Cladribine- and decitabine-containing conditioning regimen has a low post-transplant relapse rate in patients with relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome

To reduce the risk of relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT), there have been continuing efforts to optimize the conditioning regimens. Our study aimed to analyze the risk factors associated with the relapse of relapsed/refractory (R/R), high-risk acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) post-transplant and the efficacy of a new conditioning regimen involving decitabine and cladribine. Clinical data of 125 patients with R/R AML, high-risk AML and high-risk MDS who underwent allo-HSCT were collected. In addition, 35 patients with R/R AML, high-risk AML and high-risk MDS received treatment with a new conditioning regimen including decitabine and cladribine. Cox regression analysis was used to identify risk factors associated with OS, RFS and relapse. Among 125 patients who underwent allo-HSCT, CR before allo-HSCT and matched sibling donors were independent protective factors for OS. DNMT3A abnormality was an independent risk factor for both relapse and RFS. Among 35 patients who received a new conditioning regimen containing decitabine and cladribine, only six patients relapsed and 1-year cumulative incidence of relapse was 11.7%. Moreover, this new regimen showed efficient MRD clearance early after allo-HSCT. The combined decitabine- and cladribine-based conditioning regimen showed a low relapse rate and a high survival without an increased incidence of GVHD or adverse effects and thus has potential for use in allo-HSCT for R/R AML, high-risk AML and high-risk MDS.     

The role of thiotepa in allogeneic stem cell transplantation in patients with leukemia

Graft versus host disease (GVHD) and recurrence of basic disease are major obstacles to a successful allogeneic bone marrow transplantation (BMT) outcome. One of the possibilities of maintaining the therapeutic potential of marrow allografting in the absence of GVHD is to intensify the conditioning regimen administered pre-T-cell depleted BMT in order to compensate for the loss of GVH related graft versus leukemia (GVL) effect. In order to do so we used a preparative regimen consisting of three alkylating agents-Busulfan (BU), Thiotepa (TTP) and Cyclophosphamide (CY)-for T-cell depleted allogeneic stem cell transplantation (SCT) instead of the standard BU-CY protocol. The effect of this intensified regimen was investigated in 30 consecutive leukemia patients who underwent T-cell depleted SCT from HLA identical siblings. Sixteen of the patients were males and 14 females, of median age 24 (5-43) years. Fourteen patients had acute myelogenous leukemia (AML), ten acute lymphoblastic leukemia (ALL), four chronic myelogenous leukemia (CML) and two myelodysplastic syndrome. The conditioning regimen consisted of BU 4 mg/kg x 4 days (-8 to -5), TTP 5 mg/kg x 2 days (-4 and -3), and CY 60 mg/kg x 2 days (-2 and -1). Engraftment was normal, with WBC >1.0x10(9)/l at day +18 (10-32), ANC >0.5x10(9)/l at day +21 (9-33) and platelets >25x10(9)/l at day +30 (14-69). Regimen related toxicity (RRT) was moderate and transplant related complications comparable to other conventional conditioning protocols. Overall survival and disease free survival (DFS) at 60 months follow up was 50%. Only three patients (10%), with ALL, relapsed and subsequently died. From the current data it would appear that TTP does not significantly improve BMT outcome in patients with leukemia, when compared to the standard BU-CY conditioning. However, our results with the BU-TTP-CY combination followed by T-cell depleted allogeneic SCT could provide the basis for a prospective randomized study comparing this protocol with the standard BU-CY regimen.     

造血干细胞移植治疗慢性髓系白血病的疗效分析

背景与目的：慢性髓系白血病(chronic myelogenous leukemia,CML)是一种常见的恶性血液疾病,造血干细胞移植(hematopoietic stem cells transplantation,HSCT)是治疗CML最主要的手段。本研究评价自体(auto-)或异体(allo-)HSCT治疗CML的临床疗效。方法：44例CML息者接受HSCT治疗,其中8例采用净化auto-HSCT,30例采用相关allo—HSCT,6例采用无关allo-HSCT;预处理方案：31例接受TBI CY(全身放疗 环磷酰胺)方案,12例采用改良BuCY(羟基脲、马利兰、阿糖胞苷、环磷酰胺)方案,1例采用MACC(马法兰、阿糖胞苷、环磷酰胺、环已亚硝脲)方案;移植物抗宿主病(GVHD)预防：相关移植采用CsA MTX(环孢素A 甲氨蝶呤)方案,无关移植采用CsA MTX MMF(霉酚酸酯) ATG(抗胸腺细胞球蛋白)方案。此外,移植前加速期和急变期患者单用CsA。Kaplan—Meier生存模型评估移植后无病生存。结果：8例接受激活骨髓(ABM)联合反义寡核苷酸或联合STI571体内外净化auto-HSCT后,除1例死于移植中相关并发症外,其余均获得部分或完全细胞或分子遗传学缓解,其中1例急变期患者血液学完全缓解(CR)后移植获分子遗传学CR达81个月。36例allo—HSCT患者除1例死于肝静脉闭塞综合征(hepatic veno-occlusive disease,VOD)和1例移植前急变患者移植后无效以外,其余患者均获CR。移植中感染发生率为38．6％,VOD发生率为9．1％,出血性膀胱炎(hemorrhagic cystitis,HC)发生率为15．9％,巨细胞病毒(CMV)性肺炎为11．4％,VOD、HC和CMV肺炎均发生在allo-HSCT患者。急性GVHD发生率在相关与无关移植中分别为40．0％与33．3％。在相关移植中慢性GVHD发生率为43．4％。移植相关死亡率在自体与异体HSCT中分别为12．5％与16．7％,auto—HSCT复发率为37．5％,相关allo-HSCT复发率为13．3％。移植后5年无病生存率在自体与相关异体移植中分别为18．7％与53．7％。移植前慢性期与加速期和急变期患者相关allo-HSCT后5年无病生存率分别为66．4％与26．7％。结论：allo—HSCT对CML患者,尤其是慢性期患者具有较高的临床治愈率;CsA MTX MMF ATG四联方案在无关allo-HSCT中应用能降低移植后急性GVHD的发生率及程度;采用净化骨髓自体移植能延长CML患者生存期,甚至少部分患者可获得临床治愈。     

Hematopoietic Stem Cell Transplantation for Patients with Chronic Myeloid Leukemia

OBJECTIVE To evaluate the effects of autologous and allogeneic hematopoietic stem cell transplantation (HSCT) for patients with chronic myeloid leukemia(CML).METHODS Fifty-seven patients with CML were treated by HSCT, including 8 cases treated with autologous transplantation purged in vivo and in vitro of minimal residual disease (MRD), 39 cases with related donor allogeneic HSCT (allo-HSCT) and 10 cases with unrelated donor alIo-HSCT. The conditioning regimen was a TBI (total-body irradiation) CY (cyclophosphamide, CTX) protocol in 32 patients, a modified BuCY (hydroxyurea, busulfan, Ara-C, CTX) protocal in 24 patients, and a MACC ( Melphalan, Ara-C, CTX and chlorethyl cyclohexyl nitrosourea ) protocol in one patient. Cyclosporine (CsA) and methotrexate (MTX) were used in patients with related-donor allo-HSCT, and CsA and MTX were added to mycophenolate mofetil (MMF) and antithymocyte globulin (ATG) in unrelated donor allo-HSCT for graft versus host disease (GVHD) prophylaxis. Otherwise, CsA was only used for GVHD prophylaxis in patients with accelerated phase (AP) and blast crisis (BC). The Kaplan-Meier survival analysis model was used to estimate the overall survival (OS) and the disease-free survival (DSF) at 5 years after transplantation.RESULTS Eight patients with autologous transplantation, except for 1 case who died of transplantation-related complications, obtained cytogenetic part or complete remission (CR) within 3 months after transplantation. One patient, who was in BC and obtained CR in hematology before transplantation, had been in molecular CR for 92 months after autologous transplantation. Among the 49 patients treated with alIo-HSCT, all obtained CR, except for one patient who died of hepatic veno-occlusive disease (VOD) and one who had not obtained CR. The incidence of infection and VOD was 33.3% and 7.0%, respectively, during transplantation. After transplantation the incidence of hemorrhagic cystitis (HC) and cytomegalovirus (CMV) interstitial pneumonia (IP) was 22.8% and 8.8%, respectively. VOD, HC and CMV IP did not occur in patients with autologous transplantation. The incidence of acute GVHD and the frequency of chronic GVHD was 41.0% and 48.6%, respectively, in patients with related and unrelated transplantation. The rate of relapse in patients with autologous and allogeneic transplantation was 57.1% and 12.8%, respectively. The DFS at 5 years after transplantation was 25.0% and 61.7%, respectively, in patients with autologous and related donor transplantation. The DFS at 5 years was 70.7% and 34.1%, respectively, in patients with CP (chronic phase) or AP and BC before transplantation.CONCLUSION AIIo-HSCT may have a higher clinical cure rate for CML patients with CP. The CsA MTX MMF ATG protocol is more effective for acute GVHD prophylaxis and can decrease the incidence and degree of GVHD in patients with unrelated donor transplantation, Autologous transplantation with purged bone marrow can prolong the survival time of CML patients and some may be cured with transplants of this type.     

减低强度预处理异基因造血干细胞移植治疗老年人复发难治性急性髓系白血病的临床研究

目的 探讨减低强度预处理异基因造血干细胞移植（allo-HSCT）治疗老年人复发难治性急性髓系白血病（AML）的疗效和安全性.方法 采用减低强度预处理的allo-HSCT治疗北京军区总医院2012年1月至2014年1月收治的6例老年人复发难治性AML,其中男5例,女1例,年龄61～68岁,平均年龄64.6岁,供者接受粒细胞集落刺激因子动员,均采用外周血干细胞移植,预处理方案为降低预处理强度的氟达拉滨联合白消安注射液（商品名：白舒非）、阿糖胞苷及环磷酰胺等,移植物抗宿主病（GVHD）预防采用联合免疫抑制剂,移植后3个月进行预防性供者外周血干细胞输注,观察全部患者不良反应、GVHD和无病生存等情况.结果 全部患者获造血重建,中性粒细胞≥0.5×109/L及血小板计数≥20×109/L的平均时间分别为21.5 d及24.2 d,植入证据检测证实为100％为完全供者造血.中位随访18.5个月（5～30个月）,共3例发生GVHD,GVHD死亡1例,复发死亡2例,复发时间为11.5个月（5～ 18个月）,其余3例患者仍无病生存,2年的无病生存率为50％,最长无病生存时间已达30个月.结论 减低强度预处理的allo-HSCT是复发老年人AML挽救性治疗的可行方法.     

Transplantation of peripheral blood stem cells as compared with bone marrow from HLA-identical siblings in adult patients with acute myeloid leukemia and acute lymphoblastic leukemia.

PURPOSE: Several studies show that allogeneic peripheral blood stem cells (PBSCs) engraft more rapidly than bone marrow (BM). However, the data are inconsistent with regard to acute and chronic graft-versus-host disease (GVHD), relapse, transplant-related mortality (TRM), and leukemia-free survival (LFS). PATIENTS AND METHODS: Between January 1994 and December 2000, 3,465 adult patients (older than 15 years of age) were reported to the European Group for Blood and Marrow Transplantation Registry from 224 centers. Among acute myeloid leukemia (AML) patients, 1,537 patients received BM and 757 patients received PBSC. In acute lymphoblastic leukemia (ALL) patients, the corresponding figures were 826 versus 345 patients who were analyzed for engraftment, GVHD, TRM, relapse, LFS, and survival. RESULTS: In multivariate analysis, the recovery of neutrophils and platelets was faster with PBSC than with BM (P <.0001). Chronic GVHD was associated with PBSC in patients with AML (relative risk [RR], 2.11; 95% confidence interval, 1.66 to 2.7; P <.0001) and ALL (RR, 1.56; 95% confidence interval, 1.09 to 2.27; P =.02). PBSC versus BM in patients with AML or ALL was not significantly associated with acute GVHD, TRM, relapse, survival, or LFS. In multivariate analysis of patients with AML, factors significantly associated with improved LFS included first remission at transplant (P <.0001), promyelocytic leukemia (M3) versus other French-American-British types (P <.0001), and donor age below median 37 years (P =.02). In patients with ALL, first remission (P <.0001) and methotrexate included in the immunosuppressive regimen (P =.001) were associated with improved LFS. CONCLUSION: Allogeneic PBSC results in faster neutrophil and platelet engraftment and a higher incidence of chronic GVHD than BM. However, acute GVHD, TRM, relapse, survival, and LFS were similar in patients receiving PBSCs versus BM.     

异基因外周血造血干细胞移植联合骨髓移植治疗白血病30例

 目的　观察异基因外周血干细胞移植联合骨髓移植对白血病的疗效。方法　白血病患者30例,平均年龄32.6岁,其中急性髓细胞白血病（AML） 11例,急性淋巴细胞白血病（ALL） 14例,慢性粒细胞白血病（CML）5例,供者均为HLA相合同胞,动员方案为每天G-CSF 5 μg／kg,共5 d,并于外周血干细胞回输当天采集供者骨髓300 ml回输;预处理方案采用Bu／Cy,移植物抗宿主病（GVHD）预防采用环孢素A（CsA）联合甲氨蝶呤（MTX）、吗替麦考酚酯（MMF）。结果　回输外周血单个核细胞（5.13±2.6）×108／kg,骨髓单个核细胞（1.3±0.6）×108／kg,30例患者均成功植活,其中中性粒细胞＞0.5×109／L的时间为（12.1±3.25）d,血小板＞0.5×109／L的时间为（14.0±5.33）d;Ⅰ～Ⅱ度aGVHD发生率为40.0 %（12／30）,Ⅲ～Ⅳ度发生率3.3 %（1／30）,cGVHD发生率为43.3 %（13／30）,严重cGVHD发生率为3.3 %（1／30）;2年无病生存率达72.0 %。结论　异基因外周血造血干细胞移植联合骨髓移植是治疗白血病的有效方法,并有可能减少重度急、慢性GVHD的发生。     

含氟达拉滨的预处理行异基因造血干细胞移植治疗恶性血液病的远期疗效

目的:观察含氟达拉滨的预处理方案进行异基因造血干细胞移植治疗恶性血液病的长期疗效。方法:选取2003年2 月至2004年12月间厦门大学附属中山医院收治的15例恶性血液病患者,其中急性髓性白血病3 例,急性淋巴细胞白血病5 例,慢性粒细胞白血病6 例,骨髓增生异常综合症（RAEB）1 例。供受者HLA 配型同胞全相合6 例,同胞或亲缘不相合8 例,非亲缘全相合1 例。预处理方案采用氟达拉滨（Flu 30mg/m2·d,共5d）、马利兰（BU4mg/kg·d,共2～3d）、环磷酰胺（CTX 50mg/kg·d,共2d）,其中8 例加用阿糖胞苷（Ara-c 1.0～2.0g/m2·d,共2d）,9 例HLA 不全相合及非血缘移植者加用兔抗胸腺细胞球蛋白（ATG 3.0～5.0mg/kg·d,共3d）。 预防移植物抗宿主病（GVHD）均采用骁悉（MMF）+ 环孢素（CsA）+ 短程甲氨喋呤（MTX）方案。利用SPSS11.5 统计软件及Kaplan-Meier 方法进行生存分析。结果:15例患者移植后均获得快速完全的植入,无严重的预处理相关毒性。46.7% 发生急性GVHD ,85.7% 发生慢性GVHD ;带状疱疹7.1% 。5 年总生存率为53.5% ,其中移植时处于第一次完全缓解（CR1）和慢性期患者11例,5 年生存率为72.7% ,复发率9.1% ,移植时处于第二次完全缓解（CR2）、复发、加速期及急变期的患者4 例,2 年生存率为0,复发率75,两者有统计学差异（P=0.000 3 和P<0.05）,主要死亡原因为疾病复发和GVHD 。结论:对于移植时处于CR1 和慢性期患者,采用含Flu并适当减低放化疗剂量的预处理方案是有效的移植预处理方案,毒副作用较少,未增加机会性感染,复发率较低;预处理中加入Flu对GVHD 发生率无明显影响。      

Long-term follow-up of relapsed acute leukemia treated with immunotherapy after allogeneic transplantation: the inseparability of graft-versus-host disease and graft-versus-leukemia, and the problem of extramedullary relapse

Long-term outcome of 23 acute myeloid (AML, n=16) or lymphoblastic (ALL, n=7) leukemia patients who had received immunotherapy for treatment of persistent or recurrent disease 1.5-26 (median 4) months after allogeneic transplantation was studied to determine eventual survival. Immune manipulation comprised donor leukocyte infusion (n=18), interferon-alpha2b and/or interleukin-2 (n=15), and cyclosporine withdrawal (n=11) in various combinations. Graft-versus-host disease (GVHD) developed in 12 patients. Thirteen of 20 evaluable patients responded; 6 relapsing again. Eight patients died of toxicity, and 10 of progressive disease at 3-206 weeks (median 11). Five patients (3 AML, 2 ALL) are alive in remission with GVHD 2-46 months (median 23) after immunotherapy with Karnofsky scores of 70-100% (median 80). The overall survival of the whole group is 1-206 weeks (median 12), with an actuarial survival of 22% at 2 years. The development of GVHD was associated with superior survival in multivariate analysis (P=.007). Seven patients received immunosuppression because of the severity of GVHD (grade III/IV acute or extensive chronic): 3 died of GVHD, 3 improved but relapsed concomitantly, and 1 is alive in remission with extensive chronic GVHD. Four episodes of extramedullary relapse (granulocytic sarcomas) were seen in 3 patients with AML whose marrow remained in remission. We conclude that GVHD appears to be inseparable from graft-versus-leukemia in relapsed acute leukemia patients undergoing immunotherapy with a high proportion of patients dying due to toxicity or progressive disease, and isolated extramedullary relapse seems to be unusually common.     

移植物抗宿主病对26例血液肿瘤患者异基因造血干细胞移植后长期生存的影响

背景与目的:移植物抗宿主病(graft-versus-hostdisease,GVHD)是异基因造血干细胞移植的一个主要并发症,亦是影响移植结果的重要因素。一些研究显示,不管是急性GVHD或慢性GVHD,都伴随有较强的移植物抗白血病(graft-versus-leukemia,GVL)作用,这种正向效应与降低异基因造血干细胞移植后白血病复发率及延长受者无病生存密切相关。本研究探讨GVHD的发生及其对异基因造血干细胞移植结果的影响。方法:回顾分析1995年3月至2005年10月26例血液肿瘤患者接受异基因造血干细胞移植术后GVHD的发生、肿瘤复发及生存情况,分析GVHD与血液肿瘤复发率、生存率的关系。结果:异基因造血干细胞移植后中位随访时间为20个月(2～127个月),20例患者术后发生GVHD(76.9%),其中1例受者复发(1/20),6例未出现GVHD的受者3例复发(3/6),两组复发率比较差异有显著性(P<0.05);移植后无病生存16例,死亡10例,Kaplan-Meier生存曲线示3年无病生存率为60%;发生GVHD的受者其无病生存率(15/20)较无GVHD受者(1/6)高(log-rank=7.30,P<0.05),发生GVHD时移植患者发生死亡的风险明显下降(RR值为0.20,P<0.05)。20例发生GVHD的受者,经治疗17例达完全缓解(completeresponse,CR),3例未达CR。17例CR受者中,无病生存15例;而未达CR的3例受者则无一例生存,两组生存率比较差异有显著性(P<0.05)。结论:GVHD是影响异基因造血干细胞移植结果的重要因素。GVHD治疗效果与移植受者无病生存密切相关,早期识别急性GVHD并予及时处理是治疗成功的关键。     

Successful treatment of two relapsed patients with t(11;19)(q23;p13) acute myeloid leukemia by CLAE chemotherapy sequential with allogeneic hematopoietic stem cell transplantation: Case reports

The prognosis of patients with relapsed/refractory acute myeloid leukemia (R/R AML) is poor, with a 3-year overall survival rate of 10%. Patients with translocation (t)(11;19)(q23;p13) have a higher risk of relapse and there is no optimal regimen for these patients. The present study treated two young patients with t(11;19)(q23;p13) AML, who relapsed after one or two cycles of consolidation, with a salvage treatment consisting of sequential cladribine, cytarabine and etoposide (CLAE) and allogeneic hematopoietic stem cell transplantation (allo-HSCT). Both neutrophil and platelet engraftments were achieved within 15 days, and no severe transplant-related complications and graft-versus-host diseases were observed. Following allo-HSCT, both patients achieved complete hematologic and cytogenetic remission. Decitabine was used for the prophylaxis of relapse. The two patients remained alive and disease-free for 100 days following allo-HSCT. The results presented here suggest that CLAE regimen sequential with allo-HSCT may be effective in treating patients with R/R AML, with t(11;19)(q23;p13). However, further studies and a larger sample size are required to validate the effectiveness of this treatment regimen.     

白消安联合氟达拉滨低毒预处理异基因造血干细胞移植治疗恶性血液病13例

 【摘要】　目的　探讨经白消安+氟达拉滨（Bu+Flu）方案低毒清髓预处理异基因造血干细胞移植（allo-HSCT）治疗恶性血液病的临床疗效。方法　对13例接受Bu+Flu方案预处理造血干细胞移植白血病患者的临床资料进行回顾性分析。预处理方案为Bu+Flu,同胞不全相合和非血缘移植患者加用兔抗人胸腺细胞免疫球蛋白（ATG）。用环孢素A+短疗程甲氨蝶呤或环孢素A+吗替麦考酚酯预防移植物抗宿主病（GVHD）。采用DNA短串联重复序列（STR）多态性分析方法鉴定供者干细胞植入情况。结果　13例患者均能耐受Bu+Flu预处理方案,未发生严重的预处理相关并发症。中性粒细胞植活中位时间11 d（9~15 d）,血小板植活中位时间13 d（8~25 d）。10例患者造血重建,检测其外周血白细胞STR-DNA证实均为100 %完全供者植入。出现急性GVHD 5例（38.5 %）,可评估的10例患者中,出现慢性GVHD 4例（40.0 %）;无Ⅱ度以上重型GVHD。中位随访11个月（1~39个月）,总生存率为76.9 %（10／13）,无病生存率为61.5%（8／13）。死亡病例原因均为疾病复发。结论　Bu+Flu方案低毒清髓预处理可减轻移植相关并发症,患者有很好耐受性和较好疗效。     

Low-dose decitabine plus venetoclax is safe and effective as post-transplant maintenance therapy for high-risk acute myeloid leukemia and myelodysplastic syndrome

Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are usually associated with poor outcomes, especially in high-risk AML/MDS. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative option for patients suffering from high-risk AML/MDS. However, many patients relapse after allo-HSCT. Novel therapy to prevent relapse is urgently needed. Both the BCL-2 inhibitor venetoclax (VEN) and the hypomethylating agent decitabine (DEC) possess significant antitumor activity effects against AML/MDS. Administration of DEC has been shown to ameliorate graft-versus-host disease (GVHD) and boost the graft-versus-leukemia (GVL) effect post-transplantation. We therefore conducted a prospective study (ChiCTR1900025374) to examine the tolerability and efficacy of a maintenance therapy of low-dose decitabine (LDEC) plus VEN to prevent relapse after allo-HSCT for high-risk AML/MDS patients. Twenty patients with high-risk AML (n = 17) or high-risk MDS (n = 3) post-transplantation were recruited. Approximately day 100 post-transplantation, all patients received LDEC (15 mg/m² for 3 d) followed by VEN (200 mg) on d 1-21. The cycle interval was 2 mo, and there was 10 cycles. The primary end points of this study were rates of overall survival (OS) and event-free survival (EFS). The secondary endpoints included adverse events (AEs), cumulative incidence of relapse (CIR), nonrelapse mortality (NRM), incidences of acute GVHD (aGVHD) and chronic GVHD (cGVHD), and incidences of viral infection after allo-HSCT. Survival outcomes were assessed using Kaplan-Meier analysis. The median follow-up was 598 (149-1072) d. Two patients relapsed, 1 died, and 1 is still alive after the second transplant. The 2-y OS and EFS rates were 85.2% and 84.7%, respectively. The median 2-y EFS time was 525 (149-1072) d, and 17 patients still had EFS and were alive at the time of this writing. The most common AEs were neutropenia, anemia, thrombocytopenia, neutropenic fever, and fatigue. Grade 2 or 3 AEs were observed in 35% (7/20) and 20% (4/20) of the patients, respectively. No grade >3 AEs were observed. aGVHD (any grade) and cGVHD (limited or extensive) occurred in 55% and 20% of patients, respectively. We conclude that LDEC + VEN can be administered safely after allo-HSCT with no evidence of an increased incidence of GVHD, and this combination decreases the relapse rate in high-risk AML/MDS patients. This novel maintenance therapy may be a promising way to prevent relapse in high-risk AML/MDS patients.     

阿扎胞苷用于急性髓系白血病移植后维持治疗的临床疗效分析

  目的  探讨阿扎胞苷用于急性髓系白血病（acute myeloid leukemia,AML）患者异基因造血干细胞移植（allogeneic hematopoietic stem cell transplantation,allo-HSCT）后维持治疗的疗效以及安全性。  方法  回顾性分析2018年11月至2021年8月在空军军医大学第二附属医院造血干细胞移植中心接受allo-HSCT且在移植后使用阿扎胞苷维持治疗的30例AML患者的临床资料,观察患者移植后的微小残留病（minimal residual disease,MRD）转阴情况及移植物抗宿主病（graft-versus-host disease,GVHD）的发生情况,采用Kaplan-Meier法计算总体生存（overall survival,OS）率、无病生存（disease-free survival,DFS）率及累积复发率,并评估该方案的安全性。  结果  83.33%（25/30）的患者完成了4个周期的维持治疗,36.67%（11/30）的患者完成了全部6个周期的维持治疗。使用阿扎胞苷维持治疗后10例MRD阳性患者中的9例转为阴性,总体转阴率达90%。随访至2021年11月30日,30例患者的中位生存期为（33.7±1.8）个月,3年OS率为（83.2±9.9）%,3年DFS率为（81.3±9.4）%。至随访截止,共4例（13.33%）患者复发,3年累积复发率为（18.7±9.4）%。治疗中23.33%（7/30）的患者出现Ⅲ～Ⅳ度骨髓抑制。2例患者皮肤慢性移植物抗宿主病（chronic graft-versus-host disease,cGVHD）不同程度减轻,1例患者肝脏cGVHD加重,无患者出现新发GVHD的现象。  结论  应用阿扎胞苷进行AML患者allo-HSCT后的维持治疗,可降低复发率,改善患者生存期,且安全性和耐受性良好,不增加患者GVHD的发生率。      

Fludarabine, melphalan, and alemtuzumab conditioning in adults with standard-risk advanced acute myeloid leukemia and myelodysplastic syndrome.

PURPOSE: This prospective phase II study evaluated toxicity, relapse rate, progression-free survival, and overall survival after allogeneic transplantation and conditioning with fludarabine, melphalan, and alemtuzumab in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). PATIENTS AND METHODS: Fifty-two consecutive adults with AML and MDS were enrolled onto the study. Median age was 52 years (range, 17 to 71 years) and the majority of patients had high-risk disease, comorbidities, and/or modest reduction in performance status. Fifty-six percent of patients had unrelated or mismatched related donors. RESULTS: After a median follow-up of 18 months (range, 2 to 34 months), 1-year survival was 48% (95% CI, 34% to 61%), progression-free survival was 38% (95% CI, 25% to 52%), relapse rate was 27% (95% CI, 15% to 40%), and treatment-related mortality was 33% (95% CI, 20% to 46%). The cumulative probability of extensive chronic graft-versus-host disease (GVHD) was only 18% (95% CI, 8% to 40%); extensive chronic GVHD was only observed in recipients of unrelated donor transplants. Performance score and disease status were the major predictors of outcome. High-risk disease (ie, active AML or MDS with > 5% blasts) or even modest decreases in performance status were associated with poor outcomes. Patients with standard-risk leukemia (first or second complete remission) or MDS (< 5% blasts) had excellent outcomes despite unfavorable disease characteristics. CONCLUSION: Fludarabine and melphalan combined with in vivo alemtuzumab is a promising transplantation regimen for patients with AML or MDS and low tumor burden. For patients with active disease, this regimen provides at best modest palliation. Despite a low incidence of GVHD, transplantation is still associated with considerable nonrelapse mortality in patients with decreased performance status.     

HLA半相合造血干细胞移植治疗恶性血液病的临床观察

背景与目的:异基因造血干细胞移植(allogeneichematopoieticstemcelltransplantation,allo-HSCT)是目前治疗恶性血液系统疾病的最有效手段。但仅有25%～30%的患者能找到人类白细胞抗原(humanleukocyteantigen,HLA)相合的亲缘供者;在无关人群中找到相合供者的概率是1/5万～1/10万,甚至更低。若进行HLA半相合造血干细胞移植(hematopoieticstemcelltransplantation,HSCT),则有90%的患者能找到供者,本文旨在探索HLA半相合HSCT治疗恶性血液病的可行性。方法:25例恶性血液病患者进行HLA半相合(其中单倍体20例)的亲缘供者HSCT。采用延长、强化联合免疫抑制促进植入及使用抗胸腺细胞球蛋白(antithymocyteglobulin,ATG)和/或加舒莱(抗CD25单抗)加强预防移植物抗宿主病(graft-versus-hostdisease,GVHD),粒细胞集落刺激因子(granulocytecolonystimulatinfactor,G-CSF)动员的骨髓(bonemarrow,BM)或加外周血干细胞(peripheralbloodstemcell,PBSC)混合移植方案。结果:所有患者均获得造血重建及达完全供者植入。21例(21/25)发生急性GVHD(aGVHD),其中Ⅰ度8例,Ⅱ度6例,Ⅲ度2例,Ⅳ度5例(其中3例为同胞部分相合),Ⅱ～Ⅳ度和Ⅲ～Ⅳ度aGVHD累积发生率分别为48.0%和28.6%。12例(12/25)发生慢性(c)GVHD,均为局限性。16例患者无病生存,1年预计无病生存率(disease-freesurvival,DFS)为(64.00±2.98)%,1年预计总生存率(overallsurvival,OS)为(64.0±3.08)%。9例死亡,其中1例死于复发,8例死于移植相关合并症,其中肺部感染4例,Ⅳ度GVHD3例,白质脑病1例。结论:HLA配型半相合的HSCT是治疗无亲缘和无关供体全相合的高危恶性血液病的有效方法,但风险较大,需在严密监测下慎重使用。     

伊马替尼联合造血干细胞移植治疗慢性粒细胞白血病

 目的 研究伊马替尼（商品名：格列卫）对异基因造血干细胞移植（allo-HSCT）和自体外周血造血干细胞移植（APBSCT）的影响。方法 18例慢性粒细胞白血病（CML）分为2组：①al-lo-HSCT组14例,其中10例为CML加速期（AP）和急变期（BP）,4例为CML慢性期（CP）,移植之前格列卫疗程中位数为25（7～60）d,供受者HLA完全相合,亲缘相关供者9例、非亲缘供者5例,预处理方案为TBI+Cy+VP16或Bu／Cy±ATG,GVHD预防按常规方案进行;②APBSC动员4例,均为CML-CP患者,格列卫治疗的中位数疗程5.5（4～26）个月,动员前反复IFISH-bcr／abl阳性率0～2%,动员方案CAE+G-CSF,其中3例经TBI+Cy+VP16预处理后进行了APBSCT。结果 4例患者经G-CSF动员第5天分离自体外周血干细胞（APBSC）1次,得CD+34细胞的中位数6.8（3.9～9.6）×106／kg,动员产品中IFISH-bcr／abl阳性细胞比例高于动员前骨髓细胞（2.8 %∶0.8 %）,4例动员PBSC的患者中3例进行了APBSCT,移植后随访中位时间24（18～28）个月,2例复发,1例持续IFISH-bcr／abl阴性。14例allo-HSCT患者中位随访8（4～20）个月,造血重建需要8～21 d,发生GVHD 8例,白血病复发2例,移植相关并发症死亡2例,复发死亡1例,无病生存9例。结论 格列卫治疗后对CML患者造血干细胞的动员、移植结果无明显影响。     

Localized lymphoid relapse in the pancreas following allogeneic hematopoietic stem cell transplant for chronic myelogenous leukemia

The incidence of isolated extramedullary disease (EMD) following allogeneic hematopoietic stem cell transplant (allo-HSCT) for chronic myelogenous leukemia (CML) is not fully known. One review found the incidence of isolated myeloid EMD, or granulocytic sarcoma (GS), in an allo-HSCT treated CML/myelodysplastic subgroup to be just 0.22%. The incidence of lymphoid EMD in similar patients is extremely rare with only two cases reported in the literature. While the etiology of EMD in the post-transplant setting is not entirely clear, there may be inefficacy of immune surveillance function outside of the bone marrow cavity. Isolated CML GS following allo-HSCT carries a median interval to bone marrow relapse between 7 and 10 months and a median survival of 12 months. Less is known about lymphoid EMD. The treatment in these cases is ill defined with modalities ranging from involved field radiation to second allo-HSCT. We present a case of isolated pancreatic lymphoid EMD diagnosed 15 months after allo-HSCT for CML. Our patient was also treated with withdrawal of his immunosuppressive regimen. Unfortunately, at just over 4 months following pancreatic resection, he developed systemic relapse and died. While EMD can occur anywhere in the body, CML associated pancreatic EMD is not previously reported.     

Allogeneic marrow transplantation during untreated first relapse of acute myeloid leukemia.

PURPOSE: The purpose of this report was to review the Seattle experience in bone marrow transplantation (BMT) for acute myeloid leukemia (AML) during untreated first relapse. PATIENTS AND METHODS: Through 1990, 126 patients were transplanted during untreated first relapse of AML. Several preparative regimens were used, two of which involved more than 20 patients. Regimen 1 (29 patients) consisted of cyclophosphamide (CY) 120 mg/kg and 15.75 Gy of fractionated total-body irradiation (TBI) with methotrexate (MTX) given intermittently during a 102-day period to prevent graft-versus-host disease (GVHD). Regimen 2 (22 patients) consisted of the same CY and TBI treatment and a combination of MTX and cyclosporine (CSP) for GVHD prophylaxis. The remaining 75 patients were treated with 17 other transplant regimens. Outcome was compared for patients who were treated with regimen 1, regimen 2, and any other regimen. RESULTS: The 5-year probabilities of relapse-free survival (RFS), relapse, and nonrelapse mortality for 126 patients were .23, .57, and .44, respectively. With regimen 1, relapse (.26) was significantly less than for regimen 2 (.70; P = .004) or any other regimen (.76; P = .004). Regimen 1 patients developed more acute GVHD (.67) than regimen 2 patients (.26; P = .02) or patients on other regimens (.41; P = .02), and had increased nonrelapse mortality. Nevertheless, regimen 1 patients had a significantly higher 3-year RFS (.38) than those treated with regimen 2 (.18; P = .04) or any other regimen (.20; P = .05). CONCLUSIONS: For patients who received 120 mg/kg CY and 15.75 Gy TBI, relapse incidence was less and survival was better after GVHD prophylaxis with MTX alone than after a combination of MTX and CSP, despite a significantly higher incidence of acute GVHD. The results of treatment with regimen 1 justify future studies of the optimal timing of allogeneic BMT in the treatment of patients with AML.     

In relapsed patients after lymphocyte depleted bone marrow transplantation the percentage of donor T lymphocytes correlates well with the outcome of donor leukocyte infusion

Donor leukocyte infusions (DLI) from the original marrow donor have been shown to induce remission in patients with relapse after BMT. We analyzed factors that were associated with remission. Twenty-six patients with a relapse after T cell depleted BMT received DLI. The following pre-DLI factors were analyzed: sex and age of the patients and donors, GVHD after BMT, indication for DLI, percentage of donor T lymphocytes in the patient at the time of DLI, interval between relapse and DLI, and number of T lymphocytes infused. Remission was achieved in 11 of 15 patients (73%) treated for relapsed CML and in one of 11 patients (9%) treated for relapsed AML, ALL or RAEB-t (P = .002). Two of 13 patients (15%) with < or =40% of T lymphocytes from donor origin attained remission compared with 10 of 13 patients (77%) with >40% (P = .002). Two of 13 patients (15%) with an interval of < or =18 months between BMT and first DLI entered remission compared with 10 of 13 patients (77%) with an interval of >18 months (P = .002). Multivariate analysis demonstrated that indication for DLI (CML versus AML/ALL and RAEB-t) and the percentage T lymphocytes from donor origin (< or =40 versus >40) were significantly correlated with remission (P = .03). The occurrence of GVHD post DLI was highly associated with achievement of remission (P = .0001). DLI res ults in remission in a high percentage of patients with relapsed CML after BMT. The percentage of T lymphocytes from donor origin still present in the patient at the time of DLI is highly correlated with achievement of remission.