Rituximab as treatment for minimal residual disease in hairy cell leukaemia: extended follow‐up

Hairy cell leukaemia (HCL) is a rare chronic lymphoproliferative disorder accounting for about 2% of adult leukaemias. Malignant cells present features of mature activated B-lymphocytes with bright expression of light-chain-restricted surface immunoglobulin (sIg), expression of numerous clonally related heavy-chain isotypes, IGHV mutation and co-expression of mature B cell CD markers. Treatment is indicated in the presence of significant cytopenia, symptomatic splenomegaly, recurrent infection or systemic symptoms. In recent years, therapeutic advances have brought about drastic changes in HCL prognosis. Purine analogues, especially 2-chlorodeoxyadenosine (Cladribine), drastically improved the survival rate, although complete eradication of disease can be rarely achieved (Piro et al, 1990; Tallman et al, 1996). Minimal residual disease (MRD) can be detected either by polymerase chain reaction (PCR) or immunohistochemical techniques on bone marrow samples of patients in complete haematological remission after purine analogue therapy. The persistence of MRD could thus explain the high relapse rate observed in HCL patients after long-term follow-up from the end of induction therapy (Wheaton et al, 1996). Rituximab could represent one attractive option in relapsed cases, because hairy cells typically express high levels of CD20 (Juliusson et al, 1994; Hoffman & Auerbach, 2000; Hagberg & Lundholm, 2001). The optimal schedule has not yet been defined, but some data suggest that extended dosing may improve patient outcome (Thomas. et al, 2003). Moreover, Rituximab could play an interesting role even in eradicating MRD (Cervetti et al, 2004; Ravandi et al, 2006). In our Institution, between May 2002 and November 2006, 27 HCL patients (25 male and 2 female; median age 60 years, range 39–72 years) were treated with anti-CD20 after a pretreatment with Cladribrine. Patients were considered eligible for the study if in partial remission or with persistence of MRD after induction. Other inclusion criteria were: age >18 years; life expectancy >6 months; absence of renal, hepatic and respiratory failure; written informed consent. Baseline clinical characteristics of patients are summarized in Table I. Cladribrine was started if patients presented at least one of the following indications: neutropenia (absolute neutrophil count, <1Æ5 · 10/l), anaemia (haemoglobin level, <100 g/l), thrombocytopenia (platelet count, <100 · 10/l), symptomatic splenomegaly, constitutional symptoms or documented repeated infections. In 17 patients older than 60 years, Cladibrine was administered IV at a dose of 5 mg/m/weekly for a total of six cycles, whereas in 10 younger patients, Cladribine was infused at the dose of 5 mg/m/d for five consecutive days. All patients received acyclovir, fluconazole and cotrimoxazole as antiinfective prophylaxis until 8 weeks after completion of Cladribine administration. Two months after the end of treatment, patients were evaluated for early response. Response criteria were those defined by the National Cancer Institute Working Group. At the time of enrolment in the study, overall response after Cladribrine was 89% [complete remission (CR) 26%, partial remission (PR) 63%; three cases were unresponsive]. The median time between the last Cladribine infusion and the beginning of this protocol was 4Æ3 months (range 1Æ5– 113 months). Minimal residual disease was evaluated by repeating PCR assays. PCR analyses were performed on DNA extracted from mononuclear cells separated by Ficoll/Hypaque gradient, as previously reported (Cervetti et al, 2004). By this method, all cases were proven to be still PCR-positive after induction. After demonstration of persistent MRD or detectable clinical disease, patients were treated by Rituximab (375 mg/m once a week for four doses). Statistical calculations were performed using the Statistical Package for the Social Sciences (spss) for Windows, release 15