Background

Patients with rel/ref AML have very few options, despite novel targeted therapies (e.g. venetoclax, IDH inhibitors), other than allogeneic hematopoietic cell transplantation (HCT) to achieve a durable CR. In addition, patients ≥55 years of age cannot tolerate multiple cycles of intensive therapy trying to achieve a CR prior to transplant. Older patients are also unable to tolerate more intense myeloablative conditioning. The SIERRA trial is a prospective, randomized, phase 3 trial addressing the unmet need to improve access of older patients with active, rel/ref AML to HCT, the only potentially curative therapy available to them.

Methods

Patients are randomized (1:1) to receive Iomab-B (day-12) followed by FLU/TBI and HCT, or to conventional care (CC). CC patients may receive investigator's choice of salvage therapy, including newly approved targeted agents and may proceed to standard HCT if they achieve CR. If patients do not achieve CR, the study allows cross-over (CO) to Iomab-B/HCT.

Results

Preliminary data are available from 75 (50%) patients (Table 1). Patients (median age 64) were heavily pretreated with 85% failing ≥2 induction therapies and 33% failing targeted therapies. All patients transplanted after Iomab-B engrafted. After randomization, 82% (31/38) patients in the CC arm failed salvage therapy, despite 32% (12/38) receiving targeted therapy. 73% (8/11) of the patients receiving venetoclax with HMA or LDAC did not achieve remission. Of the 31 patients, 9 were not CO transplant candidates. Of the 22 patients that crossed over for transplant, majority (91%, N=20) were able to receive Iomab-B/HCT, despite a median of 35% BM blasts. The most common reason preventing CO to transplant was disease progression. CC patients showed increased incidence of Grade 3 febrile neutropenia, compared to Iomab-B patients prior to CO or HCT (34% vs 8%). Iomab-B administration was generally well-tolerated with 1 Grade 3 and no Grade 4, infusion reaction. There were no Iomab-B-related deaths and 100-day non-relapse TRM was 3% on the Iomab-B arm (Table 1).

Conclusion

Despite advanced age, active disease and heavily pre-treated patients, 100% (31/31) of all patients in the Iomab-B arm who received treatment with Iomab-B were able to undergo HCT and successfully engrafted. In comparison, only 18% (7/38) of the patients on the CC arm achieved remission and underwent conventional HCT despite a high percentage receiving recently approved agents and targeted therapies. Overall, including patients crossing over to receive Iomab-B/HCT after failure of salvage therapy in the CC arm, 68% (51/75) of all patients enrolled in the trial underwent HCT after Iomab-B. These preliminary results represent significant improvements in the current rates of transplantation in this patient population. This SIERRA trial is currently enrolling (www.sierratrial.com or clinicaltrials.gov NCT02665065).

中文翻译：

---

抗CD45碘（¹³¹ I）Apamistamab [Iomab-B]的靶向调理可导致化疗，靶向治疗药物失败后的活动，复发或难治性（rel / ref）AML老年患者高同种异体移植和成功植入：预期的随机第3期Sierra试验的中点初步结果

背景

rel / ref AML的患者除了异基因造血细胞移植（HCT）以外，尽管具有新颖的靶向疗法（例如venetoclax，IDH抑制剂），但几乎没有其他选择可实现持久的CR。此外，≥55岁的患者不能忍受多个强化治疗尝试在移植前获得CR的周期。老年患者也不能忍受更强烈的清髓性调节。SIERRA试验是一项前瞻性，随机，第3期试验，旨在解决改善活动性，相对/参照AML老年患者接受HCT（这是他们唯一可用的治疗方法）的未满足需求。

方法

患者被随机分配（1：1）接受Iomab-B治疗（第12天），然后接受FLU / TBI和HCT或常规治疗（CC）。CC患者可以接受研究者选择的挽救疗法，包括新批准的靶向药物，并且如果达到CR，可以进行标准HCT。如果患者未达到CR，则该研究允许与Iomab-B / HCT交叉（CO）。

结果

有75位（50％）患者获得了初步数据（表1）。患者（中位年龄64岁）接受了严重的预处理，其中85％≥2的诱导疗法失败，33％的目标疗法失败。Iomab-B植入后所有患者均已移植。随机分组后，尽管有32％（12/38）接受靶向治疗，但CC臂中82％（31/38）的患者挽救治疗失败。73％（8/11）接受Venetoclax合并HMA或LDAC的患者未达到缓解。在这31名患者中，有9名不是CO移植候选人。在22例交叉移植的患者中，尽管中位值为35％，但大多数（91％，N = 20）能够接受Iomab-B / HCT。阻止CO移植的最常见原因是疾病进展。CC患者显示3级发热性中性粒细胞减少症的发病率增加，与CO或HCT之前的Iomab-B患者相比（34％比8％）。通常，Iomab-B的给药耐受性为1级3级，无4级输注反应。没有Iomab-B相关的死亡，Iomab-B组的100天非复发性TRM为3％（表1）。

结论

尽管年龄高，活动性疾病和接受过大量预处理的患者，在接受Iomab-B治疗的Iomab-B组患者中，有100％（31/31）能够进行HCT并成功植入。相比之下，尽管有很高的百分比接受最近批准的药物和靶向治疗，但CC臂上只有18％（7/38）的患者实现了缓解并接受了常规HCT。总体而言，包括CC臂挽救治疗失败后交叉接受Iomab-B / HCT的患者，参加该试验的所有患者中有68％（51/75）在Iomab-B后接受了HCT。这些初步结果表明该患者群体目前的移植率有了显着改善。该SIERRA试验目前正在接受中（www.sierratrial.com或Clinicaltrials.gov NCT02665065）。