Total body irradiation–high-dose cytosine arabinoside and melphalan followed by allogeneic bone marrow transplantation from HLA-identical siblings in the treatment of children with acute lymphoblastic leukaemia after relapse while receiving chemotherapy: a Société Française de Greffe de Moelle study

We investigated the use of a new conditioning regimen followed by allogeneic bone marrow transplantation (BMT) for treating children with acute lymphoblastic leukaemia (ALL) after relapse within 6 months of the completion of therapy. One hundred and sixteen children with acute lymphoblastic leukaemia in second or subsequent complete remission (CR) underwent allogeneic bone marrow transplantation from HLA-identical siblings after a preparative regimen comprising total body irradiation (TBI), high-dose cytosine arabinoside and melphalan (TAM regimen). The Kaplan-Meier product-limit estimate (mean ± SE) of disease-free survival (DFS) at 7 years was 59.5 ± 9% (95% confidence interval). The estimated chance of relapse was 22.5 ± 15% with a median follow-up of 88.5 months (range 51–132). 26 patients (22.4%) died with no evidence of recurrent leukaemia, mainly from interstitial pneumonitis, veno-occlusive disease or acute graft-versus-host disease (GVHD). Three factors significantly affected DFS: acute GVHD, site of relapse and, for children in second remission after a marrow relapse, the disease status at the time of transplantation. The DFS were 59.02 ± 12.6%, 37.5 ± 19.8% and 77.4 ± 15% among patients in CR2 after a marrow relapse, in CR3 or in untreated partial marrow relapse, and in CR2 after an isolated CNS relapse, respectively. The lowest DFS was seen in children with acute GVHD grades 3–4. Two significant factors were associated with relapse: the marrow status at the time of transplantation and chronic GVHD. The relapse rate was lower among children in CR2 or with chronic GVHD. We conclude that transplantation after the TAM regimen is an effective therapy for this population with acceptable toxicity, particularly for children in second remission after a very early marrow relapse, or those with early isolated CNS involvement.     

FABC预处理异基因造血干细胞移植治疗难治未缓解急性白血病临床研究

目的观察FABC预处理异基因造血干细胞移植治疗未缓解急性白血病(AL)患者的疗效及安全性。方法收集2005年11月至2010年8月广东省人民医院采用FABC预处理方案进行异基因造血干细胞移植治疗18例难治未缓解AL患者。观察造血恢复、植入率、急慢性移植物抗宿主病发生率、移植相关病死率、复发、总存活率和无病存活率及预后因素分析。结果所有患者均于移植后14～21 d获得完全供者植入,中性粒细胞>0.5×109/L和血小板>20×109/L中位时间分别为12(7～72)d和13(7～60)d;急性移植物抗宿主病(GVHD)及慢性GVHD累积发生率分别为50%和73.3%。中位随访10.5(3.1～66.6)个月,移植相关病死率5.6%(1/18),复发率为36.8%(7/18)。1年的预期总生存(OS)率和无病生存(DFS)率分别是(58.9±13.2)%和(53.6±15.5%)。COX逐步回归模型分析显示,慢性GVHD是DFS独立有利因素。结论 FABC预处理异基因造血干细胞移植是治疗难治性未缓解AL安全有效的方法。     

静脉剂型白消安为主的预处理方案对接受异基因造血干细胞移植的白血病患者的疗效及相关毒性

背景与目的:白消安(busulfan,Bu)是异基因造血干细胞移植预处理方案中的常用药物,口服Bu由于胃肠道吸收不稳定,影响移植疗效且毒性风险增加.本研究评价静脉剂型Bu联合环磷酰胺(cyclophosphamide,Cy)(Bu/Cy)作为异基因外周血干细胞移植(allogeneic peripheral blood stem cell transplantation,allo-PBSCT)预处理方案的疗效和安全性.方法:15例白血病患者采用静脉剂型Bu/Cy,20例采用口服Bu/Cy预处理方案,观察两组的疗效及相关毒性.结果:静脉剂型Bu组15例(100.0%)患者获得造血重建,中性粒细胞和血小板植活中位时间分别为移植后12(9～15)天和15(11～24)天,急性移植物抗宿主病(acute graft versus host disease,aGVHD)6例(40.0%),其中Ⅰ～Ⅱ度4例,Ⅲ～Ⅳ度2例.预处理相关毒性,7例(46.6%)发生呕吐,1例(6.7%)口腔粘膜炎,1例(6.7%)出血性膀胱炎,2例(13.3%)肝功能损害.中位随访时间为180(35～420)天,14例(93.3%)截止随访时仍生存,1例死于严重aGVHD合并肺部、中枢神经系统真菌感染.静脉剂型Bu组在肝脏毒性、口腔粘膜炎发生率分别明显低于口服组(13.3% vs.60.0%、6.7% vs.80.0%),差异均有统计学意义(P＜0.01),而在造血重建、aGVHD、胃肠道反应、出血性膀胱炎等方面差异均无统计学意义.结论:静脉剂型白消安组成的Bu/Cy方案作为白血病allo-PBSCT预处理,疗效确切且毒副作用降低.     

Allogeneic immune replacement as cancer immunotherapy

The graft-versus-leukaemia (GVL) reaction that occurs after allogeneic haematopoietic cell transplantation (HCT) can cure patients with a variety of haematological malignancies. A heightened appreciation of the GVL effect has resulted in the development of reduced intensity transplant approaches, where antitumour effects occur predominantly as a consequence of the transplanted donor immune system. The recent success of these transplants in patients with acute and chronic leukaemias has led to trials investigating for graft-versus-tumour (GVT) effects in patients with treatment-refractory metastatic solid tumours. This review discusses evidence that immune replacement following allogeneic HCT is a potent form of cancer immunotherapy for patients with haematological and non-haematological malignancies.     

Controlled Epstein–Barr virus reactivation after allogeneic transplantation is associated with improved survival

Epstein–Barr virus reactivation (EBV‐R) frequently occurs in patients having allogeneic hematopoietic stem cell transplantation (HSCT). We evaluated the impact of controlled EBV‐R on survival of 190 patients (114M/76F, median age: 51 yr, range 18–69), having HSCT for hematological malignancies (105 acute leukemias and myelodysplasias, 71 lymphoproliferative disorders, 14 others). Overall survival (OS) and progression‐free survival (PFS) were compared between patients with and without EBV‐R. Of 138, patients had reduced‐intensity conditioning regimen. Various stem cell sources (141 PB, 33 umbilical cord blood and 16 bone marrow) were used. Patients with EBV‐R had longer PFS and OS than those without EBV‐R: PFS at 2 yr 69% vs. 51% and at 5 yr 47% vs. 38% (P < 0.04); OS at 2 yr 76% vs. 64% and at 5 yr 63% vs. 47%) (P < 0.001). The use of rituximab had no impact on OS and PFS, but it reduced the intensity of GVHD, despite the fact that TRM was not significantly different between the two groups of patients. So, rituximab may have an additional effect to other factors on PFS and OS. In multivariate analysis, antithymocyte globulin administration was not a significant factor for PFS (P = 0.68) and for OS (P = 0.81). Circulating NK cells were significantly increased by 22% (P = 0.03) in EBV‐R patients with no differences for other parameters. Controlled EBV‐R in the setting of HSCT is associated with better OS and PFS, with a significant increase in circulating NK cells.     

Second Allogeneic Bone Marrow Transplantation after Myeloablative Conditioning Analysis of 43 Cases from Single Institution

Between March 1984 and December 1999, a total of 43 second related allogeneic BMT procedures after myeloablative conditioning were carried out in our institution, 37 following allogeneic, and 6 following autologous BMT. Thirty one patients were males (72%). At 1st BMT (BMT<PRE>1</PRE>), median age was 11.5 years (range, 0.16-45 years). BMT<PRE>1</PRE> was carried out for the diagnosis of AML in 13 patients (30%), SAA in nine (21%), ALL in six (14%), CML in six (14%), immunodeficiency in three (7%), NHL in two, β-thal in two, HD in one, Red cell aplasia in one. HLA matching status for allogeneic BMT<PRE>1</PRE> was full match in 33, one antigen mismatch in two and haplo identical in two patients. Median age at the 2nd BMT (BMT<PRE>2</PRE>) was 14 years (range, 0.41-46.7 years). Indications for BMT<PRE>2</PRE> were recurrent hematologic neoplasm in 23 patients (53%), primary graft failure in 12 (28%) and late graft failure in 8 (19%). Median time from BMT<PRE>1</PRE> to recurrence of hematologic neoplasm or late graft failure was 10 months (range, 2.5- 88 months). Median BMT<PRE>1</PRE> to BMT<PRE>2</PRE> interval was 13 months (range, 1-107 months). For BMT<PRE>2</PRE>, the same donor was used in 29 patients, while 14 patients had alternate related donor (12 full match, 1-one Ag mismatch, 1 haplo identical). A different conditioning regimen was used in the majority of the patients (39, 91%). Radiation containing conditioning regimen were used mostly for patients previously conditioned with chemotherapy only for BMT<PRE>1</PRE> and chemotherapy conditioning±ATG for those who received radiation containing conditioning at BMT<PRE>1</PRE>. Bone marrow was the stem cell source for all patients at BMT<PRE>2</PRE> and all except three autologous peripheral stem cell transplantation patient at BMT<PRE>1</PRE>. Significant organ toxicity leading to procedure related death in 13 patients (30%) was observed after BMT<PRE>2</PRE>. At a median follow up of 36 months after BMT<PRE>2</PRE>, 22 patients (51%) are alive (20 free of disease, 2 with recurrent disease) with overall median survival of 47.5 (SD±9) months. Univariate analysis of relevant clinical factors identified the following variables as the only statistically significant favorable prognostic factors for overall survival: BMT<PRE>1</PRE>-BMT<PRE>2</PRE> interval of ≥6 months (P=0.0007) and age at BMT<PRE>2</PRE> ≤10 years (P=0.041). The nature of underlying disease (neoplastic or non-neoplastic) was not statistically significant (P=0.23). There was no statistically significant difference in survival outcome of BMT<PRE>2</PRE> using same donor vs. alternate related donor (P=0.51). Due to the relatively limited sample size, multivariate analysis was not attempted. This single institution study suggests that second allogeneic BMT after myeloblative conditioning has an acceptable treatment related morbidity/mortality and favorable outcome if performed at age ≤10 years and with an interval of ≥6 months after the first BMT. Additionally same donor can successfully be used for the second transplant with similar survival outcome to alternate donor.