β-Prumycin HCl

Hairy cell leukemia (HCL) is characterized by abnormal villous lymphoid cells that express CD103, CD123, CD25 and CD11c. HCL-like disorders, including hairy cell leukemia variant (vHCL) and splenic diffuse red pulp lymphoma (SDRPL), have similar morphologic criteria and a distinct phenotypic and genetic profile. We investigated the immunophenotypic features of a large cohort of 82 patients: 68 classical HCL, 5 vHCL/SDRPL and 9 HCL-like NOS. The HCL immunophenotype was heterogeneous: positive CD5 expression in 7/68 (10%), CD10 in 12/68 (18%), CD38 in 24/67 (36%), CD23 in 22/68 (32%) and CD43 in 19/65 (31%) patients. CD26 was expressed in 35/36 (97%) of HCL patients, none of vHCL/SDRPL and one of seven HCL-like NOS (14%). When adding CD26 to the immunologic HCL scoring system (one point for CD103, CD123, CD25, CD11c and CD26), the specificity was improved, increasing from 78.6% to 100%. We used unsupervised analysis of flow cytometry raw data (median fluorescence, percentage of expression) and the mutational profile of BRAF, MAP2K1 and KLF2. The analysis showed good separation between HCL and vHCL/SDRPL. The HCL score is not sufficient, and the use of unsupervised analysis could be promising to achieve a distinction between HCL and HCL-like disorders. However, these preliminary results have to be confirmed in a further study with a higher number of patients.

Purpose of review: This article aims to bring an update on the recent discoveries in hairy cell leukemia (HCL), especially findings in pathophysiology and therapeutic advances. Recent findings: Major discoveries have been made in genetics and epigenetics of HCL. Moreover, the importance of several signaling pathways and tumor microenvironment has been recently highlighted. These findings led to the development of new targeted therapies which have shown interesting results in recent clinical trials. HCL is a chronic B-cell lymphoproliferative disorder. Most patients respond to purine nucleoside analogs (PNA) like cladribine or pentostatin. However, relapses are frequent and the disease often becomes less sensitive to chemotherapy. Recent discoveries in pathophysiology, like the presence of the V600E mutation of the B-raf proto-oncogene (BRAF) gene and the importance of the B-cell receptor (BCR) pathway, led to the development of new drugs for relapsed/refractory (R/R) HCL patients. The variant-type of HCL (HCL-V) is usually less sensitive to PNA. Chemo-immunotherapy using PNA and rituximab (R), BRAF, MEK, or Bruton Tyrosine Kinase (BTK) inhibitors may be used. Good results were recently published and achieved with moxetumomab pasudotox (Moxe), an anti-CD22 immunoconjugate. In this review, we will present an update on HCL and HCL-V, focusing on pathophysiology and recent therapeutic advances.

In the category of mature B-cell neoplasms, splenic B-cell lymphoma and leukemia were clearly identified and include four distinct entities: hairy cell leukemia (HCL), splenic marginal zone lymphoma (SMZL), splenic diffuse red pulp lymphoma (SDRPL) and the new entity named splenic B-cell lymphoma/leukemia with prominent nucleoli (SBLPN). The BRAFV600E mutation is detected in nearly all HCL cases and offers a possibility of targeted therapy. BRAF inhibitors (BRAFi) represent effective and promising therapeutic approaches in patients with relapsed/refractory HCL. Vemurafenib and dabrafenib were assessed in clinical trials. The BRAFV600E mutation is missing in SDRPL and SBLPN: mitogen-activated protein kinase 1 (MAP2K1) mutations were found in 40% of SBLPN and VH4-34+ HCL patients, making possible to use MEK inhibitors (MEKi) such as trametinib, cobimetinib or binimetinib in monotherapy or associated with BRAFi. Other mutations may be associated and other signaling pathways involved, including the B-cell receptor signaling (BCR), cell cycle, epigenetic regulation and/or chromatin remodeling. In SDRPL, cyclin D3 (CCND3) mutations were found in 24% of patients, offering the possibility of using cell cycle inhibitors. Even if new emerging drugs, particularly those involved in the epigenetic regulation, have recently been added to the therapeutic armamentarium in HCL and HCL-like disorders, purine nucleoside analogs more and more associated with anti-CD20 monoclonal antibodies, are still used in the frontline setting. Thanks to the recent discoveries in genetics and signaling pathways in HCL and HCL-like disorders, new targeted therapies have been developed, have proven their efficacy and safety in several clinical trials and become essential in real life: BRAFi, MEKi, Bruton Tyrosine Kinase inhibitors (BTKi) and anti-CD22 immunotoxins. New other drugs emerged and have to be assessed in the future. In this article, we will discuss the main mutations identified in HCL and HCL-like disorders and the signaling pathways potentially involved in the pathogenesis of the different hairy cell disorders. We will discuss the results of the recent clinical trials, which will help us to propose an algorithm useful in clinical practice and we will highlight the different new drugs that may be used in the near future.