HCL Meeting 2010
cumbersome and is not readily available. Given the often very indolent natural history of HCL, it is not clear whether or not the detection of MRD is important in order to improve outcome.
Value of detection of minimal residual disease in predicting outcome
The presence of MRD as determined by the simple and readily available technique of IHChas been shown to predict relapse [5,12,13]. In a study from North- western University, examination of bone marrow biopsies 3 months after completion of a single cycle of cladribine with routine hematoxylin and eosin (H&E) staining and IHC usingmonoclonal antibodies anti-CD45RO, anti-CD20, and DBA.44, MRD was detected in 13% of patients by IHC that was not identified by H&E staining. Furthermore, 40% of patients in whom MRD was identified relapsed, compared to only 7% of patients in whom there was no detectable MRD with at least 1 year of follow-up [12] (Table I). Investigators in the Swiss Group for Clinical Cancer Research (SAKK) identified three patterns of MRD after cladribine [14]. Minimal residual disease as determined by IHC using CD20 and DBA.44 positivity with rare scattered suspicious hairy cells up to 1% constituted a first group, 1–5% formed the second group, and greater than 5% defined the third group. Relapse rates among patients in the three groups were 0%, 50%, and 67%, respectively. However, the number of patients in each group was very small. The true value of IHC in detectingMRDis difficult to determine because the definition of what constitutes MRD varies, and the optimal time to evaluate the maximal benefit for therapeutic interven- tions when the maximal effect of purine analogs has been achieved is not clear. For example, Bastie and colleagues showed that the rate of MRD negativity increased from 57% at 2 months after completion of cladribine to a maximum of 77% at 6 months, suggesting that the time to observe maximal benefit may be up to 6 months [13]. The sensitivity of MRD detected by patient-specific primer RQ-PCR in pre- dicting relapse after cladribine, rituximab, or the newer immunoconjugate BL22 has not been determined.
Eradication of minimal residual disease
Recent studies have suggested that the administra- tion of monoclonal antibody therapy with rituximab following cladribine can eradicate MRD [15]. Investigators at the M. D. Anderson Cancer Center treated 13 patients, generally previously untreated, with cladribine followed by eight weekly doses of rituximab at a standard dose. Minimal residual disease was eradicated in 92% of patients as detected by either consensus-primer PCR or immunopheno- typing by FC. Cervetti and co-workers also observed eradication of MRD as determined by PCR after cladribine with rituximab given at a median of approximately 4.3 months after the last exposure to cladribine [16]. The eradication of MRD was persistent in 19 of 27 patients for a median of 36 months (range 13–68). No patient had sustained a relapse at the time of publication. Whether the successful eradication of MRD following initial therapy prevents relapse has not been completely established. Furthermore, whether therapeutic inter- vention when minimal persistent or recurrent disease is identified provides an improvement in outcome compared to treatment when morphologic disease becomes evident is not clear.
Improving outcome in hairy cell leukemia by eradication of minimal residual disease
Investigators at the Scripps Clinic recently showed that some patients in apparent complete remission (CR) by peripheral blood counts of long duration can have evidence not only of minimal residual disease, but also of overt morphologic disease [4]. This is not completely unexpected, since HCL is often an indolent disease and the mechanisms by which a number of therapies eradicate disease in HCL are unknown. For example, the exact mechanism(s) that account for the benefits of splenectomy which appear independent of spleen size and include disease eradication and very prolonged remissions have remained elusive [17]. It is possible that treatment with effective therapy, whether splenectomy, a purine analog, monoclonal antibody, or an immunoconju-
Table I. Minimal residual disease (MRD) in hairy cell leukemia. Study Matutes [21]
Konwalinka [22] Wheaton [12]
n Analog
23 Pentostatin 11 Cladribine 39 Cladribine
Mhawech-Fauceglia [14] 17 Cladribine
Technique FC
IHC IHC IHC
FC, flow cytometry; IHC, immunohistochemistry; HCs, hairy cells.
MRDþ (%)
43
100 13 27
Relapse (%)
22 18 15 7
Relapse in MRDþ (%)
60 18 40
50%, HCs 1–5%; 100%, HCs 45%
Median follow-up (months)
15–108 7–29 3–36
21–108
67
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