Combination of fludarabine, amsacrine, and cytarabine followed by reduced-intensity conditioning and allogeneic hematopoietic stem cell transplantation in patients with high-risk acute myeloid leukemia

Sequential use of chemotherapy and reduced-intensity conditioning (RIC) with allogeneic stem cell transplantation (SCT) has been proposed to improve the treatment outcomes in patients with high-risk acute myeloid leukemia (AML). Here, we present our experience with this procedure in a cohort of 60 AML patients with primary induction failure (n?=?9); early, refractory, or ≥ second relapse (n?=?41); or unfavorable cytogenetics (n?=?10). A combination of fludarabine (30 mg/m²/day), cytarabine (2 g/m²/day), and amsacrine (100 mg/m²/day) for 4 days was used. After 3 days of rest, RIC was carried out, consisting of 4 Gy total body irradiation, antithymocyte globulin (ATG-Fresenius), and cyclophosphamide (fludarabine, amsacrine, and cytarabine (FLAMSA)-RIC protocol). Prophylactic donor lymphocyte infusions (pDLIs) were given in patients with complete remission (CR) and without evidence of graft-versus-host disease ≥120 days after SCT. The median time of neutrophil engraftment was 17 days. CR was achieved in 47 of 60 patients (78 %). Eleven patients received pDLIs resulting in long-term CR in eight of them. Non-relapse mortality after 1 and 3 years was 25 and 28 %, respectively. With a median follow-up of 37 months (range, 10–69), 3-year overall survival and 3-year progression-free survival were 42 and 33 %, respectively. In a multivariate analysis, dose of CD34(+) cells >5?×?10⁶/kg (p?=?0.005; hazard ratio (HR)?=?0.276), remission of AML before SCT (p?=?0.044; HR?=?0.421), and achievement of complete chimerism after SCT (p?=?0.001; HR?=?0.205) were significant factors of better overall survival. The use of the FLAMSA-RIC protocol in suitable high-risk AML patients results in a long-term survival rate of over 40 %.     

Fludarabine/intermediate-dose cytarabine with or without allogeneic hematopoietic stem cell transplantation in poor-risk leukemia: a single center experience

Disease recurrence has been and remains the leading cause of treatment failure in patients with high-risk leukemia.We retrospectively analyzed outcome in 61 patients with high-risk leukemia receiving a combination of fludarabine and intermediate-dose cytarabine as induction (n = 11) or salvage therapy (n = 35). Thirty-six patients having a suitable stem cell donor proceeded to allogeneic hematopoietic stem cell transplantation (HSCT). Ten patients received fludarabine-based salvage therapy without consecutive allogeneic transplantation and 15 patients received fludarabine/intermediate-dose cytarabine because of disease relapse following allogeneic stem cell transplantation. In patients without prior allogeneic HSCT (n = 46) the complete remission rate (CR) was 41% with a CR rate of 46 and 14% in patients with acute myeloid leukemia (AML) and with acute lymphoblastic leukemia (ALL), respectively. Overall survival for patients achieving a CR was 41 versus 0% for patients not achieving CR (P < 0.0001). The best outcome was observed in patients receiving an allogeneic HSCT in CR following fludarabine/intermediate-dose cytarabine (47 vs. 0% for patients not in CR at the time of allografting, P = 0.01). All 10 patients receiving fludarabine/intermediate-dose cytarabine without subsequent allogeneic HSCT died within 3 years either of disease relapse/progression or infection. Only 1/15 (7%) patients receiving fludarabine/intermediate-dose cytarabine because of relapse following allogeneic HSCT became a long-term survivor. By multivariate analysis achieving CR, receiving an allogeneic HSCT, and being in first relapse or untreated were the only parameters that significantly determine the outcome. Although preliminary only high-risk AML patients having a stem cell donor are candidates for fludarabine/intermediate-dose cytarabine and only those achieving a CR should be referred to subsequent allogeneic HSCT. All other patients with high-risk leukemia are candidates for experimental therapies within controlled trials.     

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.     

Autologous and allogeneic stem cell transplantations for poor-risk chronic lymphocytic leukemia

We report here on the long-term follow-up on 162 patients with high-risk chronic lymphocytic leukemia (CLL) who have undergone hematopoietic stem cell transplantation (SCT) at a single center from 1989 to 1999. Twenty-five patients with human leukocyte antigen (HLA)-matched sibling donors underwent T-cell-depleted allogeneic SCT, and 137 patients without HLA-matched sibling donors underwent autologous SCT. The 100-day mortality was 4% for both groups, but later morbidity and mortality were negatively affected on outcome. Progression-free survival was significantly longer following autologous than allogeneic SCT, but there was no difference in overall survival and no difference in the cumulative incidence of disease recurrence or deaths without recurrence between the 2 groups. At a median follow-up of 6.5 years there is no evidence of a plateau of progression-free survival. The majority of patients treated with donor lymphocyte infusions after relapse responded, demonstrating a significant graft-versus-leukemia effect in CLL. From these findings we have altered our approach for patients with high-risk CLL and are currently exploring the role of related and unrelated allogeneic SCT following reduced-intensity conditioning regimens.     

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.     

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   

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.     

Pilot study of reduced-intensity conditioning followed by allogeneic stem cell transplantation from related and unrelated donors in patients with myelofibrosis

A prospective pilot study was performed to evaluate the effect of reduced-intensity conditioning with busulphan (10 mg/kg), fludarabine (180 mg/qm) and anti-thymocyte globulin followed by allogeneic stem cell transplantation from related (n = 8) and unrelated donors (n = 13) in 21 patients with myelofibrosis. The median age of the patients was 53 years (range, 32-63). No primary graft failure occurred. The median time until leucocyte (>1.0 x 10(9)/l) and platelet (>20 x 10(9)/l) engraftment was 16 (range, 11-26) and 23 d (range, 9-139) respectively. Complete donor chimaerism on day 100 was seen in 20 patients (95%). Acute graft-versus-host disease (GvHD) grades II-IV and III/IV occurred in 48% and 19% of cases and 55% of the patients had chronic GvHD. Treatment-related mortality was 0% at day 100 and 16% [95% confidence interval (CI): 0-32%] at 1 year. Haematological response was seen in 100% and complete histopathological remission was observed in 75% of the patients and 25% of the patients showed partial histopathological remission with a continuing decline in the grade of fibrosis. After a median follow-up of 22 months (range, 4-59), the 3-year estimated overall and disease-free survival was 84% (95% CI: 67-100%).     

Lower incidence of Bronchiolitis obliterans in allogeneic hematopoietic stem cell transplantation with reduced-intensity conditioning compared with myeloablative conditioning

Bronchiolitis obliterans (BO) is one of the most devastating complications after allogeneic stem cell transplantation (HSCT). However, its true pathogenesis is still to be elucidated. We conducted this study to find whether tissue damage due to high-dose chemo-radiotherapy is related to its pathogenesis. In all, 144 patients who received allogeneic HSCT between May 1999 and October 2001, and survived more than 80 days after transplant, were analyzed. Clinical course, pulmonary function tests, imaging studies including CT scan, and pathology results were reviewed. The overall incidence of BO was 9.7% (14/144). The cumulative incidence of BO at 2 years after transplant was 17% with myeloablative conditioning, and 2.3% with reduced intensity conditioning (P=0.024). Multivariate analysis showed that myeloablative conditioning was the only factor which affected the incidence of BO. Development of BO did not significantly affect the overall survival of patients. However, if they developed BO earlier than 200 days post transplant, the prognosis was significantly worse than if they developed it later than 200 days post transplant (P=0.003) or if they did not develop BO (P=0.002). Our results imply that tissue damage secondary to intensive chemo-radiotherapy may contribute to the pathogenesis of BO.     

Secondary malignancies after allogeneic hematopoietic stem cell transplantation using reduced-intensity conditioning and outpatient conduction

Background

Patients given allogeneic hematopoietic stem cell transplants (HSCT) may develop secondary malignant neoplasms (SMN). Several variables have been identified but there are no data about the incidence of this complication in individuals given HSCT using reduced-intensity conditioning (RIC) methods.

Objective

Define the incidence of SMN in patients given HSCT using a RIC preparative regimen conducted on an outpatient basis.

Materials and methods

Patients given HSCT in two institutions between October 1998 and 2012 were analyzed. To appraise the SMN appearance, those patients dead were also regarded as censored at that moment, as well as those lost to follow up and those alive at the closing of the study. 95% Confidence intervals (CI) for the survival or failure estimate were calculated with the Greenwood's method.

Results

A total of 416 allografted patients with a Karnofsky performance index of 100% were included in the study. All patients received peripheral blood stem cells allografts. The conditioning regimen was delivered as an outpatient procedure in all individuals. No patient was given radiotherapy nor antithymocyte globulin during the conditioning. Three hundred and sixty five patients (88%) were never admitted to the hospital, whereas 12% were admitted because of grade III–IV acute graft versus host disease (aGVHD), fever, or mucositis. Median survival time was 15.7 months. Survival at 6 months (95% CI): 66.4% (61.5–70.8%), at 12 months: 53.3% (48.1–58.1%), at 60 months: 30.6% (30.5–41.5%). Eight patients with a SMN were identified in the group of 416 allografted patients, SMN rates (95% CI) were: one year post graft: 1.9% (0.7–4.9%), 5 years: 3.8% (1.6–9.2%), 10 years: 6.8% (2.6–17.7%) and 13 years post-graft: 20.2% (5.5–59.2%), the cumulative probability of SMN being 6.8 at 10 years. Since the number of expected cases in the general population is 0.62, the ratio of observed to expected cases is 12.9 (P < 0.001). This figure means that the risk of developing a malignant neoplasm in allografted individuals using our method is 12.9 times higher than that in the general population. There were three non-Hodgkin's lymphomas, two M2 acute myelogenous leukemias, one hairy cell leukemia, one tongue epidermoid carcinoma, and one breast carcinoma.

Conclusions

We have found a low incidence of SMN in this group of Mexican patients allografted with the Mexican RIC method. Possible explanations for this difference are discussed, focusing on the RIC preparative regimen.     

Alveolar hemorrhage following allogeneic hematopoietic cell transplantation using reduced-intensity conditioning

Allogeneic hematopoietic cell transplantation (HCT) using reduced-intensity conditioning (RIC) has lower morbidity and mortality compared to transplantation using myeloablative conditioning (MAC). The syndrome of alveolar hemorrhage, a life-threatening pulmonary complication of HCT, has not been well described after RIC HCT. We reviewed prospectively collected data on 206 RIC and 1112 MAC HCT performed between 1995 and 2004 to study the impact of conditioning regimen on the clinical features and outcome of alveolar hemorrhage. Alveolar hemorrhage occurred in 18 RIC HCT recipients (cumulative incidence 8% (95% confidence intervals (CI), 5-11%)) and 85 MAC HCT recipients (cumulative incidence 7% (95% CI, 6-8%), P = 0.56). The clinical presentation of hemorrhage in both cohorts was similar. Survival at 60 days from the onset of hemorrhage was 28% (95% CI, 7-49%) for RIC group compared to 26% (95% CI, 17-35%) after MAC HCT (P = 0.56). Reducing the intensity of preparative regimen does not protect against post transplant alveolar hemorrhage. Alveolar hemorrhage occurring after RIC or MAC HCT has similar incidence, clinical presentation, and associated high mortality.     

慢性淋巴细胞白血病的造血干细胞移植治疗

慢性淋巴细胞白血病（CLL）存在很大的临床异质性。尽管免疫化疗方案的进步带来了显著的疗效，部分患者仍可在短期内发生疾病进展，或处于疾病难治耐药的状态。由于移植物抗CLL效应的存在，异基因造血干细胞移植的根治性意义获得肯定。年轻CLL患者如具有高危因素，包括：嘌呤类似物耐药或治疗后早期复发，以及具有17p（TP53位点）缺失和TP53突变，异基因造血干细胞移植是合理的治疗选择。减低强度的预处理方案有效降低了患者的治疗相关死亡率。     

Use of a reduced-intensity conditioning regimen for allogeneic transplantation in patients with chronic myeloid leukemia

Reduced-intensity conditioning that harnesses the potential of a graft-versus-tumor (GVT) effect has been proposed as an alternative to conventional myeloablative allogeneic stem cell transplantation. The primary aim is engraftment and this can be achieved with minimal immunosuppression. In this report, we describe the use of such regimens for CML in 17 patients who received human leukocyte antigen (HLA)-matched sibling allografts. Conditioning was with fludarabine, antithymocyte globulin (ATG) and busulfan for the first 11 patients, whereas fludarabine, busulfan and TBI were used for the remaining six patients. Engraftment was prompt in most of the cases. Complications and need for supportive therapy in the immediate post-transplant period were reduced drastically. Only two patients (both in the TBI group) died within the first 100 days. Acute graft-versus-host disease (GVHD) grade II-IV was seen in seven patients. Complications occurred later on. Chronic GVHD was observed in 11/17 patients. Lung infection and GVHD were the major killers. In surviving patients, after a median follow-up of 30 months (range 37-21 months), 6/17 (35.3%) are alive. Five are disease free and one patient is still in relapse even after a second donor lymphocyte infusion. Total treatment time and cost were more than with conventional transplants. We conclude that reduced-intensity transplantation still requires further refinement.     

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).     

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.