Factors affecting hematopoietic recovery after autologous peripheral blood progenitor-cell transplantation in aggressive non-Hodgkin's lymphoma: a prospective study of 123 patients.

PURPOSE: To analyse prognostic factors influencing hematopoietic recovery in patients with aggressive non-Hodgkin's lymphomas prospectively treated with intensive chemotherapy followed by peripheral blood progenitor-cells transplantation. PATIENTS AND METHODS: Untreated patients with at least two unfavorable factors according to the age-adjusted international prognostic index were included in the LNH 93-3 trial. Patients received three cycles of chemotherapy and PBPC were mobilized using filgrastim. On day 60, a BEAM regimen was initiated followed by PBPC rescue. Among the 123 patients analysed, 60 received G-CSF (5 microg/kg/d) after PBPC transplantation at day 1 and 63 did not. RESULTS: Patients received a mean number of 12.4 x 10(6)/kg (1.86-111.5) CD34+ cells. After transplantation, neutrophil counts exceeded 0.5 x 10(9)/l at a median of 12.4 days (7-41 days) and platelet counts exceeded 50 x 10(9)/l at a median of 15.6 days (9-141 days). Platelets recovery > 50 x 10(9)/l was negatively influenced by BM involvement (20 s 14 days; P = 0.04). The number of CD34+ cells infused (> vs < or = 5 x 10(6)/kg) was correlated with faster platelet recovery (18.7 days vs 13.7 days) (P = 0.007). In 26 patients for whom administration of G-CSF was randomized, time to neutrophil recovery was significantly shorter for patients treated with G-CSF: 10 vs 13 days (P = 0.0005). The incidence of grade 3/4 infection, was similar in both groups. CONCLUSION: In the patient population treated with the same first-line regimen, BM involvement and infusion of fewer CD34+ cells delayed platelet recovery. Administration of G-CSF after PBPC significantly reduced neutropenia.

Clinical relevance of gallium-67 scintigraphy in lymphoma before and after therapy.

The clinical impact of gallium-67 scintigraphy before and after therapy for lymphoma remains controversial. The aims of this study were: (1) to compare the staging of lymphoma by 67Ga scintigraphy only with staging by clinical examination and conventional imaging (CI), and (2) to analyse the clinical relevance of both 67Ga imaging and CI after treatment. From March 1995 to November 1998, 86 67Ga scintigraphy studies were performed in 62 patients with Hodgkin's disease (n=52) or non-Hodgkin's lymphoma (n=10). 67Ga scintigraphy was performed at diagnosis (n=44) or after therapy (n=42) using 185-220 MBq 67Ga citrate and planar and single-photon emission tomography (SPET) studies. Treatment comprised radiotherapy, chemotherapy or combined modalities. CI included plain chest radiography, computed tomography (CT) of the chest and abdomen/pelvis, ultrasound of the abdomen, lymphography, bone marrow biopsy and, when necessary, magnetic resonance imaging (MRI) and bone scintigraphy. For individual suspected sites of disease before treatment, complete agreement between clinical examination and CI on the one hand and 67Ga scintigraphy on the other hand was observed in 25/44 patients (57%; 95% confidence interval 41%-72%). Clinical examination and CI showed more sites than did 67Ga scintigraphy in 12/44 patients (27%) and 67Ga imaging demonstrated more sites than CI in 6/44 patients (11%). The clinical stage of the disease as assessed using 67Ga scintigraphy only was in agreement with that using all diagnostic procedures in 34/44 patients (77%; 95% confidence interval 62%-89%). Compared with CI staging, 67Ga scintigraphy downstaged seven patients (16%) and upstaged three (7%). 67Ga scintigraphy downstaged mainly because of the limited value of the technique below the diaphragm and upstaged owing to the good sensitivity in the lung. After therapy, both CI and 67Ga scintigraphy were normal in 11 patients. All but one of these patients were in complete remission after a median follow-up of 31 months. In contrast, radiological residual mass was observed in 31/42 patients. 67Ga imaging was normal in 22/31 (71%); 17 of these 22 patients, including nine with a large residual mass (> or =2 cm), were in complete remission after a median follow-up of 32 months, while four suffered relapses 8-45 months later. The cause of death remained unknown in one patient. 67Ga scintigraphy showed abnormal uptake in 9 of the 31 patients with a large residual mass. Active disease was demonstrated in eight patients and one patient was in complete remission 30 months thereafter. Our data show that 67Ga imaging cannot replace CI in initial staging but can demonstrate additional individual sites of disease in more than 10% of patients and can lead to clinical upstaging with potential prognostic and therapeutic consequences. After therapy, 67Ga scintigraphy has a clinical impact when radiological abnormalities persist because it can either avoid unnecessary complementary treatment or confirm the need to change treatment modalities.

VAD or VMBCP in multiple myeloma refractory to or relapsing after cyclophosphamide-prednisone therapy (protocol MY 85).

263 patients (median age 65+/-10 years) with multiple myeloma were treated with cyclophosphamide-prednisone. Out of this cohort, 103 patients had progressive disease and were randomly assigned to either VAD (vincristine, doxorubicin, dexamethasone; 50 cases) or VMBCP (vincristine, BCNU, cyclophosphamide, melphalan and prednisone; 53 cases). There were no statistical differences between the two groups with the respect to clinical, biological and radiological parameters. There was no difference in survival between the VAD and VMBCP groups. The 4 months response rate was similar in the two groups (50% VAD, 56% VMBCP). With multivariate analysis for survival (Cox model), two factors had a statistically significant impact: Karnofsky index (> 60) and albuminaemia (< 34 g/l). With both Karnofsky index > 60 and albuminaemia > or = 34 g/l, the median survival was 29 months v 2 months with a Karnofsky index < or = 60 and albuminaemia < 34 g/l (P<0.05). In conclusion, VAD or VMBCP had similar activity for salvage treatment in MM refractory or relapsing to first-line treatment with cyclophosphamide-prednisone.

Early intensive therapy with autologous stem cell transplantation in advanced Hodgkin's disease: retrospective analysis of 158 cases from the French registry.

This retrospective study was undertaken to evaluate cure rates, toxicity and late effects of early intensive therapy followed by autologous stem cell transplantation (ASCT) in patients with advanced Hodgkin's disease (HD). One hundred and fifty-eight cases of ASCT registered in the French database (SFGM) were retrospectively analyzed. Disease status at the time of ASCT was first partial response (PR) in 85, first complete remission (CR1) in 45 or primary refractory in 28 cases. The median time interval between diagnosis and ASCT was 7 months (range 4-13). At the time of analysis in December 1995, 121/158 patients (76.6%) were alive, including 111 (70.2%) in continuous CR with a median follow-up for surviving patients of 46 months (range 8-123). Peri-ASCT toxic death rate was 3%, and the actuarial risk of new malignancies was 4.9% at 5 years. The cumulative probability of 5-year overall survival (OS) was 75.2% for the entire group of patients, 80.6% for the chemosensitive ones, and 33.9% for the primary refractory (chemosensitive vs refractory, P < 0.0001). The cumulative probability of 5-year event-free survival (EFS) was 66.1% for the entire group of patients, 73.7% for the chemosensitive ones, and 26.1% for the primary refractory (chemosensitive vs refractory, P < 0.0001). The only significant prognostic factor for both OS and EFS was disease status at the time of ASCT. Early ASCT in advanced HD is feasible, with a low risk of toxicity and without a higher rate of late effects compared with conventional treatment. Results achieved in chemosensitive patients at the time of transplantation lay the basis of future prospective randomized trials comparing ACST as front-line treatment to conventional treatment in high-risk cases.

[Neuroblastoma arising in testicular teratoma]. / Neuroblastome survenant dans un tératome testiculaire.

One case of neuroblastoma arising in an adult immature testicular teratoma is described, with multiple systemic metastases, a partial response to intensive chemotherapy and a swift recurrence leading to death. Such instances of prevailing neuroblastoma with systemic metastases, have only seldomly been reported hitherto. Because of the teratoma and the focal presence of intratubular germ cell neoplasia of unclassified type, we think this tumor must be indeed of germ cell derivation.

Cyclophosphamide/mitoxantrone/melphalan (CMA) regimen prior to autologous bone marrow transplantation (ABMT) in metastatic breast cancer.

Dose-intensive treatment followed by ABMT is currently used in different approaches to treat breast cancer patients. An active non cross-resistant regimen combining cyclophosphamide (C), mitoxantrone (M) and melphalan (A) (CMA), was developed as the conditioning regimen before ABMT. The purpose of this phase II study was to evaluate this protocol and the duration of its effect in metastatic patients, who responded to chemotherapy. Criteria for inclusion included histologically documented breast cancer, age < 55 years and the first detection of measurable metastatic lesions. Following first-line chemotherapy in responding patients, histologically negative bone marrow was collected and cryopreserved. Then, intensification with cyclophosphamide (120 mg/kg), mitoxantrone (60 mg/m2), and melphalan (140 mg/m2) was followed by ABMT. Sixty-one metastatic breast cancer patients with a mean age of 40 years were included. Sites of measurable metastases included: liver 24, lung 14, central nervous system four, pleura three, skin six, and chest wall six, nodes eight and bone marrow one. Nineteen patients had lesions in two or more sites, and 22 had bone involvement. The response of 60 patients could be evaluated: before ABMT 31 were in clinical complete response (CR), 22 in partial response > 50% (PR), and seven had new progression. After ABMT, 36 patients were in CR, 16 in PR, one progressed and one was stable. Seven (11.5%) toxic deaths occurred. Mean time for hematological recovery was 32.5 days, without hematopoietic growth factors. Median survival was 33 +/- 9.4 months from the start of therapy, and 25.7 +/- 4.6 months from the date of ABMT. Median event-free survival was 20 months from the start of therapy, and 13 +/- 2 months from ABMT. With a median follow-up of 51 months, probability of actuarial survival, measured from the beginning of initial chemotherapy, was 36%, and event-free survival was 18%. In metastatic breast cancer responding to chemotherapy, high-dose consolidation with CMA and ABMT resulted in a median survival of 33 months. These results lay the ground work for evaluation in a randomized trial in metastatic breast cancer.

Late psychosocial sequelae in Hodgkin's disease survivors: a French population-based case-control study.

PURPOSE: To evaluate late psychosocial sequelae in long-term survivors of Hodgkin's disease (HD) in the population of Calvados, France. PATIENTS AND METHODS: Ninety-three patients issued from the Calvados General Tumor Registry, treated from 1978 to 1990, free of relapse and second malignancy since January 1991, were enrolled onto cross-sectional case-control study. One hundred eighty-six healthy controls, matched for sex, age, and residency, were selected at random from electoral rolls. Two self-administered questionnaires were mailed in the spring of 1995. RESULTS: Compared with controls, HD patients reported (1) more physical (P < .001), role (P < .001), and cognitive (P = .015) functioning impairments, as well as dyspnea (P < .001) and chronic fatigue (P = .025), while no statistical difference was found in global health status; (2) to be more often childless (P = .04), fewer divorces or separations (P = .013), fewer changes in relationships with friends (P = .012), similar proportions at work but less ambitious professional plans (P < .001), and greater difficulties in borrowing from banks (P < .001); (3) a slight increase in the number of visits to a general practitioner (P = .05) and greater consumption of medical resources (mainly thyroid extracts, P = .05). CONCLUSION: The study demonstrated that French long-term HD survivors have good global health status and good psychologic, familial, and professional status, although difficulties in borrowing from banks remain a major limitation in daily life. Although physical, role, and cognitive functioning impairments persist that might limit their activities, HD survivors seem to have learned to cope with problems related to their disease and its treatment.

Efficacy of lenograstim on hematologic tolerance to MAID chemotherapy in patients with advanced soft tissue sarcoma and consequences on treatment dose-intensity.

PURPOSE: This two-arm, double-blind, randomized trial was conducted to determine the effects of lenograstim, a glycosylated recombinant human granulocyte colony-stimulating factor (rHu-G-CSF), on the hematologic tolerance of patients with sarcoma treated with mesna, doxorubicin, ifosfamide, and doxorubicin (MAID) chemotherapy. PATIENTS AND METHODS: Forty-eight patients with metastatic or locally advanced soft tissue sarcoma were, following the first cycle of a combination with doxorubicin 60 mg/m2, ifosfamide 7.5 g/m2, and dacarbazine 900 mg/m2, ifosfamide 7.5 g/m2, and dacarbazine 900 mg/m2 given on days 1 to 3, randomized to receive either lenograstim 5 micrograms/kg/d by once-daily injection from day 4 to day 13, or its vehicle. For subsequent cycles, 28 patients continued on the same chemotherapy and lenograstim was systematically given as prophylactic treatment in an open manner. RESULTS: Following the first cycle of MAID, the duration of neutropenia was reduced in patients who received lenograstim as compared with those who received placebo, with a median duration of neutropenia ( < 0.5 x 10(9)/L neutrophils) of 0 days (range, 0 to 3) and 5 days (range, 0 to 10), respectively (P < .001). All patients who received lenograstim had recovered at least 1 x 10(9)/L neutrophils (polymorphonuclear lymphocytes [PMN]) on day 14, compared with only one of 26 in the placebo group (P < .001). The median time to recover this neutrophil level was 12 days (range, 10 to 13) and 17 days (range, 14 to 21), respectively (P < .001). Neutropenic fever occurred in five (23%) and 15 (58%) patients respectively (P = .02). Twenty-eight patients received at least two cycles (median, four) of MAID at the same dose. Toxicity remained constant across all treatment cycles. A progressive increase in thrombocytopenia was noted, with median platelet nadirs of 102 x 10(9)/L at cycle 2 and 19.5 x 10(9)/L at cycle 6, but did not result in significant treatment modifications. Consequently, median relative dose-intensities remained greater than 0.95 for up to six consecutive MAID cycles. CONCLUSION: Lenograstim significantly improved hematologic tolerance in patients treated with the MAID chemotherapy regimen and, therefore, allowed optimal adhesion to the theoretic doses planned for up to six cycles. Whether such an optimization in relative dose-intensity will result in an improvement of treatment efficacy remains to be determined.

Human recombinant granulocyte-macrophage colony stimulating factor (hrGM-CSF) improves double hemibody irradiation (DHBI) tolerance in patients with stage III multiple myeloma: a pilot study.

Double hemibody irradiation (DHBI) is an alternative treatment of stage III multiple myeloma (MM) in patients aged over 55 years. Toxic side-effects such as myelosuppression are a severe limiting factor to its use. We performed DHBI associated with human recombinant granulocyte-macrophage colony stimulating factor (hrGM-CSF) as support therapy in 10 patients with stage III MM to improve the tolerance to this treatment. Ten patients received subcutaneously 5 micrograms/kg/d of hrGM-CSF during 2 weeks after each course of hemibody irradiation. All these patients had stage III MM: eight previously received chemotherapy, six of them were regarded as patients with refractory MM and two with relapse. Two patients received DHBI as first-line treatment. hrGM-CSF increased safety and tolerance of DHBI. GM-CSF support reduced the mean time between upper body irradiation (UBI) and lower body irradiation (LBI): 41 v 108 d in a cohort of 32 patients previously treated without growth factor support. Overall there was no lethal infection with hrGM-CSF or granulocytopenia (5.0 x 10(9)/l v 0.4 x 10(9)/l at day 15 in patients without growth factor). hrGM-CSF also reduced stomatitis grading and thrombocytopenia (90 x 10(9)/l v 45 x 10(9)/l at day 15). Furthermore, hrGM-CSF increased blood colony forming unit-granulocyte macrophage (CFU-GM) and was well tolerated in all but one patient. hrGM-CSF reduces toxic side-effects of DHBI, thus providing an effective treatment in patients with advanced and resistant MM.

[The role of autografts in severe or metastatic breast cancers]. / La place de l'autogreffe dans les cancers du sein graves ou métastatiques.

Intensive treatment of poor prognosis breast cancer has included bone marrow autografts. A multicentric study was conducted from 1988 to 1992, including 105 patients with a minimal follow-up of 2 years after the autograft. Inclusion criteria were: age < 55 years, measurable metastasis, inflammatory breast cancer, breast cancer with major lymph node invasion (> 8 N+). Chemotherapy (6 to 8 cycles) was used initially. In responders, bone marrow was harvested and frozen. Medullary invasion had to be absent for bone marrow harvesting. Management then included cyclophosphamide: 60 mg/kg, D-7, D-6; mitoxantrone: 12 mg/m2, D-9 to D-5; alkeran: 140 mg/m2, D-2 followed D0 for bone marrow autograft. For the 105 patients, mean age was 40 years; inflammatory breast cancer: 33 patients; > or = 8 N+: 11 patients; metastasis: 61 patients. For the cases with metastasis, the main sites were: liver: 24 patients, lung: 14 patients, bone: 22 patients, central nervous system: 4 patients. Nineteen patients had at least two metastasis localizations. Responders alone were included although 7 patients had been stabilized before the autograft. For the metastatic forms, median survival was 41 +/- 9 months from the onset to diagnosis of metastasis, with 8 patients surviving over 5 years. Median survival without progression was 12 months with a 4-year probability of 17%. For inflammatory breast cancers, the probability of survival was 50% and survival without progression was 42%. For patients with lymph node invasion > or = 8 N+, it was 72%.(ABSTRACT TRUNCATED AT 250 WORDS)

[IgM myeloma: 6 cases and a review of the literature]. / Myélome à IgM: 6 observations et revue de la littérature.

IgM myeloma is a rare plasma cell neoplasia, with an estimated incidence of 0.5% in patients with myeloma. Approximately, between 2 and 3.3% of IgM monoclonal gammopathy are IgM myeloma. Six unpublished cases of IgM myeloma, association of an IgM monoclonal gammopathy and an exclusive plasma cell neoplasia, are reported. Forty-six other cases have been found in the literature. The initial clinical characteristics of these patients are: sex-ratio of 1.1, mean age of 62 years, fatigue in 95% of the cases, bone pain in 80%, osteolytic lesions in 78%, fever in 13%, hepatomegaly and splenomegaly in 8%, lymphadenopathy in 10%, hemorrhagic diathesis in 35% and neurologic involvement in 18%. Initial biological features are: anemia in 62% of the cases, creatininemia greater than 20 mg/l in 10%, calcemia greater than 120 mg/l in 24%. Mean serum IgM level is 33 g/l, mean medullary plasmocytosis is 52%. 80% of the patients presented with IgM kappa and only 20% with IgM lambda. Proteinuria with light chains are found in 65%. One-year survival is estimated at 82%, 2-year at 62%, 3-year at 46% with a median of 30 months. No prognostic factor is found. IgM myeloma with characteristics of both myeloma and macroglobulinemia appears well individualized among B-cell neoplasia. However, the distinction between Waldenström's macroglobulinemia and IgM myeloma can be difficult in case of lympho-plasmocytic bone marrow proliferation with osteolytic lesions.