Cladribine at Scripps for hairy cell leukemia
course. These dramatic findings catapulted cladribine as the preferred front-line agent for HCL therapy.
Relapses after prior therapy with cladribine
The Scripps Clinic experience demonstrated that cladribine continued to have activity among cladri- bine-treated patients with relapsed HCL. Saven and colleagues reported that the time to treatment failure (TTF) for all 341 responders was 19% at 48 months (16% for CRs and 54% for PRs) [2]. Of 53 evaluable patients treated with a second course of cladribine at first relapse, 33 (62%) achieved CRs and 14 (26%) PRs [2]. Cladribine produced similar salvage rates with subsequent lines of relapse, although the duration of response tended to shorten. Pentostatin may have a role in patients with HCL who require re- treatment within 12 months of their initial cladribine exposure, as cladribine may be less effective in this clinical situation. However, large comparative data analyses between cladribine and pentostatin are lacking [9] (Tables II and III). A treatment algorithm for re-treatment in patients
with relapsed and refractory HCL is proposed in Figure 2. Due to concerns about cumulative marrow toxicity, we favor re-treatment with cladribine for patients who have an interval remission of at least 18 months; patients who relapse within 12 months of cladribine are probably somewhat refractory to cladribine, but may still respond to pentostatin since they have similar, but not identical, mechanisms of action. Occasionally, patients may have active op- portunistic infections or a hypoproliferative marrow and can be treated with IFN-a or splenectomy [4]. Newer agents, rituximab and BL-22 (an immuno- toxin), also have activity in the salvage setting and are reviewed elsewhere in this supplement.
Minimal residual disease in hairy cell leukemia
Investigators at Scripps Clinic did not demonstrate a plateau in the relapse curve, suggesting that all cladribine-treated patients may be at risk for relapse [8]. An explanation for the late relapses, even in patients with HCL with CRs, was the presence of
31
MRD. Historical criteria for CR only required the morphologic absence of hairy cells from the bone marrow. Pathologic review using modern techniques (reverse transcriptase-polymerase chain rection [RT- PCR], flow cytometry, and immunohistochemistries) have documented MRD in 13–50% of patients with HCL who satisfy criteria for historical morphologic CR. They also suggested that MRD predicts for clinical relapse [10,11]. Sigal et al. identified 19 patients from the 349
HCL-patient cohort at Scripps Clinic who had been in a continuous and complete hematologic remission after receiving only a single 7-day course of continuous-infusion cladribine with very long-term follow-up (median follow-up of 16 years) [3]. Of these 19 patients, bone marrow biopsies revealed nine (47%) patients without MRD. However, re- sidual HCL was noted in 10 patients: seven (37%) with MRD and three (16%) with gross morphologic disease. These results suggested that HCL is potentially curable after a single course of cladribine. In addition, many patients with MRDand even gross disease in their bone marrow did not clinically relapse with cytopenias, questioning the wisdom of more aggressive front-line therapeutic strategies. Future studies should attempt to define the subset of MRD-positive patients with HCL who are at high risk for relapse who may benefit from more aggres- sive initial combination therapies.
Acute and chronic complications of cladribine
Acute toxicities from cladribine are mainly mye- losuppression and infections. Grade 3 and 4
Table III. Relapses after prior pentostatin: re-treatment with cladribine.
Investigators
Saven et al. [2] Kraut et al. [18]
No. of patients CR (%) PR (%) MR/NE (%)
5 3
4 (80%) 1 (20%) 2 (67%) 0
Dearden et al. [9] 17 13 (76%) 4 (24%) 0
1 (33%) 0
CR, complete response; PR, partial response; MR/NE, minor response/non-evaluable.
Investigators Saven et al. [2] Dearden et al. [9]
Relapse No. of patients CR (%) 207
1 2 3 1
59 9 2 5
Table II. Relapses after prior cladribine: re-treatment with cladribine. PR (%) NR/NE (%) 0
196 (95%) 11 (5%) 44 (75%) 10 (17%) 6 (67%) 1 (50%) 4 (80%)
2 (22%) 1 (20%) CR, complete response; PR, partial response; NR/NE, no response/non-evaluable. 5 (8%)
1 (11%) 1 (50%)
Median response
98 months (8–172 months) 35 months (4 days–92 months) 20 months (10–49 months)
42þ months
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