Cyclophosphamide conditioning in patients with severe aplastic anaemia given unrelated marrow transplantation: a phase 1-2 dose de-escalation study

被引:60
作者
Anderlini, Paolo [1 ]
Wu, Juan [2 ]
Gersten, Iris [2 ]
Ewell, Marian [2 ]
Tolar, Jakob [3 ]
Antin, Joseph H. [4 ]
Adams, Roberta [5 ]
Arai, Sally [6 ]
Eames, Gretchen [7 ]
Horwitz, Mitchell E. [8 ]
McCarty, John [9 ]
Nakamura, Ryotaro [10 ]
Pulsipher, Michael A. [11 ]
Rowley, Scott [12 ]
Leifer, Eric [13 ]
Carter, Shelly L. [2 ]
DiFronzo, Nancy L. [13 ]
Horowitz, Mary M. [14 ]
Confer, Dennis [15 ]
Deeg, H. Joachim [16 ]
Eapen, Mary [14 ]
机构
[1] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA
[2] Emmes Corp, Rockville, MD USA
[3] Univ Minnesota, Minneapolis, MN USA
[4] Dana Farber Canc Inst, Boston, MA 02115 USA
[5] Phoenix Childrens Hosp, Phoenix, AZ USA
[6] Stanford Hosp & Clin, Stanford, CA USA
[7] Cooks Childrens Hosp, Ft Worth, TX USA
[8] Duke Univ, Durham, NC USA
[9] Virginia Commonwealth Univ, Richmond, VA USA
[10] City Hope Natl Med Ctr, Duarte, CA 91010 USA
[11] Univ Utah, Salt Lake City, UT USA
[12] Hackensack Univ, Med Ctr, Hackensack, NJ USA
[13] NHLBI, Bethesda, MD 20892 USA
[14] Med Coll Wisconsin, Milwaukee, WI 53226 USA
[15] Natl Marrow Donor Program, Minneapolis, MN USA
[16] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA
关键词
STEM-CELL TRANSPLANTATION; ALTERNATIVE DONOR TRANSPLANTS; TOTAL-BODY IRRADIATION; SAA WORKING PARTY; BONE-MARROW; ANTITHYMOCYTE GLOBULIN; FLUDARABINE; TOXICITY; FAILURE; REGIMEN;
D O I
10.1016/S2352-3026(15)00147-7
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background The optimum preparative regimen for unrelated donor marrow transplantation in patients with severe aplastic anaemia remains to be established. We investigated whether the combination of fludarabine, anti-thymocyte globulin, and total body irradiation (TBI) would enable reduction of the cyclophosphamide dose to less than 200 mg/kg while maintaining engraftment and having a survival similar to or better than that with standard regimens using a cyclophosphamide dose of 200 mg/kg (known to be associated with significant organ toxicity) for unrelated donor transplantation for severe aplastic anaemia. We have previously shown that cyclophosphamide at 150 mg/kg resulted in excess toxicity and its omission (0 mg/kg) resulted in unacceptable graft failure (three of three patients had secondary graft failure). Here we report results for the 50 mg/kg and 100 mg/kg cohorts. Methods In a multicentre phase 1-2 study, patients (aged <= 65 years) with severe aplastic anaemia, adequate organ function, and an unrelated adult marrow donor HLA matched at the allele level for HLA A, B, C, and DRB1 or mismatched at a single HLA locus received bone marrow grafts from unrelated donors. All patients received anti-thymocyte globulin (rabbit derived 3 mg/kg per day, intravenously, on days -4 to -2, or equine derived 30 mg/kg per day, intravenously, on days -4 to -2), fludarabine (30 mg/m.per day, intravenously, on days -5 to -2), and TBI (2 Gy). Cyclophosphamide dosing started at 150 mg/kg and was de-escalated in steps of 50 mg/kg (to 100 mg/kg, 50 mg/kg, and 0 mg/kg). The primary endpoint was the selection of the optimum cyclophosphamide dose based on assessments of graft failure (primary or secondary), toxicity, and early death during 100 days of follow-up after the transplant; this is the planned final analysis for the primary endpoint. This trial is registered with ClinicalTrials.gov, number NCT00326417. Findings 96 patients had bone marrow transplant. At day 100, 35 (92%) of 38 patients were engrafted and alive in the cyclophosphamide 50 mg/kg cohort and 35 (85%) of 41 in the 100 mg/kg cohort. Cyclophosphamide 50 mg/kg and 100 mg/kg resulted in posterior means for fatality without graft failure of 0.7% (credible interval 0-3.3) and 1.4% (0-4.9), respectively. Three patients (8%) had graft failure with cyclophosphamide 50 mg/kg and six (15%) with cyclophosphamide 100 mg/kg. Four (11%) patients had major regimen-related toxicity with cyclophosphamide 50 mg/kg and nine (22%) with cyclophosphamide 100 mg/kg. The most common organ toxicity was pulmonary (grade 3 or 4 dyspnoea or hypoxia including mechanical ventilation), and occurred in three (8%) and four (10%) patients given cyclophosphamide 50 mg/kg and 100 mg/kg, respectively. Interpretation Cyclophosphamide at 50 mg/kg and 100 mg/kg with TBI 2 Gy, fludarabine, and anti-thymocyte globulin results in effective conditioning and few early deaths after unrelated donor transplantation for severe aplastic anaemia. These doses of cyclophosphamide provide a framework for further regimen optimisation strategies.
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页码:E367 / E375
页数:9
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