Phase II Study of Sequential Therapy with Cladribine Followed by an Extended Course Rituximab in Patients with Hairy Cell Leukemia

Although the nucleoside analogs cladribine (2CDA) and pentostatin are effective in the initial therapy of patients (pts) with HCL, complete remissions (CR) are not universal and relapses do occur.

We have investigated whether an extended 8 week course of therapy with weekly rituximab after 2CDA can improve responses and eradicate minimal residual disease (MRD). Multicolor flow cytometry (MFC) was used to identify MRD by co-expression of CD103 and CD25 on CD19+ B-cells, with an assay sensitivity of 0.02%. MRD was also assessed by immunoglobulin heavy chain (IgH) polymerase chain reaction (PCR) assay using framework-1, -2 and -3 primer sets. 2CDA 5.6 mg/m² IV was administered over 2 hours daily for 5 days. Approximately 1 month after initiation of 2CDA, bone marrow (BM) MRD was assessed and rituximab 375 mg/m² IV was given weekly for 8 weeks. Responses were recorded and BM MRD was reevaluated after the completion of rituximab. Patients with untreated HCL (including variant form, HCLv) and those relapsing after 1 prior therapy were eligible.

To date, 45 pts have been treated including 38 with newly diagnosed HCL (4 with HCLv), and 7 (1 with HCLv) after relapse from 1 prior therapy (2CDA in 6 pts, chlorambucil in 1 pt). The median age of the pts was 54 years (range 32–89). Twenty five of 29 (86%) evaluable pts had mutated IgVH gene whereas IgVH was unmutated in 4 pts. 45 of 45 pts (100%) have achieved CR, defined as presence of no hairy cells in BM and blood with normalization of counts (ANC >1.5 × 10⁹/L, Hgb >12.0 g/dL, Plt > 100 × 10⁹/L), as well as resolution of splenomegaly, after completion of all therapy; MRD by MFC was positive in 33 of 37 (89%) evaluable pts after 2CDA therapy but became negative in 28 of 37 (76%) evaluable pts after rituximab. MRD by PCR was positive in 21 of 34 (62%) evaluable pts after 2CDA therapy and became negative in 27 of 38 (71%) evaluable pts after rituximab. Median serum IL-2 receptor level (reference range, 200–1100 U/mL) prior to initiation of therapy was 6661 U/mL (range, 458–44671). This fell to 1867 U/mL (range, 38–6661) after 2CDA and to 553 U/mL (range, 237–1673) after rituximab. The regimen was well tolerated with no grade 3 or 4 non-hematological adverse events directly related to the drugs. Only one pt (with HCLv) has relapsed; median CR duration has not been reached (range 3+ - 66+ months). Two pts developed another malignancy, pancreatic cancer in one and lung cancer in another, and died; while the pt with HCLv died from relapsed disease. Median survival duration has not been reached (range, 5+ - 71+ months).

Chemo-immunotherapy with 2CDA followed by an extended course of rituximab may increase CR rate and duration and is effective in eradicating MRD in HCL. This regimen is also effective in pts with HCLv although responses may be less durable.

Ravandi: Genentech: Research Funding. Off Label Use: Off label use of rituximab in hairy cell leukemia. Thomas: Novartis: Honoraria; Bristol-Meyer-Squibb: Honoraria; Pfizer:; Amgen: Research Funding.