Fludarabine with cytarabine followed by reduced-intensity conditioning and allogeneic hematopoietic stem cell transplantation in patients with poor-risk chronic lymphocytic leukemia

Allogeneic stem cell transplantation (SCT) is a treatment option for patients with poor-risk chronic lymphocytic leukemia (CLL). Sequential use of chemotherapy and reduced-intensity conditioning has been proposed to improve the treatment outcomes. Fludarabine (30 mg/m²/day) and cytarabine (2 g/m²/day) for 4 days (combination of fludarabine with cytarabine; FAraC) were used for cytoreduction. After 3 days of rest, reduced intensity conditioning (RIC) was carried out consisting of 4 Gy total body irradiation, 10–20 mg/kg/day antithymocyte globulin for 3 days, and 40–60 mg/kg/day cyclophosphamide for 2 days. The median time of neutrophil engraftment was 16 days. The most frequent toxicities were grades III/IV infections in 12 of 15 cases and gastrointestinal toxicities in 8 of 15 cases. Remission (complete remission?+?partial remission) was achieved in 14 of 15 patients (93 %), minimal residual disease negativity according to flowcytometric analysis was observed in 10 patients. Nonrelapse mortality after 1 and 2 years was 7 and 13 %, respectively. After the median follow-up from SCT of 30 months, 80 % of patients were alive (12/15), three patients have died, and three relapses occurred. The FAraC–RIC protocol seems to be a promising approach to the treatment of poor-risk CLL with a high response rate of 93 % and favorable progression-free survival and overall survival of 70 and 85 % at 2 years after SCT, respectively. Other prospective clinical trials are needed to confirm the results of this novel therapeutic strategy.     

400 cGy TBI with fludarabine for reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation

Fludarabine and 200 cGy TBI are commonly used for reduced-intensity conditioning preceding allogeneic hematopoietic SCT (HSCT). However, graft rejection and disease relapse are significant causes of treatment failure with this regimen. We modified this regimen by escalating the TBI dose to 400 cGy in 40 patients with hematologic malignancies. Thirty-four patients achieved complete donor T-cell chimerism at a median of 40 days following HSCT. The incidences of grades II-IV and III-IV acute GVHD were 40 and 15%, respectively, whereas that of limited and extensive chronic GVHD were 12 and 20%, respectively. Two patients rejected their grafts and 12 relapsed. The 100-day mortality was 18%, 2-year transplant-related mortality 20% and overall survival was 58% at a median follow-up of 16 months. There were no significant survival differences between patients with lymphoid compared to myeloid malignancies. A dose of 400 cGy TBI administered with fludarabine is well tolerated and further study is needed to determine whether outcomes are superior to those with 200 cGy TBI.     

Role of reduced-intensity conditioning allogeneic hematopoietic cell transplantation in older patients with de novo acute myeloid leukemia

Reduced-intensity conditioning (RIC) regimens extend the therapeutic use of allogeneic hematopoietic cell transplantation (HCT) to older patients. The survival trend in 2325 patients aged >50 years presenting with de novo acute myeloid leukemia (AML) who underwent first reduced-intensity HCT (RIC-HCT) was assessed by retrospectively analyzing outcomes between 2000 and 2013. The annual number of RIC-HCTs in Japan was higher in the 2008–2013 period (n?=?205/year [1229/6 years]) than in the 2000–2007 period (n?=?137/year [1096/8 years]). Overall and disease-free survival were higher in the 2008–2013 period (P?<?0.001) because of the improvement in transplant-related mortality (TRM). Survival regarding RIC-HCT for AML has improved over time, with an increased number of RIC-HCTs in patients with a Karnofsky performance status (KPS) ≥80. However, TRM remains high and the relapse rate has not improved over time. Multivariate analyses showed that a KPS ≥80 and complete remission at HCT were associated with less TRM and relapse, and better survival regardless of age ≥65 years. Accurate timing and prospective identification of patients at risk of TRM may aid the development of risk-adapted strategies for RIC-HCT in AML patients regardless of age.     

Engraftment kinetics and hematopoietic chimerism after reduced-intensity conditioning with fludarabine and treosulfan before allogeneic stem cell transplantation

Reduced-intensity conditioning with fludarabine and treosulfan before allogeneic stem cell transplantation (SCT) was introduced several years ago. Although its feasibility has recently been proven, only limited data are available on myelotoxicity, engraftment kinetics, and the significance of hematopoietic chimerism using this novel conditioning regimen. To clarify these open questions, we analyzed 27 patients with various hematological diseases, who received allogeneic SCT preceded by fludarabine/treosulfan conditioning. Further assessment endpoints included graft-vs-host disease (GvHD), mortality, and overall survival (OS). Allogeneic SCT was followed by neutropenia (absolute neutrophil count ≤ 0.5 × 10⁹/l) and thrombocytopenia (platelets ≤ 20 × 10⁹/l) in all patients. All patients showed stable neutrophil engraftment, and all except one had stable platelet engraftment. Grades II–IV acute GvHD was found in 48% of patients, whereas 52% developed chronic GvHD. The treatment-related mortality on day +100, 1 year after SCT, and at the last follow-up was 11, 26, and 33%, respectively. We found complete chimerism rates of 46, 57, and 72% on days +28, +56, and at the last follow-up or before death, respectively. The underlying malignancy tended to relapse more frequently in patients with mixed chimerism than in those with complete chimerism on day +28 as well as on day +56 (not significant). Additionally, no significant association was found between hematopoietic chimerism and donor type, GvHD, or OS, respectively. We conclude that reduced-intensity conditioning with fludarabine and treosulfan before allogeneic SCT is myeloablative, provides stable engraftment, and leads to complete chimerism in the majority of patients. Part of the abstract has been presented at the annual meeting of DGHO 2006 (Leipzig, Germany).     

Long-term results of allogeneic hematopoietic stem cell transplantation after reduced-intensity conditioning with busulfan, fludarabine, and antithymocyte globulin

Reduced-intensity conditioning (RIC) is widely used for allogeneic stem cell transplantation (SCT). Here we present our long-term experience with RIC regimen consisting of fludarabine (30 mg/m2/day on days -10 to -5), busulfan (4mg/kg/day on days -6 and -5) and antithymocyte globulin (ATG Fresenius, 10 mg/kg/day on days -4 to -1) (Flu-Bu-ATG) in a cohort of 71 patients with various hematological malignancies including chronic myeloid leukemia (24 patients), acute myeloid leukemia (19 patients), lymphoma (20 patients), multiple myeloma (3 patients), myelodysplastic syndrome (3 patients), and myelofibrosis (2 patients). The median age was 50 years. The overall response rate was 87%, including 83% CR and 4% PR. The incidence of acute and chronic GVHD was 35% and 52% and the cumulative incidence of non-relapse mortality at 1 year and 4 years was 8% and 14%. With the median follow-up of 55.0 months, the 2- and 4-year event-free survival (EFS) was 49.0% and 40.3%, and the overall survival (OS) was 73.2% and 62.6%, respectively. Gender, age at SCT, type of donor, disease status at SCT, previous autologous transplantation, and complete chimerism by day +100 did not significantly influence EFS and OS. In a multivariate analysis, no presence of chronic GVHD (p=0.029, HR: 2.5),and diagnosis other than CML (p=0.018, HR: 4.6), and CD34+ dose < 5x106/kg (p=0.010, HR: 2.8) were significant predictors of poor OS. Flu-Bu-ATG protocol is a RIC regimen that combines effective disease control with low non-relapse mortality and acceptable toxicity profile. Keywords: reduced-intensity conditioning, fludarabine, busulfan, antithymocyte globulin.     

Outcome of reduced-intensity allogeneic hematopoietic stem cell transplantation (RISCT) using antilymphocyte antibodies in patients with high-risk acute myeloid leukemia (AML)

Hemopoietic stem cell transplantation (SCT) with fully ablative conditioning is associated with an age-related increase in treatment-related mortality. It is therefore particularly unsuited to older individuals, who are most at risk of developing acute myeloid leukemia (AML). Reduced-intensity SCT (RISCT) may be of value in this group. We report 17 consecutive patients with high-risk AML whose median age was 58 years and who received stem cells from HLA-matched siblings (n=5), or alternative donors (n=12). We used lymphodepleting antibodies as a part of the reduced-intensity conditioning regimen to limit the risk of graft rejection and graft-versus-host disease (GVHD). All patients engrafted. One patient developed severe fatal GVHD, and two patients died of infection. At a median follow-up of 861 days (372-1957 days), seven patients are alive in remission, which includes two patients treated in relapse and five patients who lacked an MHC identical sibling donor. Both progression-free survival and overall survival are 40% (95% CI, 17-64%). Hence, RISCT using lymphodepleting antibodies may be of value for older patients with AML, even in those with active or high-risk disease, and even if they lack an MHC-identical sibling donor.     

Allogeneic stem cell transplantation after a fludarabine/busulfan-based reduced-intensity conditioning in patients with myelodysplastic syndrome or secondary acute myeloid leukemia

We report the feasibility and efficacy of a fludarabine/busulfan-based dose-reduced conditioning regimen followed by stem cell transplantation from related ( n=19) or unrelated HLA-matched donors ( n=18) in 37 patients with myelodysplastic syndrome (MDS) or secondary acute myeloid leukemia (sAML) who were not eligible for a standard myeloablative conditioning regimen. The conditioning regimen consisted of fludarabine (120-180 mg/m(2)), busulfan (8 mg/kg p.o. or 6.4 mg/kg i.v.), and antithymocyte globulin ( n=25). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine ( n=36) and a short course of methotrexate ( n=29) or mycophenolate mofetil ( n=3). The median age of the patients was 55 years (range: 23-72). The reasons to perform a dose-reduced conditioning were reduced performance status ( n=14), age ( n=12), prior autologous ( n=5) or allogeneic ( n=1) transplantation, or prior/active fungal infection ( n=5). Diagnoses at transplantation were refractory anemia (RA) ( n=8), refractory anemia with excess of blasts (RAEB) ( n=6), RAEB in transformation (RAEB-T) ( n=13), chronic myelomonocytic leukemia (CMML) ( n=3), and sAML ( n=7). Stem cell sources were peripheral blood stem cells (PBSC) ( n=29) or bone marrow ( n=8). One patient received a T-cell-depleted peripheral stem cell graft. Two primary graft failures were observed (6%). Engraftment of leukocytes (>1.0x10(9)/l) and platelets (>20x10(9)/l) was seen after a median of 14 days. Acute GVHD grade II-IV was seen in 37%, while severe grade III/IV GVHD was observed in six patients (17%). Chronic GVHD was seen in 13 patients (48%). There were ten deaths (27%) due to treatment (TRM). The probability of TRM was higher in patients with unrelated donors (45 vs 12%, p=0.03) and in patients with poor cytogenetics in comparison to those with a low or intermediate karyotype (75 vs 20%, p=0.009). During follow-up 12 patients relapsed (32%). Patients without chronic GVHD had a significantly higher probability of relapse compared to those with chronic GVHD (70 vs 15%, p=0.02). After a median follow-up of 20 months, the 3-year estimated disease-free survival (DFS) is 38% [95% confidence interval (CI): 21-55%] and the overall survival (OS) is 39% (95% CI: 22-56%). The OS and DFS after related and unrelated transplantations was 45% (95% CI: 19-71%) vs 31% (95% CI: 9-53%) (n.s.) and 51% (95% CI: 29-73%) vs 25% (95% CI: 4-47%) (n.s.), respectively. We conclude that dose-reduced conditioning followed by allogeneic stem cell transplantation from related or unrelated donors is an effective treatment approach in patients with MDS/sAML and might cure a substantial number of patients who are not eligible for a standard allogeneic transplantation.     

Clinical research of high-risk and refractory acute myeloid leukemia with allogeneic hematopoietic stem cell transplantation therapy

目的 探讨异基因造血干细胞移植( allo- HSCT)治疗高危难治急性髓系白血病(AML)的疗效和移植时机.方法 选取allo-HSCT治疗的AML患者47例,其中高危AML 17例,难治AML20例,骨髓增生异常综合征(MDS)转AML10例.第1次完全缓解期(CR1 )23例,第2次完全缓解期(CR2)11例,未缓解进展期(NR)13例.接受同胞供者骨髓和(或)外周血干细胞移植16例,非血缘脐血移植31例.所有患者均采用清髓性预处理方案,环孢素联合霉酚酸酯预防移植物抗宿主病(GVHD).结果 47例患者46例(97.9％)获得植入,中性粒细胞绝对计数≥0.5×109/L和血小板≥20×109/L的中位时间分别为14.5(10 ～ 36)天和26(12-90)天.16例发生急性GVHD(34.8％),Ⅲ度以上4例.在可评估的39例患者中,10例出现慢性GVHD( 25.6％),复发6例(12.8％),移植相关死亡12例(25.5％),32例(68.1％)患者存活.高危难治AML患者CR1、CR2、NR期移植生存率分别为75.5％、72.7％和40.0％.MDS转AML患者CR和NR期移植生存率分别为0％和75.0％.结论 allo-HSCT有助于提高高危难治AML疗效,降低复发率,提高生存率,且最好在首次缓解期进行移植.对于MDS转AML患者可立即行allo-HSCT,无需等待化疗达完全缓解.     

Long-term follow-up of allogeneic hematopoietic stem-cell transplantation with reduced-intensity conditioning for patients with chronic myeloid leukemia

Allogeneic hematopoietic stem-cell transplantation (HSCT) remains an effective strategy for inducing durable remission in chronic myeloid leukemia (CML). Reduced-intensity conditioning (RIC) regimens extend HSCT to older patients and those with comorbidities who would otherwise not be suitable candidates for HSCT. The long-term efficacy of this approach is not established. We evaluated outcomes of 64 CML patients with advanced-phase disease (80% beyond first chronic phase), not eligible for myeloablative preparative regimens due to older age or comorbid conditions, who were treated with fludarabine-based RIC regimens. Donor type was matched related (n =30), 1 antigen-mismatched related (n =4), or matched unrelated (n =30). With median follow-up of 7 years, overall survival (OS) and progression-free survival (PFS) were 33% and 20%, respectively, at 5 years. Incidence of treatment-related mortality (TRM) was 33%, 39%, and 48% at 100 days, and 2 and 5 years after HSCT, respectively. In multivariate analysis, only disease stage at time of HSCT was significantly predictive for both OS and PFS. RIC HSCT provides adequate disease control in chronic-phase CML patients, but alternative treatment strategies need to be explored in patients with advanced disease. TRM rates are acceptable in this high-risk population but increase over time.     

Reduced-intensity conditioning followed by allogeneic hematopoietic cell transplantation in myeloid diseases

Within the past years, reduced or modified doses of chemotherapy or radiotherapy have been widely studied for conditioning before allogeneic hematopoietic cell transplantation in patients with myeloid leukemia not eligible for conventional transplantation. The main goal was to reduce the substantial treatment-related mortality in this patient population while preserving the potential curative graft-versus-leukemia effect. This review summarizes results of published trials using reduced-intensity conditioning (RIC) in patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myeloid leukemia (CML), and myelofibrosis. In most of the published trials conditioning contained fludarabine (90–180 mg/m²) in combination with busulfan (4×10 mg/kg), melphalan (90–140 mg/m²), or 2–5 Gy total body irradiation (TBI). Peripheral blood hematopoietic stem cells from related or unrelated donors were used as graft source in most of the studies. Post-transplantation immunosuppression consisted of cyclosporine combined with methotrexate or mycophenolate mofetil. Although the majority of the patients were above the age of 50 years, early treatment-related mortality was rather low. Nevertheless, the rate of clinically significant graft-versus-host disease (GVHD) seemed to be comparable to conventional transplants in most of the protocols. The outcome differed between trials, but diagnosis and disease status pre-transplant significantly influenced outcome. In summary, this approach is feasible and provides access to the curative potential of allogeneic stem cell transplantation for patients with higher age or comorbidities. Since the majority of the reports included heterogeneous patient populations, mostly with a short follow-up, more and specifically randomized studies are needed to define the role of RIC before allogeneic hematopoietic cell transplantation.     

Successful allogeneic hematopoietic stem cell transplantation with reduced-intensity conditioning for B-cell prolymphocytic leukemia in partial remission

B-cell prolymphocytic leukemia (B-PLL) is a rare, chemotherapy-resistant lymphoid neoplasm. Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) represents a potentially curative treatment for B-PLL, the number of B-PLL patients who have been treated with allo-HSCT is small and its efficacy has not been established. We report the case of a 59-year-old woman with B-PLL in partial remission, who was successfully treated with allo-HSCT following reduced-intensity conditioning (RIC). She was initially treated with four courses of combination chemotherapy consisting of rituximab, fludarabine, cyclophosphamide, and mitoxantrone, which resulted in partial remission with residual tumor cells comprising 7 % of bone marrow nucleated cells. Although the residual B-PLL cells appeared to be indolent, as the disease progressed slowly during partial remission, these cells lost CD20 expression, and the prognosis of the patient was considered to be poor with conventional chemotherapy. She was therefore given RIC, followed by allo-HSCT from an HLA-matched sibling donor. Her clinical course following allo-HSCT was uneventful, and she remained in complete remission at 32 months post-transplantation. Although the therapeutic strategy for B-PLL should be determined based on the severity of the disease, RIC with allo-HSCT may be a therapeutic option for indolent B-PLL when the long-term prognosis of patients is markedly poor.     

Conditioning with 8-Gy total body irradiation and fludarabine for allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia

Seventy-one patients with acute myeloid leukemia (AML), most of them (63/71) considered ineligible for conventional allogeneic hematopoietic stem cell transplantation (HSCT), were enrolled into a phase 2 study on reduced-intensity myeloablative conditioning with fractionated 8-Gy total body irradiation (TBI) and fludarabine (120 mg/m2). Patients received mobilized peripheral blood stem cells (n = 68) or bone marrow (n = 3) from siblings (n = 39) or unrelated donors (n = 32). Thirty-six patients received a transplant in complete remission (CR) and 35 had untreated or refractory disease (non-CR). Median patient age was 51 years (range, 20-66 years). Sustained engraftment was attained in all evaluable patients. With a median follow-up of 25.9 months (range, 3.7-61.2 months) in surviving patients, probabilities of overall survival for patients who received a transplant in CR and non-CR were 81% and 21% at 2 years, respectively. Relapse-free survival rates were 78% and 16%. The cumulative incidence of nonrelapse mortality (NRM) in CR patients was 8% at 2 years and beyond but amounted to 37% at 2 years in non-CR patients. Outcome data in this poor-risk population indicate that allogeneic HSCT from related or unrelated donors with 8-Gy TBI/fludarabine conditioning is feasible with low NRM and preserved antileukemic activity in AML patients in first or later CR.     

氟达拉滨联合静脉马利兰的预处理方案治疗髓系恶性血液病的临床研究

目的:评价氟达拉滨(Flu)联合静脉马利兰(Bu)的预处理方案在髓系恶性血液病患者异基因造血干细胞移植(allo-HSCT)中的疗效及静脉Bu的最佳剂量。方法:45例接受allo-HSCT的髓系恶性血液病患者,预处理方案主要采用Bu3.2mg·kg-1.d-1×2～4d,Cy40～50mg/kg×2d,Flu30mg.m-2.d-1×3d,Ara-C2g.m-2.d-1×3d,无关供者移植同时加用兔抗人血清免疫球蛋白(ATG)2.5mg/kg×4d。按静脉Bu用量进一步分为2d组17例,3d组18例,4d组10例。结果:预处理过程无严重不良事件发生,无肝静脉闭塞病(VOD)发生,Ⅱ～Ⅳ度急性移植物抗宿主病(aGVHD)9例(20%),100d移植相关死亡(TRM)1例(2.2%),3年TRM15例(33.3%),3年累计复发3例(6.7%),3年无病生存率(DFS)和3年总体生存率(OS)分别为(60.5±7.5)%和(62.2±7.2)%。与Bu2d组和3d组比较,4d组患者的慢性GVHD的发生率显著增高,TRM有增高趋势;OS显著降低,DFS有降低趋势。结论:Flu联合静脉Bu的预处理方案治疗髓系恶性血液...     

Neoplastic meningitis in patients with acute myeloid leukemia scheduled for allogeneic hematopoietic stem cell transplantation

We analyzed the frequency of neoplastic meningitis in patients with acute myeloid leukemia prior to allogeneic hematopoietic stem cell transplantation at our institution. Between 1996 and 2009, cerebrospinal fluid samples of 204 adult patients were examined during pre-transplant work-up for cell counts and, if abnormal, morphologically. We found blasts in cerebrospinal fluid samples of 17 patients with either persistent (n=9) or newly diagnosed (n=8) neoplastic meningitis. All patients proceeded to transplant. The proportion of patients with central nervous system involvement was significantly higher in patients with refractory disease at the time of transplantation compared with patients responding to prior systemic therapy (19% vs. 4.6%; P=0.003). Since most of the patients with central nervous system involvement were asymptomatic, cerebrospinal fluid evaluation should be considered at least in patients with refractory acute myeloid leukemia.     

Long-term survival in refractory acute myeloid leukemia after sequential treatment with chemotherapy and reduced-intensity conditioning for allogeneic stem cell transplantation

A sequential regimen of chemotherapy, reduced-intensity conditioning (RIC) for allogeneic stem cell transplantation (SCT), and prophylactic donor lymphocyte transfusion (pDLT) was studied in 103 patients with refractory acute myeloid leukemia (AML). According to published criteria, refractoriness was defined by primary induction failure (PIF; n = 37), early (n = 53), refractory (n = 8), or second (n = 5) relapse. Chemotherapy consisted of fludarabine (4 x 30 mg/m(2)), cytarabine (4 x 2 g/m(2)), and amsacrine (4 x 100 mg/m(2)), followed 4 days later by RIC, comprising 4 Gy total body irradiation (TBI), cyclophosphamide, and antithymocyte globulin. Patients without graft-versus-host disease (GvHD) at day +120 received pDLT in escalating doses. Patients' median age was 51.8 years. Before conditioning, 99 patients had active disease, 3 were aplastic, 1 was in second complete remission (CR2). Forty-one patients had family donors, 62 had unrelated donors. With a 25-month median follow-up, overall survival (OS) at 1, 2, and 4 years was 54%, 40%, and 32%; the respective leukemia-free survival (LFS) was 47%, 37%, and 30%. Patients with PIF showed a 2-year OS of 62.5%. OS was 87% in 17 patients receiving pDLT. One-year cumulative incidence of leukemic death and non-relapse-mortality was 28.7% and 17.2%. In a multivariate analysis, more than 2 courses of prior chemotherapy were the strongest predictor for poor outcome (P = .007; HR = 3.01 [OS]; P = .002; HR = 3.25 [LFS]). These results indicate a high activity of the regimen in refractory AML.     

Health-related quality of life in patients receiving reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation

Reduced-intensity conditioning allogeneic HSCT (RIC) has less regimen-related morbidity and mortality than myeloablative allogeneic HSCT (MT) offering allogeneic transplantation to patients otherwise excluded. Whether these advantages improve health-related quality of life (HRQL) is unknown. We examined the HRQL effects of RIC and MT in patients with hematological diseases pre-transplant (baseline), days 0, 30, 100, 1 and 2 years following HSCT. HRQL was measured using the Short Form-36 Health Survey and the Functional Assessment of Cancer Therapy - General and BMT. Data were analyzed using mixed linear modeling adjusting for baseline HRQL differences. Patients (RIC=41, MT=35) were predominately male (67%), in remission/stable disease (65%) with an Eastern Cooperative Oncology Group status 相似文献   

Cytoreductive treatment with clofarabine/ara-C combined with reduced-intensity conditioning and allogeneic stem cell transplantation in patients with high-risk, relapsed, or refractory acute myeloid leukemia and advanced myelodysplastic syndrome

The combination of cytoreductive chemotherapy with reduced-intensity conditioning (RIC) is a highly effective antileukemic therapy. Purpose of this retrospective analysis was to evaluate the antileukemic efficacy and toxicity of clofarabine-based chemotherapy followed by RIC and allogeneic stem cell transplantation (SCT) for high-risk, relapsed, or refractory acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). From May 2007 until October 2009, a total of 27 patients underwent allogeneic SCT after treatment with clofarabine and ara-C for 5d and RIC (4Gy TBI/cyclophosphamide/ATG). Prophylaxis of graft-versus-host disease (GvHD) consisted of cyclosporine and mycophenolate mofetil. Unmanipulated G-CSF mobilized PBSC (n=26) or bone marrow cells (n=1) were transplanted from unrelated (n=21) or matched related (n=6) donors. Non-hematological toxicities of this regimen mainly affected liver and skin and were all reversible. Seven patients relapsed within a median time of 5.7 months. The overall survival (OS) and relapse-free survival rates were 56% and 52% at 2 yr, respectively. In this cohort of patients, cytoreduction with clofarabine/ara-C (ClAraC) followed by RIC allogeneic SCT was well tolerated and showed good antileukemic efficacy even in patients with high-risk AML or MDS, with engraftment and GvHD-incidence comparable to other RIC regimens.     

Standard versus alternative myeloablative conditioning regimens in allogeneic hematopoietic stem cell transplantation for high-risk acute leukemia.

BACKGROUND AND OBJECTIVES: To analyze the results of standard versus alternative myeloablative conditioning regimens in allogeneic hematopoietic stem cell transplantation for high-risk acute leukemia. DESIGN AND METHODS: From October 1986 to February 2000, 104 consecutive patients (male: n = 63; median age: 21, range 1.3-44.2 years) with high-risk acute leukemia underwent a non-T-cell depleted graft from an HLA-identical sibling following a standard or alternative myeloablative conditioning regimen. Sixty patients were affected by acute lymphoblastic leukemia (ALL) and 44 by acute myeloid leukemia (AML); the phase at transplant was >= 2nd complete remission (CR) in 76, untreated 1st relapse with < 20% blasts in 11, refractory leukemia or overt resistant relapse in 17. Pre-transplant regimens consisting of either 12 Gy fractionated total body irradiation (TBI) or 16 mg/kg busulphan (BU) combined with cyclophosphamide (CY) were defined standard (n = 38), whereas all other myeloablative regimens (TBI plus 60 mg/kg etoposide and three-drug combinations) were considered alternative (n = 66). RESULTS: No significant differences in terms of baseline characteristics, incidence and severity of either acute or chronic graft-versus-host disease (GVHD) were observed between the two groups, but a significantly higher proportion of patients prepared with an alternative regimen were not evaluable for chronic GVHD (36% vs 16%) (p = 0.026). Sixty-six patients died, 38 of relapse, 26 of transplant-related mortality (TRM) and 2 of other causes. Thirty-eight patients are still alive with a follow-up ranging from 0.7 to 13.8 years (median, 7.1 years); only 1 of 39 patients who relapsed after transplant is alive in CR at 5.7 years from relapse. At the median follow-up, the actuarial probabilities of overall survival, relapse and TRM for patients conditioned with standard and alternative regimens are respectively 52% vs 25% (95% CI, 36-68% vs 13-37%; p = 0.0163), 34% vs 58% (95% CI, 18-51% vs 43-73%; p = 0.0377) and 25% vs 32% (95% CI, 9-40% vs 19-44%; p = ns). After adjustment for diagnosis, age, period, leukemia phase, duration of 1st CR, GVHD prophylaxis and donor-recipient sex combination, the multivariate analysis showed that alternative regimens are associated with a significantly worse survival (hazard ratio 2.31; p = 0.0071) and relapse rate (hazard ratio 2.75; p = 0.0187). INTERPRETATION AND CONCLUSIONS: From this retrospective analysis we can conclude that the alternative myeloablative conditioning regimens we used did not improve the outcome of patients transplanted for high-risk acute leukemia.