Refractory diffuse large B-cell lymphoma after first-line immuno-CT: Treatment options and outcomes.

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 <65 years who achieved a CR, autologous stem-cell transplant was associated with higher 2-year OS (90% vs 74%, P = 0.10). Patients who were treated with a targeted therapy in the context of a clinical trial after second-line treatment had a higher 2-year OS (34% vs 19%, P = 0.06). In conclusion, patients with primary refractory disease or early relapse have very poor outcomes but may benefit from rituximab retreatment during the first salvage treatment.

Phase I/II trial of a P-glycoprotein inhibitor, Zosuquidar.3HCl trihydrochloride (LY335979), given orally in combination with the CHOP regimen in patients with non-Hodgkin's lymphoma.

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.

Profiles and prognostic values of serum LDH isoenzymes in patients with haematopoietic malignancies.

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.