Rm Lowenthal

Rituximab Maintenance Therapy After Autologous Stem-Cell Transplantation in Patients With Relapsed CD20+ Diffuse Large B-Cell Lymphoma: Final Analysis of the Collaborative Trial in Relapsed Aggressive Lymphoma

PURPOSE The standard treatment for relapsed diffuse large B-cell lymphoma (DLBCL) is salvage chemotherapy followed by high-dose therapy and autologous stem-cell transplantation (ASCT). The impact of maintenance rituximab after ASCT is not known. PATIENTS AND METHODS In total, 477 patients with CD20(+) DLBCL who were in their first relapse or refractory to initial therapy were randomly assigned to one of two salvage regimens. After three cycles of salvage chemotherapy, the responding patients received high-dose chemotherapy followed by ASCT. Then, 242 patients were randomly assigned to either rituximab every 2 months for 1 year or observation. RESULTS After ASCT, 122 patients received rituximab, and 120 patients were observed only. The median follow-up time was 44 months. The 4-year event-free survival (EFS) rates after ASCT were 52% and 53% for the rituximab and observation groups, respectively (P = .7). Treatment with rituximab was associated with a 15% attributable risk of serious adverse events after day 100, with more deaths (six deaths v three deaths in the observation arm). Several factors affected EFS after ASCT (P < .05), including relapsed disease within 12 months (EFS: 46% v 56% for relapsed disease after 12 months), secondary age-adjusted International Prognostic Index (saaIPI) more than 1 (EFS: 37% v 61% for saaIPI < 1), and prior treatment with rituximab (EFS: 47% v 59% for no prior rituximab). A significant difference in EFS between women (63%) and men (46%) was also observed in the rituximab group. In the Cox model for maintenance, the saaIPI was a significant prognostic factor (P < .001), as was male sex (P = .01). CONCLUSION In relapsed DLBCL, we observed no difference between the control group and the rituximab maintenance group and do not recommend rituximab after ASCT.

Prognostic value of quality of life scores in a trial of chemotherapy with or without interferon in patients with metastatic malignant melanoma

In a multi-centre randomised clinical trial comparing dacarbazine (DTIC) plus recombinant interferon-alfa2a (IFN) versus DTIC alone for patients with metastatic malignant melanoma, aspects of quality of life (QL) were measured prospectively by patients using linear analogue self assessment (LASA) scales including the GLQ-8 and by doctors using Spitzers QL Index. QL scores and performance status at the time of randomisation were available for 152 of 170 eligible patients. These scores carried significant prognostic information. In univariate analyses, Spitzer QL Index assessed by the doctor and LASA scores for physical wellbeing (PWB), mood, pain, appetite, nausea and vomiting, GLQ-8 total and overall QL were significant (P < 0.01) predictors of subsequent survival. QL Index and LASA scales for mood, appetite, and overall QL remained independently significant (all P < 0.05) in multivariate models allowing for significant prognostic factors other than QL (liver metastases and performance status). These findings closely parallel those in patients with metastatic breast cancer. They add further validity to the QL Index and LASA scores, provide the first evidence of the prognostic significance of the GLQ-8, and argue strongly for the routine assessment of QL in future therapy trials.

GRANULOCYTE TRANSFUSIONS IN TREATMENT OF INFECTIONS IN PATIENTS WITH ACUTE LEUKÆMIA AND APLASTIC ANÆMIA

By use of the continuous-flow blood-cell separator 137 bags of granulocyte-rich plasma were obtained from normal donors (59 bags) and patients with chronic granulocytic leukaemia (C.G.L.) (78 bags). Eighty-nine courses of granulocyte transfusion therapy consisting of 1 or more such bags were administered to forty-one ABO-compatible patients with acute leukaemia or aplastic anaemia, who had definite or probable infections that had failed to respond to antibiotics. The fever resolved after 67% of courses of transfusions of two or more bags but after only 24% of transfusions of single bags of granulocytes (p less than 0-01), and this result suggests that this form of treatment is in general effective. Granulocytes from C.G.L. and normal donors were equally effective, although transfusion reactions were commoner after C.G.L. cells (33% versus 12%, respectively, p less than 0-05). C.G.L. grafts, and probable graft-versus-host disease, occurred in three recipients of unirradiated C.G.L. cells. Recipients of normal cells whose fevers resolved received on average four times as many granulocytes per sq.m. as those fevers did not respond. No such difference was found when C.G.L. cells were used. The fever was more likely to resolve in recipients with established or clinically probable bacterial or fungal infections than in those with fever of uncertain cause. Fever was less likely to resolve in recipients with peripheral blood granulocyte counts before transfusion of greater than 1000 per mul. It is concluded that granulocyte transfusion therapy is a valuable advance in the management of infections in neutropenic patients.

TOXICITY OF CHEMOTHERAPY

Because anticancer drugs are cytotoxic for normal as well as neoplastic cells, the range of unwanted effects that accompanies their use is broad. Many of the side effects are potentially life-threatening or seriously debilitating. Many are similar to, and readily confused with, direct or indirect (paraneoplastic) consequences of the cancer itself. Recognition of drug side effects is vital for optimal patient care, because early withdrawal of the offending agent and institution of appropriate treatment have the potential to significantly reduce the overall morbidity and mortality associated with the diagnosis of cancer.

Fucoidan and Cancer: A Multifunctional Molecule with Anti-Tumor Potential

There is a wide variety of cancer types yet, all share some common cellular and molecular behaviors. Most of the chemotherapeutic agents used in cancer treatment are designed to target common deregulated mechanisms within cancer cells. Many healthy tissues are also affected by the cytotoxic effects of these chemical agents. Fucoidan, a natural component of brown seaweed, has anti-cancer activity against various cancer types by targeting key apoptotic molecules. It also has beneficial effects as it can protect against toxicity associated with chemotherapeutic agents and radiation. Thus the synergistic effect of fucoidan with current anti-cancer agents is of considerable interest. This review discusses the mechanisms by which fucoidan retards tumor development, eradicates tumor cells and synergizes with anti-cancer chemotherapeutic agents. Challenges to the development of fucoidan as an anti-cancer agent will also be discussed.

Prospective randomised trial of amifostine cytoprotection in myeloma patients undergoing high-dose melphalan conditioned autologous stem cell transplantation

Summary:In this prospective multicentre trial, 90 patients undergoing autologous stem cell transplantation (ASCT) were randomised to receive (n=43) or not receive (n=47) amifostine 910 mg/m2 prior to melphalan 200 mg/m2. Patients were monitored for regimen-related toxicity, engraftment, supportive care, response and survival. Both groups underwent ASCT at a median of 8 months from diagnosis and were matched for disease characteristics, prior therapy and pre-ASCT disease responsiveness. Amifostine infusional side-effects were frequent, occurring in 65% of patients, but of mild severity. Amifostine use was associated with a reduction in the median grade of oral mucositis (1 vs 2, P=0.01) and the frequency of severe (WHO grades 3 or 4) mucositis (12 vs 33%, P=0.02), but no reduction in the requirement for parenteral nutrition or analgesic use. Conversion to complete remission post-ASCT occurred in 30 and 14% of the amifostine and control groups, respectively (P=0.09). With a median follow-up of 35 months, there was no statistically significant difference between the median progression-free or overall survival times for the two groups. We conclude that amifostine can be safely administered prior to high-dose melphalan and significantly reduces the frequency and severity of therapy-induced oral mucositis.

Intensified Induction Chemotherapy with High Dose Cytarabine and Etoposide for Acute Myeloid Leukemia: A Review and Updated Results of the Australian Leukemia Study Group

Induction therapy of acute myeloid leukemia (AML) with standard dose chemotherapy will result in approximately 55-75% of patients achieving a complete remission (CR). Intensification of induction treatment with etoposide and high dose cytarabine does not alter the CR rate but appears to significantly improve the subsequent outcome. Updated results of the comparison of high dose cytarabine with daunorubicin and etoposide in induction (HIDAC-3-7) versus a standard dose combination (7-3-7) demonstrated a highly significant increase in relapse free survival, (RFS) on the high dose arm (p = 0.007) with RFS of 48% at 5 years with HIDAC-3-7 and 25% on 7-3-7. The high dose arm had a more modest survival advantage at 5 years of 33% compared with 25% on standard treatment, possibly because of a higher initial death rate with HIDAC-3-7. The improvement seen in patients with CR after high dose induction appear to parallel results obtained with post-remission therapies intensified with high dose cytarabine. These studies provide clinical evidence that a dose-response effect is present for cytarabine in AML. Intensified treatment is more toxic, gives more profound myelosuppression post-remission and has been shown to benefit younger patients only. Issues of patient selection and the optimal placement of intensification in the treatment sequence require further study. In the future, it is likely that remission duration may be a useful clinical tool to study the influence of new induction therapies on residual resistant leukemia.

Pilot clinical study to evaluate the anticoagulant activity of fucoidan

Seaweed-derived heparin-like substances such as fucoidan have been extensively studied in vitro as potential blood anticoagulants. However, there have been no human studies investigating the anticoagulant activity of fucoidan when administered orally. This pilot clinical trial was aimed to assess the safety and clinical effects of fucoidan ingestion on hemostasis as well as study its in-vitro anticoagulant activity. In a single-blinded clinical trial, a total of 20 human volunteers were allocated to both the placebo group (n = 10) who ingested 3 g of guar gum capsules and to the active treatment group (n = 10) who ingested 3 g of 75% fucoidan capsules for 12 days. Platelet indices, activated partial thromboplastin time, antithrombin-III, thrombin time, prothrombin time, and antifactor-Xa were analyzed according to standard methods. In vivo, activated partial thromboplastin time increased from 28.41 to 34.01 s (n = 10, P = 0.01), thrombin time decreased from 18.62 to 17.55 s (n = 10, P = 0.04), and antithrombin-III increased from 113.5 to 117% (n = 10, P = 0.03). The in-vitro fucoidan anticoagulant activity was found prominent. It increased activated partial thromboplastin time, thrombin time, and prothrombin time, whereas antithrombin-III decreased. In-vivo effect of fucoidan on hemostasis was not obvious probably due to low intestinal absorption. Thus, fucoidan in the form used in this study does not seem to have an oral anticoagulant activity, but it has a very strong in-vitro anticoagulant activity.

Residential exposure to electric power transmission lines and risk of lymphoproliferative and myeloproliferative disorders: a case–control study

Background: Studies have shown an association between electromagnetic fields and childhood leukaemia. The aim of this study was to determine whether there is an increased risk of lymphoproliferative disorders (LPD) or myeloproliferative disorders (MPD) associated with residence ≤300 m from high‐voltage power lines.

Effect of CD34 cell dose on hematopoietic reconstitution and outcome in 508 patients with multiple myeloma undergoing autologous peripheral blood stem cell transplantation.

Background: We analyzed the hematopoietic reconstitution and outcome of 508 patients with multiple myeloma (MM) with respect to the number of CD34+ cells reinfused at our center. Patients and methods: Each cohort of 390 patients (unselected CD34+ cell transplant) and 118 patients (CD34+ selected transplant) was divided into four subgroups. Among the 390 transplantations, 86 patients received a high dose (HD−) of ≥6.50 × 106 unselected CD34+ cells/kg, 116 patients a low dose (LD−) of <3.00 × 106 CD34+ cells/kg. Among the patients treated with CD34+ selected PBSC, 34 received ≥6.50 × 106 CD34+ cells/kg (HD+) and 16 <3.00 × 106 CD34+ cells/kg (LD+). Results: HD− patients experienced a reduced median time to leukocyte (13 d vs. 14 d) (P < 0.001) and platelet reconstitution >20 × 109/L (10 d vs. 12 d) (P < 0.001). Similarly, HD+ showed a reduced median time to leukocyte (12 d vs. 15 d) (P < 0.001) and platelet recovery >20 × 109/L (10 d vs. 11 d) (P = 0.058). CD34+ cell‐dose was significant for long‐term platelet recovery at day 360 (unselected transplant P = 0.015, selected transplant P = 0.023). Number of transplanted CD34+ cells had no significant impact on transplant related mortality, overall survival or CR/PR rates within 100 d. In terms of supportive care the differences of high‐/low‐dose grafts were minimal. Conclusions: These results confirm that high doses of CD34+ PBSC shorten hematopoietic reconstitution and reduce hospitalization. Nevertheless secure engraftment results from transplantation of 2.00–3.00 × 106 CD34+ cells/kg. As 60% of our pretreated patients are able to collect ≥5.00 × 106 CD34+ cells/kg within a single leukapheresis, division into two or more freezing bags allows safe tandem transplantation in the majority of MM patients.