Long-Term Treatment of Hairy Cell Leukemia Patients with Interferon: Clinical and Molecular Aspects

Introduction. Hairy cell leukemia (HCL) is a rare clonal B-cell chronic lymphoproliferative disorder. Current treatments for HCL include purine analogs (PA), which are used successfully as front-line therapy in young and fit patients. The therapeutic armamentarium has been recently extended by the introduction of rituximab, BRAF oral inhibitors and other novel agents. Interferon alpha (IFNα) has been the first agent capable of inducing a response in HCL patients and of changing the natural course of the disease. It has been extensively used up to the introduction of PA. Nowadays, IFNα front-line is limited to pregnant women (or desiring a pregnancy), to patients with severe neutropenia or frail, or to relapsed/refractory patients. We hereby report the experience of 74 patients treated continuously with IFNα at our Center in Rome.

Methods. A retrospective analysis was performed on patients with HCL or with variant HCL treated between 1990 and 2020 with IFNα until progression or toxicity. The initial dosage was 3 MUI subcutaneously three times weekly (3d/week). In responding patients, after 12 months the dose was progressively tapered to reach a very low maintenance dose, ranging from 0.1 MUI 3d/week to 0.9 3d/week. After 12 months of treatment, the degree of response was based on peripheral blood count evaluation, bone marrow biopsy and IFNα front-line; C) patients resistant to PAs who received IFNα as second or further line of treatment.

Results. After 12 months of treatment, 70 patients (95%) achieved either a PR or a CR in 52 (70%) and 18 (24%) cases, respectively. Four (5.4%) patients were considered as non-responders. After a median follow-up of 92 months (range 7-236), 55 patients (75%) still maintained their response while receiving maintenance IFNα. The estimated 5-year and 10-year PFS were 89% and 77%, respectively (Fig. 1). The median PFS for these patients has not been reached at 10 years. Patients in CR at 12 months of treatment showed a significantly superior PFS rate (p 0.001). The 10-year PFS was 94% for patients in CR compared to 73% for patients who obtained a PR during abdominal ultrasound. The mutational status of BRAF V600E by PCR analysis was assessed in a subset of patients during treatment. Three groups of patients were identified: A) patients >65 years who received IFNα front-line; B) patients <65 years with comorbidities or women desiring a pregnancy who received IFNα therapy. Univariate analysis showed a different PFS for groups A, B and C, the 5-year PFS being 95%, 68% and 96%, respectively (p 0.005) (Fig. 1). In group A, a CR was achieved by 28% of cases and a PR by 62%, in group B the rates were 16% and 80%, and in group C 28% and 68%, respectively. Group C received a median number of 2 prior lines of treatment; 89% received PAs. Patients with previous PA-based treatment obtained a PR in 55% of cases and a CR in 32%. No significant differences were observed in terms of PFS in the 10 patients with a variant HCL (p 0.5); 1/10 achieved a CR. The impact of Hb, WBC count, spleen size and platelet count were assessed in univariate analysis. A significant difference in the entire case series was observed in patients with a WBC >3500/mmc at the start of treatment: the estimated median PFS was 236 vs 108 months (p 0.004). Twenty-two patients in response during IFNα maintenance were tested for MRD basing on BRAF status: 32% were negative during treatment (7 out of 22). All patients with negative MRD were in CR. G1-2 extra-hematologic toxicity, occurred as flu-like syndrome and fatigue, was observed in 25 patients (76% in group A), 13/25 patients discontinued IFNα for toxicity; 1 case of alopecia was reported. No patient required discontinuation due to G3-4 hematologic toxicity. Four deaths occurred, 2 due to secondary neoplasms and 2 in very elderly patients.

Conclusions. IFNα still retains a role in selected HCL patients. In young patients with comorbidities front-line IFNα remains a possible option, although not as effective as PAs. In elderly patients, the continuous administration allows remarkable results with acceptable toxicity. Also in patients resistant to PAs, INFα is capable of inducing durable responses in a considerable part of patients. The data on MRD demonstrate the possibility of achieving a molecular response. Although the role of IFNα is further limited by the advent of new agents, when administered in a continuous schedule it still represents a valid therapeutic option in specific subsets of HCL patients.