Allogeneic blood stem cell and bone marrow transplantation for acute myelogenous leukemia and myelodysplasia: influence of stem cell source on outcome

We have compared the outcomes of 87 patients with acute myelogenous leukemia (AML) and myelodysplasia (MDS) receiving matched sibling transplants with stem cells from peripheral blood (blood cell transplant, BCT) or bone marrow (BMT). In good risk patients (AML in CR1) granulocytes recovered to 0.5 x 10(9)/l a median of 14 days after BCT compared with 19 days after BMT (P < 0.0001). For patients with poor risk disease (AML beyond CR1 and MDS) corresponding figures were 16 vs 26 days (P < 0.0001). Platelet recovery to 20 x 10(9)/l was also faster after BCT (good risk 12 vs 20 days, P < 0.0001; poor risk 17 vs 22 days, P = 0.04). Red cell transfusions were unaffected by cell source, but BCT recipients required less platelet transfusions (good risk 1 vs 5, P = 0.002; poor risk 5 vs 11, P = 0.004). Blood cell transplants resulted in more chronic GVHD (86% vs 48%, P = 0.005) and a significantly higher proportion of recipients with KPS of 80% or less (48% vs 5%, P = 0.004). Disease-free survival at 4 years was 23% for both groups of poor risk patients but outcome in good risk patients was better after BCT (93% vs 62%, P = 0.047) related mainly to less relapse. While disease-free survival may be better after BCT than BMT for AML in CR1, quality of life may be relatively impaired.     

自体外周血造血干细胞和自体骨髓移植治疗急性髓性白血病的临床疗效比较研究

目的：比较自体外周血干细胞移植（APBSCT）与自体骨髓移植治疗CR1期急性髓性白血病（AML）的临床疗效。方法：用APBSCT治疗AML患者27例，用非净化自体骨髓移植（ABMT）治疗AML患者13例，用净化自体骨髓移植（PABMT）治疗AML患者25例。结果：（1）APBSCT组造血重建校其他两组显著加快；（2）APBSCT组的3年无病生存率（DFS）和复发率（RR）分别为51．％和42．2％，与ABMT组的46．2％、46．7％相当，但与净化ABMT组的72．9％、23．7％相比差异有显著性意义。（3）三组的移植相关死亡率（TRM）差异无显著性意义，死亡的主要原因为感染和内脏出血。结论：APBSCT治疗CR1期AML，其造血重建显著快于ABMT，其疗效与ABMT相当，而显著低于PABMT。     

Autologous versus allogeneic stem cell transplantation in acute myeloid leukemia

Using the data of the patients in complete remission (CR) up to the age of 45 years included in the EORTC-LG/GIMEMA AML-10 trial we investigated the value of the strategy to perform either an autologous (auto-SCT) or an allogeneic (allo-SCT) stem cell transplantation on an intention to treat basis. Between 1993 and 1999, out of 1198 pts, 822 achieved CR. 734 pts, constituting the study group, received an intensieve consolidation course: 293 had a sibling donor and 441 had not. Allo-SCT and auto-SCT was performed in 68.9% and 55.8%, respectively. Cytogenetics was successfully performed in 446 pts. Risk groups were: good (t(8;21), inv(16)), intermediate (NN or -Y only), bad/very bad (all others). Median follow-up was 4 years. The 4-year disease-free survival (DFS) rate of patients with a donor vs of those without a donor was 52.2% vs 42.2%, p = 0.044; the relapse incidence was 30.4% vs 52.5%, death in first complete remission was 17.4% vs 5.3%, and the survival rate was 58.3% vs 50.8% (p = 0.18). The DFS rates in pts with and without a sibling donor were similar in pts with good or intermediate risk cytogenetics, but 43.4% and 18.4%, respectively, in pts with bad or very bad risk cytogenetics. In younger patients (15-35 yrs), the difference was more pronounced. The strategy to perform an allo-SCT in patients where a family donor was available led to better overall results than to perform an auto-SCT, especially for younger patients or those with bad or very bad risk cytogenetics.     

HLA相合同胞供者异基因外周血干细胞移植治疗急性白血病

目的:探讨HLA相合同胞供者异基因外周血干细胞移植(alloPBSCT)治疗急性白血病(AL)疗效。方法:52例AL患者,男33例,女19例,中位年龄33(13～54)岁。急性淋巴细胞白血病(ALL)24例,急性非淋巴细胞白血病(ANLL)28例;高危组16例,标危组36例。采用含TBI或不含TBI预处理方案。预防移植物抗宿主病(GVHD)采用环胞素(CsA)加短程甲氨蝶呤(MTX)或他克莫司(FK506)方案,2例二次移植未用免疫抑制剂预防GVHD。46例移植后白细胞降至最低时开始用GCSF5μg/(kg·d),直至中性粒细胞数(ANC)≥0.5×109/L;6例未用。结果:所有患者均重建造血,ANC≥0.5×109/L和血小板计数≥20×109/L的中位时间分别为移植后第11和17天。发生Ⅱ度及以上急性GVHD12例(23.0%)。慢性GVHD(cGVHD)发生率为60.9%,局限型43.5%,广泛型17.4%;发生cGVHD的复发率(18.5%)低于无cGVHD者(47.4%)(P<0.05);有cGVHD者5年无白血病生存率(DFS)[(58.7±9.7)%]高于无cGVHD者[(33.3±11.1)%,P<0.05]。100d内移植相关死亡率(TRM)为11.5%,100d后的TRM为23.9%。多因素分析结果显示,移植前缓解时间和cGVHD对DFS有显著影响(P<0.05),移植前缓解时间越长DFS越高,发生cGVHD的DFS较高;而供受者ABO血型不合DFS较低(P<0.05)。结论:alloPBSCT造血重建快,cGVHD发生率较高,移植前缓解时间较长和移植后发生cGVHD者生存率较高,ABO血型不合者生存率较低。     

Comparison of allogeneic T cell-depleted peripheral blood stem cell and bone marrow transplantation: effect of stem cell source on short- and long-term outcome.

We report the results of a retrospective single-center study comparing engraftment, acute and chronic GVHD, relapse and survival in patients with malignant hematological disorders transplanted with allogeneic peripheral blood stem cells (alloPBSCT, n = 40) or bone marrow cells (alloBMT, n = 42). All transplants were T cell depleted by in vitro incubation with the Campath-1 monoclonal antibody. Primary graft failure occurred in none of the patients receiving an alloPBSCT compared with 3/42 of the recipients of an alloBMT. In addition, two patients in the alloBMT group showed no platelet engraftment. Recipients of PBSC had a more rapid recovery of neutrophils (median 14 days) compared to BM transplant recipients (median 32 days). Platelet recovery was also accelerated in PBSC recipients compared to BM recipients (11 vs 38 days). There was an increase in the incidence of grade II acute GVHD and chronic GVHD in patients after alloPBSCT (18% and 23%, respectively) compared to patients receiving alloBMT (5% and 8%, respectively). The 2-year cumulative incidence of relapse was similar in both groups (47%). At 6 months after transplantation, transplant-related mortality (TRM) was lower in PBSCT recipients than in BMT recipients. However, at a follow-up of 3 years TRM was similar in both groups. The disease-free survival rate at 3 years after transplantation did not differ between the groups (42% for PBSCT and 41% for BMT recipients). Our results indicate that T cell-depleted alloPBSCT compared to alloBMT is associated with a more rapid hematopoietic reconstitution and a decreased TRM at 6 months follow-up after transplantation. However, at a follow-up of 3 years, no sustained survival benefits were observed.     

Autologous peripheral blood stem cell transplantation for acute myeloid leukemia

We report the results of a prospective, randomized phase 3 trial evaluating autologous peripheral blood stem cell transplantation (ASCT) versus intensive consolidation chemotherapy in newly diagnosed AML patients in complete remission (CR1). Patients with AML (16-60 years) in CR1 after 2 cycles of intensive chemotherapy and not eligible for allogeneic SCT were randomized between intensive chemotherapy with etoposide and mitoxantrone or ASCT ater high-dose cyclophosphamide and busulfan. Of patients randomized (chemotherapy, n = 259; ASCT, n = 258), more than 90% received their assigned treatment. The 2 groups were comparable with regard to prognostic factors. The ASCT group showed a markedly reduced relapse rate (58% vs 70%, P = .02) and better relapse-free survival at 5 years (38% vs 29%, P = .065, hazard ratio = 0.82; 95% confidence interval, 0.66-1.1) with nonrelapse mortality of 4% versus 1% in the chemotherapy arm (P = .02). Overall survival was similar (44% vs 41% at 5 years, P = .86) because of more opportunities for salvage with second-line chemotherapy and stem cell transplantation in patients relapsing on the chemotherapy arm. This large study shows a relapse advantage for ASCT as postremission therapy but similar survival because more relapsing patients on the chemotherapy arm were salvaged with a late transplantation for relapse. This trial is registered at www.trialregister.nl as #NTR230 and #NTR291.     

Treatment for acute myelocytic leukemia with allogeneic bone marrow transplantation following preparation with BuCy2

One hundred twenty-seven patients with acute myelocytic leukemia (AML) were given busulfan 4 mg/kg on each of 4 days and cyclophosphamide 60 mg/kg on each of 2 days (BuCy2) followed by allogeneic bone marrow transplantation from an HLA-identical or one antigen disparate sibling. For 71 patients in first complete remission, 23 in second complete remission or initial relapse, and 33 patients with primary refractory disease, second or subsequent relapse, or a preceding hematologic disorder, the 3-year leukemia-free survival (LFS) is 63.1%, 32.6%, and 24.2% respectively. The actuarial probability of relapse for each group is 14.1%, 40.6%, and 61.0%. In multivariate analyses, relapse and decreased LFS were associated with advanced disease phase and with M4/M5 French-American-British classification. The LFS of first remission patients was adversely associated with a short time interval from diagnosis to transplantation. This study indicates that BuCy2 is an attractive preparative regimen for marrow transplantation in patients with AML and that prognostic factors for relapse and LFS are similar those described for regimens containing total body irradiation.     

Nonmyeloablative allogeneic stem cell transplantation for acute leukemia

Allogeneic stem cell transplantation (ASCT) has traditionally included the administration of maximally tolerated doses of chemoradiotherapy, which have been associated with significant treatment-related toxicities. Thus, less intensive conditioning regimens have been explored as a safer alternative to conventional ASCT. Nonmyeloablative stem cell transplantation (NMSCT) has been one of the most promising recent developments in the treatment of hematologic malignancies, and early studies have yielded encouraging results with high engraftment rates and sustained remissions. This approach incorporates immunosuppressive doses of chemotherapy and radiotherapy to achieve a mixed donor-host hematopoietic chimeric state and allows the development of a donor immune-mediated graft-versus-leukemia effect as the primary means of disease eradication. This review discusses the background and rationale behind NMSCT and its impact on the treatment of patients with acute leukemia.     

Reduced-intensity stem cell transplantation using allogeneic peripheral blood stem cells from the same donor for relapsed leukemia after bone marrow transplantation

We report the clinical courses of two cases with relapsed acute lymphoblastic leukemia (ALL) after allogeneic bone marrow transplantation (BMT). After reinduction chemotherapy, the patients received reduced-intensity stem cell transplantation using allogeneic peripheral blood stem cells harvested from their previous BMT donors. The conditioning regimen used consisted of fludarabine and melphalan. Graft-versus-host disease (GVHD) prophylaxis was performed with low dose cyclosporin A (CsA, 1 mg/kg/day d.i.v.) on its own. The regimen related toxicity was minimal, and stable engraftment was achieved. Since acute GVHD had not developed by day 30, CsA was stopped abruptly in both cases. After CsA withdrawal, acute GVHD developed, and subsequent chronic GVHD. One of two cases is alive without any relapse of the leukemia 40 months after the peripheral blood stem cell transplantation (PBSCT). In the other case, ALL relapsed 15 months after the PBSCT, however, complete remission was again induced concomitantly with reactivated GVHD. In both these cases, the results suggest that using PBSC as a stem cell source and abrupt cessation of GVHD prophylaxis provided a potent graft-versus-leukemia effect.     

Cost analysis of HLA-identical sibling and voluntary unrelated allogeneic bone marrow and peripheral blood stem cell transplantation in adults with acute myelocytic leukaemia or acute lymphoblastic leukaemia

Allogeneic stem cell transplantation (SCT) is one of the most expensive medical procedures. However, only a few studies to date have addressed the costs of HLA-identical sibling transplantation and only one study has reported costs of unrelated transplantation. No recent cost analysis with a proper follow-up period and donor identification expenses is available on related or voluntary matched unrelated donor (MUD) SCT for adult AML or ALL. Therefore, we calculated direct medical (hospital) costs based on 97 adults who underwent HLA-identical sibling bone marrow transplantation (BMT) or peripheral blood stem cell transplantation (PBSCT), and patients who received a graft from a MUD between 1994 and 1999. The average costs per transplanted patient were Euro 98,334 (BMT), Euro 151,754 (MUD), and Euro 98,977 (PBSCT), including donor identification expenses, 2 years follow-up and costs of patients who were not transplanted after they had been planned to receive an allograft. The majority of these costs was generated during the hospitalisation for graft infusion. For MUD transplants, nearly one-third of these costs was spent on the search for a suitable donor. For patients who were alive after 2 years, cumulative expenses were calculated to be Euro 103,509 (BMT), Euro 173,587 (MUD), and Euro 105,906 (PBSCT).     

异基因外周血造血干细胞移植治疗急性白血病(附1例报告)

目的 :探索异基因外周血造血干细胞移植 (allo PBSCT)治疗急性白血病的疗效和移植物抗宿主病(GVHD)的防治。方法 :急性淋巴细胞白血病 (ALL )患者 1例 ,HLA配型完全相合。预处理采用白消安、环磷酰胺(BU/CTX )方案 ;GVHD的预防采用常规环胞菌素A(CsA)加短程甲氨蝶呤 (MTX)加霉酚酸酯 (MMF)方案。治疗慢性GVHD(cGVHD)采用MMF加CsA加硫唑嘌呤 (6 mp)加泼尼松加酞咪哌啶酮 (反应停 ,Thalidomide)。移植有核细胞数 (NC)为 12 .32× 10 8/kg ,CD34+ 细胞为 14 .78× 10 6/kg。结果 :移植 +13d获造血重建 ,同时DNA指纹图提示供者型。移植 +2 2d检测染色体核型为 4 6 ,XX ,10 0 %嵌合。移植 +98d血型由B型转变为A型。移植 +2 10d发生cGVHD ,随访 19个月 ,cGVHD已控制 ,患者现无病生存。结论 :异基因外周血造血干细胞移植可有效治疗急性白血病 ,本例造血重建迅速 ,cGVHD通过治疗后可有效控制     

Successful treatment of myeloid/natural killer cell precursor acute leukemia with allogeneic peripheral blood stem cell transplantation

We report a case of myeloid/NK cell precursor acute leukemia, which was successfully treated with allogeneic peripheral blood stem cell transplantation (allo PBSCT). A 31-year-old woman was admitted to our hospital with general fatigue, anorexia and leukocytosis. Bone marrow aspiration showed infiltration of many atypical blasts. She was diagnosed as having myeloid/NK cell precursor acute leukemia by morphological and immunohistochemical analysis. Complete remission was achieved by induction chemotherapy, but as myeloid/NK cell precursor acute leukemia is reported to have an extremely poor prognosis due to frequent relapse, the patient underwent allo PBSCT from her HLA-identical father, together with a myeloablative conditioning regimen. She suffered several transplantation-related complications including acute graft versus host disease (grade II) and ischemic enterocolitis associated with thrombotic microangiopathy, but these were overcome by supportive therapy. She was discharged on day 168 after allo PBSCT, and so far there has been no evidence of relapse during a follow-up period of 15 months.     

Early establishment of hematopoietic chimerism following allogeneic peripheral blood stem cell transplantation in comparison with allogeneic bone marrow transplantation

To characterize the process of the establishment of complete chimerism after allogeneic peripheral blood stem cell transplantation (allo-PBSCT), we determined the origin of leukocytes in peripheral blood (PB) obtained from 23 patients in the very early period after allo-PBSCT using amplification of mini- or microsatellite regions of genomic DNA. Donor-specific alleles were amplified from the PB obtained at day 8 post-transplant for 19 allo-PBSCT patients. Among the 19 patients, 12 showed only donor-specific alleles (complete chimerism) while 7 did both donor and host-specific alleles (mixed chimerism). Although donor specific alleles were amplified in 10 of 12 patients who received allogeneic bone marrow transplantation (allo-BMT) similarly to allo-PBSCT, all of these ten showed mixed chimerism. When the chimeric state was examined in PB samples obtained serially at 2-3-day intervals post-transplant, host-specific alleles in allo-PBSCT patients were not detectable in the PB much earlier than those in allo-BMT patients. These findings indicate that the appearance of donor-derived cells associated with the disappearance of host-derived cells in the circulation occurs earlier after allo-PBSCT as compared with allo-BMT, leading to the rapid establishment of complete chimerism.     

Successful second allogeneic peripheral blood stem cell transplantation and donor lymphocyte infusion in patients with relapsed acute leukemia using the same donors as for the initial allogeneic bone marrow transplantation

We report the successful treatment of two acute lympho- blastic leukemia (ALL) patients who relapsed following allogeneic bone marrow transplantation (allo-BMT) with allogeneic peripheral blood sem cell transplantation(allo-PBSCT) and donor lymphocyte infusion (DLI) from the same HLA-identical related donors as those used for the first allo-BMT. The patients relapsed on days 154 and 351 from the initial allo-BMT, respectively. Since conventional reinduction chemotherapy failed, allo-PBSCT was undertaken while the patients were still myelosuppressed immediately after reinduction chemotherapy. To induce and/or enhance GVL effects following allo-PBSCT, we performed rapid tapering of CsA and added DLI. After allo-PBSCT and DLI, the patients maintained their complete remission at 55 and 48 months post allo-PBSCT, respectively. From these findings, allo-PBSCT and DLI may be a useful treatment strategy for acute leukemia relapsing after allo-BMT.     

CD34+ cell dose and hematologic recovery in allogeneic peripheral blood stem cell transplantation

Allogeneic peripheral blood stem cell transplantation (Allo-PBSCT) has been performed as an alternative to bone marrow transplantation (BMT). Here we report poor mobilization with granulocyte-colony stimulating factor (G-CSF) and engraftment kinetics in Allo-PBSCT. Sixteen patients (aged 6-61 yr, median 34 yr) received allogeneic peripheral blood stem cells from related donors (aged 15-68 yr, median 37 yr) after myeloablative therapy. Nine of the patients had standard-risk disease and 7 had high-risk disease. The donors received G-CSF at a dose of 10 micrograms/kg/day by subcutaneous injection for 4 to 6 days. Peripheral blood stem cells were subsequently collected in 1 to 3 aphereses and infused immediately. All patients received G-CSF after transplantation. Fifteen patients underwent Allo-PBSCT and one underwent Allo-PBSCT plus BMT. The mean number of CD34+ cells infused in the 15 Allo-PBSCT patients was 6.32 x 10(6)/kg (range 1.28-14.20). The outcomes were compared with 9 identically treated patients who underwent Allo-BMT. The median times until engraftment for neutrophils > 500/microliter and platelets > 20,000/microliter were 14 (range 10-17) and 15 (range 11-50) days in the Allo-PBSCT group and 17 (range 13-29) and 20 (range 16-160) days in the Allo-BMT group, respectively (p = 0.0177 and p = 0.003). Three donors were considered to have poor mobilization (< 2 x 10(6) CD34+ cells/kg of the recipient); two of them yielded 1.28 and 1.78 x 10(6) CD34+ cells/kg in 3 apheresis procedures. The patients who received cells from these donors showed prompt neutrophil engraftment, but one showed delayed platelet engraftment and another died of grade IV acute GVHD before reaching 20,000 platelets/microliter. An additional bone marrow harvest was necessary from one donor because of poor mobilization(0.17 x 10(6) CD34+ cells/kg). Thus, Allo-PBSCT results in more rapid engraftment. It will be necessary to clarify the minimum CD34+ cell dose for complete engraftment in a larger series of trials.     

非清髓异基因外周血造血干细胞移植治疗慢性粒细胞白血病

目的：探索非清髓异基因外周血干细胞移植(NST)治疗不能耐受清髓性异基因造血干细胞移植的慢性粒细胞白血病(CML)患者的疗效。方法：将5例CML患者中的4例以全身放疗加氟达拉宾，1例以马利兰、氟达拉宾加抗人胸腺细胞免疫球蛋白为预处理方案，联合环孢霉素A、霉酚酸酯和(或)短程氨甲蝶呤预防移植物抗宿主病。结果：5例均造血重建，3例完全供者型植入，2例混合型植入，其中1例植入率持续低于50％，经2次清髓性异基因造血干细胞移植后达到完全供者型植入。2例发生Ⅰ度急性移植物抗宿主病，1例发生Ⅳ度急性移植物抗宿主病，无慢性移植物抗宿主病发生。中位随访时间5(3～37)个月，无病生存3例，死亡2例。结论：对不能耐受清髓性异基因造血干细胞移植的CML患者，NST是可行而有效的。