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We investigated the feasibility and efficacy of a fludarabine-based dose-reduced conditioning regimen followed by stem cell transplantation from related (n = 5) or unrelated HLA-matched donors (n = 7) in 12 patients with high risk MDS, who were not eligible for a standard myeloablative conditioning regimen. The conditioning regimen consisted of fludarabine 30 mg/m(2) daily for 6 days, busulfan 4 mg/kg daily for 2 days and anti-thymocyte globulin (ATG, rabbit) 10 mg/kg daily for 4 days in 11 patients, while one patient received fludarabine, ATG, cyclophosphamide and thiotepa. Graft-versus-host disease prophylaxis consisted of cyclosporine and a short course of methotrexate. The median age of the patients was 53 years (range 37-59). The median percentage of blasts in bone marrow aspirate at transplantation was 15% (range <5% to 35%). Diagnosis at transplant was RA (n = 1), RAEB (n = 5), RAEB-T (n = 5) and sAML (n = 1). A complex karyotype including monosomy 7 was noted in five patients. The reasons for using a dose-reduced conditioning regimen were prior autologous/syngeneic BMT (n = 4), active fungal infection (n = 2) or age/reduced performance status (n = 6). Engraftment was observed in all patients with complete donor chimerism. The incidence of acute GVHD (grade II-IV) was 33%. Eight patients died during follow-up due to relapse (n = 4), liver toxicity (n = 2), aspergillus (n = 1) or aGVHD grade IV (n = 1). After a median follow-up of 19 months, the 2-year estimated disease-free survival is 12% (95% CI: 2-23%) and the overall survival is 26% (95% CI: 4-52%). Fludarabine dose-reduced conditioning prior to allogeneic stem cell transplantation in high risk MDS patients, who were not eligible for standard transplantation, resulted in stable engraftment with complete chimerism, but the toxicity and relapse rate were considerable.

Y chromosome-specific sequences can be used to detect remaining male cells after sex-mismatched allogeneic blood stem cell transplantation (HSCT) involving a male patient and female donor, which represents approximately 25% of all cases. We developed a quantitative Y chromosome-specific PCR assay (QYCS-PCR) based on the DFFRY gene for the determination of hematopoietic donor chimerism. We analyzed blood and marrow samples from more than 40 patients at various time points after both standard and nonmyeloablative allogeneic HSCT. We found that real-time PCR combines extreme sensitivity, with a detection level of less than 1 male in 100,000 female cells (<0.001%), with very good reproducibility, especially in the important range of minor host chimerism. QYCS-PCR results were in close agreement with data from other techniques as bcr/abl-PCR and/or fluorescent in situ hybridization (FISH) analysis. In two relapsed patients, increasing numbers of Y-positive hematopoietic cells indicated recurrence of malignant disease prior to clinical confirmation. In conclusion, quantitative Y chromosome-specific PCR is a promising approach for monitoring the extent of chimerism in blood and other tissues after sex-mismatched hematopoietic stem cell transplantation (HSCT) or organ transplantation.

We evaluated the cytomegalovirus (CMV) serostatus as a risk factor for survival and treatment-related mortality (TRM) in 125 patients allografted from an unrelated donor between 1994 and 1999. All patients received pretransplant in vivo T-cell depletion using rabbit anti-thymocyte globulin (ATG). Only one patient had primary graft failure and severe grade III/IV graft-versus-host disease occurred in 14% of the patients. The overall survival (OS) at 3 years was 70% for CMV-negative patients (n = 76) and 29% in the seropositive cohort (n = 49) (P > 0.001). In multivariate analyses, CMV seropositivity remained an independent negative prognostic factor for OS (RR: 2.1; CI: 1.2-3.8; P = 0.014), apart from age > 20 years (RR: 2.74; CI: 1.2-3.8; P = 0.004) and late leucocyte engraftment (RR: 2.4; CI: 1.2-4.9; P = 0.015). The TRM for all patients was 27%. Despite monitoring for CMV antigenaemia and preemptive therapy with ganciclovir when reactivation occurred, seropositive patients had a three times higher risk of fatal treatment-related complications than seronegative patients. In multivariate analyses, CMV seropositivity remained the strongest independent negative factor for TRM (RR: 5.3; CI: 1.9-14.6; P = 0.002), followed by age > 20 years (RR: 4.8; CI: 1.3-18.1; P = 0.02) and delayed leucocyte engraftment (RR: 3.6; CI: 1.2-11; P = 0.02). The TRM was identical in seropositive patients with (n = 27) or without (n = 22) CMV reactivation (44% versus 50%). We conclude that CMV seropositivity, despite preemptive ganciclovir therapy and even without reactivation, is a major negative prognostic factor for survival as well as for TRM in unrelated stem cell transplantation using pretransplant in vivo T-cell depletion with ATG.

Two patients with persistent disease after allografting for multiple myeloma received donor T-cell lymphocyte infusion (DLI) (1.5 x 10(8) and 7 x 10(7)) to induce a graft-vs.-myeloma effect for further tumour regression after withdrawal of immunosuppression. The interval between stem cell transplantation and DLI was 8 and 14 months respectively. Both patients converted from partial to complete remission, lasting 12+ and 28+ months. Immunofixation became negative after 3 and 4 months. The main toxicity was grade II and III acute graft-vs.-host disease (GvHD) and limited or extensive chronic GvHD in each patient. We conclude that DLI induced further tumour reduction in patients with persistent disease after allografting for multiple myeloma.

We compared fractionated total body irradiation (12 Gy)/cyclophosphamide (120 mg/kg) with busulfan (16 mg/kg)/cyclophosphamide (120 mg/kg) as preparative therapy in unrelated donor stem cell transplantation of CML patients. Fifty patients with CML (1.CP = 46; aP = 4) and a median age of 36 years (range 16-52) were enrolled in this sequential trial between 1994 and 1999. In both groups patients were well balanced with respect to age, disease status, stem cell source and CMV status. All patients received standard doses of cyclosporin A, methotrexate and anti-thymocyte globulin (ATG) as GVHD prophylaxis. No graft failures occurred in either group. The median day of leukocyte engraftment was earlier in the Bu/Cy than in the TBI/Cy group (day 15 vs 17; P = 0.006). The incidence of grade II-IV GVHD was 40% in the TBI/Cy and 36% in the Bu/Cy group, whereas severe grade III/IV GVHD was only observed in 12% of patients in both groups. The incidence of chronic GVHD (limited and extensive) at 1 year was higher in the Bu/Cy arm (65% vs 30%; P = 0.02). More toxicity grade I/II of the liver (88% vs 44%; P = 0.002) and more hemorrhagic cystitis (32% vs 8%; P = 0.02) were observed in the Bu/Cy regimen. Seven relapses in the TBI and no relapse in the Bu/Cy group were observed after a median follow-up of 44 and 15 months, respectively. The estimated 3 year OS and DFS was 72% (95% CI: 55-98%) and 58% (95% CI: 39-77%) in the TBI and 70% (95% CI: 51-89%) for DFS and OS in the Bu/Cy group. We conclude that the anti-leukemic effect of the Bu/Cy regimen seems to be at least as effective as the TBI/Cy combination in unrelated stem cell transplantation of CML patients, with no graft failures, but that it correlates with a higher incidence of liver toxicity, hemorrhagic cystitis and chronic GVHD. Longer follow-up is necessary to determine the late relapse rate and late toxicity.

To evaluate the efficacy and toxicity of two different etoposide (VP-16) dosages (30 or 45 mg/kg) in combination with busulfan/cyclophosphamide as conditioning therapy followed by stem cell transplantation in acute myeloid leukemia (AML), 90 patients with AML received either 30 mg/kg (n = 60) or 45 mg/kg (n = 30) etoposide in combination with busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg). The stem cell source was allogeneic related bone marrow (BM) (n = 53), allogeneic unrelated BM (n = 5), allogeneic unrelated peripheral blood (PBSC) (n = 2), syngeneic BM (n = 2), autologous BM purged (n = 9) or unpurged (n = 9), autologous PBSC (n = 10). Fifty-six patients (62%) were in first CR, 26 (29%) were > first CR, and eight (9%) were transplanted in relapse. Principal toxicities in both groups were mucositis and hepatotoxicity. Forty-five mg/kg etoposide resulted in greater hepatic toxicity (P = 0.03), and a higher incidence of VOD (23 vs 12%, P = 0.04) and acute GVHD grade III/IV (13 vs 5%, NS). The treatment-related mortality was 17% in the 30 mg/kg group and 33% in the 45 mg/kg group, mainly due to infections, intestinal pneumonia and GVHD. Hematological recovery of leukocytes 1/nl was comparable in both groups (17 vs 16 days). After a median follow-up of 16 months 19% in the 30 mg/kg group and 23% in the 45 mg/kg group relapsed. In patients who had undergone allogeneic related bone marrow transplantation in first CR no relapses occurred after a median follow-up of 3 years. For all patients the 3-year estimated disease-free survival was 62% in the 30 mg/kg group and 40% in the 45 mg/kg group (P = 0.03). For patients in first CR who underwent allogeneic related stem cell transplantation the 3 year disease-free survivals were 80% and 66%, respectively (P = 0.4). We conclude that etoposide 30 mg/kg or 45 mg/kg in combination with busulfan/cyclophosphamide is a highly active regimen for bone marrow transplantation of patients with AML with a low relapse rate. However, conditioning with 30 mg/kg rather than 45 mg/kg etoposide resulted in less toxicity and a better overall survival due to a lower transplant-related mortality. Bone Marrow Transplantation (2000) 26, 711-716.

A five-agent GVHD prophylaxis programme consisting of cyclosporin A, methotrexate, anti-thymocyte-globulin, pentaglobin and metronidazol was given to 48 recipients of unrelated donor marrow with chronic myelogenous leukemia, acute leukemia, myelodysplastic syndromes, and familiar lymphocytic hemophagocytosis of an average age of 33.5 (0.6-56) years. GVHD grades II-IV occurred in 18 patients (39%) and grades III-IV in five patients (11%). Chronic GVHD developed in nine patients (23%), three limited and six extensive. Fifteen patients died. Clinical relapse was detected in eight patients. Four patients died as a consequence of the underlying disease and subsequent treatment, 11 patients died of transplant-related causes. After a median follow-up of 19 months, the overall and disease-free survival are 67% and 62%, respectively. Survival by age is as follows: 0-19 years: 12/13 patients; 20-39 years: 14/25 patients; 40-59 years: 7/10 patients. The five-agent GVHD prophylaxis regimen is effective. Matched-unrelated donor transplants can be carried out safely in patients younger than 50 years of age. The results in patients younger than 20 years of age should encourage matched-unrelated donor transplants at earlier stages of the disease.

Cefoperazone is a semisynthetic cephalosporin of the 3rd generation (cefobid, Pfizer, USA). It was used in monotherapy of 12 oncological patients during ++post-cytostatic aplasia of the bone marrow and peripheral pancytopenia after bone marrow transplantation. The results were favourable in 67 per cent of the patients: the body temperature normalized and no signs of any infection were evident. In 25 per cent of the patients the monotherapy failed and it was necessary to combine cefoperazone with aminoglycosides. Therefore, cefoperazone proved to be an efficient antibacterial drug, whose use was possible in the monotherapy of oncological patients after transplantation of the bone marrow.

Studies of lipid metabolism and peroxidation values, carried out in healthy newborns in the town of Irkutsk, have shown that total lipid and triglyceride levels in these newborns over the first ten days of their lives were similar to those in age-matched infants in the European USSR, whereas plasma total cholesterol levels were significantly higher in them as against the newborns in other regions of the country. The studies included measurements of malonic dialdehyde and total antioxidative activity of blood plasma and red cells, of catalase and peroxidase activities, of red cell peroxidation resistance.

During measurements of the content of malonic dialdehyde and the total antioxidant activity in blood plasma and red blood cells as well as of their peroxide resistance in healthy neonates, it has been established that in boys and girls the majority of the study parameters did not differ within the first 6 days of life. At the same time in girls, catalase and peroxidase of red blood cells were activated and the total antioxidant activity of blood plasma was increased since the first days after the birth.

A total of 45 patients were given cytosar and daunorubicin therapy at small doses. Of them 23 patients were with acute nonlymphoblastic leukemia, 12--with hemopoietic dysplasia, and 10--with chronic myeloid leukemia. Cytosar was injected subcutaneously every 12 h at a dose of 10 mg/m2 for 10-25 days, daunorubicin was injected intravenously by drop infusion at a dose of 5 mg/m2. Clinicohematological remission was obtained in 13 patients, clinicohematological improvement in 16. Thus, a positive effect was achieved in 29 patients (64%). The authors provided some data on the influence of small doses of cytosar and daunorubicin on cell maturation in vitro.