326 results on '"Forconi, F."'
Search Results
302. Massive intravascular hemolysis: a fatal complication of Clostridium perfringens septicemia in a patient with acute lymphoblastic leukemia.
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Pirrotta MT, Bucalossi A, Forconi F, Gozzetti A, Bocchia M, Mazzotta S, Sammassimo S, and Lauria F
- Subjects
- Fatal Outcome, Hemolysis, Humans, Male, Middle Aged, Bacteremia complications, Clostridium Infections complications, Clostridium perfringens, Precursor Cell Lymphoblastic Leukemia-Lymphoma microbiology
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- 2005
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303. Thrombotic thrombocytopenic purpura secondary to an occult adenocarcinoma.
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Pirrotta MT, Bucalossi A, Forconi F, Bocchia M, Mazzotta S, Sammassimo S, Gozzetti A, and Lauria F
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- Adenocarcinoma pathology, Aged, Alkaline Phosphatase analysis, Bone Marrow Neoplasms enzymology, Bone Marrow Neoplasms secondary, Fatal Outcome, Female, Humans, Plasma Exchange, Purpura, Thrombotic Thrombocytopenic etiology, Adenocarcinoma complications, Bone Marrow Neoplasms complications, Purpura, Thrombotic Thrombocytopenic diagnosis
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- 2005
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304. Effect of a p210 multipeptide vaccine associated with imatinib or interferon in patients with chronic myeloid leukaemia and persistent residual disease: a multicentre observational trial.
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Bocchia M, Gentili S, Abruzzese E, Fanelli A, Iuliano F, Tabilio A, Amabile M, Forconi F, Gozzetti A, Raspadori D, Amadori S, and Lauria F
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- Adjuvants, Immunologic administration & dosage, Aged, Benzamides, Female, Granulocyte-Macrophage Colony-Stimulating Factor administration & dosage, Humans, Imatinib Mesylate, Immunotherapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive immunology, Male, Middle Aged, Recombinant Proteins administration & dosage, Saponins administration & dosage, Antineoplastic Agents administration & dosage, Cancer Vaccines administration & dosage, Fusion Proteins, bcr-abl immunology, Interferon-alpha administration & dosage, Leukemia, Myelogenous, Chronic, BCR-ABL Positive therapy, Piperazines administration & dosage, Pyrimidines administration & dosage
- Abstract
Background: Although imatinib is the standard treatment for chronic myeloid leukaemia, not all patients reach complete cytogenetic remission (CCR) and most maintain detectable disease at the molecular level. We investigated whether a vaccine targeting the BCR-ABL-derived p210 fusion protein was an active and specific immunotherapy., Methods: We recruited 16 patients who had chronic myeloid leukaemia (with the b3a2 fusion point of p210), stable residual disease, a minimum treatment of 12 months of imatinib or 24 months of interferon alfa, and no further reduction of residual disease for at least 6 months preceding enrollment. They were given six vaccinations with a peptide vaccine derived from the sequence p210-b3a2 plus molgramostim and QS-21 as adjuvants (CMLVAX100) before assessment of immunological and disease response, which included detecting amounts of b3a2 transcripts by standardised quantitative real-time reverse-transcriptase PCR., Results: Of ten patients on imatinib, nine started CMLVAX100 having had a median of 10 months' stable cytogenetic disease (median 10% Philadelphia-chromosome-positive metaphases), whereas one started in stable CCR. All patients' cytogenetic responses improved after six vaccinations, with five reaching CCR. Notably, three of these five patients also had undetectable amounts of b3a2 transcript (BCR-ABL:beta2 microglobulin ratio <0.00001). Six patients on interferon alfa treatment with a median of 17 months' stable residual disease (median 13% Philadelphia-chromosome-positive cells) were also vaccinated. All but one had improved cytogenetic responses, and two reached CCR. Overall, we recorded peptide-specific delayed-type hypersensitivity (in 11 of 16 patients), CD4 cell proliferation (13 of 14 assessed), and interferon gamma production (five of five assessed)., Interpretation: Addition of CMLVAX100 to conventional treatment in patients with chronic myeloid leukaemia might favour further reduction of residual disease and increase the number of patients reaching a molecular response.
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- 2005
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305. Absence of surface CD27 distinguishes hairy cell leukemia from other leukemic B-cell malignancies.
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Forconi F, Raspadori D, Lenoci M, and Lauria F
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- B-Lymphocytes metabolism, Biomarkers, Tumor, Cell Membrane metabolism, Diagnosis, Differential, Flow Cytometry, Humans, Leukocytes, Mononuclear metabolism, Lymphocytes metabolism, Gene Expression Regulation, Neoplastic, Leukemia, Hairy Cell metabolism, Lymphoma, B-Cell metabolism, Tumor Necrosis Factor Receptor Superfamily, Member 7 biosynthesis
- Abstract
Surface expression of CD27 was evaluated in 75 mature leukemic B-cell neoplasms. All cases other than hairy cell leukemia (HCL) expressed CD27. Intensity was significantly higher in chronic lymphocytic leukemia. Lack of CD27 in 17/17 HCL contrasted with expression of this marker in 5/5 splenic lymphomas with villous lymphocytes. Lack of CD27 is a new distinctive feature of HCL among B-cell malignancies.
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- 2005
306. Hairy cell leukemia: at the crossroad of somatic mutation and isotype switch.
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Forconi F, Sahota SS, Raspadori D, Ippoliti M, Babbage G, Lauria F, and Stevenson FK
- Subjects
- ADP-ribosyl Cyclase metabolism, ADP-ribosyl Cyclase 1, Antigens, CD metabolism, Biomarkers, Tumor, Cytidine Deaminase, Cytosine Deaminase genetics, Gene Deletion, Gene Expression Regulation, Leukemic immunology, Germinal Center metabolism, Humans, Immunoglobulin A genetics, Immunoglobulin D genetics, Immunoglobulin G genetics, Immunoglobulin M genetics, Membrane Glycoproteins, Mutation immunology, Tumor Necrosis Factor Receptor Superfamily, Member 7 metabolism, AICDA (Activation-Induced Cytidine Deaminase), Immunoglobulin Class Switching immunology, Leukemia, Hairy Cell genetics, Leukemia, Hairy Cell immunology
- Abstract
Hairy cell leukemia (HCL) commonly expresses multiple immunoglobulin isotypes, a feature rare in other B-cell malignancies or in normal B cells. In HCL, there is no phenotypic evidence for subpopulations, and single cells from one previous case contained transcripts for several isotypes. This raises the questions of the differentiation status of the cell of origin and of posttransformation events. We have investigated 9 cases, all expressing multiple immunoglobulin isotypes. Multiple tumor-derived variable-(diversity)-joining-constant mu delta, gamma, alpha (V(D)J-Cmu, delta, gamma, alpha) transcripts were confirmed in single cells of a further case. All cases were negative for germinal center (GC)-associated markers CD27 and CD38. Seven of 9 cases had mutated V(H) genes, with low levels of intraclonal heterogeneity, but 2 of 9 were unmutated, indicative of pre-GC origin. Eight of 9 cases expressed activation-induced cytidine deaminase (AID), a molecule essential for somatic mutation and isotype switch. All cases expressed germ line heavy-chain I exon (I(H))-C(H) transcripts which paralleled surface immunoglobulin (sIg) isotype. Significantly, no circle transcripts indicative of deletional recombination of switched isotypes were detectable in 9 of 9 cases. These data indicate heterogeneity in the cell of origin in terms of mutational status, but reveal common features of AID expression and isotype-switching events occurring prior to deletional recombination. Both mutational and switching events may be influenced by environmental factors at extrafollicular sites.
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- 2004
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307. Molecular cytogenetic analysis of B-CLL patients with aggressive disease.
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Gozzetti A, Crupi R, Tozzuoli D, Raspadori D, Forconi F, and Lauria F
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- Acute Disease, Chromosomes, Human, Female, Humans, Male, Predictive Value of Tests, Sensitivity and Specificity, Chromosome Aberrations, Cytogenetic Analysis, In Situ Hybridization, Fluorescence, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis
- Abstract
We tested a set of commercially available probes to determine the feasibility and accuracy of FISH in the detection of abnormalities in 13 patients with Chronic Lymphocytic Leukemia (CLL) with a particular aggressive clinical disease. We utilized three different probes for the 13q12-14 region, one for the centromeric region of chromosome 12, one for the P53 gene at 17p13.1 and one for 3'-5' IGH at 14q32, covering the entire region of IGH, thus potentially allowing to detect more rearrangements. Conventional cytogenetic study showed a normal karyotype in 8/13 patients. FISH was able to detect chromosomal abnormalities in 10/13 pts (85%): +12 in 4 pts (38%); del 13q in 4 (38%); del 17p in 3 (35%); del of 5'-IGH in 1 (15%). In conclusion FISH confirmed its ability to improve the detection of cytogenetic abnormalities especially in patients with an aggressive disease.
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- 2004
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308. Trisomy 12 and t(14;22)(q32;q11) in a patient with B-cell chronic lymphocytic leukemia.
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Gozzetti A, Marotta G, Lenoci M, Crupi R, Tozzuoli D, Calabrese S, Forconi F, Fabbri A, and Lauria F
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- Chromosomes, Human, Pair 14, Chromosomes, Human, Pair 22, Cytogenetic Analysis, Disease-Free Survival, Female, Humans, Middle Aged, Chromosomes, Human, Pair 12, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis, Leukemia, Lymphocytic, Chronic, B-Cell therapy, Translocation, Genetic, Trisomy
- Abstract
Recurrent cytogenetic abnormalities are typically found in about one third of B-cell chronic lymphocytic leukemia patients (B-CLL) by standard cytogenetic analysis and their prognostic relevance is well known. We report a case of a B-CLL patient showing both trisomy 12 and a t(14;22)(q32;q11). Trisomy 12 is often associated with aggressive disease and resistance to chemotherapy, however, our patient is in good health and currently untreated after 7 years, suggesting in this case a relatively good prognosis and a questionable role for translocations involving the 14q32 locus.
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- 2004
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309. Towards the pharmacotherapy of hairy cell leukaemia.
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Lauria F and Forconi F
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- Antibodies, Monoclonal pharmacology, Antibodies, Monoclonal therapeutic use, Drug Administration Schedule, Humans, Interferon-alpha pharmacology, Interferon-alpha therapeutic use, Leukemia, Hairy Cell surgery, Purines pharmacology, Purines therapeutic use, Time Factors, Leukemia, Hairy Cell drug therapy
- Abstract
Hairy cell leukaemia (HCL) offers one of the few examples of rapid progress in the development of effective treatments for chronic lymphoproliferative disorders. After the first description of HCL as a separate disease in 1958, splenectomy was the treatment of choice, but rarely resulted in remission of disease and had scarce benefit on survival. In 1984, IFN-alpha became the first agent able to significantly modify the prognosis of HCL by inducing high response rates and long-term remissions. More recently, purine analogues have significantly further increased the percentages of remissions, with a reduced risk of relapse and are now generally used as first-line treatment. Monoclonal antibodies targeting CD20, CD22 and CD25 antigens, have also shown responses for resistant or relapsing disease. This article will review the current treatment strategies for HCL.
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- 2004
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310. Revisiting the definition of somatic mutational status in B-cell tumors: does 98% homology mean that a V(H)-gene is unmutated?
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Forconi F, Sahota SS, Lauria F, and Stevenson FK
- Subjects
- Genetic Heterogeneity, Humans, Immunoglobulin Variable Region genetics, Mutation, Leukemia, B-Cell genetics, Lymphoma, B-Cell genetics, Somatic Hypermutation, Immunoglobulin
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- 2004
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311. Incidence of novel N-glycosylation sites in the B-cell receptor of lymphomas associated with immunodeficiency.
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Forconi F, Capello D, Berra E, Rossi D, Gloghini A, Cerri M, Muti G, Morra E, Paulli M, Magrini U, Lucioni M, Rambaldi A, Lauria F, Carbone A, Stevenson FK, and Gaidano G
- Subjects
- Glycosylation, Humans, Lymphoma, AIDS-Related genetics, Lymphoma, B-Cell genetics, Transplantation Immunology genetics, Gene Rearrangement, B-Lymphocyte genetics, Genes, Immunoglobulin genetics, Lymphoproliferative Disorders genetics, Receptors, Antigen, B-Cell genetics
- Abstract
Novel N-glycosylation sites are introduced by somatic mutation into the V genes of the majority of follicular lymphomas. Sites are positively selected and rare in normal memory B cells, indicating a potential role in tumour survival in the germinal centre (GC). The incidence of c. 40% in diffuse large B-cell lymphomas (DLBCL) parallels the known heterogeneity of the disease. Immunodeficiency-related non-Hodgkin's lymphomas (NHL) include post-transplant lymphoproliferative disorders (PTLD) and acquired immunodeficiency syndrome-related NHL (AIDS-NHL). Most PTLD derive from B cells that carry mutated VH genes and that have completed the GC reaction. All AIDS-NHL carry mutated VH genes and variable features of GC or post-GC cells. To determine if N-glycosylation is a feature of immunodeficiency-related lymphomas, we analysed the VH genes of 19 PTLD and 36 AIDS-NHL. Novel sites were rare in PTLD (4/19), similar to memory B cells (P = 0.15). AIDS-NHL, including DLBCL and Burkitt's lymphomas (BL), showed heterogeneity with 16 of 36 (44%) having novel sites. The findings indicate no selection of N-glycosylation sites in PTLD, consistent with post-GC features. The variable incidence of N-glycosylation sites in AIDS-NHL mirrors that in DLBCL and sporadic BL of immunocompetent hosts, supporting the known heterogeneity of these disorders, and possibly pointing to distinct routes of tumour development.
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- 2004
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312. Low-dose oral fludarabine plus cyclophosphamide in elderly patients with chronic lymphoproliferative disorders.
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Fabbri A, Lenoci M, Gozzetti A, Marotta G, Raspadori D, Forconi F, and Lauria F
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- Administration, Oral, Aged, Aged, 80 and over, Chronic Disease mortality, Cyclophosphamide adverse effects, Dose-Response Relationship, Drug, Feasibility Studies, Female, Humans, Male, Middle Aged, Treatment Outcome, Vidarabine adverse effects, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Chronic Disease drug therapy, Cyclophosphamide administration & dosage, Lymphoproliferative Disorders drug therapy, Vidarabine administration & dosage, Vidarabine analogs & derivatives
- Abstract
A synergistic effect of fludarabine (FLU) and cyclophosphamide (CY) has been extensively demonstrated in the treatment of chronic lymphoproliferative disorders (CLD), although a high incidence of severe neutropenia and infectious complications, particularly in elderly patients, have been reported. Based on a previous clinical experience in elderly CLD patients treated with a combination of low-dose intravenous (i.v.) FLU and CY in whom we obtained good response rates and negligible toxicity, we tested efficacy and safety of the new oral formulation of FLU combined with CY at low doses. A total of 28 elderly patients with relapsed/refractory or untreated CLD were treated with oral FLU and CY (25 and 150 mg/m2 respectively, both for 4 days every 4 weeks). The treatment design consisted in four consecutive courses and the median value of courses per patient was 3. Overall, 25 out of 28 evaluable patients were responsive to the treatment (six CR and 19 PR; ORR 89%), while the remaining three patients did not show any appreciable response (two progressive and one stable disease). Hematological toxicity was low in the majority of patients (grade 2-3 neutropenia/anemia in 8/28 cases); however, two fatal infections occurred and one additional patient died because of disease progression. Extra-hematological toxicity was generally mild. This preliminary report suggests that oral combination of FLU and CY at low dose is effective as the i.v. formulation and standard doses, since it may induce rapid responses in about 90% of elderly patients with CLD, with an acceptable toxicity.
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- 2004
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313. Origins of the malignant clone in typical Waldenstrom's macroglobulinemia.
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Sahota SS, Forconi F, Ottensmeier CH, and Stevenson FK
- Subjects
- Amino Acid Sequence, Gene Rearrangement, B-Lymphocyte, Heavy Chain, Immunoglobulin J-Chains genetics, Immunoglobulin M immunology, Immunoglobulin Variable Region, Immunoglobulin delta-Chains genetics, Phenotype, Waldenstrom Macroglobulinemia immunology, B-Lymphocytes immunology, Genes, Immunoglobulin, Immunoglobulin Class Switching genetics, Immunoglobulin Heavy Chains genetics, Immunoglobulin M genetics, Mutation, Waldenstrom Macroglobulinemia genetics
- Abstract
Histopathology and phenotypic considerations in IgM-secreting B-cell tumors allow distinction between different diseases, but insight into pathogenesis is restricted. Here, variable region (V) gene analysis can complement classification but, more importantly, can also reveal disease origins and clonal history. We used V(H) gene analysis to probe origins in Waldenstrom's macroglobulinemia (WM), and contrasted these with the less malignant counterpart, IgM-secreting monoclonal gammopathy of undetermined significance (MGUS). Limited data on WM sequences had previously shown evidence for somatic mutation, but with conflicting analysis of intraclonal variation in tumor sequences. To further the investigation, we analyzed seven cases of WM and compared these with three cases of IgM MGUS. In both diseases, V(H) genes were somatically mutated with no evidence of intraclonal variation, even at the MGUS stage. A sensitive V(H) gene-probe assay revealed no evidence for isotype switch transcripts in any of the WM and IgM MGUS cases. These findings reveal an origin of WM and IgM MGUS from a IgM cell, which transforms after cessation of somatic mutation but without initiating switch events. In contrast, IgM-secreting multiple myeloma arises at a later stage in differentiation, when isotype switch mechanisms have been engaged., (Copyright 2003 Elsevier Inc. All rights reserved.)
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- 2003
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314. Low-grade non Hodgkin's lymphomas in the elderly: impact of a low-dose fludarabine-based combination regimen (mini-FLEC).
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Bocchia M, Gentili S, Forconi F, le Noci M, Tozzi M, and Lauria F
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- Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols toxicity, Female, Humans, Lymphoma, Non-Hodgkin complications, Male, Treatment Outcome, Vidarabine toxicity, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Lymphoma, Non-Hodgkin drug therapy, Vidarabine administration & dosage, Vidarabine analogs & derivatives
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- 2003
315. Insight into the potential for DNA idiotypic fusion vaccines designed for patients by analysing xenogeneic anti-idiotypic antibody responses.
- Author
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Forconi F, King CA, Sahota SS, Kennaway CK, Russell NH, and Stevenson FK
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- Animals, Antibody Specificity, Humans, Immunoglobulin Fragments immunology, Immunoglobulin G biosynthesis, Immunoglobulin Idiotypes immunology, Mice, Mice, Inbred C57BL, Recombinant Fusion Proteins immunology, Tetanus Toxin immunology, Th2 Cells immunology, Vaccination methods, Antibodies, Anti-Idiotypic biosynthesis, Cancer Vaccines immunology, Vaccines, DNA immunology
- Abstract
DNA vaccines induce immune responses against encoded proteins, and have clear potential for cancer vaccines. For B-cell tumours, idiotypic (Id) immunoglobulin encoded by the variable region genes provides a target antigen. When assembled as single chain Fv (scFv), and fused to an immunoenhancing sequence from tetanus toxin (TT), DNA fusion vaccines induce anti-Id antibodies. In lymphoma models, these antibodies have a critical role in mediating protection. For application to patients with lymphoma, two questions arise: first, whether pre-existing antibody against TT affects induction of anti-scFv antibodies; second, whether individual human scFv fusion sequences are able to fold consistently to generate antibodies able to recognize private conformational Id determinants expressed by tumour cells. Using xenogeneic vaccination with scFv sequences from four patients, we have shown that pre-existing anti-TT immunity slows, but does not prevent, anti-Id antibody responses. To determine folding, we have monitored the ability of nine DNAscFv-FrC patients' vaccines to induce xenogeneic anti-Id antibodies. Antibodies were induced in all cases, and were strikingly specific for each patient's immunoglobulin with little cross-reactivity between patients, even when similar VH or VL genes were involved. Blocking experiments with human serum confirmed reactivity against private determinants in 26-97% of total antibody. Both immunoglobulin G1 (IgG1) and IgG2a subclasses were present at 1.3 : 1-15 : 1 consistent with a T helper 2-dominated response. Xenogeneic vaccination provides a simple route for testing individual patients' DNAscFv-FrC fusion vaccines, and offers a strategy for production of anti-Id antibodies. The findings underpin the approach of DNA idiotypic fusion vaccination for patients with B-cell tumours.
- Published
- 2002
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316. Typical Waldenstrom macroglobulinemia is derived from a B-cell arrested after cessation of somatic mutation but prior to isotype switch events.
- Author
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Sahota SS, Forconi F, Ottensmeier CH, Provan D, Oscier DG, Hamblin TJ, and Stevenson FK
- Subjects
- Amino Acid Sequence, Humans, Immunoglobulin Heavy Chains chemistry, Immunoglobulin M metabolism, Immunoglobulin Variable Region chemistry, Molecular Sequence Data, Reverse Transcriptase Polymerase Chain Reaction, Waldenstrom Macroglobulinemia immunology, B-Lymphocytes immunology, Immunoglobulin Class Switching genetics, Immunoglobulin Heavy Chains genetics, Immunoglobulin Variable Region genetics, Mutation, Waldenstrom Macroglobulinemia genetics
- Abstract
There exists a wide spectrum of IgM-secreting B-cell tumors with different clinical behavior. Knowledge of the V(H) gene status can reveal their origin and clonal history. For Waldenstrom macroglobulinemia (WM), a distinct subtype of lymphoplasmacytic lymphoma, early data on limited sequences showed evidence for somatic mutation. A recent report of one case demonstrated intraclonal mutational activity occurring after transformation, a characteristic of germinal center lymphomas. To extend the investigation, we have analyzed 7 cases of WM. V(H) genes were somatically mutated with no evidence of intraclonal variation in all cases. In contrast to IgM-secreting multiple myeloma, there was no evidence for isotype switch transcripts in any of the cases. These data support the concept that typical WM is derived from a B cell that has undergone somatic mutation prior to transformation, at a point where isotype switch events have not been initiated. (Blood. 2002;100:1505-1507)
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- 2002
317. Efficacy of anti-CD20 monoclonal antibodies (Mabthera) in patients with progressed hairy cell leukemia.
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Lauria F, Lenoci M, Annino L, Raspadori D, Marotta G, Bocchia M, Forconi F, Gentili S, La Manda M, Marconcini S, Tozzi M, Baldini L, Zinzani PL, and Foà R
- Subjects
- Adult, Aged, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal, Murine-Derived, Female, Humans, Male, Middle Aged, Remission Induction, Rituximab, Therapeutic Equivalency, Treatment Outcome, Antibodies, Monoclonal pharmacokinetics, Antibodies, Monoclonal therapeutic use, Antigens, CD20 immunology, Antineoplastic Agents administration & dosage, Antineoplastic Agents pharmacokinetics, Leukemia, Hairy Cell drug therapy
- Abstract
Background and Objectives: Recently, a chimeric monoclonal antibody (MoAb) directed against the CD20 antigen (rituximab) has been successfully introduced in the treatment of several CD20-positive B-cell neoplasias and particularly of follicular lymphomas. Based on these premises we evaluated the efficacy and the toxicity of chimeric anti-CD20 monoclonal antibody (MoAb) in relapsed/progressed hairy cell leukemia (HCL)., Design and Methods: Ten patients with relapsed/progressed HCL entered the study. Eight patients were males and two females with a median age of 55 years (range 41-78) and all of them had been previously treated with 2-chlorodeoxyadenosine and/or deoxycoformycin and a-interferon. Two out of 10 patients were anemic (Hb < 10 g/dL), 4 thrombocytopenic (Plt < 100 x 10(9)/L), 3 had fewer than 1.0 x 10(9)/L neutrophils and 3 had circulating hairy cells (HC). All patients received 375 mg/m2 i.v. of anti-CD20 MoAb once a week for 4 doses., Results: All patients were evaluable for response, one patient showing a complete remission and 4 a partial response. Adverse reactions, such as fever, chills, bone pain, hypotension and thrombocytopenia, were transient and mild (grade 1-2) and occurred only during the first course of treatment. One month after the last infusion, patients who had had anemia, neutropenia or thrombocytopenia, recovered normal peripheral blood values. Circulating HC also disappeared within one month. Immunostained bone marrow biopsies were checked 1, 3 and 6 months after the end of therapy and in 5 out of 10 patients a >50% reduction of bone marrow HC infiltration was recorded., Interpretation and Conclusions: On the basis of these preliminary results observed in 10 patients with progressed HCL, it appears that treatment with anti-CD20 MoAb is safe and effective in at least 50% of patients, particularly in those with a less evident bone marrow infiltration (50%) and in those previously splenectomized.
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- 2001
318. Tumor cells of hairy cell leukemia express multiple clonally related immunoglobulin isotypes via RNA splicing.
- Author
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Forconi F, Sahota SS, Raspadori D, Mockridge CI, Lauria F, and Stevenson FK
- Subjects
- Adult, Aged, Base Sequence, Clone Cells immunology, Clone Cells metabolism, Clone Cells pathology, Female, Humans, Immunoglobulin Isotypes analysis, Immunoglobulin Variable Region genetics, Leukemia, Hairy Cell genetics, Male, Middle Aged, Molecular Sequence Data, RNA, Messenger analysis, Sequence Analysis, DNA, Immunoglobulin Isotypes metabolism, Leukemia, Hairy Cell immunology, Leukemia, Hairy Cell pathology, RNA Splicing immunology
- Abstract
Hairy cell leukemia (HCL) derives from a mature B cell and expresses markers associated with activation. Analysis of immunoglobulin variable region genes has revealed somatic mutation in most cases, consistent with an origin from a cell that has encountered the germinal center. One unusual feature of hairy cells (HCs) is the frequent expression of multiple immunoglobulin heavy chain isotypes, with dominance of immunoglobulin (Ig)--G3, but only a single light chain type. The origin and clonal relationship of these isotype variants have been unclear. In order to probe the isotype switching status of HCL, RNA transcripts of V(H)DJ(H)--constant region sequences from 5 cases of typical HCL, all expressing multiple surface immunoglobulin isotypes, were analyzed. Tumor V(H)DJ(H)--C(mu) sequences were identified and found to be somatically mutated (range, 1.4% to 6.5%), with a low level of intraclonal heterogeneity. Additional immunoglobulin isotypes of identical V(H)DJ(H) sequence were also identified, including IgD (5 of 5), IgG3 (5 of 5), IgG1 (3 of 5), IgG2 (2 of 5), IgA1 (4 of 5), and IgA2 (1 of 5). Derivation of multiple isotypes from individual cells was demonstrated by analyzing transcripts in single sorted cells from one patient, with evidence for coexistence of isotype variants in 10 of 10 cells. These findings indicate that clonally related multiple isotypes coexist in single HCs, with individual isotypes presumably generated via RNA splicing. Production of IgG3 appears common, but IgG1, IgG2, IgA1, and IgA2 also arise, indicating a continuing influence of a directed process on the tumor clone. These HCs appear to be arrested at the point of isotype switch, where RNA processing may precede deletional recombination. (Blood. 2001;98:1174-1181)
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- 2001
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319. The occurrence and significance of V gene mutations in B cell-derived human malignancy.
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Stevenson FK, Sahota SS, Ottensmeier CH, Zhu D, Forconi F, and Hamblin TJ
- Subjects
- B-Lymphocytes pathology, Chromosomes ultrastructure, Humans, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Lymphoma, Follicular genetics, Models, Biological, Models, Genetic, Multiple Myeloma genetics, Prognosis, Recombination, Genetic, Time Factors, Translocation, Genetic, Immunoglobulin Variable Region genetics, Leukemia genetics, Mutation
- Abstract
The classification of B cell tumors has relevance for refining and improving clinical strategies. However, consensus has been difficult to establish, and although a scheme is now available, objective criteria are desirable. Genetic technology will underpin and extend current knowledge, and it is certain to reveal further subdivisions of current tumor categories. The Ig variable region genes of B cell tumors present a considerable asset for this area of investigation. The unique sequences carried in neoplastic B cells are easily isolated and sequenced. In addition to acting as clone-specific markers of each tumor, they indicate where the cell has come from and track its history following transformation. There is emerging clinical value in knowing whether the cell of origin has encountered antigen and has moved from the naive compartment to the germinal center, where somatic mutation is activated. This is amply illustrated by the subdivision of chronic lymphocytic leukemia into two subsets, unmutated or mutated, each with very different prognosis. Other tumors may be subdivided in a similar way. Microarray technology is developing rapidly to probe gene expression and to further divide tumor categories. All these genetic analyses will provide objective data to enhance both our understanding of B cell tumors and our ability to treat them.
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- 2001
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320. Mutation of BAX occurs infrequently in acquired immunodeficiency syndrome-related non-Hodgkin's lymphomas.
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Gaidano G, Vivenza D, Forconi F, Capello D, Gloghini A, Bhatia K, Gutierrez M, Gallicchio M, Avanzi GC, Fassone L, Ariatti C, Buonaiuto D, Cingolani A, Saglio G, Tirelli U, Larocca LM, Dalla-Favera R, and Carbone A
- Subjects
- Blotting, Western, DNA Mutational Analysis, DNA, Neoplasm chemistry, DNA, Neoplasm genetics, Humans, Mutation, Polymerase Chain Reaction, Polymorphism, Single-Stranded Conformational, Proto-Oncogene Proteins metabolism, Sequence Deletion, Tumor Cells, Cultured, Tumor Suppressor Protein p53 genetics, bcl-2-Associated X Protein, Lymphoma, AIDS-Related genetics, Lymphoma, Non-Hodgkin genetics, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins c-bcl-2
- Abstract
Acquired immunodeficiency syndrome (AIDS)-related non-Hodgkin's lymphomas (AIDS-NHLs) consistently derive from B cells, are histologically heterogeneous, and are associated with distinct molecular pathways depending upon histology. Recently, it has been proposed that inactivating mutations of the bax death agonist may contribute to the pathogenesis of human tumors. In particular, among B-cell malignancies, BAX mutations have been detected at a certain frequency in Burkitt lymphomas. This study is aimed at defining the status of the BAX gene throughout the clinicopathologic spectrum of AIDS-NHL (n = 54), including AIDS-related Burkitt lymphoma (n = 14), AIDS-related Burkitt-like lymphoma (n = 8), AIDS-related diffuse large cell lymphoma (n = 15), AIDS-related primary central nervous system lymphoma (n = 6), and AIDS-related primary effusion lymphoma (n = 11). All 6 BAX exons and flanking sequences were subjected to mutational analysis by polymerase chain reaction-single strand conformation polymorphism followed by DNA direct sequencing of positive cases. Mutations of BAX among AIDS-NHL were restricted to a cell line of AIDS-related primary effusion lymphoma, which harbored a frameshift mutation causing the introduction of a proximal stop codon. All other AIDS-NHL displayed wild-type BAX alleles. In order to investigate whether BAX inactivation in AIDS-NHL may occur through mechanisms other than gene mutation, bax protein expression was investigated by Western blot analysis or immunohistochemistry in selected cases. All AIDS-NHL analyzed expressed normal bax proteins. Overall, this study indicates that deregulation of apoptotic control in AIDS-NHL is not caused by BAX alterations. Genes Chromosomes Cancer 27:177-182, 2000., (Copyright 2000 Wiley-Liss, Inc.)
- Published
- 2000
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321. CD30 positive (non-anaplastic) peripheral T-cell lymphoma of the thyroid gland.
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Forconi F, Bocchia M, Marconcini S, Bigazzi C, Milani M, Fraternali-Orcioni G, and Lauria F
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- Adult, Cell Size, Female, Humans, Immunohistochemistry, Lymphoma, T-Cell, Peripheral diagnosis, Thyroid Neoplasms diagnosis, Ki-1 Antigen analysis, Lymphoma, T-Cell, Peripheral immunology, Thyroid Neoplasms immunology
- Abstract
Primary non-Hodgkin's lymphoma of the thyroid gland are infrequent tumors. They almost exclusively derive from B cells of mucosa-associated lymphatic tissue and only a very small minority of them is represented by T cell lymphomas. CD30 molecule, other than in Hodgkin's and Redd-Sternberg' cells, is strictly associated with anaplastic large cell lymphoma and ALK lymphomas, the latter being identified by the monoclonal antibody ALK1. We report a case of CD30-positive non-anaplastic (ALK1-negative) peripheral T cell lymphoma of the thyroid gland and speculate on aspects concerning diagnosis and the morphologic and immunohistochemical findings.
- Published
- 1999
322. Favorable impact of low-dose fludarabine plus epirubicin and cyclophosphamide regimen (FLEC) as treatment for low-grade non-Hodgkin's lymphomas.
- Author
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Bocchia M, Bigazzi C, Marconcini S, Forconi F, Marotta G, Algeri R, and Lauria F
- Subjects
- Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols adverse effects, Cyclophosphamide administration & dosage, Cyclophosphamide adverse effects, Epirubicin administration & dosage, Epirubicin adverse effects, Female, Humans, Lymphoma, Non-Hodgkin pathology, Male, Middle Aged, Remission Induction, Survival Analysis, Vidarabine administration & dosage, Vidarabine adverse effects, Vidarabine analogs & derivatives, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Lymphoma, Non-Hodgkin drug therapy
- Abstract
Background and Objective: In recent years, conventional dose of fludarabine (FLU) alone or in combination with other drugs has been reported to be effective in the treatment of low-grade non-Hodgkin's lymphomas (LG-NHL). In particular, FLU and cyclophosphamide (CY) or FLU and mitoxantrone or idarubicin combined regimens have shown considerable therapeutic activity both as first line and salvage therapies, producing overall response rates ranging from 40-50% in previously treated patients and up to 70-90% in untreated ones. However severe neutropenia and infective complications have been reported in a significant number of patients. Based on these premises we evaluated the efficacy and toxicity of a new regimen combining low-doses of FLU with epirubicin (EPI) and CY (FLEC) in a group of advanced treatment-requiring LG-NHL patients. The aim of this study was to evaluate a strategy aimed at lowering therapy-related toxic effects without affecting the reported good response rate., Design and Methods: Thirty patients with de novo, relapsed or refractory LG-NHL entered the study. FLEC regimen was as follows: EPI 60 mg/m(2) i.v. on day one, plus FLU 15 mg/m(2)/day i.v. (max 25 mg) and CY 250 mg/m(2)/day i.v. for four days., Results: All 30 patients were evaluable for response, 13 (43%) fulfilled the criteria for CR and 11 (36%) for PR with an overall response rate of 79%. None of the 13 patients who achieved CR had relapsed after a follow-up of 2 to 23 months (median duration 13 months). With regard to age, 13/14 older patients (>/= 70 years) responded to the treatment and 9 of them maintained their response after a median of 13 months (range 2-22); six of the 14 (43%) obtained a CR. Therapy-related toxicity was mild regardless of age, neutropenia (43%) and fever of undetermined origin (26%) being the major side effects. Remarkably, a documented infection was recorded only in 2/30 (6%) patients., Interpretation and Conclusions: A low-dose FLU-based FLEC regimen appeared to be effective for advanced treatment-requiring LG-NHL, reproducing a similar overall response rate (79%) reported to have been achieved with other FLU based combination therapies. Toxic side effects were negligible and in particular documented infections were remarkably uncommon even in the group of elderly patients.
- Published
- 1999
323. Long-term follow-up of non-Hodgkin's lymphoma patients treated with ProMACE-CytaBOM: an effective regimen for the intermediate grade subtype.
- Author
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Marotta G, Bigazzi C, Bocchia M, Forconi F, and Lauria F
- Subjects
- Adult, Aged, Antineoplastic Combined Chemotherapy Protocols adverse effects, Bleomycin administration & dosage, Bleomycin adverse effects, Cyclophosphamide administration & dosage, Cyclophosphamide adverse effects, Cytarabine administration & dosage, Cytarabine adverse effects, Doxorubicin administration & dosage, Doxorubicin adverse effects, Etoposide administration & dosage, Etoposide adverse effects, Female, Follow-Up Studies, Humans, Lymphoma, Non-Hodgkin mortality, Male, Methotrexate administration & dosage, Methotrexate adverse effects, Middle Aged, Neutropenia chemically induced, Prednisone administration & dosage, Prednisone adverse effects, Survival Rate, Treatment Outcome, Vincristine administration & dosage, Vincristine adverse effects, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Lymphoma, Non-Hodgkin drug therapy
- Abstract
Long-lasting results achieved in 54 patients with aggressive non-Hodgkin lymphoma treated with Pro-MACE-CytaBOM regimen were evaluated. Twenty-four out of 54 (45%) patients achieved a complete remission and 13 of them are still in continuous remission with a median survival of 53.5 months. Interestingly, in 16 patients with intermediate grade histology we obtained an overall response rate of 100%.
- Published
- 1998
324. High bcl-2 expression in acute myeloid leukemia cells correlates with CD34 positivity and complete remission rate.
- Author
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Lauria F, Raspadori D, Rondelli D, Ventura MA, Fiacchini M, Visani G, Forconi F, and Tura S
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Prognosis, Antigens, CD34 analysis, Leukemia, Myeloid, Acute metabolism, Proto-Oncogene Proteins c-bcl-2 analysis
- Abstract
Flow cytometric expression of bcl-2 protein was analyzed in 90 newly diagnosed acute myeloblastic leukemia (AML) patients using an anti-bcl-2 monoclonal antibody by direct immunofluorescence technique and results were correlated with FAB cytotype, CD34 expression and clinical outcome. Bcl-2 was expressed in all AML cases with different intensity. The mean fluorescence index (MFI), expressed as the ratio of sample mean channel:control mean channel, ranged from 3.0 to 39.5 with a median value of 14. The MFI was significantly higher (P = 0.01) in M0 (20.9) and M1 (18.3) than in M2 (11.7), M3 (12.4), M4 (11.8) and M5 (9.5) cytotypes. In addition, bcl-2 MFI significantly correlated both with CD34 positivity (P = 0.001) and with CD34 MFI (P = 0.01), being CD34 antigen expressed in 65% of patients with a bcl-2 MFI >14, and only in 35% of AML cases with a bcl-2 MFI >14. When bcl-2 intensity expression was correlated with complete remission (CR) rate, a higher MFI was associated with a low CR rate after standard intensive chemotherapy. In particular, CR was achieved in 86% of patients with a bcl-2 MFI <14, but only in 57% of patients with a MFI >14 (P = 0.008). A further decrease of CR rate to 41% was observed in patients in whom a higher bcl-2 MFI was coupled with the presence of CD34 antigen on their blasts. By statistical analysis we also demonstrated that both bcl-2 high MFI (>14) and CD34 expression are independent prognostic factors for achieving CR in AML. These data raise the hypothesis that high values of bcl-2 may confer on myeloid blasts a higher resistance to standard chemotherapy. However, identification of patients with high expression of bcl-2 may be important for a different therapeutic approach.
- Published
- 1997
- Full Text
- View/download PDF
325. Long-lasting complete remission in patients with hairy cell leukemia treated with 2-CdA: a 5-year survey.
- Author
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Lauria F, Rondelli D, Zinzani PL, Bocchia M, Marotta G, Salvucci M, Raspadori D, Ventura MA, Birtolo S, Forconi F, and Tura S
- Subjects
- 2-Chloroadenosine therapeutic use, Bone Marrow pathology, Disease-Free Survival, Female, Follow-Up Studies, Humans, Leukemia, Hairy Cell mortality, Leukemia, Hairy Cell pathology, Male, Middle Aged, Neoplasms, Second Primary epidemiology, Neoplasms, Second Primary mortality, Splenomegaly, Survival Rate, Time Factors, 2-Chloroadenosine analogs & derivatives, Antimetabolites, Antineoplastic therapeutic use, Deoxyadenosines therapeutic use, Leukemia, Hairy Cell drug therapy
- Abstract
Between January 1991 and January 1994, 40 patients with hairy-cell leukemia (HCL), 30 males and 10 females, with a median age of 54 years, were treated with a single course of 2-chlorodeoxyadenosine (2-CdA) at a dose of 0.1 mg/kg/day continuous infusion for 7 days. Thirteen patients were untreated and 27 had previously received alpha-interferon. Thirty out of 40 patients (75%) achieved complete remission (CR) and 10 (25%) partial remission (PR). The median follow-up duration for patients in CR has been 48 months (range 30-66). Five of the complete responders (17%) relapsed at 12, 24, 26, 30 and 36 months after treatment as documented by the increase of hairy cells (Hc) in the bone marrow and two of them, who were retreated with 2-CdA after showing an initial impairment of peripheral blood values, obtained a second CR. The remaining three relapsed patients were never retreated and still show normal peripheral counts after 30, 38 and 40 months. Twelve of the continuous complete responder patients are still in CR after more than 5 years. In contrast, 8 out of 10 partial responders progressed after 8-36 months and all of them were retreated with 2-CdA at a dose of 0.15 mg/kg/day for 5 days i.v. Four of them (50%) achieved a CR, three a better PR and one patient died 6 months after the second 2-CdA course because of infectious complications. Two additional patients, both in CR, died after 28 and 37 months because of a second neoplasm. Toxic side-effects consisted of febrile episodes recorded in 16 patients: in seven of them, fever lasted only 24-48 h after the end of treatment and was apparently not infection-related. In the remaining nine patients, showing in addition severe neutropenia (neutrophils less than 1.0 x 10(9)/l), fever was related to bacterial infection requiring systemic antibiotics in all of them and G-CSF in three cases. In conclusion, 2-CdA induces a very high proportion of complete and long-lasting remissions in patients with HCL. In a number of cases relapse at bone marrow level may not affect peripheral blood values for prolonged time. However, in those patients with initial pancytopenia a retreatment with 2-CdA is still effective in inducing a durable second CR.
- Published
- 1997
- Full Text
- View/download PDF
326. 2-Chlorodeoxyadenosine in the treatment of relapsed/refractory chronic lymphoproliferative disorders.
- Author
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Rondelli D, Lauria F, Zinzani PL, Raspadori D, Ventura MA, Galieni P, Birtolo S, Forconi F, Algeri R, and Tura S
- Subjects
- Adult, Aged, Antineoplastic Agents adverse effects, Chronic Disease, Cladribine adverse effects, Female, Humans, Lymphoproliferative Disorders pathology, Male, Middle Aged, Recurrence, Treatment Outcome, Antineoplastic Agents therapeutic use, Cladribine therapeutic use, Lymphoproliferative Disorders drug therapy
- Abstract
2-Chlorodeoxyadenosine (2-CdA) is a purine analog with cytotoxic activity on both resting and cycling lymphocytes which has been used as salvage therapy in advanced/resistant chronic lymphoproliferative disorders. In our study 39 patients (19 B-CLL, 5 B-PLL, 9 low-grade B-NHL, 5 CTCL and 1 high-grade T-NHL) who relapsed or became resistant after 1-4 chemotherapy regimens were treated with 2-CdA 6 mg/m2 per day by 2 h infusion for 5 d every 28 d. The overall clinical response rate, including complete remission (CR) and partial remission (PR), was 66%. Two of 19 (10%) B-CLL patients achieved a CR lasting 9 months, while 11/19 B-CLL (58%) and 4/5 B-PLL (3 B-PLL/B-CLL and 1 B-PLL) (80%) achieved a PR. Interestingly, 5 of 6 patients who had been previously treated with fludarabine obtained a clinical response (2 CR and 3 PR). One of 9 (11%) low-grade B-NHL patients achieved a CR and relapsed after 26 months, and 5/9 (55%) achieved a PR. One of 5 (20%) CTCL achieved a CR lasting 32 months, while 2/5 (40%) achieved a PR. The overall mean duration of PR was 7.4 months and no differences were observed among different groups of patients. Toxicity was acceptable, as only a transient severe hematological impairment was observed in 20% of the patients while nonhematological toxicity was not documented. Two patients died because of bacterial pneumonia, 1 of meningitis due to Listeria and 9 from progression of the disease. In conclusion, treatment with 2-CdA in heavily pretreated patients with chronic lymphoproliferative disorders is well tolerated and obtains high response rates, even in patients relapsed after treatment with fludarabine.
- Published
- 1997
- Full Text
- View/download PDF
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