Risk assessment and outcome of chronic graft-versus-host disease after allogeneic peripheral blood progenitor cell transplantation in pediatric patients. Diaz MA, Vicent MG, Gonzalez ME, Verdeguer A, de la Rubia J, Bargay J, de Arriba F, Diez JL, Caballero D, Madero L, Brunet S; Spanish Group for Allogeneic Peripheral Blood Transplantation. Bone Marrow Transplant. 2004 Sep;34(5):433-8 Predicting survival for myeloid leukemia after HLA-identical sibling donor allogeneic stem cell transplantation. Gallardo D, De la Camara R, Torres A, Brunet S, Jimenez A, Vallejo JC, Sanz G, Serrano D, Carreras E, Martin C, Sanz-Rodriguez C, Sierra J, Espigado I, Caballero D, Berlanga JJ. Leukemia. 2004 Jun;18(6):1165-7. Follicular lymphoma international prognostic index. Solal-Celigny P, Roy P, Colombat P, White J, Armitage JO, Arranz-Saez R, Au WY, Bellei M, Brice P, Caballero D, Coiffier B, Conde-Garcia E, Doyen C, Federico M, Fisher RI, Garcia-Conde JF, Guglielmi C, Hagenbeek A, Haioun C, LeBlanc M, Lister AT, Lopez-Guillermo A, McLaughlin P, Milpied N, Morel P, Mounier N, Proctor SJ, Rohatiner A, Smith P, Soubeyran P, Tilly H, Vitolo U, Zinzani PL, Zucca E, Montserrat E. Blood.2004, 104(5):1258-65 Influence of biologic markers on the outcome of Hodgkin's lymphoma: a study by the Spanish Hodgkin's Lymphoma Study Group. Montalban C, Garcia JF, Abraira V, Gonzalez-Camacho L, Morente MM, Bello JL, Conde E, Cruz MA, Garcia-Sanz R, Garcia-Larana J, Grande C, Llanos M, Martinez R, Flores E, Mendez M, Ponderos C, Rayon C, Sanchez-Godoy P, Zamora J, Piris MA; Spanish Hodgkin's Lymphoma Study Group. J Clin Oncol. 2004 May 1;22(9):1664-73. Chromosomal abnormalities are related to location and grade of osteoarthritis. Castellanos MV, Hernandez JM, Ramos L, Belen Gonzalez M, Gutierrez NC, Leone PE, Lumbreras E, Robledo C, Garcia Hernandez JL. Osteoarthritis Cartilage.2004, 12(12):982-5

Abstract During the course of chronic myeloid leukemia (CML) progression to blast crisis (BC) is thought to be caused by genetic instability such as cytogenetic aberrations in addition to the translocation t(9;22)(q34;q11). We have shown previously that major route ACA indicate an unfavorable outcome (Fabarius et al., Blood 2011). We now investigate whether there is a correlation in time between appearance of major route ACA and increase in blast count. Methods: Cytogenetic data and blast count in the peripheral blood were available from 1,290 CML patients recruited to the German CML-studies III (621 patients) and IIIa (669 patients) from January 1995 to January 2004. Treatments were interferon-alpha-based or related allogeneic stem cell transplantation (HSCT). Presence of ACA and major route ACA was considered as a time-dependent covariate. Multivariate proportional hazards models were estimated taking Euro CML score, study III vs. IIIa and stem cell transplantability into account. Cumulative incidences of blast increases were calculated starting at the date of the first ACA or major route ACA, respectively, regarding death as a competing risk. Patients were censored at the date of HSCT with an unrelated donor. Results: 1,287 patients were evaluable with median observation times of 13 and 12 years and a 10-year survival of 48% and 61% in CML studies III and IIIa, respectively. 258 patients progressed to BC with a cumulative 10-year incidence of 20%. 195 patients displayed ACA during the course of disease. 45 patients (15.7%) showed ACA already at diagnosis. 44 patients showed unbalanced minor route, 29 balanced minor route aberrations, 23 -Y. 109 patients showed major route aberrations including 10 with other prior ACA. In a multivariate analysis on 1,257 patients, patients with ACA had a hazard ratio (HR) for a blast increase of between 2.0-2.2 (p<0.001) for blast increases to ≥1%, ≥5%, ≥10%, ≥15%, ≥ 20% and ≥30% compared with patients without ACA (Table). When the same model was performed for major route ACA only at any time during disease, HRs of 2.2-2.7 (p<0.001) were found. For ACA without major route ACA HRs were 1.6-2.1 (p<0.001). In the multivariate analyses of major route ACA vs. no major route ACA a blast increase of 1-5% after diagnosis of major route ACA seems already indicative of progression. 5 years after the diagnosis of any ACA the cumulative incidence for a blast increase was 30% (95%- confidence interval (CI): 23-38%), of a major route ACA 40% (95%- CI: 28-49%). The 6-year probability of death without blast increase was 10%. 14 additional patients received an unrelated transplant of which 6 died. We conclude that ACA, particularly major route ACA, precede an increase of blasts. Major route ACA have to be considered as a prognostic indicator for disease progression at any time. Table 1. Blast increase to HR (univariate): ACA vs. no ACA HR(multivariate)*: ACA vs. no ACA HR (univariate): major route ACA vs. no major route ACA HR (multivariate)*: major route ACA vs. no major route ACA ≥30% 2.409 2.139 2.646 2.203 ≥20% 2.413 2.144 2.656 2.211 ≥15% 2.415 2.161 2.868 2.426 ≥10% 2.416 2.160 2.799 2.357 ≥5% 2.286 2.047 2.719 2.278 ≥1% 2.209 1.999 3.171 2.684 *adjusted to Euro-Score, study (III vs. IIIa) and transplantability Disclosures Saussele: ARIAD: Honoraria; BMS: Honoraria, Other: Travel grant, Research Funding; Pfizer: Honoraria, Other: Travel grant; Novartis Pharma: Honoraria, Other: Travel grant, Research Funding. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Scheid:Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Baerlocher:Geron Corporation: Research Funding; Novartis: Research Funding. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Müller:BMS: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Hochhaus:ARIAD: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Pfirrmann:BMS: Consultancy, Honoraria; Novartis Pharma: Consultancy, Honoraria. Baccarani:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ARIAD Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hehlmann:BMS: Consultancy; Novartis Pharma: Research Funding.

An allogeneic hematopoietic stem cell transplantation (HSCT) can have profound and lasting adverse effects on a patient's physical and psychological well-being. So far, only few studies have investigated the effectiveness of physical activity over the entire inpatient phase of an allogeneic HSCT. Purpose: We performed a randomized controlled study to examine the influence of a controlled moderate exercise program starting parallel to chemotherapeutic conditioning and total body irradiation on the patient's physical and psychological constitution. Patients and methods: Forty-seven patients undergoing an allogeneic HSCT were randomly assigned to an exercise group (EG) or a control group (CG). While the EG took part in an endurance and activity of daily living-training twice a day, the CG received the clinic's standard physiotherapy program once a day. Results: Significant differences and/or trends in favor of the EG were observed regarding the primary endpoint endurance performance (P = 0.002), muscular strength (P = 0.022), fatigue (P = 0.046), and emotional state (P = 0.028) without posing an additional risk for the individual. Conclusion: The results show that the training program is feasible and seems to have positive influences on physical performance and quality of life in patients undergoing an allogeneic HSCT. However, further studies are necessary to confirm these results.

Analysis of donor chimerism is an important diagnostic tool to assess the risk of relapse after allogeneic stem cell transplantation, especially in patients lacking a specific marker suitable for monitoring of minimal residual disease. We prospectively investigated the predictive value of donor chimerism analyses in sorted CD34(+) peripheral blood cells in 90 patients with acute leukemia and myelodysplastic syndrome. The cumulative incidence of relapse after four years was significantly increased in cases with decreasing or incomplete CD34(+) donor chimerism (57% vs. 18%, p=0.0001). Multivariate analysis confirmed decreasing CD34(+) donor chimerism as an independent predictor of relapse and inferior survival. The interval between a decrease of CD34(+) chimerism of less than 80% and hematologic relapse was 61 days (range 0-567). Monitoring of CD34(+) donor chimerism in the peripheral blood allows prediction of imminent relapse after allogeneic stem cell transplantation even when a disease-specific marker is lacking.

Abstract Abstract 3328 Poster Board III-216 Introduction Relapse is a major cause of treatment failure after alloSCT against acute leukaemia, and no standard treatment has been established in this challenging situation. The introduction of reduced conditioning regimens, and the broader availability of alternative donors have increased the possibilities to perform a second alloSCT as salvage treatment, using different preparative regimen and/or different stem cell donors. Methods To evaluate the role of a second alloSCT (tx2) for the treatment of relapse after first alloSCT (tx1), we performed a nationwide retrospective analysis based on the German registry for stem cell transplantation (DRST). Datasets were completed by the reporting centres on request, following a specifically designed questionnaire. Results 212 patients (69% AML, 31% ALL), from 23 centres were included. Median age at tx1 was 37y. Donor at tx1 were HLA identical siblings (41%), matched unrelated (39%), mismatched family or unrelated (17%) or syngeneic donors (3%). Conditioning intensity at tx1 was standard (SIC, 62%), intermediate (intC, 25%) or reduced (RIC, 13%). Median remission after tx1 was 7 months, median time from relapse to tx2 was 74d. At tx2, patients were aplastic (4%), in CR (20%) or showed active disease (76%). In 59%, the same donor was used for tx1 and tx2, whereas a different donor was chosen in 41%. Conditioning at tx1/tx2 were SIC/SIC (14%), intC/intC (10%), (RIC/RIC (10%), less intensive at tx2 (mostly intC or RIC after SIC, 58%), or more intensive at tx2 (SIC after RIC or intC, 8%). Following tx2, CR was achieved in 56% of patients, out of which 81% relapsed again. Hence, leukemia was the most frequent cause of death. With a median FU of 23 months after tx2, median OS after tx2 is 117d. In a univariate analysis (log rank), OS after tx2 depended on stage at tx1 (CR vs. active disease, p<.001), stage at tx2 (CR vs. aplastic/active disease, p=.011) and duration of remission after tx1 (<=6m (1y OS 5%) vs. 6-12m (15%) vs. >12m (31%), p<.001). No significant difference was observed regarding age ( median), AML vs. ALL, family versus unrelated donor, or time point of alloSCT (2002). Shift to an alternative donor did not improve the results either. In a multivariate analysis (Cox Regression Model), time of remission after tx1 was the only significant factor for OS (p<.001, hazard ratio .51, 95%CI .49-.74). Conclusion Survival of acute leukemia after second allogeneic SCT is determined by the duration of remission after tx1. Using an alternative donor for tx2 did not improve the results in our series. Further analysis is required to evaluate the role of RIC regimen for tx2. Disclosures No relevant conflicts of interest to declare.

BACKGROUND:BK virus-associated hemorrhagic cystitis (BKV-HC) is a severe complication after allogeneic hematopoietic stem cell transplantation (HSCT), but antiviral treatment for this condition has not been evaluated. METHODS:We conducted a retrospective survey on the safety and outcome of cidofovir treatment for patients with BKV-HC in centers affiliated with the European Group for Blood and Marrow Transplantation. RESULTS:From 1 April 2004 to 31 December 2007, 62 patients received a diagnosis of BKV-HC after a median interval of 35 days after HSCT (range, 3-577 days). Fifty-seven patients (92%) received intravenous cidofovir, whereas 5 patients received cidofovir intravesically. Complete response (CR) was recorded in 38 (67%) of 57 patients with HC treated with intravenous cidofovir, whereas partial response (PR) was documented in 7 patients (12%). CR was documented in 3 patients and PR in 1 patient with HC treated with intravesical cidofovir. A reduction of 1-3 logs in BKV load was documented in 8 of the 10 patients achieving CR. Mild-to-moderate toxic effects were recorded in 18 of 57 patients who received intravenous cidofovir administration. In a multivariate analysis, the factors significantly associated with response to cidofovir were the stem cell source (P = .01) and the use of total body irradiation (P = .03). After a median follow-up of 287 days, overall survival and total treatment-related mortality rates were 63% and 40% for patients achieving CR, compared with 14% and 72% for patients with PR or no response to cidofovir, respectively (P = .001 and P = .001, respectively). CONCLUSIONS:Cidofovir may be a potentially effective therapy for BKV-HC, but evidence supporting its use requires randomized controlled trials.

This retrospective study reported the outcome of 97 adult acute lymphoblastic leukemia patients who received a reduced-intensity conditioning allogeneic stem cell transplantation. With a median follow-up of 2.8 years, two year overall-survival, leukemia-free survival and non-relapse mortality were significantly better in patients transplanted in first complete remission (CR1, 52 +/- 9%; 42 +/- 10%; and 18 +/- 7% respectively) compared with those transplanted in more advanced phase (p=0.003, p=0.002 and p=0.01 respectively). In multivariate analysis, disease status (CR1 vs. advanced; p=0.001) and chronic graft-vs-host disease (p=0.01) were associated with an improved overall-survival, suggesting that reduced-intensity conditioning allogeneic stem cell transplantation is feasible in patients with high risk lymphoblastic leukemia in remission at transplantation.

Relapse of hematological malignancy remains a major complication after allogeneic stem cell transplantation. This is especially true for patients receiving minimal or reduced-intensity conditioning therapy. Analysis of donor chimerism (DC) is an important diagnostic tool to assess the risk of relapse after allogeneic stem cell transplantation, especially in patients lacking a specific marker suitable for monitoring of minimal residual disease. The sensitivity of a standard PCR assay amplifying short-tandem-repeat sequences can be improved significantly by investigating sorted CD34+ peripheral blood cells. We prospectively compared the serial analysis of DC in selected CD34+ cells and unmanipulated whole blood (WB) within a randomised study in 131 patients with CD34+ hematological malignancies (AML, ALL and MDS) surviving more than 100 days after transplantation. The primary end-point was the association between decreasing CD34+ DC and haematological relapse. Whenever a decreasing CD34+ or WB DC was confirmed and no signs of active GvHD were present, a rapid taper of CsA or tracolimus (50% every 5–7 days) was suggested. If no GvHD occurred within 14 days after the stop of CsA or tacolimus, patients were scheduled to receive donor lymphocyte infusions (DLI) in incremental doses. The cumulative incidence of relapse was significantly increased in patients with decreasing or incomplete CD34+ DC (62% vs. 38%, p=0.01). This was associated with a lower probability of overall survival (20% vs. 39%, p=0.03). The interval between the decrease in CD34+ DC and hematological relapse was 35 days (range 0–567) in the study group compared to only 8 days (range 0–63) in the control group monitored by WB DC analysis (p=0.05). The median time between a decrease in CD34+ DC and WB DC was 14 days (range, 0 to 445). Patients receiving preemptive therapy triggered by decreasing CD34+ DC had a significantly higher probability of disease-free survival compared to cases monitored and treated according to WB DC (19% vs. 0%, p=0.009). Multivariate analysis revealed age, disease-risk and decreasing CD34+ DC as independent risk-factors for overall survival in the study group. In summary, we could demonstrate that the quantification of DC in CD34+ selected cells is a sensitive method to predict relapse and survival after allogeneic SCT. Although this technology opens a window for preemptive therapy, new treatment approaches have to be employed to improve the overall outcome of patients with recurrence of residual disease after allogeneic stem cell transplantation.

BACKGROUND AND OBJECTIVES:Imatinib is an effective treatment for chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). However, relapse is common in patients with advanced or high risk disease. Such patients may be eligible for allogeneic stem cell transplantation (SCT), raising the question whether imatinib therapy may compromise the outcome of subsequent SCT. DESIGN AND METHODS:We retrospectively analyzed 70 patients with CML and 21 with Ph+ ALL who had received imatinib prior to SCT. Data were retrieved by directly contacting centers. Multivariate analysis was used to define factors associated with major outcomes (engraftment, graft-versus-host disease, relapse, non-relapse mortality) in addition to descriptive statistics. For the CML patients major outcomes were compared with those of historical controls drawn from the EBMT registry. RESULTS:At SCT, 44% of CML patients were in accelerated phase or blast crisis and 40% of ALL patients had active disease compared to 84% and 95% prior to imatinib. At 24 months, estimated transplant-related mortality was 44% and estimated relapse mortality 24%. Factors associated with shorter overall and progression-free survival were advanced disease at SCT and a female donor/male recipient pairing. No unusual organ toxicities were observed. Compared to historical controls, prior imatinib treatment did not influence overall survival, progression-free survival or non-relapse mortality, while there was a trend towards higher relapse mortality and significantly less chronic graft-versus-host disease. INTERPRETATION AND CONCLUSIONS:Within the limits of a heterogeneous and relatively small cohort of patients, we found no evidence that imatinib negatively affects major outcomes after SCT, suggesting that imatinib prior to SCT is safe.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment for patients with MDS. However, the advanced age of the majority of patients with MDS poses a significant barrier to the success of transplantation. Many of these patients have co-morbidities, or lack a suitable sibling matched donor. While reduced intensity conditioning (RIC) has expanded the scope of allografting to older patients, it remains unclear as to whether it confers an improvement in overall survival in this patient sub-group. Here we report on the results of a retrospective multi-centre analysis of 1385 patients aged 50 years or older with MDS transplanted since 1993. The main variables analysed in this study were donor status (sibling vs unrelated matched), age group (50–60 years vs >60years), disease stage at time of transplantation (early:<5% blasts vs advanced:>5% blasts), type of conditioning regimen (RIC vs standard myeloablative conditioning, SMC), period of transplantation (1993–96, 1997–2000–2001-).

Seventy-one patients with acute myeloid leukemia (AML), most of them (63/71) considered ineligible for conventional allogeneic hematopoietic stem cell transplantation (HSCT), were enrolled into a phase 2 study on reduced-intensity myeloablative conditioning with fractionated 8-Gy total body irradiation (TBI) and fludarabine (120 mg/m2). Patients received mobilized peripheral blood stem cells (n = 68) or bone marrow (n = 3) from siblings (n = 39) or unrelated donors (n = 32). Thirty-six patients received a transplant in complete remission (CR) and 35 had untreated or refractory disease (non-CR). Median patient age was 51 years (range, 20-66 years). Sustained engraftment was attained in all evaluable patients. With a median follow-up of 25.9 months (range, 3.7-61.2 months) in surviving patients, probabilities of overall survival for patients who received a transplant in CR and non-CR were 81% and 21% at 2 years, respectively. Relapse-free survival rates were 78% and 16%. The cumulative incidence of nonrelapse mortality (NRM) in CR patients was 8% at 2 years and beyond but amounted to 37% at 2 years in non-CR patients. Outcome data in this poor-risk population indicate that allogeneic HSCT from related or unrelated donors with 8-Gy TBI/fludarabine conditioning is feasible with low NRM and preserved antileukemic activity in AML patients in first or later CR.

The prognosis of patients with acute myeloid leukemia (AML) failing to standard induction chemotherapy is very poor, and only a minority of such patients will be ultimately cured after salvage chemotherapy. The precise role of allogeneic stem cell transplantation (alloSCT) in primary refractory AML has not been extensively assessed and it is not commonly indicated in this setting. In this regard, we analyzed the outcome and eventual prognostic factors in a series of adult patients who received an undepleted allograft from an HLA-identical sibling using a myeloablative conditioning for a primary refractory “de novo” AML (i.e., patients who never achieved complete response (CR) before transplantation). Overall, 361 patients (median age: 39; range: 17–71; 60% male) fulfilling these criteria and registered to the EBMT during the period 1990–2004 were included in the study. Median interval from diagnosis to transplant was 132 days (24–360) and the median number of induction courses was 2 (1–5). Percentage of bone marrow (BM) blasts at time of SCT was 20% (0–93). Most patients with available information (n=126, 35%) harbored an intermediate-risk cytogenetics (67%). Stem-cell source was peripheral blood (PB) in 61% of cases, and conditioning regimen did not contain TBI in 59% of the procedures. Following alloSCT, 218 patients (60%) achieved CR and 143 failed to respond. After a median follow-up of 26 months, 3 and 5-year overall survival was 24±2% and 19±3%, respectively. Of note, among the subset of patients achieving CR after alloSCT, overall survival and leukemia-free survival at 3-year was 37±3% and 33±3%, respectively, whereas none of those patients failing to alloSCT survived further than 10 months after transplant. The comparison of main characteristics between subgroups of patients according to response attained after alloSCT only disclosed a shorter interval from diagnosis (126 vs. 143 days, p=0.01) in the subset of responding patients. Moreover, a lower WBC count at diagnosis, inferior to median value (3-yr OS: 27±6% vs. 15±5%; RR: 2.08, 95% CI: 1.05–4.17; p=0.03), and a BM involvement of blast cells <20% at time of transplantation (3-yr OS: 35±8% vs. 10±5%; RR: 2.13, 95% CI: 1.12–4; p=0.02) were the only variables associated to a longer survival. In conclusion, allogeneic SCT is a reasonable alternative for a subset of patients with AML failing to primary induction chemotherapy who have an available HLA-identical sibling. Thus, a low WBC count at diagnosis and a low degree of BM infiltration at transplant were predictive of a more favorable outcome in the subgroup of 56 patients with this information available. Confirmation of this finding in a larger proportion of patients would be helpful to identify those patients with AML who could benefit from an allogeneic transplantation in a refractory status.

Eine hämatopoetische Knochenmarktransplantation mit seinen Nebenwirkungen bedeutet immer einen tief greifenden Einschnitt auf physischer wie auch psychischer Ebene des Betroffenen. Um präventiv auf mögliche Immobilisationserkrankungen zu reagieren und dabei den Patienten die Chance auf einen eigenen Beitrag zum Genesungsprozess zu ermöglichen, zeigt die vorliegende Studie erstmals, dass selbst unter aggressivsten chemo- sowie strahlentherapeutischen und isolierten Bedingungen moderate Bewegungstherapie möglich ist. Die Ergebnisse der kontrollierten sowie randomisierten Untersuchung weisen zudem signifikante und hochsignifikante Unterschiede zwischen der Trainings- und Kontrollgruppe in Physis und Psyche der Betroffenen zugunsten der Trainingsgruppe auf.

Retroviral producer cells are generated by the introduction of a viral genome into "helper" cell lines containing all the necessary components for viral packaging and the release of infectious particles. The selection of high-titer vector producer cells is most efficient if the vector genome encodes a selectable marker, while it is extremely tedious to select high-titer producer clones if the transgene cannot be detected and selected directly. Here we describe the development of a screening system that uses reversible integration of lox-P-flanked eGFP as a qualitative and quantitative marker gene in two different vector systems, greatly facilitating the selection of viral producer cells. After selection and titration of high-titer viral producer cells based on eGFP expression, the eGFP gene could be removed from the provirus by transient introduction of Cre-recombinase into the producer cells, thus allowing the production of therapeutic relevant vectors expressing solely the gene of interest. However, after removal of the marker gene a slight but consistent increase in viral titers compared to the respective control vectors was found, independent of the transgene or backbone used. The single lox-P site retained in the vector backbone does not affect gene expression level or fidelity of RNA processing.

Introduction of a “suicide gene” into donor T-lymphocytes is a promising strategy to prevent severe graft-versus-host disease (GvHD) in the setting of allogeneic blood stem cell transplantation (B-SCT). We initiated a clinical phase I/II-study combining CD34-enriched peripheral B-SCT and Herpes simplex virus thymidine kinase- (HSV-tk) transduced donor T-cell infusions at days 0 and (optional) 60. Before our study was put on hold (after the leukemia cases in the French X-SCID trial) three patients were treated within the protocol each receiving >4x106/kg highly enriched CD34+ and appr. 5x106/kg suicide gene-modified (SGM) donor T-cells. All patients showed fast donor cell engraftment. Patient 2 (without signs of GvHD) received two SGM T-cell infusions and is well >2.5 years thereafter. Patient 1, showed an early (days 11–13) strong increase of SGM cell-counts peaking at 7.2x107/l, but did not develop GvHD. Unexpectedly, his blood was completely cleared from SGM T-lymphocytes a few days later. This patient received a second dose of SGM T-cells (day 65), which vanished within 2 days strongly indicative of their immune rejection. Indeed, MLR data confirmed anti-SGM reactivity of this patient's PBL possibly related to an HSV reactivation during transplantation. Patient 3 showed a similar early sharp rise in SGM T-cells (days 14–17), in his case associated with acute skin GvHD grade II. Treatment with ganciclovir led to complete resolution of GvHD and rapid disappearance of SGM donor T-cells. Importantly, both patients 1 and 3 developed secondary graft failure at days 156 and 119. In summary, we confirmed previous reports that the use of SGM T-lymphocytes may allow control of acute GVHD. At the same time, we made the worrying observation that early total in vivo depletion of SGM donor T-cells may be associated with an increased risk of transplant rejection. This suggests that minimum numbers of donor CD3+ cells are required post-transplant not only to facilitate engraftment, but also to prevent late rejection.

Currently, the most commonly used routes of administration of antiemetics in chemotherapeutic regimens are oral and intravenous. Patient compliance and thus efficacy of conventional drug schedules and formulations are often impaired by difficulties associated with oral or intravenous uptake of the administered chemotherapy. Alternative or new drug delivery systems should overcome these problems by improving patient compliance.Several new drug delivery systems are available and development of these new systems is ongoing, in particular to meet delivery requirements of modern biological therapeutics and the application of gene therapy. However, at the present time, the implementation of new techniques of alternative antiemetic drug administration for chemotherapy-induced emesis is very limited. The challenge for clinical investigations to further develop new delivery systems, in particular for antiemetic therapies, remains.

Objectives: To investigate mycophenolate mofetil (MMF) plasma levels and impact on acute graft versus host disease (aGvHD) after stem cell transplantation (SCT).Methods: SCT patients (n = 14) with aGvHD (greater than or equal to 11) receiving MMF (1-3 g/d) in addition to cyclosporine, prednisolone, and methotrexate for aGvHD prophylaxis were investigated. Plasma levels of mycophenolic acid (MPA) and its glucuronide metabolite (MPAG) were determined by high-performance liquid chromatography.Results: Overall median steady state pre-dose plasma MPA concentration was 0.47 mg/L and increased within 75 min after administration to 1.64 mg/L. In comparison to patients with skin aGvHD, patients with gut aGvHD had lower MPA concentrations, both pre-dose (p = 0.16) and after 75 min, (p = 0.02). All 7 patients with skin aGvHD but only 2 patients with gut aGvHD responded to MMF. Overall, the pre-dose plasma MPA concentration was significantly (p = 0.007) greater in responders (n = 9) than in non-responders (n = 5).Conclusion: MMF seems to be an effective treatment for aGvHD in SCT patients particular in those patients without gut involvement. Copyright (C) 2000 The Canadian Society of Clinical Chemists.