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We have previously shown that CD8 depletion or CD34 selection of peripheral blood stem cells (PBSC) reduced the incidence of acute graft-versus-host disease (GvHD) after nonmyeloablative stem-cell transplantation (NMSCT). In this study, we analyze the effect of CD8 depletion or CD34 selection of the graft on early T-cell reconstitution.Nonmyeloablative conditioning regimen consisted in 2 Gy total-body irradiation (TBI) alone, 2 Gy TBI and fludarabine, or cyclophosphamide and fludarabine. Patients 1 to 18 received unmanipulated PBSC, patients 19 to 29 CD8-depleted PBSC, and patients 30 to 35 CD34-selected PBSC.T-cell counts, and particularly CD4+ and CD4CD45RA+ counts, remained low the first 6 months after nonmyeloablative stem-cell transplantation (NMSCT) in all patients. CD34 selection (P0.0001) but not CD8 depletion of PBSC significantly decreased T-cell chimerism. Donor T-cell count was similar in unmanipulated compared with CD8-depleted PBSC recipients but was significantly lower in CD34-selected PBSC recipients (P=0.0012). T cells of recipient origin remained stable over time in unmanipulated and CD8-depleted PBSC patients but expanded in some CD34-selected PBSC recipients between day 28 and 100 after transplant. Moreover, whereas CD8 depletion only decreased CD8+ counts (P0.047), CD34 selection reduced CD3+(P0.001), CD8+(P0.016), CD4+ (P0.001), and CD4+CD45RA+ (P0.001) cell counts. T-cell repertoire was restricted in all patients on day 100 after hematopoietic stem-cell transplantation but was even more limited after CD34 selection (P=0.002).Despite of the persistence of a significant number of T cells of recipient origin, T-cell counts were low the first 6 months after NMSCT. Moreover, contrary with CD8 depletion of the graft that only affects CD8+ lymphocyte counts, CD34 selection dramatically decreased both CD8 and CD4 counts.

Previous trials of recombinant human erythropoietin (rHuEpo) therapy after autologous hematopoietic stem cell transplantation have administered very high doses of i.v. rHuEpo starting on day 1 and continuing for 1-2 months until erythroid engraftment and have shown no benefit of rHuEpo therapy. We sought to establish a more effective use of rHuEpo in this setting.In this report, we show in a first cohort of 45 lymphoma or myeloma patients undergoing peripheral blood stem cell transplant (control group) that endogenous erythropoietin levels are high for the degree of anemia during the first 3 weeks after transplant but become adequate or slightly decreased thereafter. We thus enrolled 41 consecutive similar patients in a trial of rHuEpo therapy at a dose of 500 units/kg/week started on day 30 after the transplant.The 12-week probability of achieving hemoglobin (Hb) levels of 13 g/dl was 87% in rHuEpo-treated patients versus 14% in controls (P = 0.0001). Mean Hb levels were significantly higher in the rHuEpo group than in the control group from day 42 through day 150 after transplant (Ps of0.05 to0.001). Two of 41 patients in the rHuEpo group versus 12 of 45 patients in the control group had Hb levels of9 g/dl between day 42 and day 100 after the transplant (P = 0.0078).Anemia after autologous peripheral blood stem cell transplant is exquisitely sensitive to rHuEpo when therapy is started soon after engraftment. This is the first convincing report showing that rHuEpo is effective in this setting. Our data set the stage for a more rational use of rHuEpo after autologous hematopoietic stem cell transplantation and should renew interest in erythropoietin therapy in this setting. Prospective, randomized trials should investigate the impact of rHuEpo therapy on transfusion requirements and quality of life.

We investigate the feasibility of CD34-selected peripheral blood stem cell (PBSC) transplantation followed by pre-emptive CD8-depleted donor lymphocyte infusions (DLI) after a minimal conditioning regimen. Six patients with advanced hematological malignancies ineligible for a conventional myeloablative transplant (n=5) or metastatic renal cell carcinoma (n=1), and with an HLA-identical (n=4) or alternative (n=2) donor were included. The nonmyeloablative conditioning regimen consisted in 2 Gy TBI alone (n=4), 2 Gy TBI and fludarabine (RCC patient, n=1) or cyclophosphamide and fludarabine (patient who had previously received 12 Gy TBI, n=1). Post transplant immunosuppression was carried out with cyclosporin (CyA) and mycophenolate mofetil (MMF). Initial engraftment was achieved in all patients. One out of six patients (17%) experienced grade > or =2 acute GVHD only after abrupt cyclosporin discontinuation and alpha interferon therapy for life-threatening tumor progression. T-cell chimerism was 23% (19-30) on day 28, 32% (10-35) on day 100, 78% (49-95) on day 180 and 99.5% (99-100) on day 365. Three out of four patients who had measurable disease before the transplant experienced a complete response. We conclude that CD34-selected NMSCT followed by CD8-depleted DLI is feasible and preserves engraftment and apparently also the graft-versus-leukemia (GVL) effect. Further studies are needed to confirm this encouraging preliminary report.

We evaluated the ability of recombinant human erythropoietin (rHuEpo) therapy, given before high-dose therapy (HDT), to allow autologous peripheral blood stem cell transplantation (PBSCT) without red blood cell (RBC) transfusions. Eleven multiple myeloma patients underwent tandem HDT and autologous PBSC, receiving 500 U/kg/week rHuEpo from d 30 after initial transplant. Haemoglobin levels were 9.5 +/- 1.1 g/dl and 12.5 +/- 0.9 g/dl at the first and second transplant respectively (P < 0.001). RBC transfusions were required for 10/11 patients for the first transplant versus 1/11 for the second (P < 0.001). To conclude, a short course of rHuEpo therapy before HDT facilitates the performance of an autologous transplant without RBC transfusions.

With the emergence of positron emission tomography (PET) from research laboratories into routine clinical use, it is important to redefine the most appropriate use of each imaging technique. The aim of this review article is to show the potential of PET in oncology. We discuss the most promising indications and the perspectives for the future. We will also point out the shortcomings and the important questions to be answered before fully considering PET as a necessary tool in the day-to-day practice of oncology. Although many studies have documented the high accuracy of 18F-FDG PET for the detection and staging of malignant tumours and for the monitoring of therapy results in these patients, it is very important to assess the impact of the technique on patient outcome and to show cost-effectiveness from the societal viewpoint.

BACKGROUND: It is not known whether increasing the dose of filgrastim after mobilizing chemotherapy improves collection of peripheral blood progenitor cells (PBPC) and leads to faster hematopoietic engraftment after autologous transplantation. STUDY DESIGN AND METHODS: A randomized, open-label, multicenter trial was carried out in patients with breast cancer, multiple myeloma, and lymphoma, in which patients were randomized to receive 5 or 10 microg per kg per day of filgrastim after standard chemotherapy to mobilize PBPCs. After high-dose chemotherapy, the components from the first two leukapheresis procedures were returned, and all patients received 5 microg per kg day of filgrastim after transplantation. RESULTS: A total of 131 patients were randomized, of whom 128 were mobilized (Group A, 5 microg/kg, n = 66; Group B, 10 microg/kg, n = 62) and 112 were transplanted. Only six patients were not transplanted because of insufficient CD34+ cell numbers. The median number of CD34+ cells collected in the first two leukapheresis procedures tended to be higher in Group B than in Group A (12.0 vs. 7.2 x 10(6)/kg, NS), but after transplantation there was no significant difference in median times to platelet (9 days in both groups) or neutrophil (8 days in both groups) engraftment or the number of platelet transfusions (three in both groups). A subsequent subgroup analysis separating patients transplanted after first- or second-line chemotherapy also showed no measurable impact of filgrastim dose on the median CD34+ cell yield or on platelet engraftment in either subgroup. CONCLUSION: PBPC mobilization with chemotherapy and 5 microg per kg of filgrastim is very efficient, and 10 microg per kg of filgrastim does not provide additional clinical benefit.

Item does not contain fulltext Variable numbers of CD34+ cells can be harvested from the blood of AML patients in CR after G-CSF supported mobilization following consolidation chemotherapy. We hypothesized that a decreased ability to mobilize stem cells reflects a chemotherapy-induced reduction in the number of normal and leukemic stem cells. We therefore analyzed whether the mobilizing capacity of these patients was of prognostic significance. 342 AML-patients in first CR received daily G-CSF from day 20 of the consolidation course and underwent 1-6 aphereses to obtain a minimum dose of 2 x 10(6) CD34+ cells/kg. Afterwards they were randomized for autologous bone marrow (BM) or blood SCT. As a surrogate marker for the mobilizing capacity, the highest yield of CD34+ cells of a single apheresis was adopted. Patients could be categorized into four groups: no harvest (n = 76), low yield ( or = 7 x 10(6) CD34+ cells/kg; n = 88). The median follow-up was 3.4 years; 163 relapses and 16 deaths in CR were reported. Autologous blood or BM SCT was performed in 36%, 64%, 81% and 88%, respectively, of the patients assigned to the no harvest, low, intermediate and high CD34+ yield group. The 3-year disease-free survival rate was 46.7%, 65.0%, 50.4% and 26.9% (P = 0.0002) and the relapse incidence was 47.5%, 30.1%, 43.1% and 71.9% (P < 0.0001). Multivariate Cox's proportional hazards model showed that the CD34+ yield was the most important independent prognostic variable (P = 0.005) after cytogenetics. Patients with the highest mobilizing capacity have a poor prognosis due to an increased relapse incidence.

Background: Relapse after treatment of Hodgkin’s disease (HD) is usually identified as a result of the investigation of symptoms. We undertook this study to examine the value of whole-body positron emission tomography (PET) for the detection of preclinical relapse. Patients and methods: Thirty-six patients underwent 2-[fluorine-18]fluoro-2-deoxy-D-glucose ( 18 F-FDG) PET at the end of treatment and than every 4–6 months for 2–3 years after the end of polychemotherapy and/or radiotherapy. In those cases of abnormal 18 F-FDG accumulation a confirmatory study was performed 4–6 weeks later. Results: One patient had residual tumor and four patients relapsed during a follow-up of 5–24 months. All five events were correctly identified early by 18 F-FDG PET. Residual tumor or relapse was never first diagnosed based on clinical examination, laboratory findings or computed tomography (CT) studies. Two patients presented B symptoms and the three others were asymptomatic at the time of residual disease or relapse. Confirmation of residual disease or relapse was obtained by biopsy in four patients 1, 1, 5 and 9 months after PET and by unequivocal clinical symptoms and CT studies in one patient 3 months after PET. False-positive 18 F-FDG PET studies incorrectly suggested possible relapse in six other patients, but the confirmatory PET was always negative. Our study also provides important information about physiological 18 F-FDG uptake in the thymus. Conclusions: Our data suggest the potential of 18 F-FDG PET to detect preclinical relapse in patients with HD. This could help identify patients requiring salvage chemotherapy at the time of minimal disease rather than at the time of clinically overt relapse. Further studies are warranted to determine the impact of PET on treatment management and outcome. In fact, the aim of follow-up procedures is not only to detect preclinical relapse but mainly to obtain better results by starting salvage treatment earlier. A cost–benefit analysis will also be necessary before 18 F-FDG PET can be used routinely in the follow-up of patients with HD.

We have previously reported the feasibility of allogeneic CD34-selected PBSC transplantation followed by pre-emptive CD8-depleted DLI (study group). In this report, we retrospectively compare the clinical outcome of the 24 patients included in this study with an historical group of 35 patients receiving unmanipulated marrow (BMT group). Patients in the study group had significantly faster neutrophil and platelet recovery and were discharged earlier than BMT patients. The actuarial 150-day (after DLI) probability of developing grade II-IV acute GVHD was 28% for the study group versus 62% for the BMT group (p=0.002). The actuarial 2-year probability of developing chronic GVHD was similar (37 versus 36% (NS)) but chronic GVHD was significantly delayed in the study group (p=0.003). The actuarial 2-year probability of relapse was 30% in the study group versus 33% in the BMT group (NS). The actuarial 2-year probability of survival was 45% in the study group versus 43% in the BMT group (NS). We conclude that allogeneic transplantation of CD34-selected PBSC followed by pre-emptive CD8-depleted DLI is feasible with rapid engraftment and minimizes the risk of severe GVHD. Large prospective trials are required to confirm these results.

PURPOSE: Randomized trial LNH93-3 was conducted on patients who had poor-prognosis aggressive lymphoma and were younger than 60 years with two to three factors of the age-adjusted International Prognostic Index to evaluate the benefit of early high-dose therapy (HDT) with autologous stem-cell transplantation (ASCT). PATIENTS AND METHODS: Patients were randomized between doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (ACVBP) chemotherapy followed by sequential consolidation and an experimental shortened treatment consisting of three cycles with escalated doses of cyclophosphamide, epirubicin, vindesine, bleomycin, and prednisone and collection of peripheral-blood stem cells. On day 60, HDT was administered with 1,3-bis(2-chloroethyl)-1-nitrosourea, etoposide, cytarabine, and melphalan followed by ASCT. RESULTS: Eligible patients (n = 370) with aggressive lymphoma were analyzed. For ACVBP (181 patients) and HDT (189 patients), respective complete remission rates were 64% and 63%. With a median follow-up of 60 months, 5-year overall survival and event-free survival for ACVBP and HDT were 60% ± 8% and 46% ± 8% (P = .007) and 52 ± 8% and 39 ± 8% (P = .01), respectively. Survival was independently affected by age greater than 40 years (P = .0003), T-cell phenotype (P = .009), bone marrow involvement (P = .003), and HDT treatment group (P = .04). CONCLUSION: Early HDT with ASCT in high-risk patients was inferior to the ACVBP chemotherapy regimen. These results indicate that the received dose-intensity before HDT was too low when compared with ACVBP and HDT and was given too early.

To decrease the incidence of graft-versus-host disease (GVHD) observed after nonmyeloablative stem cell transplantation (NMSCT), we studied the feasibility of CD8-depleted or CD34-selected NMSCT followed by CD8-depleted preemptive donor lymphocyte infusion (DLI) given in incremental doses on days 40 and 80. Fourteen patients with high-risk malignancies and an HLA-identical sibling (n = 8) or alternative donor (n = 6) but ineligible for a conventional transplant were included. Nonmyeloablative conditioning regimen consisted in 2 Gy total body irradiation (TBI) alone, 2 Gy TBI and fludarabine (previously untreated patients) or cyclophosphamide and fludarabine (patients who had previously receivedor =12 Gy TBI). Patients 1-4 (controls) received unmanipulated peripheral blood stem cells (PBSC) and DLI and patients 5-14 CD8-depleted or CD34-selected PBSC followed by CD8-depleted DLI. Post-transplant immunosuppression was carried out with cyclosporine A (CsA) and mycophenolate mofetil (MMF). Initial engraftment was seen in all patients, but 1 patient (7%) later rejected her graft. The actuarial 180-day incidence of grades II-IV acute GVHD was 75% for patients 1-4 versus 0% for patients 5-14 (p = 0.0019). Five of 14 patients were in complete remission (CR) 180 days after the transplant and 6/14 had partial responses. The 1-year survival rate was 69%, and nonrelapse and relapse mortality rates were 16 and 18%, respectively. We conclude that CD8-depleted or CD34-selected NMSCT followed by CD8-depleted DLI is feasible and considerably decreases the incidence of acute GVHD while preserving engraftment and apparently also the graft-versus-leukemia (GVL) effect. Further studies are needed to confirm this encouraging preliminary report.

To maximize graft-versus-leukemia (GVL) effects while minimizing the risk of graft-versus-host disease (GVHD), we undertook a study of allogeneic CD34-selected peripheral blood stem cell (PBSC) transplantation followed by CD8-depleted donor lymphocyte infusion (DLI).Twenty-four patients with advanced hematologic malignancies were included. PBSC were collected in matched (N=16) or one-mismatch (N=8) related donors and CD34-selected. On day 60, donors donated lymphocytes that were CD8-depleted and separated into 3 aliquots containing 2 x 10(6), 1 x 10(7) and 5 x 10(7) CD3+ cells/kg (patients 1-13) or into 2 aliquots containing 1 x 10(7) and 5 x 10(7) CD3+ cells/kg (patients 14-24). The 1st aliquot was infused on day 60 and the other 1 (2) cryopreserved and infused on days 100 (and 140).An average of 100%, 100% and 84% of the scheduled dose could be administered in DLI 1, 2 and 3, respectively. Although the study group was at very high risk of GVHD, the actuarial incidence of grade II-IV acute GVHD was 28% (13% for HLA-identical siblings) with only 1 patient developing grade III-IV GVHD (after DLI). The actuarial 2-year probability of extensive chronic GVHD was similarly low (13% for all patients and 0% for HLA-identical siblings). Individual cases as well as a 30% relapse rate (0% for standard-risk patients versus 55% for high-risk patients) indicated preservation of the GVL effect.We conclude that allogeneic transplantation of CD34-selected PBSC followed by pre-emptive CD8-depleted DLI is feasible with rapid engraftment and minimizes the risk of severe GVHD. Large prospective trials are required to prove that it preserves the GVL effect fully.

Summary Background Although PET has been shown to be highly sensitive in the primary staging of lymphoma, previous studies with small numbers of patients indicated that low-grade NHL may not always be adequately detected by PET. We undertook this study to determine factors influencing the detection of lesions by PET in low-grade NHL and to evaluate the utility of PET in this indication. Patients and methods Forty-two patients underwent conventional staging procedures (clinical examination, oto-rhinolaryngologic examination, computed tomography of the chest, abdomen and pelvis, gastroscopy and bone marrow biopsy as well as whole-body non-attenuation corrected 18F-FDG-PET. Results PET detected 40% more abnormal lymph node areas than conventional staging in follicular lymphoma but was inappropriate for the staging of small lymphocytic lymphoma where it detected less than 58% of abnormal lymph node areas. PET showed more lesions than conventional staging for peripheral (34% more lymph node areas detected) and thoracic lymph node (39% more) areas but not for abdominal or pelvic lymph nodes (26% fewer areas detected). The sensitivity to detect bone marrow infiltration was unacceptably low for PET. In contrast, PET was as effective as standard procedures for the detection of other extranodal localizations, although a few localizations were detected only by PET and a few others only by conventional procedures. Conclusions PET may contribute to the management of patients with low-grade follicular NHL. For the other low-grade lymphoma subtypes, the role of PET is less evident. Further studies using PET to evaluate the results of treatment or to diagnose disease recurrence are warranted in low-grade follicular NHL.

Little information is available on the evolution of erythropoiesis after interruption of recombinant human erythropoietin (rHuEpo) therapy. Iron-overloaded rats received 20 daily injections of rHuEpo. During treatment, reticulocytes, soluble transferrin receptor (sTfR), and hematocrit increased progressively. This was accompanied by a substantial expansion of spleen erythropoiesis but a decrease in the bone marrow. Five weeks after treatment, rats developed a significant degree of aregenerative anemia. Erythropoietic activity, as assessed by reticulocytes, sTfR, erythroid cellularity, iron incorporation into heme, and the number of erythroid colonies, was severely depressed 3 weeks after cessation of rHuEpo. This was followed by regeneration of erythroblasts and reticulocytes at weeks 6 to 7 post-Epo, but erythroid progenitors recovered only partially by that time. The anemia was definitely corrected 2 months after cessation of rHuEpo treatment. Serum Epo levels remained elevated for several weeks, but the sensitivity of marrow erythroid precursors to Epo was preserved. No rat antibodies to rHuEpo were detected, and serum from post-Epo animals did not exert any inhibitory activity on erythropoiesis. In conclusion, after cessation of intensive rHuEpo therapy, there was a strong inhibition of erythropoietic activity with secondary anemia followed by late recovery. This was not due to antibodies or other soluble inhibitory factors, a defect in endogenous Epo production, or a loss of sensitivity to Epo. This may rather represent intrinsic erythroid marrow exhaustion, mostly at the level of erythroid progenitors but also at later stages of erythropoiesis.

INTRODUCTION: A prospective randomised study involving 810 elderly patients was conducted in an attempt to compare alternating chemotherapy with conventional first-line chemotherapy in aggressive non-Hodgkin's lymphoma in order to improve prognosis with an acceptable toxicity for elderly patients. PATIENTS AND METHODS: Patients included were 55-69 years old and had at least one adverse prognostic factor. Patients were treated either with ACVBP followed by consolidation (n = 396) or with an alternating regimen (n = 414). This regimen was an association of active drugs in NHL relapsing patients, alternating VIMMM with ACVBP for induction and alternation of VIM and ACVM in consolidation. Eight hundred and sixty-six patients were randomised. After histological review, 810 patients met the inclusion criteria: 396 in arm A, 414 in arm B. RESULTS: The complete response rate after induction was superior for conventional first-line therapy (58.5% vs 48%, P = 0.003) but at the end of treatment, the CR rate was not statistically different (52% vs 48%, P = 0.19). Conventional chemotherapy had a better five-year event-free survival than alternating regimen (33% (95% CI: 30-36%) vs 28% (95% CI: 26-30%), P = 0.0289) but overall survival was not statistically different (40% (CI 95% 38-42%) vs 36% (CI 95% 34-38%), P = 0.068). In this elderly high risk population, the toxicity was very high: 19% in arm A and 26% in arm B died during treatment. CONCLUSION: Alternating regimen did not improve outcome, was less efficient and more toxic.

A patient with Jo-1 antibody-associated polymyositis (Jo-1 PM) had a Karnofsky score of 40% and severe muscle, liver and lung damage that was refractory to standard therapy. The female patient received an autologous T-cell-depleted haematopoietic stem cell transplant (HSCT) after myeloablative conditioning. The transplant procedure was complicated by severe adult respiratory distress syndrome (ARDS) and adenovirus-associated haemorrhagic cystitis as well as cytomegalovirus (CMV) reactivation. The patient's creatinine phosphokinase (CPK) and alanine transaminase (ALT) values were normal on day 21. The patient's strength has improved remarkably and her dyspnoea is subjectively improved. At 15 months after the transplant, the patient was well with a Karnofsky score of 80% and had been off any therapy, including steroids, for 14 months.

The objective of this study was to evaluate a regimen of full doses of docetaxel and cisplatin, using an alternating schedule, as first-line therapy for patients with inoperable non-small cell lung cancer (NSCLC). The standard concomitant schedule does not allow full doses of both drugs to be administered. We wanted to see if there was an advantage to be gained by administering full doses of both docetaxel and cisplatin, using a different schedule. Docetaxel 100 mg/m2 was given once every 6 weeks from week 1 and cisplatin (120 mg/m2 for two doses and 100 mg/m2 thereafter) once every 6 weeks from week 4, for six cycles (three docetaxel and three cisplatin). Thirty-six of the 44 patients enrolled were evaluable for efficacy. Forty-eight percent of the patients had good (KPS 90-100%) performance status. A median of five cycles was administered, for which no dose reductions were necessary. There were 13 of 36 partial responses (36%; 95% CI 21-54%) and 15 of 36 patients achieved stable disease (42%). The median duration of response was 10.5 months, the median time to progression was 4.5 months and the median survival was 9 months. The 1 and 2 year survival rates were 39 and 16%, respectively. The most frequent grade 3-4 toxicities were nausea (23% of patients), vomiting (18%) and neutropenia (77%). Infections were also common, but not severe. The alternating schedule produced response, toxicity and survival figures that compared favorable with those using the concomitant schedule. This study could serve as a model for future studies of non-cisplatin-containing regimens, in which full doses of docetaxel could alternate with full doses of other new agents active against NSCLC.

BACKGROUND: Mobilization with chemotherapy and G–CSF may result in poor peripheral blood HPC collection, yielding

Peritoneal carcinomatosis is a common clinical situation followed by a 4‐5-day course of ganciclovir treatment, that requires novel therapeutic approaches. We investi- showed an increased survival as compared with control gated the efficiency of an HSVtk gene therapy for the treat- rats and with those treated with a single cycle of retrovirus ment of peritoneal carcinomatosis induced in syngeneic producing cells plus ganciclovir. However, only a few anirats by DHD/K12 colon carcinoma cells. In this setting, the mals remained tumor-free after day 180. There was no difefficiency of two different retrovirus producing cell lines ference between the two producing cell lines in any of the (GP+AmEnv12 and FLYA13) was compared. Rats treated experiments. RT-PCR demonstrated a faint expression of with a single injection of retrovirus producing cells followed the tk transgene in the liver, spleen, epiploon, bowels and by a 5-day course of ganciclovir treatment showed an the lung of the animals injected with the HSVtk producing increased survival as compared with control animals. Ani- cells, reflecting most likely the transduction of only a limited mals treated with three injections of producing cells, each number of cells.

Whole-body metabolic information provided by 18F-FDG PET could help in the evaluation of lymphoma patients at diagnosis and follow-up. We studied 60 patients, 42 at initial presentation and 18 for disease recurrence (23 aggressive non-Hodgkin's lymphoma, 21 low-grade non-Hodgkin's lymphoma and 16 Hodgkin's disease). All patients underwent a clinical examination, computed tomography (CT) and a non-attenuated PET scan within 1 week. The patients received 222-296 MBq (6-8 mCi) 18F-FDG intravenously and emission scans were recorded 45-90 min later. 18F-FDG PET detected more lymph nodes than the clinical examination or CT, but this rarely resulted in upstaging (two patients). The concordance between PET and CT for the evaluation of the spleen, liver and digestive tract was quite good. Discordance was noted in 12 patients for the evaluation of bone marrow infiltration, but confirmation by MRI or focal biopsy was not always obtained. We conclude that non-attenuated 18F-FDG PET is an easy and efficient whole-body method for the evaluation of patients with lymphomas. Compared with conventional techniques, however, it does not appear to offer much improvement for staging but provides a satisfactory base for follow-up.

The use of PIXE allowed for a simultaneous determination of serum copper (Cu), zinc (Zn), selenium (Se) and bromine (Br), in various groups of patients with hematologic malignancies. In 78 patients with acute nonlymphocytic leukemia, it was observed that (1) serum Se was significantly lower than in healthy controls and correlated inversely with the tumor burden; (2) serum bromine was normal at diagnosis but dropped dramatically after intensive chemotherapy, before recovering progressively over a period of months; and (3) pretreatment serum copper and zinc were significant prognostic factors of the chance to achieve a complete remission. In 50 patients with chronic lymphocytic leukemia, it was observed that (1) serum Cu and Cu/Zn ratio were useful indices of the disease activity, which were independent of a nonspecific acute phase reaction; and (2) Zn deficiency could contribute to immune dysfunction. In 119 patients with myeloproliferative disorders or myelodysplasic syndromes, serum Cu and Zn levels were mostly dependent on nonspecific factors, such as age and inflammation.

A 37-year-old man with acute myeloblastic leukemia in first remission developed ulcerative colitis and bronchiolitis obliterans organizing pneumonia (BOOP) 7 months after bone marrow transplantation (BMT) from an HLA-matched brother who suffered from severe Crohn's disease. BOOP occurred 20 days after idiopathic interstitial pneumonia, in the context of severe ulcerative colitis. Lung and colon biopsies showed no signs of CMV infection or GVHD. The patient was treated with oral methylprednisolone 1 mg/kg/day and his clinical status and chest X-ray improved slowly. Remarkably, the symptoms of colitis also resolved with prednisone therapy and he is now symptom-free. We hypothesize that ulcerative colitis may have been transmitted from donor to recipient (adoptive autoimmunity) and that it was complicated by BOOP. However, other factors such as CMV may have contributed to the occurrence of BOOP.

PURPOSE AND METHODS Optimization of remission-induction and postremission therapy in elderly individuals with acute myeloid leukemia (AML) was the subject of a randomized study in patients older than 60 years. Remission-induction chemotherapy was compared between daunomycin (DNR) 30 mg/m2 on days 1, 2, and 3 versus mitoxantrone (MTZ) 8 mg/m2 on days 1, 2, and 3, both plus cytarabine (Ara-C) 100 mg/m2 on days 1 to 7. Following complete remission (CR), patients received one additional cycle of DNR or MTZ chemotherapy and were then eligible for a second randomization between eight cycles of low-dose (LD)-Ara-C 10 mg/m2 subcutaneously every 12 hours for 1 2 days every 6 weeks or no further treatment. RESULTS A total of 242 patients was randomized to DNR and 247 to MTZ. Median age of both study groups was 68 years. Secondary AML was documented in 26% and 25% of patients in either arm. The probability of attaining CR was greater (P = .069) with MTZ (47%) than with DNR (38%). Median duration of neutropenia was 19 (DNR) and 22 days (MTZ). The greater response rate to MTZ therapy correlated with reduced occurrence of chemotherapy resistance (32% v 47%, P = .001). With a median follow-up of 6 years, 5-year disease-free survival (DFS) is 8% in each arm. Overall survival estimates are not different between the groups (6% v 9% at 5 yrs). Poor performance status at diagnosis, high WBC count, older age, secondary AML, and presence of cytogenetic abnormalities all had an adverse impact on survival. Secondary AML and abnormal cytogenetics predicted for shorter duration of CR. Among complete responders, 74 assessable patients were assigned to Ara-C and 73 to no further therapy. Actuarial DFS was significantly longer (P = .006) for Ara-C-treated (13% [SE = 4.0%] at 5 years) versus nontreated patients (7% [SE = 3%]), but overall survival was similar (P = .29): 18% (SE = 4.6%) versus 15% (SE = 4.3%). Meta-analysis on the value of Ara-C postremission therapy confirms these results. CONCLUSION In previously untreated elderly patients with AML, MTZ induction therapy produces a slightly better CR rate than does a DNR-containing regimen, but it has no significant effect on remission duration and survival. Ara-C in maintenance may prolong DFS, but it did not improve survival.

Peritoneal carcinomatosis is a common clinical situation that requires novel therapeutical approaches. Suicide gene therapy consists of the intracellular delivery of a gene coding for an enzyme which transforms a prodrug into a cytotoxic product [1]. Thymidine kinase from the Herpes Simplex Virus type I (HSV-TK) is the most commonly used enzyme [2, 3]. HSV-tk-transduced cells as well as neighboring cells are killed in the presence of ganciclovir, because of the so-called “bystander effect” [4].

The expression of transferrin receptor (TfR) has been identified in many malignant tumours. In lung cancer, lymphoma and breast cancer, it has been shown that the expression of TfR correlates with tumour differentiation, probably implying some prognostic value. A soluble form of TfR (sTfR) in human serum has been shown to be proportional to the number of cellular TfRs. Based on these data we examined the utility of measuring sTfR in the serum and bronchoalveolar lavage (BAL) fluid of patients with lung cancer (n = 32) and patients with chronic obstructive pulmonary disease (n = 22). BAL fluid was centrifuged to separate the supernatant from the cellular component. Cells were lysed in a detergent and cell-associated TfR was measured by enzyme-linked immunosorbent assay (ELISA) and expressed as ng 10(-6) cells in this cellular component. There was no difference in serum sTfR between the cancer and chronic obstructive pulmonary disease (COPD) groups. A higher level of cell-associated TfR was found in BAL of non-small-cell lung cancer patients than in COPD patients (P = 0.01). The calculated number of TfR molecules per cell in BAL correlated positively with the percentage of macrophages in BAL (P < 0.0001), suggesting that cell-associated TfR in BAL originates primarily from macrophages in this fluid. No correlation existed between BAL cell-associated TfR and tumour size, nodal status, the presence of metastases and serum sTfR. BAL cell-associated TfR was negatively correlated with BAL supernatant neuron-specific enolase (NSE) (P = 0.01). A combination of BAL supernatant NSE and cell-associated TfR detected lung cancer with a sensitivity of 91%, a specificity of 59% and positive and negative predictive values of 81% and 71% respectively. In conclusion, BAL cell-associated TfR may help in the differential diagnosis of lung cancer vs pneumonia.

We report a patient with poor-prognosis myelodysplastic syndrome (MDS) after successful treatment of lymphoma, who was given an allogeneic BMT, engrafted and achieved complete remission, but later had a relapse of his MDS with complete disappearance of donor haemopoiesis. After two episodes of CMV pneumonia and continued prophylactic use of ganciclovir thereafter, he experienced a spontaneous complete disappearance of all signs of MDS, including myelofibrosis, and a complete return to donor haemopoiesis. This case is the first one to suggest a graft-versus-leukaemia effect (GVL) in MDS patients. It depicts the complex relationship between GVL, graft-versus-host disease (GVHD) and graft rejection. It could also constitute a clinical illustration of the possible antileukaemic effect of CMV infection and its treatment with ganciclovir.

Anaemia is a frequent complication of advanced chronic lymphocytic leukaemia (CLL) and several cytokines known to inhibit erythropoietin (Epo) formation are produced by CLL B cells. Therefore we measured serum Epo levels in 47 CLL patients to determine whether Epo was a significant factor in the development of their anaemia. Epo levels were increased compared to normal individuals and this elevation appeared adequate for the degree of anaemia. The slope of the regression of Epo versus haemoglobin (Hb) was similar to that of a reference group. Serum transferrin receptor (sTfR) levels were also appropriately elevated for the degree of anaemia and correlated with serum Epo. Advanced stage was not associated with reduction of Epo production but diminished erythropoietic activity was observed in several patients. The results indicate that anaemia in CLL is not characterized by inadequate Epo production.

Recombinant human erythropoietin (rHuEpo) has been shown to be effective in correcting the anaemia of chronic renal failure. It has been reported that reticulocytes as well as erythroid progenitors increase within 1 -2 weeks, with no further elevation beyond this time interval. However, the erythroblast pool is quantitatively the most important compartment of erythropoiesis, and the rate, extent and duration of the expansion of erythropoietic activity in response to rHuEpo is not known. Treatment with rHuEpo was given to 64 patients i.v. thrice weekly after haemodialysis. The effect of rHuEpo was obvious from the early elevation of reticulocyte counts, but much of this increase was due to a rapid output of shift reticulocytes which levelled off after a few weeks. Serum transferrin receptor (TfR), a quantitative measure of erythropoiesis, increased progressively over 6 weeks to reach a plateau phase at about twice baseline values. The Hct increased progressively and continued to rise steadily after the TfR plateau was reached. The speed and extent of the expansion of erythropoietic activity correlated with the later haematological response to rHuEpo. When rHuEpo was discontinued, erythropoietic activity returned progressively to baseline values, to rise again gradually when treatment was resumed. Part of the Hct increase was also due to haemoconcentration. The results indicate that changes in the various erythroid compartments vary considerably in intensity and speed, and that the erythroblast compartment in particular is slow to respond to modifications in the erythropoietin stimulus

Recombinant human erythropoietin (rHuEpo) has been shown to be effective in correcting the anemia of chronic renal failure, but the dose needed may be variable. The reason for this variation is not known, but several factors could be involved, such as iron deficiency, inflammation, aluminum intoxication, hyperparathyroidism, blood losses, or marrow dysfunction. Treatment with rHuEpo was given intravenously thrice weekly after hemodialysis to 64 consecutive unselected patients with the anemia of chronic renal failure. The starting dose was 50 U/kg/dose, which was increased to 75 and 100 U/kg/dose if no response was observed after 1 and 2 months of treatment. After a minimum follow- up of 6 months, response was evaluated as early (hematocrit [Hct] > or = 30% before 3 months) or late (Hct > or = 30% after 3 months) response, or failure (target Hct not attained). We examined the value of various laboratory parameters (baseline values and early changes) as predictors of response to rHuEpo. The best prediction by pretreatment parameters only was obtained with baseline serum transferrin receptor (TfR) (< or > or = 3,500 ng/mL) and fibrinogen (< or > or = 4 g/L): 100% response rate when both parameters were low, versus only 29% when they were both high, and versus 67% when one was low and the other high. When the 2-week TfR increment was greater than 20%, the response rate was 96%. When TfR increment was less than 20%, the response rate was 100% when baseline TfR and fibrinogen were low, 12% when fibrinogen was elevated, and 62% when fibrinogen was low but baseline TfR high. The predictive value of baseline TfR and fibrinogen and of the 2-week increment of TfR was confirmed by life table analysis and stepwise discriminant analysis. Major reasons for failure or late response were identified and included subclinical inflammation, iron deficiency, functional iron deficiency, marrow disorders, hemolysis, bleeding, and low Epo dose. We conclude that response to rHuEpo can be predicted early by pretreatment fibrinogen and TfR, together with early changes of TfR levels. These prognostic factors illustrate the importance of the early erythropoietic response, subclinical inflammation, and functional iron deficiency. Early recognition of a low probability of response in a given patient could help identify and correct specific causes of treatment failure to hasten clinical improvement and avoid prolonged ineffective use of an expensive medication.

Pleomorphic T cell lymphoma of the medium to large cell type expressing CD30 antigen is a most aggressive peripheral T cell lymphoma. Currently, there is no satisfactory treatment available for this neoplasm. We report the case of a woman with prominent skin and bone marrow involvement without detectable lymph node localization. This unusual presentation of disease responded well to polychemotherapy combined with autologous bone marrow transplantation.

The AML-12 randomized phase III trial of EORTC-LG and GIMEMA assessed the efficacy and toxicity of HD-AraC (3 g/m2/12 hrs for 4 days) combined with daunorubicin (50 mg/sqm for 3 days) and etoposide (50 mg/sqm for 5 days) vs SD-AraC (100 mg/sqm for 10 days) with the same drugs. Patients (pts) in complete remission (CR) received consolidation consisting of AraC (500 mg/sqm/12 hrs for 6 days) and daunorubicin. Subsequently an allogeneic (allo-SCT) or autologous stem cell transplantation (auto-SCT) was planned according to donor availability and age. A 2nd randomization was performed after CR in pts without a donor: auto-SCT followed or not by low dose IL-2. The trial was powered to detect an 8% difference in the 5-yr survival rate; secondary endpoints were response to induction, DFS, toxicity. Randomization was performed centrally; the 1st randomization was stratified for age, performance status, WBC and center. Intent-to-treat analysis was done. From 9/1999 till 1/2008, 2005 previously untreated AML pts (APL excluded), age

Background : We previously reported a retrospective study suggesting that erythropoietin therapy starting on day 28 after autologous HCT was highly effective to improve Hb levels and that i.v. iron might improve response in patients with low transferrin saturation (Baron et al., Clin Cancer Res 2003). This prompted us to conduct a multicenter prospective randomized study analyzing the impact of darbepoetin alfa with or without i.v. iron on erythroid recovery after autologous HCT. Patients and Methods : 127 autologous HCT recipients with lymphoid malignancies were randomized 1:2:2 between no treatment (group 1, n=25), darbepoetin alfa (Aranesp®) 300 μg QOW starting on day 28 after HCT for a total of 7 doses (group 2, n=52), or the same regimen of darbepoetin alfa plus i.v. iron sucrose (Venofer®) 200 mg on days 28, 42 and 56 after HCT (group 3, n=50). Once the target Hb (13 g/dL) was attained, the dose of darbepoetin alfa was reduced to 150 μg, while it was withheld when Hb was ≥ 14 g/dL. Primary endpoints included proportion of complete correctors (i.e. patients reaching Hb □ 13 g/dL) before day 126 post-transplant and median time to achieve Hb correction in each arm. Data were analyzed following the intention-to-treat principle. The proportion of complete correctors by day 126 in each group was compared using the Fisher’s exact test, and median times to reach 13 g/dL in each group were compared using the logrank test. Results : The proportion of complete correctors was 24% in group 1, 81% in group 2 (P Conclusions : This is the first prospective randomized trial demonstrating that darbepoetin alfa is safe and highly effective to ensure full erythroid reconstitution after autologous HCT when started on day 28 posttransplant. I.v. iron sucrose tended (not statistically significant) to further fasten erythroid recovery with a lower dose of darbepoetin alfa required. Future studies in this setting should aim at further investigating the impact i.v. iron might have on improving response in patients with low transferrin saturation. Figure 1. Figure 1.

Acute promyelocytic leukemia (APL) is a rare variant of acute myeloid leukemia (AML) characterized by the presence of atypical promyelocytes in the bone marrow and peripheral blood [1]. In contrast to other forms of leukemia, APL is frequently associated with severe hemorrhagic complications which may lead to premature death of patients [2, 3].

Diffuse large B-cell lymphomas (DLBCLs) are markedly heterogeneous, and there is increasing evidence that the biological features of these tumors vary according to the primary site of disease (lymph node or various extranodal organs). The Waldeyer’s ring (WR), a circular band of mucosa-associated lymphoid tissue composed of the palatine, lingual and pharyngeal tonsils, is the second most common site of extranodal invovlement by DLBCL. The presence of focal follicular features in tonsillar DLBCLs has been previously reported. In this study we included 209 adult patients with de novo DLBCL presenting in the WR consecutively included in the GELA protocols during a 10-year period (1993–2004). All patients (M/F ratio: 1,77/1, mean age 59 years) comprising 81% with stages I–II and 19% with stages III–IV disease, received intent-to-cure anthracyclin-based polychemotherapy. Morphology, pattern of growth, immunophenotype and differentiation profile were analyzed and correlated to the clinical features. Survival and outcome were analyzed in comparison to a matched cohort of patients with primary nodal DLBCL. By morphology, 55% of tonsillar cases were classified as centroblastic, 39% as centroblastic-polymorphous, 3% as immunoblastic, and 3% were unclassifiable. Among large biopsy specimens (n=79), 18% had a prominent nodular pattern consistent with transformed follicular lymphomas, 35% had a minor nodular component (

Background. Low donor T-cell chimerism levels after allogeneic hematopoietic cell transplantation (HCT) with nonmyeloablative conditioning have been associated with high risks of both graft rejection and relapse/progression (Baron et al., Blood2004, vol 104, p2254 and Baron et al., J Clin Oncol2005, vol 23, p1993). In a preclinical canine model, DLI preceded by 2 Gy TBI converted mixed to full donor chimerism after nonmyeloablative conditioning (Taranova et al., Blood2003, vol 102, 256a). Here, we investigated the ability of donor lymphocyte infusion (DLI) preceeded (n=15; TBI/DLI group) or not (n=15; DLI (“historical”) group) by 2 Gy TBI (given a few hours before DLI) to increase donor T-cell chimerism levels in patients with low donor T-cell chimerism levels after HCT. Methods. Conditioning regimen for HCT consisted of 2 Gy TBI with (n=15) or without (n=11) added fludarabine. 20 patients received PBSC from related, and 6 PBSC from HLA-matched unrelated donors. Peripheral blood stem cells (PBSC) were unmanipulated in 15 patients, and CD8-depleted in the 11 remaining patients. Indication for TBI/DLI included < 50% donor T-cell chimerism or decrement of donor T-cell chimerism by 20% (or 10% if below 60%). Depending of patient-donor relationship, DLIs were given at a dose of 1 to 10 × 107 T-cells/kg (median 2 × 107 T-cells/kg), 42 to 725 days (median 68.5 days) following HCT. Prophylactic postgrafting immunosuppression was pursued after DLI in all but one patients. Results. Before DLI, donor T-cell chimerism levels ranged from 15 to 77% (median 44%) in the DLI group, versus from 24 to 66% (median 47%) in the TBI/DLI group (P=0.66). Two months after DLI, donor T-cell chimerism levels ranged from 15 to 93% (median 53%) in the DLI group (P=0.10 in comparison to before DLI), versus from 20 to 98% (median 56%) in the TBI/DLI group (P=0.04 in comparison to before DLI) (Figure 1). In addition, 0 of 15 patients in the DLI group versus 5 of 15 patients in the TBI/DLI group had > 25% increased T-cell chimerism levels 2 months after DLI (P=0.04). Highest T-cell chimerism levels after DLI ranged from 15 to 99% (median 71%) in the DLI group, versus from 43 to 100% (median 96%) in the TBI/DLI group (P=0.06). Further, 2 of 15 patients in the DLI group, versus 0 of 15 patients in the TBI/DLI group experienced graft rejection. In the DLI group, 3 patients developed grade II–IV acute GVHD (2 grade II and 1 grade IV), while 1 patient in the TBI/DLI group experienced grade II acute GVHD. TBI/DLI was followed by grade IV hematologic toxicities in most patients, but most of them remained treated in the outpatient clinic. One-year overall survival was 67% in the DLI group versus 73% in the TBI/DLI group (NS). Conclusions. DLI increased donor T-cell chimerism levels in a number of patients when preceeded by low dose TBI. However, hematological toxicity of TBI/DLI was relatively high, with most patients requiring several RBC and Plt transfusions. Further studies are needed to assess its impact on HCT outcomes. Figure Figure

The AML-12 randomized phase III trial of EORTC-LG and GIMEMA assessed the efficacy and toxicity of HD-AraC (3 g/m2/12 hrs for 4 days) with daunorubicin (50 mg/sqm for 3 days) and etoposide (50 mg/sqm for 5 days) vs SD-AraC (100 mg/sqm for 10 days) with the same drugs. Patients (pts) in complete remission (CR) received consolidation (Co) consisting of AraC (500 mg/sqm/12 hrs for 6 days) and daunorubicin. Subsequently an allogeneic (allo-SCT) or autologous stem cell transplantation (auto-SCT) was planned according to donor availability and age. A 2nd randomization was performed after Co in pts without a donor: auto-SCT followed or not by low dose IL-2. From 9 1999 till 7 2006, 1675 AML pts (APL excluded), age 50x109/l) was longer (median 4.0 vs 3.3 weeks; P=0.01). Among 886 pts randomized until 7 2005 by EORTC centers and 6 large GIMEMA centers, median follow-up of 2.5 years, 815 were evaluable for response. Out of 643 pts who reached CR, 57 went off study (toxicity, early progression). Among the remaining 586 who received Co, 37 could not be evaluated (early death/relapse, too early) and 549 were still CR after Co: 297 pts had no donor/no sibling, 197 had a donor and 55 were not typed. In these 3 groups the present estimates of the SCT rates are: 63% (auto-SCT), 71% (allo-SCT) and 69% (auto-SCT), resp. The 2.5-yr DFS rates (SE%) were 45% (3%), 61% (4%), and 67% (7%), resp. In pts < 50 yrs, 216 pts had no donor/no sibling, 135 had a donor and 14 have not been typed. For the first 2 groups, the 2.5 yr DFS rates (SE%) were 50% (4%) vs 68% (4.5%), hazard ratio=0.64, 95% CI (0.44, 0.93), P=0.02. In pts without a donor/a sibling successful mobilization of blood stem cells (b-SC) after Co was in HD-Ara-C vs SD-Ara-C arm 53 vs 69%, of failure/postponement 37 vs 24%, and other 9.5 vs 7%. The rate of auto-SCT was similar (65 vs 64%), but harvest of BM cells was more often required in the HD-AraC group (15 vs 4.5%). Pts with an insufficient/delayed b-SC harvest had a longer (P 50x109/l) after Co than those with a successful harvest: median = 6.7 vs 3.3 wks. Among 393 pts with information on cytogenetics, 14% had good risk, 50% normal, 23% other and 13% poor risk (-5/5q-, -7/7q-, complex). The 2.5-year EFS (no CR, time to relapse or death in CR) rates (SE%) were 68% (7%), 42% (4%), 32% (5%) and 14% (5%), resp. So far: toxicity of HD-Ara-C was acceptable; in those who received HD-AraC in induction platelet recovery after Co was longer and the rate of successful b-SC collection was lower; SCT rates are high and similar in the 2 randomized arms; pts

7569 Background: We have shown that FDG PET is able to detect preclinical relapses in patients with Hodgkin’s disease but the high rate of false-positivity (55%) was a problem (Jerusalem et al, Ann Oncol, 2003; 14 : 123–130). The aim of this study was to determine the accuracy of PET during follow-up after treatment in non-Hodgkin’s lymphoma (NHL). Methods: Patients were eligible if they had a positive baseline FDG PET and a negative end of treatment work-up including a negative PET study. They underwent FDG PET every 4–6 months until 3 years after diagnosis. Forty-five aggressive NHL (diffuse large B-cell lymphoma : 34, other : 11) and eighteen low grade NHL (follicular lymphoma : 16, other : 2) were recruited prospectively between 5/94 and 12/01. Results: A total of 197 FDG PET studies were realized. Six patients relapsed (aggressive NHL : 4, low grade NHL : 2) and 3 patients died (aggressive NHL : 2, pancreatic cancer : 1) during the time interval of the study protocol. Four asymptomatic relapses (aggressive NHL : 2, low grade NHL : 2) and one symptomatic relapse (aggressive NHL) was detected by FDG PET. Disease recurrence became symptomatic or clinically detectable a week, 3 months (both aggressive NHL), 12 and 17 months (both low grade NHL) after the first positive PET study. The latter had 4 positive FDG PET studies before biopsy-proven relapse. The time interval between the only false-negative PET and clinical relapse was 5 months in a patient with aggressive NHL. We observed for the whole study population a sensitivity of 89% (8/9), a specificity of 93% (174/188), a positive predictive value of 36% (8/22), a negative predictive value (NPV) of 99% (174/175) and an accuracy of 92% (182/197). In low grade NHL PET had a sensitivity of 100% (5/5), a specificity of 93% (50/54), a PPV of 56% (5/9), a NPV of 100% (50/50) and an accuracy of 93% (55/59). In aggressive NHL, PET had a sensitivity of 75% (3/4), a specificity of 93% (124/134), a PPV 23% (3/13), a NPV of 99% (124/125) and an accuracy of 92% (127/138). Conclusions: In aggressive NHL, routine follow-up by FDG PET is not very useful and we stopped it now in unselected aggressive NHL. In contrast, FDG PET can detect a relapse several months before the development of clinical symptoms in low grade NHL suggesting further evaluation of the role of PET in the routine follow-up of these patients. No significant financial relationships to disclose.

Background: In a previous pilot study, we demonstrated that CD8-depletion of the graft apparently reduced the severity of AGvHD without impairing the GvL effect after peripheral blood stem cell (PBSC) transplantation with a nonmyeloablative conditioning (NMSCT). Aim of the study: To evaluate the effect of CD8-depletion on graft rejection, AGvHD and CGvHD, and relapse. Patients: 53 patients were randomised between CD8-depletion (group 1) (n=25) and no manipulation (group 2) (n=28). Two patients in the CD8 group were excluded for poor CD34+ cell count collected. Diagnoses were: AML (n=3), CML-AP (n=2), MDS (n=14), MPD (n=3), CLL (n=5), NHL (n=14), MM (n=8) and RCC (n=2). Median age was 57 (range 36–69) yrs. After conditioning with 2 Gy TBI with (n=39) or without (n=12) fludarabine, patients received PBSC from family (n=21) or unrelated (n=30) HLA-matched donors. CD8-depletion was carried out using the Eligix system and GvHD prophylaxis consisted in CyA and MMF. Results: CD8 depletion removed 96% of CD8+ cells so that the number of CD8+ cells infused was 6.8 vs 136.8 x108 cells/Kg in group 2 (p Conclusion: In vitro CD8-depletion results in higher rates of graft failure after NMSCT. The incidence of acute and chronic GvHD is not reduced but there is a trend towards reduced severity of AGvHD. Relapse and survival rates are not changed by this strategy.

In some recent trials high dose of Dexamethasone (Dexa) combined with chemotherapy has been used for induction therapy in adults with ALL because it may exert higher antileukemic activity. Increased level of drug in the cerebrospinal fluid might also prevent meningeal leukemic infiltration. However, high dose of Dexa may be associated with an increased risk of sepsis and fungal infections. By using a lower dose of dexamethasone these serious infections may be circumvented without jeopardize the antileukemic activity. The main aim of the EORTC ALL-4 study was to determine the efficacy and toxicity of a lower dose of Dexa administered during the induction therapy, as vs the ones of conventional dose of prednisone (Pred). In the ALL-4 study, patients (pts) ≤ 60 years had to receive either dexamethasone (10 mg/m2/day) or 6-methyl-prednisolone (60 mg/m2/day) on days 1–8 and 15–22 with standard induction chemotherapy (cyclophosphamide i.v. 750 mg/m2 on day 1 and 8; daunorubicine 30 mg/m2 on day 1–3 and 15–16; vincristine 1.4 mg/m2 (maximum 2 mg) and methotrexate /MTX/ i.t. 15 mg on days 1, 8, 15 and 22). All pts than receive the HAM consolidation course (HD-AraC 3 g/m2 every 12 hours on days 1–4; mitoxantrone 10 mg/m2 on days 5–7 and MTX 15 mg i.t. on day 1). Pts in CR received two courses of MA consolidation (MTX 1.5 g/m2 i.v on day 1 and L-asparaginase 104 IU/m2 on day 2). All pts with a family donor were assigned to undergo allo-SCT. Pts without the donor were randomized either to receive autologous stem cells from peripheral blood or continuous standard high maintenance chemotherapy. After a median follow-up of 4.9 years, 198 pts died. Between 1996 and 2003 a total of 325 pts were randomized in the ALL-4 study: 163 in the Dexa arm and 162 in the Pred arm. CR after induction/HAM was achieved in 128 (78.5%) pts receiving Dexa and in 120 (74.1%) pts treated with Pred. Among them, in Dexa group 61 pts relapsed, 19 died in CR and 48 are still in CCR, whereas in the Pred group, 58 pts relapsed, 8 died in CR and 54 are in CCR. The 5-year DFS rates was 32.7% in the Dexa group vs. 34% in the Pred group, the HR=1.15, 95% CI 0.83–1.59, p=0.40. The relapse rates were extremely similar (HR=0.99, p=0.96), whereas the death in CR rate was higher in the Dexa group compared to Pred group: HR=2.33, 95% CI 1.02–5.33, p=0.04. The overall 5-year survival rate in Dexa vs Pred group was 30.7% and 32.5% respectively (HR=1.11, 95% CI 0.84–1.43, p=0.46). The incidence of infection was similar during induction (Dexa: 55% vs Pred: 59%) and during HAM consolidation (Dexa: 85% vs Pred: 78%). More pts were allografted in CR1 in the Dexa than in the Pred arm (45 vs 33), and the mortality post allo-SCT was higher in the Dexa group (12/45=26.7%) than in the Pred group (5/33=15.2%). The results of ALL-4 trial indicate that there is no benefit of dexamethasone compared to 6-methyl prednisone during induction therapy in adult ALL-NHL pts.

Background: Thrombotic microangiopathy (TM) is a severe complication of allogeneic transplantation. The use of CsA for GvHD prophylaxis and unrelated donor appear to be the most significant risk factors for TM after transplantation with conventional myeloablative conditioning (MSCT). Allogeneic transplantation with reduced-intensity conditioning (RIC) is associated with a similar risk of TM, but TM has never been studied after NMSCT. Purpose: To determine the risk factors, incidence and outcome of TM in NMSCT compared to MSCT. Patients: Consecutive patients undergoing NMSCT (group 1, n=103) or MSCT (group 2, n=136) in our center between 1995 and 2004 were retrospectively analysed for TM. Median age was 55 vs 34 yrs in groups 1 and 2 respectively (p Results: TM was diagnosed in 18 (20%) and in 30 (26%) patients in groups 1 and 2, respectively (NS). Most cases were grade 2 TM (18/18 in group 1 and 24/30 in group 1, NS). Neurological signs were present in 50% of the patients in group 1 and 57% in group 2 (NS). In both groups, TM was significantly associated with unrelated donor (p=0.0476 in group 1, p=0.0005 in group 2) and with CMV disease (p=0.0332 in group 1, p=0.0346 in group 2) but not CMV infection. AGvHD of all grades was correlated with TM in group 1 (p=0.0004) but only severe (grade 3–4) AGvHD in group 2 (p Conclusion: TM remains a frequent and severe complication of allografting. Its incidence and severity in NMSCT is not decreased compared to MSCT and the same factors appear to contribute to its development.

Gemtuzumab ozogamicin, a conjugate of a humanized anti-CD33 monoclonal antibody linked to the cytotoxic antibiotic calicheamicin, has shown significant antileukemic activity in relapsed AML with a favorable toxicity profile. The EORTC-LG performed a phase II study to investigate the activity and toxicity of GO used alone and in combination with conventional chemotherapy for remission induction in medically fit elderly pts (age between 61 and 75 years; WHO PS 0-1) with untreated AML. GO was administered iv over 2 hrs at the FDA-approved dose of 9 mg/m2. A second dose was given on day 15 in the absence of progressive disease or excessive toxicity and response was assessed four weeks later. This was to be followed by a course of conventional chemotherapy with mitoxantrone, cytarabine and etoposide (MICE regimen) and no further treatment in complete responders. Between 09/00 and 10/01 64 pts were enrolled , 57 of whom were evaluable for response and toxicity. The median age was 68 yrs (range 61–73); 43 pts had primary AML; CD33 positivity (≥20% marrow blasts) was documented in 44 pts (85%). GO therapy was completed by 47 of the 57 pts (82%): primary reasons 10 pts did not receive the scheduled second dose were disease progression (4), early death (2), toxicity (2) and protocol violation (2). The rate of initial response to GO was 35.1% (95% CI, 22.9%–48.9%) with 13 pts achieving complete remission (CR) and 7 CRp (complete remission with incomplete platelet recovery); 6 additional pts entered partial remission (PR). There were 3 (5.3%) toxic deaths (1 ARDS, 1 VOD, 1 infection) and 28 pts had resistant disease. Severe myelosuppression was the primary toxicity to GO. Grade 3 or 4 non-hematologic toxicities in more than 5% of pts during GO therapy included febrile neutropenia (39%), infection (28%), elevations of bilirubin, SGPT and creatinine of 8%, 6% and 6%, respectively. A clinical picture compatible with hepatic VOD developed in 3 pts (5%) resulting in 2 deaths (1 early, 1 in CRp). No baseline characteristics predicted for response to GO, but pts expressing CD33 in >80% marrow blasts tended to respond more favourably to the immunoconjugate (CR+CRp 7/14, 50%). Altogether, 51 pts survived GO therapy and 38 of them (75%) went on to receive a course of MICE after a median interval of 49 days (range 12–77) from the first dose of GO. Excessive toxicity (11 pts), protocol violation (1 pt) and treatment refusal (1 pt) were the main reasons for not starting chemotherapy. The ultimate best response rate was 54.4% (31/57; CR 35.1% and CRp 19.3%) increasing up to 65.8% among the 38 pts who were able to complete the whole induction sequence. Five pts died of toxicity during the MICE segment (2 VOD, 1 infection, 1 heart failure, 1 multi-organ failure) for an overall treatment related mortality of 14.1% (8/57). With a median follow-up of 3 yrs, 2-year overall survival (OS) and disease-free survival (DFS) estimates were 11.0% (SE=4.1%) and 12.1% (SE=3.5%), respectively. We conclude that: 1) single agent, standard dose GO has significant activity in untreated AML of the elderly with an acceptable safety profile; 2) sequential combination with standard chemotherapy is feasible and may improve treatment outcome in this poor risk disease, but myelotoxicity and liver dysfunction are of concern. An ongoing randomized trial will determine the contribution of GO given at reduced dose (6 mg/m2) to the observed antileukemic effect and toxicity.

Relapse remains the major cause of failure after high-dose chemotherapy and autologous peripheral blood stem cell transplantation (PBSCT). As tumor contamination of the graft may contribute to this, CD34 selection has been used as an attempt to decrease the relapse rate. However, immune reconstitution may be delayed with CD34 selection due to the removal of T cells, natural killer (NK) cells and monocytes. The result could be an increased incidence of infectious complications. Some small series of patients have reported a higher incidence of infections, and in particular of viral infections, but others have not. Therefore, we compared the incidence of infection in 25 recipients of CD34-selected PBSC (CD34 group) and 75 case-matched recipients of unmanipulated PBSC (PBSC group) transplants. There were 52 males and 48 females with an average age of 52±11 yrs. They included 32 patients with non-Hodgkin’s lymphoma, 8 with Hodgkin’s disease, 40 with multiple myeloma and 20 with breast cancer, with 42 in first-line therapy and 58 in relapse, receiving their 1st (N=63) or 2nd (N=37) transplant. The number of CD34 cells infused as well as speed of engraftment were comparable in the two groups. There were no significant increase in the CD34 compared to the PBSC group for: actuarial incidence of infection (56 vs 49% at day 30, 70 vs 64% at 1 yr); proportion of patients with at least 1 (68 vs 68%), 2 (24 vs 17%) or 3 (0 vs 3%) infections; number of infectious events per patient before (1.32 vs 1.04) or after (0.59 vs 0.71) disease progression, before day 30 (0.84 vs 0.64), within days 31–100 (0.00 vs 0.09, p