Chemotherapy currently forms the backbone of HCL treatment. The most active group of chemotherapy drugs are the purine analogues cladribine and pentostatin, which have transformed the way HCL is treated. Prior to the purine analogues, treatment options for HCL comprised of splenectomy, chlorambucil or interferon. These therapies have now been relegated to second-line and beyond due to the high rate of durable remissions achieved in most patients by the purine analogues.

Pentostatin was first reported to be effective in HCL in 1984, achieving rapid and deep remissions in 2 previously untreated patients with HCL. These results were confirmed by subsequent phase 2 and 3 studies. Pentostatin is typically given intravenously at 4mg/m every 2 weeks until maximal response, with varying durations used. Response rates in the frontline are >80%, with complete remissions in >70%. Grade 4 myelosuppression occurs in ~15% of patients, and ~25% of patients will require systemic antibiotics for fever/infection. Median remission duration has been reported to be as long as 15 years.

Cladribine’s activity was first reported in HCL in 1988 by investigators from Scripps Clinic, who established a “classic” schedule of cladribine administered as a 7-day, continuous intravenous infusion. Response rates of >95%, and complete remission rates of >90%, was reported with this schedule. Projected median response duration exceeded 8 years. Recently, 19 patients in continuous, very long-term remissions (median 16 years from cladribine therapy) were electively reassessed with repeat bone marrow biopsy. Of these patients, approximately 50% had some degree of residual disease demonstrated either by morphology or immunohistochemistry suggesting that a single course of cladribine is not truly curative despite such durable responses. Cladribine as delivered as a single course has a higher rate of myelosuppression than intermittent pentostatin: grade 4 neutropenia occurs in >70%, and ~40% of patients will require systemic antibiotics for fever/infection. The fever associated with purine analogues in HCL is not always due to underlying infection, and routine prescription of G-CSF to shorten the neutropenic nadir does not reduce the risk of fevers.

Alternate schedules of cladribine have been explored. These deliver essentially the same total dose of cladribine (0.7mg/kg) as short daily intravenous infusions, or subcutaneous injections. Although not directly compared against the 7-day continuous infusion regimen, the results of these alternative schedules appear similar, and they are preferred in many centers due to their convenience and lack of need for an indwelling venous catheter.

Single-arm studies have explored the role of the anti-CD20 antibody rituximab in combination with chemotherapy in HCL. For example, MD Anderson investigators reported results of cladribine followed by 8 weekly courses of rituximab, with clearance of minimal residual disease in >90%. These encouraging results should be interpreted in the light of the excellent outcomes already achievable using pentostatin or cladribine monotherapy, and the lack of randomized data confirming a benefit to the addition of rituximab.

Patients who had previously responded to purine analogues can be retreated successfully with the same agent, albeit with some reduction in complete remission rates and remission durations. Based on published experience in a small number of patients, it may also be possible to obtain complete remissions in patients who had demonstrated resistance to one purine analogue, when re-treated with the alternate drug. Purine analogues profoundly suppress CD4 counts which can persist for >2 years; however, unlike the HIV experience, opportunistic infections are rare in the postremission period and most centers do not use prolonged pneumocystis jiroveci or herpesvirus prophylaxis (although many prescribe prophylaxis during and for up to 6 months following chemotherapy). Prolonged follow-up had shown an increased risk of second malignancies in patients with HCL who enter into remission after purine analogues, but it is not known if this increased risk is directly related to their chemotherapy, intrinsic to the HCL diagnosis, or related to the demographics of HCL (older males).