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  • 1
    Electronic Resource
    Electronic Resource
    Oncogene amplification correlates with dense lymphocyte infiltration in human breast cancers: A role for hematopoietic growth factor release by tumor cells? (1990)
    New York, N.Y. : Wiley-Blackwell
    Journal of Cellular Biochemistry 44 (1990), S. 189-198 
    Details
    ISSN: 0730-2312
    Keywords: breast cancer ; dense immune cell infiltrate ; c-erbB2 ; int-2 ; c-myc ; CSF-1 ; Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: One hundred six primary breast cancer samples were analysed for c-erbB2, int-2, and c-myc gene amplification. Surgically confirmed nodal involvement was observed in 42%. Level of gene amplification was studied by Southern and/or slot blottechniques. Amplified c-erbB2 gene sequences were present in 21.5% of all samples. Int-2 was amplified in 13.1% and c-myc was amplified in 10.3%. In a non-parametric test (Kruskal-Wallis) a strong negative association was found between high levels of c-erbB2 amplification and absence of estrogen receptor (ER) (P = .0009) or progesterone receptor (PR) (P = .011) expression. No correlations were found between all or high levels of amplification of each oncogene separately or combined with T, N, grade, multifocality of tumor, or associated carcinoma in situ. There was a trend approaching statistical significance for patients with c-erbB2 amplifications to have positive lymph nodes at surgery (P = 0.09). A somewhat surprising finding however was a very strong association between oncogene amplification and dense lymphocyte infiltration of the tumor (P = .05). This correlation is even stronger when only high levels of amplification are considered, either for each oncogene separately (P = .0048) or in combination (P = .007). We propose that malignant cell cytokine production may help explain this observation.
    Additional Material: 3 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/jcb.240440307
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  • 2
    Electronic Resource
    Electronic Resource
    M-CSF (monocyte colony stimulating factor) and M-CSF receptor expression by breast tumour cells: M-CSF mediated recruitment of tumour infiltrating monocytes? (1992)
    New York, N.Y. : Wiley-Blackwell
    Journal of Cellular Biochemistry 50 (1992), S. 350-356 
    Details
    ISSN: 0730-2312
    Keywords: breast cancer ; tumour infiltrating lymphocytes ; macrophage makers ; M CSF-1 / CSF-1 ; fms ; Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Infiltrating immune cells in 30 primary human epithelial breast tumours were studied using specific anti-CD3 (T cells), anti-CD68 (macrophages), anti-CD57 (NK cells), and an anti-pan-B cell antibody (L26). The majority of tumour infiltrating inflammatory cell are T cells (40-50%) and monocytes/macrophages (15-35%).The macrophage specific chemo-attractant and growth factor CSF-1 is detected by immunohistochemical techniques (IHC) at the level of invasive breast cancer cell in 46/50 tumours but not at the level of in- situ (pre-invasive) cancer. A mosaic staining patterns was usually observed with a very high expression in areas of obvious stromal invasion (90%cells positive) and absent or trace staining in intraductal carcinoma. Macrophages and plasma cell are equally intensely positive. In-situ-hybridisation experiment confirm the production of CSF-1 (mRNA) by tumour cells and show the same pattern of expression. Expression of the CSF-1 receptor protein (fms) was also observed by IHC in 41/48 invasive tumours, albeit at weaker intensities than in tumour infiltrating monocytes/macrophages. A concomitant expression of both CSF-1 and fms in in-situ carcinoma was never seen (n = 14). It is therefore proposed that the associated expression of CSF-1 and its receptor may be linked to the invasive potential of breast cancer, the monocytic infiltrate being an indication of the quantitative importance of CSF-1 production by the tumour. © 1992 Wiley-Liss, Inc.
    Additional Material: 4 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/jcb.240500403
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  • 3
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    Phase I studies of AVE9633, an anti-CD33 antibody-maytansinoid conjugate, in adult patients with relapsed/refractory acute myeloid leukemia (2011)
    Springer
    Details
    Publication Date: 2011-04-26
    Print ISSN: 0167-6997
    Electronic ISSN: 1573-0646
    Topics: Chemistry and Pharmacology , Medicine
    Published by Springer
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  • 4
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    Targeting Acute Myeloid Leukemia with a New CXCR4 Antagonist IgG1 Antibody (PF-06747143)in NOD/SCID Mice (2015)
    American Society of Hematology
    Details
    Publication Date: 2015-12-03
    Description: Chemoresistance represents a considerable barrier to improving outcomes for patients with acute myeloid leukemia (AML) and therapeutic approaches using multiple lines of therapy have been unsuccessful as cancer cells acquire resistance to the chemotherapeutic agents to which they are exposed. This vulnerable patient group needs individualizing therapy through careful selection of appropriate agents based on specific signaling pathways. The chemokine receptor CXCR4 mediates cell anchorage in the bone marrow microenvironment, is highly expressed in 25-30% of patients with AML and its expression is correlated with poor prognosis and drug resistance. The purpose of this study was to investigate a new humanized monoclonal IgG1 antibody to CXCR4 (PF-06747143) and its effects as a monotherapy in AML primary patient samples and in chemotherapy resistant patient-derived xenotransplantation (PDX) models. This antibody was previously shown to be able to induce cell death through its effector function (CDC and ADCC) and to be efficacious in cell-based xenograft models of AML, NHL, CLL and MM. Here we have shown that PF-06747143 binds strongly and specifically to AML cell lines and to AML primary cells, by flow cytometry. Of 16 samples evaluated, 7 displayed low CXCR4 expression (CXCR4neg/low) whereas 9 displayed high expression (CXCR4high). A good correlation was observed between 12G5, a commercially available CXCR4 Ab, and PF-06747143 staining, indicating that PF-06747143 can be used to stratify AML patients. Chemotaxis in response to CXCL12 was significantly inhibited in all AML patient primary samples analyzed. Administration of PF-06747143 to mice engrafted with AML patient cells (PDX models) induced rapid malignant cell mobilization into the peripheral blood at 4 hrs after a single antibody dose, with mobilized cell levels going back down to baseline at 24 hrs post-dose. This is in line with the ability of the antibody to block malignant cell homing to the bone marrow, inducing cell mobilization, as well as induction of cell death through effector function. To characterize the effects of PF-06747143 on leukemia progression, we used two different models: 1) P15 model characterized by high CXCR4 expression, inducing aggressive disease, with rapid progression of leukemia and widespread dissemination and chemoresistance; 2) P17 model characterized by a low CXCR4 expression, a less aggressive disease and limited dissemination. Weekly administration of PF-06747143 to leukemic mice previously engrafted with P17 or P15 malignant cells induced a sharp reduction of leukemia cells in the bone marrow, spleen and blood leading to increased survival of leukemic mice in both models. Activity of the antibody as monotherapy was superior to daunorubicin in the P15 chemoresistant model. Secondary transplantation of bone marrow cells from PF-06747143-treated or IgG1 control-treated animals showed that leukemic progenitors were also targeted by PF-06747143 treatment, with slower tumor growth in mice transplanted with PF-06747143-treated cells. In summary, PF-06747143, a CXCR4 IgG1 antibody, is significantly efficacious as a monotherapy and superior to daunorubicin in AML chemoresistant PDX models. These findings support evaluation of this antibody in AML therapy, with particular appeal to patients resistant to chemotherapy and to unfit patients, unable to tolerate intensive chemotherapy. Disclosures No relevant conflicts of interest to declare.
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
    Published by American Society of Hematology
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  • 5
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    Incidence of HLA Loss in a Global Multicentric Cohort of Post-Transplantation Relapses: Results from the Hlaloss Collaborative Study (2018)
    American Society of Hematology
    Details
    Publication Date: 2018-11-29
    Description: Introduction. Genomic loss of an HLA haplotype encoding incompatible alleles ("HLA loss") has been described in previous single-center studies as a mechanism by which leukemic cells evade the graft-versus-leukemia effect mediated by alloreactive donor T cells and outgrow into a clinically evident relapse. HLA loss accounts for up to 30% of relapses after HLA-haploidentical transplants (Crucitti, Leukemia 2015), but the actual frequency and clinical relevance of this phenomenon in unrelated donor HSCTs, including cord blood transplants, are largely unknown. Here we present the first global collaborative study to investigate the incidence of HLA loss across different transplant settings. Methods. Twenty transplant centers from Europe (n=16), North America (n=3) and Asia (n=1) joined to form the HLALOSS consortium. To date, we collected a total of 619 cases of hematologic relapse from adult patients with acute myeloid leukemia (78.5%), acute lymphoblastic leukemia (13.9%), myelodysplastic syndromes (4%) or myeloproliferative neoplasms (1.1%) after allogeneic HSCT from HLA-haploidentical relatives (31.7%), HLA-mismatched unrelated donors (MMUD, 21.3%), 10/10-matched unrelated donors (MUD, 37.2%), or unrelated cord blood units (UCB, 9.8%). Where available, the donor and patient germlines and the patient pre-transplant disease were collected in parallel. Until today, 476 cases were analyzed using conventional HLA typing of sorted leukemic blasts, the recently developed HLA-KMR assay (Ahci and Toffalori, Blood, 2017) or a novel Next-Generation Sequencing (NGS) method. The latter was developed adapting the HLA typing strategy in use at the DKMS (Lange, BMC Genomics 2013) to the study of chimeric samples, and allowing to cover all possible HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1 alleles and to analyze at least 48 different cases in a single run. Results. Out of the 476 relapses analyzed to date, 396 (83.2%) were informative for the study of HLA loss. Of these, 155 occurred after haploidentical HSCT, 101 after MMUD HSCT, 93 after 10/10-matched, HLA-DPB1 mismatched MUD, and 47 after UCB HSCTs. Three-hundred-two (76.2%) of cases were analyzed using the NGS platform. This method resulted particularly robust, reliable and sensitive in analyzing large sample series: the mean coverage across the 6 sequenced loci was over 8500x, up to 0.5% of the HLA allele of interest could be detected in artificial chimerism curves, and relapse samples tested in parallel via the sequencing platform and HLA-KMR (n=10) showed remarkable concordance between the two methods (R2=0.86, p
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  • 6
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    Impact of FLT3-ITD Mutational Burden in 469 Acute Myeloid Leukemia (AML) Patients (2014)
    American Society of Hematology
    Details
    Publication Date: 2014-12-06
    Description: Background: FLT3-ITD mutational status is a well known prognostic factor in AML patients. However, its prognostic value in case of low mutational burden is currently under debate, especially in patients with intermediate karyotype and NPM1 mutations. Indeed some studies suggested that patients with an allelic ratio (i.e FLT3-ITD/FLT3 WT) lower than 50 % might have the same prognosis as unmutated patients. Patients and methods: Four hundred and sixty nine (469) patients diagnosed with AML in a single center from 1995 to 2014 and who received intensive chemotherapy based on anthracycline and cytarabine were included. Patients with t(15;17)(q24;q21) or t(9;22)(q34;q11) translocations were excluded. 134 patients underwent allogeneic stem cell transplantation. FLT3-ITD allelic burden was determined using fresh or frozen cells drawn at time of diagnosis in all patients. The mutational status for FLT3-ITD was determined using high-resolution sizing of fluorescent dye-labeled PCR amplification of exons 14-15. Beyond its contribution to mutation detection, high-resolution sizing also allows to estimate the allelic burden by measuring peak height ratios (mutant/wild type) on a fluorescence scale. Low allelic burden was defined by an allelic ratio lower than 50%. NPM1 and CEBPA mutational status were determined in most patients (n=409 and n=349 respectively). Median follow-up time for patients who were still alive was 37 months. Results: Median age was 56 years (range 16-81). Karyotype was unfavorable in 110 (24%) patients, favorable in 45 (10%), intermediate in 298 (63%) patients and normal in 229 (48 %). Overall, FLT3-ITD was detected in 83 (17%) patients. Twenty three patients (5%) had a low allelic ratio and 60 (13%) had a high allelic ratio. NPM1 mutation was found in 100 (24%) patients and bi-allelic CEBPA mutations in 21 (6%). In the overall population, patients with FLT3-ITD had poorer outcome compared to other patients (OS at 3 years: 33+/-5% vs. 52 +/-3%, p =0.02). There was no difference between patients with low allelic burden or patients with high allelic burden for leukemia-free survival (7+/-7% vs. 38+/-8%, p=0.12), overall survival (25+/-5% vs. 37+/-6%, p=0.67) or CR reaching (70% in the two groups). In multivariate analysis, factors independently associated with OS were cytogenetic risk group, age, leukocyte count at diagnosis, NPM1 status, CEBPA status and FLT3-ITD status. There were no difference between patients with high vs. low allelic burden (HR=1.20 [0.59-2.42]). Results were the same when focusing on patients with intermediate karyotype. FLT3-ITD was associated with lower survival (p=0.003), but the mutational burden was not (OS at 3 years 30+/-12% vs. 36+/-7%, for low or high burden respectively, p=0.86). In multivariate analysis, factors independently associated with OS were age, leukocyte count, NPM1 status, CEBPA status and FLT3-ITD status. Again, there were no difference between patients with high versus low allelic burden (HR=0.98[0.45-2.08]. Conclusions: In this series, low FLT3-ITD allelic burden had a similar prognostic significance compared to a higher allelic burden. Therefore, patients with low FLT3-ITD allelic burden should likely be considered as having the same prognosis as patients with high burden, and FLT3-ITD detection, but not FLT3-ITD allelic burden, should be the major factor to be considered for therapeutic decisions. Disclosures No relevant conflicts of interest to declare.
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    Electronic ISSN: 1528-0020
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  • 7
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    Clono-Specific Evaluation of Minimal Residual Disease in Acute Myeloid Leukemia (2016)
    American Society of Hematology
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    Publication Date: 2016-12-02
    Description: Background: The genetic landscape of adult acute myeloid leukemias (AML) has been recently unravelled. This makes achievable the determination of a comprehensive profile of driver lesions for virtually all patients at diagnosis. Recent studies using multi-target minimal residual disease (MRD) strategies with around 1% sensitivity indicate that the clearance of all molecular events after chemotherapy is associated with better survival. To improve the clono-specificity and the sensitivity of this approach, after a precise determination of AML clonal composition, we combined cytogenetic, FISH, and high sensitivity deep sequencing technologies to monitor the MRD in a series of 69 patients. Methods: Forty-five consecutive patients reflecting the genetic diversity of AML were prospectively included and 24 patients were retrospectively studied. All patients received an anthracycline + cytarabine based regimen. The clonal architecture was established at diagnosis based on NGS-targeted resequencing (122 gene panel) and cytogenetic data. Lesions were next investigated in complete remission (CR). Based on the initial clonal composition, targeted resequencing panels were designed to improve the sensitivity by the use of unique molecular barcodes (Haloplex High Sensitivity, or HS-NGS assay). Cytogenetic events were evaluated by FISH. Results: In the 69 patients, a median of 4 genetic or chromosomal events were identified per patient (range 0-10). One patient had no evaluable target allowing MRD evaluation in 68/69 patients. To determine the threshold of detection of the HS NGS assay, we analyzed the frequency of mutant reads in multiple samples expected to be wild type for 31 given SNVs and 2 indels. A consensus threshold of detection was set at a variant allele frequency (VAF) of 0.2% for all lesions. In CR samples, early initiating events frequently persisted after treatment, especially mutations in DNMT3A, TET2, ASXL1, EZH2, IDH1, TP53, SRSF2, and U2AF1. Mutations in FLT3, NRAS, KIT, NPM1, CEBPA, WT1, IDH2 and BCOR were the most frequently cleared events. Seven patients did not reach CR after one course, and two had no available material after one course. In the 59 remaining patients, we tested whether the global response level of all targets was associated with prognosis. We used the median VAF of the first events of all clonal architectures to separate good responder from poor responders (i.e. VAF = 1.66%). At 2 years, there was a trend to lower leukemia free survival (LFS) probability in poor responders (31.7+/-9.9% vs 51.7+/-9.8%, p=0.08) with no translation in overall survival (OS). We next investigated if the persistence of two or more detectable markers was associated with prognosis. The 58 patients with more than one evaluable event were consequently separated in two groups: patients with 0 or 1 marker above the detection threshold after treatment (n=31), and patients with 2 or more detectable lesions (n=27). At 2 years, DFS was 64.9+/-9.3 % in patients with 0 or 1 detectable marker vs 19.8+/-8.7% in patients with 2 or more detectable markers (p=0.001). OS probability was higher in patients with 0 or 1 detectable marker 84+/-6.6% vs 57.1+/-10.5% (p=0.023). When focusing on the 40 patients with intermediate cytogenetics, persistence of 2 or more markers was associated with lower LFS (57+/-11.8% vs 19.4+/-10.5 p=0.0048) and with a trend to lower OS (85+/-8% vs 61+/-11.9% p=0.07). Similar results were observed when restricting the analyses to the 42 prospectively included patients (At 2 years: LFS 73+/-10% vs 24+/-10%, p=0.0026 and OS 90.2+/-6.6% vs 62.8+/-11.5%, p=0.036). In 50 patients with 3 or more identified events, the persistence of 3 or more markers after one course was associated with a very high risk of relapse (DFS 23.5+/-10.3 % vs 75.8 +/-7.5% at one year, p
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  • 8
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    Prognostic Significance of the Cell Cycle Inhibitor p27Kip1 in Chronic B-Cell Lymphocytic Leukemia (1998)
    American Society of Hematology
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    Publication Date: 1998-06-15
    Description: B-cell chronic lymphocytic leukemia (B-CLL) is characterized by the accumulation of resting lymphocytes. The identification of p27kip1, a cyclin-dependent kinase inhibitor that contributes to cell cycle arrest and represents a link between extracellular signals and cell cycle, prompted us to study p27 protein in the lymphocytes from 88 patients with B-CLL and 32 patients with other chronic B-lymphoproliferative disorders. The expression of p27 protein was higher in B-CLL samples with variations among them. In B-CLL, p27 levels were independent of absolute number of circulating lymphocytes, but strongly correlated with both lymphocyte and total tumor mass (TTM) doubling time. High p27 expression was associated with a poorer overall prognosis. In vitro, there was an increased spontaneous survival of B-CLL cells expressing high p27 levels. Interleukin-4 (IL-4) upregulated p27 levels in B-CLL cells, while fludarabine decreased p27 levels. Thus, our results indicate that p27 may be a valuable kinetic marker in B-CLL by providing instantaneous estimation of the disease doubling time. In addition, these results suggest that there is a link between p27 expression and the ability of CLL cells to undergo apoptosis.
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  • 9
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    ABC Proteins Activity Remains An Independent Prognostic Factor In 206 AML When Compared to Other Molecular Markers, FLT3, NPM1, CEBPα, and BAALC (2010)
    American Society of Hematology
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    Publication Date: 2010-11-19
    Description: Abstract 1698 Background: Many clinical and biological features are commonly used in order to predict the probability of response to standard treatment in adult acute myeloid leukaemia (AML). Although cytogenetic analysis provides the major information for prognosis, many molecular alterations like FLT3/ITD, mutations of NPM1, mutations of CEBPα, or BAALC over expression have been described these last years, in order to guide therapeutic choices, especially in patients with normal karyotype. In the other hand, prognostic implications of ABC proteins' expression and functionality, like ABCB1 (Pgp) and others, have been known for years but relationships between ABC proteins and those molecular markers haven't been fully studied. Material and methods: In this retrospective study, we explore the relationships between ABC proteins and these molecular markers, and evaluate whether ABC proteins' activity is an independent prognosis factor in 206 AML, homogenously treated in EORTC protocols. ABC proteins' activity has been assessed with JC1 functional test performed at the time of diagnosis, and all patients were screened from frozen bone marrow or peripheral blood samples for FLT3/ITD, NPM1 mutations, CEBPα mutations, and expression of BAALC. 206 patients aged from 16 to 81 years and treated either in EORTC AML 10, AML 12 or AML 13 from 1996 to 2008 have been included, with a median follow up time for alive patients of five years. Results: In the whole population, 42 patients (20%) showed a high ABC functional assay (JC1+). High ABC activity was associated with NPM1 wild type (p=0.03) and higher BAALC expression (p=0.007). FLT3-ITD was detected in only 2 patients with high ABC functional assay. There was no relationship between high ABC functionality and CEBPα mutational status. In multivariate analysis including age, leukocyte count, cytogenetic, existence of a pre leukemic phase, NPM1, FLT3/ITD, CEBPα and BAALC status and JC1 assay, high ABC proteins' activity was an independent prognosis factor for OS in the whole population (p=0.03). Others independent prognosis factors for OS were age (p=0.0004), cytogenetic (p=0,045), FLT3/ITD (p=0.0096), and NPM1 mutation (p= 0.07). When interesting to normal cytogenetic population (112 patients), high ABC proteins' activity was an independent prognosis factor for DFS (p=0.0107) and OS (p=0.0038). Age (p=0.0012), and FLT3/ITD (p=0.0173) were the only other prognosis factors for OS. In patients with normal cytogenetic, and both NPM1 WT and no FLT3/ITD, only age (p=0.0008) and high ABC proteins' activity (p=0.004) were independent prognosis factors for OS. Conclusion: ABC proteins' activity remains an independent prognosis factor in adult AML, when compared to these molecular factors. Because of its relatively high frequency (around 20 % of patients), and the easiness to perform this test, we think JC1 probe should be used in every AML patients in order to refine the treatment strategy at the time of diagnosis. Disclosures: No relevant conflicts of interest to declare.
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  • 10
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    Involvement of BAFF and APRIL in the resistance to apoptosis of B-CLL through an autocrine pathway (2004)
    American Society of Hematology
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    Publication Date: 2004-01-15
    Description: Tumor necrosis factor (TNF) superfamily members BAFF, or B-cell activation factor of the TNF family, and APRIL, a proliferation-inducing ligand, are involved in normal B-cell survival and differentiation. They interact with 3 receptors: BAFF-R, specific to BAFF; and TACI and BCMA, which are shared by BAFF and APRIL. We tested the potential role of these proteins in B-cell chronic lymphocytic leukemia (B-CLL) resistance to apoptosis. TACI and BAFF-R mRNAs were found in leukemic B cells. BAFF and APRIL mRNAs and proteins were detected in B-CLL leukemic cells and normal blood or tonsil-derived B lymphocytes. Yet, in contrast to normal B lymphocytes, BAFF and APRIL were expressed at the membranes of leukemic cells. Adding soluble BAFF or APRIL protected B-CLL cells against spontaneous and drug-induced apoptosis and stimulated NF-κB activation. Conversely, adding soluble BCMA-Fc or anti-BAFF and anti-APRIL antibodies enhanced B-CLL apoptosis. Moreover, a soluble form of BAFF was detected using surface-enhanced laser desorption/ionization–time-of-flight mass spectrometry (SELDI-TOF MS) in the sera of B-CLL patients but not of healthy donors. Taken together, our results indicate that B-CLL cells can be rescued from apoptosis through an autocrine process involving BAFF, APRIL, and their receptors. Inhibiting BAFF and APRIL pathways may be of therapeutic value for B-CLL treatment.
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