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Difference in Involved and Uninvolved Free Light Chain (dFLC) of Less Than 1mg/Dl Early Post Risk Adapted Melphalan and Autologous Stem Cell Transplantation (RA-ASCT) Predicts Renal Response (RR) at 1 Year in Light Chain (AL) Amyloidosis
Biology of Blood and Marrow Transplantation ( IF 5.609 ) Pub Date : 2020-01-23 , DOI: 10.1016/j.bbmt.2019.12.087
Sneha Purvey , Kenneth Seier , Sean M. Devlin , Josel D. Ruiz , Molly A. Maloy , Gunjan L. Shah , Hani Hassoun , Sergio A. Giralt , Heather J. Landau

Background

Deep and durable hematologic remissions following RA-ASCT are associated with improved organ function and extended overall survival in AL amyloidosis. While depth of hematologic response by standard criteria are important, this study assessed additional factors that influence RR and time to RR.

Methods

All patients (pts) with AL and renal involvement undergoing RA-ASCT at Memorial Sloan Kettering Cancer Center between January 1, 2007 to December 31, 2016 were included. Pts with follow up <12 months (mos) post RA-ASCT and hemodialysis prior to RA-ASCT were excluded. Melphalan dose was assigned based on age, cardiac involvement and renal compromise. Hematologic and organ response was assessed at 3 (early) and 12 mos post RA-ASCT. Consolidation with bortezomib and dexamethasone was offered to pts with less than complete response (CR) at 3 mos. Logistic regression models were used to assess association with RR (Palladini Blood 2014) by 12 mos. Covariates for adjustment in multivariate models were chosen based on univariate analyses and clinical relevance.

Results

Sixty-four patients with renal AL meeting the inclusion criteria were identified; 3 died within 12 mos post RA-ASCT were excluded. Median age was 61 years (44-73), 51% female and 34% had cardiac involvement. Median 24 hr proteinuria pre ASCT was 5014 mg/day (2632-7514) and eGFR 68 ml/min/1.73 m2 (44-91). Renal amyloid stage I:II:III was 33%:52%:15%. Mayo cardiac stage (2004) I:II:III was 28%:61%:11% and revised Mayo stage (2012) I:II:III:IV was 13%:57%:21%:8%. Median BM plasma cells pre ASCT was 9% (2-14%). 46% received treatment prior to ASCT. Melphalan dose (mg/m2) 200:140:100 was 44%:43%:11% and 46% received consolidation.

Hematologic response early post ASCT was CR 44%, very good partial (VGPR) 29% and partial response (PR) 20%. dFLC <1mg/dL was achieved in 63%. RR by 12 mos was achieved in 32 pts (53%); median time to RR was 5.8 mos (5.1 – 11.3). Amongst renal responders, 50% achieved CR, 53% MRD negative, and 78% dFLC <1mg/dL early post RA-ASCT. In pts with dFLC <1mg/dL early post RA-ASCT, 66% achieved RR.

By univariate analysis, early post ASCT dFLC <1mg/dL (OR 3.00, 95% CI 1.01-8.93, p = 0.048) and VGPR (7.80, 1.69-36.06, p = 0.009), at 12 mos dFLC <1mg/dL (7.20, 2.14-24.21, p = 0.001) and CR (10.27, 1.14-92.26, p = 0.038) were associated with RR. By multivariate analysis, dFLC <1mg/dL early post ASCT (OR 4.52, 95% CI 1.26-16.24, p = 0.021) was associated with RR when adjusted for renal amyloid stage and Mayo cardiac stage (2004).

Conclusion

In this single center study, we found that RA-ASCT results in RR in more than half (53%) of pts at 1 year. Achieving dFLC <1mg/dL early post ASCT is prognostic of RR independent of renal stage. Early MRD-negativity did not predict RR. Our study suggests maximal suppression of the pathologic light chains is important for organ recovery. Larger studies using dFLC <1mg/dL as an end point are warranted.



中文翻译:

早期风险适应后的Melphalan和自体干细胞移植(RA-ASCT)参与和未参与的游离轻链(dFLC)的差异小于1mg / Dl可以预测轻链(AL)淀粉样变性在1年时的肾反应(RR)

背景

RA-ASCT后深度和持久的血液学缓解与AL淀粉样变性病的器官功能改善和总体生存期延长有关。虽然按标准标准进行的血液学反应深度很重要,但本研究评估了其他影响RR和RR时间的因素。

方法

纳入2007年1月1日至2016年12月31日期间在纪念斯隆凯特琳癌症中心接受RA-ASCT的所有AL和肾脏受累患者(pts)。RA-ASCT后随访<12个月(mos)的患者和RA-ASCT前进行血液透析的患者均排除在外。根据年龄,心脏受累情况和肾功能损害确定美法仑剂量。在RA-ASCT后3个月(早期)和12个月评估血液和器官反应。在3个月内,对硼苯佐米布和地塞米松的合并症患者的完全反应(CR)不足。Logistic回归模型用于评估12个月与RR的关联(Palladini Blood 2014)。基于单变量分析和临床相关性选择在多变量模型中进行调整的协变量。

结果

确定了64例符合纳入标准的肾性AL患者。RA-ASCT后12个月内3例死亡被排除。中位年龄为61岁(44-73岁),其中有51%的女性和34%的心脏受累。ASCT前24小时蛋白尿中位数为5014 mg /天(2632-7514)和eGFR 68 ml / min / 1.73 m2(44-91)。肾淀粉样蛋白I:II:III阶段为33%:52%:15%。Mayo心脏分期(2004)I:II:III为28%:61%:11%,修订的Mayo分期(2012)I:II:III:IV为13%:57%:21%:8%。ASCT前的BM浆细胞中位数为9%(2-14%)。46%的患者在ASCT之前接受了治疗。美法仑(mg / m2)200:140:100的剂量为44%:43%:11%,46%的患者接受巩固治疗。

ASCT术后早期的血液学反应为CR 44%,非常好(VGPR)为29%,部分反应(PR)为20%。dFLC <1mg / dL达到63%。32 pts(53%)达到12 mos的RR;RR的中位时间为5.8 mos(5.1 – 11.3)。在肾反应者中,RA-ASCT早期早期CR达到50%,MRD阴性为53%,dFLC <1mg / dL。在RA-ASCT后早期dFLC <1mg / dL的患者中,有66%达到了RR。

通过单因素分析,ASCT早期dFLC <1mg / dL(OR 3.00,95%CI 1.01-8.93,p = 0.048)和VGPR(7.80,1.69-36.06,p = 0.009),在12 mos dFLC <1mg / dL( 7.20,2.14-24.21,p = 0.001)和CR(10.27,1.14-92.26,p = 0.038)与RR相关。通过多变量分析,调整肾淀粉样蛋白阶段和梅奥心脏阶段(2004年)后,ASCT早期dFLC <1mg / dL(OR 4.52,95%CI 1.26-16.24,p = 0.021)与RR相关。

结论

在这项单中心研究中,我们发现RA-ASCT在1年时导致RR的一半以上(53%)。ASCT后早期达到dFLC <1mg / dL对RR的预后与肾脏分期无关。早期MRD阴性不能预测RR。我们的研究表明最大程度抑制病理轻链对于器官恢复很重要。有必要使用dFLC <1mg / dL作为终点进行更大的研究。

更新日期:2020-01-23
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