PO.CL01.15 · 临床研究
免疫麻痹的深度预测新诊断单克隆B细胞淋巴细胞增多症和慢性淋巴细胞白血病的至首次治疗时间
Depth of immunoparesis predicts time to first therapy in newly diagnosed monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：CLL诊断时的低丙种球蛋白血症预测更短的至首次治疗时间（TTFT）。然而，免疫麻痹的深度及其对新诊断MBL/CLL患者TTFT的影响尚未得到探讨。
方法：我们从Mayo Clinic CLL数据库（2000-2024年）中识别既往未经治疗的MBL/CLL患者，这些患者在诊断1年内评估了血清免疫球蛋白（Ig；IgG、IgM和IgA）和单克隆蛋白。免疫麻痹的评估：a）定性评估，根据受抑制Ig的数量将患者分为Ig保留、部分抑制和完全抑制；b）定量评估，通过计算平均相对差值（ARD），即所有Ig低于正常值的平均百分比。两种方法中，对于有单克隆蛋白者仅考虑未受累的Ig。采用Kaplan-Meier法估计TTFT，并将死亡作为竞争风险。Cox模型估计风险比（HR）和95%置信区间（CI）。
结果：1420例患者中，诊断时中位年龄为65岁（范围28-96）；954例（67%）为男性；493例（44.8%）为IGHV未突变，86例（6.8%）有TP53破坏。血清IgG、IgA和IgM的中位数[范围，mg/dL]分别为889 [111-5290]、132 [1-4880]和49 [4-9480]。低IgG见于472例（33.2%），低IgA见于223例（16.4%），低IgM见于530例（37.3%）。122例（8.6%）患者检测到M峰；分布为：IgG（73）、IgM（30）、IgA（6）或多种（13）。定性评估中，Ig保留见于664例（46.8%），部分Ig抑制见于604例（42.5%），完全抑制见于152例（10.7%）。定量评估中，中位ARD为0.6（-0.8至11.3）；280例（19.7%）患者ARD为负，1140例（80.3%）ARD为正。在ARD为负者中，128例（9%）有部分Ig抑制，152例（10.7%）有完全Ig抑制；在ARD为正者中，664例（46.8%）Ig保留，476例（33.5%）有部分Ig抑制。中位随访14.7年；510例患者进展需要治疗。中位TTFT为9.6年。Ig保留患者的中位TTFT为12.6年，部分Ig抑制为8.0年（HR 1.4，95%CI 1.1-1.7），完全Ig抑制为1.8年（HR 3.1，95%CI 2.4-4.0）。ARD为负与为正的患者中位TTFT分别为2.3年和12.1年；ARD为负与更短的TTFT相关（HR 2.4，95%CI 2.0-2.9）。在校正性别和CLL国际预后指数（CLL-IPI）评分后，完全Ig抑制（HR 2.9，95%CI 2.2-3.9）和部分Ig抑制（HR 1.6，95% CI 1.3-2.0）与更短的TTFT相关（模型1，c统计量0.77）；ARD为负（HR 2.4，95%CI 2.0-2.9）与更短的TTFT相关（模型2，c统计量0.76）。ARD为负在完全Ig抑制之外额外识别出9%的TTFT更短的高风险患者。
结论：诊断时免疫麻痹的深度可预测TTFT，并增强新诊断MBL/CLL的风险分层。
查看英文原文 English abstract
Background: Hypogammaglobulinemia at the time of CLL diagnosis predicts shorter time to first therapy (TTFT). However, the depth of immunoparesis and its impact on TTFT in newly diagnosed MBL/CLL remains unexplored.
Methods: We identified previously untreated MBL/CLL patients from Mayo Clinic CLL Database (2000-2024) who had serum immunoglobulin (Ig; IgG, IgM and IgA) and monoclonal protein assessed within 1 year of diagnosis. Immunoparesis was evaluated: a) qualitatively by classifying patients into preserved, partial and full Ig suppression, based on the number of suppressed Igs; and b) quantitatively by calculating the average relative difference (ARD), defined as the mean percentage below normal for all Igs. For both methods, only uninvolved Igs were considered for those with monoclonal protein. TTFT was estimated by Kaplan-Meier with competing risk of death. Cox models estimated hazard ratios (HR) and 95% confidence intervals (CI).
Results: Among 1420 patients, median age at diagnosis was 65 (range 28-96); 954 (67%) were male; 493 (44.8%) had unmutated IGHV , and 86 (6.8%) had TP53 disruption. The median [range, mg/dL] serum IgG, IgA, and IgM were 889 [111-5290], 132 [1-4880], and 49 [4-9480]. Low IgG was present in 472 (33.2%), low IgA in 223 (16.4%), and low IgM in 530 (37.3%) patients. An M-spike was detected in 122 (8.6%) patients; distribution was: IgG (73), IgM (30), IgA (6), or multiple (13). By qualitative assessment, preserved Ig were seen in 664 (46.8%), partial Ig suppression in 604 (42.5%), and full suppression in 152 (10.7%) patients. By quantitative assessment, median ARD was 0.6 (-0.8 to 11.3); 280 (19.7%) patients had negative ARD, and 1140 (80.3%) had positive ARD. In those with negative ARD, 128 (9%) had partial Ig suppression and 152 (10.7%) had full Ig suppression; in those with positive ARD, 664 (46.8%) had preserved Ig and 476 (33.5%) had partial Ig suppression. Median follow-up was 14.7 years; 510 patients progressed requiring therapy. Median TTFT was 9.6 years. Median TTFT for patients with preserved Ig was 12.6 years, 8.0 years for partial Ig suppression (HR 1.4, 95%CI 1.1-1.7), and 1.8 years for full Ig suppression (HR 3.1, 95%CI 2.4-4.0). The median TTFT was 2.3 and 12.1 years for patients with negative vs positive ARD; negative ARD was associated with shorter TTFT (HR 2.4, 95%CI 2.0-2.9). After adjusting for sex and CLL-International Prognostic Index (CLL-IPI) score, full Ig suppression (HR 2.9, 95%CI 2.2-3.9) and partial Ig suppression (HR 1.6, 95% CI 1.3-2.0) were associated with shorter TTFT (model 1, c-stat 0.77); and negative ARD (HR 2.4, 95%CI 2.0-2.9) was associated with shorter TTFT (model 2, c-stat 0.76). Negative ARD identified an additional 9% of patients at higher risk for shorter TTFT beyond full Ig suppression.
Conclusions: The depth of immunoparesis at diagnosis predicts TTFT and enhances risk stratification in newly diagnosed MBL/CLL.
利益披露 Disclosure
Y. Yao, None..
K. G. Rabe, None..
E. Muchtar, None.
P. Hampel,
BeOne Medicines Ltd, Research Funding ),
.
AbbVie, Consultancy (Includes expert testimony) ).
AstraZeneca, Research Funding ).
Y. Wang,
Morphosys, Research Funding ).
Merck, Research Funding ).
Novartis, Research Funding ).
Loxo/Eli Lily, Consultancy (Includes expert testimony), Loxo/Eli Lily, Consultancy (Includes expert testimony) ).
InnoCare, Consultancy (Includes expert testimony) InnoCare, Research Funding ).
Abbvie, Consultancy (Includes expert testimony) Abbvie, Research Funding ).
Genmab, Consultancy (Includes expert testimony) Genmab, Research Funding ).
Genentech, Research Funding ).
Kite, Consultancy (Includes expert testimony) ).
Incyte, Consultancy (Includes expert testimony) Incyte, Research Funding ).
L. Roeker,
AbbVie: Consultancy; Research Funding ).
Abbott Laboratories: Current equity holder (publicly traded) Other, Abbott Laboratories: Current equity holder (publicly traded).
Adaptive Biotechnologies: Research Funding ).
Aptose Biosciences: Research Funding ).
Ascentage Pharma: Consultancy ).
AstraZeneca: Consultancy; Research Funding ).
BeiGene: Consultancy ).
Curio: Consultancy ).
DAVA: Consultancy ).
Dren Bio: Research Funding ).
Genentech: Research Funding ).
Janssen: Consultancy ).
Loxo Oncology: Consultancy; Research Funding ).
Medscape: Consultancy ).
PeerView: Consultancy ).
Pfizer: Consultancy; Research Funding ).
Pharmacyclics: Consultancy ).
Qilu Puget Sound Biotherapeutics: Research Funding ).
TG Therapeutics: Consultancy ).
S. Kenderian,
BMS: Consultancy; Research Funding ).
Capstan Bio: Consultancy ).
Carisma: Consultancy ).
Chymal: Equity (private company) Other, Chymal: Equity (private company).
Chymal Therapeutics: Patents/Royalties Other Intellectual Property.
Gilead: Consultancy; Research Funding ).
Humanigen: Consultancy; Patents/Royalties; Research Funding ), Other Intellectual Property.
Humanigen/Taran: Patents/Royalties Other Intellectual Property.
Immix Bio: Patents/Royalties Other Intellectual Property.
Juno: Consultancy; Research Funding ).
Juno/BMS: Consultancy ).
Kite: Consultancy; Research Funding ).
Lentigen: Research Funding ).
LifeEngine Animal Health Laboratories Inc: Research Funding ).
Luminary: Consultancy ).
MorphoSys: Research Funding ).
MustangBio: Patents/Royalties Other Intellectual Property.
Novartis: Consultancy; Patents/Royalties; Research Funding ), Other Intellectual Property.
Sunesis/Viracta: Research Funding ).
Tolero: Research Funding ).
A. Koehler, None..
C. Wagner, None..
A. Behnken, None..
J. F. Leis, None.
M. Tsang,
Genentech, Inc.: Consultancy ).
Lilly: Research Funding ).
ONO: Research Funding ).
Poseida Therapeutics: Current equity holder (publicly traded) Other, Poseida Therapeutics: Current equity holder (publicly traded).
T. Hilal, None.
R. D. Parrondo,
AbbVie – Consultancy; Research Funding ).
Aptitude Health – Honoraria Other, Aptitude Health – Honoraria.
AstraZeneca – Consultancy; Honoraria ).
BeOne Medicines – Honoraria; Research Funding ).
BeiGene/BeOne – Consultancy; Research Funding ).
Cullinan Therapeutics – Research Funding ).
GlaxoSmithKline – Research Funding ).
Janssen – Consultancy ).
Loxo Oncology/Lilly – Consultancy ).
Mashup Media LLC – Honoraria Other, Mashup Media LLC – Honoraria.
MJH Life Sciences / Intellisphere LLC – Honoraria Other, MJH Life Sciences / Intellisphere LLC – Honoraria.
Nurix Therapeutics – Research Funding ).
Philips Group Oncology Communications – Honoraria Other, Philips Group Oncology Communications – Honoraria.
Precisca / Ultimate Opinions in Medicine – Honoraria Other, Precisca / Ultimate Opinions in Medicine – Honoraria.
Sanofi Aventis – Consultancy; Honoraria ).
S. M. Schwager, None..
M. Shi, None..
C. A. Hanson, None..
C. M. Vachon, None.
S. K. Kumar,
AbbVie, Consultancy (Includes expert testimony) AbbVie, Research Funding ).
Sanofi, Consultancy (Includes expert testimony) ).
Adaptive, Consultancy (Includes expert testimony) Adaptive, Research Funding ).
Novartis, Consultancy (Includes expert testimony) ).
Takeda, Consultancy (Includes expert testimony) Takeda, Research Funding ).
Merck, Consultancy (Includes expert testimony) ).
Oncopeptides, Consultancy (Includes expert testimony) ).
Roche, Consultancy (Includes expert testimony) ).
Janssen, Consultancy (Includes expert testimony) Janssen, Research Funding ).
MedImmune/AstraZeneca, Consultancy (Includes expert testimony) MedImmune/AstraZeneca, Research Funding ).
Celgene, Consultancy (Includes expert testimony) Celgene, Research Funding ).
KITE, Consultancy (Includes expert testimony) KITE, Research Funding ).
E. Braggio, None.
N. E. Kay,
AbbVie: Research Funding ).
Acerta Pharma: Research Funding ).
AstraZeneca: Consultancy; Research Funding ).
Beigene: Consultancy ).
Bristol Myers Squibb / Celgene: Consultancy ).
Dren Bio: Consultancy ).
Janssen: Consultancy; Research Funding ).
Merck: Research Funding ).
Pharmacyclics: Consultancy; Research Funding ).
S. Slager, None.
S. A. Parikh,
AstraZeneca – Consultancy, Honoraria, Research Funding ).
BeOne Medicines Ltd – Consultancy, Honoraria ).
Genentech – Consultancy, Honoraria, Research Funding ).
Janssen – Consultancy, Honoraria, Research Funding ).
Kite Pharma – Consultancy, Honoraria ).
Merck – Consultancy, Honoraria, Research Funding ).
MingSight Pharmaceuticals – Consultancy, Honoraria ).
Novalgen Limited – Consultancy, Honoraria ).
Pharmacyclics – Consultancy, Honoraria ).
So Bi – Consultancy, Honoraria ).