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.     

Intensive chemotherapy followed by allogeneic or autologous stem cell transplantation for patients with myelodysplastic syndromes (MDSs) and acute myeloid leukemia following MDS

This study investigated the feasibility of allogeneic (alloSCT) and autologous stem cell transplantation (ASCT) as postconsolidation therapy for patients with myelodysplastic syndromes (MDSs) or acute myeloid leukemia after MDS. Patients with a histocompatible sibling were candidates for alloSCT and the remaining patients for ASCT. Remission-induction therapy consisted of 1 or 2 courses with idarubicin, cytarabine, and etoposide, followed by one intensive consolidation course with cytarabine and mitoxantrone. Initially, bone marrow cells were used for ASCT. Subsequently, mobilized blood stem cells were used in an attempt to shorten posttransplantation hypoplasia. With a median follow-up of 3.6 years the 184 evaluable patients showed a 4-year survival rate of 26% and a median survival of 13 months. The remission-induction chemotherapy induced complete remission (CR) in 100 patients (54%). The 4-year disease-free survival (DFS) rate was 29% and the median DFS was 12 months. Twenty-eight of 39 patients (72%) with a donor were allografted in CR-1, including 2 patients who underwent transplantation in CR-1 without a consolidation course. Thirty-six of 59 patients (61%) without a donor received ASCT in CR-1. The 4-year DFS rates in the group of patients with or without a donor were 31% and 27%, respectively. The 4-year survival rates from CR were 36% and 33%, respectively. This large prospective study shows the feasibility of both alloSCT and ASCT. This treatment approach leads to a relatively high remission rate, and the majority of patients in remission received the SCT in CR-1. The ongoing study investigates whether this approach is better than treatment with chemotherapy only.     

Autologous stem cell transplantation for therapy-related acute myeloid leukemia and myelodysplastic syndrome

We report the results of 65 patients with treatment-related myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML) who were transplanted from an autograft and reported to the EBMT. The median age was 39 years (range, 3-69), and stem cell source was bone marrow (n = 31), or peripheral blood progenitor cells (n = 30), or the combination of both (n = 4). The primary disease was solid tumors (n = 37), Hodgkin's disease (n = 13), non-Hodgkin's lymphoma (n = 10), acute lymphoblastic leukemia (n = 2) or myeloproliferative syndromes (n = 3). The types of MDS were as follows: RAEB (n = 1; 2%), RAEB-t (n = 3; 5%), or AML (n = 56; 87%). The median time between diagnosis and transplantation was 5 months (range, 3-86). The Kaplan-Meier estimates of the probability of 3-year overall and disease-free survival were 35% (95% CI: 21-49%) and 32% (95% CI: 18-45%), respectively. The median leukocyte engraftment was faster after transplantation with peripheral blood stem cells than with bone marrow: 12 (range, 9-26) vs 29 (range, 11-67) days (P<0.001). The cumulative incidence of relapse was 58% (95% CI: 44-72%) and of treatment-related mortality 12% (95% CI: 6-38%). Lower relapse rate was seen in patients transplanted in first complete remission (CR1 vs non-CR1: 3 years: 48 vs 89%; P = 0.05). Furthermore, age beyond 40 years resulted in a higher treatment-related mortality (47 vs 7%; P = 0.01). In a multivariate analysis, transplantation in CR1 age as well as their interaction influenced overall survival significantly. Autologous transplantation may cure a substantial number of patients with treatment-related MDS/AML, especially if they are in CR1 and of younger age.     

Role of allogeneic and autologous hematopoietic stem cell transplantation in acute myeloid leukemia

Most younger patients with acute myeloid leukemia will enter remission of disease. Prevention of relapse is now the central therapeutic issue. A number of factors predict the risk of relapse, the most powerful of which is cytogenetics. Both allogeneic and autologous transplantation have been extensively used as remission consolidation, but intensive chemotherapy has also provided improved results such that the choice of consolidation treatment is not clear. Recent prospective trials of allogeneic and autologous transplantation with careful analysis have not always shown a survival benefit, although both approaches have significantly reduced relapse risk. In analysis where relapse risk is taken into account based on cytogenetics, there is little evidence of the benefit of transplantation in good-risk patients, partly because patients in this group who relapse can then undergo successful salvage therapy. The results are still uncertain in standard-risk patients, so transplantation should continue to be used in the context of a trial. Poor-risk patients have a higher failure rate after transplantation, and for these patients novel approaches are required.     

Maximizing the benefit of allogeneic stem cell transplantation in myelodysplastic syndromes

Allogeneic stem cell transplantation (AHSCT) is an evolving field in the treatment of patients with myelodysplastic syndrome (MDS) and has become the third most frequent indication for AHSCT worldwide. Less toxic conditioning regimens, as well as extension of the donor pool to include haplo-identical donors, have led to a broader utility of AHSCT, especially in older patients with MDS. While disease-specific scoring systems such as the International Prognostic Scoring System (IPSS), IPSS-Revised (IPSS-R), or World Health Organization (WHO) Prognostic Scoring System (WPSS) have been used to select patients for AHSCT, new transplant-specific scoring systems have been developed to determine outcome after AHSCT, which include also transplant- and patient-related factors that determine more precisely outcome and allows to balance more properly the risk of relapse and non-relapse mortality. More recent studies suggested beside cytogenetics also a major impact of molecular genetics on outcome after AHSCT, mainly for p53 and RAS pathway mutations, which are currently not included in any available risk score. The risk of clonal evolution and the known poor outcome of worse cytogenetics and molecular mutations argue to perform AHSCT at an earlier stage of the disease, which is supported by an IPSS-R–based multistate model that recommends AHSCT at IPSS-R intermediate-risk stage.     

Current status of reduced-intensity-conditioning allogeneic stem cell transplantation for acute myeloid leukemia

Allogeneic stem cell transplantation (allo-SCT) is the most efficient antileukemic treatment for acute myeloblastic leukemia (AML). However, elderly patients can rarely benefit from standard myeloablative allo-SCT because of an unacceptable rate of procedure-related toxicities. This point is critical when considering AML patients in first complete remission. The development of the so-called reduced-intensity conditioning (RIC) regimens appears to decrease allo-SCT-related toxicities, and has emerged as an attractive modality in AML patients not eligible for standard allo-SCT. Such RIC regimens aim primarily to provide the immune graft-versus-leukemia effect while causing little toxicity. Of note, treatment-related toxicity appears to be lower with RIC regimens as compared to standard myeloablative regimens. Nevertheless, toxicity might represent only one aspect of the problem, since AML encompasses a group of chemosensitive diseases, raising concerns that significant reduction of the intensity of the preparative regimen may have a negative impact on long-term leukemic control. Furthermore, no prospective studies have been reported thus far establishing RIC allo-SCT as the preferred option in AML. Investigators are currently faced with a dilemma on how to optimize the potential role of RIC allo-SCT in AML patients, while delivering minimal myeloablation and maximizing allogeneic immunotherapy. The aim of this review is to analyze the available research evidence in this field.     

Time to engraftment following allogeneic stem cell transplantation is significantly longer in patients with myelodysplastic syndrome than with acute myeloid leukemia

Patients with myelodysplastic syndrome (MDS) commonly present with pancytopenia, suggesting that the marrow stroma fails to support the growth of both malignant and normal stem cells. We therefore retrospectively analyzed the duration to engraftment of neutrophils (> or =0.5 x 10(9)/l and > or =1.0 x 10(9)/l) and platelets (> or =20 and > or =50 x 10(9)/l) in 37 MDS patients and 42 patients suffering from primary AML, following allogeneic SCT. A significantly shorter time to engraftment was documented in AML as compared to MDS patients in all four parameters. These results held true even when we subgrouped the patients according to gender, age (50 years being the cutoff age between young and elderly patients), patient-donor relationship, donor match and intensity of conditioning. To the best of our knowledge, this is the first time that such a comparison has been made. We suggest that the longer duration of post transplant pancytopenia that is frequently observed in MDS patients may also influence post transplant outcome.     

Impact of pre-transplant marrow blasts on survival of allogeneic stem cell transplantation in adult acute myeloid leukemia

The aim of this study was to evaluate the impact of marrow blasts at transplant in adult acute myeloid leukemia (AML) patients. We analyzed 478 patients who underwent allogeneic stem cell transplantation (SCT). All patients were divided into five subgroups according to the percentage of blasts: <2 % (n = 361), ≥2 to<3 % (n = 64), ≥3 to <5 % (n = 28), ≥5 to <12 % (n = 11), and ≥12 % (n = 4). After a median follow-up of 59.5 months (range 3.3–125.9 months) for survivors, patients with higher marrow blasts at transplant showed lower overall survival (OS) and disease-free survival (DFS). In multivariate analyses, OS and DFS did not show significant differences with blast counts up to 12 %, compared with blast counts of <2 %; by contrast, the presence of >12 % marrow blasts was associated with significantly poorer OS and DFS. In the separate multivariate analyses by cytogenetic risk group, the impact of >12 % marrow blast on survival outcomes was observed in all risk groups. Thus, pre-transplant bone marrow status is an important prognostic factor for AML patients. In addition, the higher relapse rate in patients with >12 % marrow blasts may provide insights into the tolerable blast cell burden that can be overcome by the graft-versus leukemia effect.     

The clinical analysis of haploidentical stem cell transplantation in myelodysplastic syndrome-associated acute myeloid leukemia

正Objective To investigate the prognosis of haploidentical hematopoietic stem cell transplantation (haploHSCT) in the treatment of acute myeloid leukemia with myelodysplasia-related changes (AML-MRC).Method The data of 102 patients with high-risk AML in the first complete remission phase (CR1) who received haplo-     

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.     

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.