Busulfan Targeted Dose In Hematopoietic Stem Cell Transplantation: The Impact In Toxicity, Sinusoidal Obstructive Syndrome and Survival

Busulfan (BU) is one of the most used alkylating agent in mieloablative conditioning regimens (CR) for patients submited to Hematopoietic Stem Cell Transplantation (HSCT). Its therapeutic effect is correlated to area under the curve (AUC) having a wide variability among patients. Ideal AUC is not been well stablished yet but it is known that higher levels can impact survival by increasing extra medular toxicity. In the other way, lower levels can be associated to a higher incidence of relapse. Two BU formulations are available, oral (PO) or Intrvenous (IV). Although IV BU can developed more reliable AUC, there are few data comparing both formulations.

To compare the pharmacokinetics (PK) of PO and IV BU based conditioning regimens in patients submited to HSCT and to determinate the best target BU AUC in order to reduce acute toxicity after HSCT.

149 patients were prospectively evaluated. All recieved myeloablative (MA) BU based conditioning regimen (BU associated to Cyclophosphamide(Cy), Melphalan(Mel), Cy/VP-16, Fludarabine(Flu)/Thiotepa, Flu/Mel,Mel/Gencitabine, Mel/Cy, Flu/clofarabine, Clofarabine/Thiotepa). 56 (37,5%) received a MA reduced intensity CR (Bu associated to Flu). 56 (37.5%) patients recieved a stem cells from a matched related donor, 45(30.2%) from matched unrelated donor, 9(6%) from related haploidentical donor and 17 (11.4%) from cord blood. The median age was 30,2 years (range 1,3-73). 86 (57.7%) had acute leukemias and myelodisplastic syndrome, 28(18.8%) had lymphomas, multiple myeloma and chronic leucemias, 32(21.4%) had diferente benign diseases. 83 (55.7%) patients recieved PO and 63(44.3%) IV BU. All patients had BU PK monitoring at least one time during CR. 81 (54.4%) patients also performed a pre transplant BU test dose (32mg/m² for IV and 1mg/kg for PO BU). There were 3 BU targeted AUC: 4000, 5000 and 6000 µMol.min, according to institutional protocols based on disease risk and patient age. Historical control of 53 patients who received myeloablative conditioning regimen with no BU PK monitoring were used. Mucositis, Sinusoidal obstruction Syndrome (SOS) Overall survival (OS), Transplant related mortality (TRM) and relapse were analysed according to AUC targeted dose. 184 (91%) patients developed mucositis at 5 (range:0-11) days after HSCT. There were no diference in either incidence (p=0,15) or severity (p=0,19) of mucositis in patients recieving PO(n=66, 32.6%) or IV (n=83, 41%) BU and historical control (n=53, 26.2%) (p=0,15). Pre transplant test dose had also no impact on incidence and severity of mucositis (p=0,75). More importantly, AUC targeted dose had no impact in either mucositis incidence or severity (p=0.75). Among all 202 patients, 23 (11,4%) developed SOS until day 30 post HSCT. The use of pre transplant Bu test dose had no impact in SOS incidence: Gray-subhazard ratio (SHR)SHR 0.70 - CI95% 025-1.91; (p=0.48). BU formulations (PO or IV) had no impact in SOS (p=0.73) either. Patients recieving higher BU AUC targeted dose had an incresed risk to develop SOS after HSCT: Incidence of SOS in patients who recieved AUC<5000 and AUC>=5000 was 5% and 16% respectively (SHR 3.39, p=0.034, CI 95% 1.09-10.52). In contrast, this finding had no impact in day Transplant related TRM and 1 year OS: patients who revieved AUC<5000 and AUC>=5000, had 1 year OS of 61% and 66% respectivelly (p=0.52). Patients who revieved AUC<5000 and AUC>=5000, had 100 day TRM of 12% and 12% respectivelly (p=0.42). We also found that patients who recieved AUC from 4000 to 5000 had a lower OS, showing a protective effect of lower AUC: 1 year OS for patients who recieved AUC 4000t to 5000 was 65% (IC95% 55-74%) HR: 0.65, (p=0.33). In the other hand, patients who recieved lower AUC targeted dose (4000) had higher incidence of relapse: SHR: 0.42, p=0.08, CI 95% 0.15-1.1

In this cohort of patients, toxicity and survival were not influenced by BU formulation (oral or IV). More importantly, patients recieving higher Bu AUC targeted dose had higher incidence of SOS and targeting AUC between 4000 to 5000 had a positive impact in 1 year OS but are more likely to relapse (AUC 4000). We also, shown that using Bu test dose, does not increase toxicities or mortality in patients reciving Bu condicioning regimen. Therefore, we can conclude that PK Bu monitoring is important in either PO or IV BU formulation, in order to reduce toxicities such as SOS and mortality.

Santos:Novartis: Consultancy, Research Funding, Speakers Bureau.