Effect of priming with granulocyte-macrophage colony-stimulating factor in younger adults with newly diagnosed acute myeloid leukemia: a trial by the Acute Leukemia French Association (ALFA) Group.

In a multicenter trial, 259 young adults (15-49 years) with newly diagnosed acute myeloid leukemia (AML) were first randomized to receive a timed-sequential induction regimen given either alone (135 patients) or concomitantly with granulocyte-macrophage colony-stimulating factor (GM-CSF) (124 patients). Patients reaching complete remission (CR) were then randomized to compare a timed-sequential consolidation to a postremission chemotherapy including four cycles of high-dose cytarabine followed by maintenance courses. In the appropriate arm, GM-CSF was given concurrently with chemotherapy during all cycles of consolidation. CR rates were significantly better in the GM-CSF arm (88 vs 78%, P<0.04), but did not differ after salvage. Patients receiving GM-CSF had a higher 3-year event-free survival (EFS) estimate (42 vs 34%), but GM-CSF did not impact on overall survival. Patients with intermediate-risk cytogenetics benefited more from GM-CSF therapy (P=0.05) in terms of EFS than patients with other cytogenetics. This was also confirmed when considering only patients following the second randomization, or subgroups defined by a prognostic index based on cytogenetics and the number of courses required for achieving CR. Priming of leukemic cells with hematopoietic growth factors is a means of enhancing the efficacy of chemotherapy in younger adults with AML.

Identification of a leukemic counterpart of the plasmacytoid dendritic cells.

This work aims to demonstrate that CD4(+)CD56(+) malignancies arise from transformed cells of the lymphoid-related plasmacytoid dendritic cell (pDC) subset. The analysis of malignant cells from 7 patients shows that in all cases, like pDCs, leukemic cells are negative for lineage markers CD3, CD19, CD13, CD33, and CD11c but express high levels of interleukin-3 receptor alpha chain (IL-3Ralpha), HLA-DR, and CD45RA. Tumor cells produce interferon-alpha in response to influenza virus, while upon maturation with IL-3 they become a powerful inducer of naive CD4(+) T-cell proliferation and promote their T-helper 2 polarization. As pDCs, leukemic cells also express pre-Talpha and lambda-like 14.1 transcripts, arguing in favor of a lymphoid origin. In addition, malignant cells express significant levels of CD56 and granzyme B. Overall, those observations suggest that CD4(+)CD56(+) leukemic cells could represent the malignant counterpart of pDCs, both of which are closely related to B, T, and NK cells.

Late autologous transplantation in chronic myelogenous leukemia with peripheral blood progenitor cells mobilized by G-CSF and interferon-alpha.

In chronic myelogenous leukemia (CML), autologous stem cell transplantation could be a promising new approach for patients with no cytogenetic response after interferon alpha (IFN-alpha) therapy. We report data on 28 CML patients autotransplanted in chronic phase with peripheral blood progenitor cells mobilized with G-CSF (5 microg/kg/day x 5 days) given subcutaneously while continuing IFN-alpha therapy. At mobilization, 23 patients (82%) were in complete hematological remission (CHR), 16 (57%) achieved a minor cytogenetic response (mcr). We obtained, after stimulation, a median of 37.4 x 10(9)/l (6.9-108) white blood cells, 7.2 x 10(8)/kg (2.2-16.6) mononuclear cells, 39 x 10(4)/kg (4.8-403.5) CFU-GM and 4.2 x 10(6)/kg (0-58.6) CD34+ cells. Six patients received GM-CSF after transplantation. All patients engrafted, with no significant influence stemming from the Sokal index score and pretransplantation IFN-alpha therapy duration. The first cytogenetic evaluation after transplantation showed 11 (39%) major cytogenetic response (Mcr), and nine (32%) mcr with no significant correlation between these responses, the Sokal index score, and pretransplantation IFN-alpha therapy duration, although there was a significant impact from GM-CSF administration (P=0.01). After transplantation, 26 patients received IFN-alpha alone or associated with hydroxyurea. The median follow-up was 12 months after transplantation and 57 months after diagnosis. At the time of follow-up, nine patients were in CHR, six remained stable in chronic phase, three presented an mcr and one remained in Mcr. At the last follow-up, 22 patients were alive. We conclude that the results of this strategy are encouraging in poor IFN-alpha responders but that other prospective studies that try to maintain the cytogenetic responses obtained immediately after transplantation are needed.

Allogeneic vs autologous stem cell transplantation vs chemotherapy in patients with acute myeloid leukemia in first remission: the BGMT 87 study.

In 204 adult patients with de novo acute myeloid leukemia (AML), we prospectively compared allogeneic bone marrow transplantation (alloBMT), autologous stem cell transplantation (ASCT) and chemotherapy (Chemo). 162 patients (79.4%) achieved a complete remission (CR). Of the 135 patients who were still in CR after consolidation, 96 patients were less than 46 years of age: 36 patients had an HLA-identical sibling donor and were allocated for alloBMT (group I); they were compared to the 60 other patients who did not have an HLA-identical sibling donor and were treated with either ASCT or chemotherapy (group II). The 3-year disease-free survival was higher for group I patients (66.5 +/- 16%) than for the 60 group II patients (42.4 +/- 13%) (P < 0.05). The actuarial risk of relapse at 3 years was significantly lower for group I patients (24 +/- 15%) than for the other 60 group II patients (56 +/- 13%; P < 0.009). By multivariate analysis, the disease-free survival and risk of relapse were influenced by the initial WBC count (P < 0.02 and P < 0.006), the number of chemotherapy courses for CR (P < 0.001 and P < 0.01) and the type of post-induction treatment (alloBMT vs no alloBMT; P < 0.1 and P < 0.02). The 99 patients who did not fulfill the inclusion criteria for alloBMT were given intensive chemotherapy including high-dose aracytine. When they were still in CR (n = 77), these patients were then randomized for either ASCT (n = 39) or Chemo (n = 38). We were unable to detect any statistical difference between ASCT and Chemo for either disease-free survival, risk of relapse or survival. These results indicate that alloBMT seems to produce results which are at least superior to those of other therapeutic modalities. The results of either ASCT or Chemo look similar.

Sequential induction chemotherapy with vincristine, daunorubicin, cyclophosphamide, and prednisone in adult acute lymphoblastic leukemia.

Sequential chemotherapy with vincristine, daunorubicin, cyclophosphamide, and prednisone doses was administered to 57 adult patients with acute lymphoblastic leukemia (ALL). Complete remission (CR) was achieved in 51 (89%, 95% confidence intervals, [CI] 78-96%). Among patients achieving CR, 62% were in CR after one sequence of chemotherapy, 23% after two sequences, and 5% after three sequences. Six patients (11%) had resistant disease. All patients experienced profound myelosuppression. Median time to recovery of neutrophils > 0.5 x 10(9)/1 was 22 days (range: 5-89 days), and of platelets > 100 x 10(9)/1 21 days (range: 0-45 days). Nonhematologic WHO grade 3 or more side effects consisted predominantly of hyperbilirubinemia (7%), mucositis (5%), nausea and vomiting (2%), and cutaneous toxicity (1%). Severe infectious complications occurred in only 14% of cases. One patient (2%, 95% CI 0-9%) died of therapy-related toxicity while in early CR. We concluded that sequential use of prednisone seemed at least as effective as continuous administration at the expense of a few adverse side effects.

Autologous stem cell transplantation versus chemotherapy for adult patients with acute myeloid leukemia in first remission: the BGMT Group experience.

The BGMT 87 study was designed to compare prospectively Allogeneic Bone Marrow Transplantation (AlloBMT), Autologous Stem Cell Transplantation (ASCT) and Chemotherapy (CT). Of the patients who could not undergo AlloBMT and were still in remission after two cycles of intensive CT were randomized for ASCT (n = 39) or CT (n = 38). The actuarial risk of relapse was 48.7 +/- 8.8% (95% ci) in the ASCT group and 61.1 +/- 8.4% (95% ci) in the CT group (p = NS). The estimated chance of surviving without disease at three years was similar in both groups (48.3 +/- 8.5% versus 38.9 +/- 8.4; p = NS).

Role of splenectomy in incidence and severity of acute graft-versus-host disease: a multicenter study of 157 patients.

Allogeneic bone marrow transplantation is a therapeutic option for many hematological malignancies. Graft-versus-host disease (GVHD) remains one of the major complications and has a high mortality rate. The pathophysiological mechanisms involved are poorly understood and GVHD prevention regimens still give disappointing results. This study concerned 157 patients with diverse diagnoses from Bordeaux, Grenoble and Marseille who had undergone an HLA-matched transplantation without T cell depletion. Thirty-one patients (20%) had been splenectomized before transplantation. The role of splenectomy in the incidence and severity of acute GVHD was investigated using a univariate and multivariate analysis of 11 risk factors including splenectomy. Univariate analysis found three significant risk factors linked with GVHD incidence: splenectomy, age of recipient and GVHD prevention by monotherapy versus a combination of methotrexate plus cyclosporin. Multivariate analysis retained only the effects of age and GVHD prevention on GVHD incidence and showed that splenectomy was the most important factor in GVHD severity. One explanation for the role of splenectomy could be the spleen's possible function as a filter of activated T lymphocytes from the transplant. We therefore concluded that it would be preferable to abstain from splenectomizing patients before transplantation although splenectomy is still advisable in certain malignancies after transplantation.

Allogeneic bone marrow transplantation in chronic lymphocytic leukemia: 17 cases. Report from the EBMTG.

Allogeneic bone marrow transplantation (BMT) was performed in 17 patients with chronic lymphocytic leukemia (CLL): 15 resistant and two untreated forms. There were 12 males and five females with a mean age of 40 years (32-49). The conditioning regimens and graft-versus-host disease (GVHD) prophylaxis varied. Successful engraftment was obtained in 15 evaluable cases. Lymphocytosis and clinical symptoms subsided in all but one case. All 15 evaluable patients developed acute GVHD. Among the 17 patients grafted, one early death was observed at the 15th day post-BMT, and one refractory patient died 2 months after BMT. Of the remaining 15 patients in complete remission (CR), four died from GVHD, hemorrhage and graft failure, and two relapsed at 7 and 54 months after BMT and died. Nine patients are alive in CR with a mean follow-up of 25.6 months (4-48). Chimerism was complete in eight patients and partial in the two T cell-depleted cases. In one case, an immunoglobulin gene rearrangement study showed no residual disease. These results suggest that allogenic BMT might be an alternative and possible curative therapy for refractory CLL in young patients when performed relatively early in the disease.

Allogeneic Bone Marrow Transplantation in Chronic Lymphocytic Leukemia: 17 Cases. Report of the EBMT.

Allogeneic bone marrow transplantation (BMT) was performed in 17 patients with chronic lymphocytic leukemia (CLL): 15 resistant and 2 untreated forms; 12 males and 5 females with a mean age of 40 years (32-49). The conditioning regimen and graft versus host disease (GVHD) prophylaxis were varied. Successful engraftment was obtained in 15 evaluable cases. Lymphocytosis and clinical symptoms subsided in all but one case. All 15 evaluable patients developed acute GVHD. Among the 17 patients grafted, one early death was observed at the 15th day post-BMT, and one refractory form died 2 months after BMT. Of the remaining 15 patients in complete remission (CR0, 4 died from GVHD, hemorrhage, and graft failure, and 2 relapsed at 7 and 54 months after BMT and died. 9 patients are alive in CR with a mean follow-up of 25.6 months (4-48). Chimerism was complete in 8 patients and partial in the 2 T-depleted cases. In one case, an immunoglobulin gene rearrangement study was performed showing no residual disease. These results suggest that allogeneic BMT might be proposed as an alternative and possibly curative therapy for refractory CLL in young patients when performed earlier in the disease course.

Treatment of acute myeloid leukemia in elderly patients: the influence of maintenance therapy (BGM 84 protocol).

Ninety-two elderly patients (ages 50-70) with "de novo" acute myeloid leukemia were given induction chemotherapy consisting of aclacinomycin-A (ACLA) (100 mg/m2/day x 3) and cytosine arabinoside (ARA-C) (100 mg/m2 day, continuous infusion, 7 days). Fifty-one patients (55%) achieved complete remission (CR), 8 patients exhibited drug resistance and 33 patients died during chemotherapy or aplasia. Three patients had severe cardiac toxicity. The only prognostic factor significantly affecting CR was the initial leukocyte count. After consolidation using ACLA (80 mg/m2/day x 2) and ARA-C (100 mg/m2/day x 5), 47 CR patients were randomly assigned to 2 different treatment arms: 23 patients (Group A) received intensive sequential chemotherapy consisting of 4 monthly courses of 8 different drugs while 24 other patients (Group B) were given ACLA and ARA-C at regular intervals, associated with continuous chemotherapy consisting of 6-mercaptopurine, methotrexate and androgens. The probability of disease-free survival at 2 years was significantly higher (33 +/- 22%) for Group B patients than for Group A (13 +/- 16%) (P less than 0.05). We conclude that continuous maintenance chemotherapy may be useful in increasing the number of long-term survivors, at least in the elderly who have not received very intense consolidation chemotherapy following CR.

Comparison of allogeneic or autologous bone marrow transplantation and chemotherapy in patients with acute myeloid leukaemia in first remission: a prospective controlled trial.

Eighty-five adult patients under the age of 50 years with acute myeloid leukaemia (AML) were entered into a prospective controlled study conducted to compare the effectiveness of allogeneic or autologous bone marrow transplantation and intensive chemotherapy for patients in first complete remission. Sixty-one patients (72%) achieved complete remission then received a consolidation treatment. After consolidation, 58 patients who were still in remission were assigned to three different therapeutic modalities. Fifty-two patients were evaluable: 20 patients who had an HLA-identical sibling donor underwent allogeneic bone marrow transplantation within 3 months after achievement of complete remission; the other 32 patients were randomized to receive autologous bone marrow transplantation or intensive sequential chemotherapy. The actuarial risk of relapse at 3 years was 18% for the allogeneic patients, 50% for the autologous patients and 83% in the chemotherapy group. The difference was highly significant (P less than 0.0002). The disease-free survival was respectively 66% (95% confidence interval 41-85%), 41% (95% confidence interval 16-66%) and 16% (95% confidence interval 0-31%) (P less than 0.004). We conclude that allogeneic bone marrow transplantation is presently the best therapeutic approach for patients with AML in first complete remission.

Allogeneic bone marrow transplantation in chronic lymphocytic leukemia: report from the European Cooperative Group for bone marrow transplantation (8 cases).

Allogenic bone marrow transplantation (BMT) was performed in 8 patients with B chronic lymphocytic leukemia (CLL): 6 males and 2 females with a median age of 41 years (37 to 46). Seven patients were resistant to previous therapy and were grafted in the evolutive phase. Only 1 patient was grafted without any previous treatment. At the time of BMT 5 patients were classified according to the Rai classification in stage IV, 1 in stage III and 2 in stage 1. The delay between diagnosis and BMT was 47 months (5 to 68). Graft versus host disease (GVHD) prophylaxis was methotrexate (1 patient), cyclosporine (2 patients), methotrexate + cyclosporine (3 patients), cyclosporine + physical removal of T cells (2 patients). The conditioning regimen was standard for 5 patients, reinforced for 3 patients with Chlorambucil (1 patient) and etoposide (2 patients). A successful engraftment was obtained in all cases. The lymphocytosis decreased slowly and disappeared from day 0 to day 28. All patients developed an acute GVHD 5 of which resolved. Three patients died: 2 of acute GVHD and 1 of intracerebral hemorrhage. Five patients are alive in persistent complete remission without clinical symptoms and with normal peripheral blood and normal bone marrow. The median follow-up is 27 months (13-53). This small series suggests that allogeneic BMT should be investigated in selected patients as possible curative treatment of CLL.

[Deep candidiasis in agranulocytic patients: mycological and serological surveillance in 91 febrile episodes and management of an antifungal and antibacterial protocol]. / Candidoses profondes chez l'agranulocytaire: surveillance mycologique et sérologique au cours de 91 épisodes fébriles et gestion d'un protocole antibactérien et antifongique.

This study took place between February 1984 and February 1985 in 76 febrile neutropenic patients. We evaluated the whole mycological and serological results, in 91 febrile episodes. We separated two groups: group I (acute leukemia, chronic myeloïd leukemia, medullar aplasia, lymphomas) and group II (chronic lymphoïd leukemia, Hodgkin disease, myelomas, solid tumors). Patients were included in this study if they developed a temperature of 38.5 degrees C or greater and if they had less than five hundred neutrophils per mm3. They were treated with mono or bi-antibiotherapy. If the patient remained febrile more than 72 hours, an antifungal therapy was added (Amphotericin B IV). Through these weekly results, we conclude: the high frequency of digestive tract candidiasis in such patients; disseminated candidiasis occurs only in the first group patients with fungal digestive colonization; the overall response rate in this study was 77 per cent. This underlines the interest of empiric treatment with amphotericin B IV.