达雷妥尤单抗治疗免疫球蛋白轻链淀粉样变性。

Daratumumab-Based Treatment for Immunoglobulin Light-Chain Amyloidosis.

机构信息

From the Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens (E.K., M.A.D.); the Amyloidosis Research and Treatment Center, Fondazione IRCCS Policlinico San Matteo, and the Department of Molecular Medicine, University of Pavia, Pavia, Italy (G.P., G.M.); the Department of Hematology, University Medical Center Utrecht, University Utrecht, Utrecht (M.C.M.), the Amyloidosis Center of Expertise, University of Groningen, University Medical Center Groningen, Groningen (W.R.), and Janssen Research and Development, Leiden (B.T., J. Vermeulen) - all in the Netherlands; University College London, London (A.D.W.); Centre Hospitalier Universitaire (CHU) and Reference Center for AL Amyloidosis, Limoges (A.J.), Département de Néphrologie et Transplantation d'Organes, Centre de Référence des Maladies Rénales Rares, Hôpital Rangueil, CHU de Toulouse, Toulouse (A.H.), and the Department of Hematology, CHU Lille, University of Lille, Lille (S.M.) - all in France; the Department of Lymphoma and Myeloma, Division of Cancer Medicine, University of Texas M.D. Anderson Cancer Center, Houston (H.C.L.); the Amyloidosis Center, Boston University School of Medicine and Boston Medical Center (V.S.), and the Division of Hematology/Oncology, John C. Davis Myeloma and Amyloid Program, Tufts Medical Center (R.L.C.) - both in Boston; the Victorian and Tasmanian Amyloidosis Service, Department of Haematology, Monash University Eastern Health Clinical School, Melbourne, VIC (S.G.), the Department of Haematology, Princess Alexandra Hospital and University of Queensland Medical School, Brisbane (P.M.), and the Department of Clinical Haematology, Westmead Hospital, Westmead, NSW (F.K.) - all in Australia; Cross Cancer Institute, University of Alberta, Edmonton (C.P.V.), the Division of Hematology, London Health Sciences Centre, London Regional Cancer Program, Western University, London, ON (S.L.), and the Division of Hematology, Vancouver General Hospital, BC Cancer, University of British Columbia, Vancouver (K. Song) - all in Canada; Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Collaborative Innovation Center of Hematology, Beijing (J.L.); Medical Department V (Hematology/Oncology/Rheumatology), Amyloidosis Center, Heidelberg University Hospital, Heidelberg (S.S.), and Hämatologisch-Onkologische Praxis Altona, Hamburg (T.H.) - both in Germany; the Department of Hematology, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem (M.E.G.); the Department of Hematology, Japanese Red Cross Medical Center, Tokyo (K. Suzuki), and the Department of Hematology, Japan Community Health Care Organization Kyoto Kuramaguchi Medical Center, Kyoto (C.S.) - both in Japan; the Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine (K.K.), and the Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine (J.-S.K.) - both in Seoul, South Korea; the Amyloidosis and Myeloma Unit, Hospital Clinic of Barcelona, August Pi i Sunyer Biomedical Research Institute, Barcelona (M.T.C.); the Department of Hematology, Ankara University, Ankara, Turkey (M.B.); the Division of Medical Oncology, Department of Medicine, University of Washington, Seattle (E.L.); the Department of Hematology and Medical Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland (J. Valent), and the Division of Hematology, Ohio State University Comprehensive Cancer Center, Columbus (N.B.) - both in Ohio; Clínica São Germano, São Paulo (V.H.), and Clinica CEHON, Rede D'Or Oncologia, Salvador (E.C.) - both in Brazil; the Department of Medicine, University of California, San Francisco, San Francisco (S.W.W.), the Department of Hematology and Hematopoietic Cell Transplantation, Judy and Bernard Briskin Center for Multiple Myeloma Research, City of Hope, Duarte (M.R.), and Janssen Research and Development, Los Angeles (N.T.) - all in California; the Department of Internal Medicine, Division of Hematology/Oncology, Columbia University Medical Center, New York (D.B.); the Penn Amyloidosis Program, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia (A.J.W.), and Janssen Research and Development, Spring House (X.Q., S.Y.V., B.M.W.) - both in Pennsylvania; Vanderbilt University Medical Center and Veterans Affairs Tennessee Valley Healthcare System, Nashville (S.A.G.); the Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit (J.A.Z.); the Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland (K.J.); and Genmab US, Princeton (T.A.), and Janssen Research and Development, Raritan (J.M.S., S.H.Z.) - both in New Jersey.

出版信息

N Engl J Med. 2021 Jul 1;385(1):46-58. doi: 10.1056/NEJMoa2028631.

DOI:10.1056/NEJMoa2028631

PMID:34192431

Abstract

BACKGROUND

Systemic immunoglobulin light-chain (AL) amyloidosis is characterized by deposition of amyloid fibrils of light chains produced by clonal CD38+ plasma cells. Daratumumab, a human CD38-targeting antibody, may improve outcomes for this disease.

METHODS

We randomly assigned patients with newly diagnosed AL amyloidosis to receive six cycles of bortezomib, cyclophosphamide, and dexamethasone either alone (control group) or with subcutaneous daratumumab followed by single-agent daratumumab every 4 weeks for up to 24 cycles (daratumumab group). The primary end point was a hematologic complete response.

RESULTS

A total of 388 patients underwent randomization. The median follow-up was 11.4 months. The percentage of patients who had a hematologic complete response was significantly higher in the daratumumab group than in the control group (53.3% vs. 18.1%) (relative risk ratio, 2.9; 95% confidence interval [CI], 2.1 to 4.1; P<0.001). Survival free from major organ deterioration or hematologic progression favored the daratumumab group (hazard ratio for major organ deterioration, hematologic progression, or death, 0.58; 95% CI, 0.36 to 0.93; P = 0.02). At 6 months, more cardiac and renal responses occurred in the daratumumab group than in the control group (41.5% vs. 22.2% and 53.0% vs. 23.9%, respectively). The four most common grade 3 or 4 adverse events were lymphopenia (13.0% in the daratumumab group and 10.1% in the control group), pneumonia (7.8% and 4.3%, respectively), cardiac failure (6.2% and 4.8%), and diarrhea (5.7% and 3.7%). Systemic administration-related reactions to daratumumab occurred in 7.3% of the patients. A total of 56 patients died (27 in the daratumumab group and 29 in the control group), most due to amyloidosis-related cardiomyopathy.

CONCLUSIONS

Among patients with newly diagnosed AL amyloidosis, the addition of daratumumab to bortezomib, cyclophosphamide, and dexamethasone was associated with higher frequencies of hematologic complete response and survival free from major organ deterioration or hematologic progression. (Funded by Janssen Research and Development; ANDROMEDA ClinicalTrials.gov number, NCT03201965.).

摘要

背景

系统性免疫球蛋白轻链（AL）淀粉样变性的特征是由克隆性 CD38+浆细胞产生的轻链淀粉样纤维沉积。达雷妥尤单抗是一种靶向 CD38 的人源抗体，可能改善这种疾病的预后。

方法

我们将新诊断为 AL 淀粉样变性的患者随机分配接受六周期硼替佐米、环磷酰胺和地塞米松治疗，或接受硼替佐米、环磷酰胺和地塞米松联合皮下达雷妥尤单抗治疗，然后每 4 周接受一次达雷妥尤单抗单药治疗，最多 24 个周期（达雷妥尤单抗组）。主要终点是血液学完全缓解。

结果

共有 388 例患者进行了随机分组。中位随访时间为 11.4 个月。达雷妥尤单抗组的血液学完全缓解率明显高于对照组（53.3% vs. 18.1%）（相对风险比，2.9；95%置信区间[CI]，2.1 至 4.1；P<0.001）。无主要器官恶化或血液学进展的生存时间也有利于达雷妥尤单抗组（主要器官恶化、血液学进展或死亡的风险比，0.58；95%CI，0.36 至 0.93；P=0.02）。在 6 个月时，达雷妥尤单抗组的心脏和肾脏反应发生率高于对照组（分别为 41.5%、53.0% vs. 22.2%、23.9%）。最常见的 3 级或 4 级不良事件为淋巴细胞减少症（达雷妥尤单抗组 13.0%，对照组 10.1%）、肺炎（分别为 7.8%和 4.3%）、心力衰竭（分别为 6.2%和 4.8%）和腹泻（分别为 5.7%和 3.7%）。达雷妥尤单抗的全身给药相关反应发生在 7.3%的患者中。共有 56 例患者死亡（达雷妥尤单抗组 27 例，对照组 29 例），大多数死于淀粉样变性相关心肌病。

结论

在新诊断为 AL 淀粉样变性的患者中，达雷妥尤单抗联合硼替佐米、环磷酰胺和地塞米松治疗可提高血液学完全缓解率和无主要器官恶化或血液学进展的生存率。（由 Janssen Research and Development 资助；ANDROMEDA ClinicalTrials.gov 编号，NCT03201965。）