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C. E. Dearden et al.
advantages for patients in terms of convenience, safety (no IV line), and side effect profile (no infusion-related reactions), and for the healthcare system in terms of capacity and cost, without any evidence of a negative impact on outcome. A repeated cycle of cladribine is given after 4–6 months, without interim relapse, in cases where CR is not attained after the first cycle. Response rates and DFS for the two purine
analogs used at first, second, or third line are summarized in Table I. DFS was measured from the start of treatment until disease recurrence, censored at the date of latest follow-up in patients remaining disease-free. There was no significant difference in overall response (OR) or CR between pentostatin and cladribine at any line of treatment. Eighteen patients treated with cladribine (12 at first line and six at second line), who remained with partial response (PR) at the 3–4-month bone marrow (BM) evaluation, received a repeat cycle 4–7 months after the first cycle, without interim relapse. This led to a CR in 14 patients (78%), of whom all but one remained in remission at a median follow-up of 6 years (range 1–16 years). Relapse rates and DFS after treatment were also
not significantly different between the two agents. However, our series was not a prospective rando- mized comparison and the patients treated with each agent were different in number and timing, although similar in demographic characteristics [7].
Achieving a complete response is the most significant predictor of prolonged disease-free survival
The median DFS was 16 years overall: 20þyears (not reached) for patients attaining a CR and 4 years
Table I. Single-agent cladribine and pentostatin treatment of 242 patients with hairy cell leukemia: response and disease-free survival by line of treatment.
No. of patients CR PR NR
First line
Pentostatin Cladribine
Second line Pentostatin Cladribine
Third line Pentostatin Cladribine
188 82% 14% 4% 77% 54
76% 24% 0%
28 60
4*
59% 33% 8% 68% 69% 31% 0%
100% 0% 0% 58% 18* 38% 62% 0%
*Only 16/22 patients were evaluable for response (three pentos- tatin, 13 cladribine). CR, complete response; PR, partial response; NR, no response; DFS, disease-free survival.
Figure 1. Disease-free survival by response to first-line single-agent treatment with either pentostatin or cladribine, showing a significant difference between patients achieving a complete response (CR) versus a partial response (PR). The median
disease-free survival was 16 years overall: 20þyears (not reached) for patients attaining a CR and 4 years after a PR (p50.0001). There was no difference in DFS by type of treatment (pentostatin or cladribine).
DFS at 5 years
after a PR (p50.0001) (Figure 1). Overall, patients who were still in CR after 5 years had only a 25% risk of recurrence by 15 years. We observed a decline in the CR rate after
successive lines of single-agent treatment (Table I). However, the shorter DFS after second- and third- line treatment was only seen in partial responders, while CRs were equally durable, whether obtained with first-, second-, or third-line therapy. A CR (versus PR/no response [NR]) was the only factor significantly associated with longer second or sub- sequent relapse-free survival [7]. Thus, because of the importance of achieving a
CR, a proper assessment of response after complet- ing treatment should be the standard of care. Response can only be evaluated by performing good-quality BM trephine biopsies. Without this information it is not possible to predict the likely outcome following treatment. The timing of the BM is controversial. Following cladribine therapy there is often a delay in clearance of BM disease even up to 6 months and beyond in some patients. We consis- tently use a 3–4-month time point for disease response assessment. Based on this, we have been able to show that patients in whom there was a residual BM hairy cell infiltrate at that time had an inferior DFS compared to those in whom this was clear [7]. In response to this we now aim to deliver a second cycle of cladribine, 4–6 months after the first cycle, in those patients who have clear evidence of residual disease at the 3-month assessment and for whom there are no contraindications. Although only a few of our patients required this second cycle, the
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