Background

Traditionally, pre-transplant conditioning regimen is given over 4-6 days before hematopoietic cell transplant (HCT). Delivering higher dose chemotherapy preparative regimen over a longer time period has not been tested previously. We hypothesized that the delivery of myeloablative dose of busulfan over a 3-week period may reduce toxicity and non-relapse mortality (NRM), without affecting relapse, and tested this in a prospective phase II study.

Methods

Patients between 18 and 70 years of age with hematological malignancies and adequate organ function, with 8/8-HLA matched related or unrelated donor were eligible. They received a fixed dose of busulfan 80mg/m2 as outpatient on days -20 and -13. Then, fludarabine 40mg/m2 was given on days -6 to -2 followed by busulfan dosed to achieve target area under the curve (AUC) of 20,000 mol/min for the whole course based on pharmacokinetic studies. GVHD prophylaxis was cyclophosphamide (PTCy) 50mg/kg on days 3 and 4 and tacrolimus. Mycophenolate mofetil (MMF) was added to later unrelated donor recipients. All patients received standard supportive care. The primary endpoint was day 100 NRM.

Results

We enrolled 52 patients with a median age of 62 (range, 39-69) years. Almost half (n=25, 48%) had AML or MDS and the other half (n=26, 50%) had had CML or MPD; 1 (2%) had multiple myeloma. Low, intermediate, high and very-high disease risk index (DRI) was present in 3 (6%), 34 (65%), 14 (27%) and 1 (2%). HCT-comorbidity index was ≥3 in 23 (44%) and 1-2 (n=23, 44%). A majority (n=32, 62%) had an unrelated donor.

With a median follow up of 14 months (range, 3-23), NRM at day 100 was 1.9% (n=1) and 8% (95% CI, 0-15) at 1 year. Overall survival, progression-free survival and relapse at 1-year were 83% (95% CI, 73-95%), 78% (95% CI, 67-91%), and 14% (95% CI, 4-24%), respectively [Table].

There were no graft failures. The median time to neutrophil engraftment was 17 days (range, 13-33) and that of platelets (≥ 20K/µL, n=45) was 24 days (range, 9-266). Day 100 grade II-IV and III-IV acute GVHD rates were 37% (95% CI, 23-50%) and 6% (95% CI, 0-12%), respectively; 1-year chronic GVHD and extensive chronic GVHD rates were 9% (95% CI, 0-17%) and 7% (95% CI, 0-14%), respectively. Overall survival at 1-year differed significantly among patients with low/intermediate DRI (94%; 87-100%) and those with high/very high DRI (53%; 31-91%), P=0.001.

Conclusion

Myeloablative fractionated busulfan regimen with PTCy GVHD prophylaxis is feasible in older patients, has low incidence of severe acute GVHD, chronic GVHD, and NRM and results in promising overall survival.

中文翻译：

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老年患者的清髓性分级白消安调理方案：II期研究的结果

背景

传统上，在造血细胞移植（HCT）之前的4-6天内进行移植前的预处理方案。此前尚未测试过在更长的时间内提供更高剂量的化学治疗方案。我们假设在3周的时间内递送清髓性的白消安可降低毒性和非复发死亡率（NRM），而不会影响复发，并在一项前瞻性II期研究中对此进行了测试。

方法

年龄在18到70岁之间，具有血液系统恶性肿瘤和适当器官功能且具有8 / 8-HLA匹配相关或不相关供体的患者是合格的。他们在第-20天和第-13天在门诊接受了固定剂量的白消安80mg / m2。然后在药代动力学研究的基础上，在第-6天至-2天给予氟达拉滨40mg / m2，然后在整个疗程中给予白消安以达到20,000 mol / min的曲线下目标面积（AUC）。GVHD的预防是在第3天和第4天使用他克莫司的环磷酰胺（PTCy）50mg / kg。霉酚酸酯（MMF）已添加到后来的无关供者中。所有患者均接受标准支持治疗。主要终点为100天NRM。

结果

我们招募了52位中位年龄为62岁（范围：39-69岁）的患者。几乎一半（n = 25，48％）患有AML或MDS，另一半（n = 26，50％）具有CML或MPD；1（2％）有多发性骨髓瘤。低，中，高和非常高的疾病风险指数（DRI）分别为3（6％），34（65％），14（27％）和1（2％）。HCT合并症指数在23（44％）和1-2（n = 23，44％）中≥3。多数（n = 32，62％）的捐赠者无关。

中位随访14个月（范围3-23），第1天的NRM在第1天为1.9％（n = 1）和8％（95％CI，0-15）。1年总生存率，无进展生存率和复发率分别为83％（95％CI，73-95％），78％（95％CI，67-91％）和14％（95％CI，4- 24％）[表]。

没有移植失败。中性粒细胞植入的中位时间为17天（范围13-33），血小板（≥20K / µL，n = 45）的中位时间为24天（范围9-266）。第100天的II-IV级和III-IV级急性GVHD发生率分别为37％（95％CI，23-50％）和6％（95％CI，0-12％）；1年慢性GVHD和广泛慢性GVHD发生率分别为9％（95％CI，0-17％）和7％（95％CI，0-14％）。低/中级DRI（94％; 87-100％）和高/非常高DRI（53％; 31-91％）患者的1年总生存率有显着差异（P = 0.001）。

结论

PTCy GVHD预防性清髓性分级白消安方案在老年患者中是可行的，重症急性GVHD，慢性GVHD和NRM的发生率较低，并且总体存活率令人满意。