Search

In T-cell acute lymphoblastic leukemia (T-ALL), transcription factors are known to be deregulated by chromosomal translocations, but mutations in protein tyrosine kinases have only rarely been identified. Here we describe the extrachromosomal (episomal) amplification of ABL1 in 5 of 90 (5.6%) individuals with T-ALL, an aberration that is not detectable by conventional cytogenetics. Molecular analyses delineated the amplicon as a 500-kb region from chromosome band 9q34, containing the oncogenes ABL1 and NUP214 (refs. 5,6). We identified a previously undescribed mechanism for activation of tyrosine kinases in cancer: the formation of episomes resulting in a fusion between NUP214 and ABL1. We detected the NUP214-ABL1 transcript in five individuals with the ABL1 amplification, in 5 of 85 (5.8%) additional individuals with T-ALL and in 3 of 22 T-ALL cell lines. The constitutively phosphorylated tyrosine kinase NUP214-ABL1 is sensitive to the tyrosine kinase inhibitor imatinib. The recurrent cryptic NUP214-ABL1 rearrangement is associated with increased HOX expression and deletion of CDKN2A, consistent with a multistep pathogenesis of T-ALL. NUP214-ABL1 expression defines a new subgroup of individuals with T-ALL who could benefit from treatment with imatinib., Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S., SCOPUS: ar.j, info:eu-repo/semantics/published

BACKGROUND: Hyperuricemia and tumor lysis syndrome (TLS) are serious complications that can occur during chemotherapy for hematologic malignancies, even if standard management procedures, including administration of allopurinol, are undertaken. Rasburicase, a recombinant urate oxidase that converts uric acid (UA) into the soluble compound allantoin, has been shown to control hyperuricemia faster and more reliably than allopurinol.(1) METHODS: A compassionate use trial, running from January 1999 to December 2001, provided access to rasburicase for patients in nine countries who were at risk for TLS during the initiation of chemotherapy. Of the 280 patients enrolled in the study, 278 received rasburicase and were included in the analysis. A total of 166 pediatric patients who had leukemia (approximately 74%), lymphoma (approximately 24%), or solid tumors (approximately 3%) were treated with rasburicase. One hundred twelve adults with either leukemia (68%) or lymphoma (30%) also were treated. Rasburicase (0.20 mg/kg) was administered intravenously once a day for 1 to 7 days, at the investigator's discretion. Two doses daily could be administered during the first 3 days. A response was defined as a reduction in UA level or maintenance of a UA level less than 7.5 mg/dL (or less than 6.5 mg/dL, for children age < 13 years). RESULTS: UA levels at 24-48 hours after administration of the last dose of rasburicase were available for 122 pediatric patients and 97 adult patients. The mean UA level in 29 hyperuricemic children decreased from 15.1 mg/dL to 0.4 mg/dL, whereas in 27 hyperuricemic adults, the mean level decreased from 14.2 mg/dL to 0.5 mg/dL. Prophylactic administration of rasburicase to prevent TLS during chemotherapy reduced UA levels from a mean of 4.4 mg/dL to 0.8 mg/dL in 93 nonhyperuricemic children and from 4.8 mg/dL to 0.4 mg/dL in 70 nonhyperuricemic adults (for all reductions in UA levels, P < 0.001). The response rate was 100%. Rasburicase was very well to

In diffuse large B-cell lymphoma (DLBCL), the combination of rituximab and CHOP (cyclophosphamide, doxorubicine, vincristine, prednisone; R-CHOP) has been shown to be more effective than CHOP for the treatment of elderly patients. Bcl-2 protein expression has been associated with poor prognosis in patients with DLBCL. To establish whether or not rituximab reduces bcl-2-assoclated treatment failure, we studied bcl-2 protein expression and clinical outcome in patients included in the Groupe d'Etude des Lymphomes de l'Adulte LNH-98-5 trial. Patients between 60 and 80 years of age were randomized to receive 8 cycles of either CHOP or R-CHOP every 3 weeks. Of the 399 patients included, 292 with histologically proven DLBCL had material available for bcI-2 study. Tumors were considered positive when at least 50% of tumor cells expressed bcl-2 protein. There were 193 (66%) bcl-2(+) patients and 99 (34%) bcl-2 patients. The response rates for R-CHOP and CHOP were, respectively, 78% and 60% (P = .01) in bcl-2(+) patients and 76% and 73% (P = .7) in bcl-2- patients. At a median of 2 years of follow-up, R-CHOP was significantly associated with a better overall survival than CHOP in bcl-2(+) patients (67% +/- 9% versus 48% +/- 11%, P = .004). In bcl-2- patients there was no statistically significant difference ( 72% +/- 12% versus 67% +/- 14%, P = .6). In addition, R-CHOP was associated with significantly better event-free survival than CHOP in bcl-2(+) patients (58% +/- 10% versus 32% +/- 10%, P < .001) but not in bcl-2- patients (60% +/- 13% versus 40% +/- 15%, P = .13). Multivariate analysis confirmed the significant benefit for survival and event-free survival of R-CHOP in bcl-2(+) patients. These results suggest that rituximab is able to prevent chemotherapy failure in patients with bcl-2 protein overexpression. (C) 2003 by The American Society of Hematology.

BACKGROUND: Hyperuricemia and tumor lysis syndrome (TLS) are serious complications that can occur during chemotherapy for hematologic malignancies, even if standard management procedures, including administration of allopurinol, are undertaken. Rasburicase, a recombinant urate oxidase that converts uric acid (UA) into the soluble compound allantoin, has been shown to control hyperuricemia faster and more reliably than allopurinol.(1) METHODS: A compassionate use trial, running from January 1999 to December 2001, provided access to rasburicase for patients in nine countries who were at risk for TLS during the initiation of chemotherapy. Of the 280 patients enrolled in the study, 278 received rasburicase and were included in the analysis. A total of 166 pediatric patients who had leukemia (approximately 74%), lymphoma (approximately 24%), or solid tumors (approximately 3%) were treated with rasburicase. One hundred twelve adults with either leukemia (68%) or lymphoma (30%) also were treated. Rasburicase (0.20 mg/kg) was administered intravenously once a day for 1 to 7 days, at the investigator's discretion. Two doses daily could be administered during the first 3 days. A response was defined as a reduction in UA level or maintenance of a UA level less than 7.5 mg/dL (or less than 6.5 mg/dL, for children age < 13 years). RESULTS: UA levels at 24-48 hours after administration of the last dose of rasburicase were available for 122 pediatric patients and 97 adult patients. The mean UA level in 29 hyperuricemic children decreased from 15.1 mg/dL to 0.4 mg/dL, whereas in 27 hyperuricemic adults, the mean level decreased from 14.2 mg/dL to 0.5 mg/dL. Prophylactic administration of rasburicase to prevent TLS during chemotherapy reduced UA levels from a mean of 4.4 mg/dL to 0.8 mg/dL in 93 nonhyperuricemic children and from 4.8 mg/dL to 0.4 mg/dL in 70 nonhyperuricemic adults (for all reductions in UA levels, P < 0.001). The response rate was 100%. Rasburicase was very well to, Clinical Trial, Journal Article, FLWIN, info:eu-repo/semantics/published

OBJECTIVE: To evaluate the correlation between specific prognosis of hematologic malignancies on the one hand and intensive care unit and hospital mortality in critically ill patients with hematologic malignancies on the other hand. DESIGN: Observational study during a 10-yr period. SETTING: A 22-bed medical-surgical intensive care unit. PATIENTS: A total of 84 consecutive patients with nonterminal hematologic malignancies with medical complications requiring intensive care. INTERVENTIONS: None. MEASUREMENTS: Demographic factors, acute physiology and organ dysfunction scores, microbiology, therapeutic support, and hematologic factors data on admission and during the intensive care unit stay were collected, together with mortality follow-up. Based on specific-disease prognostic factors and related published survival curves, the prognosis of hematologic malignancies was assessed and defined as good, intermediate, or poor according to a 3-yr survival probability of >50%, 20-50%, or <20%, respectively. MAIN RESULTS: Prognosis of hematologic malignancies does not predict intensive care unit or hospital mortality and almost reaches significance for 6-mo mortality (53%, 71%, and 84% rate for patients with good, intermediate, and poor prognosis, respectively, p =.058), but it determines long-term survival (p =.008). Intensive care unit, hospital, and 6-mo overall mortality rates were 38%, 61%, and 75%, respectively. Using multivariate analysis, intensive care unit mortality was best predicted on admission by respiratory failure and fungal infection, whereas hospital mortality was predicted by the number of organ failures, the bone marrow transplant status, and the presence of fungal infection. The Acute Physiology and Chronic Health Evaluation II and the Simplified Acute Physiology Score II had no prognostic value, whereas the difference of the Multiple Organ Dysfunction Score between at the time of admission and at day 5 allowed quick prediction of hospital mortality. Dise

Death during the induction phase of chemotherapy remains a common event in patients with aggressive non-Hodgkin's lymphoma (NHL). In a series of patients with aggressive NHL homogeneously treated with intensive induction chemotherapy [ACVB (doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone) regimen], we determined the clinical and biological parameters that were predictive of early death. Early death was defined as death, for whatever reason, occurring within 100 d of randomization. Predictive factors were identified by logistic regression and an index predictive for individual risk of early death was designed. Among the 2210 patients treated with ACVB, there were 162 (7.3%) early deaths. There was no significant reduction in the rate of early death between 1987 and 1998. In a multivariate analysis, age > 60 years, Eastern Cooperative Oncology Group performance status > 1, serum lactate dehydrogenase > normal, serum albumin < 30 g/l, leucocyte counts > 10 x 10(9) /l and haemoglobin levels < 8.5 g/dl were found to be independent predictive factors for early death. An early death index was designed, enabling the evaluation of the individual risk of early death in young (range 2-31% risk of early death) and elderly patients (range 5-53%). Clinical and biological parameters available at diagnosis can help physicians identify patients with aggressive lymphoma at low or high risk of early death.

Rituximab is a human/mouse chimeric monoclonal antibody that binds to the CD20 antigen and is expressed at all stages of B-cell development. Rituximab has demonstrated efficacy as monotherapy and in combination with chemotherapy in the treatment of both indolent and aggressive non-Hodgkin's lymphoma (NHL). Rituximab treatment results in rapid depletion of B-cells and this has led to the consideration of other B-cell disorders as candidates for rituximab therapy. Recent studies have demonstrated the efficacy of rituximab in a variety of such disorders, including chronic lymphocytic leukemia (CLL), post-transplant lymphoprollferative disorder (PTLD),Waidenstrom's macroglobulinemia (WM), multiple myeloma (MM), idiopathic thrombocytopenic purpura (ITP), hairy-cell leukemia (HCL) and cold agglutinin disease (CAD). In patients with CLL, increasing the dose and/or frequency of rituximab treatment has given improved response rates compared with the standard dose schedule used in NHL, and combination immunochemotherapy has yielded an overall response rate of 92% (with a 60% complete response rate). Clinical trials have also demonstrated evidence of efficacy for rituximab in PTLD, WIVI and relapsed or refractory ITP. Efficacy of rituximab in CAD and relapsed or refractory HCL has also been demonstrated in small studies and case reports. Available data thus indicate that rituximab can be an effective therapy in a wide range of CD20(+) lymphoid disorders. [(C) 2002 Lippincott Williams Wilkins.]

From 1994 to 2000, 154 adults with Philadelphia chromosome-positive (Ph(+)) and/or BCR-ABL(+) acute lymphoblastic leukemia (ALL) were treated according to a prospective trial (median follow-up, 4.5 years) with the aim to study the prognostic value of early response to therapy and the role of stem cell transplantation (SCT) in first complete remission (CR). All patients received a standard induction course followed by a course of mitoxantrone and intermediate-dose cytarabine (HAM). After each course, minimal residual disease was tested by specific reverse transcriptase-polymerase chain reaction (RT-PCR) (median sensitivity, 10(-5)). Allogeneic SCT (if a donor) or autologous SCT (if not) was planned at 3 months in all patients in CR after HAM. CR rates after induction, after HAM, and at 3 months were 53%, 67%, and 62%, respectively. High leukocyte count and m-bcr subtype were the 2 identified bad-prognosis factors for CR at 3 months, both superseded by a poor early response assessed at day 8 of the induction course. HAM-associated salvage rate was higher in patients with M-bcr than in those with m-bcr ALL (55% vs 30%; P =.05). In the 103 patients eligible for SCT, the existence of a donor and the negative BCR-ABL status after HAM were independently predictive of remission duration (P <.001 and.01, respectively) and survival (P =.02 and.01, respectively). Relapse was the most common cause of treatment failure in all patient groups. Allogeneic SCT in first CR is the current best treatment option in adults with the disease. New strategies must be tested during early phases of therapy to increase the rate of BCR-ABL(-) remissions.

Intracranial meningiomas are generally slow-growing neoplasms. Symptoms depend on their critical intracranial location. The authors describe a case of rapidly enlarging meningioma that became symptomatic as a result of invasion by leukemic cells at the time of a blastic crisis in the context of chronic myeloid leukemia. Infiltration of an intracranial meningioma by cells from extracranial malignant neoplasms is a rare event. Even though central nervous system (CNS) or meningeal involvement is common in some hematologic malignancies, this is, to the best of our knowledge, the first report of invasion of an intracranial meningioma by leukemic cells.

INTRODUCTION: A prospective randomised study involving 810 elderly patients was conducted in an attempt to compare alternating chemotherapy with conventional first-line chemotherapy in aggressive non-Hodgkin's lymphoma in order to improve prognosis with an acceptable toxicity for elderly patients. PATIENTS AND METHODS: Patients included were 55-69 years old and had at least one adverse prognostic factor. Patients were treated either with ACVBP followed by consolidation (n = 396) or with an alternating regimen (n = 414). This regimen was an association of active drugs in NHL relapsing patients, alternating VIMMM with ACVBP for induction and alternation of VIM and ACVM in consolidation. Eight hundred and sixty-six patients were randomised. After histological review, 810 patients met the inclusion criteria: 396 in arm A, 414 in arm B. RESULTS: The complete response rate after induction was superior for conventional first-line therapy (58.5% vs 48%, P = 0.003) but at the end of treatment, the CR rate was not statistically different (52% vs 48%, P = 0.19). Conventional chemotherapy had a better five-year event-free survival than alternating regimen (33% (95% CI: 30-36%) vs 28% (95% CI: 26-30%), P = 0.0289) but overall survival was not statistically different (40% (CI 95% 38-42%) vs 36% (CI 95% 34-38%), P = 0.068). In this elderly high risk population, the toxicity was very high: 19% in arm A and 26% in arm B died during treatment. CONCLUSION: Alternating regimen did not improve outcome, was less efficient and more toxic.

Autologous stem-cell transplantation (ASCT) has permitted to deliver high-dose therapy (HDT). In aggressive lymphomas, the GELA group conducted prospective and retrospective studies comparing HDT + ASCT to conventional sequential chemotherapy. In relapsing patients and in partial remission, retrospective studies showed a survival advantage for HDT + ASCT over sequential chemotherapy. In complete response, advantage for HDT + ASCT was demonstrated in a prospective trial only for patients with high intermediate or high risk in the IPI score. The attainment of a maximal reduction of the tumoral mass before going HDT is very important either in first line or in relapsing patients.

Decitabine (5-aza-2'-deoxycytidine) acts as a powerful demethylating agent in vitro. Clinically, low-dose decitabine ameliorates cytopenias including induction of trilineage responses in approximate to 50% of patients with high-risk myelodysplastic syndrome (MDS). We examined the incidence and kinetics of cytogenetic responses to decitabine in these patients. Of 115 successfully karyotyped patients, 61 (53%) had clonal chromosomal abnormalities prior to treatment. Major cytogenetic responses were observed in 19 patients (31% of those with abnormal cytogenetics, 17% of all patients by intention-to-treat) after a median of three courses (range, 2-6) until best cytogenetic response. Progressive decrease of the abnormal clone over time was also determined using fluorescence in situ hybridization (FISH) analysis in two patients. Median duration of cytogenetic responses was 7.5 months (range, 3-15). Analysis of response by the International Prognostic Scoring System (IPSS) cytogenetic risk groups revealed three out of five cytogenetic responses (60%) in the IPSS 'low-risk' group, 6 out of 30 with 'intermediate risk' (20%) and 10 out of 26 in the 'high-risk' group (38%). Median survival in these cytogenetic subgroups was 30, 8 and 13 months respectively. The relative risk of death in patients achieving a major cytogenetic response was 0.38 (95% confidence interval 0.17-0.88) compared with patients in whom the cytogenetically abnormal clone persisted (P = 0.0213). In conclusion, repeated courses of low-dose decitabine induce cytogenetic remissions in a substantial number of elderly MDS patients with pre-existing chromosomal abnormalites; these are associated with improved survival compared with patients in whom the cytogenetically abnormal clone persists. Patients with 'high-risk' chromosomal abnormalities may particularly benefit from this treatment.

The rational for intensive chemo- or/and radiotherapy is based on the dose-effect relation in non-Hodgkin's lymphoma. In follicular lymphomas, candidates to intensification are patients with poor prognosis in relapse or with histological transformation. The efficacy of intensification to improve survival ire first line treatment is not proven ire follicular lymphoma. Due to the frequent marrow and blood involvement by tumoral cells in these lymphomas and the prognosis impact of this contamination, many efforts have been done to eliminate tumoral cells from the graft. Monoclonal anti-CD20 antibodies (rituximab) are indeed the best treatment to purge in vivo from tumoral cells marrow and blood In aggressive lymphomas, intensifications are now the standard regimen in case of sensitive relapse. Probably it is also true in case of partial response or in first line after complete response inpatients with 2 or 3 adverse prognostic factors. However intensification is not recommended in case of refractory disease or in first line treatment for standard-risk patients. High relapse rate after autograft justifies to test immunotherapy against minimal residual disease. The role of allogeneic transplantation, monoclonal antibodies or cytokines remains to be defined., Le rationnel des intensifications thérapeutiques avec autogreffe se base sur la relation effet-dose de la chimiothérapie et de la radiothérapie dans les lymphomes non hodgkiniens. Dans les lymphomes folliculaires, les candidats à la transplantation sont les malades à mauvais pronostic, en rechute ou en transformation histologique. Il n'y a pas de preuve actuellement que l'intensification en première ligne améliore le pronostic de ces lymphomes. Étant donné la fréquence de l'atteinte sanguine et médullaire de ces lymphomes et l'impact de celle-ci sur la survie, les techniques d'élimination des cellules malignes du greffon sont intéressantes. Les anticorps anti-CD20 (rituximab) sont sans doute le meilleur moyen d'obtenir une « purge » in vivo. Dans les lymphomes à haut degré de malignité, les intensifications sont actuellement le traitement standard en cas de rechute sensible à la chimiothérapie de rattrapage. Elles sont vraisemblablement le meilleur choix thérapeutique en cas de réponse partielle, mais aussi en première ligne en cas de réponse complète en présence de 2 à 3 facteurs de risque défavorables. En revanche, elles ne sont pas indiquées en cas de maladie réfractaire ou en première ligne chez les malades au risque standard. Le taux élevé de rechutes post-greffe justifie l'utilisation de traitements immunothérapiques pour agir contre la maladie résiduelle. La place de l'allogreffe des anticorps monoclonaux et des cytokines reste à définir.

Between 1987 and 1993, 77 of 2855 lymphomas included in the LNH87 protocol of the GELA as non-Hodgkin lymphoma (NHL) and reviewed by a panel of pathologists had a diagnosis changed to Hodgkin lymphoma (HL). Some of these lymphomas had been initially interpreted as anaplastic large-cell lymphoma Hodgkin-like (ALCL-HL subtype). The purpose of this study was to analyze the histologic pitfalls initially encountered, to define more clearly the diagnostic criteria of lymphomas placed in the gray zone around HL, and to follow the survival of these 77 patients affected with HL and initially treated with NHL regimens. The 77 cases of HL were reviewed by three hematopathologists and immunostained with a large panel of antibodies, including CD30, CD15, CD3, CD20, CD45, CD43, LMP-1, EMA, BNH-9, TiA1, and ALK1. Each case was classified according to the Lukes-Rye system and the British National Lymphoma Investigation (BNLI) grading. The initial clinical presentation of patients was analyzed, and the overall and event-free survival rates of the 77 patients were estimated. Among the 77 HLs, 46 were misinterpreted as NHL by primary individual pathologists (12 as ALCL, 8 as ALC-LHL, 12 as peripheral T-cell lymphoma (PTCL), 6 as B-cell lymphoma, and 8 as unclassifiable NHL). The other 31 cases had been first considered by the panel as consistent with ALCL-HL (n = 18) or with PTCL(n = 13) and were changed later in view of an immunophenotype concordant with HL. Fifty-five percent of the patients completed the full NHL treatment. The 5-year event-free and overall survival rates were 54% and 77%, respectively. The current results indicate that lymphomas initially called ALCL-HL should not be regarded as a variant of ALCL, but as HL. The clinical consequences of misdiagnoses seem to be a lower event-free survival rate compared with that of classical HL, probably because of more relapses of initially inappropriately treated HL.

The pharmacokinetics and safety of an intravenous hydroxypropyl-beta -cyclodextrin solution of itraconazole administered for 7 days followed by itraconazole oral solution administered at 200 mg once or twice daily for 14 days were assessed in 17 patients with hematologic malignancies, Steady-state plasma itraconazole concentrations were reached by 48 h after the start of intravenous treatment. The mean trough plasma itraconazole concentration at the end of the intravenous treatment was 0.54 +/- 0.20 mug/ml. This concentration was not maintained during once-daily oral treatment but increased further in the twice-daily treatment group, with a trough itraconazole concentration of 1.12 +/- 0.73 mug/ml at the end of oral treatment. As expected in the patient population studied, all patients experienced some adverse events (mainly gastrointestinal). Biochemical and hematologic abnormalities were frequent, but no consistent changes occurred, In conclusion, 7 days of intravenous treatment followed by 14 days of twice-daily oral treatment with itraconazole solution enables plasma itraconazole concentrations of at least 0.5 mug/ml to be reached rapidly and to be maintained. The regimen is well tolerated and has a good safety profile.

A prospective multicentric phase II study of the C5R regimen in patients with primary cerebral lymphoma: Analysis on 70 patients.

Lymphome et agglutinines froides à propos d'une observation

OBJECTIVE: The 'HICPAC guidelines', published in the USA in 1995 stressed the crucial role of restrictive usage of glycopeptides in the strategy to limit the emergence and spread of resistant enterococci. Because controversy still remains in Belgium on the necessity and feasability of restricting glycopeptide usage, the infectious diseases advisory board (IDAB) developed a consensus statement on the judicious use of glycopeptides in Belgium. METHODS: The literature on the indications for glycopeptide treatment was reviewed, categorized and discussed by a working party of the IDAB.Consequently, the IDAB reached consensus on the warranted indications for glycopeptide use in Belgium. RESULTS: The opinion of the IDAB-members is reported in a consensus statement specifying the indications for treatment and for prophylaxis with glycopeptide antimicrobials, as well as the situations where glycopeptides should not be used, taking into account the specific epidemiology of bacterial resistance, the availability of antibiotics and the common prescribing practices in Belgium. CONCLUSIONS: The IDAB concludes that restrictive usage of glycopeptides must also be a priority in Belgium. Guidelines on the judicious use of these antibiotics adapted to the national situations must contribute to this objective.

Because of their substantial in vitro synergy, we conducted a dose-escalation study of cyclophosphamide (CP) added to 2-chloro-2'-deoxyadenosine (CdA) in patients with previously treated chronic lymphocytic leukemia and non-Hodgkin's lymphoma. CdA was given at a fixed dose (5.6 mg/m2/day) as a 2-h intravenous (i.v.) infusion, immediately followed by a 1-h i.v. infusion of CP, for 3 days. The initial daily CP dose was 200 mg/m2, and was escalated by 100 mg/m2 increments in successive cohorts of three to six patients to determine the maximum-tolerated dose (MTD). Additional patients were included at the MTD to extend toxicity and response analysis. Twenty-six patients received 68 cycles of chemotherapy. The MTD of CP after CdA 5.6 mg/m2, was 300 mg/m2. Acute neutropenia was the dose-limiting toxicity of this regimen, which was otherwise well tolerated. Delivery of repeated cycles was not feasible in eight patients (31%) because of prolonged thrombocytopenia. Severe infections were seen in three of 68 cycles (4%). The overall response rate was 58% (15 of 26; 95% CI, 36-76%), with 15% complete responses and 42% partial responses. These data show the feasibility of the association of CdA with CP. Given the response rate observed, further studies of this regimen are warranted in untreated patients, in particular with chronic lymphocytic leukemia and with Waldenström macroglobulinemia.

Autologous transplantation using peripheral blood stem cells (PBSCs) collected after chemotherapy, followed by growth factor administration (ASCT), is increasingly used in the treatment of non-Hodgkin's lymphoma (NHL). However, quantitative data regarding contaminating malignant cells in the harvests are still scarce. We prospectively investigated 37 diffuse large-cell lymphomas (DLCLs) in complete remission (CR) that were treated according to multicentric protocols at our centre. DNA was extracted from the diagnostic lymph node. The complementarity-determining region (CDR) III was sequenced and a patient-specific oligomer synthesized. Contamination was evaluated semiquantitatively by polymerase chain reaction (PCR) and was confirmed by a limiting dilution analysis. PBSCs collected at regeneration after administration of granulocyte colony-stimulating factor (G-CSF), steady-state bone marrow (BM) and peripheral blood samples at CR were compared. DNA was available in 37 patients, from which 22 rearrangements could be sequenced. Patients (n = 15) who had both the required follow-up samples and a suitable clonal marker were investigated. In two cases, the patient-specific PCR assay set up at diagnosis later gave false-negative results in samples in which clonal DNA was still detectable by other sets of primers. PBSC contamination was highly variable: 7 out of 15 patients showed a PBSC/BM ratio of NHL cells greater than 1 log, whereas 8 out of 15 patients showed no difference and could vary from one apheresis to another. Eight ASCTs were performed, five of which used highly contaminated PBSCs: four patients relapsed early, three with disseminated lymphoma. Thus, 50% of DLCLs in CR seem to mobilize significantly malignant cells at regeneration under G-CSF. Considering the higher numbers of cells reinfused, this translates into a much higher number of lymphoma cells reinfused when compared with autologous bone marrow transplantation (ABMT). However, their clonogenic poten

Purpose: 5-Aza-2'-deoxycytidine (decitabine; DAC) is a DNA hypomethylating agent that has shown a 50% response rate in a small phase It study in elderly patients with high-risk myelodysplastic syndrome. We performed a second, multicenter phase II study in a larger group of patients ta confirm our findings and to study the toxicity of DAC. Patients and Methods: Between June 1996 and September 1997, 66 patients (median age, 68 years) from seven centers received PAC 45 mg/m(2)/d for 3 days every 6 weeks. For patients in whom a complete response (CR) was reached after two courses, two further cycles were administered as consolidation therapy, In case of a stable disease situation, improvement, or a partial response (PR), ct maximum of six cycles was administered, The primary end points were response rate and toxicity. The secondary end points were response duration, survival from the start of therapy, and overall survival, Results: The observed overall response rate was 49%, with a 64% response rate in the patients with an International Prognostic Scoring System (IPSS) high-risk score. The actuarial median response duration was 31 weeks, with a response duration of 39 weeks and 36 weeks for patients who reached a PR or CR, respectively. The actuarial median survival time from the time of diagnosis was 22 months and from the start of therapy was 15 months. For the IPSS high risk group, the median survival rime was 14 months. the median progression-free survival time was 25 weeks. Myelosuppression was rather common, and the treatment-related mortality rate was 7% and was primarily associated with pancytopenia and infection. Significant responses were observed with regard to megakaryopoiesis, with increases in platelet counts having already occurred after one cycle of DAC therapy in the majority of the responding patients. Conclusion: We were able to confirm our previous observation that DAC therapy was effective in half of the studied patients with high-risk myelodysplast

Purpose: To present the final analysis, with a median follow-up of 8 years, of the LNH87-2 randomized study, which compares consolidative sequential chemotherapy (ifosfamide plus etoposide, asparaginase, and cytarabine) with high-dose therapy (HDT) using cyclophosphamide, carmustine, and etoposide (CBV regimen) followed by stem-cell transplantation in patients with aggressive non-Hodgkin's lymphoma in first complete remission after induction, focusing on high/intermediate- and high-risk patients identified by the age-adjusted international prognostic index. Patients and Methods: Among the 916 eligible patients, 451 presented with two (n = 318) or three (n = 133) risk factors. After reaching complete remission to induction therapy, 236 of these higher risk patients were assessable for the consolidation phase, with 125 patients in the HDT arm and 111 in the sequential chemotherapy arm. Results: Among these 451 higher risk patients, 277 (61%) achieved complete remission after induction treatment. In the population of 236 randomized patients, HDT wets superior to sequential chemotherapy, with I-year disease-free survival rates of 55% (95% confidence interval [CI], 46% to 64%) and 39% (95% CI, 30% to 48%), respectively (P = .02; relative risk, 1.56). The 8-year survival rate was significantly superior in the HDT arm (64%; 95% CI, 55% to 73%) compared with the sequential chemotherapy arm (49%; 95% CI, 39% to 59%) (P = .04: relative risk, 1.51). Conclusion.. On the basis of the final analysis of this prospectively treated series of patients, retrospectively analyzed on the basis of the International Prognostic Index, we hypothesize that HDT benefits patients at higher risk who achieve complete remission after induction treatment. (C) 2000 by American Society of Clinical Oncology.

Purpose: To compare ct short intensified regimen followed by sequential consolidation therapy (doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone [ACVBP]) to the standard regimen of methotrexate, bleomycin, cyclophosphamide, and etoposide (m-BACOD) in patients with low-risk aggressive lymphoma. Patients and Methods: A total of 752 patients with intermediate or high-grade lymphoma and no adverse prognostic factors (Eastern Cooperative Oncology Group performance status of 2 to 4, greater than or equal to two extranodal sites of disease, tumor burden greater than or equal to 10 cm in largest dimension, bone marrow or CNS involvement, Burkitt's or lymphoblastic subtypes) were registered. Of 673 eligible patients, 332 received ACVBP and 341 received m-BACOD. Results: The complete remission rate wets identical (86%) in the two groups. With a median follow-up duration of 7 years, the 5-year failure-free survival (FFS) rate wets 65% in the ACVBP group and 61% in the m-BACOD group (P = .16), The 5-year overall survival rate wets 75% in the ACVBP group and 73% in the m-BACOD group (P = .47). ACVBP was responsible for more severe and life-threatening infections (P < .01), but m-BACOD caused more pulmonary toxicity (P < .001). The number of treatment-related deaths did not differ between the two regimens. A multivariate analysis indicated that ACVBP wets associated with a longer FFS in patients with two or three risk factors of the International Prognostic Index. Conclusion: In this population of patients with low-risk aggressive lymphoma, toxicities of the regimens are different, but the rates of response and survival are identical. The survival advantage of ACVBP over standard regimen in patients with advanced disease is suggested by this analysis but remains to be assessed in prospective studies specifically designed for this purpose. (C) 2000 by American Society of Clinical Oncology

Autologous transplantation using peripheral blood stem cells (PBSCs) collected after chemotherapy, followed by growth factor administration (ASCT), is increasingly used in the treatment of non-Hodgkin's lymphoma (NHL). However, quantitative data regarding contaminating malignant cells in the harvests are still scarce. We prospectively investigated 37 diffuse large-cell lymphomas (DLCLs) in complete remission (CR) that were treated according to multicentric protocols at our centre. DNA was extracted from the diagnostic lymph node. The complementarity-determining region (CDR) III was sequenced and a patient-specific oligomer synthesized. Contamination was evaluated semiquantitatively by polymerase chain reaction (PCR) and was confirmed by a limiting dilution analysis. PBSCs collected at regeneration after administration of granulocyte colony-stimulating factor (G-CSF), steady-state bone marrow (BM) and peripheral blood samples at CR were compared. DNA was available in 37 patients, from which 22 rearrangements could be sequenced. Patients (n = 15) who had both the required follow-up samples and a suitable clonal marker were investigated. In two cases, the patient-specific PCR assay set up at diagnosis later gave false-negative results in samples in which clonal DNA was still detectable by other sets of primers. PBSC contamination was highly variable: 7 out of 15 patients showed a PBSC/BM ratio of NHL cells greater than 1 log, whereas 8 out of 15 patients showed no difference and could vary from one apheresis to another. Eight ASCTs were performed, five of which used highly contaminated PBSCs: four patients relapsed early, three with disseminated lymphoma. Thus, 50% of DLCLs in CR seem to mobilize significantly malignant cells at regeneration under G-CSF. Considering the higher numbers of cells reinfused, this translates into a much higher number of lymphoma cells reinfused when compared with autologous bone marrow transplantation (ABMT). However, their clonogenic poten, Journal Article, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, FLWIN, info:eu-repo/semantics/published

In this multicentre, randomised, double-blind study, the safety and efficacy of oral fluconazole (200 mu g/day) and nystatin suspension (6 000 000 IU/day) for the prevention of fungal infections were compared in patients with leukaemia undergoing remission induction chemotherapy. Antifungal prophylaxis was initiated at the time chemotherapy was started and continued throughout the hospital stay or the period of neutropenia to a maximum of 42 days. Prophylaxis was successful (no evidence of fungal infection or fever of unknown origin unresponsive to antibiotics) in 38 of 56 (68%) fluconazole-treated and 25 of 53 (47%) nystatin-treated patients (P= 0.03). 2 patients (4%) in the fluconazole group and 6 (11%) patients in the nystatin group developed systemic fungal infections (P= 0.15). The overall frequency of adverse events was similar among fluconazole-treated (29%) and nystatin-treated (32%); most events in both treatment groups involved the gastrointestinal tract. These results indicated fluconazole was more effective than nystatin in preventing Candida infections in patients with leukaemia; fluconazole was well tolerated. (C) 1999 Elsevier Science Ltd. All rights reserved.