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Blood Jun 2021Hairy cell leukemia (HCL) is a rare B-cell malignancy, and there is a need for novel treatments for patients who do not benefit from purine analogs. Ibrutinib, an oral...
Hairy cell leukemia (HCL) is a rare B-cell malignancy, and there is a need for novel treatments for patients who do not benefit from purine analogs. Ibrutinib, an oral agent targeting Bruton tyrosine kinase in the B-cell receptor signaling pathway, is highly effective in several malignancies. Its activity in HCL was unknown, so we conducted a multisite phase 2 study of oral ibrutinib in patients with either relapsed classic or variant hairy cell leukemia. The primary outcome measure was the overall response rate (ORR) at 32 weeks, and we also assessed response at 48 weeks and best response during treatment. Key secondary objectives were characterization of toxicity and determination of progression-free survival (PFS) and overall survival (OS). Thirty-seven patients were enrolled at 2 different doses (24 at 420 mg, 13 at 840 mg). The median duration of follow-up was 3.5 years (range, 0-5.9 years). The ORR at 32 weeks was 24%, which increased to 36% at 48 weeks. The best ORR was 54%. The estimated 36-month PFS was 73% and OS was 85%. The most frequent adverse events were diarrhea (59%), fatigue (54%), myalgia (54%), and nausea (51%). Hematologic adverse events were common: anemia (43%), thrombocytopenia (41%), and neutropenia (35%). Ibrutinib can be safely administered to patients with HCL with objective responses and results in prolonged disease control. Although the initial primary outcome objective of the study was not met, the observation of objective responses in heavily pretreated patients coupled with a favorable PFS suggests that ibrutinib may be beneficial in these patients. This trial was registered at www.clinicaltrials.gov as #NCT01841723.
Topics: Adenine; Administration, Oral; Adult; Aged; Disease-Free Survival; Female; Follow-Up Studies; Humans; Leukemia, Hairy Cell; Male; Middle Aged; Piperidines; Survival Rate
PubMed: 33754642
DOI: 10.1182/blood.2020009688 -
Modern Pathology : An Official Journal... Nov 2018Hairy cell leukemia-variant is rare. Only a small number of cases have been reported in the literature with little cytogenetic or molecular data available. In this...
Hairy cell leukemia-variant is rare. Only a small number of cases have been reported in the literature with little cytogenetic or molecular data available. In this study, we describe the clinicopathologic and genetic features of 23 patients with hairy cell leukemia-variant (16 men and 7 women) with a median age of 70 years. Most patients had splenomegaly (90%), leukocytosis (77%), and lymphocytosis (82%); no patients had monocytopenia. Histologically, the bone marrow biopsy specimens showed a mixed pattern of predominantly interstitial and lesser intrasinusoidal infiltration by leukemic cells. In bone marrow aspirate smears most cells had villous cytoplasmic features and a small nucleolus. We describe unusual sites of hairy cell leukemia-variant involvement in 4 patients, including brain, omentum, terminal ileum, and skin at the time of initial presentation. Immunophenotyping showed monotypic B-cells positive for pan B-cell antigens, CD11c, and CD103, and negative for CD25 and annexin A1. Conventional cytogenetic or fluorescence in situ hybridization analysis showed deletions of 17p13/TP53 and 11q22/ATM gene in 5/12 (42%) and 2/9 (22%) cases, respectively. Sequencing of the variable region of IGVH showed mutations (>2% deviation from germline) in 40% of the cases assessed. MAP2K1 mutation (p.C121S) was seen in 1 of 14 (7%) patients tested. No BRAF V600E mutations were detected. The patients were treated in a heterogeneous manner, but most often with therapies designed for classical hairy cell leukemia and the 5-year overall survival was 84%. In summary, hairy cell leukemia-variant exhibits a heterogeneous spectrum of clinical, morphologic, immunophenotypic, and genetic features that may overlap with classic hairy cell leukemia and other hairy cell-like B-cell neoplasms. A subset of patients can have an aggressive clinical course. In our experience MAP2K1 mutations are uncommon in this disease.
Topics: Aged; Aged, 80 and over; Female; Humans; Immunophenotyping; Leukemia, Hairy Cell; Male; Middle Aged; Retrospective Studies
PubMed: 29955146
DOI: 10.1038/s41379-018-0093-8 -
International Journal of Molecular... Jul 2021Classic hairy cell leukemia (HCL) is a rare mature B-cell malignancy associated with pancytopenia and infectious complications due to progressive infiltration of the... (Review)
Review
Classic hairy cell leukemia (HCL) is a rare mature B-cell malignancy associated with pancytopenia and infectious complications due to progressive infiltration of the bone marrow and spleen. Despite tremendous therapeutic advances achieved with the implementation of purine analogues such as cladribine into clinical practice, the culprit biologic alterations driving this fascinating hematologic disease have long stayed concealed. Nearly 10 years ago, BRAF V600E was finally identified as a key activating mutation detectable in almost all HCL patients and throughout the entire course of the disease. However, additional oncogenic biologic features seem mandatory to enable HCL transformation, an open issue still under active investigation. This review summarizes the current understanding of key pathogenic mechanisms implicated in HCL and discusses major hurdles to overcome in the context of other BRAF-mutated malignancies.
Topics: Animals; Humans; Leukemia, Hairy Cell; Mutation; Proto-Oncogene Proteins B-raf
PubMed: 34360545
DOI: 10.3390/ijms22157780 -
Current Treatment Options in Oncology Jun 2014Hairy cell leukemia (HCL) is an uncommon chronic leukemia of mature B cells. Leukemic B cells of HCL exhibit a characteristic morphology and immunophenotype and... (Review)
Review
Hairy cell leukemia (HCL) is an uncommon chronic leukemia of mature B cells. Leukemic B cells of HCL exhibit a characteristic morphology and immunophenotype and coexpress multiple clonally related immunoglobulin isotypes. Precise diagnosis and detailed workup is essential, because the clinical profile of HCL can closely mimic that of other chronic B-cell lymphoproliferative disorders that are treated differently. Variants of HCL, such as HCLv and VH4-34 molecular variant, vary in the immunophenotype and specific VH gene usage, and have been more resistant to available treatments. On the contrary, classic HCL is a highly curable disease. Most patients show an excellent long-term response to treatment with single-agent cladribine or pentostatin, with or without the addition of an anti-CD20 monoclonal antibody such as rituximab. However, approximately 30-40 % of patients with HCL relapse after therapy; this can be treated with the same purine analogue that was used for the initial treatment. Advanced molecular techniques have identified distinct molecular aberrations in the Raf/MEK-ERK pathway and BRAF (V600E) mutations that drive the proliferation and survival of HCL B cells. Currently, research in the field of HCL is focused on identifying novel therapeutic targets and potential agents that are safe and can universally cure the disease. Ongoing and planned clinical trials are assessing various treatment strategies, such as the combination of purine analogues and various anti-CD20 monoclonal antibodies, recombinant immunotoxins targeting CD22 (e.g., moxetumomab pasudotox), BRAF inhibitors, such as vemurafenib, and B-cell receptor signaling inhibitors, such as ibrutinib, which is a Bruton's tyrosine kinase inhibitor. This article provides an update of our current understanding of the pathophysiology of HCL and the treatment options available for patients with classic HCL. Discussion of variant forms of HCL is beyond the scope of this manuscript.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antigens, CD20; Antineoplastic Agents; B-Lymphocytes; Cladribine; Disease-Free Survival; Humans; Immunophenotyping; Immunotoxins; Indoles; Leukemia, Hairy Cell; Mutation; Pentostatin; Proto-Oncogene Proteins B-raf; Recombinant Proteins; Recurrence; Rituximab; Sulfonamides; Vemurafenib
PubMed: 24652320
DOI: 10.1007/s11864-014-0285-5 -
Magyar Onkologia Jun 2016Differential diagnosis of hairy cell leukemia (HCL) and related disorders (hairy cell leukemia variant and splenic marginal zone lymphoma) is of utmost importance since... (Review)
Review
Differential diagnosis of hairy cell leukemia (HCL) and related disorders (hairy cell leukemia variant and splenic marginal zone lymphoma) is of utmost importance since the treatment and prognosis of these lymphomas differ. Since 2011 diagnosis of hairy cell leukemia has been easier because of discovery of the disease defining somatic mutation BRAF V600E mutation, which has been also known as driver mutation in malignant melanoma. The presence of this mutation enabled targeted molecular therapy in HCL as well. As first line therapy purine nucleoside analogues are the gold standard, but refractory/relapsed patient are candidates for targeted BRAF-inhibitor therapy. This manuscript serves as guidance in making diagnosis and standard treatment of HCL, and summarizes newest data about molecular therapy, including our single center experience collected from 75 patients.
Topics: Diagnosis, Differential; Genetic Markers; Humans; Leukemia, Hairy Cell; Melanoma; Mutation; Neoplasm Proteins; Proto-Oncogene Proteins B-raf
PubMed: 27275640
DOI: No ID Found -
Blood Dec 2022
Topics: Humans; Leukemia, Hairy Cell; Vemurafenib; Proto-Oncogene Proteins B-raf; Mutation; Patients
PubMed: 36548021
DOI: 10.1182/blood.2022017939 -
Biomolecules Aug 2020Hairy cell leukemia (HCL) is an indolent B-cell malignancy with excellent initial response to purine analogs pentostatin or cladribine, but patients are rarely, if ever,... (Review)
Review
Hairy cell leukemia (HCL) is an indolent B-cell malignancy with excellent initial response to purine analogs pentostatin or cladribine, but patients are rarely, if ever, cured. Younger patients will usually need repeat chemotherapy which has declining benefits and increasing toxicities with each course. Targeted therapies directed to the BRAF V600E mutation and Bruton's tyrosine kinase may be helpful, but rarely eradicate the minimal residual disease (MRD) which will eventually lead to relapse. Moxetumomab pasudotox (Moxe) is an anti-CD22 recombinant immunotoxin, which binds to CD22 on HCL cells and leads to apoptotic cell death after internalization and trafficking of the toxin to the cytosol. Phase I testing achieved a complete remission (CR) rate of 57% in relapsed/refractory HCL. Most CRs were without MRD and eradication of MRD correlated with prolonged CR duration. Patients were often MRD-free after five years. Important mild-moderate toxicities included capillary leak and hemolytic uremic syndromes which could be prevented and managed conservatively. A phase 3 trial met its endpoint of durable CR with acceptable toxicity, leading to FDA approval of Moxe for relapsed/refractory HCL, under the name Lumoxiti. Moxe combined with rituximab is currently being evaluated in relapsed/refractory HCL to improve the rate of MRD-free CR.
Topics: Animals; Antineoplastic Agents, Immunological; Bacterial Toxins; Clinical Trials as Topic; Drug Development; Humans; Immunotoxins; Leukemia, Hairy Cell; Protein Engineering
PubMed: 32756468
DOI: 10.3390/biom10081140 -
Blood Apr 2022Hairy cell leukemia (HCL) responds very well to frontline chemotherapy with purine analogs (cladribine and pentostatine). However, approximately half of patients...
Hairy cell leukemia (HCL) responds very well to frontline chemotherapy with purine analogs (cladribine and pentostatine). However, approximately half of patients experience 1 or more relapses, which become progressively resistant to these myelotoxic and immunosuppressive agents. At progression, standard therapeutic options include a second course of purine analogs alone or in combination with rituximab and, upon second relapse, therapy with the anti-CD22 immunotoxin moxetumomab pasudotox. Furthermore, blockade of the mutant BRAF-V600E kinase (the pathogenetic hallmark of HCL) through orally available specific inhibitors (vemurafenib or dabrafenib) effaces the peculiar morphologic, phenotypic, and molecular identity of this disease and its typical antiapoptotic behavior and is emerging as an attractive chemotherapy-free strategy in various clinical scenarios. These include patients with, or at risk of, severe infections and, in a highly effective combination with rituximab, patients with relapsed or refractory HCL. Other treatments explored in clinical trials are BTK inhibition with ibrutinib and co-inhibition of BRAF (through dabrafenib or vemurafenib) and its downstream target MEK (through trametinib or cobimetinib). Here, we focus on our experience with BRAF inhibitors in clinical trials and as off-label use in routine practice by presenting 3 challenging clinical cases to illustrate their management in the context of all available treatment options.
Topics: Antineoplastic Agents; Humans; Leukemia, Hairy Cell; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Recurrence; Rituximab; Vemurafenib
PubMed: 35143639
DOI: 10.1182/blood.2021013502 -
Blood Cancer Journal Nov 2020
Topics: Female; Gene Expression Regulation, Leukemic; Humans; Leukemia, Hairy Cell; Male; Neoplasm Proteins; Programmed Cell Death 1 Receptor
PubMed: 33154356
DOI: 10.1038/s41408-020-00384-1 -
British Medical Journal May 1978
Topics: B-Lymphocytes; Humans; Leukemia, Hairy Cell
PubMed: 306269
DOI: 10.1136/bmj.1.6122.1278-a