Nieto Yago, Valdez Benigno C, Pingali Sai R, Bassett Roland, Delgado Ruby, Nguyen John, Shah Nina, Popat Uday, Jones Roy B, Andersson Borje S, Gulbis Alison, Ahmed Sairah, Bashir Qaiser, Parmar Simrit, Patel Krina, Myers Alan, Rondon Gabriela, Orlowski Robert Z, Champlin Richard, Qazilbash Muzaffar
Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Lancet Haematol. 2017 Jun;4(6):e283-e292. doi: 10.1016/S2352-3026(17)30080-7. Epub 2017 May 15.
High-dose melphalan is of little benefit as a regimen for patients with relapsed or refractory myeloma undergoing an autologous stem-cell transplant (ASCT). The poor performance of single-agent melphalan in this setting prompted us to study a new high-dose combination of infused gemcitabine, busulfan, and melphalan.
We did a phase 2 trial at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). We enrolled patients with primary refractory or relapsed myeloma who had received treatment with bortezomib, an immunomodulatory drug, or both, or who were receiving a salvage ASCT. Gemcitabine was infused at 1875 mg/m for 3 h for 2 days, followed by busulfan (target area under the curve 4000 μmol/L per min per day for 4 days) and melphalan (60 mg/m per day for 2 days). The primary endpoint of this trial was to establish the proportion of patients with measurable disease at ASCT receiving gemcitabine, busulfan, and melphalan who achieved stringent complete remission in accordance with the International Myeloma Working Group criteria. We then retrospectively compared the patients in this study with all other concurrent patients at the MD Anderson Cancer Center who were eligible for this trial but declined to participate or had no financial coverage for ASCT in a clinical trial and instead received melphalan at 200 mg/m intravenously over 30 min on 1 day, followed by ASCT (control group). To compare survival outcomes, we used a statistical algorithm to select a subset of patients from this control cohort who were matched in a 1-2:1 ratio with the patients in the gemcitabine, busulfan, and melphalan group by sex, age, disease status, refractory to both proteasome inhibitors and immunomodulatory imide drugs, time from diagnosis to ASCT, and cytogenetic risk. All analyses were per protocol. This is the final analysis of the clinical trial, which is registered at ClinicalTrials.gov, number NCT01237951.
Between Nov 30, 2010, and Dec 11, 2013, we enrolled 74 patients into the gemcitabine, busulfan, and melphalan trial. In these patients, median age was 58 years (IQR 51-62), median number of previous lines of therapy was two (2-5), 38 patients had high-risk cytogenetics, 17 were unresponsive to all previous treatments, and 32 were receiving a salvage ASCT. We identified 184 patients for the concurrent control cohort. The study patients and the concurrent controls received similar post-ASCT maintenance. Among patients with measurable disease at ASCT, 16 of 65 patients (24·6%, 95% CI 14·2-35·0) in the gemcitabine, busulfan, and melphalan group had stringent complete remission compared with 22 of 174 patients (12·6%, 10·1-15·1) in the concurrent control group (p=0·040). Median follow-up time was 36 months (IQR 30-46) in the patients receiving gemcitabine, busulfan, and melphalan and 34 months (25-53) in the matched control subset (n=111). With respect to the secondary survival endpoints, the gemcitabine, busulfan, and melphalan cohort had significantly longer median progression-free survival than the matched control cohort (15·1 months [95% CI 8·7-22·1] vs 9·3 months [8·0-10·7]) with a significantly reduced risk of progression or death (HR 0·55, 95% CI 0·38-0·81, log-rank p=0·030), as well as significantly longer median overall survival (37·5 months [26-not reached] vs 23·0 months [16·6-30·5]) and a lower risk of death (HR 0·60, 0·34-0·84, log-rank p=0·0092). For only the patients treated with gemcitabine, busulfan, and melphalan, grade 3 or worse adverse events included grade 3 mucositis (12 patients), grade 3 dermatitis (five patients), grade 3 aminotransferase elevation (seven patients), grade 3 diarrhoea (two patients), and three treatment-related deaths. One death was cardiac sudden death and two were due to sepsis.
Gemcitabine, busulfan, and melphalan is a comparatively safe and active regimen for ASCT in patients with refractory or relapsed myeloma. Better outcomes were achieved in patients who received this regimen than in a concurrent matched cohort receiving melphalan, although this will need to be confirmed in a prospective, randomised trial.
Otsuka Pharmaceutical Development & Commercialization and US National Cancer Institute.
对于接受自体干细胞移植（ASCT）的复发或难治性骨髓瘤患者，高剂量美法仑作为一种治疗方案益处不大。单药美法仑在这种情况下效果不佳，促使我们研究一种新的高剂量吉西他滨、白消安和美法仑联合方案。
我们在美国德克萨斯大学MD安德森癌症中心（休斯顿，德克萨斯州，美国）进行了一项2期试验。我们纳入了原发性难治性或复发性骨髓瘤患者，这些患者曾接受过硼替佐米、一种免疫调节药物或两者的治疗，或者正在接受挽救性ASCT。吉西他滨以1875mg/m²的剂量输注3小时，共2天，随后是白消安（目标曲线下面积为4000μmol/L每分钟每天，共4天）和美法仑（60mg/m²每天，共2天）。该试验的主要终点是确定接受吉西他滨、白消安和美法仑的ASCT患者中，根据国际骨髓瘤工作组标准达到严格完全缓解的可测量疾病患者的比例。然后，我们回顾性地将本研究中的患者与MD安德森癌症中心所有其他符合该试验条件但拒绝参与或在临床试验中没有ASCT财务覆盖且改为在1天内静脉输注200mg/m²美法仑30分钟，随后进行ASCT的同期患者（对照组）进行比较。为了比较生存结果，我们使用统计算法从该对照队列中选择一组患者，这些患者在性别、年龄、疾病状态、对蛋白酶体抑制剂和免疫调节性酰亚胺药物均耐药、从诊断到ASCT的时间以及细胞遗传学风险方面与吉西他滨、白消安和美法仑组的患者以1 - 2:1的比例匹配。所有分析均按照方案进行。这是该临床试验的最终分析，该试验已在ClinicalTrials.gov注册，编号为NCT01237951。
在2010年11月30日至2013年12月11日期间，我们将74例患者纳入吉西他滨、白消安和美法仑试验。这些患者的中位年龄为58岁（四分位间距51 - 62岁），既往治疗线数的中位数为2（2 - 5），38例患者有高危细胞遗传学特征，17例对所有先前治疗均无反应，32例正在接受挽救性ASCT。我们为同期对照队列确定了184例患者。研究患者和同期对照患者接受了相似的ASCT后维持治疗。在ASCT时有可测量疾病的患者中，吉西他滨、白消安和美法仑组65例患者中有16例（24.6%，95%置信区间14.2 - 35.0）达到严格完全缓解，而同期对照组174例患者中有22例（12.6%，10.1 - 15.1）达到严格完全缓解（p = 0.040）。接受吉西他滨、白消安和美法仑治疗的患者中位随访时间为36个月（四分位间距30 - 46个月），匹配对照亚组（n = 111）的中位随访时间为34个月（25 - 53个月）。关于次要生存终点，吉西他滨、白消安和美法仑队列的中位无进展生存期明显长于匹配对照队列（15.1个月[95%置信区间8.7 - 22.1]对9个月[8.0 - 10.7]），进展或死亡风险显著降低（风险比0.55，95%置信区间0.38 - 0.81，对数秩检验p = 0.030），中位总生存期也明显更长（37.5个月[26 - 未达到]对23.0个月[16.6 - 30.5]），死亡风险更低（风险比0.60，0.34 - 0.84，对数秩检验p = 0.0092）。仅对于接受吉西他滨、白消安和美法仑治疗的患者，3级或更严重的不良事件包括3级粘膜炎（12例患者）、3级皮炎（5例患者）、3级转氨酶升高（7例患者）、3级腹泻（2例患者）以及3例与治疗相关的死亡。1例死亡为心脏性猝死，2例死于败血症。
吉西他滨、白消安和美法仑是一种相对安全且有效的难治性或复发性骨髓瘤ASCT治疗方案。接受该方案的患者比接受美法仑的同期匹配队列取得了更好的结果，尽管这需要在前瞻性随机试验中得到证实。
大冢制药开发与商业化公司和美国国立癌症研究所。
