Adolfo Porcellini

Randomized study of chlorambucil (CB) compared to interferon (alfa-2b) combined with CB in low-grade non-Hodgkin's lymphoma : an interim report of a randomized study

Alpha interferon has shown initial promise in the treatment of low-grade non-Hodgkins lymphoma (NHL), especially with the nodular form of the disease. The present study enrolled 70 NHL patients who received either chlorambucil (CB; 10 mg/day) or CB plus interferon alfa-2b (5 million units (MU)/m2 subcutaneously three times a week). Among 63 evaluable patients, similar response rates (62.1% and 64.7% respectively) were recorded for the treatment arms. In patients receiving no maintenance therapy, those who received interferon alfa-2b during the induction phase showed a favourable trend in terms of incidence of relapse compared to those who had received chlorambucil alone. During maintenance therapy with interferon alfa-2b, no significant differences in the occurrence of relapse have yet been seen compared to patients on no maintenance therapy. A longer observation period is needed to make a definitive conclusion about the usefulness of interferon maintenance therapy and to evaluate further the effects of the combined schedule of chlorambucil and interferon induction on the duration of remission.

The Impact of Progenitor Enrichment, Serum, and Cytokines on the Ex Vivo Expansion of Mobilized Peripheral Blood Stem Cells: A Controlled Trial

The aim of this study was to verify, and possibly improve, culture conditions to expand human mobilized peripheral blood stem cells (PBSCs). We investigated the role of three parameters: A) the culture medium (serum‐free versus serum‐dependent); B) the initial cell population (Ficoll‐separated mononucleated cells versus CD34+‐selected cells), and C) the low concentration of recombinant cytokines, flt3 ligand, and thrombopoietin in association with a basic cocktail of stem cell factor, interleukin (IL)‐6, IL‐3, GM‐CSF, and erythropoietin. Eighteen leukapheresis samples were monitored in static culture for 15 days. The expansion potential was assessed at day 10 and 15 by total nuclear cells, colony‐forming‐units (CFUs) (burst‐forming units‐erythroid [BFU‐E], colony‐forming units‐granulocyte‐macrophage [CFU‐GM], and colony‐forming units‐granulocyte‐erythroid‐macrophage‐megakaryocyte [CFU‐GEMM]), and flow cytometry immunophenotyping (CD34+/CD38−, CD38+, CD33+, CD41+, GlyA+ progenitor cells). The results, evaluated by multivariate analysis of variance, emphasize that some variables affected the outcome of stem and progenitor cell expansion. CD34+ enrichment increased expansion of total nuclear cells, number of CD38+ and CD33+ late precursors, and number of the CFU‐GM compartment. Interestingly, however, quantitative expansion of GlyA+ and the early progenitor cells (CD34+/CD38−, CFU‐GEMM, BFU‐E) are favored by the use of unselected mononucleated cells. Regarding the role of serum, no significant difference was observed except for expansion of total nuclear cells, CFU‐GM, and BFU‐E. Cytokine combinations, in particular the use of flt3 ligand, stimulated expansion of almost all the cellular subsets, reaching a statistical significance for total nuclear cells and CFU‐GM. Our study indicates that progenitor and late precursor multilineage cell compartments of mobilized PBSCs may be significantly expanded in short‐term cultures by well‐defined experimental conditions. Furthermore, these data might be useful when evaluating ex vivo expansion of hematopoietic cells for clinical purposes.

Autologous bone marrow transplantation for advanced stage adult lymphoblastic lymphoma in first complete remission

Thirty-six successive adult patients with lymphoblastic lymphoma entered a study of sequential chemotherapy consisting of an intensive LSA2-L2-type protocol to induce first complete remission. Eighteen patients in first CR (median age 22 years, range 15–51), underwent autologous bone marrow transplantation after receiving a conditioning regimen consisting of cyclophosphamide and total body irradiation. Of these 18 patients, 2 were in stage III and 16 in stage IV; 15 showed mediastinal and 9 bone marrow involvement at diagnosis. The transplant procedure was well tolerated and no treatment-induced deaths occurred. At this time, 14 out of 18 patients are alive and well between 1 and 60 months post transplant (median follow-up time 46 months) with an actuarial disease-free survival of 74%. This phase II study suggests that high-dose chemo-radiotherapy followed by autologous bone marrow transplantation may improve long-term disease-free survival in advanced stage adult lymphoblastic lymphoma.

A method for the removal of endotoxin from purified colony-stimulating factor.

Summary Limulus lysate assays showed that several samples of purified L-cell CSF were markedly contaminated with endotoxin. Several pools of material contained 1 to 10 μg/ml of this bacterial lipopoly-saccharide. Ultracentrifugation in sucrose density gradients led to a 95% separation of CSF and endotoxin activities. In four studies, endotoxin content of the CSF preparations was reduced to levels varying from 0.05 to 0.0001 μg/ml. In vivo studies with known quantities of E. coli endotoxin were conducted in mice. Acute and repeated injections of 0.1 μg of endotoxin led to increased serum CSF activity and increased number of splenic CFU-C and CFU-E. In contrast, similar injections of 0.01 μg of endotoxin produced virtually no effect on these parameters of hemopoiesis. Thus, the removal of endotoxin from CSF as outlined herein will permit in vivo studies of the effects of CSF on hemopoiesis, without concern for the complicating effects of endotoxin. The authors gratefully appreciate the excellent technical assistance of Florence Boegel, Lea Einsporn, and Francine C. Levin.

Cemp, A Mitoxantrone Containing Combination, in the Treatment of Intermediate and High Grade Non-Hodgkin's Lymphoma: an Effective and Non Toxic Therapeutic Alternative for Adult and Elderly Patients: On behalf of Non-Hodgkin's Lymphoma Co-operative Study Group (NHLCSG)

Here we report the results of a randomised multicenter phase III clinical trial which assesses the therapeutic efficacy and tolerability of a chemotherapy protocol CEMP (cyclophosphamide, etoposide, mitoxantrone and prednisone) in adult and elderly patients with advanced intermediate and high-grade NHL. Between October 1991 and October 1995, 139 patients, aged 55 to 79 years, with diffuse intermediate and high-grade lymphoma, were enrolled. A considerable percentage of patients had clinically aggressive disease: 32.4% had systemic symptoms, 79% had stage III or IV disease, 33.8% had bone marrow involvement, 46% had splenic involvement and 42.5% had increased values of serum lactate dehydrogenate. Complete remission was achieved in 70 of the 139 patients (51.9%) and PR in 12 (16.6%) with an overall response of 68.5%. The overall response survival rate at 6 years was 39%, whereas DFS rate was 48.7% and PFS rate was 28.5%. At four years 49% of the patients were still in CR. Dividing the patients in two groups, under and over 65 years of age, we obtained the same results as far as overall response is concerned. No toxic deaths occured, neither cardiac, renal nor liver complications happened. CEMP regimen is an effective and safe protocol with good results in elderly people, well comparable to those achieved in younger ones.

Kinetics of erythroid cell precursors in the newborn rat.

Summary The kinetics of erythroid proliferation have been studied in the newborn rat of different ages by the method of 3H-Tdr-labeled mitoses. The experimental results have been analyzed by the method of Steel and Hanes (7). A generation time of 10 hr has been obtained in the adult rats for the proerythro-blasts and basophilic erythroblasts, while in the newborn rat the generation time for the same cells was found to be of the order of 7.5 hr. It has been shown that these reductions are mainly due to decrease in the duration of G1 and G2 phases. The possibility is suggested that the shorter cell-cycle of the erythroid cells could, at least in part, account for the erythroid hyperplasia observed in the rat during the first 2 weeks of life.

T- Lymphoblastic lymphoma in adults

O linfoma linfoblastico de celula T e raro e com prognostico ruim. Apos introducao de terapeutica quimioterapica sequencial e intensificada, remissoes completas passaram a ser obtidas em 75%-95% dos pacientes. Entretanto, muitos pacientes, particularmente aqueles com a chamada doenca avancada, continuaram a recair tanto durante a terapia de inducao como na manutencao. Alem disso, todos estes estudos iniciais nao foram capazes de detectar qualquer indice prognostico capaz de prever a evolucao dos pacientes. No sentido de reduzir as taxas de recidiva, o transplante autologo de celula progenitora hematopoetica em pacientes em remissao completa foi introduzido. Os resultados obtidos com esta abordagem foram bastante homogeneos, indicando uma probabilidade de sobrevida livre de doenca de 65%-75% e uma sobrevida global de 60%. Sucessivos tratamentos desenhados ja nos anos 2000, foram capazes de obter remissoes completas acima de 90%, com taxas de recidivas da ordem de 30% e uma sobrevida global comparavel a obtida com o transplante. Ainda, estes estudos tambem nao foram capazes de detectar fatores prognosticos relacionados a evolucao validos. Mais ainda, qualquer estudo com perfil biologico foi desenvolvido. Para melhorar o prognostico do LLB-T parece ser necessario esforco multicentrico, de carater nacional ou internacional, para coletar dados clinicos e biologicos. Nesta linha, e possivel alcancar numero critico de dados com valor estatistico que poderiam ser capazes de detectar fatores com influencia prognostica. Finalmente, grupos de pacientes necessitam ser identificados para selecionar aqueles que poderiam se beneficiar do transplante de celula progenitora hematopoetica detectados ao diagnostico.