Updates in hairy cell leukemia (HCL) and variant-type HCL (HCL-V): rationale for targeted treatments with a focus on ibrutinib

Abstract

Hairy cell leukemia (HCL) and HCL-like disorders such as hairy cell leukemia variant (HCL-V) and splenic diffuse red pulp lymphoma (SDRPL) are rare indolent B-cell malignancies. Purine analogs (PNAs), alone or in association with rituximab (R), are the standard of care for HCL in the first-line setting. However, PNAs are toxic and patients may become resistant to these drugs. Therefore, new therapeutic strategies are needed. Several recent in vitro studies highlighted the importance of the interactions between HCL cells and their microenvironment, in particular with bone marrow stromal cells, endothelial cells, and the extracellular matrix. In these interactions, chemokine receptors and adhesion molecules play a major role. Moreover, the importance of signaling pathways, like BRAF, BCR, and CXCR4 has been underlined. Bruton’s tyrosine kinase (BTK) is a fundamental signal transmitter of BCR and CXCR4 in HCL. Preclinical and recent clinical data showed an efficacy of ibrutinib, a BTK inhibitor (BTKi), in HCL and HCL-V. These promising results joined those of other emerging drugs like BRAF or MEK inhibitors and anti-CD22 immunotoxins. Plain Language Summary Bruton’s tyrosine kinase (BTK) inhibitors (BTKi) in hairy cell leukemia (HCL) and variant-type HCL The treatment of hairy cell leukemia (HCL) has changed significantly in recent years. In the first-line settings, treatment with purine analogs (PNAs) with or without anti-CD20 monoclonal antibodies remains the gold standard in 2022. In relapsed/refractory HCL, other drugs are needed: BRAF inhibitors: vemurafenib monotherapy with or without rituximab or dabrafenib in combination with trametinib, an MEK inhibitor (MEKi), as well as the anti-CD22 antibody drug conjugate moxetumomab pasudotox. There are arguments for the use of Bruton’s tyrosine kinase inhibitors (BTKi). Ibrutinib was recently tested in a multisite phase 2 study in 37 patients with either HCL (28 patients: 76%) or HCL-V (nine patients: 24%) including two who were previously untreated. Patients received single-agent ibrutinib at 420 mg daily (24 patients) or 840 mg daily (13 patients) until disease progression or unacceptable toxicity. The overall response rate (ORR) at 32 weeks was 24%, increasing to 36% at 48 weeks and reaching 54% at any time since starting ibrutinib. Seven patients achieved a complete response (CR) as the best response at any time on study, while 13 patients had a partial response (PR) and 10 patients had stable disease (SD). Interestingly, the response rate was not statistically different between HCL and HCL-V patients, suggesting that ibrutinib could be an option in both entities. The estimated 36-month progression-free survival (PFS) was 73% and the estimated 36-month overall survival (OS) was 85%, with no differences between HCL and HCL-V. The frequency of cardiovascular grade 1–2 adverse events (AEs) was 16% for atrial fibrillation; 3% for atrial flutter; 32% for hypertension; and 0%, 3%, and 11%, respectively, for grade ⩾ 3 AEs. Unlike in chronic lymphocytic leukemia (CLL), where the mechanism of action of ibrutinib is well known, the mechanism of action of ibrutinib in HCL appears to be unclear. No mutations were identified in patients with progressive disease, suggesting that the mechanisms of resistance could be different between HCL and CLL. The BTKi that are not yet approved are challenged by the new other targeted treatments.

Hairy Cell Leukemia

“…The estimated 36-month PFS was 73% and OS 85%, with no differences between HCL and HCL-v. Even though the results are not as spectacular as with other novel drugs, ibrutinib remains an option for patients not suitable for other treatments (77).…”

Current Status of Novel Agents for the Treatment of B Cell Malignancies: What’s Coming Next?

“…The pro-apoptotic proteins induce apoptosis by activating Bax and Bak either directly or indirectly via inhibition of the anti-apoptotic proteins ( Figure 1 a) [ 3 , 7 ]. Active B-cell receptor (BCR) signaling also contributes to cell survival, proliferation, and resistance to apoptosis in B cell malignancies [ 8 , 9 , 10 , 11 , 12 ] ( Table 1 ). BCR-mediated proliferation of malignant B cells may be caused by BCR pathway mutations and/or chronic active stimulation of the BCR [ 8 , 9 , 10 , 11 , 12 ].…”

“…Active B-cell receptor (BCR) signaling also contributes to cell survival, proliferation, and resistance to apoptosis in B cell malignancies [ 8 , 9 , 10 , 11 , 12 ] ( Table 1 ). BCR-mediated proliferation of malignant B cells may be caused by BCR pathway mutations and/or chronic active stimulation of the BCR [ 8 , 9 , 10 , 11 , 12 ]. The mechanism of BCR pathway activation in B cell malignancies is complex and has been well reviewed by Burger and Wiestner [ 13 ]; it includes continuous BCR stimulation by microbial antigens or autoantigens, activating mutations within the BCR complex or downstream signaling partners, and antigen-independent BCR signaling [ 13 ].…”

“…The mechanism of BCR pathway activation in B cell malignancies is complex and has been well reviewed by Burger and Wiestner [ 13 ]; it includes continuous BCR stimulation by microbial antigens or autoantigens, activating mutations within the BCR complex or downstream signaling partners, and antigen-independent BCR signaling [ 13 ]. The BCR pathway includes a large array of kinases, adaptor proteins and transcription factors (such as NF-κB); in particular, Bruton tyrosine kinase (BTK) and phosphatidylinositol-3 kinase (PI3K) are critical signaling enzymes involved in uncontrolled B cell proliferation and survival [ 10 , 11 , 12 , 13 ] ( Figure 1 b). Lastly, high levels of expression of certain tumor-associated antigens (TAAs; CD19, CD20, CD22, and CD38) in most B cell malignancies are correlated with a high proliferation rate and disease progression ( Table 1 ) [ 14 , 15 , 16 , 17 ].…”

Novel targeted treatments in hairy cell leukemia and other hairy cell-like disorders

“…Thus, the cross-talk between CXCR4 and CXCL12 leads to the migration of HCL cells in the bone marrow (BM), explaining the frequent involvement of BM in HCL ( 35 – 37 ). The importance of the interactions between HCL cells and their tumor microenvironment has been reviewed elsewhere ( 38 , 39 ). CXCR4 cross-linking leads to the activation of a signaling pathway, and BTK is also a fundamental signal transducer in this CXCR4 pathway, both in normal and in CLL B-cells ( 33 , 40 , 41 ).…”