Allogeneic stem cell transplantation for myelodysplastic syndrome

Although it is only used to treat a minority of patients with myelodysplastic syndromes, stem cell transplantation (SCT) is the only proven curative treatment for this condition. Because MDS occurs in a population of older adults with significant comorbidities, reduced-intensity conditioning (RIC) regimens have been particularly important in extending safe SCT to the large MDS population over the age of 60 years. Extension of the unrelated donor pool together with the introduction of umbilical cord blood transplants in adults has extended the number of patients with suitable donors. Nevertheless overall mortality from SCT is greater than 50% because of relapse and non-relapse mortality (NRM). New developments to improve outcome include the tailoring of the transplant approach to the individual based on age and comorbidity, and the use of pretransplant chemotherapy to reduce disease bulk prior to transplant, as well as the introduction of post-transplant immunotherapy (pre-emptive donor lymphocyte infusions) and chemotherapy to prevent relapse. Further improvements in transplant outcome await better ways to reconstitute immunity and amplify the graft-versus-leukemia (GVL) effect without causing graft-versus-host disease (GVHD), as well as further extension of the donor pool and exploration of risk-adapted regimens for the population of MDS in their seventh to eighth decade.     

Allogeneic bone marrow transplantation for 93 patients with myelodysplastic syndrome

We treated 93 patients with myelodysplastic syndrome using cyclophosphamide and either total body irradiation (n = 88) or busulfan (n = 5) followed by marrow transplantation. Sixty-five marrow donors were genotypically HLA-identical siblings and 28 were other family members or unrelated donors. Before transplantation all patients had either severe neutropenia or thrombocytopenia or had greater than 5% blasts in the marrow or peripheral blood. The probabilities of disease- free survival, relapse, and non-relapse mortality at 4 years were 41%, 28%, and 43%, respectively. Multivariate analysis revealed that younger age and shorter disease duration were significantly associated with improved disease-free survival and decreased non-relapse mortality. Relapse was seen only in patients with excess blasts at the time of transplantation (51% at 4 years). Patients younger than age 40 and without excess blasts had a 4-year disease-free survival of 62%. This study confirms that allogeneic marrow transplantation can cure some patients with myelodysplasia. Because of the favorable outcome in younger patients without excess blasts, we recommend that transplantation be considered early for patients younger than age 40, before disease progression or development of life-threatening cytopenias. For older patients and those with excess blasts, changes in the transplant procedure will be necessary to improve outcome.     

Allogeneic stem cell transplantation for elderly patients with myelodysplastic syndrome

Allogeneic hematopoietic stem cell transplantation (SCT) is well accepted as a curative treatment approach for younger patients with myelodysplastic syndrome (MDS) and has become one of the most frequent indications for allogeneic SCT as reported to the Center for International Blood and Marrow Transplant Research. However, MDS patients are usually elderly with a median age of approximately 75 years at diagnosis. Large register studies have confirmed the feasibility of the procedure in elderly MDS patients; and in the register of the European Group for Blood and Marrow Transplantation, one-third of the allogeneic transplant procedures for MDS were performed in 2010 in patients older than 60 years. Despite its curative potential, its role in the treatment of elderly MDS patients is less defined. Because of the inherent complications of the transplantation leading to treatment-related mortality and the risk of relapse, a careful calculation of the benefit for each patient is mandatory, taking into account comorbidities, disease status, donor selection, and effective nontransplant therapies. Prospective multicenter studies are needed to define optimal intensity of the conditioning regimen, timing of transplantation within a treatment algorithm, including drug-based therapies, and posttransplant strategies to reduce the risk of relapse.     

Individual outcome prediction for myelodysplastic syndrome (MDS) and secondary acute myeloid leukemia from MDS after allogeneic hematopoietic cell transplantation

We integrated molecular data with available prognostic factors in patients undergoing allogeneic hematopoietic cell transplantation (alloHCT) for myelodysplastic syndrome (MDS) or secondary acute myeloid leukemia (sAML) from MDS to evaluate their impact on prognosis. Three hundred four patients were sequenced for mutations in 54 genes. We used a Cox multivariate model and competing risk analysis with internal and cross validation to identify factors prognostic of overall survival (OS), cumulative incidence of relapse (CIR), and non-relapse mortality (NRM). In multivariate analysis, mutated NRAS, U2AF1, IDH2, and TP53 and/or a complex karyotype were significant prognostic markers for OS besides age above 60 years, remission status, IPSS-R cytogenetic risk, HCT-CI > 2 and female donor sex. Mutated NRAS, IDH1, EZH2, and TP53 and/or a complex karyotype were genetic aberrations with prognostic impact on CIR. No molecular markers were associated with the risk of NRM. The inclusion of molecular information results in better risk prediction models for OS and CIR when assessed by the Akaike information criterion. Internal cross validation confirmed the robustness of our comprehensive risk model. In summary, we propose to combine molecular, cytogenetic, and patient- and transplantation-associated risk factors into a comprehensive risk model to provide personalized predictions of outcome after alloHCT.     

异基因造血干细胞移植治疗MDS临床研究

目的探讨HLA配型相合异基因造血干细胞移植（allo—HSCT）治疗骨髓增生异常综合征（MDS）的可行治疗方案和疗效。方法以HLA配型相合的骨髓移植治疗MDS患者6例,预处理方案为非清髓性预处理方案1例,清髓性预处理方案5例;以霉酚酸酯、环孢菌素A加短疗程的甲氨喋呤预防移植物抗宿主病（GVHD）。结果6例患者均造血重建。5例清髓性预处理方案仍然无病存活,非清髓性预处理方案1例移植后出现MDS,于移植后17个月死亡。移植后最长无病存活时间已达8a。移植期间发生Ⅰ、Ⅱ°急性移植物抗宿主病（aGVHD）4例。结论allo-HSCT治疗MDS可行、有效,清髓性预处理方案可能对于长期稳定植入有利。     

Allogeneic bone marrow transplantation for infants with acute leukemia or myelodysplastic syndrome

The objective of this study is to investigate the outcome of children 24 months of age or younger (infants) at the time of allogeneic bone marrow transplantation (BMT) for acute leukemia or myelodysplasia. We analyzed the survival rate, prognostic factors, incidences of late sequelae, and immune reconstitution in 22 infants who underwent allogeneic BMT. The 5-year event-free survival estimate was 45.5% (95% confidence interval (CI), 24.4% to 63.3%). Six patients died of transplant-related complications and six died of disease relapse. Remission status at the time of BMT was the most important prognostic factor (P = 0.005): no patient who received a transplant while their disease was not in remission survived, whereas the 5-year survival estimate for infants who underwent BMT during remission was 56% (95% CI, 31% to 75%). Long-term outcomes in the 10 infant survivors were compared with those of 10 older controls matched for diagnosis, disease status at the time of BMT, calendar year at the time of BMT, and source of stem cells. Immune function 1 year after transplantation and the incidences and spectra of late sequelae were similar for both groups during a median of 3.5 years (range, 1.5 to 7.2 years) of follow-up.     

Extended cytogenetic follow-up of patients with myelodysplastic syndrome (MDS)

The prognostic significance of clonal karyotype status in myelodysplastic syndrome (MDS) is assessed after an extended follow-up period of 5 years. There are three karyotype, single abnormalities or multiple abnormalities at the time of referral. However, there is no correlation between the size of the abnormal clone and prognosis. Karyotype status has independent prognostic significance in 'high risk' MDS so that patients with a refractory anaemia with excess of blasts (RAEB)/RAEB in transformation (RAEB-t) and a normal karyotype survive significantly longer than those with an abnormal karyotype (P < 0.001) and do not differ significantly from patients with refractory anaemia (RA). Significant differences in survival according to karyotype status are also seen in patients with chronic myelomonocytic leukaemia (P < 0.001) but not in those with primary acquired sideroblastic anaemia and RA. Among patients studied sequentially, those who retained a normal karyotype survived significantly longer than those who developed an abnormality on follow-up (P < 0.001). The risk of leukaemic transformation was also increased in patients who presented with or subsequently developed a clonal karyotype abnormality compared with those who remained normal (P < 0.05).     

Exisulind induces apoptosis in advanced myelodysplastic syndrome (MDS) and acute myeloid leukaemia/MDS

The influence of Exisulind on the viability and apoptosis of CD34(+) stem cells from patients with advanced myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML)/MDS was investigated. In eight out of 10 patient samples Exisulind reduced the fraction of viable cells by inducing apoptosis. We found evidence that Exisulind-mediated apoptosis depends on c-Jun NH(2)-terminal kinase (JNK) activation. Addition of a specific JNK-inhibitor to Exisulind-treated advanced MDS and AML/MDS cells partly abrogated apoptosis. We propose that Exisulind is tested in clinical phase I/II trials for the treatment of advanced MDS and AML/MDS.     

Allogeneic transplantation for the elderly patient with acute myelogenous leukemia or myelodysplastic syndrome

Acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) are diseases of the elderly. Allogeneic hematopoietic stem cell transplantation (HSCT) offers the possibility of cure for these malignancies, but until recently its use was restricted to younger patients due to prohibitive treatment-related mortality. Improvements in supportive care and development of reduced-intensity preparative regimens have allowed patients in the sixth, seventh, and to a lesser extent, eighth decade of life to be treated with allogeneic transplantation. Major obstacles to extending this form of treatment to older patients are lack of promptly available donors, graft-versus-host disease (GVHD), delayed immune recovery, and the high prevalence of refractory and relapsed disease intrinsic to the natural history of these myeloid malignancies. Here we review current results of allogeneic blood and marrow transplantation for AML and MDS in the elderly.     

骨髓增生异常综合征铁超负荷研究进展

骨髓增生异常综合征(MDS)为一组异质性的、起源于造血干细胞的恶性肿瘤性疾病,以病态造血、高风险向急性髓系白血病(AML)转化为特征。80%以上的MDS患者需要输血,而长期输血后机体将出现严重铁超负荷。本文综述了近年MDS铁超     

Lack of cytoprotective effect of amifostine following HLA-identical sibling transplantation for advanced myelodysplastic syndrome (MDS): a pilot study

The objective of this prospective study was to determine whether amifostine (Ethyol) reduced conditioning-related toxicity following a regimen of busulfan (7 mg/kg) and fractionated total body irradiation (6 x 200 cGy). In all, 12 patients with advanced myelodysplastic syndrome transplanted from HLA-identical siblings were enrolled. Patients received 340 mg/m(2) amifostine i.v. twice daily during conditioning (days -7 through -1). All patients developed oropharyngeal mucositis. Six patients had evidence of sinusoidal obstruction syndrome of the liver. Six patients experienced pulmonary toxicity of grades II-III. A total of 11 patients died, one with relapse and 10 with infectious complications or regimen-related toxicity. Nonrelapse causes of death included invasive aspergillosis in three, multiorgan failure in three, and idiopathic interstitial pneumonitis in two patients. One patient each died of organizing pneumonia and CMV pneumonia. One patient is alive in complete remission 31 months after transplantation. These results were not superior to those in patients conditioned with busulfan plus fractionated total body irradiation and not given amifostine, and suggest that amifostine, as administered here, has no protective effect against toxicity from this myeloablative regimen.     

Allogeneic hemopoietic stem cell transplantation in patients with myelodysplastic syndrome or myelofibrosis

Myelodysplastic syndrome (MDS) and myeloproliferative disorders associated with myelofibrosis (MF) are stem cell disorders, and hemopoietic stem cell transplantation (HSCT) is currently the only therapy with curative potential. Among patients with less advanced MDS, 3 year survivals of 65% to 70% are achievable with HLA-identical related and HLA-matched unrelated donors. The probability of relapse is < 5%. Among patients with advanced disease (> or = 5% marrow blasts), about 35 to approximately 45% and 25 to approximately 30%, respectively, are surviving in remission after transplantation from related or unrelated donors. The incidence of post-transplant relapse is 1035%. Criteria of the International Prognostic Scoring System (IPSS), originally developed for nontransplanted patients, also predict survival following transplantation. Patients with MF, either idiopathic or on the basis of pre-existing disorders, are also transplanted successfully with stem cells from related or unrelated donors. Transplants early in the disease, before leukemic transformation, are successful in 60 to approximately 80% of patients. Success rates are lower in patients who have developed MDS or leukemia. New conditioning regimens have permitted successful HSCT even in patients in the seventh decade of life. Results with a regimen using a combination of busulfan (targeted to predetermined plasma levels) and cyclophosphamide are particularly encouraging. Improved survival with transplants from unrelated volunteer donors may, in part, reflect selection of donors on the basis of high resolution (allele-level) HLA typing. Nevertheless, transplant-related morbidity and mortality, including graft- vs. -host disease, remain challenges that need to be addressed with innovative approaches.     

Allogeneic hemopoietic stem cell transplantation in patients with myelodysplastic syndrome or myelofibrosis

Myelodysplastic syndrome (MDS) and myeloproliferative disorders associated with myelofibrosis (MF) are stem cell disorders, and hemopoietic stem cell transplantation (HSCT) is currently the only therapy with curative potential. Among patients with less advanced MDS, 3 year survivals of 65% to 70% are achievable with HLA-identical related and HLA-matched unrelated donors. The probability of relapse is <5%. Among patients with advanced disease (?5% marrow blasts), about 35～45% and 25～30%, respectively, are surviving in remission after transplantation from related or unrelated donors. The incidence of post-transplant relapse is 1035%. Criteria of the International Prognostic Scoring System (IPSS), originally developed for nontransplanted patients, also predict survival following transplantation. Patients with MF, either idiopathic or on the basis of pre-existing disorders, are also transplanted successfully with stem cells from related or unrelated donors. Transplants early in the disease, before leukemic transformation, are successful in 60～80% of patients. Success rates are lower in patients who have developed MDS or leukemia. New conditioning regimens have permitted successful HSCT even in patients in the seventh decade of life. Results with a regimen using a combination of busulfan (targeted to predetermined plasma levels) and cyclophosphamide are particularly encouraging. Improved survival with transplants from unrelated volunteer donors may, in part, reflect selection of donors on the basis of high resolution (allele-level) HLA typing. Nevertheless, transplant-related morbidity and mortality, including graft- vs.-host disease, remain challenges that need to be addressed with innovative approaches.     

Wilms tumor gene peptide-based immunotherapy for patients with overt leukemia from myelodysplastic syndrome (MDS) or MDS with myelofibrosis

The Wilms tumor gene, WT1, is overexpressed not only in leukemias and myelodysplastic syndrome (MDS) but also in various types of solid tumors, including lung and breast cancer, and the WT1 protein is a tumor antigen for these malignancies. In clinical trials of WT1 peptide-based cancer immunotherapy, patients with overt leukemia from MDS or MDS with myelofibrosis were injected intradermally with 0.3 mg of an HLA-A*2402-restricted, 9-mer WT1 peptide emulsified with Montanide ISA51 adjuvant. Only a single dose of WT1 vaccination resulted in an increase in WT1-specific cytotoxic T-lymphocytes, which was followed by a rapid reduction in leukemic blast cells. Severe leukopenia and local erythema at the injection sites of WT1 peptide were observed as adverse effects. These results have provided us with the first clinical evidence suggesting that WT1 peptide-based immunotherapy is an attractive treatment for patients with leukemias or MDS.