Comparison between antithymocyte globulin and alemtuzumab and the possible impact of KIR-ligand mismatch after dose-reduced conditioning and unrelated stem cell transplantation in patients with multiple myeloma

We compared antithymocyte globulin (ATG) with alemtuzumab in 73 patients with multiple myeloma, who underwent reduced conditioning with melphalan/fludarabine, followed by allogeneic stem cell transplantation from human leucocyte antigen-matched or -mismatched unrelated donors. The ATG group had more prior high-dose chemotherapies (P < 0.001), while bone marrow was used more as the stem cell source in the alemtuzumab group (P < 0.001). Alemtuzumab resulted in faster engraftment of leucocytes (P = 0.03) and platelets (P = 0.02) and in a lower incidence of acute graft versus host disease (GvHD) grades II-IV (24% vs. 47%, P = 0.06). More cytomegalovirus (CMV) seropositive patients in the alemtuzumab group experienced CMV reactivation (100% vs. 47%, P = 0.001). The cumulative incidence of treatment-related mortality at 2 years was 26% [95% confidence interval (CI) = 12-37%] for ATG vs. 28% (95% CI = 15-55%) for alemtuzumab, P = 0.7. There was no significant difference in the estimated 2-year overall and progression-free survival between ATG and alemtuzumab: 54% (95% CI: 39-75%) vs. 45% (95% CI: 28-73%) and 30% (95% CI: 16-55%) vs. 36% (95% CI: 20-62%) respectively. In multivariate analysis, treatment with alemtuzumab had a higher risk for relapse (hazard ratio: 2.37; P = 0.05) while killer immunoglobulin-like receptor (KIR)-ligand mismatch was protective for relapse (P < 0.0001). We conclude that alemtuzumab produced less acute GvHD, but higher probability of relapse. The data implicated a major role of KIR-ligand mismatched transplantation in multiple myeloma.     

Early matched sibling hematopoietic cell transplantation for adult AML in first remission using an age-adapted strategy: long-term results of a prospective GOELAMS study

The LAM2001 phase 3 trial, involving 832 patients with acute myeloid leukemia (AML; median: 46 years) proposed HLA-identical sibling allograft HSCT for all patients with an identified donor. The trial compared reduced-intensity conditioning (RIC) for patients older than 50 years of age (N = 47) and myeloablative conditioning for younger patients (N = 117). BM HSCT was performed in the younger patients, while the older ones received a consolidation course, followed by peripheral blood allo-HSCT using RIC. The incidence of grade II-IV acute GVHD, was 51.9% (95% confidence interval [CI]: 42.1-61.8) and 11.3% (1.6-21.2) after myeloablative or RIC, respectively (P < .0001) and that of chronic GVHD 45.8% (95% CI: 34.8-56.7) and 41.7% (24.7-58.6; NS). Cumulative incidence of nonrelapse mortality at 108 months was 15.8% (95% CI: 9.8-23.2) for myeloablative, and 6.5% (0.2-16.2) for RIC (NS). CI of relapse at 108 months was 21.7% (95% CI: 13.9-28.6) and 28.6% (16.5-43.4; NS). Overall survival at 108 months was 63.4% (95% CI: 54.6-72.2) and 65.8% (52.2-72.2), respectively, after myeloablative or RIC (NS). RIC peripheral blood stem cell allo-HSCT is prospectively feasible for patients between the ages of 51 and 60 years without excess of relapse or nonrelapse mortality, and compares favorably with myeloablative marrow allo-HSCT proposed to younger patients.     

A fludarabine-based dose-reduced conditioning regimen followed by allogeneic stem cell transplantation from related or unrelated donors in patients with myelodysplastic syndrome.

We investigated the feasibility and efficacy of a fludarabine-based dose-reduced conditioning regimen followed by stem cell transplantation from related (n = 5) or unrelated HLA-matched donors (n = 7) in 12 patients with high risk MDS, who were not eligible for a standard myeloablative conditioning regimen. The conditioning regimen consisted of fludarabine 30 mg/m(2) daily for 6 days, busulfan 4 mg/kg daily for 2 days and anti-thymocyte globulin (ATG, rabbit) 10 mg/kg daily for 4 days in 11 patients, while one patient received fludarabine, ATG, cyclophosphamide and thiotepa. Graft-versus-host disease prophylaxis consisted of cyclosporine and a short course of methotrexate. The median age of the patients was 53 years (range 37-59). The median percentage of blasts in bone marrow aspirate at transplantation was 15% (range <5% to 35%). Diagnosis at transplant was RA (n = 1), RAEB (n = 5), RAEB-T (n = 5) and sAML (n = 1). A complex karyotype including monosomy 7 was noted in five patients. The reasons for using a dose-reduced conditioning regimen were prior autologous/syngeneic BMT (n = 4), active fungal infection (n = 2) or age/reduced performance status (n = 6). Engraftment was observed in all patients with complete donor chimerism. The incidence of acute GVHD (grade II-IV) was 33%. Eight patients died during follow-up due to relapse (n = 4), liver toxicity (n = 2), aspergillus (n = 1) or aGVHD grade IV (n = 1). After a median follow-up of 19 months, the 2-year estimated disease-free survival is 12% (95% CI: 2-23%) and the overall survival is 26% (95% CI: 4-52%). Fludarabine dose-reduced conditioning prior to allogeneic stem cell transplantation in high risk MDS patients, who were not eligible for standard transplantation, resulted in stable engraftment with complete chimerism, but the toxicity and relapse rate were considerable.     

Feasibility of conditioning with thymoglobulin and reduced intensity TBI to reduce acute GVHD in recipients of allogeneic SCT

Murine studies using anti-T-cell antibodies for conditioning in allogeneic SCT demonstrate engraftment with low rates of GVHD. On the basis of this preclinical model, we conditioned 30 patients with advanced hematologic malignancies with rabbit antithymocyte globulin (ATG) and TBI, to reduce rates of fatal acute GVHD. Patients were enrolled in two sequential groups: cohort 1 received ATG 10 mg/kg in divided doses (days -4 to -1)+200 cGy TBI (n=16), and cohort 2 received ATG (days -10 to -7)+450 cGy TBI (n=14). Median donor blood chimerism for the combined group was 94, 93 and 93% in the first, second and third months after transplant. Only three developed grade II acute GVHD despite 43% of patients receiving unrelated donor transplants. One-year survival was 71+/-11 and 54+/-14%, respectively, in recipients of related and unrelated donor SCT. Donor lymphocyte infusions were needed in 12 patients for the management of relapse and for mixed donor-recipient chimerism in 4 patients. We conclude that 10 mg/kg ATG and TBI allows engraftment with a low risk of acute GVHD; however, further dose optimization of ATG is required to achieve a balance between GVHD and disease relapse.     

Graft-versus-host disease following allogeneic transplantation from HLA-identical sibling with antithymocyte globulin-based reduced-intensity preparative regimen

Reduced-intensity conditioning (RIC) regimens are increasingly used for allogeneic stem cell transplantation (allo-SCT). RIC has been shown to allow engraftment with minimal early transplantation-related mortality (TRM). However, in the context of RIC, predictive factors for acute and chronic graft-versus-host disease (aGVHD and cGVHD, respectively) and their effect on outcome remain unknown. In this report, we analyzed the outcome of 101 high-risk patients (70 hematologic and 31 nonhematologic malignancies) who received an HLA-identical sibling allo-SCT after RIC, including fludarabine, busulfan, and antithymocyte globulin (ATG). The cumulative incidence of grade II-IV aGVHD was 36% (95% confidence interval [CI], 27%-45%), whereas the cumulative incidence of cGVHD at 2 years was 43% (95% CI, 33%-53%). In multivariate analysis, the incidence of aGVHD was significantly associated with the ATG dose infused during conditioning (P =.0005), whereas peripheral blood as stem cell source was the only predictive factor for the development of cGVHD (P =.0007). The 1-year cumulative incidences of disease progression or relapse in patients with (n = 69) and without (n = 31) GVHD (whatever its form or grade) were 30% (95% CI, 19%-41%) and 55% (95% CI, 37%-72%), respectively (P =.02), suggesting that a potent graft-versus-tumor (GVT) effect can be achieved in high-risk patients following RIC. Moreover, the GVT effect was closely associated with GVHD without an increased risk of TRM (cumulative incidence of TRM, 18% [95% CI, 10%-25%]). Collectively, these results provide a framework for the refinement of RIC approaches designed to enhance the GVT effect with an acceptable risk of GVHD.     

Hematopoietic stem cell transplantation for childhood myeloid malignancies after high-dose thiotepa, busulfan and cyclophosphamide

Seventeen children with advanced myeloid malignancies (induction failure, relapse, myelodysplasia, secondary AML, or CR >1) received thiotepa 750 mg/m2 i.v., busulfan 12 mg/kg or 640 mg/m2 p.o., and cyclophosphamide 120 mg/kg i.v. as a preparative regimen for allogeneic or autologous hematopoietic stem cell (HSC) transplantation. Of the 15 allogeneic transplants, eight were from matched siblings, one was from a mismatched sibling, and six were from unrelated donors. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine or tacrolimus and methotrexate. Regimen-related toxicity was common but tolerable, affecting mainly the skin and gastrointestinal tract. Three patients died early and were not evaluable for engraftment; engraftment occurred in the remaining patients. Nine patients with active disease at the time of transplant were evaluable for response; all achieved remission. With a median follow-up of 40 months (range, 10-71 months), nine patients are alive and disease-free. The 3-year actuarial event-free survival was 51% (95% confidence interval (CI) 27-76%). Seven patients died of transplant-related complications: infection (n = 4), chronic GVHD (n = 1), veno-occlusive disease, VOD, (n= 1) and pulmonary alveolar hemorrhage (n = 1). Only one patient had leukemia relapse and died. We conclude that the use of high-dose thiotepa, busulfan and cyclophosphamide is an effective conditioning regimen for childhood myeloid malignancies and may be tested in patients with less advanced disease (eg CR1).     

Unrelated stem cell transplantation in multiple myeloma after a reduced-intensity conditioning with pretransplantation antithymocyte globulin is highly effective with low transplantation-related mortality

We investigated the feasibility of unrelated stem cell transplantation in 21 patients with advanced stage II/III multiple myeloma after a reduced-intensity conditioning regimen consisting of fludarabine (150 mg/m(2)), melphalan (100-140 mg/m(2)), and antithymocyte globulin (ATG; 10 mg/kg on 3 days). The median patient age was 50 years (range, 32-61 years). All patients had received at least one prior autologous transplantation, in 9 cases as part of an autologous-allogeneic tandem protocol. No graft failure was observed. At day 40 complete donor chimerism was detected in all patients. Grade II to IV acute graft-versus-host disease (GVHD) was seen in 8 patients (38%), and severe grade III/IV GVHD was observed in 4 patients (19%). Six patients (37%) developed chronic GVHD, but only 2 patients (12%) experienced extensive chronic GVHD. The estimated probability of nonrelapse mortality at day 100 was 10% and at 1 year was 26%. After allografting, 40% of the patients achieved a complete remission, and 50% achieved a partial remission, resulting in an overall response rate of 90%. After a median follow-up of 13 months, the 2-year estimated overall and progression-free survival rates are 74% (95% CI, 54%-94%) and 53% (95% CI, 29%-87%), respectively. A shorter progression-free survival was seen in patients who already experienced relapse to prior autograft (26% versus 86%, P =.04). Dose-reduced conditioning with pretransplantation ATG followed by unrelated stem cell transplantation provides durable engraftment and donor chimerism, reduces substantially the risk of transplant-related organ toxicity, and induces high remission rates.     

Effect on cytokine release and graft-versus-host disease of different anti-T cell antibodies during conditioning for unrelated haematopoietic stem cell transplantation.

Three different types of anti-T cell antibody were used in patients undergoing haematopoietic stem cell transplantation (HSCT) with an HLA-A, -B and -DR compatible unrelated donor: ATG-Fresenius (ATG-F) (n = 26), Thymoglobuline (TMG) (n = 61) and OKT-3 (n = 45). The groups were comparable regarding diagnosis, stage, age, conditioning and GVHD prophylaxis, Adverse events were less frequent after ATG-F treatment. Levels of IL-2, IL-6, IFN-gamma, TNF-alpha and GM-CSF were increased after OKT-3 infusion. In multivariate analysis OKT-3 treatment (P = 0.01), G-CSF treatment (P = 0.02) and a cell dose >/=2.7 x 108/kg (P = 0.03) gave a faster engraftment. Acute GVHD grades II-IV occurred in 25% of the ATG-F patients, 12% of the TMG-patients and 43% (P < 0.001 vs TMG) of the OKT-3 patients. OKT-3 was associated with acute GVHD in multivariate analysis. TRM was 26% using TMG as compared to 43% in the OKT-3 group (P = 0.03). Patient survival at 4 years was 63%, 50% and 45% in the ATG-F, TMG and OKT-3-treated patients, respectively (NS). Relapses were 8%, 49% and 34%, respectively (ATG-F vs TMG, P = 0.03). Relapse-free survivals were 61%, 40% and 37% (NS). Among CML patients the probability of relapse was 61% in TMG-treated patients, while no patients relapsed in the other two groups. To conclude, the type of anti-T cell antibody affects GVHD and relapse after HSCT using unrelated donors.     

非血缘关系骨髓及外周造血干细胞移植的比较

目的比较非血缘关系骨髓(UBMT)及外周造血干细胞移植(UPBSCT)在移植疗效方面的差异。方法63例患者分为UBMT组30例,UPBSCT组33例。两组均采用本所的加强方案预防移植物抗宿主病(GVHD)的发生。所有患者在预处理阶段都应用了抗T细胞免疫球蛋白(ATG)或CD_3单抗,但UPBSCT组以兔源性的ATG为主(21/33),而UBMT组以猪源性的ATG为主(17/25,P=0.02)。结果UBMT和UPBSCT组分别有28/30例和32/33例患者达到完全稳定的供者植入,UBMT组输入单个核细胞中位数(2.80×10~8/kg)少于UPBSCT组(6.16×10~8/kg,P＜0.05),WBC和PLT的中位植活时间长于UPBSCT组(17d比11d;27.5d比14d,P＜0.01)。两组≥Ⅱ度急性GVHD的累积发生率分别为66.7%和33.0%;其中Ⅲ-Ⅳ度为34.5%和7.3%(P＜0.05)。在对两组ATG的来源进行分层分析后发现急性GVHD的发生率没有统计差异。两组慢性GVHD的发生率分别为63.6%(14/22)、72.0%(18/25),其中广泛型分别为7例和5例,差异无统计学意义(P＞0.05)。UBMT和UPBSCT组巨细胞病毒(CMV)血症和CMV疾病的发生率分别为60.0%％(18/30)、43.3%(13/30);60.6%(20/33)、15.1%(5/33)。截至2005年6月,UBMT复发4例,死亡15例,总体生存率(OS)为47.22%,UPBSCT组复发6例,死亡8例,OS为62.45%。1年的总生存率分别为53.13%、78.06%(P=0.05),总的移植相关病死率分别为51.52%、19.68%(P=0.06)。结论UPBSCT同骨髓移植相比,造血重建快,并不增加急性GVHD的发生,两组生存率相近。     

Evidence for a graft-versus-leukemia effect after allogeneic peripheral blood stem cell transplantation with reduced-intensity conditioning in acute myelogenous leukemia and myelodysplastic syndromes

We report the results of a prospective study of a reduced-intensity conditioning (RIC) regimen followed by allogeneic peripheral blood stem cell transplantation (PBSCT) from an HLA-identical sibling in 37 patients with acute myeloid leukemia (AML; n = 17) or myelodysplastic syndrome (MDS; n = 20). The median age was 57 years, and 22 (59%) were beyond the early phase of their disease. The incidence of grade II to IV acute graft-versus-host disease (GVHD) was 19% (5% grade III-IV), and the 1-year incidence of chronic extensive GVHD was 46%. With a median follow-up of 297 days (355 days in 24 survivors), the 1-year probability of transplant-related mortality was 5%, and the 1-year progression-free survival was 66%. The 1-year incidence of disease progression in patients with and without GVHD was 13% (95% CI, 4%-34%) and 58% (95% CI, 36%-96%), respectively (P =.008). These results suggest that a graft-versus-leukemia effect plays a crucial role in reducing the risk of relapse after a RIC allograft in AML and MDS.     

Does donor-recipient ABO incompatibility protect against relapse after allogeneic bone marrow transplantation in first remission acute myeloid leukemia?

It is not known if donor-recipient ABO blood group incompatibility contributes to graft-versus-leukemia after allogeneic BMT. One hundred and nineteen patients with acute myeloid leukemia in first remission underwent non-T cell-depleted marrow allografts from HLA-identical siblings after TBI and cyclophosphamide (n = 72) or melphalan (n = 47). GVHD prophylaxis comprised cyclosporine alone or cyclosporine-methotrexate. Twenty-two patients relapsed at 3-46 months (median 7): 18 of 76 patients with ABO-matched donors and four of 43 patients with ABO-mismatched donors (actuarial 5-year probabilities 33 +/- 6% vs 12 +/- 6%; P = 0.028). The incidence of acute and chronic GVHD was not affected by ABO mismatch. The following factors were studied in Cox analysis for effect on outcome: gender, age, FAB subtype, ABO mismatch, CR-transplant interval, conditioning, TBI dose, nucleated cell dose, lymphocyte recovery, acute GVHD, and chronic GVHD. Donor-recipient ABO match was the only factor independently associated with a higher risk of relapse (RR = 3.7; 95% Cl, 1.1-12.6; P = 0.04). ABO mismatch was also associated with superior overall and disease-free survivals. We conclude that ABO incompatibility may influence relapse rates and survival favorably after allogeneic BMT. It is not known if this holds true for allogeneic blood stem cell transplants.     

马利兰和氟达拉滨与马利兰和环磷酰胺预处理方案在急性髓性白血病异基因造血干细胞移植中的比较

 目的 比较马利兰（Bu）和氟达拉滨（Flu）组成的预处理方案（Bu/Flu）与Bu和环磷酰胺（Cy）组成的预处理方案（Bu/Cy）在急性髓性白血病第一次完全缓解（AML-CR1）患者异基因造血干细胞移植（allo-HSCT）中的移植相关毒性和疗效的差异。方法 32例接受allo-HSCT的AML-CR1患者按移植顺序交替分至Bu/Cy组（Bu 3.2 mg·kg^-1·d^-1,移植前第7~4天;Cy 60 mg·kg^-1·d^-1,移植前第3~2天）或Bu/Flu组（Bu 3.2 mg·kg^-1·d^-1,移植前第5～2天;Flu 30 mg·m^-2·d^-1,移植前第6～2天）。评价两组预处理相关毒性（RRT）、移植物抗宿主病（GVHD）发生率与严重程度、3年累积复发率、非复发死亡率（NRM）、3年无病生存（EFS）率和总生存（OS）率等方面的差异。结果 中位随访时间为617.5（6~1261）d。两组中性粒细胞和血小板中位重建时间无明显差异（P=0.121和P=0.171）,移植后30 d嵌合状态分析提示两组患者均达到完全植入。Bu/Cy组预处理后中性粒细胞持续<0.1×10⁹/L和血小板持续﹤20×10⁹/L中位时间明显长于Bu/Flu组［6（3~14）d比2.5（1~9）d,P=0.000;3（1~36）d比1（0~4）d,P=0.047］。Bu/Cy组与Bu/Flu组Ⅱ～Ⅳ度RRT发生率分别为68.8%和25.0%（P=0.032）;急性GVHD发生率分别为46.7%和75.0%（P=0.149）,慢性GVHD发生率分别为46.7%和80.0%（P=0.149）;NRM分别为25.0%和6.3%（P=0.333）;3年累积复发率分别为（17.9±11.7）%和（14.1±9.3）%（P=0.834）;3年EFS率分别为（65.5±12.7）%和（80.2±10.3）%（P=0.362）;3年OS率分别为（68.8±11.6）%和（87.5±8.3）%（P=0.111）。结论 Bu/Flu是一种清髓性预处理方案,与Bu/Cy方案比较具有低骨髓抑制毒性及RRT。Bu/Flu作为AML-CR1患者allo-HSCT预处理方案其疗效不低于Bu/Cy。     

Consequences of ABO incompatibility in allogeneic hematopoietic stem cell transplantation

Aside from causing hemolytic reactions the ABO blood group system does not have an impact on outcome after allogeneic bone marrow or peripheral blood stem cell transplantation (SCT). However, only a few studies have addressed the effect of ABO incompatibility on the incidence of GVHD, time to engraftment, relapse and survival. Therefore, we performed a retrospective two-center analysis of 562 consecutive patients receiving allogeneic SCT, including 361 ABO-identical, 98 minor, 86 major and 17 bidirectional ABO-incompatible SCT. In multivariate analysis adjusted for potential confounders survival was significantly associated with ABO incompatibility (P = 0.006). Compared to ABO-identical SCT, bidirectional ABO incompatibility increased the risk significantly (RR, 2.8; 95% CI, 1.5-5.1; P = 0.0009), whereas survival of patients with minor (RR, 1.2; 95% CI, 0.9-1.7; P = 0.27), or major ABO-incompatible SCT (RR, 1.3; 95% CI, 0.9-1.8; P= 0.18) was not significantly different. RBC engraftment was delayed in major ABO-incompatible SCT (RR, 0.66; 95% CI, 0.51-0.85; P = 0.001). The incidence of acute GVHD (grade I-IV) was higher in minor ABO-incompatible SCT as compared to ABO identity (RR, 2.8; 95% CI, 1.3-5.9, P = 0.009). This difference was limited to mild GVHD; in moderate-to-severe GVHD (grade II-IV) no significant difference was found among the groups (P = 0.53). The relapse rate was not influenced by ABO incompatibility (P = 0.78). In conclusion, these results suggest that ABO incompatibility represents a risk factor not only for post-transplant hemolysis, but also for survival and the rate of mild GVHD after allogeneic SCT.     

Impact of immune modulation with in vivo T-cell depletion and myleoablative total body irradiation conditioning on outcomes after unrelated donor transplantation for childhood acute lymphoblastic leukemia

To determine whether in vivo T-cell depletion, which lowers GVHD, abrogates the antileukemic benefits of myeloablative total body irradiation-based conditioning and unrelated donor transplantation, in the present study, we analyzed 715 children with acute lymphoblastic leukemia. Patients were grouped for analysis according to whether conditioning included antithymocyte globulin (ATG; n = 191) or alemtuzumab (n = 132) and no in vivo T-cell depletion (n = 392). The median follow-up time was 3.5 years for the ATG group and 5 years for the alemtuzumab and T cell-replete groups. Using Cox regression analysis, we compared transplantation outcomes between groups. Compared with no T-cell depletion, grade 2-4 acute and chronic GVHD rates were significantly lower after in vivo T-cell depletion with ATG (relative risk [RR] = 0.66; P = .005 and RR = 0.55; P < .0001, respectively) or alemtuzumab (RR = 0.09; P < .003 and RR = 0.21; P < .0001, respectively). Despite lower GVHD rates after in vivo T-cell depletion, nonrelapse mortality, relapse, overall survival, and leukemia-free survival (LFS) did not differ significantly among the treatment groups. The 3-year probabilities of LFS after ATG-containing, alemtuzumab-containing, and T cell-replete transplantations were 43%, 49%, and 46%, respectively. These data suggest that in vivo T-cell depletion lowers GVHD without compromising LFS among children with acute lymphoblastic leukemia who are undergoing unrelated donor transplantation with myeloablative total body irradiation-based regimens.     

Lineage-specific engraftment and outcomes after T-cell-depleted peripheral blood stem cell transplant with Flu/Cy/TBI conditioning

Sixty patients with haematological malignancies received a myeloablative regimen of total body irradiation, cyclophosphamide and fludarabine followed by a T-cell-depleted peripheral blood stem cell transplant from a human leucocyte antigen identical sibling. To improve donor immune function, 1 x 10(7) CD3+ cells/kg were added-back between d 45 and 100. T-cell and myeloid chimaerism were monitored regularly to evaluate the effect of T-cell chimaerism on outcome. The major factor affecting outcome was disease risk, with significantly lower relapse and higher survival in 29 standard risk (SR) patients compared with 31 patients at high risk (HR) for treatment failure (relapse 4.8 +/- 5% vs. 59 +/- 11%, P < 0.0001, and overall survival 93 +/- 5% vs. 39 +/- 10%, P < 0.0001, respectively). Donor myeloid chimaerism reached > or = 95% within 14 d of transplant, but in the first several months, donor T-cell chimaerism was frequently mixed. Full T-cell chimaerism was significantly more frequent in HR vs. SR patients. Landmark analysis at days 30 and 90 in HR patients with mixed versus full T-cell chimaerism, showed relapse probabilities of 50.5 +/- 14% vs. 70 +/- 16% (P = 0.62) and 34.4 +/- 20% vs. 58.8 +/- 15% (P = 0.32) respectively. Early full T-cell engraftment correlated with development of severe acute graft-versus-host disease (GVHD). However, mixed T-cell chimaerism was favourable for reducing GVHD, and did not affect relapse in this small series.     

The Beneficial Effect of Chronic Graft-versus-Host Disease on the Clinical Outcome of Transplantation with Fludarabine/Busulfan-Based Reduced-Intensity Conditioning for Patients with De Novo Myelodysplastic Syndrome

Allogeneic hematopoietic stem cell transplantation following reduced-intensity stem cell transplantation (RIST) has enabled the treatment of older or medically infirm patients with myeloid malignancies; however, determining the value of RIST outcomes for myelodysplastic syndrome (MDS) is difficult because of the heterogeneity of the diseases included in most trials. To define the role of RIST in MDS, we performed RIST for 22 consecutive patients who had de novo MDS as classified by World Health Organization (WHO) criteria and who received an allograft with fludarabine/busulfan (Busulfex) or fludarabine/Busulfex/antithymocyte globulin (ATG) conditioning. Nineteen patients (86.4%) achieved engraftment. At a median follow-up of 18.9 months (range, 13.1-24.8 months), the estimated 2-year rates of overall survival, event-free survival (EFS), transplantation-related mortality, and relapse were 78.7%, 67.7%, 12.6%, and 22.5%, respectively. Acute graft-versus-host disease (GVHD) greater than grade II developed in 3 patients (15.8%). Chronic GVHD developed in 10 patients (55.6%), none of whom received ATG as a conditioning regimen. Variables influencing EFS were chronic GVHD, marrow blasts before transplantation, and the WHO criteria. The present study clarifies the benefits of the fludarabine/Busulfex-based conditioning regimen for de novo MDS diagnosed according to the WHO criteria and shows that chronic GVHD appears to have a beneficial effect on survival rates, which are strongly associated with graft-versus-tumor effects.     

Reduced intensity compared with high dose conditioning for allotransplantation in acute myeloid leukemia and myelodysplastic syndrome: a comparative clinical analysis

We evaluated the efficacy of hematopoietic stem cell transplantation (HSCT) using reduced intensity (RI) vs. myeloablative (MA) conditioning for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome. Thirty two patients (median age 54) who underwent a RI HSCT (2000-2003) were compared with 187 patients (median age 39) who received a MA transplant (1990-2003). Neutrophil engraftment was more rapid in the RI group (median 11.5 vs. 21 days). Platelet recovery was similar and graft failure was infrequent. The incidence of graft-versus-host disease (GVHD) and treatment-related mortality was similar though relapse was more frequent after RI conditioning (RR 2.2 [95% CI = 1.1-4.6] P = 0.03). At 2 years, disease-free survival (DFS) (31% vs. 30%, P > 0.1) and overall survival (33% vs. 35%, P > 0.1) were comparable between RI and MA groups, respectively. We suggest that RI allografts can yield satisfactory DFS both for older as well as younger patients with pre-existing comorbidities, who are ineligible for MA allografts. Advances in GVHD management and new approaches for relapsed or refractory disease are necessary to improve these outcomes.     

Retrospective comparison of CD34-selected allogeneic peripheral blood stem cell transplantation followed by CD8-depleted donor lymphocyte infusions with unmanipulated bone marrow transplantation

We have previously reported the feasibility of allogeneic CD34-selected PBSC transplantation followed by pre-emptive CD8-depleted DLI (study group). In this report, we retrospectively compare the clinical outcome of the 24 patients included in this study with an historical group of 35 patients receiving unmanipulated marrow (BMT group). Patients in the study group had significantly faster neutrophil and platelet recovery and were discharged earlier than BMT patients. The actuarial 150-day (after DLI) probability of developing grade II-IV acute GVHD was 28% for the study group versus 62% for the BMT group (p=0.002). The actuarial 2-year probability of developing chronic GVHD was similar (37 versus 36% (NS)) but chronic GVHD was significantly delayed in the study group (p=0.003). The actuarial 2-year probability of relapse was 30% in the study group versus 33% in the BMT group (NS). The actuarial 2-year probability of survival was 45% in the study group versus 43% in the BMT group (NS). We conclude that allogeneic transplantation of CD34-selected PBSC followed by pre-emptive CD8-depleted DLI is feasible with rapid engraftment and minimizes the risk of severe GVHD. Large prospective trials are required to confirm these results.     

Graft versus host disease prophylaxis with low-dose cyclosporine-A reduces the risk of relapse in children with acute leukemia given HLA-identical sibling bone marrow transplantation: results of a randomized trial

Leukemia relapse is a major cause of treatment failure for patients with acute leukemia given allogeneic bone marrow transplantation (BMT). This study evaluated whether a reduction of the dosage of cyclosporine-A (Cs-A) used for graft versus host disease (GVHD) prophylaxis could reduce relapse rate (RR) in children with acute leukemia given BMT. Fifty-nine children who had transplantation from HLA-identical siblings were randomized to receive Cs-A intravenously at a dosage of 1 mg/kg/d (Cs-A1) or of 3 mg/kg/d (Cs-A3) until patients were able to tolerate oral intake. Subsequently, both groups received Cs-A orally at a dosage of 6 mg/kg/d, with discontinuation 5 months after BMT. The probability of developing grade II-IV acute GVHD was 57% for the Cs-A1 group versus 38% for the Cs-A3 group (P =.06); the probability of developing chronic GVHD was 30% for the Cs-A1 group and 26% for the Cs-A3 group (P = NS). Three patients died of grade IV acute GVHD: 2 were in the Cs-A1 and the third in the Cs-A3 group. The RR was 15% for the Cs-A1 group and 41% for the Cs-A3 group (P =.034); 1-year transplant-related mortality estimates were 17% and 7%, respectively (P = NS). With a median observation time of 44 months from BMT, the 5-year event-free survival for children belonging to Cs-A1 and Cs-A3 groups was 70% and 51%, respectively (P =.15). Our data demonstrate that the use of low Cs-A doses is associated with a statistically significant reduction of leukemia relapse, probably due to an increased graft versus leukemia effect. (Blood. 2000;95:1572-1579)     

Bone marrow as stem cell source for allogeneic HLA-identical sibling transplantation following reduced-intensity preparative regimen

OBJECTIVE: Reduced-intensity conditioning regimens (RIC) and peripheral blood stem cells (PBSC) are increasingly used for allogeneic stem cell transplantation (allo-BMT). RIC has been shown to allow engraftment with minimal early transplant-related mortality (TRM). However, in the context of RIC, the use of bone marrow (BM) as stem cell source is still little evaluated. PATIENTS AND METHODS: In this report, we analyzed the outcome of 32 high-risk patients with hematological malignancies who received an HLA-identical sibling allo-BMT after RIC including fludarabine, busulfan, and anti-thymocyte globulin (ATG). RESULTS: Sustained neutrophil and platelet recovery occurred at a median of 13 days (range, 10-19) and 17 days (range, 0-45) respectively. Early and durable full donor chimerism could be established as soon as the first month after allo-BMT. Also, a sustained and early CD8(+) T-cell recovery was observed, but the CD4(+) T-cell compartment remained profoundly low. The cumulative incidences of grade II-IV acute GVHD and chronic GVHD were 26% (95% CI, 11-41%) and 31% (95% CI, 15-47%) respectively. The overall cumulative incidence of TRM was 28% (95% CI, 12-44%) occurring mainly in patients aged over 50. In this setting, GVHD showed a protective effect on disease progression or relapse with better progression-free survival for patients with GVHD as compared to patients without GVHD (p=0.03). CONCLUSIONS: Collectively, these results confirm that the use of BM grafts for RIC is feasible with durable donor engraftment and no detrimental GVHD.