Search

In the rituximab era, one-third of diffuse large B-cell lymphoma patients experience relapse/refractory disease after first-line anthracycline-based immunochemotherapy. Optimal management remains an unmet medical need. The aim of this study was to report the outcomes of a cohort of refractory patients according to their patterns of refractoriness and the type of salvage option. We performed a retrospective analysis, which included 104 diffuse large B-cell lymphoma patients treated at Lyon Sud University Hospital (2002-2017) who presented with refractory disease. Refractoriness was defined as progressive/stable disease during first-line treatment (primary refractory, N = 47), a partial response after the end of first-line treatment that required subsequent treatment (residual disease, N = 19), or relapse within 1 year of diagnosis after an initial complete response (CR) (early relapse, N = 38). The 2-year overall survival (OS) rates for primary refractory, early relapse, and residual disease patients were 27%, 25%, and 52%, respectively, while the event-free survival rates for those groups were 13%, 13%, and 42%, respectively. In a univariate analysis, lactate dehydrogenase level, Ann Arbor stage, poor performance status, high age-adjusted International Prognostic Index score, and age > 65 years were associated with shorter OS. The use of rituximab and platinum-based chemo during the first salvage treatment was associated with prolonged OS. In a multivariate analysis, age (HR:2.06) and rituximab use (HR:0.54) were associated with OS. Among patients

Patients receiving high-dose cyclophosphamide as a conditioning regimen for peripheral stem cell collection are subjected over a short period of time to significant exposure to reactive oxygen species (ROS). All these patients undergo profound leucopenia. Various other short-term toxicities are observed in a fraction of the patients, including febrile aplasia requiring hospitalization, thrombocytopenia and mucositis. Although stem cell collection is feasible in the majority of patients stimulated with haematopoietic growth factors, in some instances, graft collection cannot be performed because of insufficient concentrations of stem cells in peripheral blood. There is currently no predictive assay to determine which patients treated with high-dose cyclophosphamide have a high risk of febrile aplasia or will successfully undergo cytaphereses for stem cell collection. In order to identify such predictive factors, we analysed the level of expression before treatment of various ROS detoxification mechanisms in the peripheral blood of 37 patients receiving high-dose cyclophosphamide for lymphoproliferative diseases. Various parameters involved in the metabolism of ROS were measured in plasma and/or erythrocytes, including superoxide dismutase, glutathione, glutathione peroxidase, glutathione reductase and malondialdehyde. High levels of erythrocyte superoxide dismutase before cyclophosphamide therapy were correlated with an increased risk of hospitalization for febrile aplasia (65% vs. 29%, P = 0·013). High superoxide dismutase and low erythrocyte glutathione reductase were associated with lower CD34 yields. These data suggest that components of the ROS detoxification system modulate the degree of short-term toxicity of cyclophosphamide and could be used as predictive markers in individual patients.

A phase I/II trial was performed to investigate the safety and tolerance of zosuquidar.3HCL, a potent inhibitor of P-glycoprotein (P-gp), when administered orally alone and in combination with the CHOP regimen in patients with untreated non-Hodgkin's lymphoma and to determine whether zosuquidar.3HCL affects pharmacokinetics of doxorubicin and vincristine. Doses of CHOP remained constant and the doses of zosuquidar.3HCL were increased from 200 to 500 mg per dose. A total of 15 patients were treated at three dose levels. A target dose providing peak and trough levels compatible with prolonged modulation of P-gp function was obtained in patients receiving three doses of 500 mg of zosuquidar.3HCL p.o. At this dose level, toxicity was minimal and no enhancement of CHOP-related toxicity was observed. Zosuquidar.3HCL did not significantly affect the pharmacokinetics of doxorubicin and had moderate effects on the pharmacokinetics of vincristine. Zosuquidar.3HCL can be safely administered with CHOP therapy using a 24-h schedule.

Serum lacticodehydrogenase (LDH) is commonly increased in patients with haematopoietic malignancies and has been shown to be a prognostic factor in patients with non-Hodgkin's lymphoma (NHL) and myeloma. We have examined the LDH isoenzyme content in serum of 326 patients, including 252 patients with NHL (202 at diagnosis and 50 at relapse), 28 patients with Hodgkin's disease, 17 patients with CLL, 16 patients with myeloproliferative syndromes and 13 patients with multiple myeloma. Among these, 160 pts (49%) had increased serum LDH. The analysis of LDH isoenzyme profiles in all patients showed increased percentages of isoenzyme 2 in patients with NHL, CLL and myeloproliferative syndromes, but not in samples from patients with myeloma or Hodgkin's disease. Isoenzyme alterations were then analyzed for their prognostic value in patients with NHL. In univariate analyses, increased isoenzyme 2 percentages, increased isoenzyme 3 values, total serum LDH, performance status, stage and tumour aggressiveness were prognostic variables for survival. In a multivariate analysis increased LDH isoenzyme 3 values, high isoenzyme 2 percentages and the performance status, but not total serum LDH, were independent prognostic factor for survival. High isoenzyme 3 values were predictive of early death in NHL patients. In patients with relapsing NHL, the overall survival was 12 months in patients with normal isoenzyme 3 but only 2 months in patients with increased isoenzyme 3 values. We conclude that there are characteristic alterations in serum LDH profiles in patients with haematopoietic malignancies and that some of these may be more interesting in terms of prognostic value than total serum LDH.

Background: Patients with relapsing or refractory multiple myeloma have poor prognosis. Few compounds are active in these patients and response duration remains short. We report the results of an open phase II trial evaluating the efficacy and safety of fotemustine monotherapy. Patients and methods: Twenty-one patients with relapsing (17) or refractory (four) multiple myeloma received fotemustine 100 mg/m 2 on an outpatient basis on days 1 and 8 of the induction cycle, followed after a 6-week rest period by fotemustine 100 mg/m 2 every 3 weeks until progression or unacceptable toxicity. Fotemustine pharmacokinetics during the first day of induction was compared between patients with normal or abnormal renal function. Results: Five of 20 eligible patients had an objective response giving an intention-to-treat response rate of 25% [95% confidence interval (CI) 6% to 44%] and a 35.7% response rate (95% CI 11% to 61%) in the 14 patients having received at least four injections of fotemustine. The median time to objective response was 8.9 months. The median times to progression and survival were 13.8 and 23.1 months, respectively, with a 2-year survival rate of 49%. The main toxicity was myelosuppression with grade 3–4 neutropenia and thrombocytopenia in 66% and 71% of patients, respectively. There was one toxic death by sepsis after induction. The pharmacokinetic parameters in renal-impaired patients were not significantly different from those in patients with normal renal function with a similar incidence of grade 3–4 toxicity in both groups. Conclusions: Fotemustine as a single agent has definite activity in patients with relapsing or refractory multiple myeloma, with acceptable toxicity and can be administered at conventional doses in patients with mild or moderate renal impairment.

Summary Objectives: Retrospective evaluation of anemia frequency and its prognostic value in patients with different subtypes of nonHodgkin's lymphoma and comparison with other clinical characteristics. Patients and methods: Anemia was defined as a hemoglobin value less than or equal to 12 g/dl for all men and women over 50 years of age, and less than or equal to 11 g/dl for women under 50 years of age. The study included 1077 adult lymphoma patients treated between 1980 and 1995 with the following histologic subtypes: 127 patients with small lymphocytic or lymphoplasmacytoid, 62 with marginal zone, 50 with mantlecell, 208 with follicular, 104 with T-cell lymphoma, 426 with diffuse large-cell and, finally, 73 patients with other high-grade lymphomas. Results: Anemia was present in 341 patients (32%). It was an adverse prognostic factor (P < 0.0001) for overall survival (OS) and progression-free survival (PFS) but not for relapsefree survival (RFS). When patients with and those without bone marrow involvement were considered separately, anemia remained an adverse factor. Anemia was significantly associated with shorter PFS in small lymphocytic or lymphoplasmacytoid, mantle cell, diffuse large cell and high-grade lymphomas and with shorter OS in all histologic subgroups except marginal zone lymphoma. In multivariate analysis, anemia was a significant prognostic factor for OS and PFS for the population as a whole (P = 0.0001 and P = 0.0048, respectively) and in patients with bone marrow involvement (P - 0.007 and P 0.005, respectively) but not in patients without bone marrow involvement. Finally, the addition of anemia to the International Prognostic Index led to an improvement for OS (P — 0.0004) and PFS (P = 0.0004). Conclusions: Anemia is an important adverse prognostic factor for the outcome of lymphoma patients, particularly in some histologic subgroups and in patients with bone marrow involvement.

Mantle cell lymphoma (MCL) patients represent a difficult prob-lem, sometimes to establish the diagnosis but mostly becauseof their refractoriness to standard lymphoma treatments. Whichtreatments to apply and to whom is not yet defined. In thisstudy, we attempted to analyze the clinical features, to identifythe major prognostic factors, and to evaluate the outcome of121 MCL patients treated in our institution between 1979 and1997. Clinical data, treatment modalities, and InternationalPrognostic Index (IPI) score were evaluated. Median age was 63years. Patients usually presented with advanced stage disease(87%), disseminated lymph nodes (57%), bone marrow involve-ment (79%), but with a good performance status (PS) (81%).Lymphocytosis .4000/ml and/or peripheral blood involvementwas present in 36% of cases, and gastrointestinal disease in18%. The t(11;14)(q13;q32) and/or bcl-1 rearrangement wasdetected in 47/57 studied cases. Median overall survival (OS)was 3.12 years and a longer survival was significantly associa-ted with younger age (,70 years), good PS (,2), localized dis-ease (stage I–II), fewer than two extra-nodal sites, absence ofspleen or peripheral blood involvement, normal serum LDH andb2-microglobulin levels, and hemoglobin level greater than12 g/dl. However, the IPI failed to identify patients with longerOS and in a multiparametric analysis, only older age, hemoglo-bin less than 12 g/dl, poor PS, and blood involvement wereassociated with a poorer outcome. Treatment modalities hadno impact on survival with 75% of patients relapsing or pro-gressing. Our data showed that the poor outcome of MCLpatients is mainly related to adverse patient characteristics, ahighly disseminated tumor, and some unknown parametersassociated with the refractoriness to standard therapy.Keywords: mantle cell lymphoma; prognostic factors; outcome

Summary Background: Despite improved detection of mantle cell lymphoma (MCL), results of its treatment with conventional therapies remain disappointing and the survival rate poor. The role of high-dose chemotherapy has recently been investigated but no potential benefit has been clearly established. We report here our experience with MCL patients treated with intensive chemotherapy and autologous stem cell transplantation (ASCT). Patients and methods: Of the 16 MCL patients who received high-dose chemotherapy and ASCT beginning in 1989, six were treated in first-line and 10 in sensitive relapse. Twelve of 16 patients received regimens which included total body irradiation. All patients received peripheral blood stem cells (PBSC) with the exception of one, who underwent bone marrow transplantation. Results: Three patients died of toxic effects of treatment. Three months after transplant, seven achieved complete responses (CR) and two partial responses (PR), two were stable and two had progressed. With a median follow-up after transplant of 22 months, five of the six surviving patients were without progression, and three were in CR. The median times for event-free survival (EFS) and overall survival (OS) were, respectively, 249 and 317 days. The expected three-year EFS and OS were 24%. The median survival after diagnosis was only 29 months. None of the criteria appeared to be significantly associated with a better outcome, but first-line intensification and a short delay after initial diagnosis may be favorable. Conclusion: In this study we were not able to confirm the hypothetical benefit of high-dose chemotherapy and PBSC transplantation in mantle cell lymphoma, even though this approach may be promising in a subgroup of patient.