Allogeneic HCT for Hematologic Malignancies: Pharmacologic Manipulations

低剂量TBI（2戈伊）+/-氟达拉滨（30 mg/m2 x 3）的非清髓性预处理和移植后 环孢霉素和霉酚酸酯免疫抑制为 同种异体G-CSF动员来自HLA匹配的相关或无关供体的外周血干细胞。这 导致完全供体嵌合并提供免疫移植物抗肿瘤（GVT）效应。事实上，有了这个 在该平台上，几乎所有的抗肿瘤活性都来自GVT免疫应答， 条件反射疗法我们的结果表明，这种反应可能提供长期的抗肿瘤作用， 在许多B细胞恶性肿瘤患者中， 非霍奇金淋巴瘤（NHL）、套细胞NHL和慢性淋巴细胞白血病（CLL）。的局限性 方法也很明显，因为患有侵袭性、体积大或快速增殖性疾病的患者可能会发展为 肿瘤进展之前的发展，或尽管GVT的影响。项目4的重点是增加 非清髓性预处理通过改善治疗B细胞恶性肿瘤的抗肿瘤作用 移植前细胞减少，增强同种异体GVT效应，并结合额外的药物， 抗肿瘤活性和有限的毒性。最后，我们计划将这种方法扩展到没有HLA的患者 匹配的相关或无关的捐赠者，通过使用一种新的协议，允许成功植入相关的 HLA半相合移植物。具体目标是用途： 1.大剂量细胞减灭疗法联合自体造血细胞的串联移植 移植（HCT），然后是非清髓性同种异体HCT，来自： a.来自淋巴瘤相关或无关供体的HLA匹配的同种异体HCT。 B.来自相关或无关供体的HLA匹配的同种异体HCT，随后进行维持治疗 与硼替佐米联合治疗高危或复发性多发性骨髓瘤（MM）。; C. HLA半相合的同种异体HCT治疗复发性或难治性淋巴瘤 2.在非清髓性预处理（Flu/TBI）基础上增加靶向治疗， 来自HLA匹配的相关或无关供体的同种异体HCT： a.单甲基金抑素E结合抗CD 30抗体（SGN 35）治疗复发性或难治性HL。 B.酪氨酸激酶抑制剂治疗费城染色体阳性白血病 C.抗CD 20抗体利妥昔单抗治疗CD 20阳性B细胞NHL和氟达拉滨难治性CLL。 该项目的公共卫生效益是，患有各种恶性血液病的患者。 否则将因年龄和合并症而被排除， 同种异体血细胞比容。此外，HLA半相合供体的使用将使HCT的选择范围扩大到更大。 患者人数，包括少数民族。

Nonmyeloablative conditioning with low dose TBI (2 Gy) +/- fludarabine (30 mg/m2 x 3) and post grafting immunosuppression with cyclosporine and mycophenolate mofetil provides reliable engraftment for allogeneic G-CSF mobilized peripheral blood stem cells from HLA matched related or unrelated donors. This results in full donor chimerism and provides immunologic graft-vs-tumor (GVT) effects. Indeed, with this platform, nearly all of the anti-tumor activity comes from GVT immune responses with little contribution from the conditioning regimen. Our results demonstratethat this response may provide long term anti-tumor activity in many patients with B cell malignancies with outstanding activity noted in patients with low-grade non-Hodgkin Lymphoma (NHL), mantle cell NHLand chronic lymphocytic leukemia (CLL). Limitations of this approach were also evident as patients with aggressive, bulky or rapidly proliferating disease may develop tumor progression before the development of, or despite GVT effects. The focus of Project 4 is to augment the anti-tumor effect of nonmyeloablative conditioning for the treatment of B cell malignancies by improving pre-transplant cytoreduction, augmenting allogeneic GVT effects and incorporating additional agents with anti tumor activity, and limited toxicity. Lastly, we plan to expand this approach to patients without HLA matched related or unrelated donors by using a newprotocol that allows successful engraftment of related HLA haploidentical grafts. The Specific Aims are to use: 1. Tandem transplants using cytoreductive high-dose therapy and autologous hematopoietic cell transplantation (HCT) followed by nonmyeloablative allogeneic HCT from : a. HLA matched allogeneic HCT from related or unrelated donors for lymphoma. b. HLA matched allogeneic HCT from related or unrelated donors followed by maintenance therapy with bortezomib for high risk or relapsed Multiple Myeloma (MM). ; c. HLA haploidentical allogeneic HCTfrom related donors for relapsed or refractory lymphoma. 2. Addition of targeted therapies to nonmyeloablative conditioning with Flu/TBI followed by allogeneic HCT from HLA matched related or unrelated donors: a. Monomethyl Aurostatin E conjugated anti-CD30 antibody (SGN35) for relapsed or refractory HL. b. Tyrosine kinase inhibitors for Philadelphia chromosome positive leukemia. c. Anti-CD20 antibody Rituximab for CD20 positive B cell NHL and fludarabine refractory CLL. The public health benefits of this Project are that patients with various malignant blood disorders who . otherwise would have been excluded because of age and comorbidities have benefited from treatment by allogeneic HCT. Inaddition, the use of HLA-haploidentical donors will extend the option of HCT to a greater number of patients, including ethnic minorities.