Recommendations for the Management of Patients with Hairy-Cell Leukemia and Hairy-Cell Leukemia-like Disorders: A Work by French-Speaking Experts and French Innovative Leukemia Organization (FILO) Group

Abstract

Introduction: Hairy-cell leukemia (HCL) is a rare B-cell chronic lymphoproliferative disorder (B-CLPD), whose favorable prognosis has changed with the use of purine nucleoside analogs (PNAs), such as cladribine (CDA) or pentostatin (P). However, some patients eventually relapse and over time HCL becomes resistant to chemotherapy. Many discoveries have been made in the pathophysiology of HCL during the last decade, especially in genomics, with the identification of the BRAF^V600E mutation and cellular biology, including the importance of signaling pathways as well as tumor microenvironment. All of these new developments led to targeted treatments, especially BRAF inhibitors (BRAFis), MEK inhibitors (MEKis), Bruton's tyrosine kinase (BTK) inhibitors (BTKis) and recombinant anti-CD22 immunoconjugates.

Results: The following major changes or additions were introduced in these updated guidelines: the clinical relevance of the changes in the classification of splenic B-cell lymphomas and leukemias; the increasingly important diagnostic role of BRAF^V600E mutation; and the prognostic role of the immunoglobulin (IG) variable (V) heavy chain (H) (IGHV) mutational status and repertory. We also wish to insist on the specific involvement of bones, skin, brain and/or cerebrospinal fluid (CSF) of the disease at diagnosis or during the follow-up, the novel targeted drugs (BRAFi and MEKi) used for HCL treatment, and the increasing role of minimal residual disease (MRD) assessment.

Conclusion: Here we present recommendations for the diagnosis of HCL, treatment in first line and in relapsed/refractory patients as well as for HCL-like disorders including HCL variant (HCL-V)/splenic B-cell lymphomas/leukemias with prominent nucleoli (SBLPN) and splenic diffuse red pulp lymphoma (SDRPL).

Keywords: BRAF inhibitors; BRAFV600E mutation; HCL; HCL-V; SDRPL; diagnosis; flow cytometry; hairy-cell leukemia; hairy-cell leukemia variant; recommendations; splenic diffuse red pulp lymphoma; treatment.

Figure 1

Diagnostic algorithm for hairy-cell leukemia (HCL) and HCL-like disorders: HCL variant (HCL-V), splenic diffuse red pulp lymphoma (SDRPL), splenic marginal zone lymphoma (SMZL), B-cell prolymphocytic leukemia (B-PLL). # Determination of % of villous lymphocytes/total abnormal lymphocytes ($\mathrm{i}\mathrm{f}\ge 20\%$ → SDRPL). * Exclusion of MCL or CLL related-PLL if CD5+: karyotype t(11;14) or SOX11/CCND1 and Matutes RMH score. Dim: diminished expression, med: medium expression; neg: negative expression.

Figure 2

Therapeutic algorithm for treatment of patients with hairy-cell leukemia (HCL). * one or more of the following criteria: (1) Hb < 11 g/dL and/or platelets < 100 G/L and/or neutrophils < 1 G/L, (2) symptomatic organomegaly, (3) constitutional symptoms (fever, weight loss, night sweats), (4) recurrent infections. ** sc cladribine or iv pentostatin.

Figure 3

Therapeutic algorithm for treatment of patients with hairy-cell leukemia variant (HCL-V). * one or more of the following criteria: (1) Hb < 11 g/dL and/or platelets < 100 G/L and/or neutrophils < 1 G/L, (2) symptomatic organomegaly, (3) constitutional symptoms (fever, weight loss, night sweats), (4) recurrent infections.

Figure 4

Therapeutic algorithm for treatment of patients with splenic diffuse red pulp lymphoma (SDRPL). * one or more of the following criteria: (1) Hb < 11 g/dL and/or platelets < 100 G/L and/or neutrophils < 1 G/L, (2) symptomatic organomegaly, (3) constitutional symptoms (fever, weight loss, night sweats), (4) recurrent infections.