Non-Hodgkin's lymphoma in very elderly patients over 80 years. A descriptive analysis of clinical presentation and outcome.

BACKGROUND: Non-Hodgkin's lymphoma (NHL) in patients older than 80 years is not a rare disease and treatment strategies are often difficult because of associated comorbidities. PATIENTS AND METHODS: We entered 205 NHL patients older than 80 years treated in a single institution in a retrospective analysis to describe clinical presentation and outcome and to identify specific prognostic factors. RESULTS: The median age was 83 years, and 91% of the cases were B-cell lymphomas consisting mainly of diffuse large B-cell lymphoma and marginal zone lymphoma. Among patients presenting comorbidities (87%), Charlson index was low in almost half of the patients (43%). Patients did not receive any treatment or received corticosteroids alone in 15%, surgery, radiotherapy, or monochemotherapy in 35%, polychemotherapy without anthracycline in 18%, and anthracycline based in 32%. Median overall survival was of 2.2 years. Main reason for death was disease progression (57%). Independent prognostic factors of survival were poor performance status (P < 10(-4)) and high lactate dehydrogenase level (P < 10(-5)). Comorbidities were not found to influence survival. CONCLUSIONS: Very elderly NHL patients showed similar features and prognostic factors than younger patients. Death was related mainly to the disease, meaning that these patients should be more frequently treated with standard treatments.

Subclinical late cardiomyopathy after doxorubicin therapy for lymphoma in adults.

PURPOSE: To assess the cardiac status of the long-term survivors and to estimate the incidence and the features of subclinical cardiotoxicity induced after conventional treatment with doxorubicin for non-Hodgkin's lymphoma or Hodgkin's lymphoma. PATIENTS AND METHODS: We analyzed a group of patients who previously received doxorubicin-based chemotherapy for lymphoma. Echocardiograms were performed at least 5 years after therapy with anthracyclines. Clinical cardiomyopathy was defined by the presence of clinical signs of congestive heart failure (CHF). Subclinical cardiomyopathy was defined by decrease of left ventricular fractional shortening (FS) without clinical signs of CHF. Cumulative dose of doxorubicin, male sex, older age, relapse, radiotherapy (mediastinal or total-body irradiation), autologous stem-cell transplantation, high-dose cyclophosphamide, and cardiovascular risk factors (hypertension, diabetes, hypercholesterolemia, familial history of cardiac disease, being overweight, and smoking history) were evaluated as potential risk factors for the development of cardiac dysfunction. RESULTS: Of 141 assessable patients (median age, 54 years; median cumulative dose of doxorubicin, 300 mg/m(2)), only one developed CHF. Criteria of subclinical cardiomyopathy were found in 39 patients. In multivariate analysis, factors that contributed to decreased FS were male sex (P <.01), older age (P <.01), higher cumulative dose of doxorubicin or association with another anthracycline (P =.04), radiotherapy (P =.04), and being overweight (P =.04). CONCLUSION: Cardiac abnormalities can occur in patients treated with doxorubicin for lymphoma in the absence of CHF, even in patients who received moderate anthracycline doses. Male sex, older age, higher dose of doxorubicin, radiotherapy, and being overweight were risk factors for the development of cardiomyopathy.

A prospective study of intensive induction therapy with high-dose consolidation in patients with aggressive non-Hodgkin's lymphoma and two or three adverse prognostic factors.

Patients with NHL and two or three factors of the International Prognostic Index (IPI) have a poor prognosis. We performed a prospective trial of intensive induction therapy followed with high-dose consolidation in such patients to determine the feasibility of this approach, as well as the response rate and survival. Untreated patients with aggressive lymphoma under the age of 60 with two or three adverse prognostic factors (disseminated stage, increased serum LDH, ECOG performance status >1) were prospectively included between June 1995 and April 1998 in a trial evaluating intensive induction chemotherapy with the ACE regimen (adriamycin day 1; cyclophosphamide days 1-2; etoposide days 1-3), with G-CSF support. Patients in complete remission after induction received one course of intensification with stem cell support (BEAM regimen), whereas patients in partial response received two intensifications (BEAM, then ICE regimens). Thirty-three patients (median age 38 years) were included. All patients presented WHO grade 4 leukopenia and 84% grade 3-4 thrombocytopenia during induction. There was one toxic death during induction. Twenty-nine patients proceeded to high-dose consolidation, including 12 patients who received a second high-dose treatment. The overall response rate was 88% (95% CI 76-99%), both after induction therapy and treatment completion. Thirty-nine percent of the patients had achieved complete remission after induction, and 73% after treatment completion. With a median follow-up after treatment onset of 29 months, the projected 3-year overall survival was 71% (95% CI 64-78%) and the event-free survival 58% (95% CI 50-66%). Event-free survival was significantly shorter in patients who did not achieve CR after induction therapy or after treatment completion. Early therapeutic intensification after intensive induction chemotherapy is feasible in patients with poor prognosis aggressive NHL and shows promising response and survival rates.

Peripheral blood stem cells harvested after chemotherapy and GM-CSF for treatment intensification in patients with advanced lymphoproliferative diseases.

Peripheral blood stem cells (PBSC) from 15 patients with advanced non-Hodgkin's lymphoma (NHL), two patients with chronic lymphocytic leukemia, and two patients with myeloma were collected by continuous-flow leukapheresis after chemotherapy with MIV (mitoxantrone, ifosfamide, and etoposide, five patients) or high-dose cyclophosphamide (14 patients), followed by administration of GM-CSF. Sixteen patients (84%) had persistent marrow involvement at time of inclusion. Results were compared to those obtained in a control group of similar age and disease status in whom collection had been performed after MIV chemotherapy alone. The number of mononuclear cells, granulocyte-macrophage colony-forming units (CFU-GM), CD34+ cells were higher in GM-CSF treated patients with a lower mean number of leukapheresis (3.5 versus 6.4). Among the 19 patients harvested after chemotherapy plus GM-CSF, more progenitor cells were obtained in the cyclophosphamide group than in the MIV group. In all these patients except one, the number of mononuclear cells was sufficient to realize a transplantation. Seventeen patients received intensification with BEAM regimen (8 patients) or cyclophosphamide plus etoposide and total body irradiation (9 patients). Two patients failed to reconstitute correct hematopoiesis and three early toxic deaths occurred for a total of five procedure-related deaths. Nine of these 17 patients are in persistent complete remission with a median post-transplant follow-up of 18 months. Time to reach granulocyte and platelet recovery was not correlated with the number of mononuclear cells, CFU-GM, granulocyte-erythroid-macrophage-megakaryocyte colony-forming units (CFU-GEMM), CD34+ cells, and CD34+ CD33- cells but with the number of previous chemotherapy regimens. PBSC harvesting is achievable after chemotherapy plus GM-CSF in heavily pretreated patients with persistent marrow involvement. Moreover, these cells are able to reconstitute correct hematopoiesis after intensive treatment in these patients.

Infections following peripheral blood progenitor cell transplantation for lymphoproliferative malignancies: etiology and potential risk factors.

PURPOSE: We sought to describe the infections that occur after large-dose chemotherapy, which was followed by autologous peripheral blood progenitor cell transplantation, and to determine their risk factors. PATIENTS AND METHODS: We retrospectively analyzed the occurrence and the characteristics of infections in 277 consecutive patients who received intensive chemotherapy for non-Hodgkin's lymphoma (n = 207), Hodgkin's disease (n = 27), or multiple myeloma (n = 43) in a single institution. Conditioning regimens included total body irradiation in 47% of the cases. Infections occurring within the 30 days after transplant were defined as early infections, whereas infections after that time in patients who had achieved a neutrophil count greater than 1.0 x 10(9)/L (1,000 per microL) were considered as late infections. RESULTS: Within the first 30 days, 172 patients had unexplained fever (62%); infections were documented in 83 patients (30%), most commonly bacteremia (57 patients). Late infections occurred in 64 (26%) of 244 evaluable patients and consisted mainly of varicella zoster virus infections (n = 36) and pneumonia (n = 16). Administration of total body irradiation [odds ratio (OR) = 2.50; 95% confidence interval (CI) 1.4 to 4.5; P = 0.002) and previous use of fludarabine (OR 2.5; CI 1.2 to 5.2; P = 0.02) and a diagnosis of myeloma (OR 2.6; CI 1.2 to 5.6; P = 0.04) were significantly associated with late infections. CONCLUSIONS: This study confirms that infectious toxicity after peripheral blood progenitor cell transplantation is usually moderate, although bacteremia remains a serious problem. Late infections are encountered in about 25% of patients and are more common in those with myeloma, or those who received total body irradiation or fludarabine.

Intensive radio-chemotherapy with peripheral blood stem cell transplantation in young patients with chronic lymphocytic leukemia.

Two patients with previously treated CLL received autologous PBSC transplantation after total body irradiation and high-dose chemotherapy. Before intensification, a partial marrow response had been obtained in both patients, with disappearance of peripheral blood involvement as shown by immunophenotypic assessment using fludarabine. PBSC collection was performed after a single course of high-dose cyclophosphamide followed by GM-CSF administration. One patient failed to reconstitute normal hematopoiesis and died 3 months post-transplant. The other is in continuous complete remission 12 months after intensification. This strategy in young patients with poor prognosis CLL warrants further investigation.

Autoimmune thrombocytopenic purpura after autologous stem cell transplantation.

The pathogenesis of thrombocytopenia occurring after autologous stem cell transplantation (ASCT) remains unclear. Six cases of classical peripheral thrombocytopenia that developed after ASCT for non-Hodgkin's lymphoma (NHL) are presented. Resolution of this complication was obtained by usual treatment such as steroids, splenectomy or progressively resolved without specific treatment. Five out of six patients have been followed for more than 5 years after hematopoietic transplantation and are still alive in complete remission despite poor prognostic factors at diagnosis. Several arguments suggest that this phenomenon represents autoimmune thrombocytopenia and may be the consequence of an altered immune balance. Consequently, development of autoimmune reactions after bone marrow transplantation might be associated with an antitumoral effect (graft-versus-lymphoma effect).

Rituximab-related late-onset neutropenia after autologous stem cell transplantation for aggressive non-Hodgkin's lymphoma.

Rituximab, an anti-CD20 monoclonal antibody, is increasingly used in the treatment of B-cell non-Hodgkin's lymphoma. Late-onset neutropenia in relation to rituximab has been recently described. In this report, we present six cases occurring after stem cell transplantation and discuss the potential impact of this complication.

Toxicities after peripheral blood progenitor cell transplantation for lymphoid malignancies: analysis of 300 cases in a single institution.

Two hundred and seventy-seven consecutive patients with non-Hodgkin's lymphoma (n = 207), Hodgkin's disease (n = 27) and multiple myeloma (n = 43) were intensified from October 1989 until April 1997 and received unmanipulated PBPC transplants. Twenty-three patients received a double intensification, out of a total of 300 PBPC transplantations analyzed. Conditioning regimens consisted of total body irradiation (TBI)-containing regimens (n = 141), BEAM (n = 104), high-dose melphalan (n = 26), ICE (n = 23) or other regimens (n = 6). Eighty-four percent of the patients (119/142) evaluable for long-term hematological reconstitution beyond 180 days achieved normal trilineage blood counts. Abnormal hematological parameters were associated with low numbers of CD34+ cells re-infused and with prior exposure to fludarabine. The 100-day and long-term treatment-related mortality rates were 4% and 4%, respectively. Late complications and treatment-related toxicities were influenced by disease history, use of TBI and exposure to fludarabine. Patients older than 60 years did not have greater toxicities or more frequent treatment-related deaths. This analysis suggests that while leading to a limited morbidity and a low mortality rate, intensive chemotherapy with PBPC transplantation still remains a procedure leading to significant short- and long-term toxicities. Better recognition of the risk factors associated with these complications might allow a further decrease in their incidence.

Reduced progression-free survival in elderly patients receiving intensification with autologous peripheral blood stem cell reinfusion for multiple myeloma.

Between 1990 and 1997, 55 patients with high risk multiple myeloma underwent high-dose therapy with peripheral blood stem cell transplantation. Intensification consisted of high-dose L-PAM in 54 patients, and 15 patients underwent a second high-dose treatment. Thirty patients received total body irradiation. Twenty patients were more than 60 years old. Thirty-five patients were intensified during first response. The overall response rate was 78%. There were four toxic deaths. The median overall survivals after intensification and after first treatment of myeloma were greater than 48 months and 71 months, respectively. Conversely freedom from progression after intensification was short, with a median of 22 months. Freedom from progression was significantly shorter in patients older than 60 (12 months), and in patients who had received more than 75 mg/m2 of L-PAM before intensification (16 months). Although intensification is feasible in elderly patients the benefit appears to be reduced in this subgroup of patients. Prior therapy with high cumulative doses of L-PAM should be avoided in patients who will receive high-dose L-PAM for therapeutic intensification.

Amifostine reduces mucosal damage after high-dose melphalan conditioning and autologous peripheral blood progenitor cell transplantation for patients with multiple myeloma.

High-dose melphalan (HDM) has been adopted as standard therapy in the treatment of multiple myeloma. This treatment is associated with non-selective cytotoxicity, causing oral mucositis as the major non-hematological side-effect. Amifostine is a cytoprotector which prevents toxicity induced by anticancer therapy. We prospectively compared two groups of patients who either received (group A, n = 21) or did not receive (group B, n = 20) amifostine (740 mg/m(2)) before HDM (200 mg/m(2)) followed by autologous peripheral blood progenitor cell transplantation. The occurrence of severe oral mucositis was significantly decreased in group A in comparison to group B (33% vs 65%, P < 0.05). Six patients in group A required opioid analgesic therapy during a mean period of 4.8 days as compared to eight patients for 6.5 days in group B (P = NS). Delayed vomiting was less frequent in group A (43% vs 70%, P = 0.07) and significantly less severe in group A (grade 2-4) vomiting: two patients vs nine patients, P < 0.02). No difference was observed between the two groups in either hematological toxicity after HDM or in response rate. Grade I emesis was the only immediate side-effect observed after amifostine administration. We conclude that amifostine can reduce mucositis induced by HDM.

Isepamicin once daily plus ceftriaxone versus amikacin plus ceftriaxone in febrile neutropenic patients.

Isepamicin is a new aminoglycoside with in-vitro activity superior to amikacin. It is a poor substrate for the 6'-aminoacetyltransferase-I enzyme which inactivates amikacin and therefore organisms possessing this enzyme are not resistant to isepamicin. The aim of this study was to compare the efficacy and safety of co-administration of isepamicin once daily plus ceftriaxone to amikacin twice daily plus ceftriaxone to amikacin twice daily plus ceftriaxone in febrile neutropenic cancer patients. Febrile episodes in 235 patients (156 in isepamicin group and 79 in amikacin group) were treated in this study. They occurred in 218 different patients. Fifteen patients were enrolled twice and one three times. Response rates to the two treatment regimens for microbiologically documented episodes, clinically documented episodes and further unexplained fever were similar. Tolerance of the treatment regimens, as measured by serum creatinine levels, hypoaccousia and cutaneous allergy was also similar in both treatment groups. In conclusion, isepamicin given once daily when combined with ceftriaxone in the treatment of febrile episodes in neutropenic cancer patients was as effective and no more toxic than amikacin.

[IgM kappa gastric plasmacytoma]. / Plasmocytome gastrique à IgM kappa.

A case of gastric plasmacytoma in a 50-year old woman was reported. Immunofluorescent and immunoperoxidase studies were performed. Polyclonal antibodies reactive with immunoglobulin chains and a panel of 14 monoclonal antibodies reactive with B and T cells, and epithelial cells were used. These studies showed that the tumor cells produced IgM Kappa molecules whereas no monotypic immunoglobulin could be detected in the serum and urine. On the other hand the tumor cells had the immunologic phenotype of plasma cells. This helps diagnosis: some lymphomas with plasmocytic differentiation could also produce a monotypic immunoglobulin. Treatment using a combination of surgery, radio and polychimiotherapy was effective, leading to complete remission.

[An imipenem-cilastatin combination in the treatment of infection in hemato-oncology]. / L'association imipénème-cilastatine dans le traitement des infections en hémato-cancérologie.

The efficacy and tolerability of imipenem-cilastatin were studied in 66 haemato-oncology patients from 16 centres presenting with a bacteriologically proven infection; 29 of the patients had neutropenia (less than 500/sq.mm). The drug was given as monotherapy in 30 cases, as bitherapy in 29 cases and as tritherapy in 7 cases. The initial clinical diagnosis was septicaemia in 29 patients, various severe infections in 31 and fever of unknown origin in 6. The infection was bacteriologically documented in 55 patients; the remaining 11 patients were kept in the study and the results of their treatment were taken into account. One-hundred and fourteen bacterial strains were isolated, including 64 Gram-negative organisms, 48 Gram-negative organisms and 2 anaerobes. Treatment was discontinued in 4 patients, due to lack of response in 2 and to adverse events (haemolytic shock, Lyell's syndrome) in 2. Five patients died during the study: 4 of an underlying pathology, the infection having subsided, and 1 of persistent infection and the above-mentioned Lyell's syndrome. Clinical success was achieved in 63 patients (95.5 per cent), including 27 of the 29 patients with neutropenia (93.1 per cent). Among the 114 strains isolated, 106 were eradicated, 5 persisted and only 1 became resistant (outcome not available in 10 cases). Apart from the haemolytic shock and Lyell's syndrome, haematological and hepatic alterations were minor and not obviously due to imipenem-cilastatin. Three cases of colonization and 3 cases of superinfection were recorded during the study.

[Occurrence of a circulating anticoagulant, factor V inhibitor after surgical intervention]. / Apparition d'un anticoagulant circulant antifacteur V après intervention chirurgicale.

A case is reported of an endogenous inhibitor to factor V occurring one month after subtotal gastrectomy and splenectomy, with peroperative radiotherapy, for gastric adenocarcinoma. Preoperative coagulation tests were normal: 31 s for activated kephalin time (control 31 s) and 93% for prothrombin level. There was a fall in this latter during the first three postoperative days. Four hundred ml plasma without cryoprotein were therefore given, bringing the coagulation tests back to the normal range. On day 25, a routine check showed an activated kephalin time of 71 s (control 31 s), a prothrombin level of 13% with a thrombin time of 18 s (control 18 s). There was no associated haemorrhagic diathesis. Measurement of all the individual coagulation factors showed that there was a fall in factor V level (0.05 IU.ml-1). A large amount of antifactor V antibody was then found (47 IU.ml-1). No treatment was undertaken, the patient being so well. Two months later, the antibody had disappeared. The usual circumstances in which this antibody can be seen and the management of the related severe haemorrhages are discussed.

[Neurosarcoma associated with neurofibromatosis 1. Apropos of a case and review of the literature]. / Neurosarcome associé à une neurofibromatose de type 1. A propos d'un cas et revue de la littérature.

BACKGROUND: Type 1 neurofibromatosis considerably increases the risk of cancer development, particularly neurosarcoma. We report a case in a patient with chemosensitive metastatic neurosarcoma. CASE REPORT: A young female patient with familial type 1 neurofibromatosis developed pleural metastasis of a neurosarcoma located on the arm. This tumor was initially highly sensitive to chemotherapy, but relapse occurred. DISCUSSION: Follow-up in the order members of the family was particularly difficult to organize. One sister developed cerebral astrocytoma. Neurosarcomas develop earlier in patients with type 1 neurofibromatosis, worsening prognosis. We suggest a prospective and structured registration of such cases using a network of clinicians and pathologists in order to improve management schemes.

A randomised phase II study of the efficacy, safety and cost-effectiveness of pegfilgrastim and filgrastim after autologous stem cell transplant for lymphoma and myeloma (PALM study).

AIM: To evaluate in a multicentre randomised study the effect on duration of febrile neutropenia (FN), the safety and cost-effectiveness of a single subcutaneous pegfilgrastim injection compared with daily injections of filgrastim after peripheral blood stem cell transplantation in patients receiving high dose chemotherapy for myeloma and lymphoma. METHODS: Patients were randomly assigned to a single dose of pegfilgrastim at day 5 (D5) or daily filgrastim from D5 to the recovery of absolute neutrophil count (ANC) to 0.5 G/L. Duration of FN, of neutrophil and platelet recovery, transfusion and antibiotic requirements were the main end-points of the study. Costs were calculated from D0 until transplant unit discharge. The incremental cost-effectiveness ratio was expressed as the cost per day of FN prevented. Probabilistic sensitivity analysis was performed by non-parametric bootstrap methods. RESULTS: Between October 2008 and September 2009, 10 centres enrolled 151 patients: 80 patients with lymphoma and 71 patients with myeloma. The mean duration of FN was 3.07 days (standard deviation (SD) 1.96) in the pegfilgrastin arm and 3.29 (SD 2.54) in the filgrastim one. Mean total costs were 23,256 and 25,448 euros for pegfilgrastim and filgrastim patients, respectively. There was a 62% probability that pegfilgrastim strictly dominates filgrastim. CONCLUDING STATEMENT: Pegfilgrastim after PBSC transplantation in myeloma and lymphoma is safe, effective when compared with filgrastim and could represent a cost-effective alternative in this setting.