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Journal of Clinical Oncology, Vol 26, No 16 (June 1), 2008: pp. 2607-2609 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.15.7420
Hairy Cell Leukemia: Treatment Successes in the Past 25 YearsUniversity of Chicago, Chicago, IL It has been approximately 50 years since hairy cell leukemia (HCL) was first recognized as a distinct clinical-pathologic entity.1 It has been 25 years since I summarized lessons learned during the first 25 years.2 In 1983, it was clear that progress had been made in establishing the diagnosis of HCL with a bone core biopsy3 and that newer immunology methods helped to characterize the disease as lymphoproliferative, probably of the B-cell type, in 95% of cases.4,5 Treatment knowledge was summarized by the statements that some patients initially required no systemic therapy, but that most required splenectomy; that one third of splenectomy patients ultimately required further therapy; and that most patients with progressive disease could be successfully treated with low-dose chlorambucil.5 In 1983, the survival with this sequential approach was 68% at 5 years.6 New drugs have been developed and improved survivals obtained in the past 25 years; these are the subjects of this editorial. These advances in treatment since 1983 have been dramatic and have improved the expected survival. Several systemic therapies lead to complete clinical responses, such that splenectomy is now only a rare consideration. However, complete eradication of hairy cells in the bone marrow seems to occur in only a minority of patients.7 The use of interferon alfa (IFN) in the treatment of HCL was first recommended in 1984. In the original report by Quesada et al,8 normalization of the blood counts occurred in all seven patients; three complete remissions (CRs) and four partial remissions (PRs) were reported. In a large series of studies using various species of IFN at differing doses and duration of treatment, CRs were reported in 4% to 30% of patients, with an additional 43% to 86% of patients achieving a PR.9-15 In the majority of studies, the CR rate is 5% to 10%, but even in these cases, careful review of the bone marrow often reveals a few persistent hairy cells.16,17
Failure-free survival, defined as the time from the end of IFN therapy to the time when further antileukemic therapy was needed, was the subject of several reports. Rai et al18 reported on 55 previously untreated patients with HCL treated with 1 year of IFN- Pentostatin (2-deoxycoformycin) inhibits adenosine deaminase, an enzyme in purine metabolism. In 1984, Spiers et al20 were the first to report the dramatic responses achieved with pentostatin in HCL. They documented resolution of splenomegaly, normalization of blood counts, and complete elimination of hairy cell infiltrate and excess reticulum from the bone marrow of two previously untreated patients. These results were confirmed and updated by other investigators, with an overall pathologic CR rate ranging from 56% to 89% in five phase II trials on 292 patients with HCL.21-25 Nearly all patients benefit from pentostatin therapy, given overall response rates of greater than 95%. No significant impact of previous therapy in this responsiveness is apparent. Response is fairly rapid, with an initial increase in the platelet count 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 1995, Grever et al26 reported on a randomized comparison of pentostatin and IFN- Cladribine (2-chlorodeoxyadenosine), a purine analog resistant to deamination by adenosine deaminase, was first reported by Piro et al27 in 1988 to have a significant impact in HCL. A single course of cladribine (0.1 mg/kg/d) was given for 7 days by continuous infusion. Of the first 12 patients treated, 11 obtained a CR, and there were almost none of the adverse effects usually associated with chemotherapy.28 Subsequently, this group updated their results in 148 patients, with an 85% CR rate and a 12% PR rate; only two patients subsequently experienced relapse.29 Saven et al30 summarized the results in 1998 from 349 patients with HCL treated with cladribine. They reported that 319 patients (91%) had an initial CR, and 22 patients (6%) had a PR. Ninety patients (26%) experienced relapse after a median of 29 months. Of 53 patients treated with a second course of cladribine at the time of first response, 33 patients (62%) had a CR, and 14 patients (26%) had a PR, thus establishing that cladribine resistance in patients with HCL is a rare occurrence. Further, Saven and Piro31 documented that despite structural and mechanistic homology between cladribine and pentostatin, cladribine induced durable CRs in patients with HCL that was truly resistant to pentostatin, suggesting the absence of cross-resistance between these two drugs. They also noted that, although 6 months after treatment 58 of 59 patients who had a CR had no detectable circulatory hairy cells, it had been demonstrated that "some patients in CR have evidence of minimal residual disease on immunohistochemical staining of bone marrow."31 It was confirmed by Pileri et al32 as well as Konwalinka et al33 that 100% of cladribine-treated patients had residual hairy cells in their bone marrow when a variety of immunohistologic analyses were performed. In 2006, Mhawech-Fauceglia et al34 documented three patterns of minimal residual disease, which seemed to be correlated with clinical outcome. Group 1 patients had less than 1% hairy cells and did not experience relapse, group 2 had 1% to 5% hairy cells and half experienced relapse, and group 3 had more than 5% hairy cells and three quarters experienced relapse. The authors concluded that quantitative assessment of minimal residual disease may be of value in identifying patients at risk for relapse of HCL. More recently, several studies have shown that a 2-hour infusion on 5 consecutive days is equally efficacious and equally well tolerated.35,36 In our institution, we advise a dosage of cladribine of 0.14 mg/kg/d for 5 days given by intravenous drip over 1 hour. It has been shown that classic or variant hairy cells are virtually always strongly positive for CD22, an adhesion molecule expressed exclusively in B cells. Kreitman et al37 developed the recombinant immunotoxin RFB4 (dsFv)-PE38, known as BL22, that contains variable domain (Fv) of the anti-CD22 monoclonal antibody RFB4. The Fv is fused to a fragment of Pseudomonas exotoxin called PE38, which contains domains responsible for cell death but lacks the domain necessary for cell binding. They treated 16 patients who had an inadequate response to their last treatment with cladribine. Of the 16 patients treated with an intravenous infusion of BL22 every other day for a total of three doses, 11 patients achieved a CR and two achieved a PR.38 Of the 11 patients in CR, two patients had minimal residual disease in the bone marrow or blood. During a median follow-up of 16 months (range, 10 to 23 months), three of the 11 patients who experienced CR experienced relapse and were re-treated, with all three patients obtaining a CR. Of concern was that two of the 16 treated patients developed serious, but completely reversible, hemolytic-uremic syndrome during the second cycle of treatment with BL 22. Updated data in 2006 documented treatment in a total of 31 patients, with 19 patients obtaining a CR.39 It has been shown that HCL cells exhibited a CD20 antigen density approximately five times greater than CLL cells. Rituximab is a chimeric immunoglobulin monoclonal antibody that targets the CD20 antigen expressed in most malignant B-cell leukemias and lymphomas. In a study reported in 2003 by Thomas et al,40 15 patients with relapsed or primary refractory HCL after nucleoside analogs received rituximab 375 mg/m2 weekly for a total of eight planned doses. The overall response rate was 80%, with eight patients (53%) achieving CR and two patients (13%) attaining CR by hematologic parameters with residual marrow disease; two patients (13%) had a PR. Three patients failed to achieve treatment response. Of the 12 responders observed for a median of 32 months, five patients (42%) experienced disease progression at 8 to 39 months from the start of therapy. In the same year, Nieva et al41 reported on 24 patients who had experienced relapse after cladribine who were treated with four weekly doses of rituximab at 375 mg/m2 and reported only three patients (13%) achieving CR and only three patients (13%) attaining a PR. In 2006, Ravandi et al42 reported 13 patients treated with cladribine followed by weekly doses of rituximab (375 mg/m2) to try to eradicate minimal residual disease. They reported that all patients obtained a CR, and 92% had eradication of minimal residual disease. They stated that eradication of minimal residual disease was possible, but it would take longer follow-up to determine whether it would lead to a reduced risk of relapse.
The last 25 years have been exciting years for clinicians involved in the care of patients with HCL. Four new agents, IFN- AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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-2b. 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. Speilberger et al
