scholarly journals The Treatment of Hairy Cell Leukemia with a Focus on Long Lasting Responders to Cladribine: A Thirty-Year Experience from the Institute of Hematology of Bologna

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4005-4005
Author(s):  
Alessandro Broccoli ◽  
Carolina Terragna ◽  
Vittorio Stefoni ◽  
Cinzia Pellegrini ◽  
Beatrice Casadei ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Peripheral Blood ◽  
Hairy Cell Leukemia ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
First Line ◽  
Advisory Committees ◽  
Purine Analogs

The treatment of hairy cell leukemia (HCL) has deeply changed over years. Purine analogs, namely cladribine (2CdA) now represent the treatment of choice. The BRAF V600E mutation is now regarded as the pathogenic event. One hundred and eighty-four patients were followed between 1986 and 2018 and treated according to era-specific guidelines. This is the largest monocentric series reported. Responses were classified by combining Consensus Resolution criteria and marrow immunohistochemistry. Patients were grouped according to the number of treatment lines they received (table). Ten patients treated with frontline 2CdA and in complete response (CR) for at least 5 years were tested for the presence of the BRAF V600E mutation in peripheral blood by droplet digital PCR as a molecular marker for active disease. Patients treated first line responded in 86% of cases, with 44% CR. Response rates remained high throughout the first 4 lines (84%, 81%, 79% for the second line onward, with CR in 38%, 37%, 15% of cases respectively), although decreasing progressively with the number of treatments received. One hundred and twenty-two patients received 2CdA as first line treatment, with a response rate of 86% and a CR rate of 54%. Among the 66 CR patients, 45 (68%) have never received further therapy: 11 patients are in continuous CR between 5 and 10 years after treatment, 14 between 10 and 20 years and 3 patients at more than 20 years. Median time-to-next treatment (TTNT) for patients after receiving 2CdA was 8.2 years: partial responders had a significantly shorter median TTNT than CR patients (5.3 years versus median not reached at 25.8 years, p=0.0001) (figure). Seven patients in CR for more than 5 years after front line 2CdA were BRAF V6500E negative in peripheral blood. One of these displayed disease recurrence and required further treatment roughly 2 years later. Three patients were positive for the BRAF V600E mutation at 6.5, 8.4 and 13.7 years after treatment and developed an overt disease relapse between 4 months and 2 years. Patients with HCL require subsequent lines of therapy in more than 50% of cases. Purine analogs allow significant response rates when applied first line and upon retreatment. Some patients may enjoy long lasting responses after one course of 2CdA and display no evidence of BRAF V600E mutation in peripheral blood. A PCR-based evaluation of the allelic burden in peripheral blood may provide information regarding disease activity over time. Figure Disclosures Cavo: Celgene, Janssen, Amgen, BMS, Abbvie, Takeda: Honoraria; Janssen, Celgene: Other: Travel Accommodations; Janssen, Celgene: Speakers Bureau; Janssen, Celgene, Amgen, Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Zinzani:TG Therapeutics: Honoraria, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Identification of the BRAF V600E mutation in Japanese patients with hairy cell leukemia and related diseases using a quenching probe method

2018 ◽  
Vol 108 (4) ◽  
pp. 416-422
Author(s):  
Hidekazu Itamura ◽  
Masaru Ide ◽  
Akemi Sato ◽  
Naoko Sueoka-Aragane ◽  
Eisaburo Sueoka ◽  
...  
Keyword(s):  
Hairy Cell Leukemia ◽  
Japanese Patients ◽  
Braf V600e Mutation ◽  
Probe Method ◽  
Braf V600e ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Quenching Probe

scholarly journals Hairy cell leukemia with CCND1/IGH fusion gene and BRAF V600E mutation

2020 ◽  
Vol 13 ◽  
pp. 100197 ◽  
Author(s):  
Zaid Abdel Rahman ◽  
Firas Muwalla ◽  
Liuyan Jiang ◽  
James Foran
Keyword(s):  
Hairy Cell Leukemia ◽  
Fusion Gene ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Hairy Cell ◽  
Cell Leukemia

scholarly journals Genomics of Hairy Cell Leukemia

2017 ◽  
Vol 35 (9) ◽  
pp. 1002-1010 ◽  
Author(s):  
Enrico Tiacci ◽  
Valentina Pettirossi ◽  
Gianluca Schiavoni ◽  
Brunangelo Falini
Keyword(s):  
B Cell ◽  
Hairy Cell Leukemia ◽  
Ex Vivo ◽  
Braf Inhibitor ◽  
Braf V600e ◽  
Leukemic Cells ◽  
Splenic Marginal Zone Lymphoma ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Purine Analogs

Hairy cell leukemia (HCL) is a chronic mature B-cell neoplasm with unique clinicopathologic features and an initial exquisite sensitivity to chemotherapy with purine analogs; however, the disease relapses, often repeatedly. The enigmatic pathogenesis of HCL was recently clarified by the discovery of its underlying genetic cause, the BRAF-V600E kinase-activating mutation, which is somatically and clonally present in almost all patients through the entire disease spectrum and clinical course. By aberrantly activating the RAF-MEK-ERK signaling pathway, BRAF-V600E shapes key biologic features of HCL, including its specific expression signature, hairy morphology, and antiapoptotic behavior. Accompanying mutations of the KLF2 transcription factor or the CDKN1B/p27 cell cycle inhibitor are recurrent in 16% of patients with HCL and likely cooperate with BRAF-V600E in HCL pathogenesis. Conversely, BRAF-V600E is absent in other B-cell neoplasms, including mimickers of HCL that require different treatments (eg, HCL-variant and splenic marginal zone lymphoma). Thus, testing for BRAF-V600E allows for a genetics-based differential diagnosis between HCL and HCL-like tumors, even noninvasively in routine blood samples. BRAF-V600E also represents a new therapeutic target. Patients’ leukemic cells exposed ex vivo to BRAF inhibitors are spoiled of their HCL identity and then undergo apoptosis. In clinical trials of patients with HCL who have experienced multiple relapses after purine analogs or who are refractory to purine analogs, a short course of the oral BRAF inhibitor vemurafenib produced an almost 100% response rate, including complete remission rates of 35% to 42%, without myelotoxicity. To further improve on these results, it will be important to clarify the mechanisms of incomplete leukemic cell eradication by vemurafenib and to explore chemotherapy-free combinations of a BRAF inhibitor with other targeted agents (eg, a MEK inhibitor and/or an anti-CD20 monoclonal antibody).

scholarly journals Both variant and IGHV4-34–expressing hairy cell leukemia lack the BRAF V600E mutation

Blood ◽  
2012 ◽  
Vol 119 (14) ◽  
pp. 3330-3332 ◽  
Author(s):  
Liqiang Xi ◽  
Evgeny Arons ◽  
Winnifred Navarro ◽  
Katherine R. Calvo ◽  
Maryalice Stetler-Stevenson ◽  
...  
Keyword(s):  
B Cell ◽  
Hairy Cell Leukemia ◽  
Poor Prognosis ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Wild Type ◽  
Ighv Gene ◽  
Gene Usage

Abstract Recently, the BRAF V600E mutation was reported in all cases of hairy cell leukemia (HCL) but not in other peripheral B-cell neoplasms. We wished to confirm these results and assess BRAF status in well-characterized cases of HCL associated with poor prognosis, including the immunophenotypically defined HCL variant (HCLv) and HCL expressing the IGHV4-34 immunoglobulin rearrangement. Fifty-three classic HCL (HCLc) and 16 HCLv cases were analyzed for BRAF, including 5 HCLc and 8 HCLv expressing IGHV4-34. BRAF was mutated in 42 (79%) HCLc, but wild-type in 11 (21%) HCLc and 16 (100%) HCLv. All 13 IGHV4-34+ HCLs were wild-type. IGHV gene usage in the 11 HCLc BRAF wild-type cases included 5 IGHV4-34, 5 other, and 1 unknown. Our results suggest that HCLv and IGHV4-34+ HCLs have a different pathogenesis than HCLc and that a significant minority of other HCLc are also wild-type for BRAF V600.

Continued Response off Treatment After BRAF Inhibition in Refractory Hairy Cell Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4600-4600
Author(s):  
Sascha Dietrich ◽  
Jennifer Hüllein ◽  
Michael Hundemer ◽  
Nicola Lehners ◽  
Alexander Jethwa ◽  
...  
Keyword(s):  
Disease Control ◽  
Peripheral Blood ◽  
Hairy Cell Leukemia ◽  
Drug Exposure ◽  
Objective Response ◽  
Braf V600e ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Recurrent Mutations ◽  
Hairy Cells

Abstract Abstract 4600 Targeted intervention against driver mutations is beginning to transform cancer treatment. A particular activating mutation of the BRAF serine/threonine protein kinase, BRAF V600E, is found in virtually all cases of hairy-cell leukemia (HCL), suggesting disease-specific oncogene dependence. Here, we present the extended follow up of a patient with chemotherapy refractory HCL who was treated with a short course of vemurafenib, a specific BRAF inhibitor. Before vemurafenib treatment, the patient had an almost complete bone marrow (BM) infiltration by hairy cells and massive splenomegaly (24.8×8.3 cm) leading to severe cytopenias (leukocytes, 680/μl; hemoglobin, 10 g/dl; platelets, 36,000/μl). No objective response could be achieved by three lines of purine analogue based treatment regimens (Cladribine, Pentostatin and R-Cladribine). We demonstrated the presence of the BRAFV600E mutation with a mutation specific antibody and 454 sequencing. In order to investigate if recurrent mutations may have contributed to refractoriness to purine analogues, a panel of genes commonly mutated across lymphoid malignancies were analysed (EZH2, KRAS, MYD88, NOTCH1, NRAS, PIK3CA, SF3B1, or TP53). No mutations were demonstrated Because of limited treatment options and recent success with vemurafenib in BRAF mutated melanoma we decided to use experimental treatment with vemurafenib after intensive counseling and started treatment with 240 mg twice daily after a single loading dose of 960 mg. The dose was slowly escalated to 1,920 mg/d which is the standard dose used in melanoma. After 6 and 16 days of 240mg bid the spleen size had shrunk to 18.8 × 5.8 and 14×5 cm, respectively. Blood counts rapidly recovered and sCD25 which is considered a reliable marker of HCL cell load dropped quickly to normal levels already at the lowest dose of 240 mg vemurafenib bid (Figure 1). There was no evidence of tumor lysis. Response was further evaluated by repeated trephine biopsies on days -1, 6, 17 and 36. After only 6 days of vemurafenib treatment p-ERK signaling was almost completely abolished in HCL cells in vivo, followed by apoptosis of HCL cells as shown by Tunnel staining and finally complete clearance of hairy cells on day 36. CR criteria were achieved on day 43. Because of the excellent disease control and the risk of short-latency non-melanoma skin cancers during therapy with vemurafenib, we discontinued vemurafenib after 56 days. CR continues to persist in the absence of drug exposure for more than 6 months at the time of abstract preparation (Figure 1). Massively parallel DNA sequencing was used to detect remaining mutant BRAF alleles in peripheral blood leukocytes on day 36. Among over 105 sequencing reads, the BRAF V600E mutation was not detectable above background (<0.3% of variant reads). Minimal residual disease (MRD by FACS) assessment of the peripheral blood revealed an approximately 100-fold reduction of hairy cells by day 22 of treatment and a complete eradication from day 36, which continues to persist for more than 6 months. Our observations show that targeting of a single mutated oncogene can provide durable disease control in this leukemia. Trials exploring chemotherapy-free treatment approaches with BRAF inhibitors in HCL are highly warranted. Disclosures: No relevant conflicts of interest to declare.

Real-time detection of BRAF V600E mutation from archival hairy cell leukemia FFPE tissue by nanopore sequencing

2017 ◽  
Vol 45 (1) ◽  
pp. 1-7 ◽  
Author(s):  
Davide Vacca ◽  
Valeria Cancila ◽  
Alessandro Gulino ◽  
Giosuè Lo Bosco ◽  
Beatrice Belmonte ◽  
...  
Keyword(s):  
Real Time ◽  
Hairy Cell Leukemia ◽  
Braf V600e Mutation ◽  
Ffpe Tissue ◽  
Braf V600e ◽  
Nanopore Sequencing ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Real Time Detection

scholarly journals Immunoconjugates and new molecular targets in hairy cell leukemia

Hematology ◽  
2012 ◽  
Vol 2012 (1) ◽  
pp. 660-666 ◽  
Author(s):  
Robert J. Kreitman
Keyword(s):  
Hairy Cell Leukemia ◽  
Poor Prognosis ◽  
Residual Disease ◽  
Single Agent ◽  
Braf V600e ◽  
Late Relapse ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Purine Analogs ◽  
Purine Analog

Abstract Hairy cell leukemia (HCL) is a B-cell malignancy that in its classic form is exquisitely sensitive to single-agent purine analog therapy, but that is associated in many patients with late relapse and eventual purine analog resistance. Minimal residual disease, which is present in most patients achieving complete remission with purine analogs, retains Ags that are ideal for targeted therapy. Rituximab, which targets CD20, is active as a single agent, particularly if combined with purine analogs. Recombinant immunotoxins targeting either CD25 or CD22 and containing truncated Pseudomonas exotoxin have achieved major responses in relapsed/refractory HCL. Moxetumomab pasudotox in phase 1 testing achieved responses in 86% of such patients (complete in 46%) without dose limiting toxicity and often without MRD. Soluble CD22 has been used for improved detection and monitoring of HCL, particularly the poor-prognosis variant that lacks CD25. Ig rearrangements unique for each HCL patient have been cloned, sequenced, and followed by real-time quantitative PCR using sequence-specific reagents. Analysis of these rearrangements has identified an unmutated IGVH4-34–expressing poor-prognosis variant with immunophenotypic characteristics of either classic or variant HCL. The BRAF V600E mutation, reported in 50% of melanomas, is present in > 85% of HCL cases that are both classic and express rearrangements other than IGVH4-34, making HCL a potential target for specific inhibitors of BRAF V600E. Additional targets are being defined in both classic and variant HCL, which should improve both detection and therapy.

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