Claude Linassier

High-dose chemotherapy with autologous stem cell transplantation as first-line therapy for primary CNS lymphoma in patients younger than 60 years: a multicenter phase II study of the GOELAMS group

The optimum treatment of primary CNS lymphoma (PCNSL) is not yet determined. The objective of this study was to assess the safety and efficacy of initial methotrexate-based chemotherapy followed by high-dose chemotherapy (HDT) with autologous stem cell transplantation (ASCT) in patients with newly diagnosed PCNSL. Twenty-five patients received two courses of initial chemotherapy combining methotrexate, etoposide, carmustine and methylprednisolone, and one course of ifosfamide–cytarabine followed by peripheral stem cell collection. Seventeen responsive patients then received HDT using carmustine, etoposide, cytarabine and melphalan with autologous stem cell rescue. After ASCT for responding patients or after salvage therapy for non-responders, whole brain radiation therapy at a dose of 30 Gy was delivered. The objective response rate to the induction chemotherapy was 84%. Four of the 21 responding patients did not have ASCT because of toxicity or refusal. With a median follow-up time of 34 months, the projected event free survival rate is 46% at 4 years. Projected overall survival is 64% at 4 years. Sixteen patients are actually in continuous complete response. No evidence of late treatment-related toxicity was observed. This treatment approach appears feasible in newly diagnosed PCNSL with encouraging results.

Early secondary acute myelogenous leukemia in breast cancer patients after treatment with mitoxantrone, cyclophosphamide, fluorouracil and radiation therapy

BACKGROUND The topoisomerase II-targeted drugs, epipodophyllotoxins and anthracyclines, have been shown to induce therapy-related AML (t-AML) characterized by a short latency period after chemotherapy, the absence of prior myelodysplastic syndrome and stereotyped chromosome aberrations. Few reports have been published on patients treated with the anthracenedione mitoxantrone which also targets topoisomerase II. We observed 10 cases of such t-AML over a 7-year-period in breast cancer patients treated with mitoxantrone combined with fluorouracil, cyclophosphamide and regional radiotherapy, and in three cases with vindesine. PATIENTS AND METHODS We retrospectively analyzed patients referred to our hospital for AML with a past history of polychemotherapy for breast cancer, including mitoxantrone, either as adjuvant (8 patients)/neoadjuvant (1 patient) therapy or for metastatic disease (1 patient). We studied the probability of developing t-AML in a prospective series of 350 patients treated with an adjuvant FNC regimen (mitoxantrone, fluorouracil, cyclophosphamide) and radiation therapy. RESULTS The median age was 45 years (range 35-67). t-AML developed 13-36 months (median 16) after beginning chemotherapy for breast cancer, and 4-28 months (median 10.5) after ending treatment. As described in t-AML following treatment with epipodophyllotoxins or anthracyclines, we found a majority of FAB M4, M5 and M3 phenotypes (7 of 10), and characteristic karyotype abnormalities that also can be found in de novo AML: breakpoint on chromosome 11q23 (3 patients), inv(16)(p13q22) (2 patients), t(15;17)(q22;q11) (1 patient), t(8;21)(q22;q22) (1 patient) and del(20q)(q11) (1 patient). The prognosis was poor. All patients died of AML shortly after diagnosis. Since two patients had been enrolled in a prospective trial for the treatment of breast cancer which included 350 patients, the probability of developing t-AML was calculated to be 0.7% from 25-40 months, using the Kaplan-Meier method (95%, confidence interval (95% CI): 0.1-4.5). CONCLUSIONS The combination of mitoxantrone with cyclophosphamide, fluorouracil, and radiation therapy can induce t-AML, as with other topoisomerase II-targeted drugs. Despite a low incidence, the prognosis appears to be poor.

Haemopoiesis of transplanted patients with autologous marrows assessed by long‐term marrow culture

Summary. We assessed the effect of antitumoural therapy at intensive doses on the haemopoietic system using long‐term marrow cultures (LTMC) established from 33 patients (25 with haematological diseases and eight with solid tumours) after autologous bone marrow transplantation (ABMT). When compared to 42 pre‐graft patients, a decreased CFU‐GM Production and a defect in stromal layer (SL) confluence were found after ABMT on day 90 but also on day 365. However, these abnormalities were observed only in patients with haematological diseases and no differences between pre‐graft and post‐graft results were found in patients with solid tumours. Among the patients with haematological diseases, on day 90 those with acute lymphoid leukaemias showed lower CFU‐GM production whereas patients with non‐Hodgkins lymphomas developed more frequently subconfluent or confluent SL. Other factors studied such as sex, patient age, disease status, marrow purging and post‐graft administration of growth factors did not appear to influence post‐graft LTMC results. Multivariate analysis including all the patients has shown (a) that solid tumours were associated with higher CFU‐GM production, and (b) that conditioning regimens with total body irradiation (TBI) or busulfan led more frequently to non‐confluent SL. In conclusion, high‐dose therapy followed by ABMT can induce a persistent impairment of the stem cell and stromal cell compartments, particularly in patients with haematological diseases conditioned with TBI, despite the absence of any alloimmune reaction and post‐graft immunosuppressive therapy.

Multiple myeloma in elderly patients: presenting features and outcome

Abstract: Few studies have been performed regarding multiple myeloma (MM) in elderly patients. We report a retrospective series of 130 unselected patients with MM aged 75 yr or more at diagnosis. Presenting features were identical to those reported in younger patients, except for a higher rate of infection. Heavy comorbidity was characteristic of unselected geriatric patients. Ninety‐four patients received conventional chemotherapy. The response rate was 62%. Treatment toxicity was mild. Median survival was 22 months. Durie–Salmon (DS) clinical stages II and III MM were severe and often led to death, while significantly more patients with DS stage I MM died from unrelated causes (p<0.0001). Univariate analysis showed that age 85 yr, performance status 2, creatinine level 120 µmol/l, beta 2 microglobulin level >4 mg/l, C‐reactive protein level >6 mg/l, platelet count <100×109/l, presence of infection and lack of response to chemotherapy were adverse prognostic factors for survival. In Cox multivariate regression analysis, age 85 yr (p<0.0001), performance status 2 (p<0.0001) and creatinine level 120 µmol/l (p<0.0001) were independent factors in predicting short survival. This study provides evidence that in patients with symptomatic MM age should not be considered as a major obstacle to active treatment. Prospective clinical trials are needed in this population of patients and should include an assessment of quality of life.

A new serologic index for low-grade non-Hodgkin's lymphoma based on initial CA125 and LDH serum levels

BACKGROUND Serum CA125 (sCA125) was recently reported to be of clinical value in the staging and follow-up of patients with non-Hodgkins lymphoma (NHL). This report aims to investigate the prognostic value of a new serologic index combining sCA125 and LDH serum levels. PATIENTS AND METHODS One hundred thirty-seven patients were studied, sixty-three with histologically proven low-grade NHL, and seventy-four with a high-grade subtype. RESULTS sCA125 and LDH levels were elevated in more than one third of patients. sCA125 was more frequently increased than LDH in low-grade NHL. In this group, complete remission (CR) was achieved in 87, 45, and 0% (P = <2 x 10(-6)) of patients with normal sCA125 and LDH serum levels (Low-risk group), one parameter increased (Intermediate-risk group), and increased sCA125 and LDH serum levels (high-risk group), respectively. The estimated five-year overall survival was 97%, 67% and 22% for low, intermediate, and high-risk groups, respectively. This combination was the only parameter predictive of RFS and OS in multivariate analysis (P < 0.0001). CONCLUSIONS In this study the combination of s-LDH and sCA125 levels (normal vs. abnormal) was found to be an important prognostic factor in low-grade lymphoma and may be used in the selection of appropriate therapeutic approaches for individual patients.

CD5 Negative B-cell Chronic Lymphocytic Leukemia: Clinical and Biological Features of 42 cases

Chronic lymphocytic leukemia cell (CLL) usually (95%) express B-phenotype and the CD5 antigen which is usually present on the surface of normal T cells. However, among B CLL, 7 to 20% do not express CD5. The significance of the lack of CD5 expression remains unclear. We reviewed 42 consecutive CD5- B CLL seen in three French medical centers from 1985 to 1991 and compared them with 79 CD5+ B CLL. Immunophenotype studies were performed using indirect immunofluorescence under light microscopy as well as flow cytometry after 1988. B CLL was considered to be CD5 negative when less than 5% of mononuclear cells expressed CD5 after subtraction of the number of T-cells. Cases with CD5- B CLL had isolated splenomegaly more frequently (p = 2.10(-7)). They frequently expressed a higher level of surface immunoglobulin (S-Ig) or the switch mu/delta phenotype (p = 4.7 10(-2)). The median survival time was not reached but no significant difference between CD5 negative and positive B CLL was observed at the time of our data analysis (p = 0.97). Clinical presentation of CD5- B CLL seems to be different from other forms of B CLL. Although, no conclusion can be reached in terms of prognosis, CLL with low expression of CD5 should be regarded as a subtype of CLL with a different clinical presentation than CD5+ CLL.

Acute hepatitis B after autologous stem cell transplantation in a man previously infected by hepatitis B virus

We report a case of acute hepatitis B after autologous stem cell transplantation (ASCT) in a patient with low-grade non-Hodgkin’s lymphoma. At diagnosis of the hematological disease, the patient had the characteristic serology of a previous hepatitis B infection, being Ag HBs negative, hepatitis B virus core antibody positive (anti-HBC) and hepatitis B virus surface antibody weakly positive. He developed fatal hepatitis B after autologous stem cell transplantation, suggesting reactivation consequent to immunosuppression.

High-Dose Therapy and Autologous Bone Marrow Transplantation in First Complete or Partial Remission for Poor Prognosis Hodgkin's Disease

We report the experience of three French centres which evaluated high-dose therapy (HDT) as consolidation therapy for poor prognosis Hodgkins disease (HD). From March 1986 to April 1990, 23 consecutive patients with poor prognosis stage IV HD underwent HDT followed by autologous bone marrow transplantation (ABMT) after achieving either complete remission (CR1) or good partial response (GPR1) (reduction mass> 75%). The median age was 31 years (range 18 to 55 years), 14 were male. All patients except one initially had at least 2 poor prognosis factors such as: systemic symptoms (n = 19), bulky tumor (n = 16), more than one extranodal site (n = 9), bone marrow involvement (n = 5), lymphocyte count < or = 1.10(9)/1 (n = 8) and biological stage B (n = 21). All patients had previously been treated with alternating MOPP/ABVD. Ten patients were in GPR1 and 13 in CR1 before transplant. The conditioning regimens were: CBV (n = 17), BEAM (n = 5), BEAC (n = 1) followed by bone marrow rescue. Radiotherapy was introduced just before the conditioning regimen for 6 patients or after ABMT for 5 patients. Nine of 10 patients in GPR1 achieved CR after ABMT but one died early of treatment-related toxicity. Five of 22 patients who were in CR posttransplant, relapsed (3, 4, 4, 18, 36 months). Seventeen patients remain alive in continuous CR with a median follow-up of 60 months (range: 30-100 months). The overall survival (OS) and disease-free survival (DFS) projected at 5 years are 92% and 77% respectively. Consolidation by HDT and ABMT proved to be well tolerated. An international trial is currently underway to attempt to demonstrate a clear benefit on survival for this subset of poor prognosis HD patients.

High Dose Chemotherapy with Autologous Marrow Transplantation in Follicular Lymphomas

Twenty six adult patients with low grade nodular non Hodgkins lymphoma (NHL) were treated with autologous bone marrow transplantation. Conditioning regimen was BEAM-BEAC in 15 patients and TBI + Cyclophosphamide in 11 patients. Twenty one patients were grafted with haematopoietic stem cells, 12 after bone marrow purging and five with peripheral blood stem cells (PBSC). Two patients were treated in CR1 of leukemic phase, six in PR1 and eighteen in sensitive relapse. With a median follow-up of 30 months, the actuarial survival is 91% and actuarial event free survival 67%. These data confirm some interest of ABMT in the treatment of low grade follicular NHL.

Long-term marrow reconstitutive ability of autologous grafts in lymphoma patients using peripheral blood mobilized with granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor compared to bone marrow

OBJECTIVES The aim of this study was designed to compare the in vivo long-term hematopoietic potential of bone marrow and peripheral blood grafts. MATERIALS AND METHODS Marrow progenitor cell recovery was assessed for up to 4 years in 227 patients. One hundred patients were treated for malignant lymphomas by autologous bone marrow transplantation (BMT) and 127 by peripheral blood progenitor cell transplantation (PBPCT). RESULTS Marrow progenitor cell counts were decreased for several years with both bone marrow and peripheral blood grafts. They were not different according to the origin of the graft, despite the reduced duration of peripheral blood cell recovery observed after PBPCT. Granulocyte colony-stimulating factor (G-CSF) used for PB graft mobilization and after transplantation resulted in faster neutrophil recovery compared to granulocyte-macrophage colony-stimulating factor (GM-CSF) with no evidence of decreased marrow progenitor cell recoveries. On the other hand, postgraft administration of GM-CSF enhanced long-term colony-forming unit granulocyte-macrophage reconstitution only after BMT. Factors that influenced marrow progenitor cell reconstitution have been identified by univariate and multivariate analysis: age, gender, type of lymphoma, and postgraft administration of hematopoietic growth factors (HGF) for the whole patient group; gender, graft progenitor cell yields, and type of HGF (G-CSF vs GM-CSF) for the PBPCT group; and only type of HGF for the BMT group. Despite faster peripheral blood cell recovery, persistent deficiency of marrow progenitor cells was found several years after PBPCT, as observed after BMT. G-CSF-mobilized PBPCT resulted in faster neutrophil recovery compared to GM-CSF mobilization, with no difference in long-term hematopoietic reconstitution.