Novel therapeutic options for relapsed hairy cell leukemia

Abstract

The majority of patients with hairy cell leukemia (HCL) achieve a response to therapy with cladribine or pentostatin with or without rituximab. However, late relapses can occur. Treatment of relapsed HCL can be difficult due to a poor tolerance to chemotherapy, increased risk of infections and decreased responsiveness to chemotherapy. The identification of BRAFV600E mutations and the role of aberrant MEK kinase and Bruton's tyrosine kinase (BTK) pathways in the pathogenesis of HCL have helped to develop novel targeted therapies for these patients. Currently, the most promising therapeutic strategies for relapsed or refractory HCL include recombinant immunoconjugates targeting CD22 (e.g. moxetumomab pasudotox), BRAF inhibitors such as vemurafenib and B cell receptor signaling kinase inhibitors such as ibrutinib. Furthermore, the VH4-34 molecular variant of classic HCL has been identified to be less responsive to chemotherapy. Herein, we review the results of the ongoing clinical trials and potential future therapies for relapsed/refractory HCL.

Biomarker Accessible and Chemically Addressable Mechanistic Subtypes of BRAF Melanoma

“…In consequence, this seemingly monolithic mechanistic subtype has rightfully been the object of intense targeted therapy (66–69). The overall patient response frequency to targeted therapy is high (~50%) (19, 70–72), yet intrinsic resistance, and ready emergence of acquired resistance, indicate that collateral genomic variation produces mechanistic diversity within the class of BRAF(V600) tumors. Consistent with this notion, we identified a cohort of 15 different context-specific genetic vulnerabilities, in melanoma cancer cell lines, that are individually linked to distinct genomic features detectable in tumors from melanoma patients (Supplementary Fig.…”

Response of relapsed central nervous system hairy cell leukemia to vemurafenib

“…in patients with systemic relapsed/ refractory HCL. [12][13][14] Additionally, vemurafenib demonstrates remarkable clinical efficacy in BRAF V600E-mutated melanoma with brain metastases, suggesting good CNS penetration in the setting of metastatic lesions. [15] Given the relapsing/refractory nature of our patient's HCL, as well as vemurafenib's documented CNS penetration, we decided to treat our patient with high dose vemurafenib (960 mg b.i.d.).…”

Are Cladribine and Rituximab Enough for the Treatment of Relapsed Hairy Cell Leukemia?

“…According to the French Society of Hematology, rituximab is indicated in combination with nucleoside analogues in the first relapse of disease (3), but we used this combination only in the second relapse, due to the lack of immunohistochemistry at first relapse. Rituximab was added due to the known tendency to decreased responsiveness to chemotherapy in relapsed disease [16]. In a recent study made on 41 patients, the combination of purine analogs with rituximab conduced to a 100 % response rate, even beyond frontline therapy [15].…”

“…moxetumomab pasudotox), BRAF inhibitors such as vemurafenib [16] or dabrafenib, MEK inhibitors such as trametinib [17], and B cell receptor signaling kinase inhibitors such as ibrutinib [16]. Vemurafenib (2 × 240 mg daily) used in induction, followed by a maintenance treatment with 240 mg once a day (after complete hematological remission) could also be useful to manage the relapsed HCL [2].…”