Therapeutic discovery for marrow failure with MDS predisposition using pluripotent stem cells.

Monosomy 7 or deletion of 7q (del(7q)) are common clonal cytogenetic abnormalities associated with high grade myelodysplastic syndrome (MDS) arising in inherited and acquired bone marrow failure. Current non-transplant approaches to treat marrow failure may be complicated by stimulation of clonal outgrowth. To study the biological consequences of del(7q) within the context of a failing marrow, we generated induced pluripotent stem cells (iPSCs) derived from patients with Shwachman Diamond Syndrome (SDS), a bone marrow failure disorder with MDS predisposition, and genomically engineered a 7q deletion. The TGFß pathway was the top differentially regulated pathway in transcriptomic analysis of SDS versus SDSdel(7q) iPSCs. SMAD2 phosphorylation was increased in SDS relative to wild type cells consistent with hyperactivation of the TGFbeta pathway in SDS. Phospho-SMAD2 levels were reduced following 7q deletion in SDS cells and increased upon restoration of 7q diploidy. Inhibition of the TGFbeta pathway rescued hematopoiesis in SDS-iPSCs and in bone marrow hematopoietic cells from SDS patients while it had no impact on the SDSdel(7q) cells. These results identified a potential targetable vulnerability to improve hematopoiesis in an MDS-predisposition syndrome, and highlight the importance of the germline context of somatic alterations to inform precision medicine approaches to therapy.

Association of Chemotherapy for Solid Tumors With Development of Therapy-Related Myelodysplastic Syndrome or Acute Myeloid Leukemia in the Modern Era.

Importance: Therapy-related myelodysplastic syndrome or acute myeloid leukemia (tMDS/AML) is a rare, usually fatal complication of chemotherapy, including certain alkylating agents, topoisomerase II inhibitors, and platinum compounds. With the introduction of new chemotherapeutic agents, expanded indications for established agents, and increased neoadjuvant and adjuvant chemotherapy, tMDS/AML risks in the modern age are poorly understood. Objectives: To quantify tMDS/AML risk after chemotherapy for solid cancer among United States adults since 2000 and correlate tMDS/AML risk patterns with chemotherapy treatment practices. Design, Setting, and Participants: A population-based cohort study was conducted using cancer registries from the Surveillance, Epidemiology, and End Results (SEER) Program and Medicare claims. Risk analyses included 1619 tMDS/AML cases among 700 612 adults (age, 20-84 years) who were diagnosed with first primary solid cancer during 2000 to 2013 (followed up through 2014), received initial chemotherapy, and survived 1 year or longer, as reported to SEER. Descriptive analyses were conducted of SEER records linked with Medicare claims for chemotherapy in 165 820 older adults (age, 66-84 years) receiving initial chemotherapy for a first primary solid cancer in 2000-2013. Data analysis was conducted from October 2017 to April 2018. Exposures: Receipt of initial chemotherapy for solid cancer. Main Outcomes and Measures: Second primary tMDS/AML. Results: Based on 1619 tMDS/AML cases in the SEER database (mean [SD] age, 64.3 [12.2] years; 1148 [70.9%] female), tMDS/AML risks were statistically significantly elevated after chemotherapy for 22 of 23 solid cancers (all except colon). Relative risks ranged from 1.5 to greater than 10 and excess absolute risks from 1.4 to greater than 15 cases per 10 000 person-years compared with the general population. Overall survival following tMDS/AML diagnosis was poor (1270 of 1619 patients [78.4%] died; median overall survival, 7 months). For patients treated with chemotherapy at the present time, approximately three-quarters of tMDS/AML cases expected to occur within the next 5 years will be attributable to chemotherapy. In the SEER-Medicare database, use of known leukemogenic agents, particularly platinum compounds, in initial chemotherapy increased substantially since 2000, most notably for gastrointestinal tract cancers (esophagus, stomach, colon, and rectum; 10% in 2000-2001 to 81% during 2012-2013). Conclusions and Relevance: Large-scale, United States population-based data demonstrate excess tMDS/AML risks following chemotherapy for nearly all solid tumor types, consistent with expanded use of known leukemogenic agents in the 21st century. Continued efforts to reduce treatment-related adverse events, particularly for solid cancer patients with favorable prognosis, are needed.

A novel ASXL1-OGT axis plays roles in H3K4 methylation and tumor suppression in myeloid malignancies.

ASXL1 plays key roles in epigenetic regulation of gene expression through methylation of histone H3K27, and disruption of ASXL1 drives myeloid malignancies, at least in part, via derepression of posterior HOXA loci. However, little is known about the identity of proteins that interact with ASXL1 and about the functions of ASXL1 in modulation of the active histone mark, such as H3K4 methylation. In this study, we demonstrate that ASXL1 is a part of a protein complex containing HCFC1 and OGT; OGT directly stabilizes ASXL1 by O-GlcNAcylation. Disruption of this novel axis inhibited myeloid differentiation and H3K4 methylation as well as H2B glycosylation and impaired transcription of genes involved in myeloid differentiation, splicing, and ribosomal functions; this has implications for myelodysplastic syndrome (MDS) pathogenesis, as each of these processes are perturbed in the disease. This axis is responsible for tumor suppression in the myeloid compartment, as reactivation of OGT induced myeloid differentiation and reduced leukemogenecity both in vivo and in vitro. Our data also suggest that MLL5, a known HCFC1/OGT-interacting protein, is responsible for gene activation by the ASXL1-OGT axis. These data shed light on the novel roles of the ASXL1-OGT axis in H3K4 methylation and activation of transcription.

Smoking and alcohol and subsequent risk of myelodysplastic syndromes in Japan: the Japan Public Health Centre-based Prospective Study.

Smoking and alcohol are important modifiable risk factors for human cancers. However, few epidemiological studies have investigated their association with the risk of myelodysplastic syndromes (MDS). Here, we investigated the association of smoking and alcohol consumption and the risk of MDS in a large-scale population-based cohort study in Japan. We included 95 510 Japanese subjects (45 451 men and 50 059 women; age 40-69 years at baseline) and identified 70 MDS cases (50 men and 20 women) during 18·3 years of follow-up. Hazard ratios (HRs) and 95% confidence intervals (95% CI) were estimated using a Cox regression model adjusted for potential confounders. Smoking was marginally associated with an increased risk of MDS among men, with a HR for current smokers relative to never smokers of 2·11 (95% CI: 0·91-4·89). In contrast, alcohol consumption was associated with a dose-dependent decrease in the risk of MDS among men (nondrinkers: reference, occasional drinkers: HR = 0·48, 0·16-1·41; 0-299 g/week: HR = 0·37, 0·19-0·73; ≥300 g/week: HR = 0·49, 0·22-1·08, P for trend = 0·010). This study showed that alcohol has a significant protective effect on the risk of MDS. In addition, this study might indicate that smoking increases the risk of MDS among Japanese population, as it does in Western populations.

Inhibition of WNT signaling in the bone marrow niche prevents the development of MDS in the Apcdel/+ MDS mouse model.

There is accumulating evidence that functional alteration(s) of the bone marrow (BM) microenvironment contribute to the development of some myeloid disorders, such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). In addition to a cell-intrinsic role of WNT activation in leukemia stem cells, WNT activation in the BM niche is also thought to contribute to the pathogenesis of MDS and AML. We previously showed that the Apc-haploinsufficient mice (Apcdel/+ ) model MDS induced by an aberrant BM microenvironment. We sought to determine whether Apc, a multifunctional protein and key negative regulator of the canonical ß-catenin (Ctnnb1)/WNT-signaling pathway, mediates this disease through modulating WNT signaling, and whether inhibition of WNT signaling prevents the development of MDS in Apcdel/+ mice. Here, we demonstrate that loss of 1 copy of Ctnnb1 is sufficient to prevent the development of MDS in Apcdel/+ mice and that altered canonical WNT signaling in the microenvironment is responsible for the disease. Furthermore, the US Food and Drug Administration (FDA)-approved drug pyrvinium delays and/or inhibits disease in Apcdel/+ mice, even when it is administered after the presentation of anemia. Other groups have observed increased nuclear CTNNB1 in stromal cells from a high frequency of MDS/AML patients, a finding that together with our results highlights a potential new strategy for treating some myeloid disorders.

APG101 efficiently rescues erythropoiesis in lower risk myelodysplastic syndromes with severe impairment of hematopoiesis.

CD95, a member of the death receptor family initiates a caspase-dependent apoptosis, when activated by its ligand CD95L, thought to negatively regulate erythrocyte production in the bone marrow. We have previously shown that CD95 is overexpressed in two thirds of patients with a lower risk myelodysplastic syndrome (MDS) and that resistance to erythropoiesis-stimulating agents (ESA) is linked to poor residual erythropoiesis. In the present study, we show that CD95 overexpression and previous transfusion are independent predictive factors of ESA resistance. To investigate an alternative therapeutic strategy of anemia in ESA-resistant patients, we have conducted a preclinical study of the effects of APG101, a fusion protein consisting of the extracellular domain of human CD95 and the Fc region of human IgG1 on MDS erythropoiesis in vitro. APG101 increases the number of burst-forming unit-erythroid (BFU-E) progenitors derived from CD34+ progenitors in liquid culture and improves overall proliferation rate of erythroid precursors by inhibiting apoptosis. APG101 rescues BFU-E growth in MDS patients presenting with attrition of erythroid progenitors at baseline, independently of CD95 or CD95L expression level. Our data show that overexpression of CD95 at diagnosis is a hallmark of ESA resistance and that severe impairment of erythropoiesis is predictive of erythroid response to APG101 in vitro. These data provide a rationale for further clinical investigation of APG101 in an attempt to treat anemia in lower risk MDS patients.

Genetic predisposition to myelodysplastic syndrome and acute myeloid leukemia in children and young adults.

Myelodysplastic syndrome (MDS) is a clonal blood disorder characterized by ineffective hematopoiesis, cytopenias, dysplasia and an increased risk of acute myeloid leukemia (AML). With the growing availability of clinical genetic testing, there is an increasing appreciation that a number of genetic predisposition syndromes may underlie apparent de novo presentations of MDS/AML, particularly in children and young adults. Recent findings of clonal hematopoiesis in acquired aplastic anemia add another facet to our understanding of the mechanisms of MDS/AML predisposition. As more predisposition syndromes are recognized, it is becoming increasingly important for hematologists and oncologists to have familiarity with the common as well as emerging syndromes, and to have a systematic approach to diagnosis and screening of at risk patient populations. Here, we provide a practical algorithm for approaching a patient with a suspected MDS/AML predisposition, and provide an in-depth review of the established and emerging familial MDS/AML syndromes caused by mutations in the ANKRD26, CEBPA, DDX41, ETV6, GATA2, RUNX1, SRP72 genes. Finally, we discuss recent data on the role of somatic mutations in malignant transformation in acquired aplastic anemia, and review the practical aspects of MDS/AML management in patients and families with predisposition syndromes.

Dietary isoflavone intake is associated with a reduced risk of myelodysplastic syndromes.

Isoflavones have been suggested to have protective effects on certain cancers. However, the association of soya foods or dietary isoflavones with the risk of myelodysplastic syndromes (MDS) has not been examined. Thus, the aim of this hospital-based case-control study undertaken in China in 2012-2013 was to investigate the association between dietary isoflavone intake and MDS risk. The analysis included 208 cases aged 19-85 years with MDS and 208 controls individually matched to the cases by sex, birth quinquennium and residential locality. Information on habitual food intakes, including nine items of soya foods, was sought from in-person interviews using a validated 107-item FFQ. Dietary intakes of daidzein, genistein, glycitein and total isoflavones were estimated using the 2008 US Department of Agriculture Isoflavone Database. OR were calculated from conditional logistic regression after adjustment for potential confounding by demographics, lifestyle and dietary factors. The mean daily intake of total isoflavones was 19·0 mg in cases and 23·0 mg in controls. Dietary intake of isoflavones was inversely associated with the risk of MDS. The adjusted OR in the highest tertile compared with the lowest tertile of intake were 0·43 (95 % CI 0·21, 0·85) for daidzein, 0·36 (95 % CI 0·18, 0·74) for genistein, 0·49 (95 % CI 0·25, 0·97) for glycitein and 0·40 (95 % CI 0·20, 0·81) for total isoflavones. The findings suggest that higher dietary intake of isoflavones is associated with a reduced risk of MDS in a Chinese population.

Tea consumption reduces the risk of de novo myelodysplastic syndromes.

Epidemiologic data suggest that green tea consumption may protect against certain cancers, but no previous study has examined myelodysplastic syndromes (MDS). A hospital-based case-control study was conducted in China in 2012-2013 to investigate the association between tea intake and the risk of de novo MDS in adults. The study included 208 cases aged 19-85 years with MDS and 208 controls individually matched to the cases by gender, 5-year age group and residential locality. Odds ratios (ORs) were estimated using conditional logistic regression. Compared with non-tea drinkers, the adjusted ORs (95% confidence intervals) for all MDS combined were 0.39 (0.20-0.74), 0.45 (0.25-0.79), and 0.40 (0.21-0.77) for those who consumed tea >20 years, ≥2 cups daily, and dried tealeaves ≥750g per annum, respectively. Significant dose-response trends were observed across all the measures. The inverse association existed in both genders, in the refractory anemia with excessive blasts subtype, in cytogenetic 'good' and 'intermediated/poor' prognosis groups, and in the International Prognostic Scoring System lower and higher risk groups, but not in the refractory cytopenia with multilineage dysplasia subtype. The study suggests that regular tea consumption reduces the risk of de novo MDS in the Chinese population.

Fanconi anemia and the development of leukemia.

Fanconi anemia (FA) is a rare autosomal recessive cancer-prone inherited bone marrow failure syndrome, due to mutations in 16 genes, whose protein products collaborate in a DNA repair pathway. The major complications are aplastic anemia, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and specific solid tumors. A severe subset, due to mutations in FANCD1/BRCA2, has a cumulative incidence of cancer of 97% by age 7 years; the cancers are AML, brain tumors, and Wilms tumor; several patients have multiple events. Patients with the other genotypes (FANCA through FANCQ) have cumulative risks of more than 50% of marrow failure, 20% of AML, and 30% of solid tumors (usually head and neck or gynecologic squamous cell carcinoma), by age 40, and they too are at risk of multiple adverse events. Hematopoietic stem cell transplant may cure AML and MDS, and preemptive transplant may be appropriate, but its use is a complicated decision.

Depletion of STAT5 blocks TEL-SYK-induced APMF-type leukemia with myelofibrosis and myelodysplasia in mice.

The spleen tyrosine kinase (SYK) was identified as an oncogenic driver in a broad spectrum of hematologic malignancies. The in vivo comparison of three SYK containing oncogenes, SYK(wt), TEL-SYK and IL-2-inducible T-cell kinase (ITK)-SYK revealed a general myeloexpansion and the establishment of three different hematologic (pre)diseases. SYK(wt) enhanced the myeloid and T-cell compartment, without leukemia/lymphoma development. ITK-SYK caused lethal T-cell lymphomas and the cytoplasmic TEL-SYK fusion induced an acute panmyelosis with myelofibrosis-type acute myeloid leukemia (AML) with up to 50% immature megakaryoblasts infiltrating bone marrow, spleen and liver, additional MPN features (myelofibrosis and granulocyte expansion) and MDS stigmata with megakaryocytic and erythroid dysplasia. LKS cells were reduced and all subsets (LT/ST/MPP) showed reduced proliferation rates. SYK inhibitor treatment (R788) of diseased TEL-SYK mice reduced leukocytosis, spleen and liver infiltration, enhanced the hematocrit and prolonged survival time, but could not significantly reduce myelofibrosis. Stat5 was identified as a major downstream mediator of TEL-SYK in vitro as well as in vivo. Consequently, targeted deletion of Stat5 in vivo completely abrogated TEL-SYK-induced AML and myelofibrosis development, proving Stat5 as a major driver of SYK-induced transformation. Our experiments highlight the important role of SYK in AML and myelofibrosis and prove SYK and STAT5 inhibitors as potent treatment options for those diseases.

Genistein protects hematopoietic stem cells against G-CSF-induced DNA damage.

Granulocyte colony-stimulating factor (G-CSF) has been used to treat neutropenia in various clinical settings. Although clearly beneficial, there are concerns that the chronic use of G-CSF in certain conditions increases the risk of myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML). The most striking example is in severe congenital neutropenia (SCN). Patients with SCN develop MDS/AML at a high rate that is directly correlated to the cumulative lifetime dosage of G-CSF. Myelodysplastic syndrome and AML that arise in these settings are commonly associated with chromosomal deletions. We have demonstrated in this study that chronic G-CSF treatment in mice results in expansion of the hematopoietic stem cell (HSC) population. In addition, primitive hematopoietic progenitors from G-CSF-treated mice show evidence of DNA damage as demonstrated by an increase in double-strand breaks and recurrent chromosomal deletions. Concurrent treatment with genistein, a natural soy isoflavone, limits DNA damage in this population. The protective effect of genistein seems to be related to its preferential inhibition of G-CSF-induced proliferation of HSCs. Importantly, genistein does not impair G-CSF-induced proliferation of committed hematopoietic progenitors, nor diminishes neutrophil production. The protective effect of genistein was accomplished with plasma levels that are attainable through dietary supplementation.

CD16xCD33 bispecific killer cell engager (BiKE) activates NK cells against primary MDS and MDSC CD33+ targets.

Myelodysplastic syndromes (MDS) are stem cell disorders that can progress to acute myeloid leukemia. Although hematopoietic cell transplantation can be curative, additional therapies are needed for a disease that disproportionally afflicts the elderly. We tested the ability of a CD16xCD33 BiKE to induce natural killer (NK) cell function in 67 MDS patients. Compared with age-matched normal controls, CD7(+) lymphocytes, NK cells, and CD16 expression were markedly decreased in MDS patients. Despite this, reverse antibody-dependent cell-mediated cytotoxicity assays showed potent degranulation and cytokine production when resting MDS-NK cells were triggered with an agonistic CD16 monoclonal antibody. Blood and marrow MDS-NK cells treated with bispecific killer cell engager (BiKE) significantly enhanced degranulation and tumor necrosis factor-α and interferon-γ production against HL-60 and endogenous CD33(+) MDS targets. MDS patients had a significantly increased proportion of immunosuppressive CD33(+) myeloid-derived suppressor cells (MDSCs) that negatively correlated with MDS lymphocyte populations and CD16 loss on NK cells. Treatment with the CD16xCD33 BiKE successfully reversed MDSC immunosuppression of NK cells and induced MDSC target cell lysis. Lastly, the BiKE induced optimal MDS-NK cell function irrespective of disease stage. Our data suggest that the CD16xCD33 BiKE functions against both CD33(+) MDS and MDSC targets and may be therapeutically beneficial for MDS patients.

Pharmacological methods to reduce disease recurrence.

Allogeneic stem cell transplantation is an increasingly important treatment option in patients with high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Although there has been substantial progress in reducing transplantation-related mortality (TRM), little progress has been made in reducing the risk of disease relapse, which continues to represent the major cause of treatment failure in patients allografted for AML and MDS. Experience with myeloablative conditioning regimens has demonstrated that, although intensification of the preparative regimen reduces relapse risk, any survival benefit is blunted by a concomitant increase in TRM. A similar inverse correlation between relapse risk and TRM is observed in patients allografted using a reduced-intensity conditioning regimen. However, the markedly lower toxicity of such regimens has permitted the design of novel conditioning strategies aimed at maximizing antitumor activity without excessive transplant toxicity. Coupled with recent advances in drug delivery and design, this has allowed the development of a spectrum of new conditioning regimens in patients with high-risk AML and MDS. At the same time, the optimization of a graft-versus-leukemia (GVL) effect by minimizing posttransplantation immunosuppression, with or without the infusion of donor lymphocytes, is essential if the risk of disease relapse is to be reduced. Recently, the delivery of adjunctive posttransplantation therapies has emerged as a promising method of augmenting antileukemic activity, either through a direct antitumor activity or consequent upon pharmacological manipulation of the alloreactive response. Taken together these advances present a realistic possibility of delivering improved outcome in patients allografted for high-risk AML or MDS.

CMV reactivation after allogeneic HCT and relapse risk: evidence for early protection in acute myeloid leukemia.

The association between cytomegalovirus (CMV) reactivation and relapse was evaluated in a large cohort of patients with acute myeloid leukemia (AML) (n = 761), acute lymphoblastic leukemia (ALL) (n = 322), chronic myeloid leukemia (CML) (n = 646), lymphoma (n = 254), and myelodysplastic syndrome (MDS) (n = 371) who underwent allogeneic hematopoietic cell transplantation (HCT) between 1995 and 2005. In multivariable models, CMV pp65 antigenemia was associated with a decreased risk of relapse by day 100 among patients with AML (hazard ratio [HR] = 0.56; 95% confidence interval [CI], 0.3-0.9) but not in patients with ALL, lymphoma, CML, or MDS. The effect appeared to be independent of CMV viral load, acute graft-versus-host disease, or ganciclovir-associated neutropenia. At 1 year after HCT, early CMV reactivation was associated with reduced risk of relapse in all patients, but this did not reach significance for any disease subgroup. Furthermore, CMV reactivation was associated with increased nonrelapse mortality (HR = 1.31; 95% CI, 1.1-1.6) and no difference in overall mortality (HR = 1.05; 95% CI, 0.9-1.3). This report demonstrates a modest reduction in early relapse risk after HCT associated with CMV reactivation in a large cohort of patients without a benefit in overall survival.

[Myelodysplastic syndromes]. / Myelodysplastische Syndrome.

The myelodysplastic syndromes (MDS) are clonal disorders of hematopoietic stem cells. The transformation rate to acute myeloid leukemia reaches 30-40 %. In early phases of the disease, the clonal cells have a growth advantage but suffer from premature apoptosis, which explains the paradox of a cellular bone marrow coupled to peripheral blood cytopenias. At later stages, additional genetic aberrations accumulate and lead to proliferation with leukemic transformation. Patients with early MDS benefit from supportive therapy or growth factors. Sometimes, immunological or immunomodulatory treatments can suppress the malignant clone and strengthen normal hematopoiesis for sustained periods. Patients with advanced MDS are usually treated with cytotoxic therapy followed by allogeneic stem cell transplantation or with epigenetic therapy to initiate differentiation and slow down proliferation.

Metastatic bone disease in the era of bone-targeted therapy: clinical impact.

Advances in the diagnosis and treatment of tumors by surgery, chemotherapy, biotherapy, radiotherapy and other modalities have increased the survival of cancer patients over the last 20 years. As a consequence, bone now represents the third most common site of metastatic involvement after the lung and liver. Approximately 20-25% of patients with neoplastic disease develop clinically evident bone metastases (BMs) during the natural course of their illness, with a further 50% of such lesions being identified during autopsy. BMs are the major cause of morbidity in cancer patients because of their epidemiological and clinical impact. Pain is the most frequent symptom in about 75% of patients but other serious complications can also occur, such as pathological fractures, spinal cord compression, hypercalcemia and bone marrow suppression. These complications worsen the patient's general condition and reduce patients' mobility, facilitating the development of lung infections, skin ulcers, deep vein thrombosis, etc., and ultimately reducing prognosis and quality of life. The frequency of serious complications depends on the site and type of lesions and the treatment administered. Over the last 10 years, the introduction of bisphosphonates for the treatment of patients with BMs has led to a marked decrease in the frequency of complications, thus improving quality of life and clinical outcome. Furthermore, progress in understanding the pathophysiology of bone metastases has resulted in the development of new bone-targeted molecules such as denosumab. We therefore felt it would be useful to report on the epidemiological, clinical and economic impact of bone disease in a cancer setting.

Anti-thymocyte globulins capable of binding to T and B cells reduce graft-vs-host disease without increasing relapse.

Anti-thymocyte globulin (ATG) is polyclonal, containing Ab specificities capable of binding to various immune-cell subsets implicated in the pathogenesis of GVHD, including T cells, B cells, natural killer cells, monocytes/macrophages, neutrophils and DC. We wished to determine which ATG specificities are important for GVHD prevention. We measured day 7 serum levels of 23 ATG specificities in 120 hematopoietic cell transplant recipients whose myeloablative conditioning included 4.5 mg/kg ATG (thymoglobulin). High levels of ATG specificities capable of binding to T- and B-cell subsets were associated with a low likelihood of acute GVHD (aGVHD). High levels of these ATG specificities were associated with increased rates of viral but not bacterial or fungal infections. They were not associated with an increased risk of malignancy relapse; on the contrary, high levels of ATG specificities capable of binding to regulatory T cells and invariant NKT cells were associated with a low risk of relapse. In conclusion, high levels of ATG antibodies to Ag(s) expressed on T and B cells are associated with a low risk of aGVHD and a high risk of viral but not bacterial or fungal infections. These antibodies have neutral or beneficial effects on relapse.

Allogeneic hematopoietic stem cell transplantation (HSCT) for high-risk acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS): how can we improve outcomes in the near future?

Substantive advances in the past decade or so have allowed for a wider spectrum of patients to undergo allo-HSCT and have increased its safety, thus broadening the application of this therapy[36]. That said, disease persistence or (more commonly) recurrence remains as primary problems. A combination of "extrinsic" and "intrinsic" methods is now available and ready for additional clinical testing and/or utilization. Fortunately, one can be somewhat optimistic that better results will be achieved, perhaps very soon. However, and as these strategies and techniques are evaluated, it should be realized that some may be too complex and/or expensive for widespread use as the need to reduce costs becomes more pressing.