4
H. M. Golomb
The median time to failure, defined as the time from splenectomy to the need for a second therapy or death, was 18.8 months. Systemic therapy was the consideration for patients
with progressive disease after splenectomy. The use of interferon a (IFNa) was first recommended by Quesada et al. in 1984 [3], where normalization of blood counts occurred in all seven patients treated, with three patients reported as having a CR. In a large series of studies using various species of IFN at differing doses and duration of treatment, CRs were reported in 4–30% of patients, with an additional 43– 86% of patients achieving a PR [4]. There is no significant difference in response rates among any of the interferons. A 10-year follow-up published in 1994 on 69 patients initially treated with IFNa-2b documented that the median time to failure was 31.3 months and that the probability of survival at 6 years was 85%. It was noted that 14 of the 61 surviving patients had not required further treatment after their initial IFN therapy. In 1984, Spiers et al. [5] were the first to report the
dramatic responses achieved with pentostatin, a drug that inhibits adenosine deaminase, an enzyme in purine metabolism. They documented resolution of splenomegaly, normalization of blood counts, and complete elimination of hairy cell infiltration and excess reticulin 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 [4]. 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 2–6 months. In a very important rando- mized study published in 1995, Grever et al. [6] reported a comparison of pentostatin and IFNa-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 had a confirmed CR, and 121 (79%) of 154 patients achieved a confirmed CR or PR. This study documented that response rates were signifi- cantly higher (p50.0001) and relapse-free survival was significantly longer with pentostatin than with
IFN (p¼0.013). In 1990, Piro et al. established that cladribine (2-
chlorodeoxyadenosine), a purine analog resistant to deamination by adenosine deaminase, had a signifi- cant impact in HCL [7]. Of the first 12 patients treated, 11 obtained a CR and had almost none of the side effects usually associated with chemother-
apy. Subsequently, this work was updated and summarized in 1998 by Saven et al. [8] in 349 patients with HCL. 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 relapse, 33 (62%) had a CR, and 14 (26%) had a PR, thus establishing that cladribine resistance in patients with HCL is a rare occurrence. However, both Pileri et al. in 1994 and Konwalinka et al. in 1995 confirmed that 100% of cladribine-treated patients had residual hairy cells in their bone marrow when a variety of immunohistologic analyses were per- formed. In 2006, Mhawech-Fauceglia et al. [9] documen-
ted three patterns of minimal residual disease, which seemed to be correlated with clinical outcome. Patients in group 1 had fewer than 1% hairy cells and did not experience relapse, patients in group 2 had 1–5% hairy cells and half experienced relapse, and those in group 3 had more than 5% hairy cells and three-quarters experienced relapse. It was con- cluded that quantitative assessment of minimal residual disease may be of value in identifying patients at risk for relapse of HCL. In 2010, Sigal et al. [10] commented on minimal residual disease (MRD) in patients with long-term CR treated with 2- CDA (cladribine). They evaluated 19 patients (of 358 treated) in continuous and complete hematolo- gic response (median time from 2-CDA: 16 years) and found that nine (47%) had no evidence of MRD, seven (37%) had MRD, and three (16%) had morphologic evidence of HCL. As for the appropriate dosage used currently,
several studies have shown that a 2 h infusion on 5 consecutive days is as equally efficacious and well tolerated as a continuous 7-day infusion. In our institution, we advise a dosage of cladribine of 0.14 mg/kg/day for 5 days given by intravenous drip over 1h. In 2001, Kreitman’s group at the National Cancer
Institute ( NCI) published two reports on the efficacy of the anti-CD22 recombinant immunotoxin BL22 in chemotherapy-resistant hairy cell leukemia. 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 had a CR and two had a PR. Of the 11 patients in CR, two had MRD in the bone marrow or blood. Updated data were reported in 2006, which docu- mented a total of 31 patients treated and 19 patients obtaining CR. Rituximab is a chimeric immunoglobulin mono- clonal antibody that targets CD20 antigen expressed
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