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© 2003 American Society for Clinical Oncology Extended Follow-Up of Patients With Hairy Cell Leukemia After Treatment With Cladribine
From the Division of Hematology/Oncology and Ida M. and Cecil H. Green Cancer Center of Scripps Clinic/Scripps Cancer Center, and Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA. Address reprint requests to Alan Saven, MD, Division of Hematology and Oncology, Scripps Clinic, 10666 N Torrey Pines Rd, La Jolla, CA 92037; saven.alan{at}scrippshealth.org.
Purpose: Hairy cell leukemia (HCL) is an uncommon, indolent, chronic B-cell lymphoproliferative disorder involving the marrow and spleen. Therapy for HCL includes splenectomy, interferon alfa-2a and alfa-2b, pentostatin, and cladribine. The purpose of this article was to report the extended follow-up of HCL patients treated with cladribine. Patients and Methods: Two hundred nine patients with HCL who were treated with cladribine had at least 7 years of follow-up. A course of cladribine constituted a 7-day continuous intravenous infusion at a dose of 0.1 mg/kg/d. Results: Of the 207 assessable patients who had at least 7 years of follow-up, 196 (95%) achieved a complete response (CR) and 11 (5%) achieved a partial response (PR) after a single course of cladribine (overall response rate, 100%). The median first-response duration for all responders was 98 months. Seventy-six patients (37%) experienced relapse after their first course of cladribine. The median time to first relapse for all responders was 42 months. Time to treatment failure of CRs compared with PRs was statistically significant (P < .0005). The overall survival rate was 97% recorded at 108 months. Forty-seven patients developed 58 second malignancies. The observed-to-expected ratio for second malignancies was 2.03 (95% confidence interval, 1.49 to 2.71). Conclusion: These results confirm previous observations that single courses of cladribine administered to patients with HCL induce high response rates, the majority of which are CRs. Most patients enjoy long-lasting complete remissions, and those patients who experience relapse can be successfully re-treated with cladribine.
HAIRY CELL LEUKEMIA (HCL) is an indolent, chronic B-cell lymphoproliferative disorder involving the marrow and spleen and was first described by Bouroncle et al1 in 1958. It is an uncommon disease, accounting for approximately 2% of all adult leukemias in the United States. On diagnosis, HCL patients commonly present with pancytopenia, splenomegaly, and circulating hairy cells that classically coexpress CD11c, CD25, and CD103 antigens in addition to the pan B-cell antigens CD19, CD20, or CD22. Until the mid-1980s, splenectomy was the standard treatment for HCL. Subsequently, three effective systemic therapies have been used, namely interferon alfa-2a and alfa-2b, pentostatin (2'-deoxycoformycin), and cladribine (2-chlorodeoxyadenosine; 2-CdA; Leustatin; Ortho Biotech, Raritan, NJ). Interferon alfa induces partial responses in the majority of HCL patients but produces complete responses only in the minority of patients.2 Cladribine is an established and efficacious treatment for HCL.3–6 It is a deoxyadenosine analog that is resistant to deamination by adenosine deaminase and induces lymphocytic apoptosis.7,8 In 1990, investigators at Scripps Clinic first reported on the profound activity of cladribine in the treatment of HCL.5 Twelve patients were treated, with 11 achieving a complete response and one achieving a partial response. We report the extended follow-up of 209 HCL patients treated with cladribine between April 1986 and June 1993 at a single institution, with a study cutoff at November 2000. All of the patients in this report had at least 7 years of follow-up.
Eligibility Criteria and Treatment Indications Patients required a diagnosis of HCL on the basis of a review of the peripheral blood, bone marrow, and/or splenic tissue (in splenectomized patients) as reviewed by hematopathologists at Scripps Clinic. Neutropenia (absolute neutrophil count < 1.0 x 109/L), anemia (hemoglobin < 10 g/dL), thrombocytopenia (platelets < 100 x 109/L), symptomatic splenomegaly, or repeated infections were required before cladribine was administered. Patients were eligible for cladribine treatment regardless of the percentage of infiltration of the bone marrow by HCL if any of these criteria were met. There were no age restrictions. Patients were excluded if they had received treatment within 4 weeks of cladribine therapy, if they had an active infection, or if they had abnormal renal or hepatic function tests. The exact same criteria were used for re-treatment with cladribine at the time of relapse. The Scripps Clinic institutional review board approved the study, and written informed consent was obtained for each study participant.
Patient Population
Drug Therapy and Supportive Care Patients received cladribine as a 7-day continuous intravenous infusion at a dose of 0.1 mg/kg/d. The clinical management of these patients has been previously reported.6,9 Patients generally underwent repeat bone marrow examinations at 3, 6, 12, and 24 months, and then every 12 to 24 months thereafter. Bone marrow examinations were repeated earlier for new-onset cytopenia or splenomegaly to document marrow relapse (if present) and before the institution of any chemotherapeutic agent after cladribine. For the 209 patients analyzed in this study, 84.7% had bone marrow biopsies at 3 months, 65.6% at 6 months, 66.5% at 12 months, 57.9% at 24 months, 41.1% from 25 to 48 months, 12.0% from 49 to 72 months, and 2.9% at 84 months. The resolution of splenomegaly for response assessment was determined by physical examination only.
Response Criteria and Relapse Definition Partial response required greater than 50% reduction in the absolute hairy cell count in the peripheral blood and bone marrow, greater than 50% improvement of all cytopenias, and greater than 50% reduction in abnormal lymphadenopathy or hepatosplenomegaly (assessed either clinically or radiologically). Patients not meeting response criteria were classified as nonresponders. Relapse after complete response was defined as the reappearance of hairy cells in the peripheral-blood smear and/or bone marrow (regardless of the degree of infiltration), development of peripheral-blood cytopenias, and/or splenomegaly on physical examination. Relapse after partial response was defined as a greater than 50% increase of residual hairy cells in the marrow, development of cytopenias, splenomegaly on physical examination insufficient to qualify as a partial response, or reappearance of hairy cells in the bone marrow of those patients classified as partial responders only on the basis of residual splenomegaly.
Statistical Analysis Time at risk for second malignancy was computed from the date of cladribine to the date of diagnosis of the second malignancy, date of the last patient contact, or date of death, whichever applied. Excess of second malignancies was expressed by the ratio of observed-to-expected cases from the United States general population. Expected numbers were calculated by using cancer incidence rates specific for age (in 5-year categories) and sex, for 1973 to 1991, as prepared by the Surveillance Epidemiology and End Results (SEER) Program of the National Cancer Institute (NCI).11 Cancer incidence rates were multiplied by observed person-years at risk in each age category to estimate expected frequency of second malignancies. Confidence intervals (CIs) of observed-to-expected ratios were obtained by assuming a Poisson distribution for the observed numbers.
Of the 207 assessable patients, 196 (95%) achieved a complete response and 11 (5%) achieved a partial response after a single course of cladribine; thus, the overall response rate was 100%. The median first response duration for all responders was 98 months (range, 8 to 172 months). Patients who achieved a complete response had a median first-response duration of 99 months (range, 8 to 172 months) and patients who had achieved a partial response had a median first-response duration of 37 months (range, 10 to 116 months).
Seventy-six patients (37%) relapsed after their first course of cladribine. Of these, 67 patients (88%) had achieved a prior complete response and nine patients (12%) had achieved a prior partial response. The median time to first relapse after the first course of cladribine was 42 months (range, 8 to 118 months) for all responders. Patients who had achieved a prior complete response had a median time to first relapse of 44 months (range, 8 to 118 months), and patients who had achieved a prior partial response had a median time to first relapse of 31 months (range, 10 to 108 months). Time to treatment failure of complete responders compared with partial responders was statistically significant (
Twenty patients (33%) suffered a second relapse. Of these patients, 10 (50%) received a third course of cladribine: six patients achieved a complete response, two patients achieved a partial response, one patient had no response, and one patient was nonassessable because neither bone marrow biopsy nor blood parameters were available for review. The median third-response duration for all responders was 20 months (range, 10 to 49 months). Patients who achieved a complete response had a median third-response duration of 15 months (range, 10 to 37 months). Patients who had achieved a partial response had a median third response duration of 47 months (range, 46 to 49 months). Two patients received a fourth course of cladribine. One patient achieved a complete response and the other was nonassessable because neither bone marrow biopsy nor blood parameters were available for review. The response duration for this single patient was 42 months (censored at last follow-up).
We examined whether baseline parameters were predictive of relapse after treatment with cladribine (Table 2
Of the 209 patients who had at least 7 years of follow-up, six patients (3%) have died (all complete responders). The causes of death were HCL and diverticular abscess after rituximab (one patient), acute myocardial infarction (one patient), Alzheimer’s disease and multi-infarct dementia (one patient), metastatic prostate cancer (one patient), and unknown (two patients; details of death unavailable for review). The overall survival rate was 97% recorded at 108 months (Fig 2  ).
The incidence of second malignancies in the 379 patients was analyzed. Forty-seven patients (22%) developed 58 second malignancies, which are summarized in Table 3 . The observed-to-expected ratio of developing a second malignancy, as compared with NCI SEER data,11 was 2.03 (95% CI, 1.49 to 2.71). Further analysis using logistic regression to model the risk of second malignancies revealed that the older the patient, the more likely was the occurrence of a second malignancy (2.45-fold greater for individuals in successive age quartiles; 95% CI, 1.45 to 4.14) and that patients who had had a malignancy before the diagnosis of HCL had a 3.7-fold increased risk of developing an additional malignancy compared with those who did not (95% CI, 1.33 to 10.31).
This study describes the extended follow-up of 209 patients with HCL treated at Scripps Clinic in La Jolla, CA, between April 1986 and June 1993, who had at least 7 years of follow-up recorded. One limitation of this study is that other than analysis of second malignancies, analysis was performed on the subset of patients who had at least 7 years of follow-up. This may have potentially induced a bias in the results; however, the aim of this study was to analyze long-term response, second malignancy, and survival data in a large number of HCL patients treated with cladribine. The results reported confirm previous observations that cladribine administered to patients with HCL induces high response rates, the majority of which are complete responses.3,5,6,12 In 1998, Saven et al6 reported the follow-up of 358 HCL patients treated with cladribine. Two hundred five of the 209 patients analyzed in the current study were included in the 1998 study, but the follow-up reported here is 7 years or greater. From the 358 patients, 349 were assessable, and from these, 91% achieved an initial complete response and 7% achieved a partial response, with an overall median duration of response follow-up of 52 months. Twenty-six percent of patients had experienced relapse at a median of 29 months. Of the 53 assessable HCL patients treated with a second course of cladribine, 62% achieved a complete response and 26% achieved a partial response. Twenty-seven patients (8%) developed second malignancies (only one hematopoietic) with an observed-to-expected ratio of 1.88 (using NCI SEER data11). The overall survival rate was 96% at 48 months. Other groups have reported similar results. Hoffman et al12 described the Long Island Jewish Medical Center experience of 49 HCL patients treated with cladribine. The initial complete response rate was 76% and the partial response rate was 24% (overall response rate, 100%). The median follow-up duration was 55 months. The relapse-free survival rate was 80% and the overall survival rate was 95%. Five second malignancies were seen in four patients (only one hematopoietic). Tallman et al3 reported on the Northwestern University experience, in which 52 patients received a single course of cladribine and had a median follow-up duration of 33 months. The complete response rate was 80% and the partial response rate was 18%. Two percent of patients failed to respond initially but had achieved a complete response by 6 months. The relapse rate was 14%. One second malignancy was reported (prostate cancer). In this report, 209 of 379 HCL patients had at least 7 years of follow-up. The outcome of these patients is excellent, with an overall survival rate of 97% at 108 months. It is important to note that even with extended follow-up of at least 7 years, there is no obvious plateau of the time-to-treatment-failure curve. Hence, it is unclear what proportion of patients, if any, will be cured. For the 207 HCL patients who had at least 7 years of follow-up, the initial response rate with the first course of cladribine was 100%, and the majority of responses were complete responses (95%). Responses were maintained for long-lasting periods, with a 98-month median response duration for patients receiving their first course of cladribine. The median time to treatment failure for first relapse was 42 months; patients who had achieved a prior complete response had a longer time to treatment failure than patients who had achieved a prior partial response (44 months v 31 months). Those patients requiring a second course of cladribine achieved a 92% response rate, demonstrating that cladribine is effective therapy even in patients who had experienced relapse from prior cladribine treatment. The response duration for patients treated with a second course of cladribine was shorter than that after the first course of cladribine (for all responders, 35 months v 98 months). Those patients requiring a third course of cladribine achieved an 89% response rate (eight of nine assessable patients). The median response duration after a third course of cladribine was even shorter at 20 months for all responders. The median third-response duration for complete responders was 15 months and for partial responders was 47 months. This discrepancy is most likely explained by the small patient numbers (six complete responders and two partial responders), because only 10 patients received a third course of cladribine. Two patients were treated with a fourth course of cladribine; the assessable patient achieved a complete response, indicating that even after a fourth course, a complete response is possible with cladribine. Patients with a shorter disease duration, lower hemoglobin levels, and a higher WBC count at baseline were more likely to experience treatment failure with cladribine. This may indicate a greater biologic tendency to aggressive behavior in this subset of patients, or, alternatively, the early use of cladribine in this subgroup of HCL patients may confer a disadvantage. Similar findings were noted in the NCI Group C Protocol study of cladribine in HCL patients13; patients who were younger, had higher hemoglobin levels, a lower WBC count, a better Eastern Cooperative Oncology Group performance status, and who had received no prior pentostatin generally had a better response to cladribine. Fifty-eight second malignancies developed in 22% of the HCL patients treated with cladribine, representing a low to moderate (2.03-fold) increase in developing a second neoplasm. Only three patients developed a hematologic malignancy after cladribine therapy. Risk factors for developing a second malignancy after the establishment of a diagnosis of HCL included advancing age and the diagnosis of a malignancy before the diagnosis of HCL, suggesting that factors other than cladribine itself contributed to the risk of developing a second malignancy. It has been suggested that the impairment in natural killer cell and T-cell function documented after cladribine in HCL patients may play a role in the formation of second malignancies.14–17 However, in the study by Cheson et al,16 an additional risk of second malignancies in HCL patients treated with either cladribine or pentostatin was not found. The percentage of HCL patients who develop second malignancies has varied widely and has been reported to be as high as 30.7% in a study by Au et al,18 who described a 20-year experience in British Columbia, Canada. In this study, there were 117 patients (90 men and 27 women). Thirty-six patients had a total of 44 separate additional malignancies. In contrast, Kurzrock et al19 reported on the M.D. Anderson Cancer Center experience of 350 HCL patients treated since 1968. There were 285 men and 65 women, the median age was 50 years, and the mean follow-up time after diagnosis was 7.1 years. Twenty-six patients (7.4%) had a total of 31 malignancies. They reported that there was no statistically significant increase in second malignancies in HCL patients as compared with data derived from the Connecticut Tumor Registry. Flinn et al20 reported on the long-term follow-up of HCL patients treated with pentostatin. This was an intergroup phase III study that used a randomized cross-over design with pentostatin and interferon alfa-2a. Two hundred forty-one patients were either treated with pentostatin as initial therapy or after experiencing treatment failure with interferon alfa. The median duration of follow-up was 9.3 years. The complete response rate was 72%, the 5-year survival rate was 90%, and the 10-year survival rate was 81%. Thirty-nine patients developed 44 second malignancies (eight hematopoietic). Kraut et al21 reported on a small cohort of 24 HCL patients who achieved a complete response with pentostatin. The median follow-up duration was 82 months. Twenty-three patients were alive at a median time of 84 months after achieving complete response. One patient died of refractory HCL. Of the 23 patients, 11 experienced relapse at a median of 30 months. Seven patients were re-treated after relapse, four with pentostatin and three with cladribine. Of the four patients re-treated with pentostatin, three achieved a complete response. Of the three patients re-treated with cladribine, two patients achieved a complete response and one patient achieved a clinical complete response. There were three second malignancies (one stage IA Hodgkin’s disease at 70 months, one basal cell carcinoma, and one squamous cell carcinoma). Direct comparisons cannot be made between the pentostatin and cladribine trials because of differences in study design. No head-to-head trials have been thus far performed. Novel therapies continue to be tested in the treatment of HCL. Rituximab, a monoclonal antibody targeting CD20, has been studied in refractory or relapsed HCL and has been shown to be active. Nieva et al22 from Scripps Clinic reported on a phase II study of rituximab in patients with HCL who had experienced treatment failure with cladribine. Of 15 assessable patients, there were two complete responses, one complete response with minimal residual disease, and two partial responses. A recent article by Kreitman et al23 demonstrated the efficacy and safety of recombinant immunotoxin BL22 in the treatment of HCL. In this small study of 16 cladribine-resistant patients, 11 achieved a complete response and two achieved a partial response. Two patients developed reversible hemolytic-uremic syndrome. Although BL22 represents an exciting new approach to the treatment of this disease, these results need to be interpreted cautiously, given the potential life-threatening toxicity of this agent. In addition, these results need to be compared with the long-term results for cladribine reported here. In conclusion, this extended follow-up of HCL patients confirms that cladribine is a safe and effective treatment for patients with HCL. The majority of patients enjoy long-lasting complete remissions and those patients who experience relapse frequently can be successfully re-treated with cladribine. Purine nucleoside analogs are currently the treatment of choice for HCL, and the decision of which purine analog to use should be based on physician and patient preference. It is the authors’ opinion that cladribine has the advantage of single administration over 7 days, compared with pentostatin, which is given every 2 weeks until best response, which is usually 3 to 6 months in duration. Novel treatment modalities must be interpreted within this context.
Supported in part by research funding and a free supply of cladribine from Ortho Biotech, Raritan, NJ. Presented in part at the Thirty-Seventh Annual Meeting of the American Society of Clinical Oncology, San Francisco, CA, May 12–15, 2001.
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9. Saven A, Burian C, Adusumalli J, et al: Filgrastim for cladribine-induced neutropenic fever in patients with hairy cell leukemia. Blood 93:2471–2477, 1999 10. Kaplan EL, Meier P: Non-parametric estimation from incomplete observations. J Am Stat Assoc 53:457–481, 1958[CrossRef] 11. Ries LA, Miller BA, Hankey BF, et al (eds): SEER Cancer Statistics Review, 1973–1991: Tables and Graphs, National Cancer Institute. National Institute of Health Publication No. 94-2789. Bethesda, MD, National Cancer Institute, 1994
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18. Au WY, Klasa RJ, Gallagher R, et al: Second malignancies in patients with hairy cell leukemia in British Columbia: A 20-year experience. Blood 92:1160–1164, 1998
19. Kurzrock R, Strom SS, Estey E, et al: Second cancer risk in hairy cell leukemia: Analysis of 350 patients. J Clin Oncol 15:1803–1810, 1997
20. Flinn IW, Kopecky KJ, Foucar MK, et al: Long-term follow-up of remission duration, mortality, and second malignancies in hairy cell leukemia patients treated with pentostatin. Blood 96:2981–2986, 2000
21. Kraut EH, Grever MR, Bouroncle BA: Long-term follow-up of patients with hairy cell leukemia after treatment with 2'-deoxycoformycin. Blood 84:4061–4063, 1994 22. Nieva J, Bethel K, Baker T, et al: Phase II study of rituximab in the treatment of cladribine-failed patients with hairy cell leukemia. Blood 98:364a, 2001 (abstr)
23. Kreitman RJ, Wilson WH, Bergeron K, et al: Efficacy of the anti-CD22 recombinant immunotoxin BL22 in chemotherapy-resistant hairy-cell leukemia. N Engl J Med 345:241–247, 2001 Submitted May 14, 2002; accepted November 6, 2002.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
1.5 x 109 neutrophils/L, 
2 cm in diameter. Peripheral-blood immunophenotypic analysis, tartrate resistant acid phosphatase staining, and marrow immunohistochemical staining (L26 and DBA.44) were not included in the definition of complete response. 
21 = 18.9; P < .0005) (Fig 1
