Allogeneic Hematopoietic Stem Cell Transplantation with Clofarabine/Busulfan × 4 (CloBu4) Conditioning Exhibits Significant Anti-Tumor Activity In Non - Remission Hematologic Malignancies, Especially In AML
Allogeneic Hematopoietic Stem Cell Transplantation with Clofarabine/Busulfan × 4 (CloBu4) Conditioning Exhibits Significant Anti-Tumor Activity In Non - Remission Hematologic Malignancies, Especially In AML
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采用氯法拉滨/白消安 × 4 (CloBu4) 调理的同种异体造血干细胞移植在非缓解性血液恶性肿瘤（尤其是 AML）中表现出显着的抗肿瘤活性
DOI：
10.1182/blood.v116.21.35.35
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发表时间：
2010
期刊：
影响因子：
20.3
通讯作者：
J. Levine
中科院分区：
文献类型：
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作者：
S. Mineishi;J. Magenau;H. Tobai;A. Pawarode;E. Peres;P. Reddy;C. Kitko;S. Choi;H. Erba;Lisa A Kujawski;G. Yanik;J. Ferrara;J. Levine
摘要 35 例在异基因造血干细胞移植 (HSCT) 前未达到缓解的血液恶性肿瘤患者预后较差。为了在不增加毒性的情况下提高预处理的抗肿瘤活性，我们在一项针对非缓解性血液恶性肿瘤的 I/II 期研究中，将已知具有显着抗白血病活性的氯法拉滨与清髓剂量的白消安联合使用。白消安每日单次剂量为 3.2 mg/kg IV × 4d（第 -5 至 -2 天），氯法拉滨每日单次剂量为 20、30 或 40 mg/m 2 IV × 5d（第 -6 至 -2 天），具体剂量由事件发生时间连续重新评估方法（TITE-CRM）确定。所有患者在氯法拉滨治疗当天均接受 12 mg 地塞米松静脉注射，以预防毛细血管渗漏综合征。除一名患者外，所有患者均采用他克莫司/MMF（他克莫司/甲氨蝶呤）预防移植物抗宿主病（GVHD）。已登记四十六名患者。患者的特征如表 1 所示。在 HSCT 之前，患者平均 3 个治疗方案失败（范围：1-5 个），没有一个达到缓解，68% 的白血病患者有外周原始细胞。大多数人接受了不相关和/或 HLA 不匹配的移植物。 CloBu4 通常具有良好的耐受性。从调理开始到+30天观察到的3-4级非血液学毒性包括：短暂性转氨炎（50%）、粘膜炎（26%）、手足综合征（13%）、短暂性缺氧（13%）、恶心/呕吐（11%）、腹泻（11%）、高血压（7%）、静脉闭塞性疾病（4%）、高胆红素血症（4%）、过敏（2%）、关节痛（2%）和癫痫发作（2%）。无肾功能不全病例，所有转氨炎病例均在 14 天内恢复至 ≤ 1 级。所有患者均已移植（中性粒细胞平均 11 天[范围：9–16]；血小板平均 10 天[范围：1–20]。在第 30、100、180 和 365 天分析谱系特异性嵌合。当天，54%、75%、94% 和 100% 的患者实现了 CD3 谱系的完全供体嵌合第30、100、180和365天的绝对CD4计数分别为228±170、238±147、307±151和341±184个细胞/μl。48%的患者发生急性GVHD（≥2级）并导致5例死亡。总体而言，80% 的患者在第 30 天达到 CR（AML = 94%，其他 = 53%，未进行异基因 HSCT 的 AML = 100%）。 AML 患者的累积复发率为 38%，非 AML 患者的中位缓解时间为 15.4 个月（范围 2-34 m）。 p=0.008）和较短的缓解（8.6 m，范围 2-29 m），在 18 个月的中位随访中，移植后 18 个月时整个队列的总生存率为 42%（AML 为 50%，n=31）。 总之，这些数据表明氯法拉滨与清髓剂量的白消安联合使用具有良好的耐受性，促进移植，并具有显着的抗肿瘤作用。鉴于 CloBu4 可靠地使非缓解 AML 患者持续了 15.4 个月的缓解期，该方案可能为此类患者提供维持治疗等进一步干预的平台。 Erba：Genzyme：咨询、酬金、研究经费。
Abstract 35 Patients with hematologic malignancies who are not in remission prior to allogeneic hematopoietic stem cell transplantation (HSCT) have a poor prognosis. In an effort to improve the anti-tumor activity of conditioning without added toxicity, we combined clofarabine, which is known to have a significant anti-leukemia activity, with myeloablative doses of busulfan in a phase I/II study in non-remission hematologic malignancies. Busulfan was administered as a single daily dose of 3.2 mg/kg IV × 4d (days -5 to -2) and clofarabine as a single daily dose of 20, 30 or 40 mg/m 2 IV × 5d (days -6 to -2) with the specific dose determined by the Time to Event-Continuous Reassessment Method (TITE-CRM). All pts received dexamethasone 12 mg IV on the days of clofarabine to prevent capillary leak syndrome. Graft-versus-host-disease (GVHD) prophylaxis was tacrolimus/MMF in all but one patient (tacrolimus/methotrexate). Forty six pts were enrolled. Characteristics of pts are shown in table 1. Prior to HSCT, pts failed an average of 3 regimens (range: 1–5), none were in remission, and 68% of leukemic pts had peripheral blasts. The majority received unrelated and / or HLA mismatched grafts. CloBu4 was generally well tolerated. Grade 3–4 non-hematological toxicities observed from initiation of conditioning to day +30 include: transient transaminitis (50%), mucositis (26%), hand-foot syndrome (13%), transient hypoxia (13%), nausea/vomiting (11%), diarrhea (11%), hypertension (7%), veno-occlusive disease (4%), hyperbilirubinemia (4%), hypersensitivity (2%), joint pain (2%) and seizure (2%). There were no cases of renal insufficiency and all cases of transaminitis resolved to ≤grade 1 within 14 days. All patients engrafted (median 11 days for neutrophils [range: 9–16]; 10 days for platelets [range: 1–20]. Lineage specific chimerism was analyzed at day 30, 100, 180, and 365. Full donor chimerism in CD3 lineage was achieved in 54%, 75%, 94% and 100% of pts on days 30, 100, 180 and 365, respectively. Absolute CD4 counts were 228±170, 238±147 307±151, and 341±184 cells/μ l on days 30, 100, 180, and 365, respectively. Acute GVHD (≥ grade 2) occurred in 48% of pts and resulted in five deaths. Overall, 80% of pts achieved CR by day +30 (AML = 94%, Others = 53%, AML without prior allo HSCT = 100%). Cumulative incidence of relapse in AML patients was 38%. The median duration of remission for AML pts was 15.4 months (range 2–34 m). Non-AML pts experienced a higher incidence of relapse/progression (67%, p=0.008) and shorter remissions (8.6 m, range 2–29 m). At a median follow up of 18 months, overall survival for the entire cohort was 42% at 18 months post-transplant (50% for AML, n=31). In conclusion, these data suggest that clofarabine combined with myeloablative doses of busulfan is well tolerated, facilitates engraftment, and has significant anti-tumor activity, particularly in patients with non-remission AML at HSCT. Given that CloBu4 reliably led to remissions that lasted a median of 15.4 months in non-remission AML pts, this regimen may provide a platform for further interventions such as maintenance therapy for this population of pts. Disclosures: Mineishi: Genzyme: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding. Off Label Use: Clofarabine use for transplant conditioning regimen. Erba: Genzyme: Consultancy, Honoraria, Research Funding.