Long-term follow-up of young patients with essential thrombocythemia treated with pipobroman.
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Adult↗
Biomedical subjects
Mario Lazzarino
Publications and source records attributed to Mario Lazzarino.
Splenic and nodal marginal zone lymphomas are indolent disorders at high hepatitis C virus seroprevalence with distinct presenting features but similar morphologic and phenotypic profiles.
BACKGROUND: Splenic and nodal marginal zone lymphomas (MZL) are subtypes of marginal zone-derived neoplasms. Due to their rarity, little is known concerning their relation, pattern of dissemination, and treatment outcome. METHODS: The authors analyzed the clinicopathologic features and outcome of 43 patients (34 patients with splenic MZL and 9 patients with nodal MZL). All lesional tissues obtained at diagnosis were reviewed histologically. RESULTS: Among the patients with splenic MZL, 30 patients had Stage IV disease (based on the Ann Arbor staging system). Twenty-six patients presented with splenomegaly with or without limited involvement of abdominal lymph nodes, whereas 7 patients showed disease extension to superficial lymph nodes. Hepatitis C virus (HCV) serology was positive in 35% of patients. Seventeen patients underwent splenectomy, 8 patients received chemotherapy, and 7 patients were followed without initial treatment. Interferon produced a lymphoma response in three of four HCV positive patients. Of 27 treated patients, 13 patients achieved a complete response, and 12 patients achieved a partial response. The median event-free survival (EFS) was 3.3 years (5.1 years for patients with disease confined to the abdomen and 2.1 years for patients with disease extension to superficial lymph nodes). Among nine patients with nodal MZL, four patients had Stage IV disease. HCV serology was positive in two patients. Five patients responded to chemotherapy. The median EFS was 2.8 years. The median overall survival was not reached for patients with both types of MZL. CONCLUSIONS: The results of the current study demonstrated that splenic and nodal MZL are indolent lymphomas with different presenting features but common morphologic and biologic characteristics, including high HCV seroprevalence. Studies will be required to identify specific biologic markers and to define the best treatment.
Adult↗
Dendritic cell recovery after allogeneic stem-cell transplantation in acute leukemia: correlations with clinical and transplant characteristics.
We have analyzed the kinetics of reconstitution of circulating dendritic cell (DC) subsets (myeloid-DC1 and lymphoid-DC2) in 19 patients affected by acute leukemia undergoing allogeneic hematopoietic stem-cell transplantation (HSCT). We have found that pretransplant DC1 and DC2 were lower in leukemic patients than in healthy subjects (P = 0.003 and P = 0.004, respectively) and that the number of DC2 (but not DC1) infused with the graft was higher in patients receiving peripheral blood stem cells (PBSC) (P = 0.03). Patients recovered to the pretransplant DC1 and DC2 levels within day +60; however, a normal DC1 number was reached on day +365, while DC2 remained lower than in controls up to 1 yr after transplant. DC1 reconstitution did not differ significantly between patients receiving bone marrow stem cells (BMSC) or PBSC, while patients receiving PBSC presented increased levels of DC2 on day +30 (P = 0.008) and +100 (P = 0.047) and a higher number of T lymphocytes and natural killer cells until day +365. The occurrence of graft vs. host disease (GVHD) was not influenced in our cases by DC1/DC2 graft composition, but patients with acute GVHD when compared with patients without acute GVHD presented a significantly less rapid DC recovery (DC1 P = 0.03, DC2 P = 0.009 on day +30, and DC1 P = 0.012, DC2 P = 0.006 on day +100). At the moment of relapse, a decrease of DC1/DC2 numbers was observed in four patients and the presence of two different DC populations one with a normal karyotype, and the other with the same cytogenetic abnormality as the malignant clone was detected by fluorescence in situ hybridization analysis. In conclusion, these observations suggest that in allogeneic HSCT recipients, DC recovery is a slow process possibly contributing to the high risk of infections in the post-transplant period and is possibly influenced by the source of HSC, the occurrence of GVHD and relapse. Further studies are warranted to investigate the significance of DC reconstitution in the transplant setting.
Adolescent↗
Clinical significance of neutrophil CD177 mRNA expression in Ph-negative chronic myeloproliferative disorders.
The PRV-1 gene has been proposed as a marker of polycythaemia vera (PV). PRV-1 and NB1 are alleles of the polymorphic gene CD177, which belongs to the Ly-6/uPAR superfamily, and their coding regions differ at only four nucleotides. We studied neutrophil CD177 mRNA levels in normal subjects and in 235 patients with Ph-negative chronic myeloproliferative disorders (CMD), including PV, essential thrombocythaemia and myelofibrosis with myeloid metaplasia. Additional disease states were investigated for comparison. Highly variable neutrophil CD177 mRNA levels were observed in normal individuals. Neutrophils isolated from the bone marrow, or from peripheral blood following granulocyte colony-stimulating factor administration showed markedly higher CD177 expression than circulating granulocytes on steady state. Increased neutrophil CD177 mRNA levels were detected in all CMD. Elevated values were also found in reactive conditions and in disorders such as chronic myeloid leukaemia and myelodysplastic syndromes. In the differential diagnosis between PV and secondary erythrocytosis, the assay sensitivity was 68% while its specificity was 60%. These findings indicate that an elevated neutrophil CD177 mRNA level is not a specific marker for the diagnosis of PV nor for that of CMD. From a clinical viewpoint, neutrophil CD177 mRNA overexpression is rather a marker of abnormal neutrophil production and/or release in patients with CMD.
Adult↗
Combination of rituximab, cyclophosphamide, and vincristine induces complete hematologic remission of splenic marginal zone lymphoma.
Optimal treatment for splenic marginal zone lymphoma (MZL) is not clearly established. Splenectomy has been proposed as the treatment of choice in patients with cytopenias and/or symptoms caused by an enlarged spleen. Splenic MZL, which expresses the CD20 antigen on tumor cell surfaces, is a disease entity candidate to treatment with anti-CD20 monoclonal antibodies. We employed an immunochemotherapy regimen with rituximab/cyclophosphamide/vincristine in 3 patients with splenic MZL who had only a partial response following CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) or CHOP-like therapy. The immunochemotherapy regimen was well tolerated and all patients exhibited complete remission. To our knowledge, this is the first report of splenic MZL showing response to a combination of rituximab with chemotherapy.
Antibodies, Monoclonal↗
First episode of acute hemolysis due to G6PD deficiency in a middle-aged woman and transmission of the enzymatic defect through bone marrow transplant.
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Acute Disease↗
The VAD-DCEP sequence is an effective pre-transplant therapy in untreated multiple myeloma.
BACKGROUND AND OBJECTIVES: Standard treatment for patients with multiple myeloma is debulking chemotherapy with non-alkylating agents followed by a regimen to mobilize peripheral blood stem cells (PBSC) and the transplantation of the mobilized, autologous PBSC. The aim of this study was to evaluate the efficacy of a new regimen and compare it with that of a previous regimen. DESIGN AND METHODS: In a large cohort of 106 patients (group I) we administered a new pre-transplant program which includes 2 courses of pulsed-VAD (vincristine, adriamycin, dexamethasone) followed by 2 courses of DCEP (dexamethasone, cyclophosphamide, etoposide and cis-platinum). We compared the efficacy of this new VAD-DCEP sequence, in terms of mobilizing capacity, toxicity and anti-myeloma activity in comparison with that of the previous VAD-high-dose cyclophosphamide program (group II, 40 patients). RESULTS: In group I 81/106 (76.4%) patients yielded >or= 4x10(6)/kg CD34+ cells, as did 30/40 (75%) in group II but with a significantly higher toxicity in this latter group. In detail, 9 patients in group I (8.5%) had WHO grade III neutropenia versus 35 in group II (87.5%), 5 patients of group I (4.7%) had grade III thrombocytopenia versus 12 patients in group II (30%), and 8 patients in group I (7.5%) experienced an infections fever versus 9 patients in group II (22.5%). Therefore, nearly all patients in group II had to be admitted to hospital (39/40, 97.5%). There was a higher percentage of responses (CR+VGPR+PR) in group I than in group II: 73% versus 50% (p=0.02). INTERPRETATION AND CONCLUSIONS: the VAD-DCEP sequence has an adequate mobilizing capacity, without significant toxicity, and a good anti-myeloma activity, and therefore represents a safe and effective therapeutic approach for multiple myeloma patients at the onset of their disease.
Adult↗
Predictive variables for malignant transformation in 452 patients with asymptomatic IgM monoclonal gammopathy.
The natural history of asymptomatic IgM monoclonal gammopathies (MG) and variables predicting evolution to symptomatic lymphoproliferative disorders were investigated in 452 patients diagnosed from 1975 to 2001. Univariate and multivariate Cox models were used to identify possible predictors of disease progression. At a median follow-up of 49 months (range, 12 to 233), 41 cases (9.1%) evolved to symptomatic Waldenstrom's macroglobulinemia (n = 36), non-Hodgkin's lymphoma (n = 2), B-cell chronic lymphocytic leukemia (n = 1), IgM multiple myeloma (n = 1), and primary amyloidosis (n = 1); the median interval from diagnosis was 53 months (range, 12 to 154). The cumulative probabilities of transformation into a symptomatic lymphoproliferative disease at 5 and 10 years were 8% (95% confidence interval [CI], 6% to 12%) and 21% (95% CI, 16% to 29%), respectively. At univariate analysis, monoclonal component size and hemoglobin level as continuous parameters, lymphocytosis (>4 x 10(9)/L), bone marrow lymphoplasmacytoid infiltration (>10%), erythrocyte sedimentation rate (>40 mm/h), and detectable Bence Jones proteinuria were significantly related with evolution probability. At multivariate analysis, paraprotein level (P <.0001), hemoglobin level (P <.05), and lymphocytosis (P <.0001) independently predicted malignant evolution (P <.0001). In conclusion, patients with asymptomatic IgM-MG showing hematological features predictive of progression should be carefully monitored in view of an early treatment of the disease.
Adult↗
Treatment of polycythemia vera and essential thrombocythemia: the role of pipobroman.
Pipobroman (PB) is a neutral amide of piperazine with a chemical structure close to that of alkylating agents, although the exact mechanism of action of PB has not been demonstrated. PB has well documented clinical activity in polycythemia vera (PV) and essential thrombocythemia (ET). Recent long-term follow-up studies on PV and ET patients receiving PB have facilitated the definition of the risk of late transformation into myelofibrosis with myeloid metaplasia (MMM) or acute leukemia (AL). This report gives an overview of the treatment with PB in patients with PV and ET focusing on clinical activity, administration dose and schedule, toxicity, impact on short- and long-term complications. From our experience and from the data reported in the literature the high clinical activity of PB in both PVand ET becomes evident. This drug allows, within 3 months, to attain a response in more than 90% of patients, without clinically relevant toxicities. The 10-years risk of thrombosis of patients treated with PB is about 15%, similar to that registered with hydroxyurea, the most widely used agent in PVand ET. The antiproliferative activity of PB on bone marrow megakaryocytes seems of particular value in lowering the occurrence of post-PV and post-ET MMM, whose risk (< 4% at 10 years) is the lowest registered with available treatments. The 10-year risk of acute leukemia with PB is 5% in PVand 3% in ET, which is only slightly higher than that expected as a natural evolution of the disease. In conclusion, the use of PB is a definite alternative to hydroxyurea in patients with PV and ET at high risk of thrombosis.
Abortion, Spontaneous↗
Polycythemia vera in young patients: a study on the long-term risk of thrombosis, myelofibrosis and leukemia.
BACKGROUND AND OBJECTIVES: Polycythemia vera (PV) is unusual in young patients, so that little information is available on long-term clinical evolution in this particular group. The aim of this study was to define the long-term risk of thrombosis, acute leukemia (AL) and myelofibrosis with myeloid metaplasia (MMM) in young PV patients. DESIGN AND METHODS: From 1975 to 2000, 70 PV patients aged less than 50 years were followed for a median time of 14 years (range 2-26). About three quarters were treated with pipobroman. The Kaplan-Meier method and Cox regression were used for survival analysis. The standardized mortality ratio (SMR) was calculated using Italian age/sex specific mortality rates. RESULTS: The risk of thrombosis increased during the observation period, reaching a plateau of 14% at 10 years and was markedly higher in individuals with a previous history of thrombosis (p=0.0023). No patient had progression into AL or MMM before the 9th year of follow-up. Subsequently, five patients (7%) developed AL and five (7%) MMM, with a 20-year cumulative risk of 15% and 10%, respectively. Overall survival at 20 years was 62%, with nine patients dying of progression into AL or MMM, four of vascular events, one of lung cancer, and four of non-PV-related causes. The SMR was 5.3, indicating a mortality significantly higher than that of the general population (p<0.000). INTERPRETATION AND CONCLUSIONS: This long-term retrospective cohort study shows that although the median survival of young patients with PV exceeds 23 years, their life expectancy is markedly lower than that of the general population because of disease evolution into AL or MMM.
Adolescent↗
Marginal zone-related neoplasms of splenic and nodal origin.
BACKGROUND: The marginal zone is an anatomically distinct B-cell compartment of lymphoid tissue with an abundant antigenic influx. Among marginal zone-derived lymphomas the WHO classification listed, in addition to extranodal marginal zone B-cell lymphoma of MALT type, two other marginal zone B-cell neoplasms: splenic marginal zone B-cell lymphoma (+/- villous lymphocytes) and nodal marginal zone B-cell lymphoma (+/- monocytoid B cells). These two entities are well characterized histologically, but specific biological markers are lacking. Treatment options are heterogeneous, including a watch-and-wait policy, surgery with or without chemotherapy, purine analogs, and interferon. No prospective studies have been conducted so far. INFORMATION SOURCES: Clinical and pathologic data were reviewed by searches of the published medical literature, including searches in PubMed , important printed publications, and abstracts presented at recent hematology and pathology meetings. STATE OF THE ART: Splenic and nodal marginal zone lymphomas are typical low-grade lymphomas with an indolent course. A subset of patients, however, presents with more aggressive disease and have a shorter survival. Clinical and biological prognostic factors identified in reported series are heterogeneous. The role played by hepatitis C virus (HCV) in marginal zone lymphomas is not fully elucidated, but there is demonstration that eradication of HCV infection in splenic lymphoma with villous lymphocytes causes regression of the lymphoma. The optimal treatment has not yet been identified. Retrospective series, however, show that splenectomy is a good option if symptoms from the presence of spleen enlargement or cytopenias need to be treated. The utility of purine analogs and of anti-CD20 immunotherapy needs to be clarified in prospective trials. PERSPECTIVES: Clinicians and pathologists should co-operate to define stringent diagnostic criteria for these indolent disorders. The optimal therapeutic approach and the role of new treatments need to be assessed in prospective clinical trials.
Humans↗
Early changes in bone marrow morphology induced by thalidomide in refractory myeloma patients.
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Angiogenesis Inhibitors↗
Clinical utility of the absolute number of circulating CD34-positive cells in patients with chronic myeloproliferative disorders.
BACKGROUND AND OBJECTIVES: Flow cytometry enumeration of peripheral blood CD34-positive cells provides reliable measurements of circulating hematopoietic progenitors in humans. Since the absolute number of circulating CD34-positive cells has been previously found to be elevated in myelofibrosis with myeloid metaplasia (MMM), we prospectively studied the clinical utility of this parameter in the work-up of patients with chronic myeloproliferative disorders. DESIGN AND METHODS: Of the 248 consecutive patients enrolled in this study, 106 had polycythemia vera (PV), 90 essential thrombocythemia (ET), and 52 myelofibrosis with myeloid metaplasia (MMM). The study population included both newly diagnosed and established cases, and of these latter some patients were on cytoreductive treatment while others were chemotherapy naive. Both cross-sectional and longitudinal investigations were carried out. Flow cytometry enumeration of CD34-positive cells was performed using a single-platform assay. RESULTS: Median numbers and ranges of circulating CD34-positive cells were 2.3x10(6)/L (0-5) in 20 control subjects, 2.2x10(6)/L (0-14) in those with PV, 2.4x10(6)/L (0-14) in those with ET, and 114x10(6)/L (6-2,520) in MMM patients. Analysis of variance demonstrated that values were markedly higher in MMM patients than in the remaining groups, and counts did not appear to fluctuate over short periods of follow-up. In both cross-sectional and longitudinal investigations on patients at clinical onset and/or out of cytoreductive treatment, a CD34-positive count of > or = 15x10(6)/L was always associated with MMM, clearly indicating a disease-related specificity. INTERPRETATION AND CONCLUSIONS: The absolute number of circulating CD34-positive cells is normal or anyhow lower than 15x10(6)/L in patients with uncomplicated PV or ET, whereas it is equal or above this cut-off in those with MMM, likely reflecting abnormal hematopoietic progenitor cell trafficking. Thus, enumeration of circulating CD34-positive cells may be useful in the work-up of patients with myeloproliferative disorders.
Adolescent↗
Induction therapy with idarubicin alone significantly influences event-free survival duration in patients with newly diagnosed hypergranular acute promyelocytic leukemia: final results of the GIMEMA randomized study LAP 0389 with 7 years of minimal follow-up.
Shortly before the all-trans retinoic acid (ATRA) era, the GIMEMA cooperative group initiated a randomized study comparing idarubicin (IDA) alone with IDA plus arabinosylcytosine (Ara-C) as induction treatment in patients with newly diagnosed hypergranular acute promyelocytic leukemia (APL). Of the 257 patients evaluable for induction treatment, 131 were randomized to receive IDA alone (arm A) and 126 to receive IDA + Ara-C (arm B). Treatment in arm A consisted of 10 mg/m(2) IDA daily for 6 consecutive days, whereas in arm B it consisted of 12 mg/m(2) IDA daily for 4 days combined with 200 mg/m(2) Ara-C daily in continuous infusion for 7 days. Once in complete remission (CR), patients received 3 consolidation courses of standard chemotherapy, and those still in CR at the end of the consolidation were randomized to receive or not receive 1 mg/kg 6-mercaptopurine daily and intramuscular injections of 0.25 mg/kg methotrexate weekly for 2 years. Overall, 100 (76.3%) patients in arm A and 84 (66.6%) patients in arm B achieved CR (P = NS). Event-free survival (EFS) rates were 35% and 23% for patients in arm A and arm B, respectively (P =.0352). Multivariate analysis revealed that EFS was favorably influenced by induction treatment with IDA alone (P =.0352) and unfavorably influenced by white blood cell (WBC) counts greater than 3000/microL (P =.0001) and increasing age (P =.0251). These results indicate that anthracycline monochemotherapy with IDA favorably influences the EFS of patients with newly diagnosed hypergranular APL.
Adolescent↗
Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia.
BACKGROUND: Chronic myelogenous leukemia (CML) is caused by the BCR-ABL tyrosine kinase, the product of the Philadelphia chromosome. Imatinib mesylate, formerly STI571, is a selective inhibitor of this kinase. METHODS: A total of 532 patients with late--chronic-phase CML in whom previous therapy with interferon alfa had failed were treated with 400 mg of oral imatinib daily. Patients were evaluated for cytogenetic and hematologic responses. Time to progression, survival, and toxic effects were also evaluated. RESULTS: Imatinib induced major cytogenetic responses in 60 percent of the 454 patients with confirmed chronic-phase CML and complete hematologic responses in 95 percent. After a median follow-up of 18 months, CML had not progressed to the accelerated or blast phases in an estimated 89 percent of patients, and 95 percent of the patients were alive. Grade 3 or 4 nonhematologic toxic effects were infrequent, and hematologic toxic effects were manageable. Only 2 percent of patients discontinued treatment because of drug-related adverse events, and no treatment-related deaths occurred. CONCLUSIONS: Imatinib induced high rates of cytogenetic and hematologic responses in patients with chronic-phase CML in whom previous interferon therapy had failed.
Administration, Oral↗
Monitoring of minimal residual disease after CHOP and rituximab in previously untreated patients with follicular lymphoma.
Minimal residual disease (MRD) following sequential administration of CHOP and rituximab was studied in previously untreated patients with follicular lymphoma. At diagnosis, the presence of Bcl-2/IgH-positive cells in the peripheral blood (PB) and/or bone marrow (BM) was demonstrated in all patients (n = 128) by polymerase chain reaction (PCR) analysis. Patients who achieved a clinical response following CHOP but remained PCR-positive were eligible for rituximab (375 mg/m(2) intravenously, weekly for 4 weeks). After CHOP, 57% achieved a complete response (CR), 37% a partial response (PR), and 6% were nonresponders (NR). At this stage, patients proving PCR-negative (n = 41) or failing to achieve a clinical response (n = 8) were excluded from rituximab treatment. Seventy-seven patients received rituximab and entered a scheduled MRD follow-up program. At the first molecular follow-up (+12 weeks), 59% had converted to PCR negativity in the BM and PB, with a further increase documented at the second control (+28 weeks) with 74% PCR negative. At the last molecular follow-up (+44 weeks), 63% of the patients remained PCR negative. At 3 years, the estimated overall survival of all patients is 95% (95% confidence interval [CI], 86-98). For patients achieving PCR-negative status following CHOP and therefore excluded from rituximab treatment, freedom from recurrence (FFR) was 52% (95% CI, 28-71). For patients treated with rituximab, a durable PCR-negative status was associated with a better clinical outcome since FFR was 57% (95% CI, 23-81) compared with 20% (95% CI, 4-46) in patients who never achieved or lost the molecular negativity (P <.001).
Adult↗
A novel deletion of the L-ferritin iron-responsive element responsible for severe hereditary hyperferritinaemia-cataract syndrome.
In the last few years, mutations that cause disease through increased efficiency of mRNA translation have been discovered. Hereditary hyperferritinaemia-cataract syndrome (HHCS) arises from various point mutations or deletions within the iron-responsive element (IRE) in the 5'-UTR of the L-ferritin mRNA. Each unique mutation confers a characteristic degree of hyperferritinaemia and severity of cataract in affected individuals. We report a novel six-nucleotide deletion identified in an Italian family presenting with elevated serum ferritin and early onset bilateral cataract. This deletion involves a sequence with a TCT repetition and may have occurred through a mechanism of slippage mispairing. Because of the above repetition, the observed mutation can be interpreted as deletion 22-27, 23-28, 24-29 or 25-30. Structural modelling predicted an IRE stem modification that is expected to markedly reduce the binding to iron-regulatory proteins. A double-gradient denaturing gradient gel electrophoresis (DG-DGGE) method easily detected the above deletion.
Adult↗
Pipobroman is safe and effective treatment for patients with essential thrombocythaemia at high risk of thrombosis.
Essential thrombocythaemia (ET) is a disease associated with an elevated risk of thrombosis. This study evaluated the efficacy and safety of pipobroman (PB) in the long-term control of ET patients who had, at diagnosis, one or more of the following currently known risk factors for thrombosis or haemorrhage (high-risk patients): age > 60 years, history of thrombosis or haemorrhage, platelets >1000 x 10(9)/l. From 1978 to 2000, with a median follow-up of 10 years, 118 previously untreated high-risk ET patients (median age 62 years, range 25-82), were treated with PB at the starting dose of 0.8-1 mg/kg/d. All patients reached a platelet count <600 x 10(9)/l and 91% achieved a platelet count <400 x 10(9)/l. During follow-up, 13 patients had thrombosis, with a 10-year cumulative risk of 14%. Acute myeloid leukaemia, myelofibrosis and solid tumours occurred in three, two and seven patients with a 10-year cumulative risk of 3%, 2% and 7% respectively. Actuarial survival at 20 years was 64% and the standardized mortality ratio was 1.1 (95% CI: 0.7-1.7), not statistically different from the general population (P = 0.54). Age was associated with a higher risk of death (P = 0.00009) and thrombosis (P = 0.003). The duration of PB treatment did not correlate with the occurrence of second malignancies. This study, with a median follow-up of 10 years, demonstrates that pipobroman is effective and well tolerated. The low cumulative 10-year risk of thrombosis, leukaemia and solid tumours indicates that pipobroman is an adequate treatment for patients with high risk ET.
Adult↗