Lf Verdonck

Donor Lymphocyte Infusions for Relapsed Multiple Myeloma After Allogeneic Stem-Cell Transplantation: Predictive Factors for Response and Long-Term Outcome

PURPOSE To determine the efficacy, toxicity, and long-term outcome and prognostic factors of donor lymphocyte infusions (DLI) in patients with relapsed multiple myeloma (MM) after allogeneic stem-cell transplantation (AlloSCT). MATERIALS AND METHODS Twenty-seven patients received 52 DLI courses at a median of 30 months after the previous AlloSCT. Reinduction therapy was administered to 13 patients before DLI. RESULTS Reinduction therapy was successful in eight of 13 patients. Fourteen patients (52%) responded to DLI, including six patients (22%) who achieved a complete remission (CR). Five patients responded after T-cell dose escalation in subsequent DLIs. Four patients experienced relapse or disease progression (three from partial response and one from CR). Five patients remain in remission more than 30 months after DLI. Major toxicity was acute and chronic graft-versus-host disease (GVHD), which was present in 55% and 26% of patients, respectively. Two patients died from bone marrow aplasia. Median overall survival of all patients was 18 months. Overall survival was 11 months for DLI-resistant patients and has not been reached for the responding patients. In two patients, sustained molecular remission was observed. The factors that were correlated with response to DLI were a T-cell dose of more than 1.10(8) cells/kg, response to reinduction therapy, and chemotherapy-sensitive disease before AlloSCT. CONCLUSION These data confirm the potential and durable graft-versus-myeloma effect of DLI in patients with relapsed MM after AlloSCT. Future studies should be aimed at increasing response rates, especially in patients with chemoresistant disease, and reducing toxicity by limiting GVHD. Adjuvant DLI seems an attractive and promising approach for patients who do not achieve a molecular remission after AlloSCT.

Graft-versus-myeloma effect in two cases

BACKGROUND Allogeneic bone-marrow transplantation (BMT) is associated with the graft-versus-leukaemia effect because of the antileukaemic action of donor lymphocytes. We describe a graft-versus-myeloma effect after BMT in multiple myeloma. METHODS Two patients with recurrent multiple myeloma after allogeneic BMT (T cells partly depleted, 10(5) T cells infused per kg) received leucocyte infusions obtained by leukapheresis from their original marrow donors. The patients were a 48-year-old woman and a 49-year-old man. FINDINGS Both patients developed graft-versus-host disease and achieved complete remission of myeloma. Chimerism was complete in both patients in that all peripheral blood cells were of donor origin. INTERPRETATION We see our results as evidence for a graft-versus-myeloma effect. Using this form of adoptive immunotherapy, we could administer 1000-3000 times more T cells than with the earlier BMT.

CHOP Compared With CHOP Plus Granulocyte Colony-Stimulating Factor in Elderly Patients With Aggressive Non-Hodgkin’s Lymphoma

PURPOSE To investigate whether the relative dose-intensity of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy could be improved by prophylactic administration of granulocyte colony-stimulating factor (G-CSF) in elderly patients with aggressive non-Hodgkins lymphoma (NHL). PATIENTS AND METHODS Patients aged 65 to 90 years (median, 72 years) with stage II to IV aggressive NHL were randomly assigned to receive standard CHOP every 3 weeks or CHOP plus G-CSF every 3 weeks on days 2 to 11 of each cycle. RESULTS In 389 eligible patients, the relative dose intensities (RDIs) of cyclophosphamide (median, 96.3% v 93.9%; P =.01) and doxorubicin (median, 95.4% v 93.3%; P =.04) were higher in patients treated with CHOP plus G-CSF. The complete response rates were 55% and 52% for CHOP and CHOP plus G-CSF, respectively (P =.63). The actuarial overall survival at 5 years was 22% with CHOP alone, compared with 24% with CHOP plus G-CSF (P =.76), with a median follow-up of 33 months. Patients treated with CHOP plus G-CSF had an identical incidence of infections, with World Health Organization grade 3 to 4 (34 of 1,191 cycles v 36 of 1,195 cycles). Only the cumulative days with antibiotics were fewer with CHOP plus G-CSF (median, 0 v 6 days; P =.006) than with CHOP alone. The number of hospital admissions and the number of days in hospital were not different. CONCLUSION In elderly patients, G-CSF improved the RDI of CHOP, but this did not lead to a higher complete response rate or better overall survival. G-CSF did not prevent serious infections.

Value of different modalities of granulocyte-macrophage colony-stimulating factor applied during or after induction therapy of acute myeloid leukemia.

PURPOSE The hematopoietic growth factors (HGFs) introduced into induction chemotherapy (CT) of acute myeloid leukemia (AML) might be of benefit to treatment outcome by at least two mechanisms. HGFs given on days simultaneously with CT might sensitize the leukemic cells and enhance their susceptibility to CT. HGFs applied after CT might hasten hematopoietic recovery and reduce morbidity or mortality. MATERIALS AND METHODS We set out to evaluate the use of granulocyte-macrophage colony-stimulating factor (GM-CSF; 5 microg/kg) in a prospective randomized study of factorial design (yes or no GM-CSF during CT, and yes or no GM-CSF after CT) in patients aged 15 to 60 years (mean, 42) with newly diagnosed AML. GM-CSF was applied as follows: during CT only (+/-, n = 64 assessable patients), GM-CSF during and following CT (+/+, n = 66), no GM-CSF (-/-, n = 63), or GM-CSF after CT only (-/+, n = 60). RESULTS The complete response (CR) rate was 77%. At a median follow-up time of 42 months, probabilities of overall survival (OS) and disease-free survival (DFS) at 3 years were 38% and 37% in all patients. CR rates, OS, and DFS did not differ between the treatment groups (intention-to-treat analysis). Neutrophil recovery (1.0 x 10(9)/L) and monocyte recovery were significantly faster in patients who received GM-CSF after CT (26 days v 30 days; neutrophils, P < .001; monocytes, P < .005). Platelet regeneration, transfusion requirements, use of antibiotics, frequency of infections, and duration of hospitalization did not vary as a function of any of the therapeutic GM-CSF modalities. More frequent side effects (eg, fever and fluid retention) were noted in GM-CSF-treated patients predominantly related to the use of GM-CSF during CT. CONCLUSION Priming of AML cells to the cytotoxic effects of CT by the use of GM-CSF during CT or accelerating myeloid recovery by the use of GM-CSF after CT does not significantly improve treatment outcome of young and middle-aged adults with newly diagnosed AML.

For which patients with aggressive non-Hodgkin's lymphoma is prophylaxis for central nervous system disease mandatory?

PURPOSE Data of a multicenter study in non-Hodgkins lymphoma (NHL) by the Dutch Hovon Group were reanalyzed to assess the risk of relapse in the central nervous system (CNS) related to the international risk index for NHL. In addition we assessed the risk for CNS disease in relation to the presence of bone marrow localisation at presentation. DESIGN We focused our analysis on those patients reaching a complete remission (CR). Two hundred eighty-six patients (histological subtypes D-H Working Formulation) and with stages II-IV were analyzed. One hundred ninety-three (67%) patients reached a CR. RESULTS Relapse occurred in 78 patients of whom 10 patients with concomitant or isolated CNS disease. According to the international risk index the following observations were made: low risk (n = 38) nine out of 34 CR relapsed, none had CNS involvement; low-intermediate risk (n = 115) 27 out of 83 CR relapsed, three had CNS involvement; high-intermediate risk (n = 110) 37 out of 68 CR relapsed, six had CNS involvement; high risk (n = 22) four out of seven CR relapsed, one had CNS involvement. Two out of 10 developed isolated CNS disease and eight out of 10 patients developed CNS disease with systemic relapse. CONCLUSION Our data show that the number of CNS relapses after CR is relatively low (10 out of 193 = 5%), with an increasing incidence in the high-risk groups according to the international risk index. The occurrence of CNS relapse seems to be related to the risk of systemic relapse after CR. No subgroup could be discriminated in which prophylactic treatment would be of substantial benefit.

Prevention of primary transfusion‐associated cytomegalovirus infection in bone marrow transplant recipients by the removal of white cells from blood components with high‐affinity filters

Summary. A prospective study was carried out to determine whether use of cytomegalovirus (CMV) unscreened red blood cells and platelet concentrates, white blood cell (WBC) depleted with high‐efficiency filters, would prevent transfusion‐associated (TA) CMV infection in CMV seronegative bone marrow transplant recipients. Blood components were filtered in the bloodcentre under quality control and after filtration residual WBC counts were always below 5 × 106 cells/U. Since 1990, 23 consecutive allogeneic and 37 autologous CMV seronegative marrow transplant recipients, have been transfused with filtered blood components and followed for 6 months for evidence of CMV infection by monitoring culture and CMV serology. None of the patients showed clinical symptoms of CMV infection, and CMV cultures during episodes of fever were always negative. IgM anti‐CMV antibodies were negative during the study in all patients. Low titres of IgG anti‐CMV antibodies (5‐12 relative ELISA units) were found in 24/60 patients during the first month after bone marrow transplantation (BMT), probably due to passive transfer of IgG administered with the platelet transfusions. 3 and 6 months after BMT, 56 and 48 patients respectively were still alive; and CMV serology was negative in all patients. The results show that TA‐CMV infection is preventable by filtration of blood through high‐efficiency filters in patients undergoing autologous and allogeneic BMT.

Autologous peripheral blood stem cell transplantation in patients with relapsed lymphoma results in accelerated haematopoietic reconstitution, improved quality of life and cost reduction compared with bone marrow transplantation: the Hovon 22 study.

The present study analysed whether autologous peripheral blood stem cell transplantation (PSCT) improves engraftment, quality of life and cost‐effectiveness when compared with autologous bone marrow transplantation (ABMT). Relapsing progressive lymphoma patients (n = 204; non‐Hodgkins lymphoma n = 166; Hodgkins disease n = 38) were, after induction treatment with the DHAP–VIM (cisplatin, cytarabine, dexamethasone, etoposide, ifosfamide, methotrexate) regimen, randomly (2:1) assigned to the harvest of granulocyte–macrophage colony‐stimulating factor‐mobilized stem cells after the second DHAP course or autologous bone marrow cells before the second DHAP course. These stem cells were reinfused following high‐dose myeloblative chemotherapy. After induction, 118 patients obtained a partial or complete response and were eligible for randomization. In the PSCT arm (n = 76) significantly faster engraftment of neutrophils [≥ 0·1 and ≥ 0·5 × 109/l: 10·7 d (7–36, median, range), 15 (9–45) versus 13 (8–25) and 26 (14–80), P < 0·01] and thrombocytes [≥ 20 × 109/l: 13 d (7–51) versus 18 (11–65), P < 0·01] were observed. In addition, significantly fewer transfusions of red blood cells [6 (0–23) versus 8 (2–24), P < 0·01] and platelets [4 (0–60) versus 8 (2–55), P = 0·01] were required in the PSCT arm. These findings were associated with a significant reduction in the median days of intravenous antibiotics in patients with fever [8·5 (0–30) versus 14 (0–34), P = 0·04] and hospital stay [27 (8–51) versus 34 (24–78), P < 0·05]. Quality of life demonstrated a significant difference in favour of the PSCT arm. Total transplantation costs were significantly lower in the PSCT arm [

Peripheral blood stem cell transplantation as an alternative to autologous marrow transplantation in the treatment of acute myeloid leukemia

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Intensive postremission chemotherapy without maintenance therapy in adults with acute lymphoblastic leukemia. Dutch Hemato-Oncology Research Group.

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Autologous bone marrow transplantation for acute leukaemia in remission

17 668 (