Targeted Radiotherapy with 90Y-BC8 Monclonal Antibody, Fludarabine and TBI Follow

描述（由申请人提供）：在多发性骨髓瘤（MM）患者的治疗方面取得了重要进展。自体干细胞移植（ASCT）与单独常规治疗的随机试验表明，生存率显著提高。沙利度胺、来那度胺和硼替佐米加ASCT的新型药物组合与旧的诱导方案相比进一步改善了无进展生存期。然而，很少有MM患者生存超过10年而无疾病进展。正在研究双ASCT、ASCT后维持治疗或ASCT后同种异体移植等策略，以改善预后。异基因干细胞移植（allo SCT）提供了一种无肿瘤移植物和一种免疫学的移植物抗骨髓瘤效应。MM的清髓性allo SCT与15-30%的无病生存期超过10年的概率相关，这是治愈的最佳证据。然而，清髓性allo SCT在历史上与30- 50%的高移植相关死亡率（TRM）相关。已采用强度较低的非清髓性allo SCT，其可将死亡率降低至15- 20%，但要获得成功，这种方法需要MM患者在allo SCT之前接受细胞减灭治疗（通常采用ASCT）。然而，即使在串联自体异体SCT之后，复发仍然是治疗失败的主要原因。因此，迫切需要改进的方法来提供骨髓中残留骨髓瘤细胞的更好根除。我们已经证明，131 I-抗-CD 45（BC 8）Ab可以提供至少2-3倍以上的辐射骨髓，脾脏和白血病部位比任何正常器官。我们进一步表明，高剂量131 I-BC 8 Ab可以安全地与非清髓性方案联合用于老年骨髓恶性肿瘤患者。虽然CD 45在MM患者的肿瘤细胞上没有广泛表达，但CD 45在所有其他白细胞上的广泛表达将允许有效靶向骨髓，骨髓是MM的主要疾病部位。尽管131 I在递送靶向放射治疗方面非常成功，由于131 I的高γ发射和131 I的相对低的ss能量，人们对这种技术的安全性和可运输性的关注促使战略的转变，90 Y-BC 8 Ab偶联物在多发性骨髓瘤试验中的应用。90 Y由于其缺乏γ发射、较高的ss能量和对骨的天然亲和力，应该是靶向骨髓的更好同位素。我们将使用111 In-BC 8 Ab进行剂量测定试验，以确定靶向骨髓的CD 45多于非靶组织（如肝、肺和肾）。患者接下来将接受90 Y-BC 8的消融剂量，随后是同位素衰变期，然后施用氟达拉滨90 mg/m2、外部TBI 200 cGY和来自HLA匹配的同胞或无关供体的allo SCT。该治疗方案将涉及对患者进行同位素的2阶段剂量递增，旨在确定90 Y抗CD 45与氟达拉滨和TBI联合治疗接受allo SCT的MM患者时的最大耐受剂量。在非清髓性allo-SCT方案中加入骨髓靶向放射治疗应能增加缓解率并提高生存率。 公共卫生相关性：多发性骨髓瘤是一种致命的骨髓癌，通常用常规剂量或非常高剂量的化疗、放射治疗，然后从患者体内回输血细胞（自体骨髓移植）。虽然缓解（没有疾病的证据）可以在一段时间内获得，但患者最终会复发（疾病复发）。在某些情况下，来自供体的血细胞可用于进行同种异体移植，这可能会产生更长的缓解期。这项研究将测试是否可以安全地向靶骨髓中添加放射性抗体并增加缓解率。

DESCRIPTION (provided by applicant): Important progress has been made in the treatment of patients with multiple myeloma (MM). Randomized trials of autologous stem cell transplant (ASCT) v. conventional therapy alone have demonstrated significant improvements in survival. Novel drug combinations of thalidomide, lenalidomide and bortezomib plus ASCT have further improved progression-free survival compared older induction regimens. Nevertheless few patients with MM survive without disease progression beyond 10 years. Strategies such as double ASCT, maintenance therapy after ASCT or an allogeneic transplant after ASCT are being studied as ways to improve outcomes. Allogeneic stem cell transplant (allo SCT) provides a tumor-free graft and an immunologic, graft-versus- myeloma effect. Myeloablative allo SCT for MM is associated with a 15-30% probability of disease free survival extending beyond 10 years, the best evidence for cure. Myeloablative allo SCT is, however, historically associated with high transplant related mortality (TRM) of 30-50%. Less intensive, nonmyeloablative allo SCT has been adopted which can reduce mortality to 15-20%, but to be successful, this approach requires that patients with MM receive cytoreductive therapy usually with ASCT, prior to the allo SCT. Even after a tandem auto-allo SCT, however, relapses remain the principal cause of treatment failure. Thus, there is a critical need for improved ways to provide better eradication of residual myeloma cells in the bone marrow. We have shown that 131I-anti-CD45 (BC8) Ab can deliver at least 2-3-fold more radiation to marrow, spleen and sites of leukemia than to any normal organ. We have further shown that high-dose 131I-BC8 Ab can be safely combined with a non-myeloablative regimen in older patients with myeloid malignancies. While CD45 is not widely expressed on the tumor cells of patients with MM, the broad expression of CD45 on all other leukocytes will allow effective targeting to marrow, the principal disease site in MM. Although 131I has been highly successful with regard to delivering targeted radiotherapy, concerns about safety and the transportability of this technology due to high gamma emissions of 131I and the relatively low ss energy of 131I have prompted a shift in strategy to the use of a 90Y-BC8 Ab conjugate for trials in multiple myeloma. 90Y with its lack of gamma emissions, higher ss energy and natural affinity for bone, should be a better isotope for targeting marrow. We will perform dosimetry testing with 111In-BC8 Ab, to establish that more CD45 is targeted to marrow than non-target tissues such as liver, lung and kidneys. Patients will next receive an ablative dose of 90Y-BC8, followed by a period for isotope decay, then the administration of fludarabine 90 mg/m2, external TBI 200 cGY and allo SCT from an HLA matched sibling or unrelated donor. The treatment protocol will involve a 2-stage dose escalation of isotope in patients designed to determine the maximum tolerated dose of 90Y anti-CD45, when combined with fludarabine and TBI in patients with MM receiving allo SCT. Adding marrow targeted radiation to a nonmyeloablative allo-SCT regimen should increase remissions and improve survival. PUBLIC HEALTH RELEVANCE: Multiple myeloma, a fatal form of cancer of the bone marrow, is usually treated with chemotherapy, radiation, in regular doses or very high doses, followed by re-transfusion of blood cells from the patient (autologous bone marrow transplant). Although remissions (no evidence of disease) can be obtained for some length of time, patients eventually relapse (recurrence of disease). In some cases blood cells from a donor can be used to perform an allogeneic transplant which may produce longer remissions. This study will test whether the addition of a radioactive antibody to target marrow can be done safely and increase remissions.