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Alcohol can interfere with the function of each of these components, thereby causing impotence, infertility, and reduced male secondary sexual characteristics.1 In the testes, alcohol can adversely affect the Leydig cells, which produce and secrete the hormone testosterone. Studies found that heavy alcohol consumption results in reduced testosterone levels in the blood. Alcohol also impairs the function of the testicular Sertoli cells that play an important role in sperm maturation. In the pituitary gland, alcohol can decrease the production, release, and/or activity of two hormones with critical reproductive functions, luteinizing hormone and follicle-stimulating hormone. Finally, alcohol can interfere with hormone production in the hypothalamus.




Hairy cell leukemia (HCL) is an uncommon chronic B cell lymphoproliferative disorder. Its name is derived from the prominent irregular cytoplasmic projections of the malignant cells [1,2].



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Many patients with hairy cell leukemia (HCL) are asymptomatic and can be observed for months and occasionally years after the diagnosis is established before requiring treatment. There is no clear advantage to early therapy. As the goal of treatment is alleviation of symptoms and cytopenias. There is a theoretic risk of infection in such patients, occasionally with opportunistic organisms if asymptomatic patients are treated.

Indications for treatment include (see 'Indications for treatment' above):

●Significant cytopenias; typical peripheral blood counts that warrant treatment include an absolute neutrophil count <1000/microL with repeated infections, symptomatic anemia with a hemoglobin concentration <11.0 g/dL, or bleeding due to a platelet count <100,000/microL

●Symptomatic splenomegaly (common) or adenopathy (uncommon)

●Constitutional symptoms (eg, fever, night sweats, fatigue, weight loss)

Hairy cell leukaemia (HCL) was first described in 1959. Median survival was then 4 years. The purine analogues, introduced in the 1980s, transformed this prognosis. We reviewed data retrospectively from 233 patients, treated with pentostatin (n = 188) or cladribine (n = 45), to investigate the current long-term outlook. Median follow-up was 16 years. There were no significant differences in outcome between the two agents. Overall, the complete response (CR) rate was 80% and median relapse-free survival was 16 years. After relapse (n = 79) or non-response (n = 5), 26 patients received pentostatin and 58 cladribine; 69% achieved CR and median relapse-free survival was 11 years. After third-line therapy (n = 23), 50% achieved CR and median relapse-free survival was 6.5 years. However, CRs were equally durable, whether after first, second or third-line therapy. Complete responders and those with both haemoglobin>100 g/l and platelet count>100 x 10(9)/l before treatment had the longest relapse-free survival (P<0.0001). Patients still in CR at 5 years had only a 25% risk of relapse by 15 years. Outcomes for patients with recurrent disease improved with the monoclonal antibody rituximab, combined with either purine analogue. Overall only eight patients died of HCL-related causes. Patients achieving a CR can expect a normal lifespan.1

Patients with HCL may be at increased risk of developing infections.


INITIAL TREATMENT — A number of treatment options are available for patients with symptomatic hairy cell leukemia (HCL), including splenectomy, interferon, and cytotoxic chemotherapy [10]. If therapy is indicated, the purine analogs cladribine and pentostatin have replaced splenectomy and interferon as initial agents of choice. Because of ease of administration, a single cycle of cladribine may be the preferred choice (see 'Choice of purine analog' below).

Purine analogs — The purine analogs pentostatin (2'-deoxycoformycin, 2'-DCF) and cladribine (2-chlorodeoxyadenosine, 2-CdA) are naturally targeted to lymphocytes and are cytotoxic to both resting and dividing cells. Both drugs induce durable complete remissions (CRs) in the overwhelming majority of patients with HCL. Equally high rates of durable CRs are achieved with these two agents in both untreated and previously treated patients [9,11], and those with large or minimal tumor burdens. For these reasons, these agents have emerged as the treatments of choice for all patients with HCL [5,12]. There are no large series of patients with HCL treated with the other major purine analog fludarabine. Initial reports suggest that purine analogs may be safely combined with monoclonal antibodies, such as rituximab, resulting in high response rates [13]. (See 'Anti-CD20 antibody (rituximab)' below.)

Cladribine — Cladribine (2-CdA) is our preferred initial therapy for most patients with previously untreated HCL. Unlike pentostatin, cladribine is resistant to deamination by ADA because of its chlorinated purine ring structure [14]. Instead, cladribine is phosphorylated to its lymphocytotoxic form by deoxycytidine kinase (DCK). Lymphocytes have high levels of DCK and the resultant phosphorylated cladribine, 2-chlorodeoxyadenosine triphosphate, is cytotoxic to both dividing and non-dividing lymphocytes [15]. In dividing cells, cladribine impairs DNA synthesis by inhibiting ribonucleotide reductase and competing with dATP for incorporation into DNA. The net effect is lymphotoxicity analogous to that seen in ADA-deficient children [16].

The standard regimen is a seven-day continuous intravenous infusion program (0.10 mg/kg per day) [17-23]. Alternative routes and schedules of administration of cladribine have included five-day two-hour infusion at a dose of 0.14 mg/kg per day [24-26], weekly two-hour infusion [27,28], subcutaneous administration [24,25,29], and oral administration [24,25,30].

Support for the use of cladribine comes from case series and retrospective analyses that have demonstrated complete response in the vast majority of patients. As examples:

Cladribine was first reported to be effective for HCL in 1990 [17]. Twelve patients were treated with a single cycle of cladribine (0.1 mg/kg per day by continuous infusion for seven days), and a complete pathologic remission was obtained in 11 within eight weeks of treatment. None of the patients had relapsed after a median follow-up of 16 months. No patients experienced the usual toxicities of cytotoxic chemotherapy (ie, nausea, emesis, alopecia, or other constitutional symptoms).

●The largest series of cladribine therapy in HCL provided outcome data on 861 evaluable patients through the group C protocol mechanism from the National Cancer Institute [23]. The complete remission rate was 50 percent, considerably less than in other reports; four-year disease-free survival was 84 percent. There was no central pathology review for these subjects, who may have had other indolent lymphoproliferative disorders.

●The largest single institution experience with cladribine (0.1 mg/kg per day for seven days by continuous intravenous infusion) consisted of 349 evaluable patients with previously treated or untreated disease [20,21]. The complete and partial remission rates were 91 and 7 percent, respectively. At four years, the overall survival was 96 percent; the relapse rates for patients achieving CR and PR were 16 and 54 percent, respectively. Of the 53 patients in first relapse after a cladribine-induced remission, retreatment with cladribine yielded CR and PR rates of 62 and 26 percent, respectively.

●Extended follow-up from the same institution of 88 young adults (≤40 years) treated with cladribine and followed for a median of 251 months reported an 88 percent CR rate with a median duration of CR of 57 months (range 7 to 246 months) [31]. A partial response was achieved in 12 percent with a median duration of response of 20 months (range 7 to 108 months). There was great variation in the length of response and, except for the degree of response (partial versus complete), the study could not identify clinical or pathologic features that were associated with longer or shorter duration of response. Data regarding minimal residual disease after treatment were not available. Of interest, the median duration of response in this population of younger adults was shorter than the median duration of response in an age-unrestricted population from the same center (57 versus 98 months, respectively).

In other studies, including our own, 76 to 80 percent of assessable patients with HCL treated with cladribine achieved CR and 7 to 24 percent achieved PR, with minimal toxicity [9,18,19,32]. The majority of patients remained disease-free for a prolonged period of time, with relapse rates of 14 to 20 percent at 24 to 30 months and 36 percent at 9.7 years [32]. Progression-free survival and overall survival at four years have been 72 to 84 percent and 86 to 96 percent, respectively [18,20-22,33,34]. Overall survival in two series, including our own, was 79 to 87 percent after 12 years [32,35].

Fever occurs in about 40 percent of patients treated with cladribine, coinciding with a rapid decline in the number of circulating hairy cells and neutrophils [36]. In some series, no viral, fungal, or other opportunistic infections were observed other than a single case of dermatomal herpes zoster 16 months after treatment. Infections are rarely documented, and it is believed that the fever may reflect cytokine release from hairy cells.

To explore the relationship between cladribine-induced fever and neutropenia, a phase II trial of granulocyte colony-stimulating factor (5 mcg/kg per day SQ on days -3, -2, and -1, and again after the completion of cladribine) was initiated [36]. Treatment with G-CSF shortened the period of neutropenia, as compared with historical controls treated with cladribine alone. However, the incidence of febrile patients, number of febrile days, or frequency of admission for treatment with antibiotics was not changed.

Cladribine therapy may be associated with the development of unexpected foci of hypoplasia and aplasia in bone marrow biopsies performed as part of their evaluation [37]. These foci are present in patients in CR with normal peripheral blood counts; their long-term significance is unclear [37].

Pentostatin — Pentostatin was the first drug reported which induced a high rate of complete remissions in HCL [38,39]. It is an irreversible inhibitor of adenosine deaminase (ADA) [16], an enzyme critical to purine metabolism found in all lymphoid cells. Deoxyadenosine triphosphate metabolites accumulate within hairy cells after treatment with pentostatin and are thought to be responsible for the cytotoxicity [15,40]. The dose of pentostatin approved by the US Food and Drug Administration for the treatment of HCL is 4 mg/m2 every two weeks until maximal response.

A number of studies have been published using pentostatin in a variety of different doses and schedules [30,38,39,41-49]. In an Eastern Cooperative Oncology Group (ECOG) study, 50 patients with HCL were treated with pentostatin (5 mg/m2 per day intravenously (IV) for two consecutive days every two weeks until maximum response) [42]. The overall response rate and complete remission rate were 84 and 64 percent, respectively, with the majority of patients achieving maximal response within six months.

Toxicities were moderate and included nausea, vomiting, skin rash and conjunctivitis, as well as significant neurologic toxicities in four patients. Neutropenia was "life-threatening" in 70 percent of patients; however, this was limited to the first two to three cycles of therapy. Mortality as a result of therapy was attributable to infection in 6 percent of patients.

Other investigators have administered a lower dose of pentostatin and have produced similar results with reduced toxicity [30,48]. In one study, for example, patients were treated with pentostatin at a dose of 4 mg/m2 IV every other week; complete remission was attained in 20 of 23 patients (87 percent) with infrequent infections and no treatment-related deaths [30]. CD4 positive cells were significantly, but only temporarily, decreased after treatment, with no opportunistic infections or second malignancies being noted after two years of follow-up.

Another series evaluated a regimen of pentostatin at 4 mg/m2 IV weekly for three consecutive weeks, with therapy repeated every eight weeks [48]. Complete remission was achieved in 25 of 28 patients (89 percent) after completion of two cycles of therapy. Transient neutropenia occurred only during the first cycle and 12 patients developed fever and/or infection; there were no deaths.

The relative efficacy of pentostatin and IFNa was evaluated in a prospective intergroup study which randomly assigned 313 patients with HCL to receive either pentostatin (4 mg/m2 IV every two weeks for six months) or IFNa (three million units SQ three times per week) [46]. Pentostatin therapy was associated with higher rates of confirmed complete remission (76 versus 11 percent) and confirmed complete or partial remission (79 versus 38 percent). Estimated overall and relapse-free survival of patients achieving CR with pentostatin were 87 and 76 percent, respectively [50]. Factors predictive of CR with pentostatin were high hemoglobin concentration, young age, and little or no splenomegaly [46].

At a median follow-up of over nine years, 83 percent of patients treated with pentostatin on this protocol were still alive, and only 18 percent of those who achieved CR have relapsed [50]. Of the 40 deaths, only two were related to HCL; the standard mortality rate for the cohort of pentostatin-treated patients, as compared with the 1990 age- and sex-specific mortality for the white United States population was 1.05 (95 percent confidence limits: 0.75 to 1.43).

In addition, pentostatin is usually effective in patients who are refractory to treatment with IFNa [47].

Choice of purine analog — The majority of patients with previously treated or untreated HCL achieve durable remissions with either multiple cycles of pentostatin or a single cycle of cladribine [5,51]. In one study of 233 patients followed for a median period of 16 years, overall response rates (100 versus 96 percent), rates of complete remission (76 versus 82 percent), and 10-year survivals (100 versus 96 percent) were similar for initial treatment with either cladribine or pentostatin, respectively [9,11]. Patients achieving a complete response with either agent showed significantly longer median disease-free survival than those attaining only a partial remission (not reached at 14 years versus 5.5 years).

Although these outcomes with both pentostatin and cladribine are excellent, the ease of administration of a single cycle of cladribine and the paucity of toxicities with cladribine are attractive advantages. However, it is not clear whether one or the other of these agents has a lesser risk of second malignancies (see 'Second malignancies' below).

Side effects — Both pentostatin and cladribine produce prolonged immunosuppression [52-55]. Pentostatin therapy is associated with a decrease in the total lymphocyte count, with a reduction in T cells proportionately greater than that for B cells or natural killer cells [55]. Absolute numbers of CD4+ and CD8+ cells fall to less than 200 cells/microL for at least six months after pentostatin is discontinued. In two studies, the median time to recovery of CD4+ cell counts following cessation of therapy was 54 months with pentostatin [56] and 40 months with cladribine [34].

Despite this degree of immunosuppression, opportunistic infections, other than an occasional case of herpes zoster, are uncommon unless purine analog treatment is associated with concomitant glucocorticoid exposure [53]. Prophylaxis against Pneumocystis carinii pneumonia may be reasonable if glucocorticoids are being given for a separate indication. (See "Prevention of infections in patients with chronic lymphocytic leukemia" and "Risk of infections in patients with chronic lymphocytic leukemia", section on 'Other purine analogs'.)

Interferon alfa — Numerous large studies have confirmed the activity of interferon alfa (IFNa) in HCL [52,57-63]. The precise mechanism of action of IFNa is not known. HCL may involve a deficiency in the production of cytokines such as granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, interleukin (IL)-3, and IL-6, perhaps related to the characteristic monocytopenia. Treatment with IFN-alpha may upregulate their production [64].

IFNa increases intracellular IL-6 in HCL and induces secretion of IL-6 from peripheral blood mononuclear cells from HCL patients, but not healthy donors [64]. Thus, the benefits of IFNa may result in part from the induction of hematopoietic growth factors within the leukemic cell population.

IFNa is commonly administered at a dose of two million units/m2 subcutaneously three times a week for 12 to 18 months. This regimen produces a high overall response rate of 75 to 90 percent; however, the majority of patients achieve only partial remission (defined as normalization of all peripheral blood counts) [61,63]. Furthermore, the median failure-free survival after discontinuing IFNa ranges from 6 to 25 months in different series [58,61,63,65]. The risk of early relapse is increased in patients with more than 30 percent hairy cells in the bone marrow or a platelet count <160,000/microL at the end of treatment [65]. Patients with HCL who express the CD5 antigen appear to respond poorly to IFNa [66].

Treatment outcome can be improved by long-term maintenance IFNa in patients who respond to initial therapy at a dose of three million IU subcutaneously given three times a week [52]. In this report, 60 percent of patients sustained their initial response for a median of five years, 9 percent discontinued therapy early due to unacceptable neurologic toxicity, and only 13 percent stopped therapy because of progressive disease.

Although treatment of HCL with IFNa results in normalization of the peripheral blood counts in most patients, "true" complete remissions are uncommon, since residual disease can be demonstrated in splenic tissue after splenectomy in complete responders [67]. Treatment with IFNa may rarely play a role in the following instances:

●Patients failing treatment with purine analogs [68,69]

●Patients with HCL and pancytopenia who are treated initially with IFNa to improve their counts may tolerate subsequent purine analog therapy with fewer infectious complications [70]. However, this has not become routine practice.

Common toxicities of IFNa include flu-like symptoms, anorexia and fatigue, nausea and vomiting, diarrhea, dry skin, peripheral neuropathies and central nervous system dysfunction, including depression or memory loss. Elevated serum aminotransferases are the most common laboratory abnormality other than myelosuppression.

Splenectomy — Removal of the spleen was the first effective therapy for HCL [71-73]. Although splenectomy does not produce pathologic remissions, peripheral blood counts return to normal in approximately 40 to 70 percent of patients, particularly those with a hairy cell index of 0.7 or less [71]. The hairy cell index is defined as the cellularity of the bone marrow core biopsy specimen (stated as a fraction) multiplied by the fraction of hairy cells present in the cellular portion of the bone marrow core biopsy specimen.

The response to splenectomy is maintained for a median of 20 months, approximately one-half have disease progression within five years, and the overall survival at five years is 60 to 70 percent [71,74]. Possible indications for splenectomy in HCL include:

●Symptomatic splenomegaly (massive enlargement, pain, infarction, rupture)

●Pancytopenia which is still present after other treatments [75]

●As a temporizing measure in symptomatic pregnant women [76]

Highly effective therapy with purine analogs generally obviates the need for splenectomy in other settings (see 'Purine analogs' above).

Residual disease post-treatment — It has been suggested that cell proliferation in HCL is regulated by growth factors and cytokines, such as tumor necrosis factor (TNF)-alpha and interleukins (IL), and that serum levels of the TNF and IL family may be used as sensitive markers for monitoring disease activity [77]. In a retrospective study in eight patients with relapsed HCL, a doubling of serial soluble IL-2 receptor levels was noted at a mean of 17 months before the onset of neutropenia and subsequent clinical relapse [78].

The remarkable activity of the purine analogs has led to the examination of posttreatment bone marrow biopsies to detect minimal residual disease (MRD) in patients otherwise in CR. Immunohistochemistry using anti-CD20 antibodies in paraffin embedded biopsies is one technique used to identify MRD [79-84]. Depending upon the criteria used, 13 to 53 percent of patients in apparent CR have evidence of MRD, which may or may not predict future relapse [79,80,82,85]. However, molecular studies using polymerase chain reaction suggest that the malignant clone of cells may remain in patients in apparent morphologic remission [86,87] or even in apparent molecular remission using flow cytometry [88].

Although MRD-negative status has been achieved in patients with hairy cell leukemia using sequential cladribine followed by rituximab, it is not known yet whether this strategy will lead to long-term disease-free survival compared with cladribine alone [89].


Resistant disease — Overall and complete response rates to initial treatment with purine analogs are approximately 96 to 100 and 80 percent, respectively, meaning that up to 4 percent of patients obtain no initial benefit and up to 20 percent achieve only a partial remission [9,11,32,51]. The suggested therapeutic option in such patients is use of a different purine analog from the one initially chosen. Other options include IFNa, splenectomy, or one of the available monoclonal antibodies directed against B cell determinants on the malignant cell. (See 'Investigational targeted therapies' below.)

Variant hairy cell leukemia — Most patients with HCL variants are poorly responsive or resistant to standard treatment (ie, splenectomy, interferon, purine analogs) [90-92]. Although treatment data are sparse, patients with variant HCL are candidates for treatment with monoclonal antibodies (eg, rituximab, BL-22, alemtuzumab) [93].

Relapsed disease — Since appreciable numbers of patients relapse after initial treatment, especially those attaining only a partial remission, developing a salvage treatment approach is important [94]. As an example, in one long-term study the 10-year rates of relapse were 48 and 42 percent for subjects initially treated with cladribine or pentostatin, respectively [11]. (See 'Choice of purine analog' above.)

Retreatment with a second cycle of cladribine or pentostatin leads to a second complete remission in up to 70 percent of patients, and is the recommended approach [9,11,18,20,31,32]. In one study, the probability of achieving a complete remission was not affected by whether the patient was retreated with the same purine analog (71 percent) or switched to the alternative one (68 percent) [11].

While overall response rates are 97 to 100 percent after second- and third-line treatment with the purine analogs, the rates of complete remission as well as the lengths of disease-free survival become progressively shorter with each course of therapy. In one study, disease-free survivals after first, second, and third-line treatment with purine analogs were "not reached after 14 years", 7.5, and 4 years, respectively [11].

Some patients with resistant or relapsed disease respond to treatment with IFNa, although relapse is common when therapy is discontinued [68].

Investigational targeted therapies — At least three monoclonal antibodies, directed against CD22, CD20, or CD25, have been evaluated in the treatment of resistant or relapsed HCL. These agents appear to be highly active and well tolerated even in patients resistant to treatment with the purine analogs [95]. However, all must be considered experimental at this time.

Anti-CD20 antibody (rituximab) — The anti-CD20 antibody rituximab has been evaluated in patients with relapsed/refractory hairy cell leukemia. It may be useful in some patients who have failed at least two courses of cladribine although this is a "non-approved" indication for its use. The use of rituximab has yielded mixed results in clinical trials. Toxicity in all of these trials has been minimal. The following is an overview of some of the studies that have evaluated this treatment approach.

●A phase II study of rituximab in 24 patients with relapsed disease after treatment with cladribine demonstrated overall response rates of 24 percent (three complete, three partial) [96].

●A number of small studies have reported higher overall (64 to 100 percent) and complete (53 to 92 percent) responses, as well as overall molecular response rates as high as 70 percent [9,87,97-99].

●A retrospective review evaluated pentostatin or cladribine combined concurrently or sequentially with rituximab as second-line therapy [100]. All eight patients responded to therapy with seven complete responses. At a median follow-up of 29 months, only one patient had developed recurrent disease. The relative benefits of concurrent or sequential cladribine followed by rituximab will require further study.

●A retrospective review of 15 patients with relapsed or refractory HCL treated with fludarabine plus rituximab reported disease response in all evaluable patients (13 patients) [101]. Three patients achieved minimal residual disease negativity. After a median follow-up of 35 months, 14 patients remain progression-free, while one succumbed to complications of the disease. It is not clear that fludarabine provided additional benefit to the rituximab therapy.

●A phase II trial evaluated five days of intravenous cladribine followed approximately one month later with eight weekly treatments of rituximab in 36 patients with newly diagnosed HCL requiring treatment [13]. There were no severe (grade 3/4) events and all patients achieved a complete response. After a median follow-up of 25 months, the median progression-free and overall survival durations had not been reached. It is not clear if overall survival is improved with the addition of rituximab following cladribine as compared with cladribine alone.

Anti-CD22 antibody (BL22) — Initial trials of the pseudomonas exotoxin-linked recombinant anti-CD22 antibody (BL22) have shown high response rates in patients with previously treated HCL [102-105].

In a phase II trial in 36 patients with relapsed/refractory HCL who required treatment because of cytopenias, complete and overall responses were obtained in 25 and 50 percent, respectively, after one cycle of treatment and in 47 and 72 percent, respectively, after retreatment [105]. Complete and overall responses were highest (64 and 95 percent, respectively) in patients without massive splenomegaly or prior splenectomy, and were 21 and 36 percent, respectively, for those with a prior splenectomy or massive splenomegaly.

Toxicities of BL22 have included reversible hemolytic uremic syndrome (HUS), a cytokine-release syndrome (fever, hypotension, myalgia or arthralgia), transient hypoalbuminemia, and elevated aminotransferase levels, and the presence of neutralizing antibodies in some patients, which prevented re-treatment [105]. When routinely available, BL22 will likely become the treatment of choice for patients who have relapsed or who are refractory to treatment with purine analogs.

A second generation recombinant immunotoxin, CAT-8015, is closely related to BL22, from which it differs by three amino acids [106]. This change appears to improve its binding affinity to CD22, resulting in better cytotoxic activity against B cell cancer cell lines and malignant cells isolated from patients with HCL. Clinical trials of this agent are underway.

Anti-CD25 antibody (LMB-2) — A recombinant anti-CD25 antibody linked to a truncated form of pseudomonas exotoxin (LMB-2) has been used in phase I trials in patients with HCL who had experienced treatment failure with cladribine and IFNa [107,108]. Major responses were seen in these studies, with maximum reduction of malignant cells in the peripheral blood varying from 98 to 99.8 percent.

BRAF inhibition (vemurafenib) — Vemurafenib is a potent inhibitor of the kinase domain in mutant BRAF used in the treatment of metastatic or unresectable melanoma. Initial reports have demonstrated activity in patients with HCL and activating point mutations in BRAF [109-114]. Partial, transient responses are common in cases with BRAF mutations. The drug is likely not effective in patients with the HCL-variant since such cases do not usually express the BRAF mutation. Until further data are available, we generally reserve vemurafenib for patients with HCL enrolled on clinical trials.

Two phase 2 multicenter studies evaluated the efficacy of vemurafenib (960 mg twice daily) in patients with HCL relapsed after or refractory to treatment with purine analogs [115]:

●In the Italian study of 28 patients, the overall response rate (ORR) was 96 percent (35 percent complete) after a median of eight weeks of treatment. After a median follow-up of 23 months, those with a complete response (CR) had median relapse free and treatment free survivals of 19 and 25 months, respectively. Partial responders had median relapse-free and treatment-free survival times of 6 and 18 months, respectively.

●In the US study, all 26 patients demonstrated a response (42 percent complete) after a median of 12 weeks. Rates of progression-free and overall survival at one year were 73 and 91 percent, respectively.

Most toxicities were mild (grade 1/2). The most common toxicities included rash, photosensitivity, arthralgias/arthritis, fever, and elevations in liver and pancreatic enzymes. Secondary cutaneous tumors developed in 14 percent, all of which were treated with excision. Squamous cell carcinomas and keratoacanthomas are known cutaneous side effects with vemurafenib. (See "Molecularly targeted therapy for metastatic melanoma", section on 'Vemurafenib'.)

CLINICAL TRIALS — Often there is no better therapy to offer a patient than enrollment onto a well-designed, scientifically valid, peer-reviewed clinical trial. Additional information and instructions for referring a patient to an appropriate research center can be obtained from the United States National Institutes of Health (

Many agents are under active investigation or in development. These include combinations of agents already used in hairy cell leukemia (HCL), agents approved for other diseases (eg, vemurafenib), novel monoclonal antibodies (eg, LMB-2, BL-22), and other novel agents. Some of these are described in the sections above. (See 'Investigational targeted therapies' above.)

SECOND MALIGNANCIES — There are conflicting data on the risk of second malignancies following therapy for hairy cell leukemia (HCL) [50,116-121]. The range of findings can be illustrated by the following:

●In a study of 117 patients with HCL, there were 44 second malignancies in 36 patients; the majority being nonhematologic [118]. Ninety percent confidence intervals for the relative risk of second malignancies varied widely, being 0.2 to 3.8 for splenectomy, 0.6 to 5.7 for purine analogs, 1.6 to 4.3 for interferon followed by purine analogs, and 1.6 to 8.4 for interferon alone.

●In 358 patients with HCL treated with cladribine, second malignancies, only one of which was hematologic, were noted in 8 percent (observed-to-expected ratio [OER] 1.9; 95% CI 1.2-2.7) [20,21]. A similar OER for second malignancies of 1.5 for cladribine and 1.4 for pentostatin was noted in another series of more than 1300 patients [119]. These ratios are similar to those reported in HCL before the purine analog era [119].

●The Italian Cooperative Group for the Study of Hairy Cell Leukemia observed a cumulative risk for development of a second malignancy of 14 percent at 15 years, similar to the expected rate (standard incidence ratio [SIR] of 1.01) [120]. However, the SIR for non-Hodgkin lymphoma was higher than expected, at 5.3. Use of interferon did not affect the incidence of second malignancies in this group.

●Data on 3104 patients with HCL reported to 16 population-based registries in the SEER Program indicated a statistically increased incidence of second cancers compared with the general population (SIR 1.2; 95% CI 1.1-1.4), especially for Hodgkin lymphoma (SIR 6.6), non-Hodgkin lymphoma (SIR 5.0), and thyroid cancer (SIR 3.6) [121]. The cumulative probability of all second cancers was 32 percent at 25 years following the diagnosis of HCL. It was estimated that, among 1000 HCL patients, a total excess of 3.4 cancers might be observed per year (ie, 34/10,000).

PROGNOSIS — The prognosis of patients with hairy cell leukemia (HCL) has improved over the past three decades with the incorporation of new agents into the management strategy. This was best illustrated by an analysis of the Surveillance Epidemiology and End Results (SEER) database that included over 3300 patients diagnosed with HCL between 1973 and 2008 [122]. Over this time period, the age-adjusted risk of death decreased by 85 percent, with the greatest improvement seen in younger patients who have survival rates only slightly lower than the general population. Older age and African American ethnicity were independent predictors of higher mortality.

In an attempt to address the issue of quality of life in patients, a questionnaire was sent to individuals with a prior diagnosis of HCL who had been treated by this author [123]. There was a 61 percent response rate, with the following observations:

●Lifestyle changes were noted by 40 to 60 percent of respondents (eg, more frequent exercise, healthier diets, a greater appreciation of life, loved ones, and physical health).

●More than 60 percent paid for some aspect of medical care in spite of having health insurance coverage at the time of diagnosis.

●Twelve percent could not obtain health insurance following treatment.

●Ten of 13 subjects had difficulty obtaining a life insurance policy or were denied coverage.

ADDITIONAL INFORMATION — The Hairy Cell Leukemia Research Foundation is a non-profit, all volunteer, patient-run organization whose primary goal is to provide support and information concerning this disease and its treatment. Information about this Foundation can be found at: [124].

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Hairy cell leukemia (The Basics)")


Indications for treatment — Many patients with hairy cell leukemia (HCL) are asymptomatic and can be observed for months and occasionally years after the diagnosis is established before requiring treatment. There is no clear advantage to early therapy. As the goal of treatment is alleviation of symptoms and cytopenias, we believe that asymptomatic patients with HCL should not be treated. There is a theoretic risk of infection in such patients, occasionally with opportunistic organisms.

Indications for treatment include (see 'Indications for treatment' above):

●Significant cytopenias; typical peripheral blood counts that warrant treatment include an absolute neutrophil count <1000/microL with repeated infections, symptomatic anemia with a hemoglobin concentration <11.0 g/dL, or bleeding due to a platelet count <100,000/microL

●Symptomatic splenomegaly (common) or adenopathy (uncommon)

●Constitutional symptoms (eg, fever, night sweats, fatigue, weight loss)

Initial treatment — For patients in whom treatment is indicated, we recommend a purine analog as first line therapy (Grade 1A). Because of ease of administration, we prefer cladribine over pentostatin. (See 'Choice of purine analog' above.)

A single cycle of cladribine (a seven-day continuous intravenous infusion program at a dose of 0.1 mg/kg per day) is most commonly used as initial therapy. Alternative outpatient treatment schedules may be equally effective. (See 'Cladribine' above.)

Resistant or relapsed disease

●Resistant disease – For patients who do not respond to initial therapy with a purine analog, we recommend switching to an alternative purine analog (Grade 1B). (See 'Resistant disease' above.)

●Relapsed disease – For patients who relapse after initial therapy, we recommend repeat treatment with a purine analog over use of other modalities (Grade 1A). Cladribine and pentostatin are equally effective in this setting, leading to a second complete remission in approximately 70 percent of patients and a third complete remission in approximately 50 percent. (See 'Relapsed disease' above.)

●Disease resistant to purine analog therapy – While it is not clear if there are any potentially curative treatment regimens for patients with HCL who are clearly resistant to purine analog therapy, the immunoconjugate BL22 appears particularly promising and is the treatment of choice if available. Rituximab is a reasonable alternative. Participation in a properly conducted randomized trial is always an excellent option for such patients.



Complications of Injecting Drug Use

  • Local problems—Abscess (Figures 240-2 
    Image not available.

    A 32-year-old woman with type 1 diabetes developed large abscesses all over her body secondary to injection of cocaine and heroin. Her back shows the large scars remaining after the healing of these abscesses. (Courtesy of ­Richard P. Usatine, MD.)

    and 240-3; Abscess), cellulitis, septic thrombophlebitis, local induration, necrotizing fasciitis, gas gangrene, pyomyositis, mycotic aneurysm, compartmental syndromes, and foreign bodies (e.g., broken needle parts) in local areas.2
    • IDUs are at higher risk of getting methicillin-resistant Staphylococcus aureus(MRSA) skin infections that the patient may think are spider bites (Figure 240-4).
    • Some IDUs give up trying to inject into their veins and put the cocaine directly into the skin. This causes local skin necrosis that produces round atrophic scars (Figure 240-5).
  • IDUs are at risk for contracting systemic infections, including HIV and hepatitis B or hepatitis C.
    • Injecting drug users are at risk of endocarditis, osteomyelitis (Figures 240-6and 240-7), and an abscess of the epidural region. These infections can lead to long hospitalizations for intravenous antibiotics. The endocarditis that occurs in IDUs involves the right-sided heart valves (see Chapter 50, Bacterial Endocarditis).2 They are also at risk of septic emboli to the lungs, group A β-hemolytic streptococcal septicemia, septic arthritis, and candidal and other fungal infections.


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The presence of Howell-Jolly bodies, Heinz bodies, basophilic stippling, and nucleated red blood cells in a patient with hairy cell leukemia prior to any treatment intervention implies which of the following?

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The answer is A.  The presence of Howell-Jolly bodies (nuclear remnants), Heinz bodies (denatured hemoglobin), basophilic stippling, and nucleated red blood cells in the peripheral blood implies that the spleen is not properly clearing senescent or damaged red blood cells from the circulation. This usually occurs because of surgical splenectomy but is also possible when there is diffuse infiltration of the spleen with malignant cells. Hemolytic anemia can have various peripheral smear findings depending on the etiology of the hemolysis. Spherocytes and bite cells are an example of damaged red cells that might appear due to autoimmune hemolytic anemia and oxidative damage, respectively. Disseminated intravascular coagulation is characterized by schistocytes and thrombocytopenia on smear, with elevated international normalized ratio (INR) and activated partial thromboplastin time as well. However, in these conditions, damaged red cells are still cleared effectively by the spleen. Transformation to acute leukemia does not lead to splenic damage.


A 75-year-old triathlete complains of gradually worsening vision over the past year. It seems to be involving near and far vision. The patient has never required corrective lenses and has no significant medical history other than diet-controlled hypertension. He takes no regular medications. Physical examination is normal except for bilateral visual acuity of 20/100. There are no focal visual field defects and no redness of the eyes or eyelids. Which of the following is the most likely diagnosis?

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The correct answer is A. You answered A.

Age-related macular degeneration is a major cause of painless, gradual bilateral central visual loss. It occurs as nonexudative (dry) or exudative (wet) forms. Recent genetic data have shown an association with the alternative complement pathway gene for complement factor H. The mechanism link for that association is unknown. The nonexudative form is associated with retinal drusen that leads to retinal atrophy. Treatment with vitamin C, vitamin E, beta-carotene, and zinc may retard the visual loss. Exudative macular degeneration, which is less common, is caused by neovascular proliferation and leakage of choroidal blood vessels. Acute visual loss may occur because of bleeding. Exudative macular degeneration may be treated with intraocular injection of a vascular endothelial growth factor antagonist (bevacizumab or ranibizumab). Blepharitis is inflammation of the eyelids usually related to acne rosacea, seborrheic dermatitis, or staphylococcal infection. Diabetic retinopathy, now a leading cause of blindness in the United States, causes gradual bilateral visual loss in patients with long-standing diabetes. Retinal detachment is usually unilateral and causes visual loss and an afferent pupillary defect.


Mr. Jenson is a 40-year-old man with a congenital bicuspid aortic valve who you have been seeing for more than a decade. You obtain an echocardiogram every other year to follow the progression of his disease knowing that bicuspid valves often develop stenosis or regurgitation requiring replacement in middle age. Given his specific congenital abnormality, what other anatomic structure is important to follow on his biannual echocardiograms?

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The answer is A. (Chap. 282) Bicuspid aortic valve is among the most common of congenital heart cardiac abnormalities. Valvular function is often normal in early life and thus may escape detection. Due to abnormal flow dynamics through the bicuspid aortic valve, the valve leaflets can become rigid and fibrosed, leading to either stenosis or regurgitation. However, pathology in patients with bicuspid aortic valve is not limited to the valve alone. The ascending aorta is often dilated, misnamed “poststenotic” dilatation; this is due to histologic abnormalities of the aortic media and may result in aortic dissection. It is important to screen specifically for aortopathy because dissection is a common cause of sudden death in these patients.



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