肿瘤细胞治疗研究
英文原题：Donor Peripheral Stem Cell Transplant in Treating Patients With Advanced Hematologic Cancer or Other Disorders
这是一项 II 期注册临床试验，评估TIL（肿瘤浸润淋巴细胞）治疗移植物抗宿主病、白血病、淋巴瘤的安全性、可行性及初步疗效。当前状态：进行中（不再招募）。计划入组 260 例。登记号：NCT00544115。
不限性别 · ≥ 0 Years 且 ≤ 120 Years
疾病特征： * 确诊以下疾病之一： * 急性淋巴细胞白血病（ALL），并符合以下任一条件：首次复发或之后复发；或属于高危ALL，包括低倍体（≤44条染色体）、伴易位或分子证据提示t(9;22)、11q23或t(8;14)的假二倍体（B细胞ALL除外），或初诊时白细胞计数升高（18岁以上患者>20,000/mm³；12–18岁患者>200,000/mm³）。 * 急性髓系白血病（AML），并符合以下任一条件：首次完全缓解、未能缓解、首次复发或之后复发、继发性AML（骨髓抽吸物原始细胞>30%）。继发性AML患者如条件允许，应先接受诱导化疗争取缓解，再进行移植。 * 慢性髓性白血病：处于第一或第二慢性期、加速期，或急变期（定义为骨髓中早幼粒细胞与原始细胞合计>30%）。 * 骨髓增生异常综合征，包括伴原始细胞增多的难治性贫血（RAEB）、慢性粒单核细胞白血病，或转化期RAEB。 * 难治性非霍奇金淋巴瘤、慢性淋巴细胞白血病、霍奇金淋巴瘤或多发性骨髓瘤，且一线治疗、高剂量治疗联合自体干细胞移植或挽救治疗失败。 * 骨髓增殖性疾病/骨髓纤维化可由研究者个案评估后纳入。 * 重型再生障碍性贫血、阵发性睡眠性血红蛋白尿，或其他需要移植的血液系统疾病。 * 年龄>55岁、患有可通过异基因干细胞移植治疗的血液疾病，且不符合IRB 99190条件者也可入组。 * 无未控制的中枢神经系统（CNS）疾病累及。 * 无6/6匹配的亲缘供者。 * 有HLA相同的无关供者：通过DNA分型，供者在HLA-A、HLA-B表型及DRB1等位基因上相同，涵盖I类和II类抗原。若无其他供者，可接受HLA I类等位基因不匹配（如B*2701与B*2702）；对于≤35岁且需紧急移植者，可接受II类等位基因不匹配（如DRB1*0401与*0402）或I类交叉反应组（CREG）轻度不匹配（如A2与A28）。 患者特征： * Karnofsky体能状态评分50–100%。 * 预期生存期>8周。 * 静息左心室射血分数（LVEF）≥45%。 * AST≤正常值的2倍（肝功能异常由基础疾病导致者除外）。 * 总胆红素<正常值的1.5倍（肝功能异常由基础疾病导致者除外）。 * 肌酐≤正常值的1.5倍，或肌酐清除率≥60 mL/min。 * 经血红蛋白校正的DLCO≥预测值的40%。 * 无会显著增加移植手术风险的合并症。 * HIV阴性。 * 未妊娠。 既往/同期治疗： * 见“疾病特征”。
DISEASE CHARACTERISTICS:
* Diagnosis of one of the following:
* Acute lymphocytic leukemia (ALL), meeting one of the following criteria:
* In first relapse or beyond
* High-risk ALL, defined by any of the following:
* Hypoploidy (≤ 44 chromosomes)
* Pseudodiploidy with translocations or molecular evidence of t(9;22), 11q23, or t(8;14), excluding B-cell ALL
* Elevated WBC at presentation (WBC \> 20,000/mm³ \[for patients \> 18 years of age\]; WBC \> 200,000/mm³ \[for patients 12-18 years of age\])
* Acute myeloid leukemia (AML), meeting one of the following criteria:
* In first complete remission
* Failed to achieve remission
* In first relapse or beyond
* Secondary AML (\> 30% blasts in marrow aspirate)
* Should receive induction chemotherapy to obtain remission, if possible, before transplant
* Chronic myelogenous leukemia, meeting one of the following criteria:
* In first or second chronic phase or accelerated phase
* In blast crisis, defined as \> 30% promyelocytes plus blasts in the bone marrow
* Myelodysplastic syndromes, including any of the following:
* Refractory anemia with excess blasts (RAEB)
* Chronic myelomonocytic leukemia
* RAEB in transformation
* Refractory non-Hodgkin lymphoma, chronic lymphocytic leukemia, Hodgkin lymphoma, or multiple myeloma
* Received and failed front-line therapy, high-dose therapy and autologous stem cell transplantation, or salvage therapy
* Myeloproliferative disorders/myelofibrosis may be allowed on a case by case basis
* Severe aplastic anemia, paroxysmal nocturnal hemoglobinuria, or any other hematologic disorder requiring transplantation
* Patients \> 55 years of age with hematologic diseases treatable by allogeneic stem cell transplantation who are not eligible for IRB 99190 are eligible
* No uncontrolled CNS involvement of disease
* No matched (6/6) related donor available
* HLA-identical unrelated donor available
* HLA-phenotypically identical for HLA-A and HLA-B alleles and identical for DRB1 alleles by DNA typing for both class I and class II antigens
* Allele mismatch for HLA class I (i.e., B 2701 vs B 2702) allowed if no alternative donors
* Allele mismatch for class II (i.e., DRB1 0401 vs 0402) or minor mismatch for class I cross reactive group (CREG) (i.e., A 2 vs A 28) allowed in patients ≤ 35 years of age requiring urgent transplant
PATIENT CHARACTERISTICS:
* Karnofsky performance status 50-100%
* Life expectancy \> 8 weeks
* LVEF ≥ 45% at rest
* AST ≤ 2 times normal (unless liver function abnormality is due to underlying disease)
* Total bilirubin \< 1.5 times normal (unless liver function abnormality is due to underlying disease)
* Creatinine ≤ 1.5 times normal OR creatinine clearance ≥ 60 mL/min
* DLCO ≥ 40% of predicted (corrected for hemoglobin)
* No coexisting medical problem that would significantly increase the risk of the transplant procedure
* HIV negative
* Not pregnant
PRIOR CONCURRENT THERAPY:
* See Disease Characteristics以上为辅助阅读译文。是否适合入组须由主治医生判断，最终以登记平台与研究者确认为准。
主要终点：Neutrophil Engraftment - The Days Till ANC Recovery · The primary engraftment endpoint, neutrophil engraftment, is defined as the first of three consecutive days on which the absolute neutrophil count is \> 500/µL. The duration and extent of neutrophil engraftment is the time from transplant to neutrophil engraftment. · Up to 180 days post transplant
次要终点：Two-year Overall Survival
患者于第-7至-4天接受全身照射（TBI），并于第-3和-2天静脉给予环磷酰胺。或者，可于第-7和-6天给予环磷酰胺，并于第-4至-1天接受TBI。
患者于第-8天静脉输注白消安2小时，随后在第-7至-4天每6小时给药一次；同时于第-3和-2天静脉给予环磷酰胺。
患者于第-7至-4天接受全身照射（TBI），并于第-3天静脉给予依托泊苷。
患者于第-7至-3天静脉输注磷酸氟达拉滨，每次30分钟；并于第-2天静脉给予美法仑。
患者于第-4至-2天静脉输注磷酸氟达拉滨，每次30分钟，并于第0天接受全身照射（TBI）。
患者于第-5至-2天静脉输注白消安（每次3小时）和磷酸氟达拉滨（每次30分钟）。
研究依据：供者外周血干细胞移植前给予化疗和全身照射，有助于抑制癌细胞或异常细胞生长，并降低患者免疫系统排斥供者干细胞的风险。输注供者健康干细胞后，可能帮助患者骨髓生成干细胞、红细胞、白细胞和血小板。移植的供者细胞有时会攻击患者正常组织；移植前后使用他克莫司、甲氨蝶呤、环孢素、吗替麦考酚酯和西罗莫司可能有助于预防这一情况。 研究目的：本Ⅱ期试验评估供者外周血干细胞移植治疗晚期血液系统恶性肿瘤或其他疾病的效果。
RATIONALE: Giving chemotherapy and total-body irradiation before a donor peripheral stem cell transplant helps stop the growth of cancer or abnormal cells. It also helps stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving tacrolimus, methotrexate, cyclosporine, mycophenolate mofetil, and sirolimus before and after transplant may stop this from happening. PURPOSE: This phase II trial is studying how well donor peripheral stem cell transplant works in treating patients with advanced hematologic cancer or other disorders.
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