (2) intermediate risk (cellularity less than 85% and platelet count less than 60,000/microliters), and (3) high risk (cellularity greater than or equal to 85%). The median FFS for each of these subsets was 56.5 months, 11.7 months, and 5.4 months, respectively. The median overall survival after splenectomy has not been reached with follow-up of up to 22 years. Patients diagnosed since 1982 have a better overall prognosis than those diagnosed earlier, with 4-year survivals of 88% and 68%, respectively (P less than 0.01). We conclude that splenectomy should continue to be the standard initial therapy in HCL. However, patients with bone marrow cellularity of 85% or greater have a short duration of response to splenectomy, and thus, may be considered for initial systemic therapy.
Long-term results in hairy cell leukemia treated by splenectomy. Chrobak L, Podzimek K, Kerekes Z, Spacek J, Voglova J. Department of Clinical Hematology, Charles University, Faculty of Medicine, Hradec Kralove, Czech Republic.	Neoplasma 1993;40(2):133-6 Abstract quote Splenectomy as a therapeutic modality has been evaluated in a group of 24 consecutive patients. Before and after splenectomy only supportive therapy was applied with the exception of two patients in whom corticosteroids were administered because of vasculitis. Radiation therapy was applied in one patient because of massive retroperitoneal lymphadenopathy. One patient received Leukeran shortly before the fatal outcome because his response to splenectomy was poor. Out of 24 patients 14 patients died. The median survival for the partial responders and non-responders was 6 months only. Patients with a complete response did not reach median survival yet and 8 of them (33% of the whole group) have been alive for more than 9 years, one patient for more than 20 years. Two distinct groups of patients with respect to the outcome of splenectomy can be distinguished: The first group is characterized by a rapid fatal outcome mostly within two years after splenectomy, the second group has a more favorable course with a plateau and only occasional deaths after the fourth year.
Hairy cell leukemia: a clinical review based on 725 cases of the Italian Cooperative Group (ICGHCL). Italian Cooperative Group for Hairy Cell Leukemia. Frassoldati A, Lamparelli T, Federico M, Annino L, Capnist G, Pagnucco G, Dini E, Resegotti L, Damasio EE, Silingardi V. Cattedra di Oncologia Medica, Universita di Modena, Italy.	Leuk Lymphoma 1994 Apr;13(3-4):307-16 Abstract quote The Italian Registry for hairy cell leukemia (HCL) has recorded 725 patients with HCL diagnosed over 25 years. We analysed this large series of patients with the aim of providing an evaluation of changes in clinical presentation, impact of initial therapy and modifications in prognostic factors over the period of two decades. Over time, a progressive down-staging of the disease at the onset, along with a reduction of patients with severe anemia and marked splenomegaly, has been observed. A second malignancy was found in 3.7% of patients, mostly detected several years after the onset of HCL. A striking improvement of survival rates has been observed, from 58.9% survival at five years for patients diagnosed before 1985 to 87.5% at five years for patients diagnosed after 1985 (p < 0.0001). Before 1985 hemoglobin alone provided prognostic information, whereas after 1985, clinical stage and the number of leukocytes correlated better with patient outcome. Survivals at 5 and 10 years were 34.4% and 29.6% respectively for untreated patients, 58.8% and 44.1% for patients receiving chemotherapy, steroids or other drugs, 64.1% and 56.1% for splenectomized patients and 88.9% (at 5 years) for alpha interferon (IFN)-treated patients (p < 0.0001). Our findings suggest that IFN has improved the prognosis of HCL, and that it must be considered a good initial treatment for patients with HCL
The degree of bone marrow infiltration in patients with hairy cell leukemia treated with splenectomy compatible with long-term hematological remission. Zak P, Chrobak L, Dedic K. Faculty of Medicine and University Hospital in Hradec Kralove, Czech Republic.	Neoplasma 2001;48(1):72-5 Abstract quote To determine the degree of bone marrow infiltration with hairy cells which is compatible with long-term hematological remission in patients treated with splenectomy, we have investigated 7 patients surviving in hematological remission 61 to 255 months (median 184 months) after splenectomy. As hematological remission has been considered absence of hairy cells (HCs) in the peripheral blood, normalization of peripheral blood cell counts (hemoglobin 120 g/l, white cell count 4.0 x 10(9)/l, absolute granulocyte count 1.5 x 10(9)/l, platelet count 100 x 10(9)/l) and absence of lymfadenopathy and any other activity of the disease. For detection of HCs a very sensitive method of immunostaining with monoclonal antibody DBA.44 in our own modification has been used. Low values of sIL-2R which is considered to be a non invasive marker of tumor burden and activity in HCL were in agreement with the opinion that the bone marrow was the only locality of tumor involvement in splenectomized patients. Infiltration up to 20% with HCs (range 4% to 20%, median 10%) was found to be compatible with long-term hematological remission and long-term overall survival. Patient (No 1) with 30% infiltration of bone marrow with HCs, still normal peripheral blood cell counts, but a very high level of sIL-2R represents extraordinary finding which has been discussed in details.
TREATMENT
Alpha interferon for induction of remission in hairy-cell leukemia. Quesada JR, Reuben J, Manning JT, Hersh EM, Gutterman JU.	N Engl J Med 1984 Jan 5;310(1):15-8 Abstract quote We treated seven patients who had progressive hairy-cell leukemia with daily doses of 3 million units of partially pure alpha (leukocyte) interferon by the intramuscular route. Three patients had a complete remission, and four had a partial remission, according to strict criteria for a response. After treatment, bone-marrow aspirates showed an absence of leukemia cells in three patients and 5 per cent or fewer in three others. Normalization of subnormal peripheral-blood values occurred in six of six patients with anemia, in seven of seven with granulocytopenia, and in four of four with thrombocytopenia. Remissions have been maintained for over 6 to over 10 months. Alpha interferon appears to be highly effective in patients with hairy-cell leukemia.
Splenectomy vs. alpha interferon: a randomized study in patients with previously untreated hairy cell leukemia. Smalley RV, Connors J, Tuttle RL, Anderson S, Robinson W, Whisnant JK. University of Wisconsin, Madison.	Am J Hematol 1992 Sep;41(1):13-8 Abstract quote Twenty patients with previously untreated hairy cell leukemia were randomized to undergo either splenectomy or to receive interferon alfa-N1, a highly purified natural alpha interferon, as primary therapy. A response in the peripheral blood elements to a hemoglobin greater than 110 gm/l, a granulocyte count greater than 1 x 10(9)/l, and a platelet count greater than 100 x 10(9)/l (Catovsky criteria) was noted in all ten patients receiving alpha interferon but in only three of the patients undergoing splenectomy (P = less than .01). Median time to response was longer in the ten interferon patients (153 days) than in the three splenectomy responders (20 days). Median time to treatment failure was significantly greater in the alpha interferon patients (greater than 18 months) than in the splenectomy patients (less than 1 month). Survival was no different since patients relapsing following splenectomy subsequently responded to alpha interferon. A significant decrease in leukemic bone marrow infiltration was observed in seven of ten patients receiving alpha interferon and in none of the patients undergoing splenectomy. Side effects, primarily infections, were more frequent in patients receiving interferon. Alpha interferon is preferable to splenectomy as initial treatment for hairy cell leukemia.
Five years follow-up after 2-chloro deoxyadenosine treatment in thirty patients with hairy cell leukemia: evaluation of minimal residual disease and CD4+ lymphocytopenia after treatment. Bastie JN, Cazals-Hatem D, Daniel MT, D'Agay MF, Rabian C, Glaisner S, Noel-Walter MP, Dabout D, Flandrin G, Dombret H, Poisson D, Degos L, Castaigne S. Service d'hematologie, Centre hospitalier de Versailles, Le Chesnay, France	Leuk Lymphoma 1999 Nov;35(5-6):555-65 Abstract quote Between March 1992 and August 1993, thirty patients with hairy cell leukemia (HCL) were treated in a single institution with 2-chlorodeoxyadenosine (2-CdA) for one course (N=27) or two courses at six month interval (N=3). Sixteen patients were previously untreated, 14 had been treated with alpha interferon (alpha IFN) (N=5), alpha IFN and splenectomy (N=8) and splenectomy, alpha IFN and Deoxycoformycin (N=1). Overall results in 29 evaluable patients were: 25 CR (86%), 3 PR (10%), one failure. The three PR patients relapsed after 18, 24 months and five years. Two were retreated successfully. Two CR patients relapsed after five years. Careful clinical survey, sequential bone marrow biopsies (BMB) with DBA44 immunostaining for assessment of response and detection of residual disease and serially evaluation of lymphocyte subsets counts were performed. Results of bone marrow biopsies study show 1) a progressive reduction in hairy cell infiltration during the first six months after therapy and not after that indicating that the best moment for the evaluation of response may be the sixth month, 2) the persistence of a very small number of DBA44+ cells (80% of BMB). There was a correlation between the presence of > 5% DBA44 positive cells on 6th month BMB and relapse. 60% had an absolute CD4+ lymphocyte count less than 0.2 10(9)/l at least on one examination after treatment. CD4+ lymphocyte level persisted less than baseline level in 8/18 patients tested after four and/or five years. Lymphopenia was less marked in splenectomized patients: 7/7 splenectomized patients tested have recovered a CD4+ lymphocyte count equal to pretherapy level compared to 3/11 non splenectomized patients (p: 0.004). Three opportunistic infections were observed early (first 6 months) after 2CdA therapy: pneumocystis pneumonia, retinitis due to toxoplasma in the patient who failed and legionella pneumonia in a patient retreated after relapse. Two patients developed a second carcinoma 6 and 12 months after therapy. Five patients died, three from a cause unrelated to HCL, one from HCL and one from infection while in second CR. At five years, overall survival is 83% and progression free survival is 66%. Our study shows 1) long-lasting response in the majority of patients after 2-CdA, 2) a correlation between persistent minimal residual disease detected with DBA44 immunostaining and occurrence of relapse and 3) a profound and persistent CD4+ lymphopenia more marked in non splenectomized patients.
Pentostatin in T-cell malignancies--a phase II trial of the EORTC. Leukemia Cooperative Group. Ho AD, Suciu S, Stryckmans P, De Cataldo F, Willemze R, Thaler J, Peetermans M, Dohner H, Solbu G, Dardenne M, Zittoun R. Department of Medicine V, University of Heidelberg, Germany.	Ann Oncol 1999 Dec;10(12):1493-8 Abstract quote PURPOSE: Within this phase II EORTC trial, we have investigated the safety and efficacy of pentostatin in lymphoid malignancies. We have previously reported the results in T- and B-cell prolymphocytic leukemia, B-cell chronic lymphocytic leukemia (B-CLL) and hairy cell leukemia. This report focuses on the outcome in T-cell malignancies: T-CLL, Sezary syndrome (Sezary), mycosis fungoides (MF) and T-zone lymphoma (TZL). PATIENTS AND METHODS: Of the 92 patients with these diagnoses enrolled, 76 were evaluable for response and toxicity, i.e., 25 of 28 with T-CLL, 21 of 26 with Sezary, 22 of 26 with MF, and 8 of 12 with TZL. All patients had progressive and advanced disease. Pentostatin was administered at a dosage of 4 mg/m2 every week for the first 3 weeks, then 4 mg/m2 every 14 days for another 6 weeks, followed by maintenance therapy of 4 mg/m2 monthly for a maximum of 6 months. RESULTS: Response rates (complete and partial responses) in patients with Sezary (n = 22) or MF (n = 21) were 33% and 23%, respectively, and in patients with T-CLL (n = 21) or TZL (n = 8) 8% and 25%, respectively. Sixteen (21%) patients died during the first ten weeks of treatment: twelve of progressive disease, two of infectious complications with progressive disease, one of myocard infarction and one of renal failure related to administration of i.v. contrast. Major toxicity (grade 3-4) included infection in 11% of patients, nausea/vomiting in 4%, diarrhea in 3%. Hematologic toxicity was mild to non-existent. CONCLUSIONS: We conclude that pentostatin is active in Sezary and MF but showed marginal activity in T-CLL or TZL. Toxicities are mild to moderate at the dose schedule administered. Due to its relatively specific lympholytic effect and its favorable toxicity spectrum, pentostatin might be especially useful for the palliative treatment of T-cell malignancies.
Deoxycoformycin in the treatment of patients with hairy cell leukemia: results of a Spanish collaborative study of 80 patients. Rafel M, Cervantes F, Beltran JM, Zuazu F, Hernandez Nieto L, Rayon C, Garcia Talavera J, Montserrat E. Department of Hematology, Hospital Clinic, IDIBAPS, University of Barcelona, Spain.	Cancer 2000 Jan 15;88(2):352-7 Abstract quote BACKGROUND: Deoxycoformycin (DCF) has been reported to produce high response rates in patients with hairy cell leukemia (HCL), but to the authors' knowledge data regarding experience with such therapy in a large HCL series are scarce. METHODS: Between 1988-1997, DCF (4 mg/m(2)/day, every 2 weeks) was administered to 80 HCL patients in 32 Spanish institutions. In 35 of 78 evaluable patients DCF was the first-line therapy; the remaining 43 patients had received other therapies. Pretreatment variables influencing the achievement of complete remission (CR) and event free survival were identified by multivariate analyses. RESULTS: The median number of cycles administered was 7 (range, 1-22 cycles). A CR was obtained in 56 patients (72%) and a partial remission was obtained in 13 patients, for an overall response rate of 88%. In the multivariate analysis previous splenectomy and an Eastern Cooperative Oncology Group (ECOG) performance status > or = 2 were the parameters adversely influencing CR achievement. With a median follow-up of 31.2 months (range, 0.4-126.5 months), disease recurrence was observed in 11 of the CR patients, 5 of whom showed a further response to DCF. An ECOG performance status > or = 2 was the only pretreatment variable associated with a shorter event free survival. Seven patients died, four during the treatment period. The actuarial median event free survival was 46 months (95% confidence interval, 22.5-69.5 months), and 48.7% of the 56 patients who achieved a CR were expected to be alive and disease free at 5 years. Hematologic toxicity (marked neutropenia [22 cases], anemia [6 cases], and thrombocytopenia [1 case]) was the main side effect, followed by nausea and emesis (5 cases); 14 patients required hospitalization. CONCLUSIONS: The results of the current study confirm the effectiveness and acceptable toxicity of DCF in the treatment of patients with HCL.
Long-term follow-up of hairy cell leukemia patients treated with 2-chlorodeoxyadenosine. Zinzani PL, Magagnoli M, Bendandi M, Tani M, Stefoni V, Cellini C, Poggi S, Piccioli M, Pileri S, Tura S. Istituto di Ematologia e Oncologia Medica "Seragnoli", Policlinico S.Orsola, Via Massarenti 9, 40138 Bologna, Italy	Haematologica 2000 Sep;85(9):922-5 Abstract quote BACKGROUND AND OBJECTIVES: The management of patients with hairy cell leukemia (HCL) has evolved significantly over the past two decades. In fact, both 2'-deoxycoformycin (DCF) and 2-chlorodeoxyadenosine (2-CdA) induce complete response (CR) in the majority of the patients with HCL. However, fewer data exist on the long-term follow-up of patients who have undergone the characteristically brief exposure to 2-CdA therapy. Thus, it is important to evaluate such long-term outcome data in order to increase understanding of the efficacy of this agent in the management of HCL. DESIGN AND METHODS: We reviewed the long-term follow-up data of 23 HCL patients pretreated with a-interferon and then treated with 2-CdA administered as a single continuous IV infusion for 7 days at the dose of 0.1 mg/kg/day in our institute between January 1991 and February 1992. RESULTS: Of 23 patients, 19 (83%) achieved a CR and 4 (17%) a partial response (PR), with an overall response rate of 100%. After a median follow-up of 102 months (range: 96-108), there have been 9 (39%) relapses. In the PR subset 100% of patients relapsed within the first 45 months of follow-up. In the group of patients who obtained a CR, 26% relapsed; all these relapses occurred between 54 and 86 months. Overall, the median time to relapse was 54 months (range: 16-86). All relapsed patients were re-treated with 2-CdA at the dose of 0.15 mg/kg/day for 5 days in a 2-hour infusion, and 67% and 22% then obtained CR or PR, respectively. The median duration of this second response was 48 months (range: 22-80). All but one of these patients are still maintaining the second response to 2-CdA. The 9-year overall and the relapse-free survivals are 91% and 70%, respectively. INTERPRETATION AND CONCLUSIONS: In HCL patients a single dose of 2-CdA induces a long-term CR with a 9-year survival > 90%. Over 50% of patients appear to be clinically cured by this procedure, but the lack of a long-term plateau in the relapse-free survival curve means caution on this point is still warranted.
Long-term outcome following treatment of hairy cell leukemia with pentostatin (Nipent): a National Cancer Institute of Canada study. Johnston JB, Eisenhauer E, Wainman N, Corbett WE, Zaentz SD, Daeninck PJ. Manitoba Cancer Treatment and Research Foundation, Winnipeg, Canada.	Semin Oncol 2000 Apr;27(2 Suppl 5):32-6 Abstract quote We have previously demonstrated that pentostatin (Nipent; SuperGen, San Ramon, CA) is highly effective in the treatment of hairy cell leukemia and report here the long-term outcome of this study. Pentostatin was administered intravenously in cycles of 4 mg/m2 weekly x 3 repeated every 8 weeks. Patients who achieved a complete remission (CR) received two further cycles for consolidation. Of 28 evaluable patients, 25 achieved a CR and three a partial remission. Twenty-three patients are alive at a median follow-up duration of 118 months (range, 55 to 133 months). Of the 25 patients who achieved a CR, 14 (56%) remain in CR at a median of 119 months (range, 109 to 133 months) from the time of CR. Nine additional patients relapsed at a median time of 49 months (range, 15 to 122 months). Only three of the relapsed patients have required treatment: two patients who received cladribine achieved CRs; the third received interferon-alpha and died from hairy cell leukemia. The three patients in partial remission continue to have normal blood counts at 58, 105, and 120 months. Five patients have developed a second malignancy: one mycosis fungoides and four solid tumors. Three patients died from the second malignancies. There were no treatment-related deaths due to toxicity or opportunistic infection. Pentostatin is a highly effective agent for hairy cell leukemia and produces prolonged remissions in the majority of patients.
Alpha-interferon as induction and maintenance therapy in hairy cell leukemia: a long-term follow-up analysis. Damasio EE, Clavio M, Masoudi B, Isaza A, Spriano M, Rossi E, Casciaro S, Cerri R, Risso M, Nati S, Siccardi M, Truini M, Gobbi M. Department of Haematology, Azienda Ospedale S Martino e Cliniche Universitaire Convenzionate, Genova, Italy.	Eur J Haematol 2000 Jan;64(1):47-52 Abstract quote Although in recent years the use of purine analogues has increased the percentage of long-term complete response the effect on overall survival of patients with hairy cell leukemia (HCL) is not yet clear. This study aimed to evaluate the long-term outcome (mean follow up of 92 months) of 64 patients receiving IFN as first-line therapy. IFN was well tolerated and effective. The overall response rate was 91% (PR 65%, CR 13%, GPR 13%). Forty-one patients (63%) received IFN 3 MU/ wk as maintenance therapy. The 10-yr projected survival rate of responding patients (CR and GPR 100%; PR 95%) and non-responders (SD, PD 80%) clearly shows that type of response does not affect survival. Patients receiving IFN maintenance had a statistically higher PFS than those who did not (p <0.01). This study shows that IFN is still one of the standard therapies for this disease, that achieving CR has no primary relevance for the control of the disease, and that good utilization of therapeutic resources may assure HCL patients a survival rate comparable to that of a normal, healthy population.
Efficacy of the anti-CD22 recombinant immunotoxin BL22 in chemotherapy-resistant hairy-cell leukemia. Kreitman RJ, Wilson WH, Bergeron K, Raggio M, Stetler-Stevenson M, FitzGerald DJ, Pastan I. Laboratory of Molecular Biology, National Cancer Institute, Bethesda, MD 20892, USA.	N Engl J Med 2001 Jul 26;345(4):241-7 Abstract quote BACKGROUND: Hairy-cell leukemia that is resistant to treatment with purine analogues, including cladribine, has a poor prognosis. We tested the safety and efficacy of an immunotoxin directed against a surface antigen that is strongly expressed by leukemic hairy cells. METHODS: RFB4(dsFv)-PE38 (BL22), a recombinant immunotoxin containing an anti-CD22 variable domain (Fv) fused to truncated pseudomonas exotoxin, was administered in a dose-escalation trial by intravenous infusion every other day for a total of three doses. RESULTS: Of 16 patients who were resistant to cladribine, 11 had a complete remission and 2 had a partial remission with BL22. The three patients who did not have a response received low doses of BL22 or had preexisting toxin-neutralizing antibodies. Of the 11 patients in complete remission, 2 had minimal residual disease in the bone marrow or blood. During a median follow-up of 16 months (range, 10 to 23), 3 of the 11 patients who had a complete response relapsed and were retreated; all of these patients had a second complete remission. In 2 of the 16 patients, a serious but completely reversible hemolytic-uremic syndrome developed during the second cycle of treatment with BL22. Common toxic effects included transient hypoalbuminemia and elevated aminotransferase levels. CONCLUSIONS: BL22 can induce complete remissions in patients with hairy-cell leukemia that is resistant to treatment with purine analogues.

Sternberg S. Diagnostic Surgical Pathology. Third Edition. Lipincott Williams and Wilkins 1999.

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