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Bast RC Jr, Kufe DW, Pollock RE, et al., editors. Holland-Frei Cancer Medicine. 5th edition. Hamilton (ON): BC Decker; 2000.

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Holland-Frei Cancer Medicine. 5th edition.

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Chapter 128Hairy-Cell Leukemia

, MD and , MD.

Hairy-cell leukemia (HCL), a malignant lymphoproliferative disease of B-cell origin, was first described in the United States in 1958 and referred to initially as leukemic reticuloendotheliosis.1 By the mid-1970s, it had become a more easily recognized disease, characterized by splenomegaly and pancytopenia without lymphadenopathy.2–8 The peripheral blood smear showed a low percentage of abnormal mononuclear cells with irregular, cytoplasmic projections. These cells were present in many organs, but were of pathophysiologic significance in their presence in the bone marrow and spleen. The disease constitutes approximately 2% of the adult leukemias, which suggests there are approximately 1,000 new cases diagnosed per year in the United States.

Although splenectomy was the indicated treatment in the 1970s to correct the effects of hypersplenism, by the early 1980s, recombinant interferon-alpha (IFN-α) was shown to be effective systemically. By the mid-1980s, the adenosine deaminase inhibitor deoxycoformycin (pentostatin) was found to induce a higher percentage of complete responses than did interferon. In 1990, a deoxyadenosine analogue, 2-chlorodeoxyadenosine (cladribine), was shown to induce lasting clinical complete remissions with few residual hairy cells in the bone marrow after a single 7-day continuous intravenous infusion of the drug. Currently, the disease has an extremely favorable prognosis with various intermittent therapies. It is well controlled but, probably, still not curable.

Epidemiology and Etiology

The epidemiology of the disease remains to be defined; HCL occurs more often in men than in women (ratio of 4:1). An association with radiation exposure has been suggested,9 but a subsequent study failed to verify the association.10 Familial involvement in HCL has been reported.11–14 A fragile-site analysis of the chromosomes has been made of leukemic and unaffected family members.12 All members had a significant increase in the number of common fragile sites, suggesting environmental exposure of some type.12 Egli and colleagues showed that two siblings with HCL had an associated glucose-6-phosphate dehydrogenase (G-6-PD) deficiency and suggested that a gene involved in HCL might be located adjacent to the G-6-PD locus on the X chromosome.11

Diagnosis: Morphologic and Immunophenotypic Features

The usual approach to firmly establish a diagnosis of hairy-cell leukemia involves examination of peripheral blood and bone marrow biopsy specimens to identify the characteristic morphologic features of the disease, and the utilization of flow cytometry or immunohistochemical techniques to demonstrate an antigenic profile that is distinctive for hairy cells.

Morphologic Features

In peripheral blood smears, hairy cells vary from 10 to 20 mm in diameter (Fig. 128.1). The cytoplasm is pale blue or blue-gray and demonstrates shaggy, irregular projections that are distributed around the entire circumference of the cell.15–16 The nucleus is often eccentrically placed and may be oval or indented, with loosened chromatin. Occasionally, the nucleus may be bilobate or dumbbell-shaped—a feature that is particularly evident in patients with a true leukemic phase. Usually a nucleolus is not apparent.

Figure 128.1. Hairy-cell leukemia.

Figure 128.1

Hairy-cell leukemia. The cell is characterized by an eccentrically located nucleus with fine chromatin, indistinct nucleoli, and an abundant amount of gray-blue cytoplasm with shaggy margins. (Wright’s stain x 1,000).

Because hairy cells are frequently scarce in the peripheral blood and because increased marrow reticulin fibers in the bone marrow usually prevent adequate aspiration of marrow spicules for smear preparations, the bone marrow biopsy specimen often provides the best means for confirming the diagnosis of HCL.2,15,17 In virtually all patients with HCL, the marrow biopsy demonstrates a diffuse or patchy interstitial infiltrate that is characterized by a halo of pale-staining cytoplasm that surrounds and separates the relatively monotonous, bland, hairy-cell nuclei.2,17 These features are apparent even at low power and are in contrast to the nodules or focal aggregates of lymphoid cells with closely packed nuclei found in other mature B-cell lymphoproliferative disorders (Fig. 128.2). The nuclei of hairy cells are usually round, ovoid, or slightly indented, but small numbers of cells may demonstrate irregular or even convoluted nuclei and they can rarely assume a spindled, fusiform appearance.7,17 Although silver stains demonstrate increased stromal reticulin fibers, overt collagen fibrosis is rarely observed.7 Extravasation of red cells into the area of hairy-cell infiltrates is common.17 At the time of diagnosis, the biopsy usually demonstrates hypercellularity of the marrow,7,18 but hypocellular specimens that mimic aplastic anemia have been reported.19 Varying amounts of residual normal marrow elements may persist. The myeloid-to-erythroid ratio is usually less than 1:1,7,20 and islands of erythropoiesis with immature erythroid precursors may be prominent. Hematopoiesis may be reduced in quantity, even when hairy cells involve the marrow only focally. Plasma cells and mast cells are sometimes numerous.20,21

Figure 128.2. Hairy-cell leukemia.

Figure 128.2

Hairy-cell leukemia. The marrow biopsy shows leukemic cells with abundant clear cytoplasm, oval or slightly indented nuclei, and the appearance of a “water-clear” rim separating each nucleus. (H&E, x 400).

The splenic enlargement in HCL is due primarily to diffuse infiltration of the splenic red pulp cords and sinuses by hairy cells.1,2 The white pulp is frequently atrophic. Blood-filled spaces lined by hairy cells, referred to as “pseudosinuses,” are often present.22 Mild to moderate hepatomegaly may be identified in 20 to 40% of patients, which is most commonly due to an infiltrate by hairy cells that is present in both the portal areas and the hepatic sinusoids.2 Angiomatous lesions, similar to the pseudosinuses described in the spleen, are not uncommon in the liver as well.22 Although palpable lymphadenopathy is uncommon in HCL, when lymph node involvement is discovered, it is characterized by a diffuse infiltration of the subcapsular sinuses and the cortex and medullary cord regions by hairy cells, with sparing of the lymphoid follicles.2

Immunophenotype and Cytochemical Features

Although the morphologic features of HCL in the blood and marrow are usually characteristic and virtually diagnostic, determination of the immunophenotype of the neoplastic cell will more firmly establish the diagnosis and will distinguish HCL from other lymphoproliferative disorders with which it may be confused. Monoclonal antibody and gene rearrangement studies have indicated that the hairy cell is of B-lymphocyte lineage,23–27 although a normal counterpart cell has not yet been clearly identified. There is no single marker that is specific for hairy cells. Rather, a combination of antibodies to a number of antigens gives a profile that not only aids in the identification of hairy cells but also provides a clue about the place of the hairy cell in B-cell ontogeny. The most complete immunophenotypic study of HCL is accomplished by flow cytometry, but this technique requires that a sufficient number of neoplastic cells be present in the peripheral blood or marrow aspirate for analysis, and that the unique light scatter characteristics of hairy cells be recognized so that the proper cells are analyzed.26 However, the bone marrow biopsy also provides tissue that can be used to determine a partial, if not entirely diagnostic, immunophenotypic profile.

Analysis by flow cytometry shows that hairy cells display bright expression of the pan–B-cell antigens, CD19, CD20, and CD22, although they usually lack CD21 (Table 128.1).23,25,26 They also express bright (sIg), which may be IgM with or without IgD in about one-half of the patients, and IgG or IgA in the remainder.25,26 Hairy cells also express an early plasma cell marker, PCA-1, which has prompted some authors to suggest that the hairy cell is a relatively mature B cell, perhaps at a pre-plasma cell stage of development.23,25,27,28 In most reported series, virtually all cases of HCL also express CD103, CD11c, FMC7, DBA.44, and the interleukin-2 receptor, CD25.25,26,29,30 Fewer than 5% of cases are reported to express CD5 or CD10, and CD23 and CD24 are usually negative as well.25 However, aberrant, unexpected phenotypes have been reported in a number of cases,25,31,32 so careful correlation of the phenotype with the morphologic and clinical findings is always necessary. Unfortunately, at the current time, monoclonal antibodies that detect many of the antigens described above are not available for use on paraffin-embedded biopsy specimens. However, antibodies for CD20, CD103, and DBA.44 do work well in routinely processed tissue sections. Although none are specific for HCL, they do provide the advantage of simultaneous morphologic and immunophenotypic analysis and thus can be very useful in arriving at a correct diagnosis. In addition, they also aid in the recognition of small numbers of residual leukemic cells following therapy.33–35

Table 128.1. Characteristics of Hairy-Cell Leukemia and Similar Disorders.

Table 128.1

Characteristics of Hairy-Cell Leukemia and Similar Disorders.

Tartrate-resistant acid phosphatase (TRAP) activity is present in the leukemic cells of most patients with HCL, and its detection by cytochemical techniques has been a traditional test for substantiating the diagnosis.36,37 However, up to 5% of patients with otherwise typical HCL lack TRAP activity,2,18,36 and the enzyme has been occasionally found in other low-grade lymphoproliferative disorders.38 Furthermore, interpretation of TRAP studies is often hampered by the scarcity of neoplastic cells in the blood and marrow aspirate specimens which are used for the cytochemical procedure. Consequently, as the availability of immunophenotyping procedures has increased, TRAP studies are less frequently used to confirm the diagnosis. Recently, however, monoclonal antibodies to TRAP have been described that work well in biopsy sections, and when used in conjunction with markers such as CD20 and DBA.44, have proven to be useful in the diagnosis of HCL.39,40

Electron Microscopy

The irregular cytoplasmic processes that characterize the circulating hairy cells seen on light microscopy are well demonstrated by both phase and scanning electron microscopy. Large, undulating ruffles as well as interspersed finger-like projections are easily seen (Fig 128.3). By transmission electron microscopy, the presence of a ribosome-lamellar complex can be found in the cytoplasm of about 50% of cases. This cytoplasmic inclusion is a cylindrical structure composed of a central hollow space and an outer sheath of multiple parallel lamellae (the number of lamellae can vary from structure to structure) with ribosome-like granules in the interlamellar space.41 These structures may also be seen by light microscopy as rod-shaped inclusions, which may be helpful in diagnosis.42

Figure 128.3

Figure 128.3

Scanning electron micrograph of a hairy cell (x 15,000)

Clinical Manifestations

Clinical Features

The clinical features of HCL have been reviewed in several large series.1,18,43 The most common symptoms at presentation are those related to cytopenia, including fatigue, easy bruising, and infection. Symptoms related to splenomegaly occur in about 20% of patients. Up to 20% of new patients are asymptomatic and come to attention when abnormalities are noted on routine blood tests. Physical examination reveals palpable splenomegaly in 80 to 90% of patients at presentation. Peripheral adenopathy is uncommon, but an autopsy series noted mediastinal, abdominal, and retroperitoneal adenopathy in 68% of 22 cases.44

Laboratory studies demonstrate pancytopenia in over half the cases at presentation. Only 15 to 20% of patients present with the leukemic phase of the disease (white blood cells [WBC] greater than 10,000 mL with more than 50% hairy cells), which is more common in disease progression after splenectomy. Neutrophil alkaline phosphatase (NAP) is elevated in HCL.20

Clinical Course and Complications

The clinical course of HCL is variable, but most often it is chronic. Median survival was over 5 years prior to the introduction of effective systemic therapy.1,18 Up to 10% of patients have mild disease, require no treatment, and have prolonged survival. But most patients suffer from disease-related complications, including cytopenias, altered immune status, and tissue infiltration by leukemic cells (Table 128.2). Cytopenias result from a combination of splenic sequestration and bone marrow underproduction owing to leukemic infiltration. Reversing one or both of these problems with splenectomy or systemic therapy improves blood counts, at least temporarily, in most patients.

Table 128.2. Complications in Hairy-Cell Leukemia.

Table 128.2

Complications in Hairy-Cell Leukemia.

Recurrent or severe infections, often with opportunistic organisms, are a significant cause of morbidity and the most common cause of death in HCL.1,44 Fever in a patient with HCL must be considered to be caused by infection until proved otherwise. In one series of 127 patients, 68% had infectious episodes at some point in their course, often without neutropenia, as a result of the impaired immune system in this disease.45 Systemic therapy to treat the underlying disease is recommended even though a brief period of neutropenia may result initially.

Bone involvement causing pain and, rarely, pathologic fracture, is an infrequent problem in HCL.46 Lytic lesions are the most common presentation and tend to occur in the axial distribution. Low-dose radiotherapy provides symptomatic relief, but systemic therapy should be instituted because of the concern about high tumor burden in these individuals.

Autoimmune syndromes characterized most often by vasculitic skin lesions, arthritis, and polyarteritis were observed in over 25% of cases in one series.47 Little is known about the etiology of these complications,48 although reduced clearance of immune complexes has been postulated. Corticosteroids can improve symptoms but are not recommended as long-term therapy because of the increased risk of infection in these patients.

Differential Diagnosis

Hairy-cell leukemia is usually considered in the differential diagnosis of any adult patient who has pancytopenia associated with splenomegaly. Malignant lymphoma of B- or T-cell origin, some myeloproliferative disorders, myelodysplastic syndromes and mast cell disease may have similar clinical features but can usually be distinguished from HCL by a careful morphologic examination of peripheral blood and bone marrow specimens. Nevertheless, several low-grade lymphoproliferative disorders of mature B-cell phenotype have been described that have clinical, morphologic, or immunophenotypic features similar to HCL. Of these latter disorders, the variant form of HCL (HCL-V), and splenic marginal zone lymphoma with villous lymphocytes (SLVL) pose the most frequent problems in diagnosis.

The variant form of HCL is an uncommon disorder that has features intermediate between HCL and B-prolymphocytic leukemia (B-PLL).49–51 Patients with HCL-V usually present with high leucocyte counts without neutropenia or monocytopenia and have easily aspirated bone marrow specimens. The neoplastic cells in HCL-V are slightly smaller than classic hairy cells, and vary from 10 to 15 μm in diameter, with variable amounts of slightly basophilic cytoplasm with fine hairy projections that are unevenly distributed around the membrane. The nucleus is generally centrally located and is round or indented, with open to slightly condensed chromatin. Most cases have variable numbers of binucleate cells.51 The most distinctive feature is a prominent, usually single nucleolus. In biopsy sections, the cells may be distributed in an interstitial pattern or sometimes found in a diffuse nodular pattern. The nuclei may appear clumped together or may be widely separated by abundant clear cytoplasm, although some cases may show both patterns. The nucleolus is usually visible in the tissue sections. Although TRAP activity may be present in up to 60% of cases of HCL-V, it is usually weak. The immunophenotype shows some similarities to classic HCL in that the neoplastic cells in HCL-V do express the pan–B-cell markers, CD19, CD20, and CD22, and lack CD5, CD10, and CD24. Importantly, however, they do not express CD25, in contrast to typical HCL.51 Other differences include a higher frequency of expression of lambda light chains, less intense expression of CD11c, and a lower frequency of CD103 expression in HCL-V than in HCL. There is some overlap of the phenotype with B-PLL, but the latter disorder frequently expresses CD24 and almost never has CD103 or CD11c, in contrast to HCL-V.51

Although any malignant lymphoma may clinically mimic HCL by presenting with primarily splenic involvement, only one, SLVL, is also characterized by cells in the peripheral blood that bear a striking resemblance to hairy cells. Splenic marginal zone lymphoma is characterized by splenomegaly, lymphocytosis, and frequently, a monoclonal protein in the serum.52,53 The neoplastic cells are slightly smaller than hairy cells, and have condensed nuclear chromatin and a small, indistinct nucleolus. They often have short, thin cytoplasmic villi that are localized to one or both poles of the cell.52,53 Some cells show lymphoplasmacytoid features. The bone marrow histology is variable, ranging from virtually no detectable involvement to pronounced diffuse or nodular infiltration that differs from the interstitial pattern of infiltration usually seen with HCL.52 In the spleen, the white pulp is always involved, particularly the mantle and marginal zones, and the red pulp is usually infiltrated as well.54 The immunophenotype reported for this B-cell lymphoma shows some overlap with classic HCL, but some differences as well. The neoplastic SLVL cells express CD19, CD20, and CD22. As many as 20% of cases may demonstrate CD5, but such cases are usually FMC7 positive and CD23 negative, which will help to distinguish them from B-cell chronic lymphocytic leukemia.53 In contrast to HCL, SLVL almost always exhibits CD24, but usually lacks CD103. Nearly one-half have CD11c, and about 25% exhibit CD25 as well.26,52

Some T-cell lymphoproliferative disorders may also mimic HCL clinically and may also demonstrate a histologic pattern of diffuse splenic involvement that closely resembles that seen in HCL.55 The distinguishing features of some lymphoproliferative disorders similar to HCL are outlined in Table 128.1.

Lastly, it must be remembered that occasional patients with HCL may present with very hypocellular bone marrow specimens that may be erroneously interpreted as aplastic anemia, particularly when there is pancytopenia and infrequent hairy cells in the peripheral blood.19 The presence of coexisting splenomegaly in an adult patient in whom a diagnosis of aplastic anemia is being considered should always prompt careful examination of the blood for hairy cells and study of the bone marrow biopsy specimen with CD20 or DAB.44 to detect occult HCL. Hairy cells vary from 10 to 15 μm in diameter in the dried blood film (see Fig. 128.1). The cytoplasm is pale blue or blue-gray and demonstrates fine, irregular projections that are usually distributed around the entire circumference of the cell.15,16 The nucleus is often eccentrically placed and may be oval or indented, with loose, lacy chromatin and inconspicuous, usually single, nucleoli. The nucleus may be bilobate or dumbbell-shaped, a feature which is often particularly evident in patients with a true leukemic phase.

Treatment

At this time, it is clear that several systemic therapies lead to complete clinical responses, but complete eradication of hairy cells in the bone marrow seems to occur in only a minority of patients.56 Before the development of the newer systemic therapies that induce complete remissions, the intent of therapy had been to relieve symptoms and to prevent the frequent complications of progressive disease.

Treatment indications for HCL include severe anemia (HCT below 25%), thrombocytopenia (below 50,000 platelets per microliter), marked granulocytopenia (fewer than 1,000 neutrophils per microliter), splenic pain or rupture, recurrent infections, bone involvement, vasculitis, and bulky retroperitoneal disease. Approximately 10% of newly diagnosed patients never require therapy. These patients are typically 10 years older than the median age of 52 years and have less splenomegaly, fewer circulating hairy cells, and more granulocytes at the time of presentation.

The large majority of patients require some form of treatment for their disease, either at the time of diagnosis or within several years of presentation. The options for treatment have expanded greatly in the past 10 years, allowing the clinician to individualize therapy. Splenectomy is rarely offered to most patients anymore, unless they have an impending rupture of the spleen or a life-threatening infection with severe granulocytopenia and need to achieve improved blood counts as rapidly as possible. Interferon-alpha has been used extensively in the treatment of HCL with excellent control of the cytopenias but is rarely, if ever, curative. Deoxycoformycin (pentostatin) and 2-chlorodeoxyadenosine (cladribine) both lead to complete clinical remission in the majority of patients; deoxycoformycin has to be administered every 2 weeks for 3 months and then monthly for an additional 3 to 9 months, while 2-chlorodeoxyadenosine can be administered in a single course over a 7-day period. In addition, GM-CSF (filgrastim) has been of benefit in ameliorating the leukopenia associated with HCL and its treatment.57 However, a recent report showed that even with the decrease in the number of days to reaching an absolute neutrophil count (ANC) greater than 1,000, there was no clinical advantage to the use of filgrastim combined with cladribine.58 The sequential use of these treatment modalities and the possible integration of them will be elucidated.

Splenectomy

Until the late 1980s, splenectomy was often the first therapeutic modality offered to patients with symptomatic cytopenias or splenomegaly. Splenectomy was attractive because it addressed the problem of splenic sequestration, which was felt to be an etiologic factor in the cytopenias associated with HCL. Several investigators have retrospectively reviewed the results of splenectomy in patients with HCL and report an overall response rate of 80 to 100%, with hematologic complete remissions occurring in 40 to 60%.43,59–62

It is important to note that remissions in the splenectomy series are defined solely by improvement in peripheral blood cytopenias and do not imply eradication of the malignant clone. The Catovsky criteria (or a modification) are used by these investigators to judge response: a complete remission requires a hematocrit above 36%, a neutrophil count above 1,000 per microliter, and a platelet count above 100,000 per microliter; a partial remission requires this degree of improvement in only one or two cell lines with persistent cytopenia in the other line(s); and no response is anything less than a partial response. Survival time was prolonged in those patients who underwent splenectomy.43,59,62 The hematologic response to splenectomy (complete versus partial) did not appear to influence the survival time.59,60,62

The pattern of hematologic response to splenectomy has been well characterized. The platelet count is the most likely to respond, often rising within days after surgery.59,63 The anemia and granulocytopenia may improve gradually over the course of weeks to months after the splenectomy.59,63 In a group of 170 patients who underwent splenectomy, the median platelet count doubled, the median granulocyte count tripled, and the median hemoglobin rose by 1 g/Dl.63

Golomb and Vardiman60 have shown that spleen size did not affect the response to splenectomy. In a group of 64 patients with HCL the spleen size varied from 250 to 4,600 g, but no difference in the hematologic response to splenectomy was identified. Extensive bone marrow involvement was more predictive of an inadequate hematologic response to splenectomy. Their observations showed that maximal sequestration could be caused by minimally enlarged spleens.

Ratain and colleagues64 analyzed the case histories of 194 patients with HCL who underwent splenectomy as initial therapy. The median time to failure, defined as the time from splenectomy to the need for a second therapy or death, was 18.8 months. Prognostic factors indicate low risk of failure if the marrow cellularity is less than 85% and platelet count at least 60,000 per microliter; an intermediate risk with cellularity below 85% but platelet count below 60,000 per microliter; and a high risk if cellularity is at least 85%.64 Overall, 65% of the patients eventually progressed after splenectomy, most requiring systemic therapy. The median survival for this group of patients has not yet been reached; the 9-year survival rate is 60 ± 8%.64 Those diagnosed after 1982 received interferon-alpha as second-line therapy and enjoyed longer overall survival, as compared with those receiving chlorambucil as second-line therapy.

Interferon

The use of interferon-alpha in the treatment of HCL was first recommended by Quesada and colleagues in 1984.65 Partially purified interferon-alpha at 3 × 106 units SC was given daily to seven patients. Normalization of the peripheral blood counts occurred in all patients. Three complete remissions were reported, and four patients entered a partial remission.

The ability to eradicate hairy cells from the bone marrow led to the use of new definitions of response. A complete remission was reported only if hairy cells were absent from the marrow, the organomegaly was resolved, and the peripheral blood counts were restored to the following values: hemoglobin above 12 g/dL, an absolute neutrophil count above 1,500 cells per microliter, and a platelet count above 100,000 per microliter. A partial remission was defined as a decrease in the hairy-cell infiltration of the marrow by 50% with restoration of peripheral blood counts as defined for a complete remission. The species of interferon and the dose and duration of interferon treatment vary considerably from one trial to the next. Complete remissions were reported in 4 to 30% of patients with an additional 43 to 86% of patients achieving a partial remission (Table 128.3).66–73 There is no significant difference in response rates between any of the interferons. In the majority of studies, the complete remission rate is 5 to 10%, but even in these cases, careful review of the bone marrow often reveals a few persistent hairy cells.74,75 The higher cumulative dose used in some trials may have led to the higher complete response rate reported by some investigators.

Table 128.3. Interferon Therapy in Patients with Hairy-Cell Leukemia.

Table 128.3

Interferon Therapy in Patients with Hairy-Cell Leukemia.

Ratain and colleagues reported the duration of response as failure-free survival (FFS), defined as the time from the end of interferon therapy to the time when further antileukemia therapy was needed. Of 60 responding patients treated for 12 or 18 months, 27 relapsed and required further therapy. The median actuarial FFS for these 27 patients was 25.4 months. Re-treatment of a group of 14 patients who relapsed resulted in a 50% response rate. The estimated overall survival for all patients treated with interferon in this study was 91% at 4 years after the start of treatment.76 Rai and colleagues reported a multi-institutional study on 55 previously untreated HCL patients treated with interferon-alpha-2b beginning in 1985.77 After 1 year of therapy, the patients were observed for a median of 5 years. There was a continual trend toward relapse throughout the 5-year period, but 28% remained in remission beyond 6 years. Forty-six (83%) of the patients were alive at 6 years.

The toxicity of interferon is generally tolerable and does not require discontinuation of the drug.78–80 Influenza-like symptoms are quite common; the fever and myalgias are partially alleviated by acetaminophen and fade away over the first few weeks of therapy.64,69,71,81 The fatigue that occurs in most patients is a persistent complaint but typically is not debilitating.

More recently, Spielberger and colleagues82 reported follow-up information through April 1993 on 69 HCL patients treated with interferon-alpha-2b as primary treatment from 1983 to 1986; only 14 patients had died. Forty-seven of the 61 patients who completed the intended 12 months or more of initial interferon treatment were eventually considered “interferon failures.” The median time to interferon failure was 31.3 months. Fourteen patients were alive and had not required further treatment after their initial interferon therapy. Thirteen patients developed a second malignancy; 6 of these patients developed a hematologic malignancy between 44.6 months and 99.1 months after initiation of interferon therapy. A more recent report by Kurzrock and colleagues in 199783 analyzed the second cancer risk in 350 HCL patients. Twenty-six patients developed a second cancer at least 6 months after the HCL diagnosis (observed expected [O/E] ratio, 1.34; p = .08). They found no excess of malignancy among patients treated with interferon alfa (p = .27), cladribine (p = .37) or pentostatin (p = .7). However, an excess of myeloma-related neoplasms and lymphomas was observed. Further studies will be necessary to determine if there is any association between the various treatments and the development of second malignancies.

Pentostatin (2’Deoxycoformycin; DCF)

Pentostatin (2’deoxycoformycin) inhibits adenosine deaminase (ADA), an enzyme in purine metabolism. Spiers and colleagues84 were the first to report, in 1984, the dramatic responses achieved with pentostatin in HCL. They documented resolution of splenomegaly and lymphadenopathy, normalization of blood counts, and complete elimination of hairy-cell infiltrate and excess reticulin from the bone marrow of two previously untreated patients. These results have been confirmed and updated by other investigators with an overall complete pathologic response rate ranging from 56 to 89% in phase II trials (Table 128.4).85–89

Table 128.4. Deoxycoformycin (Pentostatin) Therapy in Patients with Hairy-Cell Leukemia.

Table 128.4

Deoxycoformycin (Pentostatin) Therapy in Patients with Hairy-Cell Leukemia.

Nearly all patients benefit from pentostatin therapy with overall response rates of greater than 95%. No significant impact of previous therapy on this responsiveness is apparent. The treated population has included patients with and without splenectomy, as well as some refractory to interferon therapy. Response is fairly rapid; the initial rise in the platelet count is observed within 2 weeks of treatment. Other hematologic parameters improve over the next 2 months, and bone marrow remissions occur by 2 to 6 months. In the studies reported to date, in several patients, the median duration of remission has not yet been achieved without maintenance therapy for more than 2 years. Relapses have been infrequent; typically, they are demonstrated by a return of less than 10% hairy cells in bone marrow specimens. These have remained subclinical in all but one patient, who achieved successful re-induction with pentostatin.86 Martin and colleagues reported a series of 15 patients treated with alternating courses of pentostatin and interferon-alpha-2a. Although all patients had normalization of their blood counts and 95% clearing of their hairy-cell infiltrate from their bone marrow by 6 months of therapy, small collections of residual hairy cells could be detected intermittently on at least one side of bilateral marrow samples in all patients.90

The dosing schedules of pentostatin in HCL (see Table 128.4) have generally been tolerated well. The major acute toxicities have included nausea and vomiting, skin rash, conjunctivitis, lethargy, and myelosuppression. The latter is of some concern in this population of patients, who often have pre-existing neutropenia and a propensity for infection. Although myelosuppression rarely occurs after the first course of pentostatin, febrile neutropenia and/or documented infections were found in more than 40% of patients in one study.85 At least two deaths were attributable to infections during pentostatin therapy in an uncontrolled setting.89 Renal insufficiency is rare and reversible. Since pentostatin is cleared by the kidneys, in the presence of renal insufficiency, dose modifications are recommended.

The long-term toxicity of pentostatin therapy is not known. One major issue is the possibility of prolonged immunosuppression in patients treated with this drug. Urba and colleagues91 reported that pentostatin-induced lymphopenia (especially of T cells) in HCL can be observed for at least 1 year after treatment. They also noted multiple functional defects in the remaining lymphocytes. The clinical significance of these findings has yet to be determined; however, 6 of their 13 patients developed localized herpes zoster. No significant change in the number of infectious episodes related to pentostatin therapy for HCL has appeared in early trials. Four systemic infections, all pneumonia, occurred in 23 patients treated by Kraut and colleagues,86 each occurring during the first 8 weeks in patients who were neutropenic.

Catovsky and colleagues88 documented a complete response rate of 74.3% in 148 HCL patients treated from 1986 onward. He found that only 5 patients did not respond to treatment, despite an adequate trial, and 4 of them had abdominal lymphadenopathy. At the time of publication, only 12 patients had relapsed (median time, 22 months), and in 5 of them HCL was also associated with massive abdominal lymphadenopathy. The duration of remission after stopping DCF in the first 105 responders with long follow-up showed that 84% were still in remission (complete response and partial response) at 4 years. The proportion still in remission at 4 years was 86% for complete and 77% for partial remitters; the difference was not statistically significant. They noted the toxicity associated with DCF treatment was minimal or nonexistent in 79% of patients; only 27% of patients had infectious complications associated with neutropenia and lymphopenia and in 6% they were life threatening. There had been only 10 deaths so far, of which 7 were unrelated to HCL. They noted that DCF had changed the natural fatal course of HCL and introduced the possibility of very prolonged disease-free periods and the chance of genuine cure. They felt the toxicity profile of DCF with the schedule of injections given every 2 weeks (4 mg/m2 IV) was excellent.

Grever and colleagues,92 in 1995, reported on a randomized comparison of pentostatin versus interferon-alpha-2a in previously untreated patients with HCL. Among interferon patients, 17 of 159 (11%) achieved a confirmed complete remission and 60 of 159 (38%) had a confirmed complete or partial remission. Among pentostatin patients, 117 of 154 (76%) achieved a confirmed complete remission, and 121 of 154 (79%) had a confirmed complete or partial remission. Response rates were significantly higher (p < .0001) and relapse-free survival was significantly longer with pentostatin than interferon (p = .013).

More recently, in 1999, Ribeiro and colleagues93 reported on the long-term outcome of 50 patients treated with pentostatin from 1989 through 1996. Their overall response rate was 96%. They documented 5 recurrences between 12 and 66 months. The overall survival rate was 86% at a median follow-up of 38 months.

Cladribine (2-Chlorodeoxyadenosine)

A new inhibitor of adenosine deaminase, 2-chlorodeoxyadenosine (2-CDA) has been reported to have major activity in HCL.94 A single course of 2-chlorodeoxyadenosine, 0.1 mg/kg/d, was given for 7 days by continuous infusion. In 1990, the same group95 reported a total of 12 patients treated with the same dosage of 2-CDA.

Eleven of the first 12 patients obtained a complete response and had almost none of the side effects usually associated with chemotherapy. Subsequently, they have updated their results on 148 patients and reported an 85% complete response rate and a 12% partial response rate; only 2 patients subsequently have had relapses96 (Table 128.5). Also, they noted that 36% of patients had febrile episodes within several weeks of receiving 2-CDA. Estey and co-workers reported on 46 patients treated with the same dosage of 2-CDA and found a complete response rate of 78% and a partial response rate of 11%.97 They had three resistant patients and one who had a relapse; 46% had febrile episodes. More recently, Saven and Piro reviewed all the reported patients treated with 2-CDA and compared them with the reported patients treated with pentostatin.98–102 They showed a complete response rate of 82% for 245 2-CDA–treated patients and of 64% for 264 pentostatin-treated patients. They showed no response in 21% of the pentostatin-treated patients, as compared with only 5% of the 2-CDA–treated patients. They also noted that fever was the principal adverse effect of treatment with 2-CDA (44% of patients) and felt it was related to the rapid disappearance of circulating hairy cells and shrinkage of the spleen. Febrile episodes occurred by day 6 (range, 4 to 10 days) in half the patients and lasted for a median of 3 days (range, 1 to 13 days). They noted that the fever tended to resolve with granulocyte recovery. They also noted that, like pentostatin, 2-CDA is immunosuppressive. It causes decreases in B- and T-lymphocyte counts (both CD4 and CD8), and recovery tends to occur between 6 and 12 months after treatment. In addition, the group at M.D. Anderson Cancer Center reported prolonged suppression of CD4 1 lymphocyte counts in patients treated with 2-CDA for up to 40 months after therapy.103 Although Saven and Piro noted that 6 months after treatment 58 of 59 patients who had a complete response had no detectable circulating hairy cells, they did state that it had been demonstrated that “some patients in complete remission have evidence of minimal residual disease on immunohistochemical staining of bone marrow.” It was shown by Pileri and colleagues that 100% of 2-CDA–treated patients had residual hairy cells in their bone marrow when immunohistologic analyses were carried out.104 Konwalinka and colleagues reported on 11 patients treated with cladribine who were judged to be in complete remission and were studied with immunohistologic staining with the monoclonal antibody B-ly 7.105 In all 11 cases, residual hairy cells could be detailed. At a median follow-up of 19 months, 9 patients remained in complete remission, whereas 2 patients relapsed at 22 and 27 months after cladribine therapy.

Table 128.5. CDA Therapy for Hairy-Cell Leukemia.

Table 128.5

CDA Therapy for Hairy-Cell Leukemia.

Although most investigators utilized the recommended schedule of 0.1mg/kg IV as a continuous infusion over 7 days, a number of investigators have reported a more convenient variation that seems to retain the same efficacy. Damasio and colleagues106 compared a 2-hour infusion on 5 consecutive days (0.15mg/kg/d) in 22 patients with continuous IV infusion for 7 consecutive days (0.1mg/kg/d). Overall response at 6 months was, respectively, 88.8% and 81.2%. They concluded that the 5-day intermittent schedule appeared efficient and was well tolerated. Robak and colleagues101 utilized a very similar 2-hour infusion for 5 consecutive days at a daily dose of 0.12mg/kg and obtained results similar to studies using 7-day continuous infusions (see Table 128.5)

Future Prospects

The 1980s to 1990s have been exciting years for clinicians involved in the care of patients with HCL. Three new agents—interferon-alpha, deoxycoformycin, and 2-chlorodeoxyadenosine—have been identified as being highly effective in the treatment of this rare disease. As the options expand, and until we know whether deoxycoformycin and/or 2-CDA are curative or not, it remains important to identify patients who will require no therapy. These generally elderly patients have an adequate blood count and an impalpable spleen. About 85% of newly diagnosed patients with HCL require some form of treatment. For those patients requiring treatment, it is time to declare that splenectomy is no longer indicated as first-line therapy, that pentostatin or 2-CDA produces a more rapid and more complete response than interferon, and that progression-free survival is significantly longer with pentostatin or 2-CDA treatment, as compared with interferon treatment.

If HCL cannot be cured by single-agent therapy with interferon, pentostatin, or 2-CDA, then could some combination of these three cure it? Since the disease is controlled so well with any of these agents in sequence for such a long time, a randomized study to answer this question probably cannot be completed. Currently, we would recommend initial therapy with 2-CDA, as a high complete response rate can be obtained with a single 7-day course. If this were not available, we would choose pentostatin, which requires at least a 3-month course of every-other-week treatment. If neither 2-CDA nor pentostatin were available, we would consider interferon therapy, which requires administration at least 3 times per week for approximately a year. The advances in the treatment of this rare disease has resulted in survival curves similar to those for the appropriate age-related cohorts.

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