Durable Responses Observed in Chronic Myelomonocytic Leukemia Treated with Lenzilumab and Azacitidine

Durable Responses Observed in Chronic Myelomonocytic Leukemia Treated with Lenzilumab and Azacitidine

Introduction: Chronic myelomonocytic leukemia (CMML) is a rare cancer orchestrated by granulocyte-macrophage colony-stimulating factor (GM-CSF), a pro-inflammatory cytokine that drives leukemic monocyte proliferation. Standard of care (SOC) for CMML treatment includes azacitidine (AZA), with a complete response (CR) rate of 16-21%. The PREcision Approach to CHronicMyelomonocytic Leukemia (PREACH-M; ACTRN12621000223831) trial investigates novel CMML therapies directed by molecular profiling. Lenzilumab(LENZ; Taran Therapeutics, Short Hills, NJ) a proprietary Humaneered® first-in-class monoclonal antibody with best-in-class off-rate and affinity that neutralizes GM-CSF. PREACH-M interim results show that LENZ/AZA improves hematologic parameters, decreases spleen size, and dampens pro-inflammatory responses in CMML with RAS-pathway mutations. This report details the objective clinical responses from an interim analysis of the first 20 subjects who completed at least three months LENZ/AZA treatment. Methods: PREACH-M is a Phase 2/3 non-randomized, uncontrolled, open-label trial in 54 adults aged at least 18 years, newly diagnosed with WHO 2016 criteria for CMML stratified according to mutation status. Subjects exhibiting RAS-pathway mutations (NRAS, KRAS, CBL) receive 24 cycles (every 28 days) of AZA (SC; 75 mg/m2 for 7 days) and LENZ (IV; 552 mg; d1 & d15 of cycle 1 and d1 only for all subsequent cycles); while those with only TET2 mutations receive the same AZA regimen and sodium ascorbate (IV; 30 g for 7 days [15 g for 1st dose only, 30g thereafter if no evidence of tumor lysis syndrome]; PO; 1.1g on all other days). Subjects who complete 24 cycles of treatment are followed every 6 months for an additional 24 months. The primary endpoint is the frequency of complete response (CR) or partial response (PR) during the first 12 cycles according to Savona Criteria. Secondary endpoints include responses according to modified 2006 International Working Group criteria, 2 year overall survival, and symptom improvement. Interim analyses are planned when at least 33% (n=18) and 66% (n=36) patients have completed 12 months of treatment. Results: As of August 1st 2024, 27 subjects were enrolled overall (18 receiving > 12 months of treatment) and 20 subjects were enrolled in the LENZ/AZA arm (9 females, 11 males with mean age 69; mean white cell count 37.8x109/L, mean Hb 108 g/L; mean platelet count, 72x109/L, mean blast count, 9%). Mutations included CBL (65% of subjects), NRAS (20%), KRAS (50%), ASXL1 (55%) and TET2 (70%). Subjects exhibited CPSS-MOL scores, of intermediate risk 1 (n=2), intermediate risk 2-3 (n=12), and high risk 4-6 (n=6). Overall, subjects had completed a median number of 13.5 cycles of LENZ/AZA at the time of reporting. 14 (70%) of subjects had not progressed, 2 went to allogeneic transplant and 4 (20%) had progressive disease. 85% of patients attained a complete remission (CR) or marrow complete remission (mCR) within the first 12 months on study, according to IWG 2006 criteria. According to Savona criteria, 85% of patients achieved a complete response or an optimal marrow response within the first 12 months on treatment. Importantly, 64% of patient achieving CR or marrow CR had detectable CBL mutations at baseline. Of the 10 subjects with dominant CBL mutations (VAF>10%), 90% achieved a CR or mCR in first 12 months with durable suppression of CBL clones. Of the 11 subjects with major clone KRAS/NRAS mutations (VAF>10%), 81% achieved a CR or mCR. Significantly, of all subjects who achieve CR or mCR at 3 months, 83% were still on study without progression at 12 months. Safety and tolerability for LENZ was excellent with no patients experiencing infusion related reactions. A total of nineteen grade 3 or 4 serious adverse events were reported, including anemia and febrile neutropenia, none of which were considered causally related to LENZ and six possibly related to azacitidine. Conclusion: Interim analysis of the PREACH-M trial shows promising results with LENZ/AZA resulting in durable complete responses beyond 12 months with 85% of subjects achieving a complete remission or marrow complete remission without significant LENZ related toxicity. Significantly, 90% of patients with major clone CBL mutations achieved complete remission or marrow complete remission.

引言：慢性粒单核细胞白血病（CMML）是一种由粒细胞 - 巨噬细胞集落刺激因子（GM - CSF）引发的罕见癌症，GM - CSF是一种促炎细胞因子，可驱动白血病单核细胞增殖。CMML治疗的标准护理（SOC）包括阿扎胞苷（AZA），其完全缓解（CR）率为16 - 21%。慢性粒单核细胞白血病的精准治疗方法（PREACH - M；ACTRN12621000223831）试验研究基于分子图谱的新型CMML疗法。伦齐单抗（LENZ；Taran Therapeutics，Short Hills，NJ）是一种专利的Humaneered®同类首创单克隆抗体，具有同类最佳的解离速率和亲和力，可中和GM - CSF。PREACH - M的中期结果显示，LENZ/AZA可改善血液学参数，减小脾脏大小，并抑制伴有RAS通路突变的CMML的促炎反应。本报告详细介绍了对完成至少3个月LENZ/AZA治疗的前20名受试者进行中期分析的客观临床反应。 方法：PREACH - M是一项2/3期非随机、无对照、开放标签试验，纳入54名至少18岁的成年人，这些患者根据突变状态分层，新诊断符合WHO 2016年CMML标准。表现出RAS通路突变（NRAS、KRAS、CBL）的受试者接受24个周期（每28天一个周期）的AZA（皮下注射；75mg/m²，持续7天）和LENZ（静脉注射；552mg；第1周期的第1天和第15天，以及后续所有周期仅第1天）；而仅有TET2突变的受试者接受相同的AZA方案和抗坏血酸钠（静脉注射；30g，持续7天[首次剂量为15g，若无肿瘤溶解综合征迹象，此后为30g]；口服；其他所有日子为1.1g）。完成24个周期治疗的受试者每6个月随访一次，再持续24个月。主要终点是根据萨沃纳标准在最初12个周期内完全缓解（CR）或部分缓解（PR）的频率。次要终点包括根据2006年国际工作组修订标准的反应、2年总生存率和症状改善。当至少33%（n = 18）和66%（n = 36）的患者完成12个月治疗时计划进行中期分析。 结果：截至2024年8月1日，共招募了27名受试者（18名接受了>12个月的治疗），LENZ/AZA组招募了20名受试者（9名女性，11名男性，平均年龄69岁；平均白细胞计数37.8×10⁹/L，平均血红蛋白108g/L；平均血小板计数72×10⁹/L，平均原始细胞计数9%）。突变包括CBL（65%的受试者）、NRAS（20%）、KRAS（50%）、ASXL1（55%）和TET2（70%）。受试者的CPSS - MOL评分包括中危1级（n = 2）、中危2 - 3级（n = 12）和高危4 - 6级（n = 6）。总体而言，在报告时受试者完成LENZ/AZA治疗的中位数为13.5个周期。14名（70%）受试者未进展，2名进行了异基因移植，4名（20%）出现疾病进展。根据IWG 2006标准，85%的患者在研究的前12个月内达到完全缓解（CR）或骨髓完全缓解（mCR）。根据萨沃纳标准，85%的患者在治疗的前12个月内达到完全反应或最佳骨髓反应。重要的是，64%达到CR或骨髓CR的患者在基线时可检测到CBL突变。在10名具有显性CBL突变（变异等位基因频率>10%）的受试者中，90%在最初12个月内达到CR或mCR，且CBL克隆受到持久抑制。在11名具有主要克隆KRAS/NRAS突变（变异等位基因频率>10%）的受试者中，81%达到CR或mCR。值得注意的是，在3个月时达到CR或mCR的所有受试者中，83%在12个月时仍在研究中且无进展。LENZ的安全性和耐受性良好，没有患者出现输液相关反应。共报告了19例3级或4级严重不良事件，包括贫血和发热性中性粒细胞减少症，均未被认为与LENZ有因果关系，6例可能与阿扎胞苷有关。 结论：PREACH - M试验的中期分析显示，LENZ/AZA具有良好的结果，可导致12个月以上的持久完全缓解，85%的受试者达到完全缓解或骨髓完全缓解，且无明显的LENZ相关毒性。值得注意的是，90%具有主要克隆CBL突变的患者达到完全缓解或骨髓完全缓解。