Mixed Chimerism in the Treatment of B-Cell Malignancies

采用200cGy全身照射+/-氟达拉滨+/-氟达拉滨联合霉酚酸酯和环孢素A抑制移植后免疫的非清髓性条件下的异基因造血细胞移植(HCT)可以可靠地植入各种恶性血液病患者的人类白细胞抗原相合同胞移植物。这将同种异体移植(移植物抗肿瘤[GVT]效应和骨髓功能替代)的好处扩展到老年患者或那些无法接受常规大剂量调理的患者，所有这些患者都具有较低的无复发死亡率(NRM)。这种方法将抗肿瘤活性的负担从细胞毒剂转移到GVT和移植物抗宿主免疫反应上。这些反应需要时间来形成，对于那些疾病发展缓慢或之前的治疗已经减轻了负担的患者来说，这些反应更成功。我们已经利用先前大剂量自体HCT的抗肿瘤作用来减轻疾病负担，并为GVT效应留出时间以消除残留疾病。这种两步法可能为老年非霍奇金淋巴瘤(NHL)和骨髓瘤(MM)患者提供治疗。我们在目标1中的假设是，串联的自体/异体移植将使异基因HCT比传统的同种异体移植实现更好的肿瘤控制和更低的NRM，这可能扩展到老年患者。对于多发性骨髓瘤患者，我们假设结果将优于串联自体移植。我们对54例多发性骨髓瘤患者的初步经验表明，中位年龄54岁的患者存活率为79%，中位随访时间为18个月，这构成了全国性试验的基础。当自体移植是 对于MM患者，我们将评估在目标2中将中等剂量的马法兰添加到异基因HCT方案中。目标3将探索将具有更强肿瘤特异性的新药物与非清髓性HCT相结合，用于控制NHL(放射性标记抗CD20抗体)、霍奇金病(嵌合抗CD30抗体)和费城染色体阳性急性淋巴细胞白血病(STI-571)患者的疾病。这些方法将进一步推动潜在的同种异体移植治疗对B细胞恶性肿瘤患者的使用。

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.