Summary:Among 551 consecutive recipients of allogeneic bone marrow transplants, 451 survived more than 3 months and were evaluated for chronic graft-versus-host disease (GVHD). Most of the donors were HLA-identical siblings or parents (n = 334). Patients with HLA-mismatched donors (n = 30) and matched unrelated donors (MUD) (n = 87) were also included in the study. In the analysis of all patients, the 5-year cumulative incidence of chronic GVHD was 45%. We analysed 34 risk factors. High recipient age was the single most important risk factor (P Ͻ 0.001). Other significant risk factors in multivariate analysis were: acute GVHD grades I-IV (P Ͻ 0.001), immune female donor to male recipient (P = 0.006) and chronic myelogenous leukaemia (CML), compared with all other diagnoses (P = 0.014). The cumulative 5-year incidence of chronic GVHD, with no significant risk factors present, was 9%, 29% with one risk factor, 53% with two, 68% with three and 75% with all four risk factors present. In patients with HLAidentical sibling donors and GVHD prophylaxis consisting of a combination of methotrexate (MTX) and cyclosporin A (CsA) (n = 208), increasing recipient age (P Ͻ 0.001) and CML (P = 0.007), were found to be significant risk factors for chronic GVHD. Finally, a multivariate analysis in recipients of bone marrow from unrelated donors (n = 89) showed recipient age alone (P = 0.006) to be significantly associated with chronic GVHD.

Preemptive therapy based on polymerase chain reaction for CMV DNA was associated with reduced risks for CMV disease, CMV-associated death, and TRM, whereas other prophylactic modalities did not give additional benefit.

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Using HLA-A-, HLA-B-, and HLA-DR-compatible unrelated bone marrow and immunosuppression with antithymocyte globulin, methotrexate, and cyclosporine, the probability of GVHD was low and survival was favorable.

Summary:Low-dose cyclosporine (CsA), starting at 1 mg/kg/day i.v. with early discontinuation, and four doses of methotrexate (MTX), was given to 82 consecutive leukaemic patients receiving HLA-identical sibling marrow transplants. Retrospective controls (n = 40) received CsA, starting at 5-7.5 mg/kg/day i.v., given for 1 year, and MTX. In the low-dose group, the risk of acute GVHD grades I-II was 78% as compared to 57% among the controls (P Ͻ 0.01). The risk of acute GVHD grades III-IV was 2% and 5%, respectively (NS). Chronic GVHD occurred in 60% in the low-dose group and 24% in the controls (P Ͻ 0.001). Extensive chronic GVHD did not differ between the groups (3% vs 6%). In multivariate analyses, low-dose CsA was the only factor associated with acute GVHD grades I-IV (P = 0.02). Significant risk factors for chronic GVHD included low-dose CsA (P = 0.002) and CML (P = 0.03). Transplant-related mortality at 3 years post-BMT was 22% and 19%, in the low-dose group and controls, respectively (NS). The probability of relapse was 26% in the low-dose group and 53% in the controls (P = 0.06). In multivariate analysis, high-dose CsA was the strongest risk factor for relapse (P = 0.03). The 3-year relapse-free survival was 58% in the low-dose group and 43% in the controls (P = 0.1).

Between 1991 and 1999, 44 leukemic patients received donor lymphocyte infusions (DLIs) at our center (22 patients with chronic myelogenous leukemia [CML]; 10 with acute myelogenous leukemia; 11 with acute lymphatic leukemia; and 1 with myelodysplastic syndrome). Seventeen patients received graft-versus-host disease (GVHD) prophylaxis with methotrexate (MTX) at the time of DLI. In CML patients, 15 of 22 (68%) re-entered complete remission after DLI. At 3 years post-DLI, patients with cytogenetic (n = 10) or molecular (n = 3) relapse had a current leukemia-free survival (cLFS) rate of 85% compared with 0% for patients with hematologic relapse (P < .001). Among 15 CML patients who initially responded to DLI, 4 patients relapsed within the first 2 years. Four of 16 patients (25%) with acute leukemia had an initial response with complete remission after DLI. Two of them subsequently relapsed within 1 year. Patients with acute leukemia who relapsed within 1 year of hematopoietic stem cell transplantation (n = 9) had 0% cLFS at 18 months; patients with later relapse had 29% cLFS (P = .015). The overall probability of cLFS at 3 years for CML patients was 46%. For other diseases, cLFS was 13% at 18 months after DLI. Patients who developed chronic GVHD secondary to DLI showed a 3-year cLFS of 51% compared with 18% for patients without chronic GVHD (P = .022). This study emphasizes the importance of early disease stage and presence of chronic GVHD for effective DLI.

Summary:A study was done to compare treatment with Filgrastim (r-metHuG-CSF) given at three different times after unrelated bone marrow transplantation (BMT). Sixtynine patients grafted with HLA-A, -B and -DR-compatible unrelated bone marrow were randomized to Filgrastim (5 g/kg/day) starting on day 0 (n = 23), day +5 (n = 23) or day +10 (n = 23) after BMT. No significant differences were detected in hematological recovery, days with fever, days on antibiotics, incidence of bacteremia or need for erythrocyte, platelet and granulocyte transfusions between the three groups. Patients given Filgrastim starting on day 0, day +5 or day +10, respectively, reached an absolute neutrophil count (ANC) Ͼ Ͼ Ͼ0.5 ؋ 10 9 /l on a median of 17, 16 and 16 days after BMT. Starting Filgrastim treatment on day +10, rather than on day 0, reduced the costs of Filgrastim by $1060, with no significant change in the median number of days-tohospital discharge in the three Filgrastim-treated groups. The incidences of acute and chronic GVHD, transplantation-related mortality, relapse, leukemiafree survival and patient survival (PS) were similar in all groups. Keywords: BMT; unrelated donors; G-CSF; engraftment During the past few years, hematopoietic stem cells (HSC) from unrelated donors have been increasingly used for transplantation.1,2 Almost 4 million volunteer donors of HSC are available worldwide. Therefore, one can find an HLA-A, -B and -DR-identical donor for approximately 70% of all Caucasian patients who need an allogeneic hematopoietic stem cell transplant (HSCT). If unrelated HSC are used, there is an increased risk of acute graft-versushost disease (GVHD), infections and a higher transplantrelated mortality.3,4 It is well established that recombinant human granulocyte-macrophage and granulocyte colonystimulating factors (rHuGM-CSF, rHuG-CSF) can accelerate neutrophil recovery after treatment with chemotherapy and autologous or allogeneic HSCT. penia, and some studies a reduction in the duration of antibiotic treatment, infections and the length of hospitalization.13-18 Experience of G-CSF treatment after unrelated BMT is limited. [19][20][21][22] The present study compares initiation of Filgrastim (r-metHuG-CSF) treatment at 0, +5 or +10 days after HLA-A,-B and -DR-compatible unrelated HSCT. Patients and methods PatientsThe protocol was approved by the local ethics review committee at Huddinge Hospital, and all patients gave informed consent before the study. Sixty-nine consecutive patients receiving bone marrow from HLA-A, -B and -DR-compatible unrelated donors between April 1994 and September 1997 were studied. The patients were stratified for children Ͻ18 years and adults у18 years, and for patients with or without malignancies. Patients were randomized to receive Filgrastim treatment starting on day 0, day +5 or day +10. Conditioning and prophylaxis against GVHDThe conditioning regimen and graft-versus-host disease (GVHD) prophylaxis were the same throughout the study period.23 Sixty-six patients were treated with cyclopho...

Summary:Recently, it has been reported that prophylactic administration of ciprofloxacin during cyclophosphamide (CY) conditioning was a high-risk factor for relapse in patients undergoing allogeneic BMT. In the present study, we investigated the possible mechanisms of this interaction in male Sprague-Dawley rats. The kinetics of CY and its active 4-OH-CY metabolite were determined, after 3 days pretreatment with ciprofloxacin (200 mg/kg) and compared to control rats without treatment. CY was administered as a high or low single intravenous dose (150 and 90 mg/kg, respectively). The expression of the CYP2B1, CYP2B2, CYP2C11, CYP3A1 and CYP3A2 genes was evaluated by SYBR Green I Dye real-time PCR for quantification of mRNA. The administration of ciprofloxacin resulted in a significant increase in the AUC (P ¼ 0.007) and a significant decrease in clearance (P ¼ 0.007) when CY was given as a high dose. In accordance, the metabolic ratio (AUC4-OH-CY/ AUCCY) was significantly lower (P ¼ 0.007) compared to that found in the control group. Ciprofloxacin significantly suppressed gene expression of CYP2C11 (P ¼ 0.01) and CYP3A1 (P ¼ 0.04); however, no effect was observed on the gene expression of CYP3A2, CYP2B1 and CYP2B2. Our study revealed that ciprofloxacin interacts with CY and suppressed relevant cytochromes P450 at the transcriptional level. This study may have a great clinical impact when ciprofloxacin is used in therapy. Bone Marrow Transplantation (2003Transplantation ( ) 31, 197-203. doi:10.1038 Keywords: cyclophosphamide; ciprofloxacin; interaction; cytochrome P450; gene expression; bone marrow transplantation Cyclophosphamide (CY) is a prodrug, which requires hepatic biotransformation to exert its cytotoxic effect. 1 An alternative but minor pathway is the inactivation of CY and both pathways are dependent on cytochrome P450 enzymes. [2][3][4][5] In humans, CYP2B6 is the main catalyst of CY activation, along with the contribution from CYP2C, CYP3A4, and CYP2A6 isoenzymes. 5-7 CY inactivation is mostly catalysed by CYP3A4. 5 In noninduced male rats, the constitutively expressed CYP2C11 and CYP3A2 are the major enzymes involved in CY bioactivation, while the inducible CYP2B1 was shown to be a major catalyst of CY activation in induced rats. 2,4 Thus, in vivo or in vitro alteration of hepatic CYPs could change the rate and pattern of CY metabolism. 8 Concomitant use of CY with other drugs that are inhibitors or inducers of CYP2B, CYP2C, or CYP3A enzymes could cause interactions. [9][10][11][12] Ciprofloxacin is a DNA gyrase inhibitor used as an antibacterial drug. 13 This fluoroquinolone agent has gained widespread use in the treatment of a broad range of infections. 14 Investigations focused on drug interactions between ciprofloxacin and other drugs have been reported in recent years. Particularly, interactions between ciprofloxacin and drugs metabolised by the hepatic cytochrome P450 (CYP) system have attracted attention. 15 Studies with hepatic microsomes demonstrated that ciprofloxacin can decrease CYP3A-me...