5-Aza-2'-deoxycytidine (Decitabine) induces trilineage response in unfavourable myelodysplastic syndromes.

The preliminary results of a disease-oriented phase I-II study aimed at evaluating the clinical activity of 5-aza-2'-deoxycytidine (Decitabine) in patients affected by advanced myelodysplastic syndromes (MDS) are reported. Two patients affected by refractory anemia with excess of blasts (RAEB) and eight with RAEB in transformation (RAEB-T) were treated with Decitabine at a daily dose of 45 mg/m2, divided into three 4 h infusions for 3 days (six patients) or as continuous infusion of 50 mg/m2 for 3 days (four patients). Treatment with Decitabine resulted in a significant increase in circulating neutrophils, platelets, and hemoglobin with respect to pretreatment values in over 50% of patients. These changes were accompanied by the improvement of the marrow myeloid relative differentiation index (median fivefold increase in the whole group of patients) and of the myeloid to erythroid cell ratio (median twofold increase) in most of the patients. In four out of ten patients a complete normalization of peripheral blood (PB) and bone marrow (BM) picture (complete hematologic response) was obtained. The evaluation of the percentage of CD34-positive BM cells showed a slow but progressive reduction of early leukemic progenitors in most of the patients. A transient slight BM hypoplasia was obtained in less than 50% of patients while a severe marrow aplasia was never observed in our group of MDS patients during treatment with Decitabine. Extra-hematological toxicity was very mild in all the patients. The preliminary results of our study indicate that Decitabine is able to induce trilineage hematological responses in advanced MDS patients along with a stable normalization of the PB and BM picture in some of the subjects. Decitabine appears an active agent in advanced MDS and this deserves careful investigation in this heterogeneous group of disorders.

Antithrombin III deficiency as a risk factor for catheter-related central vein thrombosis in cancer patients.

The fibrin sleeve of venous catheters (VC) and parietal thrombi represent frequent and dangerous side-effects of central venous catheterization (CVC), due to the risk of embolism. Reduced levels of coagulation clotting factors inhibitors (such as Antithrombin III) are known to be associated with increased thrombogenic risk. The aim of this study was to evaluate the role of Antithrombin III (AT III) deficiency as a risk factor for thrombosis in cancer patients undergoing CVC. The study groups included patients with a reduced AT III activity (< 70%, 20 consecutive patients) and with normal AT III values (> 70%, 20 randomly selected patients), requiring a VC for chemotherapy and/or total parenteral nutrition. The study protocol included evaluation of Hb, PLTs, PT (INR), aPTT, Fibrinogen and AT III at days 0, 1, 3 and 8 after CVC and upon VC removal. Peripheral and pullout phlebographies were performed in all patients on catheter withdrawal. A quantitative scale was developed to evaluate both VC and parietal thrombus degree in each catheter-containing venous segment (subclavian, innominate, superior vena cava); the sum of the mean values was defined as overall thrombus. The average VC dwelling time was similar in both groups. There were no significant differences in Hb, PLTs, PT (INR), aPTT, Fibrinogen and in the remaining parameters of the study between the two groups. The group with AT III deficiency presented a higher degree of both parietal (p < 0.05) and overall thrombus (p < 0.02). Data showed a higher severity of CVC-related thrombosis in patients with AT III deficiency than in the control group. Further studies are needed to evaluate whether the therapeutically-induced normalization of AT III levels can reduce the thrombosis degree.

Treatment of multiple myeloma and acute myelogenous leukemia in the elderly: an update.

The optimal management of hematopoietic malignancies in the elderly requires the development of specific therapeutic strategies based on the peculiar clinico-biologic features of aged patients. Multiple myeloma arising in elderly patients remains at this time an incurable disease, while attention to supportive therapy and palliation can make a great impact on the quality of life. Fortunately advances have been made in last years in this field. Therapy at the time of diagnosis is usually recommended for patients with symptomatic disease, or for those who may be asymptomatic, but have evidence of high tumor burden of a biologically aggressive disease, and may be expected to progress and develop complications over a short period of time. Melphalan combined with prednisone remains the standard therapy choice in elderly patients. Radiotherapy maintains an important place in the palliation of destructive bone disease in poorly controlled myeloma, particularly in elderly patients. In Acute Myelogenous Leukemia, age has been concordantly reported as an adverse prognostic indicator in affecting both remission rates and survival. The overall unsatisfactory therapeutic results appear connected with host-related factors, and intrinsic differences in the biology of leukemia. Patients with standard risk should be included in collaborative trials aimed at improving the long-term results of conventional therapy. Patients with high risk and unfavorable prognostic factors, could be enrolled in controlled studies aimed at better assessing, in the elderly, the long term results of newer drug combinations. A watch and wait strategy, consisting of transfusion support and leukocytosis control, should be limited to patients with extremely poor performance status (PS), very limited life-expectancy and/or severe comorbidity displaying unfavorable biologic factors, including secondary Acute Myelogenous Leukemia.

Cost-benefit of granulocyte colony-stimulating factor administration in older patients with non-Hodgkin's lymphoma treated with combination chemotherapy.

BACKGROUND: Older patients with non-Hodgkin's lymphoma (NHL) display a poorer response to chemotherapy and a significantly higher treatment-associated toxicity than do younger individuals. We investigated the potential clinical benefits and the cost-effectiveness of accelerated granulocyte recovery induced by recombinant granulocyte colony-stimulating factor (G-CSF) in patients with aggressive NHLs, aged 60-70 years, during treatment with a second-generation combination chemotherapy. PATIENTS AND METHODS: 12 consecutive patients (median age 66 years) treated with six to eight courses of CHVmP/VB plus subcutaneous G-CSF (5 micrograms/kg/day) were compared with 11 consecutive subjects (median age 65 years) who received the same chemotherapy regimen without growth factor support. The two groups of patients were fully comparable as to the clinicopathologic features. A comparative analysis of treatment costs (including hospitalization, antimicrobial prophylaxis and therapy, supportive and diagnostic procedures, and G-CSF) was also performed. RESULTS: Both the overall response rate and the percentage of complete remissions were comparable in the two treatment groups. In the control group, 32.5% of chemotherapy courses were delayed, as opposed to 19% in the G-CSF group (p = 0.05). The mean duration of delay for patients receiving or not receiving G-CSF was 10.1 and 25.9 days, respectively (p = 0.02). Grade 3 and 4 granulocytopenia complicated 27.7% of chemotherapy courses in control patients and only 4.8% in subjects receiving G-CSF (p < 0.001). Similarly, severe infections and mucositis were significantly higher in patients receiving chemotherapy alone (15.6% and 3.6%, respectively) compared to the G-CSF group (4.8%, p = 0.01; p = 0.04, respectively). A mean of 1.1 days/course of hospitalization was required in the control group, as opposed to 0.2 days/course in patients receiving G-CSF (p = 0.05). Although overall treatment costs were higher in the control group, single cost of the recombinant growth factor exceeded by far all the other expenses in the G-CSF group, reaching a statistical relevance (p = 0.01). CONCLUSIONS: The inclusion of prophylactic G-CSF in the treatment plan for aggressive NHL in older patients appears safe and cost-effective in view of the peculiar clinical features of aged subjects and the possibility of delivering effective doses of antineoplastic drugs on an outpatient setting.

Gastroduodenal involvement in staging of nodal non-Hodgkin lymphomas: a clinical and endoscopic prospective study of 235 patients.

OBJECTIVES: The gastrointestinal tract is often the site of involvement of non-Hodgkin lymphomas (NHL). The aim of this endoscopic prospective study was to verify the prevalence of the gastroduodenal involvement in patients in staging for NHL and to assess its impact on the choice of therapeutic strategies. METHODS: Two hundred and thirty-five consecutive patients were included in the study. Upper gastrointestinal endoscopy was performed, and biopsy samples were taken on every mucosal lesion and on macroscopically illness-free duodenal and gastric mucosa. The samples were submitted to histological examination, and the clinical stage of NHL was reevaluated. RESULTS: Sixty-one of the 235 patients exhibited histological involvement of gastric (40), duodenal (7), or both (14) mucosae. Endoscopic lesions were recorded in 51 patients, but the involved mucosa appeared macroscopically normal in 10 patients (16.3%). In 13 patients, the gastroduodenal involvement modified the clinical stage from I and II to III, indicating a different therapeutic approach. No difference was detected in the frequency of gastrointestinal involvement among the high, intermediate, and low grades of lymphoma malignancies. Thirty-five positive patients underwent a further endoscopic examination after the chemotherapy treatment. Although clinical remission was expected in all cases, 42.8% of them subsequently exhibited NHL. CONCLUSIONS: Upper digestive endoscopy plus biopsy sampling plays a necessary diagnostic role, not only when major clinical signs (hemorrhage) are present, but also in earlier stages of NHL (I and II), when a reevaluation of the therapeutic strategy may be indicated. In stages III and IV of illness, it may also prove useful in evaluating the efficacy of chemotherapy.

Burkitt's lymphoma in adults with and without human immunodeficiency virus infection: a single-institution clinicopathologic study of 75 patients.

BACKGROUND: Burkitt's lymphoma (BL) accounts for 1-2% of all cases of non-Hodgkin's lymphoma (NHL) in the general population and for 35-40% in the setting of human immunodeficiency virus (HIV) infection. The authors report a 9-year single-institution experience with 75 adult BL patients (46 with and 29 without HIV infection) and compare the clinical and pathologic features of the disease in the two groups of patients. METHODS: Between May 1987 and June 1995, 131 patients with HIV infection and systemic NHL were diagnosed and treated at the National Cancer Institute in Aviano, Italy. In 46 cases (35%), the diagnosis was BL. During the same period, 29 of 1004 HIV negative NHL patients (2.8%) were diagnosed with BL and treated at the same institution. RESULTS: No statistical differences were found in the general characteristics of the two groups at the time that BL was diagnosed. Complete response rate was significantly lower for patients with HIV infection than for those without HIV infection (40% vs. 65%, P = 0.03). The median overall survival was significantly shorter for patients with HIV infection (7 months vs. not yet reached, P = 0.0001). However, the disease free survival (DFS) at 4 years was identical for the two groups of patients (74% for HIV positive patients vs. 73% for HIV negative patients, P = 0.70). CONCLUSIONS: The data from this study show that patients with BL with and without HIV infection share similar clinicopathologic characteristics at presentation. Although the median overall survival is significantly shorter for patients with HIV infection, the DFS is identical for both groups.

Human granulocyte-macrophage colony-stimulating factor supports the clonogenic growth of B-lineage acute lymphoblastic leukemias expressing myeloid antigens.

The effects of granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-3 and IL-6 on clonogenic growth of blast-cell progenitors from 19 immunologically defined CD10-positive B-lineage acute lymphoblastic leukemias (ALL) coexpressing (My+ALLs) or not (My-ALLs) myeloid antigens have been studied. Our results demonstrate that GM-CSF was able to support the clonogenic growth of blast cells from My+ALLs, being totally ineffective on My-All samples. Accordingly, both alpha and beta chains of GM-CSF receptor (R) were expressed by My+ALL blasts, as investigated by reverse-transcriptase polymerase chain reaction (RT-PCR). Colony cells from GM-CSF-stimulated My+ALL cultures displayed the same immunophenotype as primary leukemic cells at diagnosis (CD10+, CD19+, CD22+), and retained the expression of myeloid-associated antigens and of GM-CSF-R transcripts. Moreover, My+ALL blasts showed a preferential sensitivity to the growth-promoting activity of IL-3 and IL-6, as compared with My-ALL cells. In addition to rearrangements of the JH region of immunoglobulin genes, My+ALL cells showed aberrant rearrangements of gamma (three cases) and beta (two cases) T-cell receptor genes, as well as of bcr sequences (three cases). Our data, showing an unexpected cross-lineage response of My+ALLs to GM-CSF, and their preferential stimulation by IL-3 and IL-6, as compared with My-ALLs, further support the concept that My+ALLs represent a separate entity with unique biological features.

CD30 ligand is frequently expressed in human hematopoietic malignancies of myeloid and lymphoid origin.

CD30 ligand (CD30L) is a type-II membrane glycoprotein capable of transducing signals leading to either cell death or proliferation through its specific counterstructure CD30. Although several lines of evidence indicate that CD30L plays a key role as a paracrine- or autocrine-acting surface molecule in the deregulated cytokine cascade of Hodgkin's disease, little is known regarding its distribution and biologic significance in other human hematopoietic malignancies. By analyzing tumor cells from 181 patients with RNA studies and immunostaining by the anti-CD30L monoclonal antibody M80, we were able to show that human hematopoietic malignancies of different lineage and maturation stage display a frequent and broad expression of the ligand. CD30L mRNA and surface protein were detected in 60% of acute myeloid leukemias (AMLs), 54% of B-lineage acute lymphoblastic leukemias (ALLs), and in a consistent fraction (68%) of B-cell lymphoproliferative disorders. In this latter group, hairy cell leukemia and high-grade B-cell non-Hodgkin's lymphoma (B-NHL) expressed a higher surface density of CD30L as compared with B-cell chronic lymphocytic leukemia and low-grade B-NHL. Purified plasmacells from a fraction of multiple myeloma patients also displayed CD30L mRNA and protein. A more restricted expression of CD30L was found in T-cell tumors that was mainly confined to neoplasms with an activated peripheral T-cell phenotype, such as T-cell prolymphocytic leukemia, peripheral T-NHL, and adult T-cell leukemia/lymphoma. In contrast, none of the T-lineage ALLs analyzed expressed the ligand. In AML, a high cellular density of CD30L was detected in French-American-British M3, M4, and M5 phenotypes, which are directly associated with the presence on tumor cells of certain surface structures, including the p55 interleukin-2 receptor alpha-chain, the alpha(M) (CD11b) chain of beta2 integrins, and the intercellular adhesion molecule-1 (CD54). Analysis of normal hematopoietic cells evidenced that, in addition to circulating and tonsil B cells, a fraction of bone marrow myeloid precursors, erythroblasts, and subsets of megakaryocytes also express CD30L. Finally, we have shown that native CD30L expressed on primary leukemic cells is functionally active by triggering both mitogenic and antiproliferative signals on CD30+ target cells. As opposed to CD30L, only 10 of 181 primary tumors expressed CD30 mRNA or protein, rendering therefore unlikely a CD30-CD30L autocrine loop in human hematopoietic neoplasms. Taken together, our data indicate that CD30L is widely expressed from early to late stages of human hematopoiesis and suggest a regulatory role for this molecule in the interactions of normal and malignant hematopoietic cells with CD30+ immune effectors and/or microenvironmental accessory cells.