Rituximab combination treatment for relapsed hairy cell leukemia
in patients remaining disease-free. The study was approved by the Royal Marsden/Institute of Cancer Research Committee for Clinical Research.
Results
All 18 patients responded to therapy, 16 with a CR, one with a PR (case no. 12, Table I), and another with a PR pending further assessment (case no. 13). This CR rate (89%) was significantly higher than that which these same patients had achieved after their first-line treatment with a single-agent purine analog
(p¼0.02) and it also compared favorably with the CR rates of 68% after second-line therapy (n¼88) and 47% after third-line therapy (n¼22) in patients in the RMH series retreated with a purine analog
alone (see Dearden et al., this issue). All 13 patients who were assessed for MRD status were found to be MRD negative. The median follow-up from the start of the combination treatment was 36 months (range 5–83 months) and all 16 complete responders remained in CR. One partial responder (case no. 12), who had 15–20% residual disease in the bone marrow, relapsed at 10 months. Two patients whose bone marrow showed no evidence of hairy cells nevertheless had continued splenomegaly after treat- ment, requiring splenectomy. In the first of these (case no. 2), no hairy cells were found in any part of the spleen. The spleen of the other, recently treated patient (case no. 13) has yet to be removed and analyzed, and the platelet count currently remains below 1006109/L. This patient, initially deemed a non-responder until the bone marrow CR was known, is therefore currently recorded as a PR, pending further assessment of the spleen histology and the platelet count. There was only one case of recorded toxicity (asymptomatic eosinophilia), which resolved when the next rituximab infusion was delayed by a week. Disease-free survival, after the combination treat-
ment, was significantly longer than it had been in these same 18 patients previously, after their first-line treatment with single-agent pentostatin or cladribine
(p¼0.006, Figure 1). The estimated recurrence rate at 3 years after the combination treatment was 7%, compared with 55% after their initial first-line treatment. As a further point of comparison, the 3- year recurrence rate was 21% after second-line therapy and 42% after third-line therapy in the RMH series of patients retreated with a purine analog alone.
Discussion
The results in these 18 patients who received a purine analog with the addition of rituximab appear
Figure 1. Disease-free survival after combination of a purine analog with rituximab compared with disease-free survival previously seen in these same 18 patients after their first-line therapy with a purine analog (cladribine or pentostatin) alone (p¼0.006).
encouraging. There is a tendency in HCL toward a lower CR rate with each successive line of therapy and a correspondingly shorter time until relapse [2–8]. Yet, in these multiply treated patients, out- comes after the combination treatment were similar to those seen after first-line treatment in our series as a whole, that is, a CR rate in excess of 80% and an estimated relapse rate of around 7–11% by the end of the first 3 years. The majority of the combination- treated patients had a history of short-lived responses to single-agent purine analogs, and their disease-free survival was significantly longer after the combina- tion therapy than it had been after their own first-line
treatment (p¼0.006, Figure 1). None of the 16 patients who achieved a CR had yet relapsed, thus supporting the conclusion reached previously in this series that a CR may be equally durable if obtained after disease recurrence and that hence a CR should be the aim of any line of treatment [7]. No evidence has emerged to suggest a difference in
efficacy or safety between cladribine and pentostatin when combined with rituximab, and the choice of agent will depend largely on the patient’s previous history. As in chronic lymphocytic leukemia (CLL) [12], the results were similar whether rituximab was given concurrently with the purine analog, or sequentially. However, only 4/18 received it sequen- tially, and a larger series will be needed to resolve this issue. Similarly, the optimum number of rituximab infusions is not yet established, but on the current evidence, 6–8 infusions may perhaps be required in order to reach an MRD-negative CR in most patients. Rituximab monotherapy, used as a previous line of treatment in two patients (case nos. 12 and 18), resulted in a short-lived PR (6 months) and a non-response, respectively, contrasting markedly in
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