Therapeutic advances in the treatment of hairy cell leukemia

Leukemia Research 25 (2001) 361– 368 www.elsevier.com/locate/leukres

Millennium review

Therapeutic advances in the treatment of hairy cell leukemia Jeffrey Andrey, Alan Saven * Di6ision of Hematology and Oncology, Scripps Clinic, Ida M. and Cecil H. Green Cancer Center Di6ision, Scripps Cancer Center, 10666 North Torrey Pines Road, La Jolla, CA 92037, USA Received 30 May 2000; accepted 2 July 2000

Keywords: Hairy cell leukemia; Interferon; 2%-Deoxycoformycin; 2%-Chlorodeoxyadenosine

1. Introduction Hairy cell leukemia (HCL) is a rare chronic lymphoproliferative disorder typified by the presence of circulating monoclonal B-lymphocytes that have prominent cytoplasmic projections, and which display distinctive infiltration patterns in the bone marrow and spleen. In the USA it represents 2 – 3% of all adult leukaemias. There is a 4:1 male to female predominance with the median age at presentation being 52 years. The clinical presentation often includes a history of repeated infections, symptoms related to low peripheral blood counts, and splenomegaly on physical examination. Circulating hairy cells, which may not be present in large numbers, appear slightly larger than regular lymphocytes and display irregular, ruffled, pale blue cytoplasm (Fig. 1). The morphologic finding on the bone marrow core biopsy consists of a diffuse infiltration by lymphocytes that are spaced wider than expected — the ‘fried-egg’ appearance (Fig. 2). Reticulin staining is increased reflecting the fibrosis, which accounts for the difficulty usually encountered when attempting to aspirate the bone marrow (Fig. 3). Hairy cells exhibit tartrate-resistant acid phosphatase (TRAP) activity although this may also occasionally be seen in other lymphoproliferative disorders. Immunophenotypic analysis of the abnormal cells in HCL reveals CD11c, CD19, CD20, CD22, CD25, CD103, and

* Corresponding author. Tel.: +1-858-5548388; fax: + 1-8585546941. E-mail address: [email protected] (A. Saven).

kappa or lambda light chain positivity [1], and the absence of CD5 and CD21 antigen expression.

2. Treatment indications Watchful waiting is appropriate for asymptomatic HCL patients. It is unclear if early treatment confers an advantage with respect to response or survival. Patients who develop significant neutropenia (absolute neutrophil count B 1× 109/l) anemia (hemoglobin concentration B 10.0 g/dl) or thrombocytopenia (platelets B 100×109/l) in the course of their disease should be considered for treatment. Patients with symptomatic splenomegaly, constitutional symptoms such as fever or night sweats due to HCL, or repeated infections may benefit from treatment.

3. First-line therapy for hairy cell leukemia

3.1. Splenectomy Splenectomy was the treatment of choice for HCL patients before the advent of regularly effective systemic therapies. Normalization of peripheral blood counts is seen in 50–77% of patients, with a median response duration of 5–20 months and an overall survival at 5 years of 70% [2,3]. Not all HCL patients respond to splenectomy because in some the underlying cause of their pancytopenia may be diffuse marrow infiltration with HCL rather than just hypersplenism from splenic enlargement.

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Fig. 1. Circulating hairy cells, with oval to reniform nuclei, partly condensed chromatin, and a rim of agranular but ‘textured’ cytoplasm, with multiple delicate hair-like projections (100 × ).

Fig. 3. Reticulin silver stain demonstrates the dense reticulin network seen in the bone marrow biopsy characteristic of hairy cell leukemic infiltrates (40 × ).

3.2. Interferon

HCL patients [8]. How this immune reconstitution by interferon translates to clinical activity is unknown. The most common side effect of interferon therapy is a flu-like syndrome consisting of malaise, myalgias, and fever that generally partially responds to acetaminophen, and which may diminish over time as therapy is continued (tachyphylaxis).

Interferon a-2b (Intron A; Schering Corporation, Kenilworth, NJ) demonstrated an overall response rate of 75% in untreated HCL patients, with 5% of patients achieving a complete response [4]. The dose studied was 2 mU/m2 injected subcutaneously three times weekly for 1 year. Interferon a-2a also has similar activity in HCL [5]. Interferon a-2a (Roferon A; Roche Laboratories, Nutley, NJ) was administered subcutaneously daily in the amount of 3 mU/m2 for 6 months, then three times weekly for an additional 6 months. Following interferon administration, platelet counts generally normalize after 2 months, hemoglobin after 3 months and neutrophils after 5 months. Time to treatment failure was 18–25 months. Readministration of interferon at hematologic relapse resulted in a 77% response rate [6]. Interferons restore natural killer cell activity [7] as well as susceptibility to cytotoxic T-lymphocytes in

Fig. 2. Hairy cell leukemic infiltrate seen in the bone marrow biopsy, characterized by well-spaced cells with a ‘fried egg’ appearance due to distinct round-to-oval nuclei that are centrally placed within a palestaining cytoplasmic domain. Extravasated red cells are frequently seen within the infiltrate (100 × ).

3.3. 2 %-Deoxycoformycin 2%-Deoxycoformycin (dCF, Pentostatin; SuperGen, Pleasanton, CA) is a direct inhibitor of adenosine deaminase. This enzyme normally catalyzes the irreversible deamination of 2%-deoxyadenosine to 2%-deoxyinosine. Intracellular accumulation of deoxyadenosine triphosphate is thought to be responsible for the lymphopenia associated with severe combined immunodeficiency (SCID) [9] and adenosine deaminase deficiency. A study conducted by the Eastern Cooperative Oncology Group (ECOG) [10] with 2%-deoxycoformycin reported an overall response rate of 84%, with 20% achieving a complete response. The dosage of dCF was 5 mg/m2 for 2 days every other week until maximal response was noted. The most common side effects following dCF in this study were nausea, vomiting, photosensitivity, and myelosuppression. These adverse reactions were more severe in patients with underlying renal insufficiency, and thus the use of dCF in patients with a creatinine clearance B60 ml/min is not recommended. The encouraging high overall response rates and complete remissions seen with dCF prompted a National Cancer Institute (NCI)-sponsored prospective, randomized intergroup trial of dCF versus interferon2a in previously untreated HCL patients [11]. Patients were randomized to interferon a-2a, 3 mU injected subcutaneously 3 times per week for 6 months, versus dCF, 4 mg/m2 intravenously every 14 days. Patients

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who did not respond after 6 months to initial treatment were then crossed over to the alternative treatment. The overall response rates for the interferon and dCF groups were 38 and 79%, respectively, and the complete response rates were 11 and 76%. A total of 66% of patients who progressed on interferon and who were then treated with dCF achieved a complete response, and 9% a partial response. No patient who had progressed on dCF responded to interferon. The difference in overall survival between the two groups was not statistically significant, likely reflecting the crossover study design. It can be inferred from these study results that dCF is substantially more active than interferon when administered as first-line therapy to patients with HCL.

3.4. 2 -Chlorodeoxyadenosine 2-Chlorodeoxyadenosine (2-CdA, Cladribine, Leustatin; Ortho Biotech, Raritan, NJ) is a purine nucleoside analogue that acts as a substrate analogue to the enzyme adenosine deaminase. Upon entry into the cell, 2-CdA is phosphorylated and is, therefore, unable to exit from the cell. Intracytoplasmic accumulation of the triphosphate derivative of 2-CdA is ultimately lethal to the lymphocyte. In 1990, investigators from the Scripps Clinic reported durable and complete remissions in HCL patients following a single 7-day continuous intravenous infusion of 2-CdA in the amount of 0.1 mg/kg per day [12]. Eleven of 12 patients attained a complete response, the twelfth patient a partial response. Saven et al. recently reported on the long-term follow-up of 349 evaluable HCL patients who had received 2-CdA [13], 91% achieved a complete response and 7% a partial response, for an overall response rate of 98%. The overall survival for all patients was 96% at 48 months. The principal toxicities were myelosuppression and fever related to cladribine infusion, often seen as the hairy cells disappeared from the peripheral circulation. Tallman et al. reported on 50 HCL patients who received 2-CdA [14]; 80% achieved a complete response and 18% a partial response, for an overall response rate of 98%. The overall survival for all patients was 86% at 48 months. As in the Scripps Clinic study, the major toxicities were myelosuppression and fever related to the 2-CdA infusion. No late opportunistic infections were reported. A large trial from the NCI Group C Protocol involving 861 evaluable HCL patients demonstrated an overall response rate of 87%, but only 50% complete responses. Overall survival was 86% at 48 months, and the progression-free-survival was 76%. The 2-CdA was similarly administered as in the Scripps Clinic study, and the response criteria were also the same in both studies. In this NCI study, however, central pathology

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review was not performed and it is possible that some of the patients may have had atypical forms of HCL or other low-grade B-cell neoplasms, that would be less likely to respond favorably to 2-CdA. There has not been a prospective trial of dCF versus 2-CdA treatment of HCL An historical comparison of 165 HCL patients treated with either dCF or 2-CdA was published by Dearden and colleagues [15]. For dCF and 2-CdA, the complete response rates were 82 and 84%, respectively, and the partial response rates were 15 and 16%. For patients achieving a complete response with either therapy, the overall survival at 5 years was 97%. The results of interferon, dCF and 2-CdA treatment of HCL are summarized in Table 1. The optimum route of administration and dose schedule for 2-CdA remains under investigation. The successful administration of subcutaneous [16] and oral 2-CdA [17] has been reported as well as a weekly intravenous administration method [18]. These methods of drug delivery remain to be tested in large numbers of patients and also longer follow-up will be needed to determine whether these methods of drug administration are equivalent to the continuous intravenous infusion method.

3.5. Fludarabine Fludarabine (Fludara; Berlex Laboratories, Richmond, CA), which has been used extensively in indolent B-cell lymphoma and chronic lymphocytic leukemia, has been only used sparingly in the treatment of HCL. Response rates are less than those seen with 2-CdA or dCF, but may be slightly higher in HCL-variant diseases [19].

4. Salvage treatment of relapsed or refractory hairy cell leukemia

4.1. Relapses after primary interferon therapy In the Intergroup trial, 13% of the HCL patients having relapsed after primary interferon therapy achieved complete responses and 18% partial responses, when retreated with interferon [11]. In the same study, patients refractory to interferon who then received dCF achieved an overall response rate of 75%. The NCI Group C Protocol treated 429 HCL patients with 2CdA who had relapsed disease following interferon therapy; the overall response rate was 86% which was not significantly different from untreated patients receiving 2-CdA on the same protocol. In the Scripps Clinic study, responses to 2-CdA were independent of prior treatment status. These data suggest that patients with relapsed disease following interferon treatment should be treated with a purine nucleoside analogue.

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4.2. Relapses after primary 2 %-deoxycoformycin therapy In the Intergroup trial, of the nine patients who relapsed following initial treatment with dCF, 44% had a complete response to retreatment with dCF. Five patients with relapsed HCL following dCF were treated with 2-CdA [20]; four of the five patients had complete responses, and the fifth had a partial response, suggesting a lack of cross-resistance between the two agents despite structural and mechanistic similarities. The NCI Group C Protocol treated 68 patients with 2-CdA who had relapsed following dCF therapy; the overall response rate was 79% [11].

4.3. Relapses after primary 2 %-chlorodeoxyadenosine therapy In the Scripps Clinic series [12], 26% of patients relapsed at a median time of 29 months. The overall response rate following a second course of 2-CdA was 88%, similar to the overall response rate seen in the primary treatment of HCL with 2-CdA. Seymour et al. [21] reported responses to interferon in three patients who had relapsed following treatment with 2-CdA, but two of the three progressed within months after discontinuation of the interferon. These results tend to suggest

that 2-CdA has the highest response rate in this salvage circumstance regardless of the type of primary therapy. 2%-Deoxycoformycin may represent a reasonable alternative therapeutic option although response rates and duration information in large numbers of patients is lacking.

4.4. Other therapeutic options in purine analogue refractory hairy cell leukemia For HCL patients that prove refractory to purine analogue therapy, splenectomy remains an option [2]. Kreitman et al. have published preliminary results on a novel recombinant immunotoxin administered to patients with refractory HCL. The toxin targets CD25-expressing malignancies by means of an Fv portion of anti-Tac (CD25) fused to a truncated portion of the Pseudomonas exotoxin. The product is administered intravenously over 30 min every other day for three doses. Of four reported patients, one entered a complete remission, and the remaining three patients demonstrated over 98% clearance of circulating hairy cells. Toxicity in this small series was limited to fever, transaminase elevation, and rash. A reversible cardiomyopathy was noted in one patient [22].

Table 1 Interferon and purine nucleoside analogue treatment results in hairy cell leukemia Investigators

No. patients

Interferon Queseda et al. [37] Foon et al. [38] Rai et al. [39] Golomb et al. [40] Grever et al. [41]

30 14 25 195 159

9 1 7 7 17

17 12 6 152 43

Total

423

41 (10%)

230 (54%)

2%-Deoxycoformycin Cassileth et al. [10] Kraut et al. [42] Ho et al. [43] Grem et al. [44] Grever et al. [41] Dearden et al. [15]

50 23 33 66 154 165

32 20 11 37 117 135

10 1 15 15 4 25

8 2 7 14 33 5

Total

491

352 (72%)

70 (14%)

69 (14%)

Chlorodeoxyadenosine Saven et al. [29] Estey et al. [45] Juliusson et al. [46] Hoffman et al. [47] Tallman et al. [48] Dearden et al. [15]

349 46 16 49 50 45

319 36 12 37 40 38

22 5 0 12 9 7

Total

555

482 (87%)

55 (10%)

0 (0%)

2 (67%)

Fludarabine Kantarjian et al. [19]

3

Complete response

Partial response

Minor or no response

4 1 12 36 99 152 (36%)

8 5 4 0 1 0 18 (3%) 1 (33%)

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Recently, investigators from MD Anderson have reported responses using rituximab (Rituxan; IDEC Pharmaceuticals, San Diego, CA) in eight refractory HCL patients [23]. Four out of five patients achieved responses, and two being complete responses. Toxicity was minimal and limited to rigors accompanying the rituximab infusion in seven of eight patients.

5. Complications of purine analogue treatment in hairy cell leukemia

5.1. Immunosuppression Immunosuppression as a result of purine analogue therapy is likely due to both a reduction in the number of immunocompetent lymphocytes as well as inhibition of lymphocyte activation. Populations of CD4+ lymphocytes decline rapidly after 2-CdA therapy and remain depleted up to 40 months [24]. At concentrations achieved during 2-CdA therapy for HCL, inhibition of T- and B-lymphocyte activation has been documented in vitro [25,26]. This T-cell immunosuppression may account for the slight increase in early and late infections documented in patients who receive purine nucleoside analogue therapy.

5.2. Infections Culture-negative neutropenic fever occurs in 42% of HCL patients treated with 2-CdA [27]. A total of 13% of patients had early documented infections, including bacteremia, herpes simplex reactivation, herpes zoster reactivation, and cytomegalovirus retinitis. Dermatomal herpes zoster was the commonest late infection seen following 2-CdA therapy occurring in 2% of patients. This increased infectious risk is likely related to the 2-CdA induced immunosuppression [28]. A total of 35 HCL patients who received filgastrim before and after 2-CdA therapy were compared to a historical matched group of HCL patients who were treated with 2-CdA alone [29]. While there were fewer neutropenic days in the filgastrim-treated group, total numbers of patients hospitalized and hospital days were equivalent between the two groups. Routine use of filgastrim as a component of 2-CdA therapy for HCL cannot therefore be routinely recommended. Filgastrim, however, may be of benefit in patients with severe neutropenia and either active infection or repeated episodes of documented infections.

5.3. Second malignancies Whether HCL itself, or the systemic treatment thereof, places patients at an increased risk for the development of second malignancies is unclear. Au et

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al. [30] reported on the relative risk of second malignancies in 117 HCL patients compared to an agedmatched cohort; 36% of patients developed a second malignancy and 5% had two or more malignancies. Of note is that 10% of patients had malignancies diagnosed before their HCL was even diagnosed. The increased relative risk of malignancy in the HCL group slowly declined to baseline over time, suggesting that hairy cell burden rather than the therapy itself contributed to this phenomenon. Kampmeier et al. reported an increased risk of second malignancies following interferon therapy for HCL [31]. It is reasonable to conclude that it is the HCL itself that places patients at risk for second malignancies and not the treatment thereof. Saven et al. [29] reported a series of 358 patients treated with 2-CdA in which 27 (8%) developed second malignancies. As in other series, the most common malignancies were melanoma, prostate, and gastrointestinal. Kurzrock et al. [32] had reported that 26 out of 350 HCL patients developed a second malignancy. No excess of cancer risk was observed but a higher incidence of myeloma and lymphoma was noted. Another group of patients who were treated with a purine analogue for HCL [33] did not demonstrate an increased incidence of second malignancies.

6. Minimal residual disease and the curative potential of purine analogue treatment The malignant cells of HCL exhibit strong cytoplasmic reactivity to anti-CD22, CD25, CD103, DBA.44 and kappa or lambda light chain staining [1]. Ellison et al. [34] reported a series of HCL patients treated with 2-CdA who had serial bone marrow biopsies performed while in morphologic complete remission. Approximately 50% of the biopsies stained for CD20 and DBA.44 in cells that were morphologically consistent with hairy cells. These represented B 1% of the total marrow cellularity. Wheaton et al. [35] published results on bone marrow examinations in 39 HCL patients in apparent morphologic complete remission; 5 patients (13%) had minimal residual disease based on positive staining for CD20 and DBA.44 in cells morphologically consistent with HCL. A total of 40% of patients with detectable minimal residual disease went on to relapse, compared to only 7% of those without detectable minimal residual disease. The time to relapse from the point of detection of minimal residual disease was variable. A polymerase chain reaction assay for clonospecific immunoglobulin heavy chains of hairy cells was employed by Filleul et al. [36] to evaluate minimal residual disease in patients who had achieved morphologic complete response following 2-CdA. All of the evaluable patients in this series showed evidence of minimal resid-

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Table 2 Treatment characteristics in hairy cell leukemia

Dose Duration of treatment Responses Progression-free survival at 4 years Major toxicities

Interferon-a

2%-Deoxycoformycin

2-Chlorodeoxyadenosine

2 mU (three times per week) 12 months

4 mg/m2 (every other week) 3–6 months

0.1 mg/kg/day for 7 days 1 week

38% overall 11% complete 30%

79–88% overall 72–76% complete 72–76%

87–98% overall 50–91% complete 50–88%

Flu-like symptoms, early infections, fatigue

Nausea, early infections, immunosuppression, myelosuppression

Culture-negative fever, immunosuppression, myelosuppression

ual disease. The clinical significance of the detection of a small amount of residual malignant cells in the bone marrow or peripheral blood of patients with HCL in morphologic complete remission remains to be defined. These data suggest that durable remissions are achieved following purine analogue therapy in HCL but patients do not have their disease entirely eradicated. In support of this conclusion is that on the time to treatment failure graphs no plateau has been yet observed, suggesting that patients are, in fact, not cured by purine nucleoside analogue treatment but rather enjoy protracted remissions.

7. Future strategies The survivals of patients with HCL have been greatly improved following the introduction of interferon and the purine nucleoside analogues. Either 2CdA or dCF should be administered as first-line therapy for HCL patients given the high complete and durable response rates achieved with either agent. These agents and interferon are compared in Table 2. A 2-CdA treatment consists of only a single course of therapy over 1 week compared to the sequential administration every other week of dCF over 3–6 months. A significant number of patients in an apparent morphologic complete remission still have residual hairy cells in their bone marrow as evidenced by immunohistochemical stains. This may identify a group of patients at higher risk for relapse, but it remains to be proven whether treatment directed at eliminating their minimal residual disease will have any impact on the time to treatment failure or overall survival of these patients. This should be viewed in perspective as repeat courses of the original successful treatment effectively salvages the majority of relapsed HCL patients. Antibody therapy directed at antigens exhibited on the hairy cells, with or without conjugated toxin, is another therapeutic strategy which offers new hope in the salvage treatment of patients who have failed purine nucleoside analogues.

Acknowledgements The authors gratefully acknowledge the assistance of Kelly Bethel, Department of Pathology, Scripps Clinic, for her review and analysis of the pathology materials illustrated in Figs. 1–3. Contributions: A. Saven provided the concept and design of this review while J. Andrey wrote the manuscript. Both were equally responsible for the critical review as well as fund approval of the paper.

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