The role of autocrine FGF-2 in the distinctive bone marrow fibrosis of hairy-cell leukemia (HCL)

Blood ◽  
2003 ◽  
Vol 102 (3) ◽  
pp. 1051-1056 ◽  
Author(s):  
Khalil A. Aziz ◽  
Kathleen J. Till ◽  
Haijuan Chen ◽  
Joseph R. Slupsky ◽  
Fiona Campbell ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Growth Factor ◽  
Hairy Cell Leukemia ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Cd44 Isoforms ◽  
Hairy Cells

Abstract Bone marrow (BM) fibrosis is a central diagnostic and pathogenetic feature of hairy-cell leukemia (HCL). It is known that fibronectin (FN) produced and assembled by the malignant hairy cells (HCs) themselves is a major component of this fibrosis. It is also known that FN production is greatly enhanced by adhesion of HCs to hyaluronan (HA) via CD44. The aim of the present study was to establish the roles of fibrogenic autocrine cytokines (fibroblast growth factor-2 [FGF-2] and transforming growth factor β [TGFβ]) and of different isoforms of CD44 in this FN production. We show that HC adhesion to HA stimulates FGF-2, but not TGFβ, production and that HCs possess FGF-2 receptor. In a range of experiments, FN production was greatly reduced by blocking FGF-2 but not TGFβ. Moreover FN, but not FGF-2, secretion was blocked by down-regulation of the v3 isoform of CD44 and by addition of heparitinase. These results show that autocrine FGF-2 secreted by HCs is the principal cytokine responsible for FN production by these cells when cultured on HA. The central role of FGF-2 in the pathogenesis of the BM fibrosis of HCL was supported by our immunohistochemical demonstration of large amounts of this cytokine in fibrotic BM but not in HCL spleen where there is no fibrosis. As regards CD44 isoforms, the present work demonstrates that CD44v3 is essential for providing the heparan sulfate necessary for HC stimulation by FGF-2, whereas the signal for production of the cytokine was provided by HA binding to CD44H, the standard hematopoietic form of the molecule.

scholarly journals Low-dose deoxycoformycin in the treatment of hairy cell leukemia

Blood ◽  
1986 ◽  
Vol 68 (5) ◽  
pp. 1119-1122 ◽  
Author(s):  
EH Kraut ◽  
BA Bouroncle ◽  
MR Grever
Keyword(s):  
Bone Marrow ◽  
Complete Remission ◽  
Hairy Cell Leukemia ◽  
Low Dose ◽  
Intravenous Bolus ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Normal Peripheral Blood ◽  
Hairy Cells ◽  
Reversible Reduction

Abstract Ten patients with progressive hairy cell leukemia were treated with 2′deoxycoformycin (dCF) by intravenous bolus (4 mg/m2) given every other week. All ten patients are evaluable for response and nine of the ten patients have achieved a complete remission. In addition to clearing of hairy cells from the bone marrow, eight patients had resolution of their monocytopenia. Seven of the nine patients remain in unmaintained remission with a median duration of 6.2 months. Two patients have had relapse in the bone marrow alone and continue to have normal peripheral blood counts. They are being followed without treatment. Toxicity was minimal at this low dose with one patient having a mild reversible reduction in creatinine clearance. Four other patients had reversible neutropenia. There were no significant infections associated with treatment. Low-dose deoxycoformycin administered intravenously every other week represents an extremely effective treatment for hairy cell leukemia.

Treatment of hairy cell leukemia with alternating cycles of pentostatin and recombinant leukocyte A interferon: results of a phase II study.

1990 ◽  
Vol 8 (4) ◽  
pp. 721-730 ◽  
Author(s):  
A Martin ◽  
S Nerenstone ◽  
W J Urba ◽  
D L Longo ◽  
J B Lawrence ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Hairy Cell Leukemia ◽  
Pathologic Complete Response ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Cell Infiltrate ◽  
Recombinant Interferon ◽  
Bone Marrow Biopsies ◽  
Hairy Cells

Fifteen patients with hairy cell leukemia (HCL) were treated with deoxycoformycin (pentostatin; dCF) (4 mg/m2 intravenous [IV] every week x 3) and recombinant interferon-alpha 2a (rIFN-alpha 2a) (3 x 10(6) units subcutaneously [SC] daily x 4 weeks) in alternating months for a total of 14 months. Eleven patients had undergone splenectomy; four had received prior systemic therapy with chlorambucil and/or steroids. All 15 are evaluable for toxicity and peripheral blood response, while 14 are assessable for bone marrow response. Toxicity was tolerable with grade 3 or 4 nausea and vomiting in three patients, neutropenic fevers in five, transient but significant depression in eight, and localized cutaneous herpes zoster in four. Circulating hairy cells were undetectable by the end of the first month in 10 of 13 patients, and by the end of the second month in the other three. Fourteen patients had bilateral bone marrow biopsies performed at baseline after 6 months of treatment, at the end of treatment (14 months), and at 6-month intervals during follow-up. Before treatment, all patients had hypercellular marrows with hairy cels replacing normal marrow elements; all showed at least a 95% clearing of their hairy cell infiltrate by 6 months of therapy. However, small collections of residual hairy cells could be detected intermittently on at least one side of bilateral samples in all patients. All patients have completed treatment with a median duration of follow-up off therapy of 27 months (range, 15 to 31 months). To date, all peripheral counts and serum soluble interleukin-2 receptor (sIL2R) levels remain stable, and no patient has had progression of the hairy cell infiltrate in the bone marrow. Although no patient achieved a pathologic complete response, alternating monthly cycles of dCF and rIFN-alpha 2a produced durable partial remissions (PRs) in all patients. Continued follow-up is required to determine the length of such remissions.

Hairy-cell leukemia: induction of complete remission with pentostatin (2'-deoxycoformycin).

1984 ◽  
Vol 2 (12) ◽  
pp. 1336-1342 ◽  
Author(s):  
A S Spiers ◽  
S J Parekh ◽  
M B Bishop
Keyword(s):  
Bone Marrow ◽  
Complete Remission ◽  
Hairy Cell Leukemia ◽  
Bone Marrow Aspiration ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Highly Active ◽  
Extensive Evaluation ◽  
Ann Arbor ◽  
Hairy Cells

Two men with advanced but previously untreated B cell hairy-cell leukemia were treated with low doses of pentostatin (2'-deoxycoformycin) in intermittent courses. There was prompt clearance of hairy cells from the blood, regression of splenomegaly and lymphadenopathy, and correction of anemia, thrombocytopenia, and granulocytopenia. Side effects were tolerable and myelosuppression was not observed. Both patients achieved complete remission documented by bone marrow aspiration and biopsy and radionuclide scans of liver and spleen. They remain in complete remission nine and six months, respectively, after their last treatment. Pentostatin (Warner-Lambert, Ann Arbor, Mich) is highly active in hairy-cell leukemia and merits more extensive evaluation in this disease. A woman with hairy-cell leukemia has begun treatment with pentostatin, and at ten weeks there is disappearance of gross splenomegaly and clearance of hairy cells from the blood. Bone marrow studies have not yet been repeated.

scholarly journals Treatment of hairy cell leukemia with recombinant alpha interferon: I. Quantitative study of bone marrow changes during the first months of treatment

Blood ◽  
1986 ◽  
Vol 67 (3) ◽  
pp. 817-820 ◽  
Author(s):  
G Flandrin ◽  
F Sigaux ◽  
S Castaigne ◽  
C Billard ◽  
M Aguet ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Hairy Cell Leukemia ◽  
Alpha Interferon ◽  
Initial Increase ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Bone Marrow Biopsies ◽  
Biopsy Specimens ◽  
Hairy Cells ◽  
Normal Controls

Abstract Seventeen patients with hairy cell leukemia (HCL) were treated with low doses of recombinant alpha interferon (IFN) for over 4 months. Marked improvement was observed in peripheral blood and bone marrow in 15 of 17 patients. Comparison of pretreatment values and hemograms obtained after 4 months of treatment showed a marked decrease in circulating hairy cells (P less than .01), a decrease in the number of lymphocytes (P less than .01), a rise in the number of platelets (P less than .05), granulocytes (P less than .05), and monocytes (P less than .01), and a rise in the hemoglobin level (P less than .01). Transient reduction in the number of granulocytes was noted during the first month. Correction of thrombocytopenia often appeared within 2 months and usually preceded improvement of anemia, monocytopenia, and neutropenia. Bone marrow biopsy specimens were taken before treatment and 2, 4, and 7 months after its initiation. The volumes occupied by hairy cells, cells of the myeloid lines, and adipocytes were studied by stereological analysis of semithin sections. Decrease in the volume occupied by hairy cells was seen after 4 months of treatment (P less than .01), and the volume continued to decrease at the seventh month (P less than .05). Hairy cells were no longer detected on bone marrow biopsies of 4 of 17 patients by the fourth month and in 3 of 8 additional patients by the seventh month. A rise in the volume occupied by normal myeloid cells was visible by the second month of treatment (P less than .01). Nevertheless, the volume occupied by granulocytes remained lower than in the normal controls (P less than .01). After an initial increase during the first 2 months of treatment (P less than .01), the overall cellularity remained unchanged at 4 months and decreased significantly (P less than .05) at 7 months. Except for biopsies at 2 months, mean cellularity was below that of control biopsies (P less than .01).

scholarly journals Morphologic confounders and CD19 negativity in a case of hairy cell leukemia.

2017 ◽  
Vol 9 (1) ◽  
pp. e2017033
Author(s):  
Pulkit Rastogi ◽  
Sreejesh Sreedharanunni ◽  
Uday Yanamandra ◽  
Man Updesh Singh Sachdeva ◽  
Neelam Varma
Keyword(s):  
Bone Marrow ◽  
Hairy Cell Leukemia ◽  
Plasma Cell Dyscrasia ◽  
Molecular Testing ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Cell Hyperplasia ◽  
Reactive Plasmacytosis ◽  
Cd10 Expression ◽  
Hairy Cells

Objectives:We report a case of hairy cell leukemia (HCL) initially misdiagnosed as plasma cell dyscrasia due to various clinical, morphological and immunophenotypic confounders.Methods and results:In a patient diagnosed of marrow plasmacytosis and serum monoclonal protein elsewhere and referred to our hospital, morphological evaluation of bone marrow aspirate smears and trephine biopsy, immunophenotyping, and molecular testing (BRAFV600E mutation) were done. Clinically, the patient was asymptomatic, bone marrow revealed plasmacytosis, mastocytosis and lymphocytosis with a few “hairy” cells. Immunophenotyping revealed features of HCL with aberrant CD10 expression and a subclone of CD19neg cells. A diagnosis of HCL with reactive plasmacytosis and mast cell hyperplasia was made and confirmed by immunophenotyping and molecular studies.Conclusion:Hematopathologists must be aware of various confounding factors and should judiciously use flow cytometric and molecular studies for attaining a proper diagnosis of HCL. We also report a very rare immunophenotypic aberrancy (CD 19 negativity) in HCL

scholarly journals Flow cytometry of blood and bone marrow cells from patients with hairy cell leukemia: phenotype of hairy cells and lymphocyte subsets after treatment with 2-chlorodeoxyadenosine

Blood ◽  
1994 ◽  
Vol 83 (12) ◽  
pp. 3672-3681 ◽  
Author(s):  
G Juliusson ◽  
R Lenkei ◽  
J Liliemark
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
Nk Cells ◽  
Hairy Cell Leukemia ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Cd4 Cells ◽  
Normal Range ◽  
Hla Dr ◽  
Hairy Cells

Abstract By flow cytometry and an extensive set of markers, we characterized leukemic cells from the blood and bone marrow of 68 symptomatic patients with hairy cell leukemia (HCL). Hairy cells identified in the large cell gate always expressed CD19, CD20, HLA-DR, CD45RA, and B-ly 7. Other markers were occasionally expressed, such as CD38, CD45RO, CD23, CD15, CD4, CD5, and CD10 (expressed on more than 20% of the hairy cells in 44%, 25%, 21%, 18%, 12%, 10%, and 5% of evaluated cases, respectively). During treatment with 2-chlorodeoxyadenosine (CdA), the median lymphocyte counts decreased from 2,000/microL to 300/microL. Flow cytometry was repeated at the nadir (n = 24) of lymphocyte counts, at 3 months (n = 46), at 6 months (n = 50), at 1 year (n = 39), and at 2 years (n = 12) after treatment. The initial decrease of CD8+ and CD20+ cells was greater than that of CD4+ and natural killer (NK) cells, leading to an increasing CD4/CD8 ratio. Median nadir values of CD4+, CD8+, CD20+, and NK cells were 128/microL, 78/microL, 10/microL, and 13/microL, respectively. The subsequent recovery was quicker for CD8+ and NK cells, leading to a normalization within 3 months, whereas CD20+ and CD4+ cells required 1 or 2 years to enter the normal range. The CD4/CD8 ratio thus decreased after the nadir and remained less than 1. CD45RA+ CD4 cells and CD45RA+/CD45RO+ double-positive cells were less affected by CdA. Activated T cells, ie, HLA-DR+ cells, rarely decreased below the normal range and often recovered with an overshoot. CD10+ cells increased in the bone marrow posttreatment as an indication of normal B-cell regeneration in 16 of 36 (44%) patients. The quick regeneration of certain lymphoid subsets might explain the lack of late infections in CdA-treated HCL patients.

scholarly journals Progress report on chlorambucil therapy in postsplenectomy patients with progressive hairy cell leukemia

Blood ◽  
1981 ◽  
Vol 57 (3) ◽  
pp. 464-467 ◽  
Author(s):  
HM Golomb
Keyword(s):  
Bone Marrow ◽  
Hairy Cell Leukemia ◽  
Progressive Disease ◽  
Single Agent ◽  
Objective Response ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Hairy Cells ◽  
Total Bone Marrow ◽  
Single Agent Chemotherapy

Abstract Of eight patients with progressive hairy cell leukemia who were treated with daily doses of an alkylating agent (chlorambucil, 4 mg) for at least 6 mo, seven have had an objective response, as measured by improved blood counts. Two patients were pancytopenic and had almost total bone marrow replacement with hairy cells at the initiation of chemotherapy; approximatley 6 mo later, their blood counts and bone marrow had improved dramatically. The five other patients had the leukemic form of the disease, and all responded to therapy. It is important to identify postsplenectomy patients with progressive disease in order to initiate low-dose single-agent chemotherapy.

Series of Hairy Cell Leukemia Patients with Co-Existent Plasma Cell Disorders

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5647-5647
Author(s):  
Neha Korde ◽  
Sham Mailankody ◽  
Evgeny Arons ◽  
Raul C. Braylan ◽  
Mark Raffeld ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cyclin D1 ◽  
Plasma Cell ◽  
Hairy Cell Leukemia ◽  
Plasma Cells ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
First Line ◽  
Plasma Cell Disorders ◽  
Hairy Cells

Abstract Despite a reported increased incidence of secondary hematologic malignancies and plasma cell disorders in the literature, the specific co-existence of hairy cell leukemia (HCL) and monoclonal gammopathies of unknown significance (MGUS) or plasma cell multiple myeloma (MM) has been based on a few case reports. In the following report, we compile clinico-pathologic data on a series of hairy cell leukemia patients with myeloma precursor diseases using immunohistochemistry, molecular polymerase chain reaction (PCR) and multi-parametric flow cytometry (MFC) techniques with an aim to deep sequence these parallel lymphoid processes in the future. Between 2004 and 2014, 6 HCL patients followed at the National Institutes of Health were identified with associated plasma cell disorders, based on presence of increased clonal plasmacytosis in bone marrow and abnormal serum and/or urine protein electrophoresis/immunofixation. Immunohistochemical (IHC) staining for CD20, TRAP, CD138, cyclin D1, kappa and lambda light chains was performed on bone marrow biopsies. MFC using a panel of B-cell antibodies and PCR clonality studies targeting immunoglobulin heavy and light chain loci were performed prior to treatment to confirm the presence of malignant lymphoid clonal processes. Among the 6 hairy cell leukemia patients with associated plasma cell disorders, there were 5 males and one female. Median age was 67 (range, 47-74). Patients prior to treatment showed bone marrow involvement by HCL with 5-90% infiltration. Hairy cells in all patients tested were TRAP positive, Cyclin D1 was positive in 5, and BRAF V600E was detected in 5 of 5 patients tested. All patients were diagnosed as classic HCL, although 1 patient had an additional population consistent with HCL variant. In addition, 3/6 patients (50%) showed mild increase in marrow plasma cells (5-10%) and the other 3 patients (50%) had over 10% of plasma cells in the core biopsy. The mean plasma cell percentage was 10% (3-25%), mean monoclonal protein concentration was 1.3 g/dL, and isotypes included: 4 IgG, 1 IgA, and 1 free kappa only. 3 patients were classified as MGUS and 3 as smoldering MM (SMM). Interestingly, three out of 6 (50%) patients had positive cyclin D1 expression by IHC in both plasma cells and hairy cells. Several patients had evidence of multiple clonal rearrangements by PCR studies. In addition, two patients demonstrated evidence of monoclonal B-cell lymphocytosis (MBL) on MFC. So far, 3 patients achieved complete remission without minimal residual disease (MRD) using moxetumomab pasudotox in one multiply relapsed case, and first line cladribine plus rituximab in 2 newly diagnosed HCL cases, without significant progression to MM. No patients demonstrated end organ damage due to MGUS/SMM after a median follow-up of 4.6 (range 0.9-10.1) years. By using serum studies, IHC staining, PCR and MFC tools, we identified a group of HCL patients with evidence of additional precursor malignant lymphoid disease states, including MGUS/SMM and MBL. Underlying mechanisms of these parallel malignant processes may include global lymphoid dysregulation through common lymphocyte ancestry pathways; or, it could be due to post-immune HCL therapy exposure, or a combination. Currently, we are conducting deep sequencing of these samples with the aim to uncover mechanisms of pathogenesis. Treatments capable of eliminating HCL MRD, including addition of rituximab to first-line cladribine, or single-agent moxetumomab pasudotox for multiply relapsed HCL, might be advantageous for patients who may need treatment for MM in the future. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Immunomorphologic analysis of bone marrow biopsies after treatment with 2-chlorodeoxyadenosine for hairy cell leukemia

Blood ◽  
1994 ◽  
Vol 84 (12) ◽  
pp. 4310-4315 ◽  
Author(s):  
DJ Ellison ◽  
RW Sharpe ◽  
BA Robbins ◽  
JC Spinosa ◽  
JD Leopard ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Complete Remission ◽  
Hairy Cell Leukemia ◽  
Residual Disease ◽  
Positive Staining ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Bone Marrow Biopsies ◽  
Hairy Cells

Treatment of hairy cell leukemia with 2-chlorodeoxyadenosine (2-CdA) induces complete remissions in 85% of patients. Complete remission has been defined as the absence of hairy cells in the bone marrow after routine morphologic examination. To determine if hairy cells could be detected in complete remission bone marrows using immunohistochemical techniques with antibodies L26 (CD20) and DBA.44, 154 bone marrow biopsies performed between 3 months and 25 months after therapy were studied. Of the biopsies, 50% exhibited staining with L26 and/or DBA.44 in five or more cells with morphologic features of hairy cells. Minimal residual disease was usually less than 1% of the total cellular population. DBA.44-positive cells were demonstrated in 91% of the biopsies, although in 48% of these the morphologic features of the positive cells were not sufficiently distinctive for hairy cells. The proportion of biopsies with residual hairy cells was similar over the 25 months of follow up, indicating a relatively stable amount of residual disease. Immunomorphologic analysis is a more sensitive method for detecting residual hairy cells than morphology alone. Although further follow up is necessary to determine the clinical significance of the L26/DBA.44-positive staining in cells with and without distinctive morphologic features of hairy cells, we conclude that many patients in a stable clinical remission may have residual hairy cells.

Subcutaneous injections of 2-chlorodeoxyadenosine for symptomatic hairy cell leukemia.

1995 ◽  
Vol 13 (4) ◽  
pp. 989-995 ◽  
Author(s):  
G Juliusson ◽  
D Heldal ◽  
E Hippe ◽  
M Hedenus ◽  
C Malm ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Hairy Cell Leukemia ◽  
Subcutaneous Injection ◽  
Bone Marrow Cells ◽  
Clinical Relapse ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Bone Marrow Plasma ◽  
Hairy Cells ◽  
Beta 2 Microglobulin

PURPOSE To evaluate the clinical efficacy and safety of 2-chlorodeoxyadenosine (CdA) when administered by subcutaneous injection to patients with symptomatic hairy cell leukemia (HCL), and to evaluate predictive factors for response. PATIENTS AND METHODS Seventy-three patients were given CdA as a subcutaneous injection once daily for 7 days. Complete remission (CR) required normalized blood counts and the absence of B-ly 7-positive bone marrow cells by flow cytometry. CdA concentrations in plasma following the first injection were analyzed by high-pressure liquid chromatography. RESULTS Fifty-nine patients (81%) achieved a durable CR after one (n = 55) or two courses, and 10 had a partial remission (PR). With a median follow-up duration of 20 months, no patient had a clinical relapse. Neutropenic fever that required intravenous antibiotics occurred in 28 patients (38%). No toxicity at injection sites was observed. Incomplete response was predicted by an elevated lymphocyte count and serum beta 2-microglobulin level, and by a high percentage of hairy cells in the bone marrow. Plasma CdA levels were similar to those achieved from intravenous administration. CONCLUSION Subcutaneous injection of CdA is safe and as effective as continuous infusion without problems associated with the mode of administration. Our schedule simplifies CdA treatment and can be generally recommended.

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