异基因造血干细胞移植预后与白舒非剂量相关分析解析.docx

1、异基因造血干细胞移植预后与白舒非剂量相关分析解析Biol Blood Marrow Transplant. Author manuscript; available in PMC 2014 Jun 11.Published in final edited form as:Biol Blood Marrow Transplant. 2013 Mar; 19(3): 474480. Published online 2012 Dec 7. doi: 10.1016/j.bbmt.2012.12.001PMCID: PMC4052712NIHMSID: NIHMS580149Dose intensi

2、fication of Busulfan in the preparative regimen is associated with improved survival: A Phase I/II Controlled, Randomized StudyS Parmar,1 G Rondon,1 M deLima,1 P Thall,2 R Bassett,2 P Anderlini,1 P Kebriaei,1 I Khouri,1 P Ganesan,1 R Champlin,1 and S Giralt31Dept of Stem Cell Transplantation and Cel

3、lular Therapy, The University of Texas at MD Anderson Cancer Center, Houston, TX 770302Dept of Biostatistics, The University of Texas at MD Anderson Cancer Center, Houston, TX 770303Memorial Sloan Kettering Cancer Center, New YorkCorresponding Author: Simrit Parmar, MD, Assistant Professor, MD Ander

4、son Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, Email: gro.nosrednadmramrapsAuthor information Copyright and License information Copyright notice and DisclaimerThe publishers final edited version of this article is available at Biol Blood Marrow TransplantSee other articles in PMC that ci

5、te the published article.Go to:AbstractDose intensity is important for disease control in patients undergoing allogeneic stem cell transplantation. We conducted a phase I/II controlled adoptive randomized study to determine the optimal dosing schedule of i.v. busulfan. Patients with advanced hematol

6、ogic malignancies, 75 years with HLA-compatible donor were eligible. All patients received fludarabine at 30mg/m2/d for 4 days and busulfan was administered in different doses in oral or i.v. formulations. As determined by the phase I trial, i.v. busulfan at a dose of 11.2 mg/kg/d was utilized for t

7、he phase II expansion cohort. Altogether, 80 patients with a median age of 56 years were enrolled. Forty percent had active disease at the time of transplant. Engraftment occurred in 91% and a complete response was achieved in 79% of patients post-transplant. At a median follow up of 91 months in th

8、e surviving patients, the outcomes for i.v. busulfan dose of 11.2 mg/kg/d vs. other doses were: non-relapse mortality: 34% vs. 23% (p=0.4); cumulative incidence of relapse: 43% vs. 68% (p=0.02); relapse-free-survival (RFS): 25% vs. 9% (p=0.017); overall-survival (OS): 27% vs. 9% (p=0.02). We conclud

9、e that optimizing intravenous busulfan dose intensity in the preparative regimen may overcome disease associated poor prognostic factors.Go to:INTRODUCTIONReduced intensity conditioning (RIC) regimen is associated with low non-relapse mortality (NRM) and has made it possible to offer allogeneic stem

10、 cell transplant (alloSCT) to the older population. Several large registry studies have shown that the lower NRM seen in RIC comes at the cost of increased relapsed rate13. Although myeloablative doses of i.v. busulfan in combination with either fludarabine or cyclophosphamide have been associated w

11、ith favorable outcomes, significant toxicities and treatment related morbidity and mortality remain a major concern 46. Slavin et al first reported the successful combination of oral busulfan with fludarabine, which resulted in 100% engraftment and was associated with long-term disease control in 77

12、.5%7. Since then, i.v. busulfan has largely replaced its oral formulation as part of the preparative due to more predictable pharmacokinetics and ability to perform dose adjustments to avoid excess toxicities4, 6, 8. Bypassing the oral route to achieve 100% bioavailability has translated into improv

13、ed control over drug administration, with increased safety and reliability in order to maximize the anti-leukemic efficacy. A recent report revealed a promising association with use of the i.v. form of busulfan and a lower NRM, even in sicker or older populations9. However, high-risk disease and/or

14、active disease at the time of transplantation is still associated with poor outcomes1014. Levine et al have demonstrated poor outcome associated with lower doses of busulfan in conditioning regimen, especially in patients with advanced disease12. In a retrospective analysis of 31 patients, busulfan

15、dose of 8mg/kg was associated with better disease control when compared to a less intense regimen of 4 mg/kg15. However, other studies have not found an advantage with higher dose busulfan containing regimens. Hamadani et al reported (in a retrospective analysis) that there was no difference in the

16、outcomes between RIC busulfan/ fludarabine (6.4mg/kg total dose of busulfan) compared with a more intense regimen (130mg/m2 of busulfan for 4 days-roughly equivalent to 12.8mg/kg cumulative dose)16. However, there were major differences in the patient profiles of two study arms with more acute leuke

17、mias in the intense therapy arm and more indolent diseases like chronic lymphocytic leukemia in the less intense arm. Therefore, optimization of busulfan containing conditioning regimens is needed for improvement clinically relevant patient outcomes.We conducted a prospective phase I/II Bayesian ado

18、ptively randomized study to determine the best dose, dosing schedule and efficacy of i.v. busulfan in combination with fludarabine as a preparative regimen for AlloSCT.Patients and MethodsPatients under 75 years of age undergoing AlloSCT from HLA A, B and DR matched unrelated donors or 5/6 matched r

19、elated donors with the following diagnoses were eligible: chronic myeloid leukemia (CML), that was either transformed or Interferon-resistant; acute myeloid leukemia (AML); intermediate or high-risk myelodysplastic syndrome (MDS) as defined by the International Prognostic Scoring System (IPSS); lymp

20、homa or myeloma beyond 1st remission. Eligible patients were considered unqualified to undergo ablative preparative regimen because of advanced age or the presence of co-morbidities. Patients had to be in Zubrod Performance status (PS) 2 with adequate hepatic (bilirubin 3mg/dL), and renal (creatinin

21、e 1.5 109/L for three days. Filtered and irradiated blood product transfusions were given to maintain hemoglobin 8g/dL and platelets 20,000/cmm3.Statistical design and analysisThis was a phase I/II Bayesian adoptively randomized dose finding study that took into account both toxicity and efficacy. P

22、atients were evaluated based on age, organ function and donor-match.Study End Points The major end points assessed during the study were engraftment (defined as absolute neutrophil count 0.5 109 /L, for 3 days in a row), platelet recovery (platelet recovery 20 109/L, independent of platelet transfus

23、ions), infectious complications, achievement of complete remission (CR) (0.5 109/L), development and grade of acute GVHD, chimerism over time, and toxicity. Overall Survival (OS) time was calculated as the time from the date of transplant to the date of death or censored at the date of last follow-u

24、p. Non-relapse mortality (NRM) 100 was defined as the binary indicator of death within the first 100 days without relapse. Relapse free survival (RFS) time was calculated as the time from the transplant date to the date of disease relapse or death, whichever was earlier. Patients who were alive with

25、out relapse at end of the study were censored at the date of last follow-up. There were four covariates of interest: age, cytogenetic risk category (good, intermediate, or bad), dose of busulfan received and the percent of bone marrow blasts.Dose Finding Strategy Based on factors influencing toxicity occurring from the preparative regimen; including patient age, organ function and degree of donor match; patients were separated into two strata in consideration for the toxicity for phase I endpoints: “good” risk as defined by good