Prevalence of 46/1 JAK2 Haplotype in Patients with Budd-Chiari Syndrome with and without JAK2V617F and TET2 Mutations.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 434-434
Author(s):  
Nicholas C Lea ◽  
Lara N Roberts ◽  
Raj K Patel ◽  
Rachel Westbrook ◽  
Michael A Heneghan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Skin Biopsy ◽  
Peripheral Blood ◽  
Conflicts Of Interest ◽  
Family Members ◽  
Uniparental Disomy ◽  
Cellular Growth ◽  
Jak2v617f Mutation ◽  
Budd Chiari Syndrome ◽  
Chiari Syndrome

Abstract Abstract 434 Budd-Chiari Syndrome (BCS) is a group of disorders resulting from obstruction to hepatic venous outflow; myeloproliferative disorder (MPD) accounts for 10-40% of cases. We previously described latent MPD in 58.5% of patients with idiopathic BCS, detected with allele-specific PCR for the JAK2V617F mutation and proposed its use as a screening tool for occult MPD. A predisposing germline JAK2 haplotype (designated 46/1) has since been described as a strong genetic risk factor for MPD and may further characterise latent MPD in BCS. We studied 28 patients with BCS (23 from our original cohort; female n=16, mean age 30.3 years, SD 10) presenting between 1985 and 2008; 14 with the JAK2V617F mutation. Genomic DNA was obtained from archived bone marrow films, fractionated and unfractionated peripheral blood or bone marrow leucocytes. Skin biopsy or CD3+ cells were used as a source of constitutional DNA. DNA was analysed by pyrosequencing for 2 SNPs (rs12340895, rs12343867) which tag the 46/1 JAK2 haplotype. The 46/1 haplotype was detected in 16/28 (57.1%) subjects; 50% of those with the JAK2V617F mutation and 64.3% of those without it. The prevalence in those lacking the JAK2V617F mutation is significantly higher than the frequency in the Wellcome Trust Case Control Consortium cohort of 24% (P=0.0023). 3/28 subjects had previously diagnosed JAK2V617F positive Polycythemia Vera (PV) and all had the 46/1 haplotype, resulting in a prevalence of 36.4% in those with JAK2V617F positive latent MPD. Age at presentation of BCS was significantly lower in those with the 46/1 haplotype (26.4 years compared to 34.8 years, P=0.03). This difference remained significant in those lacking the JAK2V617F mutation (24.0 years compared to 37.6 years, P=0.024) but was not seen in those with the JAK2V617F mutation (P=0.547). There was no difference in presenting clinical features, haematological parameters or treatment between those with and without the 46/1 haplotype. Overall survival in 26/28 patients was 76.9% (median 90 months, range 2 days to 266 months). 17/28 subjects underwent OLT of which 14/17 (11/12 with 46/1 haplotype) are alive at a median of 90 months post transplant (range 9-266 months). 3/17 patients developed post-OLT veno-occlusive disease, all with the JAK2V617F mutation and 2/3 with the 46/1 haplotype. Overt MPD has not developed in any patient without the JAK2V617F mutation; repeat JAK2 mutational analysis was undertaken in 3/14 (2/3 with 46/1 haplotype) and none have acquired the mutation at a mean of 54 months. 19/28 cases were genotyped using SNP markers (Affymetrix SNP6); 3/19 have acquired uniparental disomy (aUPD) on 9p overlapping the JAK2 gene. As TET2 has been postulated as a ‘pre-JAK2' aberration, we sequenced the complete TET2 gene using massively parallel high throughput sequencing (Roche 454); 2/15 patients samples were positive for TET2 mutations. One of our cases had a familial history of PV; the patient, his father and uncle all have JAK2V617F positive PV and were heterozygous for the 46/1 haplotype in DNA extracted from a skin biopsy. 2/3 were homozygous for both the 46/1 haplotype and JAK2V617F mutation in bone marrow granulocytes with SNP6 array data confirming aUPD on 9p. JAK2V617F was detected in cultured in vitro colonies from all 3 family members. All 3 affected family members had normal cytogenetics and normal TET2 gene. 3 unaffected siblings were heterozygous for the 46/1 haplotype both in peripheral blood, CD3+ cells and granulocytes but negative for JAK2V617F mutation and lacked aUPD on 9p. We have found a highly significant prevalence of the 46/1 haplotype in our cohort of BCS, as well as in family members of a patient with JAK2V617F positive BCS and PV. The 46/1 haplotype was detected in patients with idiopathic BCS with and without the JAK2V617F mutation, suggesting a predisposition to idiopathic BCS independent of JAK2V617F mutation acquisition and latent MPD. The prevalence and lower age of presentation in those with the 46/1 haplotype lacking the JAK2V617F mutation supports an alternate, as yet unknown, mechanism predisposing to BCS. The presence of the 46/1 haplotype in unaffected relatives of our JAK2V617F BCS patient suggests that additional germline variation may predispose to or protect from acquisition of JAK2V617F positive disease. Alternatively the 46/1 haplotype may directly confer a cellular growth advantage via increased responsiveness of JAK2 to cytokine stimulation. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Expression of HMGA2 Cooperates with Jak2V617F in the Development of Myelofibrosis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 797-797
Author(s):  
Avik Dutta ◽  
Robert E Hutchison ◽  
Golam Mohi
Keyword(s):  
Bone Marrow ◽  
Peripheral Blood ◽  
Conflicts Of Interest ◽  
Flow Cytometric Analysis ◽  
Jak2v617f Mutation ◽  
Sequencing Analysis ◽  
Wild Type ◽  
Control Vector ◽  
Hematopoietic Progenitors ◽  
Hematopoietic Stem

Abstract High Mobility Group AT Hook 2 (HMGA2) is a non-histone chromatin protein that regulates gene transcription and controls cell proliferation, survival and self-renewal of stem cells. HMGA2 is expressed at a low level in normal adult hematopoietic progenitors but is highly expressed in hematopoietic progenitors of patients with Myelofibrosis (MF). However, the contribution of HMGA2 to the pathogenesis of MF remains unknown. MF is the deadliest form of myeloprolifearative neoplasm (MPN) characterized by deposition of fibrous tissues in the bone marrow, increased megakaryopoiesis, ineffective erythropoiesis and extramedullary hematopoiesis. Median survival of patients with MF is less than 6 years. The JAK2V617F mutation has been found in 50-60% patients with MF. However, it is not clear whether JAK2V617F mutation alone is sufficient to cause MF. Interestingly, up-regulation of HMGA2 expression has been found in association with the JAK2V617F mutation in a significant percentage of patients with MF. To understand the role of JAK2V617F mutation in the pathogenesis of MPN, we previously generated a conditional Jak2V617F knock-in mouse. We observed that expression of heterozygous Jak2V617F in mouse hematopoietic compartments is sufficient to induce a polycythemia vera (PV)-like MPN. Recently, we have shown that deletion of EZH2 promotes the development of MF in Jak2V617F knock-in mice and EZH2 deletion increases the expression of HMGA2 in hematopoietic progenitors of EZH2-deleted Jak2V617F mice. To directly assess the effects of concomitant expression of HMGA2 and heterozygous Jak2V617F in mice hematopoietic compartments, we expressed control vector or HMGA2 in wild type and heterozygous Jak2V617F knock-in mice BM by lentiviral transduction and performed bone marrow transplantation into lethally irradiated C57BL/6 recipient mice. Whereas recipients of vector-transduced Jak2V617F knock-in BM cells exhibited a PV-like MPN characterized by increased red blood cells (RBC), hemoglobin, hematocrit and platelets in their peripheral blood, recipients of HMGA2-transduced Jak2V617F knock-in BM showed reduced hemoglobin and hematocrit parameters compared with recipients of vector-expressing Jak2V617F BM cells. Interestingly, peripheral blood neutrophil and platelet counts were further increased in transplanted animals receiving HMGA2-transduced Jak2V617F BM cells. Expression of HMGA2 also resulted in significantly larger spleen size in the transplanted animals receiving HMGA2-expressing Jak2V617F BM cells. Flow cytometric analysis showed significant increase in megakaryocytic precursors (CD41+) but decrease in erythroid precursors (CD71+/Ter119+) in the BM and spleens of transplanted animals receiving HMGA2-expressing Jak2V617F BM compared with control vector-expressing Jak2V617F BM. Furthermore, the frequency of hematopoietic stem/progenitor cells (LSK; Lin-Sca-1+c-kit+) was significantly increased in recipients of HMGA2-transduced Jak2V617F knock-in BM compared with control vector-transduced Jak2V617F knock-in BM or HMGA2-transduced wild type BM. Histopathologic analysis revealed extensive fibrosis in the BM and spleens from recipients of HMGA2-expressing Jak2V617F mice at 32 weeks after transplantation while BM and spleens from recipients of vector-transduced Jak2V617F knock-in BM or HMGA2-transduced wild type BM showed very little or no fibrosis at this age. Together, these data suggest that expression of HMGA2 promotes megakaryopoiesis and accelerates the development of MF in mice expressing Jak2V617F. To gain insights into the mechanisms by which expression of HMGA2 accelerates the development of MF in Jak2V617F mice, we performed RNA-sequencing analysis on purified LSK (Lin-Sca-1+c-kit+) cells. Gene set enrichment and pathway analyses revealed that the genes related to chemokine, TGF-β, MAP Kinase, PI3 kinase-Akt, mTOR and WNT signaling pathways were up-regulated in HMGA2-expressing Jak2V617F mice LSK compared with vector-expressing Jak2V617F LSK cells. We also found that HMGA2 directly binds to the promoter regions of some of these target genes and regulate their expression. Further studies will validate the targets of HMGA2 and determine their contribution in MF mediated by Jak2V617F. In conclusion, our studies show that expression of HMGA2 cooperates with Jak2V617F in the development of MF. Disclosures No relevant conflicts of interest to declare.

scholarly journals Presence of JAK2V617F Mutation in Endothelial Cells from Budd-Chiari Syndrome Patients Is Not Correlated with Ph-Negative Myeloproliferative Neoplasm

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4998-4998
Author(s):  
Ricardo Helman ◽  
Welbert Oliveira Pereira ◽  
Paulo Vidal Campregher ◽  
Luciana Cavalheiro Marti ◽  
Nelson Hamerschlak ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Endothelial Cell ◽  
Exome Sequencing ◽  
Jak2v617f Mutation ◽  
Adherent Cells ◽  
Budd Chiari Syndrome ◽  
Whole Exome ◽  
Chiari Syndrome ◽  
Washington University ◽  
Allele Fraction

Abstract Introduction The role of the endothelial cell in the pathogenesis of Ph-negative MPNs is still not elucidated. Some have reported the presence of the JAK2V617F mutation in endothelial colony forming cells (ECFC) isolated from peripheral blood in patients with Ph-negative MPNs (Teofili L et all, Blood 2011). Others, however, did not find such an association (Piaggio G et al, Blood 2009). In patients with Budd-Chiari Syndrome (BCS), the JAK2V617F mutation has been found in endothelial cell (ECs) isolated by micro dissection from liver biopsies in patients both with and without MPN (Sozer S et al, Blood 2009). Besides the JAK2V617F mutation, other mutations (e.g. ASXL1, TET2, DNMT3A, SRSF2) have been described in patients with Ph-negative MPNs, but their presence has not been evaluated in patients with BCS who carried the JAK2V617F mutation. Objectives 1. To evaluate the presence of the JAK2V617F mutation in CECs from patients with BCS both with and without concomitant Ph-negative MPNs; 2. To determine the mutational landscape of granulocytes in patients with BCS who harbored the JAK2V617F mutation but did not have the clinical diagnosis of a Ph-negative MPN. Methods We identified 10 patients from our institution who had a diagnosis of BCS and harbored the JAK2V617F mutation in granulocytes. Three patients died from hepatic failure before they could be evaluated by bone marrow biopsy, so 7 patients remain for the analysis. All patients were investigated for the presence of Ph-negative MPNs with bone marrow trephine biopsy. ECs assays were performed according to the method of Hill. Briefly, Ficoll-Paque density gradient–isolated mononuclear cells were plated on fibronectin coated 6-well dishes with EndoCult medium (Stem Cell Technologies) for 48 hours, when non adherent cells were recovered and re-plated in a new dish at 106/mL concentration. After an additional 5 days, adherent cells were plucked and analyzed by flow cytometry. The ECs population was sorted using a FACS Aria BD Biosciences sorter according to the following phenotype: CD45-PerCP-negative, CD31-FITC-positve, VEGFR2-PE-positive, CD34-PECy7-positive, CD133-APC-negative. The presence of the JAK2V617F mutation was investigated by allele-specific PCR. Paired DNA (sorted CD66b-granulocytes/skin biopsy) from 3 patients with JAK2V617F-positive BCS without a clinical diagnosis of Ph-negative MPN was subjected to whole exome sequencing on a Illumina HiSeq 2000 platform using Agilent SureSelect kit. Tumor coverage was 150x and germline coverage was 60x. Somatic variants calls were generated by combining the output of Somatic Sniper (Washington University), Mutect (Broad Institute) and Pindel (Washington University), followed by in-house filters to reduce false positive calls. Results We were able to obtain CECs from all 7 patients. The purity of the CECs populations obtained was over 96% in all cases. Among the 7 patients with BCS, five did not have any clinical feature of a Ph-negative MPN, with a normal bone marrow biopsy. Results are summarized in the table. The JAK2V617F mutation was positive in the CECs from 5 cases, including 3 patients who only had BCS. In one patient with BCS solely the reaction did not work, and in another the JAK2 was wild-type in the ECs. The mutation was positive in CECs from both patients with myelofibrosis and BCS. Three patients with BCS solely were evaluated by whole exome sequencing. The only known pathogenic abnormality found was the JAK2V617F mutation, albeit at a low allele fraction (5%, 6% and 12.6%). Conclusion The presence of the JAK2V617F mutation in CECs from patients with BCS who did and did not have a diagnosis of Ph-negative MPN suggest that the mutation plays an important role in the development of vascular complications in these patients. Further studies with a larger number of patients are needed to precisely define the importance of CECs in the pathogenesis of MPNs. The sole presence of the JAK2V617F mutation in circulating granulocytes at a very low allele fraction in patients with BCS without Ph-negative MPNs suggest that these patients have a pre-malignant clone that would probably remain undiagnosed had it been not for the development of hepatic venous thrombosis. Disclosures No relevant conflicts of interest to declare.

Monitoring of Minimal Residual Disease in NPM1 Mutated Acute Myeloid Leukemia (AML) – a Single Center Experience in 27 Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4672-4672
Author(s):  
Dana Dvorakova ◽  
Zdenek Racil ◽  
Ivo Palasek ◽  
Marketa Protivankova ◽  
Ivana Jeziskova ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Minimal Residual Disease ◽  
Peripheral Blood ◽  
Conflicts Of Interest ◽  
Residual Disease ◽  
Quantitative Polymerase Chain Reaction ◽  
Npm1 Mutation ◽  
Mgb Probe ◽  
Minimal Residual

Abstract Abstract 4672 Background Mutations within NPM1 gene occurs in about 60% of adult cytogenetic normal AML (CN-AML) and represent the single most frequent molecular aberration in this subgroups of patients. These mutations usually occur at exon 12 and induce most frequently a net insertion of four base pairs. Aims To examine the applicability and sensitivity of DNA-based real-time quantitative polymerase chain reaction (RQ-PCR) with mutation-specific reverse primers and common minor groove binding (MGB) probe and to evaluate whether minimal residual disease levels are of prognostic relevance in CN-AML patients with NPM1 mutations. Methods Patients were treated within different AML trials and follow-up samples of peripheral blood or bone marrow were referred to perform an RQ-PCR. Samples were analysed at diagnosis, during, and after therapy. The NPM1 mutations were A (17 pts), B (1 pt), D (2 pts) and 7 patients with individual rare types. For all cases, levels of minimal residual disease were determined by DNA-based RQ-PCR with mutation-specific reverse primer, one common forward primer and one common MGB probe. The NPM1 mutation value was normalized on the number of albumin gene copies and expressed as the number of NPM1 mutations every 106 genomic equivalents. This assay is highly specific as no wildtype NPM1 could be detected. Maximal reproducible sensitivity was 10 plasmide molecules per reaction. Results A total of 950 samples of bone marrow and/or peripheral blood from 27 patients have been analyzed. Twenty of 27 patients (74%) achieved molecular remission (MR), twenty-six of 27 patients (96%) achieved hematological remission (HR). 6 of 27 (22%) patients achieved HR without MR and one patient failed therapy. 8 of 20 patients (40%) with MR after treatment relapsed at molecular level and except one in all these patients hematological relaps occured (one patient is still in HR with bone marrow blast present, but < 5%). Considering relapsed patients, time from molecular to hematological relapse was 1 to 5 months (median: 3 months). Considering all 14 patients with HR without MR (6 pts) or with molecular relapse (8 pts), in 11 of them hematological relaps occured (79%) and molecular positivity anticipating hematological relaps with median of 3,5 month (1-7 months). 3 of these 14 patients are still in HR. Conclusions Mutations within NPM1 gene are a sensitive marker for monitoring minimal residual disease in CN-AML patients. RQ-PCR using a MGB probe is an efficient approach to long-term follow-up of residual leukemia cells and frequent quantitative monitoring is useful for reliably predicting hematological relapse. Achievement of negativity appears to predict favorable clinical outcome. This work was partially supported by research grant No. MSM0021622430 Disclosures: No relevant conflicts of interest to declare.

High Incidence of Peripheral Blood Plasmacytosis In Patients with Dengue Virus Infection: a Prospective Study

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2772-2772
Author(s):  
Khao T.D. Thai ◽  
Josta A. Wismeijer ◽  
Catrien M. Zumpolle ◽  
Menno D. de Jong ◽  
Peter J. Vde ries ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Viral Load ◽  
Dengue Virus ◽  
Peripheral Blood ◽  
Extreme Values ◽  
Conflicts Of Interest ◽  
Dengue Infection ◽  
Denv Infection ◽  
Bone Marrow Suppression ◽  
Median Percentage

Abstract Abstract 2772 Introduction: One of the characteristic features of dengue virus (DENV) infection is the occurrence of leukopenia and thrombocytopenia, probably resulting from virus induced bone marrow suppression. Despite the general bone marrow suppression, polyclonal peripheral blood plasmacytosis has occasionally been described in DENV infected patients. The frequency of peripheral blood (PB) plasmacytosis in patients with dengue infection, the origin of these plasma cells (PCs) and the mechanisms by which they appear in the blood are not known. We initiated this prospective observational study to quantify and describe the kinetics and phenotype of PB plasmacells (PCs) in these patients. Methods: Morphological examination of the peripheral blood smear was performed in 35 sequential returned travelers suspected of DENV infection, with a history of less than 14 days of fever. Flow cytometric (FC) analysis for the characterization and immunophenotyping of lymphocyte subsets and PCs was performed in 31 patients. Follow-up samples were available for 8 patients. Results: Our results show that PB plasmacytosis is a very common hematological finding in DENV infection, with extreme values of up to 36% of total white blood cells in some patients. Depending on the number of days since the onset of fever at presentation, PB plasmacytosis was observed in 64% to 73% of 28 patients with confirmed DENV infection, and in none of 7 patients with other febrile illnesses. PB plasmacytosis was the most pronounced before 7 days after onset of illness and declined rapidly thereafter, to completely disappear after 14 days of illness. The median percentage of PCs at day 7 was 2.5% (range 0–36%; 25–75 interquartile range: 0–8%). The median percentage of PCs was significantly higher in patients with secondary DENV infection than in patients with primary infection (4.5% versus 1.0%; p=0.05). Viral RNA was detectable in 18 of 28 DENV infected patients with a highly variable viral load, but there was no correlation between viral load and percentage of PCs. We found an excellent correlation between percentage of PCs as assessed by morphology and by flow cytometry (r2= 0.85). The majority of CD138+ PCs (89%) had a shared immunophenotype (CD45+/CD19−/CD56−), which differed from normal plasmacells which are generally CD19+. In all cases the PCs were polyclonal. Conclusion: PB plasmacytosis, characterized by a transient presence of polyclonal PCs in the circulation, is a common event in DENV infection and is probably the result of a vigorous humoral immune response to dengue. With an increasing number of travelers to areas where dengue virus is endemic, it is important also for hematologists to recognize this benign cause of sometimes extreme plasmacytosis, for which no invasive procedures such as bone marrow examinations are needed. Disclosures: No relevant conflicts of interest to declare.

Combination Targeted Therapy to Impair Self-Renewal Capacity of Human Blast Crisis Leukemia Stem Cells

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1693-1693 ◽  
Author(s):  
Angela C Court Recart ◽  
Anil Sadarangani ◽  
Daniel Goff ◽  
Alice Y Shih ◽  
Russell Wall ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Combination Therapy ◽  
Active Site ◽  
Peripheral Blood ◽  
Drug Exposure ◽  
Conflicts Of Interest ◽  
Blast Crisis ◽  
Single Agent ◽  
Self Renewal ◽  
Immunomagnetic Bead

Abstract Abstract 1693 The aim of this study is to develop clinical strategies that will HALT progression of CML by reducing leukemia stem cell (LSC) burden using a clinical grade JAK2 inhibitor, SAR302503 (SAR503, Sanofi, Cambridge, MA), alone or in combination with a potent BCR-ABL inhibitor, dasatinib. For this, CML patient samples in blast crisis phase (BC CML) were subjected to immunomagnetic bead CD34 selection or FACS Aria ll sorted to obtain leukemic progenitors (LSC/CD34+CD38+Lin−). Malignant progenitors were then transplanted into neonatal RAG2−/−gc−/− mice, and 8 weeks post-transplant, mice were treated with SAR503, dasatinib and vehicle for 14 days. Following treatment, hematopoietic tissues were analyzed for human engraftment by FACS analysis. Our results revealed that single agent experiments with SAR503 had a cytostatic rather than a cytoreductive effect on BC LSC. The treatment alone (60 mg/kg twice daily administered by oral gavage) did not significantly reduce leukemic progenitor burden in the liver, spleen, bone marrow and peripheral blood. Conversely, combination therapy with SAR503 and dasatinib (50mg/kg/day) significantly reduced LSC progenitors in all tissues examined. Interestingly, we observed that dasatinib alone therapy reduced the LSC burden in the liver, spleen, and peripheral blood, but the bone marrow retained a significant population of BC LSC. Also we found that the GMP population, previously shown to be enriched for BC LSC (Jamieson et al NEJM 2004; Abrahamsson et al PNAS 2009), was preferentially localized in the bone marrow. As shown by our laboratory and others, LSC therapeutic resistance may be influenced by extrinsic cues provided by the niche (e.g. promoting quiescence). Because quiescence has been implicated in driving tyrosine kinase inhibitor resistance and LSC survival and because the bone marrow retains a resistant population, we decide to perform secondary transplantation experiments to determine relapse potential (self-renewal). LSC progenitors were isolated by immunomagnetic bead selection of human CD34+ cells from marrows and spleens of treated mice. After serially transplanting an equal number of this cells into secondary recipients, we observed a significant reduction in LSC serial transplantation only following combination treatment, suggesting that the combination therapy can abolish LSC self-renewal capacity and thereby potentially prevent relapse. To validate drug exposure, we have been performing both genomic and nanoproteomic analysis. Regarding the proteomics validation studies, we analyzed sorted LSC derived from spleen (pooled 5 mice per group) that were treated with vehicle or SAR503 for 14 days. The analysis was performed to detect status of p-JAK2, JAK2, p-STAT5 and B2-microglobulin (loading control). We observed a down regulation on the levels of p-JAk2 (active site Tyr 1007–08) and p-Stat5 (active site Tyr 694) (35% and 42% respectively), while no changes are observed for total JAK2 protein or B2M between both conditions. The full transcriptome sequencing, on sorted LSC treated with SAR503 alone and in combination with dasatinib, identified specific isoform changes in the JAK/STAT pathway that could be used as biomarkers of response and could explain the synergistic effect of the combination therapy. We have also characterized, at an isoform level, biomarkers of resistance that could explain relapse of disease after single agent therapy and we are currently validating these findings. Disclosures: No relevant conflicts of interest to declare.

Treatment of Burkitt's Like Lymphoma: A Single Institution Case Series

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4962-4962
Author(s):  
Vishal Ranpura ◽  
Shilpan S. Shah
Keyword(s):  
Central Nervous System ◽  
Bone Marrow ◽  
Nervous System ◽  
Peripheral Blood ◽  
Chemotherapy Regimen ◽  
Conflicts Of Interest ◽  
Case Series ◽  
B Cell Lymphoma ◽  
Response To Treatment ◽  
Single Institution

Abstract Abstract 4962 Background: Burkits's like (BL) lymphoma is a new pathologic entity with features partially resembling to Burkitt's lymphoma and diffuse large B cell lymphoma. The incidence of BL lymphoma is infrequent and may present with lymph node enlargement, involvement of bone marrow and peripheral blood. The natural history of BL lymphoma and its treatment remains unclear. Here we present a single institution case series of five patients diagnosed with BL lymphoma and their treatment. Methods: We searched the pathology reports of all patients diagnosed with lymphoma over the last one year. No inclusion or exclusion criteria were used. Results: We identified a total of five patients with diagnosis of BL lymphoma. All patients presented with lymphadenopathy and with no involvement of bone marrow, central nervous system or peripheral blood. Table 1 summarizes characteristics of all patients, their chemotherapy regimen and subsequent response to treatment. Conclusion: BL lymphoma is a new pathologic entity with low incidence. Treatment with DA-EPOCH and R-HyperCVAD has very good response rate. The data is limited by single institution case series and limited follow up time. Further studies are recommended to evaluate optimal chemotherapy regimen. Table 1: Characteristics, presentation, treatment and response in patients with BL lymphoma No Age Sex LDH, Presentation Treatment Response Duration of response 1 68 F 386 Parotid and abdominal lymphadenopathy DA-R-EPOCH CR 16months 2^ 44 M 536 Neck, Axillary, media, abdomen pelvis and sacral mets R-HyperCVAD PR 3months 3* 66 F 310 Inguinal and pelvic lymphadenopathy R-HyperCVAD f/b Autologus BMT, CR 14months 4** 71 M 237 Parotid mass 3 cycles of DA-EPOCH f/b 3 cycles of R-CHOP CR 9months 5^ 52 M 186 Neck Lymphadenopathy R-HyperCVAD CR 3months DOX, DOXOL, and anthracenediones in soluble fractions of human myocardial strips after sequential DOX loading/clearance and anthracenedione treatment Notes: DA-REPOCH: Dose Adjusted Rituximab-Etoposide, Vincristine, Cyclophosphamide, Doxorubicine, Prednisone, R-HyperCVAD: Rituximab, hyperfractionated Cyclophosphamide, Vincristine, Doxorubicin, Dexamethasone, CR: complete remission, BMT: bone marrow transplantation, R-CHOP: rituximab, doxorubicin, cyclophosphamide, vincristine and prednisone. CNS: central nervous system * patient underwent bone marrow transplant because of relapse at current presentation. ** patient was changed from DA EPOCH to R-CHOP as patient was not able to tolerate EPOCH ^ Epatients are halfway through their treatment cycles and are actively getting treatment Disclosures: No relevant conflicts of interest to declare.

Neutropenia Does Not Delay Lymphopoietic Regeneration in NODSCIDcγ−/− Mice

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4831-4831
Author(s):  
Stefanie Bugl ◽  
Stefan Wirths ◽  
R Müller Martin ◽  
Märklin Melanie ◽  
Tina Wiesner ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Peripheral Blood ◽  
Nk Cell ◽  
Conflicts Of Interest ◽  
Control Group ◽  
Early Event ◽  
Wild Type ◽  
Hematopoietic Stem ◽  
Lymphoid Progenitors ◽  
Fate Decision

Abstract Abstract 4831 Introduction: Previously it was demonstrated that lymphopoiesis is rapidly established after transplantation of wild type stem cells into lymphopenic NODSCIDcγ−/− mice. These data were interpreted as evidence for an “empty” preformed lymphopoietic niche being replenished by lymphoid progenitors. We hypothesized that antibody-induced neutropenia might influence early post transplant fate decision to myeloid rather than lymphoid differentiation resulting in delayed lymphoid reconstitution. Materials and Methods: 25,000 flow sorted CD45.2-expressing wild type Lin-/Sca1+/c-Kit+ (LSK) cells from C57BL/6 mice were transplanted into sublethally irradiated B-/T-/NK-cell deficient NODSCIDcγ−/− mice (CD45.1). Three groups of n = 7 mice received anti-Gr1 or anti-1A8 i.p. every 48 h to induce continuous antibody-mediated neutropenia vs. PBS as control. Blood was harvested at regular intervals to monitor the engraftment. After 16, 22, and 34 days, animals were sacrificed and underwent blood and bone marrow analysis. Results: Hematopoietic regeneration started with the emergence of donor-derived monocytes in all groups as well as neutrophils in the control group as early as 9 days after transplantation. On day 14, B cells were to be detected for the first time, followed by T lymphocytes approximately 20 days after transplantation. Besides the fact that neutrophils were undetectable in the antibody treated groups, the peripheral blood revealed no significant changes between the neutropenic mice and the control group at any point of time. At the bone marrow level, an increase of LSK and granulocyte-macrophage progenitors (GMPs) at the expense of megakaryocyte erythrocyte progenitor cells (MEPs) was found in neutropenic mice. Common lymphoid progenitors (CLPs), however, were not significantly different. Conclusions: The engraftment of wild type donor cells after hematopoietic stem cell transplantation into NODSCIDcγ−/− mice started with the production of monocytes and neutrophils. B-lymphocytes were detectable by day 14 after transplantation. The production of T-cells started around day 20. Continuous antibody-mediated neutropenia did not significantly delay lymphoid regeneration. Although the marrow of neutropenic mice displayed increased proliferation of granulocyte progenitors, CLPs were unchanged. We conclude that the detection of donor-derived lymphocytes in the host peripheral blood is a relatively early event after LSK transplantation. Moreover, antibody induced neutropenia is not sufficient to induce sustainable changes in early hematopoietic fate decisions on the bone marrow level. Disclosures: No relevant conflicts of interest to declare.

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