Mixed Chimerism in the Treatment of B-Cell Malignancies

采用200 cGy全身照射的非清髓性造血细胞移植(HCT) +/-氟达拉滨联合移植后霉酚酸酯和环孢素的免疫抑制，可以在各种血液恶性肿瘤患者中可靠地植入HLA相同的同胞移植物。这将同种异体移植（移植物抗肿瘤[GVT]效应和骨髓功能替代）的益处扩展到老年患者或那些患有常规高剂量治疗的疾病的患者，所有这些患者都具有较低的非复发死亡率（NRM）。这种方法将抗肿瘤活性的负担从细胞毒性药物转移到GVT和移植物抗宿主免疫反应。这些反应需要时间来发展，并且对于那些疾病发展缓慢或先前治疗减轻了负担的患者更成功。我们利用先前高剂量自体HCT的抗肿瘤作用来减轻疾病负担，并为GVT效应消除残留疾病留出时间。这种两步法可能为老年非霍奇金淋巴瘤（NHL）和骨髓瘤（MM）患者提供根治性治疗。我们在Aim 1中的假设是，自体/同种异体移植将使同种异体HCT获得比传统同种异体移植更好的肿瘤控制和更低的NRM，这可能扩展到老年患者。对于MM患者，我们假设结果将优于串联自体移植。我们对54例MM患者的初步研究显示，中位年龄54岁的患者生存率为79%，中位随访时间为18个月，这为一项全国性试验奠定了基础。当自体移植物

AIIogeneic hematopoietic cell transplantation (HCT) using non-myeloablative conditioning with 200 cGy total body irradiation +/- fludarabine combined with postgrafting immunosuppression by mycophenolate mofetil and cyclosporine allows reliable engraftment of HLA identical sibling grafts in patients with a variety of hematologic malignancies. This extends the benefits of allografting (graft-vs-tumor [GVT] effects and replacement of marrow function) to older patients or those with medical conditions that preclude conventional high-dose conditioning, all with a lower non-relapse mortality (NRM). This approach shifts the burden of anti-tumor activity from the cytotoxic agents to the GVT and graft-vs-host immune responses. These responses take time to develop, and are more successful in patients with diseases that are either slow growing or whose burden has been reduced by prior therapy. We have used the anti-tumor effects of preceding high dose autologous HCT to reduce disease burden and allow time for GVT effects to eliminate residual disease. This two-step approach may provide curative therapy to elderly patients with non-Hodgkin lymphoma (NHL) and myeloma (MM). Our hypothesis in Aim 1 is that tandem auto/allo transplants will allow allogeneic HCT to achieve better tumor control and lower NRM than conventional allografting, and this may be extended to older patients. For MM patients, we hypothesize that results will be superior to tandem autologous transplants. Our preliminary experience with 54 MM patients, median age of 54 years, has shown 79% survival with a median follow-up of 18 months and forms the basis for a national trial. When autografts are not possible for MM patients, we will evaluate the addition of intermediate dose melphalan to the allogeneic HCT protocol in Aim 2. Aim 3 will explore the inclusion of newer agents with greater tumor specificity combined with non-myeloablative HCT for control of disease in patients with NHL (radiolabeled anti-CD20 antibody), Hodgkin's Disease (chimeric anti-CD30 antibody) and Philadelphia chromosome positive acute lymphocytic leukemia (STI-571). These approaches will further advance the use of potentially curative allogeneic GVT therapy to patients with B cell malignancies.