Dexamethasone compared to prednisolone for adults with acute lymphoblastic leukemia or lymphoblastic lymphoma: final results of the ALL-4 randomized, phase III trial of the EORTC Leukemia Group.

BACKGROUND: Corticosteroids are a standard component of the treatment of acute lymphoblastic leukemia and lymphoblastic lymphoma. Our aim was to determine whether dexamethasone results in a better outcome than prednisolone. DESIGN AND METHODS: Adult patients with acute lymphoblastic leukemia or lymphoblastic lymphoma were randomized to receive, as part of their induction therapy on days 1-8 and 15-22, either dexamethasone 8 mg/m(2) or prednisolone 60 mg/m(2). Those who reached complete remission were given two courses of consolidation therapy with high-dose cytarabine and mitoxantrone and methotrexate and asparaginase. Subsequently patients younger than 50 years, with a suitable donor, were to undergo allogeneic stem cell transplantation, whereas the others were planned to receive either an autologous stem cell transplant or high-dose maintenance chemotherapy with prophylactic central nervous system irradiation. Randomization was done with a minimization technique. The primary endpoint was event-free survival and the analyses was conducted on an intention-to-treat basis. RESULTS: Between August 1995 and October 2003, 325 patients between 15 to 72 years of age were randomized to receive either dexamethasone (163 patients) or prednisolone (162 patients). After induction and the course of first consolidation therapy, 131 (80.4%) patients in the dexamethasone group and 124 (76.5%) in the prednisolone group achieved complete remission. No significant difference was observed between the two treatment groups with regards to 6-year event-free survival rates (+/-SE) which were 25.9% (3.6%) and 28.7% (3.5%) in the dexamethasone and prednisolone groups, respectively (P=0.82, hazard ratio 0.97; 95% confidence interval, 0.75-1.25). Disease-free survival after complete remission was also similar in the dexamethasone and prednisolone groups, the 6-year rates being 32.3% and 37.5%, respectively (hazard ratio 1.03; 95% confidence interval 0.76-1.40). The 6-year cumulative incidences of relapse were 49.8% and 53.5% (Gray's test: P=0.30) while the 6-year cumulative incidences of death were 18% and 9% (Gray's test: P=0.07). CONCLUSIONS: In the ALL-4 trial in adult patients with acute lymphoblastic leukemia or lymphoblastic lymphoma, treatment with dexamethasone did not show any advantage over treatment with prednisolone.

Relapse risk after autologous transplantation in patients with newly diagnosed myeloma is not related with infused tumor cell load and the outcome is not improved by CD34+ cell selection: long term follow-up of an EBMT phase III randomized study.

BACKGROUND AND OBJECTIVES: This European Group for Blood and Marrow Transplantation (EBMT) multicentre randomized phase III study was designed to assess the safety and efficacy of CD34+ selection in newly diagnosed myeloma patients undergoing autologous transplantation. DESIGN AND METHODS: One hundred and eleven patients responsive to initial chemotherapy were randomized to receive CD34+ selected (arm A) or unselected PBPC (arm B) after conditioning with high-dose melphalan and TBI. ASO-PCR was used to assess purging efficacy and reinfused tumor load. Tumor load could be assessed in 59 patients. RESULTS: CD34+ selection gave a median tumor cell depletion of 2.2 logs (0.77-5.96). No tumor cells were detected in products infused in 17/26 (A) and 5/33 (B) patients. The five year overall survival (OS), event free survival (EFS) and relapse rate (RR) were 51%, 20% and 80% in arm A and 45%, 18% and 80% in arm B respectively with no significant difference between the two groups. Thirteen patients in arm A and 2 in arm B experienced episodes of serious early infection (p=0.02). There were 3 early transplant related deaths in A but none in B. INTERPRETATION AND CONCLUSIONS: Despite significant tumor cell reduction, CD34+ selection does not reduce RR and increases the risk of severe post-transplant infections. There was also no difference in RR between patients in either arm who received grafts with detectable tumor cells and those receiving grafts with no detectable tumor cells, suggesting that reinfused tumor cells may not be the main cause of relapse after autologous transplant in myeloma.

Autologous stem cell transplantation after complete remission and first consolidation in acute myeloid leukemia patients aged 61-70 years: results of the prospective EORTC-GIMEMA AML-13 study.

BACKGROUND AND OBJECTIVES: The optimal post-remission treatment for elderly patients with acute myeloid leukemia (AML) is presently unknown. Recent studies have reported the feasibility of autologous peripheral blood stem cell transplantation (PBSCT) in this population. We evaluate the outcome of this post-remission approach after complete remission (CR) and consolidation in elderly patients included in the EORTC-GIMEMA AML-13 trial. DESIGN AND METHODS: PBSCT after induction and consolidation chemotherapy was evaluated in patients aged 61 to 70 years with a WHO performance status 0-1. The induction therapy was mitoxantrone, etoposide and cytarabine (MICE) with or without granulocyte colony-stimulating factor (G-CSF) during and/or after chemotherapy. The consolidation therapy consisted of non-infusion or infusional idarubicin, etposide and cytarabine (mini-ICE). RESULTS: Sixty-one patients were scheduled for stem cell harvest by leukapheresis after s.c. recombinant human G-CSF administration initiated after hematopoietic recovery from consolidation. Stem cells were effectively harvested from 54 patients. A median of two aphereses (range, 1-5) were performed, resulting in a median collection of 11.7 x 10(8) nucleated cells/kg (range, 2.4-99.8) containing 40.2 x 10(4) CFU-GM/kg (range, 0-786.8), and 5 x 10(6) CD34+ cells/kg (range, 0.1-99.8). For the whole group of 61 patients, the median disease-free survival (DFS) was 1.0 years and the 3-year DFS rate was 21%, while the median overall survival (OS) was 1.4 years and the 3-year OS rate was 32%. A total of 26 patients could not be autografed due to inadequate/no harvest (21 patients), early relapse (3 patients), or treatment refusal (2 patients). Autologous transplantation was performed in 35 patients following conditioning with the BAVC regimen. The median time for granulocyte recovery >0.5 109 yen/L was 24 days and for platelets >20 x10(9)/L was 23 days following transplantation. After a median follow-up of 5.0 years from transplantation, the median DFS and OS were 1.1 and 1.6 years respectively, and the 3-year rates were 28% and 39% respectively. Eight autografted patients were still in continuous complete remission, 22 patients had relapsed and five had died in CR. INTERPRETATION AND CONCLUSIONS: Intensification of remission including autologous PBSCT is feasible in about half of harvested patients aged 61 to 70 years old, and did not improve the general outcome. This shows the limitations of autologous PBSCT and other intensive treatment modalities in elderly AML patients. Key words: acute myeloid leukemia, elderly, autologous stem cell transplantation.

Arsenic trioxide in patients with myelodysplastic syndromes: a phase II multicenter study.

PURPOSE: Evaluation of the safety and efficacy of arsenic trioxide in patients with myelodysplastic syndromes (MDS). PATIENTS AND METHODS: MDS patients diagnosed according to standard French-American-British criteria received a loading dose of 0.3 mg/kg per day of arsenic trioxide for 5 days followed by a maintenance dose of 0.25 mg/kg arsenic trioxide twice weekly for 15 weeks. Patients were divided into two cohorts: lower-risk MDS (International Prognostic Scoring System risk category low or intermediate 1) and higher-risk MDS (International Prognostic Scoring System risk category intermediate 2 or high). Modified International Working Group criteria were used for response evaluation. RESULTS: Of 115 patients enrolled and treated in the study, 67% of patients were transfusion dependent at baseline; median age was 68 years. Most treatment-related adverse events were mild to moderate. The overall rate of hematologic improvement (intent-to-treat) was 24 (19%) of 115, including one complete and one partial response in the higher-risk cohort. The hematologic response rates were 13 (26%) of 50 and 11 (17%) of 64 in patients with lower-risk and higher-risk MDS, respectively. Major responses were observed in all three hematologic lineages; 16% of RBC transfusion-dependent patients and 29% of platelet transfusion-dependent patients became transfusion independent. At data cut off, the median response duration was 3.4 months, with responses ongoing in nine patients. CONCLUSION: Arsenic trioxide treatment consisting of an initial loading dose followed by maintenance therapy has moderate activity in MDS, inducing hematologic responses in both lower- and higher-risk patients. This activity combined with a manageable adverse effect profile warrants the additional study of arsenic trioxide, particularly in combination therapy, for the treatment of patients with MDS.

Post-transplant lymphoproliferative disorders after lung transplantation: first-line treatment with rituximab may induce complete remission.

BACKGROUND: Post-transplant lymphoproliferative disorders (PTLD) are potentially lethal complications of solid organ transplantation. We, here, report on our experience with rituximab, an anti-CD20 monoclonal antibody, as first-line treatment for PTLD in six lung transplant recipients. PATIENTS AND METHODS: Two of the patients developed PTLD during the first year after transplantation, while four developed late-onset PTLD. One patient presented with PTLD localized to the graft, one had unilateral cervical lymph nodes, and the others presented with multi-organ involvement. All patients had diffuse large B-cell lymphoma. Immunosuppressive therapy was reduced and rituximab was administered at a dose of 375 mg/m(2)/wk for 4 wk. RESULTS: One patient did not respond to the first two courses of rituximab, received conventional chemotherapy, and achieved complete remission; four patients achieved complete remission after four courses with a median relapse-free survival of 34 months (range: 14-55); and one patient did not respond and died. The diagnosis of complete remission was established by conventional imaging techniques combined to whole-body positron emission tomography scan. CONCLUSIONS: We conclude that reduction in immunosuppression combined to first-line treatment with rituximab may induce long-term complete remission in lung transplant recipients presenting PTLD.

Efficacy and safety of rituximab in B-cell post-transplantation lymphoproliferative disorders: results of a prospective multicenter phase 2 study.

B-cell posttransplantation lymphoproliferative disorder (B-PTLD) is a rare but severe complication of transplantation, with no consensus on best treatment practice. This prospective trial, the first to test a treatment for PTLD, was designed to evaluate the efficacy and safety of rituximab in patients with B-PTLD after solid organ transplantation (SOT). Forty-six patients were included and 43 patients were analyzed. Patients were eligible if they had untreated B-PTLD that was not responding to tapering of immunosuppression. Treatment consisted of 4 weekly injections of rituximab at 375 mg/m2. At day (d) 80, 37 (86%) patients were alive, and the response rate was 44.2%, including 12 complete response/unconfirmed complete response (CR/CRu). The only factor predictive of a response at d80 was a normal lactate dehydrogenase level (P = .007, odds ratio [OR] = 6.9). At d360, responses were maintained in 68% of patients, and 56% of patients were alive. The overall survival rate at 1 year was 67%. We conclude that rituximab is effective and safe in PTLD, with stable responses at 1 year. The response rate and overall survival might be improved by combining rituximab with other treatments.

Allogeneic stem cell transplantation in acute lymphoblastic leukemia and non-Hodgkin's lymphoma for patients

BACKGROUND AND OBJECTIVES: In the EORTC ALL-3 trial, the efficacy of allogeneic transplantation was compared with that of autologous marrow transplantation and maintenance chemotherapy in patients

Atypical recurrent varicella in 4 patients with hemopathies.

Relapsing varicella may occur in children with HIV infection and more rarely in younger adults. Our aim was to report unusual clinical, histologic, and virologic aspects of 4 elderly patients with malignant hemopathies who had an unusual form of recurrent varicella develop. Conventional microscopy, immunohistochemistry, and in situ hybridization were applied to smears and skin biopsy specimens. The patients presented a few dozen, scattered, large, papulovesicular lesions with central crusting. No zoster-associated pain or dermatomal distribution of the lesions was noted. Conventional microscopy revealed vascular changes and epidermal alterations typical for alpha-herpes virus infection. The varicella zoster virus major viral envelope glycoproteins gE and gB, and the immediate-early varicella zoster virus IE63 protein and the corresponding genome sequence for gE were detected on Tzanck smears; they were localized in endothelial cells and keratinocytes on skin biopsy specimens. The varicella zoster virus infection in endothelial cells, the vascular involvement, and the widespread distribution of the lesions suggest that the reported eruptions are vascular rather than neural in origin. These findings invalidate the diagnosis of herpes zoster but strongly support the diagnosis of recurrent varicella in an indolent and yet unreported presentation. Furthermore, these eruptions differ from relapsing varicella in children and young adults by the age of the patients, the paucity of clinical lesions, the larger diameter of the lesions and their peculiar clinical aspect, the significantly longer time interval between primary varicella and the recurrence, the prolonged healing time of the lesions, their mild disease course, and the fact that all the lesions are in the same stage of development.