Definition

Hairy cell leukemia variant (HCL-V) is an example of an unclassifiable splenic B-cell leukemia/lymphoma. It is included in the World Health Organization (WHO) classification as a provisional entity, no longer biologically related to classic HCL. HCL-V is a more aggressive disease than the classic form of HCL.

Epidemiology

It is a rare disorder accounting for approximately 0.4% of chronic lymphoid malignancies and 10% of all HCL cases. The disease affects the elderly population without sexual predominance. The median age of the patients is 71 years.

Diagnosis

A diagnosis of HCL should be established by morphological and flow cytometric analysis of peripheral blood, bone marrow and/or spleen specimens according to WHO criteria. HCL-V features are intermediate between those of classical HCL and prolymphocytic leukemia (PLL). Patients with HCL-V have elevated WBC and unique morphology and immunophenotype. HCL-V cells are CD19+, CD20+ and CD22+, and are positive for B-cell antigens on flow cytometric analysis. Leukemic cells are also positive for CD103 and CD11c and negative for CD25. In contrast to the classic HCL, patients with HCL-V have no monocytopenia, and the leukemic leukocytes demonstrate both weak TRAP activity and lack CD25 antigens. Moreover, HCL-V is not associated with the BRAF V600E mutation.

Differential Diagnosis

The differential diagnosis includes classic hairy cell leukemia, splenic lymphoma with villous lymphocytes (SLVL) and prolymphocytic variant of hairy cell leukemia.

Treatment

There is currently no curative treatment for HCL-V. The results of the therapy with cladribine or pentostatin are rather poor. In one study, 2-CdA was given in two-hour infusions for 5 days in a daily dose of 0.12 mg/kg. Four out of 6 patients did not respond to cladribine treatment and only two entered a PR lasting for 60+ and 29+ months. The mean number of 2-CdA cycles was 3.5. One patient achieved a CR, and a PR was noted in two. An analysis of 19 cases reported in various centers shows a response rate of 55% including only two CR. In addition, the majority of HCL-V patients required more than one cycle to maintain a PR. In addition, the majority of HCL-V patients required more than one cycle to maintain a response. Pentostatin induced a PR in 8 out of 15 (54%) patients and no CR was observed.

Rituximab alone or splenectomy followed by rituximab therapy can also induce CR in HCL-V. More recently, cladribine combined with rituximab was found to be more effective than cladribine alone or rituximab alone. Kreitman et al report a case of 10 patients with HCL-V treated simultaneously with cladribine and rituximab. Previously untreated patients or those previously treated with one course of cladribine were administered 0.15 mg/kg cladribine for 5 days, with 8 weekly 375 mg/m2 doses of rituximab beginning on day 1 and then administered weekly. Nine patients (90%) achieved a CR with this regimen, compared with 3 of 39 cases (8%) reported in the literature who were treated with cladribine alone (P < 0.0001). In addition, 7 patients (88%) had a CR with MRD negativity at 12-38 (median 24) months of follow-up. These results indicate that patients with HCL-V should be initially treated with cladribine combined with rituximab.

Alemtuzumab is an active agent in selected cases with HCL-V. Splenectomy induces clinical responses and corrects cytopenias in some patients with HCL-V. In one study, splenectomy resulted in good partial remission in 2/3 patients. Splenic irradiation could be also considered in elderly patients, particularly with high surgical risk. Some case studies indicate that autologous or allogenic hematopoietic cell transplantation can be effective in refractory patients.

Emerging Drugs

Moxetumomab pasudotox (CAT-8015, HA22) is a new generation of CD22-specific targeted immunotoxin composed of the Fv fragment of an anti-CD22 monoclonal antibody fused to a 38-kDa fragment of Pseudomonas exotoxin A, called PE38. The results of a Phase 1 trial of the drug in 28 patients with refractory/relapsed HCL, comprising 26 with classic HCL and two with HCL-V have been recently reported: Overall response rate of 86% was observed in the 28 patients, including a CR rate of 46%. The duration of overall response had not been reached at the time of publication. However, 15 (63%) of 24 patients were in remission after 13 to 43 months (median, 30 months).

The B-cell antigen receptor (BCR) signal transduction inhibitors, ibrutinib (PCI-32765) and idelalisib (GS-1101, CAL-101), represent a promising new strategy for treatment of B-cell lymphoid neoplasms, including HCL and possibly HCL-V. In the coming years, new agents will assist and perhaps replace standard therapy for HCL-V patients who now have suboptimal results after available treatment with purine nucleoside analogs and rituximab. Future research should focus on the novel therapeutic strategies based on molecular pathogenic mechanisms and the development of new targeted therapies.