Furman Richard R, Eradat Herbert A, DiRienzo Christine G, Hofmeister Craig C, Hayman Suzanne R, Leonard John P, Coleman Morton, Advani Ranjana, Chanan-Khan Asher, Switzky Julie, Liao Qiming M, Shah Damini, Jewell Roxanne C, Lisby Steen, Lin Thomas S
Weill Cornell Medical College, New York, NY, USA.
University of California, Los Angeles, CA, USA.
Lancet Haematol. 2017 Jan;4(1):e24-e34. doi: 10.1016/S2352-3026(16)30166-1. Epub 2016 Dec 1.
The development of more effective and safer treatments, especially non-chemotherapeutics, is needed for patients with Waldenström's macroglobulinaemia. The aim of the study was to assess the safety and clinical activity of intravenous ofatumumab monotherapy for untreated and relapsed Waldenström's macroglobulinaemia.
We did a phase 2, open-label, single-arm study at six centres (hospitals and cancer clinics) in the USA. Patients aged at least 18 years who were diagnosed with untreated or relapsed Waldenström's macroglobulinaemia and required treatment, received up to three cycles of weekly ofatumumab for 5 weeks. For cycle 1, patients received one of two treatment regimens. Group A received ofatumumab 300 mg during week 1 followed by 1000 mg during weeks 2-4. Because of the acceptable safety of the 1000 mg dose in treatment group A and clinical activity of the 2000 mg dose established in chronic lymphocytic leukaemia, the study was amended on Dec 9, 2009, to change cycle 1 for group B who received ofatumumab 300 mg during week 1 and 2000 mg during weeks 2-5. We followed up patients during weeks 5-16 for treatment group A and during weeks 6-16 for treatment group B (no treatment was given during this follow-up). Patients in both groups with stable disease or a minor response after 16 weeks were eligible to then receive a redosing cycle of ofatumumab 300 mg during week 1 and 2000 mg during weeks 2-5. We followed up patients during weeks 6-16 after the redosing cycle (no treatment was given during this follow-up). Patients responding to cycle 1 or the redosing cycle who developed disease progression within 36 months could receive cycle 2 of ofatumumab 300 mg during week 1 and 2000 mg during weeks 2-5. The primary endpoint for this study was the proportion of patients who achieved an overall response (complete responses plus partial responses plus minor responses) after each treatment cycle in the intent-to-treat population every 4 weeks starting at week 8. This trial is registered at www.ClinicalTrials.gov, NCT00811733, and is now complete.
Between March 17, 2009, and Feb 24, 2011, we enrolled and assigned 37 patients to treatment (15 in treatment group A and 22 in treatment group B). All 37 were included in the efficacy and safety analyses. 19 (51%, 95% CI 34·4-68·1) of 37 patients achieved an overall response after cycle 1 and 22 (59%, 42·1-75·2) of 37 achieved an overall response after the redosing cycle; 15 (41%) with partial responses, seven (19%) with minor responses. 13 patients received treatment cycle 2; ten (77%) of the 13 achieved a response. All 37 patients had at least one adverse event; 16 (43%) patients had events of grade 3 or more (30 grade 3, one grade 4). The most common grade 3 or 4 adverse events were infusion reactions (four [11%] of 37), chest pain (two [5%] of 37), haemolysis (two [5%] of 37), and neutropenia (two [5%] of 37). Two (9%) of 22 patients (both in treatment group B) had an IgM flare. 12 patients reported serious adverse events; haemolysis and pyrexia were the most common (each occurring in two [5%] of 37 patients).
A high proportion of patients achieved an overall response with ofatumumab monotherapy and this treatment was well tolerated, with a low incidence of IgM flare. This therapy might be a non-chemotherapeutic treatment option for patients with Waldenström's macroglobulinaemia, especially those with high IgM concentrations.
GlaxoSmithKline and Genmab.
对于华氏巨球蛋白血症患者，需要研发更有效、更安全的治疗方法，尤其是非化疗方法。本研究的目的是评估静脉注射奥法木单抗单药治疗初治及复发华氏巨球蛋白血症的安全性和临床活性。
我们在美国的六个中心（医院和癌症诊所）开展了一项2期、开放标签、单臂研究。年龄至少18岁、被诊断为初治或复发华氏巨球蛋白血症且需要治疗的患者，接受为期5周、每周一次的奥法木单抗治疗，最多三个周期。在第1周期，患者接受两种治疗方案之一。A组在第1周接受300mg奥法木单抗，随后在第2 - 4周接受1000mg。由于A组1000mg剂量的安全性可接受，且在慢性淋巴细胞白血病中已证实2000mg剂量具有临床活性，该研究于2009年12月9日进行修正，将B组第1周期改为在第1周接受300mg奥法木单抗，在第2 - 5周接受2000mg。我们在第5 - 16周对A治疗组患者进行随访，在第6 - 16周对B治疗组患者进行随访（此随访期间不给予治疗）。两组中在16周后疾病稳定或有轻微反应的患者，有资格在第1周接受300mg奥法木单抗、在第2 - 5周接受2000mg的重新给药周期。我们在重新给药周期后的第6 - 16周对患者进行随访（此随访期间不给予治疗）。对第1周期或重新给药周期有反应但在36个月内出现疾病进展的患者，可在第1周接受300mg奥法木单抗、在第2 - 5周接受2000mg进行第2周期治疗。本研究的主要终点是在意向性治疗人群中，从第8周开始每4周每个治疗周期后达到总体缓解（完全缓解加部分缓解加轻微缓解）的患者比例。该试验已在www.ClinicalTrials.gov注册，编号为NCT00811733，现已完成。
在2009年3月17日至2011年2月24日期间，我们招募并分配了37例患者接受治疗（A治疗组15例，B治疗组22例）。所有37例患者均纳入疗效和安全性分析。37例患者中有19例（51%，95%CI 34.4 - 68.1）在第1周期后达到总体缓解，37例中有22例（59%，42.1 - 75.2）在重新给药周期后达到总体缓解；15例（41%）为部分缓解，7例（19%）为轻微缓解。13例患者接受了第2周期治疗；13例中有10例（77%）有反应。所有37例患者均至少发生过一次不良事件；16例（43%）患者发生3级或更高级别的事件（30例3级，1例4级）。最常见的3级或4级不良事件为输液反应（37例中有4例[11%]）、胸痛（37例中有2例[5%]）、溶血（37例中有2例[5%]）和中性粒细胞减少（37例中有2例[5%]）。22例患者中有2例（9%）（均在B治疗组）出现IgM激增。12例患者报告了严重不良事件；溶血和发热最为常见（各发生在37例患者中的2例[5%]）。
高比例患者通过奥法木单抗单药治疗达到总体缓解，且该治疗耐受性良好，IgM激增发生率低。这种疗法可能是华氏巨球蛋白血症患者，尤其是IgM浓度高的患者的一种非化疗治疗选择。
葛兰素史克公司和Genmab公司。
