Update on hairy cell leukemia

Abstract

Hairy cell leukemia (HCL) is a chronic B-cell malignancy with multiple treatment options, including several that are investigational. Patients present with pancytopenia and splenomegaly, owing to the infiltration of leukemic cells expressing CD22, CD25, CD20, CD103, tartrate-resistant acid phosphatase (TRAP), annexin A1 (ANXA1), and the BRAF V600E mutation. A variant lacking CD25, ANXA1, TRAP, and the BRAF V600E mutation, called HCLv, is more aggressive and is classified as a separate disease. A molecularly defined variant expressing unmutated immunoglobulin heavy variable 4-34 (IGHV4-34) is also aggressive, lacks the BRAF V600E mutation, and has a phenotype of HCL or HCLv. The standard first-line treatment, which has remained unchanged for the past 25 to 30 years, is single-agent therapy with a purine analogue, either cladribine or pentostatin. This approach produces a high rate of complete remission. Residual traces of HCL cells, referred to as minimal residual disease, are present in most patients and cause frequent relapse. Repeated treatment with a purine analogue can restore remission, but at decreasing rates and with increasing cumulative toxicity. Rituximab has limited activity as a single agent but achieves high complete remission rates without minimal residual disease when combined with purine analogues, albeit with chemotherapy-associated toxicity. Investigational nonchemotherapy options include moxetumomab pasudotox, which targets CD22; vemurafenib or dabrafenib, each of which targets the BRAF V600E protein; trametinib, which targets mitogen-activated protein kinase enzyme (MEK); and ibrutinib, which targets Bruton tyrosine kinase (BTK).

Figure 1.

The schematic structures of anti–hairy cell leukemia agents. The traditional purine analogues pentostatin and cladribine have similar structures but slightly different mechanisms of action. Bendamustine contains the benzimidazole ring of cladribine, which makes it a purine analogue, but has alkylating groups for additional mechanisms of action. LMB-2 contains the variable domains (VH and VL) of the anti-CD25 monoclonal antibody anti-Tac connected by a (G₄S)₃ peptide linker, with VL fused to PE38. The anti-CD22 recombinant immunotoxins BL22 and moxetumomab pasudotox contain a disulfide-stabilized Fv made by engineering a disulfide bond into the framework regions, replacing Arg44 of VH and Gly100 of VL. In moxetumomab pasudotox, the amino acids 100, 100a, and 100b of VH, in the third complementarity-determining region (CDR3), are mutated from SSY (serine, serine, and tyrosine) to THW (threonine, histidine, and tryptophan), resulting in 14-fold improvement in binding affinity. Rituximab is a chimeric monoclonal antibody containing human CH3 and CH4 constant domains, whereas the remainder is of murine origin. The structures of the oral small molecules ibrutinib, vemurafenib, dabrafenib, and trametinib are shown. CDA, 2-chlorodeoxyadenosine; DCF, 2-deoxycoformycin; Fv, variable fragment.

Figure 2.

Treatment algorithm for HCL and HCLv. Both standard and investigational treatment options are shown for (1) patients with HCL without prior purine analogue therapy, (2) patients with HCL treated with 1 prior purine analogue, (3) patients with HCLv treated with 0 or 1 prior purine analogue, and (4) patients with multiply relapsed HCL/HCLv. BR, bendamustine/rituximab; CDA, cladribine (2-chlorodeoxyadenosine); CDAR, cladribine/rituximab; DCF, pentostatin (2’-deoxycoformycin); DCFR, pentostatin/rituximab; HCL, hairy cell leukemia; HCLv, hairy cell leukemia variant; tx, therapy.