Jochen Casper

Hintergrund und Fragestellung: Viele Patienten mit hämatologischen Erkrankungen müssen von einer allogenen Transplantation aufgrund drohender Nebenwirkungen der Konditionierung ausgeschlossen werden. Dosisreduzierte Verfahren umgehen zwar dieses Problem, können aber Effektivität einbüßen. Wir haben deshalb ein dosisintensives, aber toxizitätsreduziertes Konditionierungsverfahren mit Treosulfan und Fludarabin entwickelt und berichten über die ersten Erfahrungen. Patienten und Methodik: Bei 65 Patienten mit einem medianen Alter von 50 Jahren erfolgte eine Blutstammzelltransplantation von verwandten (n = 21) oder unverwandten Spendern (n = 44) nach Konditionierung mit Treosulfan (3 × 10, 3 × 12 oder 3 × 14 g/m² i. v.) und Fludarabin (5 × 30 mg/m² i. v.). 21 Patienten waren zum Zeitpunkt der Transplantation in kompletter Remission (CR), 44 Patienten hatten keine CR erreicht. 59 der 65 Patienten waren für eine konventionelle Konditionierung nicht geeignet. Ergebnisse: Die Gesamtüberlebensrate nach 3 Jahren (nach Kaplan-Meier) lag bei 59,2 %, das ereignisfreie Überleben bei 40,1 %. Patienten mit verwandtem Spender oder Transplantation in CR hatten eine deutlich bessere Gesamt- (85,4 % bzw. 74,2 %) und ereignisfreie Überlebensrate (52,2 % bzw. 61,9 %). Rezidive waren bei 26,2 % der Patienten nach 3 Jahren aufgetreten. Die transplantationsbedingte Mortalität an Tag 100 betrug 17,4 %. Die schrittweise Cox-Regressionsanalyse zeigte, dass bei unseren Patienten die Kovariablen Transplantation in CR vs. nicht in CR und der Spenderstatus einen signifikanten Einfluss auf das Gesamt- und ereignisfreie Überleben bzw. die transplantationsbedingte Mortalität hatten. Folgerungen: Unsere Erfahrungen mit einer dosisintensiven Konditionierungstherapie mit Treosulfan und Fludarabin zeigen, dass auch bei Patienten höheren Alters, mit schweren Begleiterkrankungen oder nach intensiver Vorbehandlung eine Blutstammzelltransplantation erfolgreich und ohne erhöhte transplantationsbedingte Mortalität verlaufen kann. Background and objective: Allogeneic transplantation can not be offered to many patients due to potential side-effects of conventional conditioning. Dose-reduced conditioning approaches improve tolerability, however, treatment efficacy may be reduced as well. We have, therefore, developed a dose intense but toxicity reduced conditioning regimen based on treosulfan and fludarabine and report first results. Patients and methods: 65 patients with a median age of 50 years were transplanted from related (n = 21) or unrelated donors (n = 44) after conditioning with treosulfan (3 × 10, 3 × 12 or 3 × 14 g/m² i. v.) and fludarabine (5 × 30 mg/m² i. v.). 21 patients were in complete remission (CR) and 44 patients had not reached a CR at the time of transplantation. 59 of 65 patients were considered unfit for a conventional conditioning regimen. Results: The actuarial overall survival after 3 years is 59.2 %, the event-free survival 40.1 %. Patients with a related donor or transplantation in CR had a better overall (85.4 resp. 74.2 %) and event-free survival (52.2 % resp. 61.9 %). The cumulative incidence of relapse at 3 years was 26.2 %. Non-relapse mortality at day 100 is 17.4 % (cumulative incidence). In stepwise Cox regression analyses for overall survival, event-free survival and non-relapse mortality the covariables transplantation in CR vs. not in CR and the donor status were shown to be influential. Conclusions: These results with a conditioning therapy of treosulfan and fludarabine indicate that patients despite higher age, concomitant disease or after intensive pretreatment can be successfully transplanted without increased treatment-related mortality.

New conditioning regimens are being explored to reduce toxicity and enable allogeneic bone marrow transplantation in patients not eligible for conventional transplantation. We have investigated treosulfan, an alkylating agent, with the aim of developing an efficient and reliable but less-toxic conditioning regimen. A series of 30 patients who were not eligible for standard conditioning therapy received transplants from HLA-matched related (n = 14) or unrelated (n = 16) donors after administration of treosulfan 10 g/m² intravenously daily for 3 days and fludarabine 30 mg/m² intravenously daily for 5 days. Patients receiving grafts from unrelated donors also were given rabbit antithymocyte globulin 10 mg/kg intravenously daily for 3 days. All patients achieved prompt neutrophil and platelet recovery. Extramedullary toxicity was generally mild with Common Toxicity Criteria (CTC) grade 3 or 4 attributable to the conditioning seen only with transaminases. Complete donor chimerism was achieved by 90% of the patients. Acute graft-versus-host disease (GVHD) grade III or IV developed in 14% of the patients and chronic GVHD in 39%. An estimated overall survival rate of 73% and an event-free survival rate of 49% have been reached after a median of 22 months (range, 7.4-33.4 months). In summary, the combination of treosulfan and fludarabine is a safe and efficient conditioning regimen.

A Phase I dose escalation and pharmacokinetic study of the alkylating cytotoxic agent treosulfan was conducted to evaluate the maximum tolerated dose and the dose-limiting toxicities in patients with advanced malignancies rescued by autologous peripheral blood stem cell transplantation. Twenty-two patients (15 ovarian and 7 other carcinomas/lymphomas) with a median age of 48 years were treated with 28 high-dose courses. Treosulfan was infused over 2 h at escalating doses from 20 to 56 g/m2, and pharmacokinetic parameters were analyzed. At 56 g/m2, three of six patients experienced dose-limiting toxicities: diarrhea grade III/IV in three patients; mucositis/stomatitis grade III in one patient; toxic epidermal necrolysis in one patient; and grade III acidosis in one patient. Other low-grade side effects, including erythema, pain, fatigue, and nausea/vomiting, were recorded. Two patients died within 4 weeks after treatment because of rapid tumor progression and fungal infection, respectively. Plasma half-life, distribution volume, and renal elimination of treosulfan were independent of dose, whereas the increase in area under the curve was linear up to 56 g/m2 treosulfan. The maximum tolerated dose of high-dose treosulfan is 47 g/m2. A split-dose or continuous infusion regimen is recommended for future high-dose trials. In consideration of antineoplastic activity and limited organ toxicity, inclusion of high-dose treosulfan in combination protocols with autologous peripheral blood stem cell transplantation seems worthwhile.

Twelve dogs suffering from acute lymphoblastic leukaemia were investigated concerning the following tests: platelet count, prothrombin time (PT, standard test, modified test), activated partial thromboplastin time (APTT), activity of the individual coagulation factors II, V, VII, X, VIII:C, IX, XI, XII, prekallikrein, and high-molecular weight kininogen, the activity of antithrombin III (AT III), protein C, plasminogen, and alpha 2-antiplasmin as well as concentration of fibrinogen, soluble fibrin and fibrin(ogen) degradation products (FDP). All patients showed a decreased platelet count due to suppression of megakaryopoesis by infiltration of the bone marrow with leukaemic cells. In addition, in most of the patients a moderate activity decrease of one or more individual coagulation factors has been found, especially regarding factor II (median, x0.50 = 51%, p = 0.0001), but also factors X (x0.50 = 71%, p = 0.0003) and XI (x0.50 = 68%, p = 0.0006). This was reflected by the APTT and the PT activity (modified test), which were prolonged or decreased, respectively, in the majority of the cases. Furthermore, the activity of AT III and of plasminogen was distinctly diminished (p < 0.001). Like the concentration of FDP, the plasma level of soluble fibrin was significantly higher than in normal dogs (p < 0.001). This indicates that besides thrombocytopenia disseminated intravascular coagulation occurs frequently in dogs with acute lymphoblastic leukaemia and is a main cause for the decreased activity of several plasmatic components of the haemostatic system. The lack of correlation between the concentration of soluble fibrin as an indicator of intravascular coagulation and the total blast cell count (rS = 0.011) shows the importance of other factors like degree of cell lysis as well as participation of organs such as the liver for generation of consumption coagulopathy in dogs with acute lymphoblastic leukaemia.

From January 1986 until August 1995 230 adult patients received an allogeneic or autologous transplantation of bone marrow or hematopoietic blood stem cells. The conditioning and myeloablative treatment regimens were chosen according to the underlying disease and type of transplant. The observation period comprises 1 to 115 months after transplantation. After allogeneic transplantation from HLA-identical family donors, the probabilities of disease-free survival were for acute myeloid leukemia in first complete remission (CR) (n = 35) 77%, for acute lymphoid leukemia in 1st CR (n = 7) 72% and in 2nd CR (n = 10) 40%, in first chronic phase of chronic myeloid leukemia (n = 34) 50% and in severe aplastic anemia (n = 7) 100%. Following myeloablative therapy and autologous transplantation the probabilities of disease-free survival were 47% in relapsed Hodgkin's disease (n = 22) and 42% for relapsed high-grade non-Hodgkin's lymphoma (n = 12). Eight of 10 patients with acute myeloid and 7 of 8 with acute lymphoid leukemia suffered a leukemic relapse after autologous bone marrow transplantation. Three of 8 patients with relapsed testicular cancer survived relapse-free. Treatment failures were due to more advanced acute graft versus host disease after allogeneic transplantation and caused by relapse after autologous transplantation. Current protocols evaluate the allogeneic transplantation of enriched CD34+ blood stem cells. In chronic myeloid leukemia the autologous transplantation of blood stem cells after myeloablative therapy is being studied.