PMID- 35450208 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20220716 IS - 2040-6207 (Print) IS - 2040-6215 (Electronic) IS - 2040-6207 (Linking) VI - 13 DP - 2022 TI - Updates in hairy cell leukemia (HCL) and variant-type HCL (HCL-V): rationale for targeted treatments with a focus on ibrutinib. PG - 20406207221090886 LID - 10.1177/20406207221090886 [doi] LID - 20406207221090886 AB - 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. CI - (c) The Author(s), 2022. FAU - Paillassa, Jerome AU - Paillassa J AD - Service des Maladies du Sang, CHU d'Angers, Angers, France. FAU - Safa, Firas AU - Safa F AD - Service des Maladies du Sang, CHU d'Angers, Angers, France. FAU - Troussard, Xavier AU - Troussard X AUID- ORCID: 0000-0001-6863-9992 AD - Laboratoire Hematologie, CHU de Caen Normandie, avenue de Cote de Nacre, 14033 Caen Cedex, France. LA - eng PT - Journal Article PT - Review DEP - 20220413 PL - England TA - Ther Adv Hematol JT - Therapeutic advances in hematology JID - 101549589 PMC - PMC9016521 OTO - NOTNLM OT - BCR OT - BTK OT - hairy cell leukemia OT - hairy cell leukemia variant OT - ibrutinib COIS- Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Xavier Troussard: Consultant for Innate Pharma, Astra Zeneca, Abbvie, Beigene. Jerome Paillassa and Firas Safa: The authors declare that there is no conflict of interest. EDAT- 2022/04/23 06:00 MHDA- 2022/04/23 06:01 PMCR- 2022/04/13 CRDT- 2022/04/22 06:38 PHST- 2021/12/07 00:00 [received] PHST- 2022/03/14 00:00 [accepted] PHST- 2022/04/22 06:38 [entrez] PHST- 2022/04/23 06:00 [pubmed] PHST- 2022/04/23 06:01 [medline] PHST- 2022/04/13 00:00 [pmc-release] AID - 10.1177_20406207221090886 [pii] AID - 10.1177/20406207221090886 [doi] PST - epublish SO - Ther Adv Hematol. 2022 Apr 13;13:20406207221090886. doi: 10.1177/20406207221090886. eCollection 2022.