Hairy Cell Leukemia: Treatment Successes in the Past 25 Years

It has been approximately 50 years since hairy cell leukemia (HCL) was first recognized as a distinct clinical-pathologic entity. It has been 25 years since I summarized lessons learned during the first 25 years. In 1983, it was clear that progress had been made in establishing the diagnosis of HCL with a bone core biopsy and that newer immunology methods helped to characterize the disease as lymphoproliferative, probably of the B-cell type, in 95% of cases. 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. In 1983, the survival with this sequential approach was 68% at 5 years. 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. The use of interferon alfa (IFN) in the treatment of HCL was first recommended in 1984. In the original report by Quesada et al, 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. 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. 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 al reported on 55 previously untreated patients with HCL treated with 1 year of IFN-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 reported a 10-year follow-up on 69 patients initially treated with IFN-2b and documented that the median time to IFN failure was 31.3 months and that the probability of survival at 6 years was 85%. These authors noted that 14 of the 61 surviving patients had not required further treatment after their initial IFN therapy. Pentostatin (2-deoxycoformycin) inhibits adenosine deaminase, an enzyme in purine metabolism. In 1984, Spiers et al 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. 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 al reported on a randomized comparison of pentostatin and IFN-2a in previously untreated patients with HCL. Among patients treated with IFN, 17 (11%) of 159 patients achieved a confirmed CR and 60 (38%) of 159 patients had a confirmed CR or PR. Among patients treated with pentostatin, 117 (76%) of 154 patients achieved a confirmed CR, and 121 (79%) of 154 patients had a confirmed CR or PR. Response rates were significantly higher (P .0001) and relapse-free survival was significantly longer with pentostatin than with IFN (P .013). Cladribine (2-chlorodeoxyadenosine), a purine analog resistant to deamination by adenosine deaminase, was first reported by Piro et al 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. 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. Saven et al 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 Piro 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, JOURNAL OF CLINICAL ONCOLOGY C E L E B R A T I N G 2 5 Y E A R S O F J C O VOLUME 26 NUMBER 16 JUNE 1 2008