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1.
Blood ; 138(11): 948-958, 2021 09 16.
Article in English | MEDLINE | ID: mdl-33895809

ABSTRACT

Genomic classification has improved risk assignment of pediatric, but not adult B-lineage acute lymphoblastic leukemia (B-ALL). The international UKALLXII/ECOG-ACRIN E2993 (#NCT00002514) trial accrued 1229 adolescent/adult patients with BCR-ABL1- B-ALL (aged 14 to 65 years). Although 93% of patients achieved remission, 41% relapsed at a median of 13 months (range, 28 days to 12 years). Five-year overall survival (OS) was 42% (95% confidence interval, 39, 44). Transcriptome sequencing, gene expression profiling, cytogenetics, and fusion polymerase chain reaction enabled genomic subtyping of 282 patient samples, of which 264 were eligible for trial, accounting for 64.5% of E2993 patients. Among patients with outcome data, 29.5% with favorable outcomes (5-year OS 65% to 80%) were deemed standard risk (DUX4-rearranged [9.2%], ETV6-RUNX1/-like [2.3%], TCF3-PBX1 [6.9%], PAX5 P80R [4.1%], high-hyperdiploid [6.9%]); 50.2% had high-risk genotypes with 5-year OS of 0% to 27% (Ph-like [21.2%], KMT2A-AFF1 [12%], low-hypodiploid/near-haploid [14.3%], BCL2/MYC-rearranged [2.8%]); 20.3% had intermediate-risk genotypes with 5-year OS of 33% to 45% (PAX5alt [12.4%], ZNF384/-like [5.1%], MEF2D-rearranged [2.8%]). IKZF1 alterations occurred in 86% of Ph-like, and TP53 mutations in patients who were low-hypodiploid (54%) and BCL2/MYC-rearranged (33%) but were not independently associated with outcome. Of patients considered high risk based on presenting age and white blood cell count, 40% harbored subtype-defining genetic alterations associated with standard- or intermediate-risk outcomes. We identified distinct immunophenotypic features for DUX4-rearranged, PAX5 P80R, ZNF384-R/-like, and Ph-like genotypes. These data in a large adult B-ALL cohort treated with a non-risk-adapted approach on a single trial show the prognostic importance of genomic analyses, which may translate into future therapeutic benefits.


Subject(s)
Fusion Proteins, bcr-abl/genetics , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Transcriptome , Adolescent , Adult , Female , Gene Rearrangement , Humans , Male , Middle Aged , Mutation , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/therapy , Prognosis , Proto-Oncogene Proteins c-abl/genetics , Proto-Oncogene Proteins c-bcr/genetics , Risk Assessment , Young Adult
3.
Leuk Lymphoma ; 56(11): 3031-7, 2015.
Article in English | MEDLINE | ID: mdl-25721902

ABSTRACT

Fludarabine (F) and cyclophosphamide (C) remain backbones of up-front chemotherapy regimens for chronic lymphocytic leukemia (CLL). We report long-term follow-up of a randomized F vs. FC trial in untreated CLL (#) . With median follow-up of 88 months, estimated median progression-free survival (PFS) was 19.3 vs. 48.1 months for F (n = 109) and FC (n = 118), respectively (p < 0.0001), and median overall survival (OS) was 88.0 vs. 79.1 months (p = 0.96). In multivariable analyses, variables associated with inferior PFS and OS respectively were age (p = 0.002, p < 0.001), Rai stage (p = 0.006, p = 0.02) and sex (p = 0.03, PFS only). Del(17)(p13.1) predicted shorter PFS and OS (p < 0.0001 for each), as did del(11q)(22.3) (p < 0.0001, p = 0.005, respectively), trisomy 12 with mutated Notch1 (p = 0.003, p = 0.03, respectively) and unmutated IGHV (p = 0.009, p = 0.002, respectively), all relative to patients without these features. These data confirm results from shorter follow-up and further justify targeted therapies for CLL.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Chromosome Aberrations , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Vidarabine/analogs & derivatives , Adult , Aged , Aged, 80 and over , Biomarkers , CpG Islands , Cyclophosphamide/administration & dosage , DNA Methylation , DNA Mutational Analysis , Female , Follow-Up Studies , Humans , Immunoglobulin Heavy Chains/genetics , In Situ Hybridization, Fluorescence , Kaplan-Meier Estimate , Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis , Leukemia, Lymphocytic, Chronic, B-Cell/mortality , Male , Middle Aged , Multivariate Analysis , Mutation , Prognosis , Treatment Outcome , Vidarabine/administration & dosage , Vidarabine/therapeutic use , ZAP-70 Protein-Tyrosine Kinase/genetics
4.
Leuk Res ; 36(7): 832-40, 2012 Jul.
Article in English | MEDLINE | ID: mdl-22537394

ABSTRACT

In patients with myelodysplastic syndromes (MDS), chromosome anomalies are detected by conventional cytogenetic studies (CCS) and/or interphase fluorescence in situ hybridization (FISH) of bone marrow (BM) samples and provide prognostic and diagnostic information, which can direct therapy. Whether peripheral blood (PB) can be substituted for bone marrow in these cases and can provide the same information remains unknown. Concurrent BM and PB specimens collected from 100 patients with recently diagnosed MDS were studied using both CCS and FISH. While 68% of BM samples showed an abnormal karyotype by CCS, only 31% of PB samples were abnormal by CCS. In 12% of patients, FISH and CCS were discordant due to the inability of the FISH panel to detect all possible abnormalities. However, only one case (1%) had a cryptic abnormality detected by FISH. BM and PB FISH were discordant in 3% of cases, most likely due to the smaller clone size in PB vs. BM. While PB should not be substituted for BM at diagnosis, it is a viable alternative for monitoring patients using the appropriate FISH probe(s).


Subject(s)
Cytogenetic Analysis/methods , Medical Oncology/methods , Myelodysplastic Syndromes/diagnosis , Adolescent , Adult , Aged , Aged, 80 and over , Biopsy, Needle , Bone Marrow Examination/methods , Child , Cytogenetics/methods , Female , Hematologic Tests/methods , Humans , Karyotyping/methods , Male , Middle Aged , Models, Biological , Myelodysplastic Syndromes/blood , Myelodysplastic Syndromes/pathology , Prognosis , Young Adult
5.
Cancer Genet Cytogenet ; 203(2): 141-8, 2010 Dec.
Article in English | MEDLINE | ID: mdl-21156226

ABSTRACT

Five laboratories in the Chronic Lymphocytic Leukemia (CLL) Research Consortium (CRC) investigated standardizing and pooling of fluorescence in situ hybridization (FISH) results as a collaborative research project. This investigation used fixed bone marrow and blood cells available from previous conventional cytogenetic or FISH studies in two pilot studies, a one-day workshop, and proficiency test. Multiple FISH probe strategies were used to detect 6q-, 11q-, +12, 13q-, 17p-, and IGH rearrangements. Ten specimens were studied by participants who used their own probes (pilot study 1). Of 312 FISH interpretations, 224 (72%) were true-negative, 74 (24%) true-positive, 6 (2%) false-negative, and 8 (3%) false-positive. In pilot study no. 2, each participant studied two specimens using identical FISH probe sets to control for variation due to probe sets and probe strategies. Of 80 FISH interpretations, no false interpretations were identified. At a subsequent workshop, discussions produced agreement on scoring criteria. The proficiency test that followed produced no false-negative results and 4% (3/68) false-positive interpretations. Interpretation disagreements among laboratories were primarily attributable to inadequate normal cutoffs, inconsistent scoring criteria, and the use of different FISH probe strategies. Collaborative organizations that use pooled FISH results may wish to impose more conservative empiric normal cutoff values or use an equivocal range between the normal cutoff and the abnormal reference range to eliminate false-positive interpretations. False-negative results will still occur, and would be expected in low-percentage positive cases; these would likely have less clinical significance than false positive results. Individual laboratories can help by closely following rigorous quality assurance guidelines to ensure accurate and consistent FISH studies in their clinical practice and research.


Subject(s)
Cytogenetics/standards , In Situ Hybridization, Fluorescence/methods , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Bone Marrow Cells/cytology , False Negative Reactions , Humans , Karyotyping , Microscopy, Fluorescence/methods , Oligonucleotide Probes/genetics , Pilot Projects , Reproducibility of Results
6.
Br J Haematol ; 148(2): 217-25, 2010 Jan.
Article in English | MEDLINE | ID: mdl-19804455

ABSTRACT

The treatment of relapsed acute myeloid leukaemia (AML) remains unsatisfactory. We conducted a phase II randomized trial where patients received intermediate-dose cytarabine for 4 d followed by gemtuzumab ozogamicin on day 5 (Arm A), or combined with liposomal daunorubicin for 3 d (Arm B), or cytarabine given for 5 d combined with cyclophosphamide for 3 d and topotecan by continuous infusion for 5 d (Arm C). Eligible patients had primary refractory AML, a first relapse after a remission of <1 year, or a second or greater relapse. The primary objective of this trial was attainment of a conventional complete remission (CR) or a CR without platelet recovery (CRp) in at least 40% of patients. The CR/CRp rates for the 82 eligible patients were 3/26 (12%) in Arm A, 2/29 (7%) in Arm B, and 1/27 (4%) in Arm C. No patients who had relapsed within 6 months of initial CR or who had suffered multiple relapses responded. More than 95% of patients subsequently died of AML. No unexpected toxicities were encountered. We conclude that none of these three regimens were effective enough in the treatment of high-risk relapsed or refractory AML to warrant further study. This trial was registered at http://www.clinicaltrials.gov as #NCT00005962.


Subject(s)
Antimetabolites, Antineoplastic/therapeutic use , Antineoplastic Agents/therapeutic use , Immunosuppressive Agents/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , Adult , Aged , Aged, 80 and over , Aminoglycosides/therapeutic use , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , Cyclophosphamide/therapeutic use , Cytarabine/therapeutic use , Daunorubicin/administration & dosage , Daunorubicin/therapeutic use , Drug Therapy, Combination , Female , Gemtuzumab , Humans , Leukemia, Myeloid, Acute/mortality , Liposomes , Male , Middle Aged , Recurrence , Remission Induction , Survival Analysis , Topotecan/therapeutic use
7.
Mayo Clin Proc ; 84(9): 801-10, 2009 09.
Article in English | MEDLINE | ID: mdl-19720778

ABSTRACT

OBJECTIVE: To use fluorescence in situ hybridization (FISH) to visualize genetic abnormalities in interphase cell nuclei (interphase FISH) of acinar cell carcinoma, ductal adenocarcinoma, and islet cell carcinoma of the pancreas. PATIENTS AND METHODS: Between April 4, 2007, and December 4, 2008, interphase FISH was used to study paraffin-embedded preparations of tissue obtained from 18 patients listed in the Mayo Clinic Biospecimen Resource for Pancreas Research with a confirmed diagnosis of acinar cell carcinoma, ductal adenocarcinoma, islet cell carcinoma, or pancreas without evidence of neoplasia. FISH probes were used for chromosome loci of APC (see glossary at end of article for expansion of all gene symbols), BRCA2, CTNNB1, EGFR, ERBB2, CDKN2A, TP53, TYMP, and TYMS. These FISH probes were used with control probes to distinguish among various kinds of chromosome abnormalities of number and structure. RESULTS: FISH abnormalities were observed in 12 (80%) of 15 patients with pancreatic cancer: 5 of 5 patients with acinar cell carcinoma, 5 of 5 patients with ductal adenocarcinoma, and 2 (40%) of 5 patients with islet cell carcinoma. All 3 specimens of pancreatic tissue without neoplasia had normal FISH results. Gains of CTNNB1 due to trisomy 3 occurred in each tumor with acinar cell carcinoma but in none of the other tumors in this study. FISH abnormalities of all other cancer genes studied were observed in all forms of pancreatic tumors in this investigation. CONCLUSION: FISH abnormalities of CTNNB1 due to trisomy 3 were observed only in acinar cell carcinoma. FISH abnormalities of genes implicated in familial cancer, tumor progression, and the 5-fluorouracil pathway were common but were not associated with specific types of pancreatic cancer.


Subject(s)
Carcinoma, Acinar Cell/genetics , Carcinoma, Islet Cell/genetics , Carcinoma, Pancreatic Ductal/genetics , Chromosome Aberrations , Pancreatic Neoplasms/genetics , Carcinoma, Acinar Cell/pathology , Carcinoma, Islet Cell/pathology , Carcinoma, Pancreatic Ductal/pathology , Female , Humans , In Situ Hybridization, Fluorescence , Interphase/genetics , Male , Pancreatic Neoplasms/pathology
8.
N Engl J Med ; 361(13): 1249-59, 2009 Sep 24.
Article in English | MEDLINE | ID: mdl-19776406

ABSTRACT

BACKGROUND: In young adults with acute myeloid leukemia (AML), intensification of the anthracycline dose during induction therapy has improved the rate of complete remission but not of overall survival. We evaluated the use of cytarabine plus either standard-dose or high-dose daunorubicin as induction therapy, followed by intensive consolidation therapy, in inducing complete remission to improve overall survival. METHODS: In this phase 3 randomized trial, we assigned 657 patients between the ages of 17 and 60 years who had untreated AML to receive three once-daily doses of daunorubicin at either the standard dose (45 mg per square meter of body-surface area) or a high dose (90 mg per square meter), combined with seven daily doses of cytarabine (100 mg per square meter) by continuous intravenous infusion. Patients who had a complete remission were offered either allogeneic hematopoietic stem-cell transplantation or high-dose cytarabine, with or without a single dose of the monoclonal antibody gemtuzumab ozogamicin, followed by autologous stem-cell transplantation. The primary end point was overall survival. RESULTS: In the intention-to-treat analysis, high-dose daunorubicin, as compared with a standard dose of the drug, resulted in a higher rate of complete remission (70.6% vs. 57.3%, P<0.001) and improved overall survival (median, 23.7 vs. 15.7 months; P=0.003). The rates of serious adverse events were similar in the two groups. Median follow-up was 25.2 months. CONCLUSIONS: In young adults with AML, intensifying induction therapy with a high daily dose of daunorubicin improved the rate of complete remission and the duration of overall survival, as compared with the standard dose. (ClinicalTrials.gov number, NCT00049517.)


Subject(s)
Antibiotics, Antineoplastic/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Daunorubicin/administration & dosage , Leukemia, Myelomonocytic, Acute/drug therapy , Adolescent , Adult , Age Factors , Antibiotics, Antineoplastic/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Combined Modality Therapy , Cytarabine/administration & dosage , Daunorubicin/adverse effects , Female , Histone-Lysine N-Methyltransferase , Humans , Infusions, Intravenous , Kaplan-Meier Estimate , Leukemia, Myelomonocytic, Acute/genetics , Leukemia, Myelomonocytic, Acute/mortality , Leukemia, Myelomonocytic, Acute/therapy , Male , Middle Aged , Mutation , Myeloid-Lymphoid Leukemia Protein/genetics , Proportional Hazards Models , Remission Induction/methods , Risk Factors , Stem Cell Transplantation , Young Adult , fms-Like Tyrosine Kinase 3/genetics
9.
J Clin Oncol ; 27(11): 1844-9, 2009 Apr 10.
Article in English | MEDLINE | ID: mdl-19255329

ABSTRACT

PURPOSE: Smudge cells are ruptured chronic lymphocytic leukemia (CLL) cells appearing on the blood smears of CLL patients. Our recent findings suggest that the number of smudge cells may have important biologic correlations rather than being only an artifact of slide preparation. In this study, we evaluated whether the smudge cell percentage on a blood smear predicted survival of CLL patients. PATIENTS AND METHODS: We calculated smudge cell percentages (ratio of smudged to intact cells plus smudged lymphocytes) on archived blood smears from a cohort of previously untreated patients with predominantly early-stage CLL enrolled onto a prospective observational study. The relationship between percentage of smudge cells, patient survival, and other prognostic factors was explored. RESULTS: Between 1994 and 2002, 108 patients were enrolled onto the study and had archived blood smears available for review; 80% of patients had Rai stage 0 or I disease. The median smudge cell percentage was 28% (range, 1% to 75%). The percentage of smudge cells was lower in CD38(+) versus CD38(-) patients (P = .019) and in Zap70-positive versus Zap70-negative patients (P = .028). Smudge cell percentage as a continuous variable was associated with prolonged survival (P = .042). The 10-year survival rate was 50% for patients with 30% or less smudge cells compared with 80% for patients with more than 30% of smudge cells (P = .015). In multivariate analysis, the percentage of smudge cells was an independent predictor of overall survival. CONCLUSION: Percentage of smudge cells on blood smear is readily available and an independent factor predicting overall survival in CLL.


Subject(s)
B-Lymphocytes/pathology , Leukemia, Lymphocytic, Chronic, B-Cell/blood , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Lymphocyte Count , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Predictive Value of Tests , Prognosis , Survival Analysis
10.
Am J Hematol ; 83(9): 708-13, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18634051

ABSTRACT

To better estimate prognosis for patients with myelodysplastic syndromes (MDS) associated with clonal interstitial deletions of the long arm of chromosome 5 (del(5q)), we reviewed the medical records of 130 adults with del(5q) MDS seen at our institution over a 15-year period. Overall median survival of this cohort was 9.5 months, shorter than reported in earlier series. The least favorable outcomes are associated with complex cytogenetics, lack of any normal metaphases, normocytic rather than macrocytic erythrocyte indices, and low baseline lymphocyte counts. Lymphopenia but not neutropenia at the time of diagnosis appears to be a new adverse prognostic indicator. Cytogenetic breakpoints defined by G-banded karyotyping correlate poorly with particular disease features. Surprisingly, survival of patients with treatment-related MDS was equivalent to that of de novo MDS with del(5q) in this series. Morphologic features associated with del(5q) are diverse. Most patients with del(5q) MDS do not meet criteria for WHO-defined 5q-syndrome, and the presence of del(5q) does not appear to modify the clinical phenotype otherwise risk-stratified by the International Prognostic Scoring System (IPSS). Additional important prognostic factors not taken into account by the IPSS include the baseline erythrocyte indices, lymphocyte count, and clonal burden.


Subject(s)
Chromosome Deletion , Chromosomes, Human, Pair 5/ultrastructure , Myelodysplastic Syndromes/genetics , Adult , Aged , Aged, 80 and over , Chromosome Aberrations , Chromosome Breakage , Clone Cells/pathology , Cohort Studies , Erythrocyte Indices , Female , Humans , Leukemia, Myeloid/epidemiology , Leukemia, Myeloid/etiology , Leukocyte Count , Male , Middle Aged , Minnesota/epidemiology , Myelodysplastic Syndromes/drug therapy , Myelodysplastic Syndromes/epidemiology , Myelodysplastic Syndromes/etiology , Phenotype , Prognosis , Retrospective Studies , Survival Analysis , Treatment Outcome
11.
Leuk Res ; 32(12): 1927-30, 2008 Dec.
Article in English | MEDLINE | ID: mdl-18538839

ABSTRACT

Among 23 cases of myeloproliferative neoplasms (MPNs) with an associated del(5q) seen at our institution, 14 (61%) fulfilled diagnostic criteria for primary myelofibrosis (PMF). Other diagnoses included polycythemia vera (PV; n=2), essential thrombocythemia (ET; n=1), post-ET myelofibrosis (n=1), systemic mastocytosis (SM; n=1), and MPN, unclassifiable (n=4). Compared to their del(5q)-negative counterparts, del(5q)-positive PMF cases were significantly more anemic (p<0.001) and thrombocytopenic (p<0.001). However, survival and leukemic transformation rates appear to be similar between the two groups. del(5q)-positive PMF was histologically characterized by a mixture of both small and monolobated megakaryocytes as well as large and bizarre megakaryocytes. When used, lenalidomide therapy induced hematological and cytogenetic remissions in del(5q)-positive PMF. The current study identifies PMF as another del(5q)-associated myeloid malignancy with characteristic megakaryocyte morphology.


Subject(s)
Chromosomes, Human, Pair 5 , Myeloproliferative Disorders/genetics , Primary Myelofibrosis/genetics , Sequence Deletion , Bone Marrow/pathology , Humans , Megakaryocytes/pathology , Myeloproliferative Disorders/pathology , Primary Myelofibrosis/etiology , Primary Myelofibrosis/mortality , Primary Myelofibrosis/pathology , Survival Analysis
13.
Leuk Res ; 32(9): 1329-32, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18423850

ABSTRACT

The inaugural meeting of the International Working Group on MDS cytogenetics convened 22-23 October 2007 in Chicago, IL. Under the sponsorship of the Myelodysplastic Syndromes Foundation, the group was organized to address the substantial need for worldwide standardized cytogenetic testing for MDS in clinical practice and research. Eighteen cytogeneticists from 10 countries attended the first working group meeting. Representatives from France and Austria were unable to attend the Chicago meeting. Marilyn L. Slovak, PhD (City of Hope, USA) served as Working Group Chair and Gordon Dewald, PhD (Mayo Clinic, USA), served as Working Group Advisor and Co-Chair. Other members in attendance included: Mette Andersen, Rigshospitalet, Denmark; Lynda Campbell, St. Vincent's Hospital Melbourne, Australia; Athena Cherry, Stanford University, USA; Kathy Chun, North York General Hospital, Canada; Mike Griffiths, West Midlands Regional Genetics Lab, UK; Detlef Haase, Georg-August-Universität, Germany; Claudia Haferlach, MLL Münchner Leukämielabor GmbH, Germany; Anne Hagemeijer, University of Leuven, Belgium; Barbara Hildebrandt, Institut für Humangenetik & Anthropologie Dupsilonsseldorf, Germany; Douglas Horsman, BC Cancer Agency, Canada; M. Anwar Iqbal, University of Rochester, USA; Suresh Jhanwar, Memorial Sloan-Kettering Cancer Center, USA; Bertil Johansson, University Hospital, Sweden; Michelle LeBeau, University of Chicago, USA; Kazuma Ohyashiki, Tokyo Medical University, Japan; Francesc Solé, Hospital del Mar, Spain. The focus of the working group was to establish the natural history and clinical significance of cytogenetic anomalies associated with the myelodysplastic syndromes (MDS), and to incorporate cytogenetic testing into the development of new treatments to cure MDS. Three specific goals were discussed in an effort to rapidly improve the care of patients with MDS. The first goal was how to educate physicians on the appropriate use of cost effective cytogenetic testing for their patients with MDS. The second goal discussed was how best this working group could assist pharmaceutical companies with the use of appropriate cytogenetic testing in their evaluation of new drugs. The final goal discussed was how to advance cytogenetic research into the origin, progression and clinical significance of genetic anomalies associated with MDS.


Subject(s)
Cytogenetic Analysis/methods , International Cooperation , Myelodysplastic Syndromes/diagnosis , Clinical Trials as Topic , Humans , Myelodysplastic Syndromes/therapy
14.
Diagn Pathol ; 3: 16, 2008 Apr 18.
Article in English | MEDLINE | ID: mdl-18423023

ABSTRACT

BACKGROUND: The extent of enhanced bone marrow angiogenesis in chronic lymphocytic leukemia (CLL) and relationship to proangiogenic factors and prognostic indicators is largely unexplored. METHODS: To further investigate the role of angiogenesis in CLL by evaluating the topography and extent of angiogenesis in a group of CLL bone marrow biopsies, to study the expression of pro and antiangiogenic vascular factors in CLL cells to more precisely document the cell types producing these factors, and to evaluate the role, if any, of localized hypoxia in upregulation of angiogenesis in CLL We used immunohistochemistry (IHC) (n = 21 pts) with antibodies to CD3 and CD20, proangiogenic (VEGF, HIF-1a) and antiangiogenic (TSP-1) factors, and VEGF receptors -1 and -2 to examine pattern/extent of CLL marrow involvement, microvessel density (MVD), and angiogenic characteristics; flow cytometry (FC) was performed on 21 additional cases for VEGF and TSP-1. RESULTS: CLL patients had higher MVD (23.8 vs 14.6, p~0.0002) compared to controls (n = 10). MVD was highest at the periphery of focal infiltrates, was not enhanced in proliferation centers, and was increased irrespective of the presence or absence of cytogenetic/immunophenotypic markers of aggressivity. By IHC, CLL cells were VEGF(+), HIF-1a (+), TSP-1(-), VEGFR-1(+), and VEGFR-2(+). By FC, CLL cells were 1.4-2.0-fold brighter for VEGF than T cells and were TSP-1(-). CONCLUSION: CLL demonstrates enhanced angiogenesis, with increased MVD, upregulated VEGF and downregulated TSP-1. Upregulation of HIF-1a in all CLL cases suggests localized tissue hypoxia as an important stimulant of microvessel proliferation. The presence of VEGF receptors on CLL cells implies an autocrine effect for VEGF. Differences in MVD did not correlate with traditional genetic/immunophenotypic markers of aggressiveness.

15.
Br J Haematol ; 140(5): 537-46, 2008 Mar.
Article in English | MEDLINE | ID: mdl-18275431

ABSTRACT

In vitro studies have demonstrated that surface expression of CD49d on chronic lymphocytic leukaemia (CLL) B cells facilitates leukaemic cell-stromal interactions by binding to fibronectin. This interaction reduces both spontaneous and drug-induced apoptosis. The present study measured CD49d expression by flow cytometry in a cohort of untreated CLL patients previously accrued to a prospective observational study and evaluated the relationship with overall survival (OS). Among the 158 CLL patients tested, the percentage of leukaemic B cells expressing CD49d ranged from 0 to 100%. When all risk factors were treated as continuous variables, CD49d expression showed moderate correlation with expression of ZAP-70 (r = 0.54; P < 0.0001) and CD38 (r = 0.58; P < 0.0001) but not %IGHV mutation. As a continuous variable, CD49d expression strongly correlated with OS (P < 0.0001). Recursive partitioning analysis suggested the 45% threshold of CD49d expression best predicted OS. Multivariate analysis, controlling for disease stage, ZAP-70, IGHV status and fluorescent in situ hybridization defects identified CD49d as an independent predictor of OS and was a better predictor of clinical outcome than ZAP-70, IGHV, or cytogenetics. This observational cohort study suggests that CLL B-cell expression of CD49d is an easily measurable and independent predictor of OS and CD49d expression in CLL. Importantly, anti-CD49d antibodies are already approved for treatment of other human diseases. Clinical testing of anti-CD49d therapy in CLL appears warranted.


Subject(s)
Biomarkers, Tumor/blood , Integrin alpha4/blood , Leukemia, Lymphocytic, Chronic, B-Cell/blood , Adult , Aged , Aged, 80 and over , Antigens, Neoplasm/blood , Female , Humans , In Situ Hybridization, Fluorescence , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Male , Middle Aged , Neoplasm Staging , Prognosis , Prospective Studies , Survival Analysis
16.
Leuk Res ; 32(10): 1597-600, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18241918

ABSTRACT

Among 59 consecutive patients with myelofibrosis (MF) in whom peripheral blood (PB) cytogenetic studies were performed, at least two analyzable metaphases (median 20, range 2-31) were obtained in 49 (81%) patients and in all 37 (100%) cases with PB myeloid progenitor cell count of 0.1 x 10(9)L(-1) or above (p=0.02). Twenty-two patients had concomitant PB and bone marrow (BM) cytogenetic studies; 6 showed similarly abnormal findings in both BM and PB. In another 2 cases, results were abnormal in BM but normal in PB; the opposite was seen in 1 case. These results suggest that PB can be considered as an alternative to BM for cytogenetic studies as currently used in MF but additional prospective studies are needed to support change in practice.


Subject(s)
Blood Cells/ultrastructure , Bone Marrow Cells/ultrastructure , Cytogenetic Analysis , Primary Myelofibrosis/diagnosis , Adult , Female , Humans , Male , Metaphase
17.
Leuk Res ; 32(3): 407-11, 2008 Mar.
Article in English | MEDLINE | ID: mdl-17707907

ABSTRACT

The purpose of this study was to define the spectrum of hematologic neoplasms and chromosomal breakpoints associated with del(5q); separate analyses were performed to account for prior cytotoxic treatment. A total of 358 consecutive del(5q) cases were identified; specific diagnoses included myelodysplastic syndrome (MDS; 53%), acute myeloid leukemia (AML; 22%), plasma cell proliferative disorder (PCPD; 9%), myeloproliferative disorder (MPD; 7%), acute lymphoblastic leukemia (ALL; 2%), PCPD with MDS (2%), MDS/MPD (2%), and malignant lymphoma (ML; 2%). The corresponding figures in the absence/presence of prior cytotoxic treatment (n=250/108) were 61%/34% for MDS, 24%/19% for AML, 4%/20% for PCPD, 6%/8% for MPD, 1%/4% for ALL, and 2%/4% for ML. del(5q) occurred as the sole cytogenetic abnormality in 88 cases (25%) including 76 without prior cytotoxic therapy. Among the latter, 82% had MDS, 8% AML, 5% MPD, 4% PCPD, and 1% ML. Chromosome 5 breakpoints included q13q33 in 49% of the cases, q15q33 in 22%, q22q33 in 8%, and q13 in 3% and their distribution was not affected by specific diagnosis or treatment history. del(5q)-associated lymphoid disorders featured a higher prevalence of previous cytotoxic therapy and smaller number del(5q)-positive metaphases, when compared to their counterparts with myeloid neoplasms. We conclude that del(5q), although most prevalent in MDS, is seen across the spectrum of myeloid disorders including MPD and its occurrence in lymphoid disorders might signify, for the most part, an occult myeloid clone.


Subject(s)
Chromosome Deletion , Hematologic Neoplasms/genetics , Myelodysplastic Syndromes/genetics , Myeloproliferative Disorders/genetics , Antineoplastic Agents/pharmacology , Bone Marrow/pathology , Databases, Factual , Humans , Karyotyping , Lymphoma/genetics , Phenotype
18.
J Clin Invest ; 118(1): 306-15, 2008 Jan.
Article in English | MEDLINE | ID: mdl-18064298

ABSTRACT

Survival of patients with B cell chronic lymphocytic leukemia (B-CLL) can be predicted by analysis of mutations in the immunoglobulin heavy chain variable gene (IGHV). Patients without mutations (unmutated [UM]) are at greater risk for disease progression and death than patients with mutations (M). Despite this broad prognostic difference, there remains wide intragroup variation in the clinical outcome of UM patients, especially those with low/intermediate Rai risk disease. We evaluated UM B-CLL patients with low/intermediate Rai risk to determine the relationship between IGHV, IGH diversity (IGHD), and IGH joining (IGHJ) gene usage and time to treatment (TTT). Irrespective of IGHV usage, UM patients whose B-CLL cells expressed the IGHD3-3 gene had a significantly shorter TTT than other UM B-CLL patients, and specifically, use of the IGHD3-3 gene in reading frame 2 (RF2) predicted shorter TTT. As expected, Rai risk was the best single prognostic factor for TTT; however, IGHD usage was also a significant variable for TTT. Therefore, both IGHD gene and IGHD RF usage have prognostic relevance in UM B-CLL patients with low/intermediate Rai risk disease. In addition, these data support the concept that antigen-driven selection of specific Ig receptors plays a role in the clinical course of B-CLL.


Subject(s)
Immunoglobulin Heavy Chains/genetics , Immunoglobulin Joining Region/genetics , Immunoglobulin Variable Region/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/mortality , Mutation , Adult , Aged , Aged, 80 and over , Antigens, Neoplasm/genetics , Antigens, Neoplasm/immunology , Disease-Free Survival , Female , Gene Expression Regulation, Leukemic/immunology , Humans , Immunoglobulin Heavy Chains/immunology , Immunoglobulin Joining Region/immunology , Immunoglobulin Variable Region/immunology , Leukemia, Lymphocytic, Chronic, B-Cell/immunology , Leukemia, Lymphocytic, Chronic, B-Cell/therapy , Male , Middle Aged , Mutation/immunology , Reading Frames/genetics , Reading Frames/immunology , Risk Factors , Survival Rate
19.
Blood ; 111(1): 86-93, 2008 Jan 01.
Article in English | MEDLINE | ID: mdl-17893227

ABSTRACT

Lenalidomide is approved for red blood cell (RBC) transfusion-dependent anemia due to low or intermediate-1 (int-1) risk myelodysplastic syndromes (MDSs) associated with a chromosome 5q deletion with or without additional cytogenetic abnormalities. We report results of a multicenter, phase 2 trial evaluating lenalidomide therapy for transfusion-dependent patients with low- or int-1-risk MDS without deletion 5q. Eligible patients had 50,000/mm(3) or more platelets and required 2 U or more RBCs within the previous 8 weeks; 214 patients received 10 mg oral lenalidomide daily or 10 mg on days 1 to 21 of a 28-day cycle. The most common grade 3/4 adverse events were neutropenia (30%) and thrombocytopenia (25%). Using an intention-to-treat analysis, 56 (26%) patients achieved transfusion independence (TI) after a median of 4.8 weeks of treatment with a median duration of TI of 41.0 weeks. In patients who achieved TI, the median rise in hemoglobin was 32 g/L (3.2 g/dL; range, 10-98 g/L [1.0-9.8 g/dL]) from baseline. A 50% or greater reduction in transfusion requirement occurred in 37 additional patients, yielding a 43% overall rate of hematologic improvement (TI response + ||>or= 50% reduction in transfusion requirement). Lenalidomide has clinically meaningful activity in transfusion-dependent patients with low- or int-1-risk MDS who lack the deletion 5q karyotypic abnormality.


Subject(s)
Antineoplastic Agents/administration & dosage , Myelodysplastic Syndromes/drug therapy , Myelodysplastic Syndromes/genetics , Thalidomide/analogs & derivatives , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Blood Transfusion , Chromosome Deletion , Chromosomes, Human, Pair 5 , Female , Humans , Karyotyping , Lenalidomide , Male , Middle Aged , Myelodysplastic Syndromes/epidemiology , Prognosis , Risk Factors , Thalidomide/administration & dosage , Thalidomide/adverse effects , Treatment Outcome
20.
Leuk Lymphoma ; 48(11): 2137-40, 2007 Nov.
Article in English | MEDLINE | ID: mdl-17926177

ABSTRACT

In chemotherapy-treated patients with chronic myeloid leukemia (CML), the karyotypic detection of Philadelphia chromosome (Ph)-negative metaphases at diagnosis (i.e. Ph mosaicism) is not considered significant as a prognostic factor for survival. In the current retrospective study, clinical correlates and prognostic relevance of Ph mosaicism were evaluated in 63 Ph-positive patients with CML, including 59 in chronic phase and 4 in accelerated phase, receiving imatinib mesylate as either first (n = 46) or second (n = 17) line therapy. Thirteen patients (21%) displayed Ph-negative metaphases at diagnosis and, compared to the other 50 patients with 100% Ph-positive metaphases, presented with significantly lower leukocyte count (p = 0.0004), circulating blast percentage (p = 0.02), and incidence of palpable splenomegaly (p = 0.02). Ph mosaicism did not correlate with other CML-pertinent prognostic factors including Sokal score (p = 0.4) or the presence of additional chromosome changes (p = 0.96) found in 10 patients (16%). Neither Ph mosaicism nor the presence of additional chromosome changes affected complete or partial cytogenetic remission rates to IM. Multivariable analysis identified Ph mosaicism as a risk factor for shortened survival. Due to the small sample size, the current preliminary observations require validation in a larger group of patients.


Subject(s)
Leukemia, Myelogenous, Chronic, BCR-ABL Positive/diagnosis , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Mosaicism , Philadelphia Chromosome , Piperazines/therapeutic use , Pyrimidines/therapeutic use , Adolescent , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/therapeutic use , Benzamides , Chromosome Aberrations , Female , Follow-Up Studies , Humans , Imatinib Mesylate , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/mortality , Male , Middle Aged , Mosaicism/drug effects , Prognosis , Retrospective Studies , Survival Analysis , Treatment Outcome
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