Molecular Characteristic of Variant and Classic Hairy Cell Leukemia.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1063-1063
Author(s):  
Evgeny Arons ◽  
Tara Suntum ◽  
Joel Sunshine ◽  
Anna Orthwein ◽  
Inger Margulies ◽  
...  
Keyword(s):  
Hairy Cell Leukemia ◽  
Rank Order ◽  
Tumor Burden ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Monoclonal Immunoglobulin ◽  
Purine Analogs ◽  
Purine Analog ◽  
Vh Gene ◽  
Germline Sequence

Abstract 10–20% of patients with hairy cell leukemia (HCL) have a variant (HCLv) and present with high tumor burden in spleen and peripheral blood, and are less responsive to purine analogs. HCLv cells lack CD25 and sometimes CD103. Differentiating HCLv from classic HCL (HCLc) is sometimes difficult and it is unclear whether HCLv and HCLc are different disorders. Detailed molecular distinctions between HCLv and HCLc have not been reported. Patients with HCL were studied by flow cytometry and PCR to sequence the monoclonal immunoglobulin heavy chain rearrangements. 50 and 21 VH-D-JH rearrangements were obtained from 49 HCLc and 19 HCLv patients, respectively. All rearrangements except 2 each for HCLc and HCLv were productive. The incidence of VH4 usage was higher in HCLv than in HCLc (57% vs 20%, p=0.0041). VH4-34 was the most common VH gene in HCLv and was more common in HCLv than in HCLc (33% vs 8%, p=0.012). The percentage of rearrangements which were unmutated (defined as < 2% somatic mutations) was higher in HCLv than in HCLc (43% vs 18%, p=0.038), but % homology was similar in both groups by rank order (94.9 vs 94.3% p=0.22). However, in comparing 11 VH4-34 with 60 other rearrangements, homology was higher with VH4-34 (median 99.2 vs 95.2%, p < 0.0001). In fact, the higher frequency of unmutated rearrangements in HCLv vs HCLc was due to VH4-34 cases, since the 7 HCLv VH4-34 rearrangements were all unmated and had higher homology than the other 14 HCLv rearrangements (median 99.6 vs 94.2%, p=0.006). Moreover, unmutated rearrangement incidence was similar between HCLv and HCLc for non-VH4-34 cases (14 vs 13%, p=1.0, median homology 94.2% vs 95.3%, p=0.5). Of the 4 VH4-34+ HCLc (CD25+) patients, 3 (75%) had unmutated rearrangements, and these 3 all had clinical features of HCLv, including presenting with lymphocytosis, large splenomegaly, absent cytopenias, and primary failure of purine analog treatment. Our data shown that homology of monoclonal immunoglobulin rearrangement to the germline sequence of HCL patients appears more related to VH4-34 status than to whether patients have HCLv or HCLc. In fact, no molecular distinctions between HCLv and HCLc were observed in VH4-34-negative patients. Our data suggest VH4-34-positive HCL is itself a variant of HCL affecting ~15% of our patients. Such patients have features of HCLv, but their HCL cells can be CD25+.

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.

Presence and Absence of the BRAF V600E Mutation in Hairy Cell Leukemia and Its Variants

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 931-931
Author(s):  
Robert J. Kreitman ◽  
Liqiang Xi ◽  
Winnifred Navarro ◽  
Maryalice Stetler-Stevenson ◽  
Evgeny Arons ◽  
...  
Keyword(s):  
Hairy Cell Leukemia ◽  
Braf Mutation ◽  
Braf V600e ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Wild Type ◽  
Purine Analogs ◽  
Ighv Gene ◽  
Purine Analog ◽  
Gene Usage

Abstract Abstract 931 Background: Hairy cell leukemia (HCL) is a B-cell malignancy with distinctive immunophenotype. Purine analog therapy achieves durable complete remissions in 65–90% of patients. HCL variant (HCLv), recognized by the World Health Organization (WHO) as a different disease, lacks CD25, annexin A1 and/or TRAP, and responds poorly to purine analogs with only partial responses (PR) in <50% and lower overall survival (OS) from diagnosis. The recently described HCL variant expressing the immunoglobulin rearrangement IGHV4-34 also has poor response to purine analogs and OS, but can resemble HCL or HCLv immunophenotypically. The V600E BRAF mutation was recently reported present in 100% of 48 patients with HCL and absent in 16 with related disorders including at least 1 case of HCLv. We wished to confirm these results and test well-characterized cases of HCLv and IGHV4-34+ HCL. Methods: DNA was prepared from the blood of 70 patients with HCL and HCLv, 64 of whom were molecularly characterized with respect to IGHV gene usage. The mutation analysis of BRAF c.1799T>A (V600E) and other variants among codons 599–601 within exon 15 was performed using a target-specific mutant allele enriching COLD-PCR technique followed by pyrosequencing. The apparent percentage of mutant versus wild-type alleles was calculated with allele quantification (AQ) mode using PyroMark Software. The threshold AQ value for classifying samples as positive as a mutation was calculated as 3 standard deviations above the mean value of 24 normal blood samples. Results: Out of 70 total patients tested, 16 (23%) were diagnosed as HCLv based on WHO criteria, and the other 54 were classic HCL. Thirteen (19%) of the 70 cases expressed IGHV4-34, 5 classic HCL and 8 HCLv immunophenotypically. All 6 cases not characterized for IGHV gene usage were classic HCL. The analytic sensitivity of the pyrosequencing assay using cell line controls containing BRAF mutations was <5% tumor cells, and all cases were required to have ≥10% of total white blood cells as HCL. As shown in the table, 28 (40%) of the cases were wild-type with respect to BRAF, including all cases of HCLv. In addition, all 13 cases of IGHV4-34+ HCL, including 5 with classic immunophenotype, were negative for the V600E mutation. Moreover, 7 classic HCL cases were wild-type at V600 of BRAF, including 1 with unknown IGHV and 6 expressing IGHV2-70, IGHV3-15, IGHV3-23, IGHV3-48, IGHV4-39 and IGHV4-59. These 7 cases were relatively resistant to purine analog therapy although numbers were too few for statistical comparisons. In one of these 7 classic HCL cases, CD25 expression had decreased over time. Conclusions: The V600E BRAF mutation is not present in HCLv or in HCL cases with typical immunophenotype expressing IGHV4-34. A significant minority of other classic HCL cases, 7 (14%) of 49, were negative for the V600E BRAF mutation. It is possible that the V600E BRAF mutation is related to factors other than those affecting immunophenotype, including those influencing prognosis. Additional studies will be needed to better understand the role of V600E-mutated BRAF in HCL and the molecular basis of variants of this disease (Supported in part by NCI, intramural research program, NIH). Disclosures: No relevant conflicts of interest to declare.

scholarly journals VH gene analysis of hairy cell leukemia reveals a homogeneous mutation status and suggests its marginal zone B-cell origin

Leukemia ◽  
2004 ◽  
Vol 18 (10) ◽  
pp. 1729-1732 ◽  
Author(s):  
V Vanhentenrijk ◽  
A Tierens ◽  
I Wlodarska ◽  
G Verhoef ◽  
C D Wolf-Peeters
Keyword(s):  
B Cell ◽  
Hairy Cell Leukemia ◽  
Marginal Zone ◽  
Gene Analysis ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Mutation Status ◽  
Vh Gene

scholarly journals Serum interleukin-2 receptor as index of tumor burden in hairy cell leukemia [letter; comment]

Blood ◽  
1991 ◽  
Vol 77 (11) ◽  
pp. 2540-2542 ◽  
Author(s):  
G Pizzolo ◽  
A Ambrosetti ◽  
F Vinante ◽  
M Chilosi ◽  
G Semenzato
Keyword(s):  
Hairy Cell Leukemia ◽  
Interleukin 2 ◽  
Tumor Burden ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Interleukin 2 Receptor ◽  
Letter Comment

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).

Hairy Cell Leukemia and Secondary Lymphoproliferative Disorders.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4529-4529
Author(s):  
Monique Chang ◽  
Jennifer Kujawa ◽  
Michael Garrison ◽  
Alexander Hindenburg
Keyword(s):  
T Cell ◽  
Immune Function ◽  
Hairy Cell Leukemia ◽  
Hodgkin’S Lymphoma ◽  
Lymphoproliferative Disorders ◽  
Hodgkin's Lymphoma ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Purine Analogues ◽  
Purine Analogs

Abstract Prolonged immunosuppression is generally associated with an increase in incidence of lymphoid cancers. Transplant recipients, primary or genetic immunodeficiencies and patients with the acquired immunodeficiency syndrome (AIDS) have a known increased incidence of lymphoproliferative disorders. Patients who develop hairy cell leukemia (HCL) also have impaired immune function at the T-cell level that is present before definitive therapy. The lack of T-cell responsiveness is due to a decrease in memory T helper cells, abnormal activation of spleen T lymphocytes that behave like tumor infiltrating cells, and selection of oligoclonal T-cell populations with a very restricted and skewed T-cell repertoire. Inadequate antigen presentation may also play a role due to monocytopenia and lack of CD 28 on T-cells. Treatment with purine analogs, particularly pentostatin and cladribine, targets both resting and proliferating lymphocytes. This further impairs immune function by producing a prolonged reduction of normal lymphocytes, mainly CD4 cells, for as long as two years. There are reports of lymphoproliferative disorders as a second malignancy after treatment for HCL. However, it is not clear if treatment with purine analogs can induce second malignancies due to immune suppression. We reviewed the literature for cases of secondary lymphoproliferative disorders in patients treated with and without purine analogues for HCL. Purine analogues do not appear to have an increased risk for a secondary lymphoproliferative disorder. However, a preexisting immunosuppressed state may exist that antecedes the treatment of HCL and predisposes some patients to secondary lymphoproliferative disorders. Secondary Lymphoproliferative Disorders in Patients Treated for Hairy Cell Leukemia (HCL) Prior Treatment for HCL Non Hodgkin’s Lymphoma Hodgkin’s Lymphoma Waldenstrom’s Macroglobulinemia Multiple Myeloma Purine Analogues 16 3 2 1 Other Systemic Therapies 7 2 0 1 No Systemic Therapy 10 0 0 0 Unknown 3 1 0 0

Long term outcomes of hairy cell leukemia patients treated with first and subsequent line with purine analog: The Cleveland Clinic experience.

2015 ◽  
Vol 33 (15_suppl) ◽  
pp. e18034-e18034
Author(s):  
Yazan Madanat ◽  
Lisa A. Rybicki ◽  
Deepa Jagadeesh ◽  
Robert M. Dean ◽  
Brad L. Pohlman ◽  
...  
Keyword(s):  
Hairy Cell Leukemia ◽  
Cleveland Clinic ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Long Term Outcomes ◽  
Purine Analog ◽  
Clinic Experience

scholarly journals Fludarabine and rituximab for relapsed or refractory hairy cell leukemia

Blood ◽  
2012 ◽  
Vol 119 (9) ◽  
pp. 1988-1991 ◽  
Author(s):  
Alina S. Gerrie ◽  
Leslie N. Zypchen ◽  
Joseph M. Connors
Keyword(s):  
Hairy Cell Leukemia ◽  
Therapeutic Option ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
First Line ◽  
Response Data ◽  
Purine Analog ◽  
Duration Of Response ◽  
Effective Therapeutic Option

Abstract The purine analogs, pentostatin and cladribine, induce high remission rates when used as first-line monotherapy for hairy cell leukemia (HCL); however, patients continue to relapse. Re-treatment with the same or alternate purine analog produces lower response rates and a shorter duration of response. Fludarabine is another purine analog widely used in indolent lymphoid cancers, often in combination with rituximab, but there are few reports of its use in HCL. We identified 15 patients treated in British Columbia with fludarabine and rituximab (FR) from 2004 to 2010 for relapsed/refractory HCL after first-line cladribine (n = 3) or after multiple lines of therapy (n = 12). All patients with available response data responded to FR. With median follow-up of 35 months, 14 patients remain progression-free, whereas 1 patient has developed progressive leukemia and died. Five-year progression-free and overall survivals are 89% and 83%, respectively. FR is a safe and effective therapeutic option for relapsed/refractory HCL.

scholarly journals Vemurafenib Has Potent Antitumor Activity in Patients with Relapsed/Refractory BRAF Mutant Hairy Cell Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 24-24
Author(s):  
Jae H Park ◽  
Stephen S. Chung ◽  
Young Rock Chung ◽  
Helen Won ◽  
Eunhee Kim ◽  
...  
Keyword(s):  
Map Kinase ◽  
Hairy Cell Leukemia ◽  
Response Rate ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Purine Analogs ◽  
Promising Therapeutic Target ◽  
Map Kinase Pathway ◽  
Braf Mutant

Abstract Background: Although treatment with purine analogs is associated with a high response rate, hairy cell leukemia (HCL) remains incurable with a 30-40% relapse rate. For these patients (pts) and those intolerant to purine analogs, novel therapies are needed. The major finding that BRAFV600E mutations occur in 98% of HCL suggests BRAF as a promising therapeutic target. We therefore designed a phase II trial to (1) determine the clinical efficacy of the BRAF inhibitor vemurafenib in pts with relapsed/ refractory HCL and (2) identify biologic determinants of response and resistance to vemurafenib in HCL. Patients and Methods: Pts with BRAF mutant HCL who were refractory or resistant to purine analogs, or who had ≥2 relapses with an indication for treatment (ANC ≤1.0, HGB ≤10, or PLT ≤100K) were enrolled. Eligible pts received vemurafenib 960mg twice daily for 3 months. Bone marrow (BM) evaluations were performed after 3 months to assess response. Pts with partial (PR) or complete response (CR) with detectable minimal residual disease (MRD) were allowed to receive vemurafenib for up to 3 additional months. The primary endpoint of the study was overall response rate (ORR: CR + PR). Using a Simon’s mini-max two-stage design, if at least 4 of the 19 pts (≥20%) achieve ORR in the first stage, an additional 17 patients will be accrued to the second stage. If 11 or more pts achieve ORR out of the 36 pts, the study would be considered worthy of further investigation. Serial peripheral blood and/or BM samples were collected during the study for quantitative BRAF mutant allele burden, serum cytokine, multiparameter flow cytometry, and targeted next-generation sequencing analysis of a 350-gene panel to detect potential predictors of resistance and identify genes collaborating with BRAF mutations in HCL. Results: 22 pts have been enrolled and 20 pts received treatment. The median age was 61 years (range 44-77), and the median number of prior treatments was 3.5 (range 1-7). 20 pts are evaluable for toxicity and 17 patients for disease response with a median follow up of 10 months (range 2-19). The most common adverse events were rash (40%, Gr1-2), arthralgia (30%, Gr1-2), photosensitivity (20%, Gr1), and pruritis (15%, Gr1). Three pts developed squamous cell carcinoma (SCC), all of whom had previous history of SCC. All patients were able to complete the intended treatment (3 cycles: 11 pts, >3 cycles: 6 pts). All 17 evaluable pts achieved complete hematologic recovery with an overall response rate (ORR) of 100%. 6 pts achieved CR (4 MRD- and 2 MRD+) and 11 pts achieved PR with very minimal disease (Figure 1). Responses were rapid with reduction of circulating hairy cells within 24 hours and normalization of sCD25 within 2-3 weeks (Figure 2). This correlated with dephosphorylation of ERK at 1 month. Several additional inflammatory cytokines correlated with the leukemic cell burden identifying novel tumor markers in HCL including sTNF-R2, sIL-1R2, and sIL4R. Genetic analysis identified a median of 3 (range 0-5) somatic mutations co-existing with the BRAFV600E mutation in HCL including recurrent mutations in MLL2 and CREBBP (Figure 2). Several of these alterations were present as minor clones identifying a clonal architecture in HCL which was not previously appreciated. One pt was found to have de novo resistance to vemurafenib. Genetic analysis identified that this pt’s pretreatment HCL cells harbored a previously undescribed missense mutation in IRS1 (IRS1P1201S) in addition to BRAFV600E mutation. Given prior knowledge that IRS1 (Insulin Receptor Substrate 1) activates both MAP kinase and PI3K-AKT signaling, we compared the effects of expression of wildtype and mutant IRS1 cDNAs on signaling. This revealed robust activation of PI3K-AKT signaling induced by IRS1P1201S-mutant cells relative to wildtype. Conclusions: While longer follow-up is needed to assess the durability of the response, our results indicate that vemurafenib has potent antitumor activity in pts with relapsed/refractory BRAF mutant HCL. These data confirm the MAP kinase pathway as a rational promising therapeutic target in HCL and identify activation of signaling pathways parallel to the MAP kinase pathway as a first mechanism of RAF inhibitor resistance in a hematological malignancy. Subsequent studies will be required to prove that inhibition of B-raf may be the best initial therapy in HCL pts who require treatment. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Park: Genentech: Research Funding. Off Label Use: Vemurafenib in hairy cell leukemia. Rosen:Novartis: Consultancy.

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