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Background: The mixed-lineage leukemia (MLL) gene is located on chromosome 11q23. The MLL gene can be rearranged to generate partial tandem duplications (MLL-PTD), which occurs in about 5-10% of acute myeloid leukemia (AML) with a normal karyotype and in 5-6% of myelodysplastic syndrome (MDS) patients. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is currently one of the curative therapies available for AML and MDS with excess blasts (MDS-EB). However, how the prognosis of patients with high levels of MLL-PTD after allo-HSCT, and whether MLL-PTD could be used as a reliable indicator for minimal residual disease (MRD) monitoring in transplant patients remains unknown. Our study purposed to analyze the dynamic changes of MLL-PTD peri-transplantation and the best threshold for predicting relapse after transplantation., Methods: We retrospectively collected the clinical data of 48 patients with MLL-PTD AML or MDS-EB who underwent allo-HSCT in Peking University People's Hospital. The MLL-PTD was examined by real-time quantitative polymerase chain reaction (RQ-PCR) at the diagnosis, before transplantation and the fixed time points after transplantation. Detectable MLL-PTD/ABL > 0.08% was defined as MLL-PTD positive in this study., Results: The 48 patients included 33 AML patients and 15 MDS-EB patients. The median follow-up time was 26(0.7-56) months after HSCT. In AML patients, 7 patients (21.2%) died of treatment-related mortality (TRM), 6 patients (18.2%) underwent hematological relapse and died ultimately. Of the 15 patients with MDS-EB, 2 patients (13.3%) died of infection. The 3-year cumulative incidence of relapse (CIR), overall survival (OS), disease-free survival (DFS) and TRM were 13.7 ± 5.2, 67.8 ± 6.9, 68.1 ± 6.8 and 20.3% ± 6.1%, respectively. ROC curve showed that post-transplant MLL-PTD ≥ 1.0% was the optimal cut-off value for predicting hematological relapse after allo-HSCT. There was statistical difference between post-transplant MLL-PTD ≥ 1.0% and MLL-PTD < 1.0% groups (3-year CIR: 75% ± 15.3% vs. 0%, P < 0.001; 3-year OS: 25.0 ± 15.3% vs. 80.7% ± 6.6%, P < 0.001; 3-year DFS: 25.0 ± 15.3% vs. 80.7 ± 6.6%, P < 0.001; 3-year TRM: 0 vs. 19.3 ± 6.6%, P = 0.277). However, whether MLL-PTD ≥ 1% or MLL-PTD < 1% before transplantation has no significant difference on the prognosis., Conclusions: Our study indicated that MLL-PTD had a certain stability and could effectively reflect the change of tumor burden. The expression level of MLL-PTD after transplantation can serve as an effective indicator for predicting relapse., (© 2021. The Author(s).)

Background: The value of pre-transplant cytoreductive therapy for patients with myelodysplastic syndromes (MDS) is controversial. Here, we conducted a meta-analysis to explore the effects of cytoreduction before transplantation., Methods: PubMed, Embase, Cochrane, and Chinese databases were searched to identify studies comparing post-transplant outcomes in MDS patients receiving different pre-transplant therapy. Pooled hazard ratios (HRs) and 95 % confidence intervals (CI) were calculated., Results: Eighteen reports were included. Post-transplant outcomes were similar for MDS patients receiving pre-transplant cytoreductive therapy and upfront transplantation in terms of overall survival (OS: HR, 0.92; 95 % CI, 0.79-1.07), relapse-free survival (RFS: HR, 1.18; 95 % CI, 0.94-1.47), cumulative incidence of relapse (CIR: HR, 1.08; 95 % CI, 0.88-1.33), and non-relapse mortality (NRM: HR, 0.93; 95 % CI, 0.74-1.18). Pre-transplant hypomethylating agents (HMAs) and chemotherapy were not different regarding post-transplant OS, RFS, CIR, and NRM. Achieving complete remission (CR) before transplantation was associated with increased RFS (HR, 0.80; 95 %CI, 0.63-1.00) and decreased NRM (HR, 0.53; 95 % CI, 0.32-0.90) when compared with upfront transplantation., Conclusions: Timely transplantation is of great value for MDS patients. Suitable pre-transplant cytoreduction could be used during the search for donors., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative therapy for advanced myelodysplastic syndrome (MDS). However, the value of pretransplant cytoreduction remains debatable., Patients and Methods: We retrospectively compared the outcomes of upfront transplantation and pretransplant cytoreduction. Of 69 patients, 39 received upfront allo-HSCT and 30 received pretransplant cytoreduction, including chemotherapy (n = 16), hypomethylating agents (HMAs, n = 6), and HMAs with chemotherapy (n = 8)., Results: The upfront group achieved similar overall survival (OS) and a trend of better progression-free survival (PFS) from diagnosis compared with the cytoreduction group (3-year PFS, 64.0% vs. 44.4%, P = .076). Posttransplant outcomes were comparable between the two groups in terms of OS, relapse-free survival (RFS), cumulative incidence of relapse (CIR), and non-relapse mortality (NRM). In patients with ≥2 mutations, the upfront group achieved better OS and PFS (3-year OS, 100.0% vs. 68.6%, P = .044; 3-year PFS: 92.3% vs. 43.9%, P = .016) than the cytoreduction group. Patients achieving remission in the cytoreduction group had outcomes similar to the upfront group, but those without remission before transplantation had a significantly worse posttransplant OS (3-year OS, 46.7% vs. 75.7%, P = .038). Patients with pretransplant HMAs had better PFS than those with chemotherapy or HMAs plus chemotherapy (P < 0.05)., Conclusion: Compared with pretransplant cytoreduction, upfront allo-HSCT might provide more benefit to some patients with advanced MDS if there are suitable donors. HMAs would be a good alternative during the donor search., Competing Interests: Declarations of Competing Interest None., (Copyright © 2021. Published by Elsevier Inc.)

Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are usually associated with poor outcomes, especially in high-risk AML/MDS. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative option for patients suffering from high-risk AML/MDS. However, many patients relapse after allo-HSCT. Novel therapy to prevent relapse is urgently needed. Both the BCL-2 inhibitor venetoclax (VEN) and the hypomethylating agent decitabine (DEC) possess significant antitumor activity effects against AML/MDS. Administration of DEC has been shown to ameliorate graft-versus-host disease (GVHD) and boost the graft-versus-leukemia (GVL) effect post-transplantation. We therefore conducted a prospective study (ChiCTR1900025374) to examine the tolerability and efficacy of a maintenance therapy of low-dose decitabine (LDEC) plus VEN to prevent relapse after allo-HSCT for high-risk AML/MDS patients. Twenty patients with high-risk AML (n = 17) or high-risk MDS (n = 3) post-transplantation were recruited. Approximately day 100 post-transplantation, all patients received LDEC (15 mg/m 2 for 3 d) followed by VEN (200 mg) on d 1-21. The cycle interval was 2 mo, and there was 10 cycles. The primary end points of this study were rates of overall survival (OS) and event-free survival (EFS). The secondary endpoints included adverse events (AEs), cumulative incidence of relapse (CIR), nonrelapse mortality (NRM), incidences of acute GVHD (aGVHD) and chronic GVHD (cGVHD), and incidences of viral infection after allo-HSCT. Survival outcomes were assessed using Kaplan-Meier analysis. The median follow-up was 598 (149-1072) d. Two patients relapsed, 1 died, and 1 is still alive after the second transplant. The 2-y OS and EFS rates were 85.2% and 84.7%, respectively. The median 2-y EFS time was 525 (149-1072) d, and 17 patients still had EFS and were alive at the time of this writing. The most common AEs were neutropenia, anemia, thrombocytopenia, neutropenic fever, and fatigue. Grade 2 or 3 AEs were observed in 35% (7/20) and 20% (4/20) of the patients, respectively. No grade >3 AEs were observed. aGVHD (any grade) and cGVHD (limited or extensive) occurred in 55% and 20% of patients, respectively. We conclude that LDEC + VEN can be administered safely after allo-HSCT with no evidence of an increased incidence of GVHD, and this combination decreases the relapse rate in high-risk AML/MDS patients. This novel maintenance therapy may be a promising way to prevent relapse in high-risk AML/MDS patients., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Purpose: Patients with myelodysplastic syndrome (MDS) are at risk of relapse after allogeneic hematopoietic cell transplantation. The utility of ultra-deep genomic testing to predict and the impact of conditioning intensity to prevent MDS relapse are unknown., Methods: Targeted error-corrected DNA sequencing was performed on preconditioning blood samples from patients with MDS (n = 48) from the Blood and Marrow Transplant Clinical Trials Network 0901 phase III randomized clinical trial, which compared outcomes by allogeneic hematopoietic cell transplantation conditioning intensity in adult patients with < 5% marrow myeloblasts and no leukemic myeloblasts in blood on morphological analysis at the time of pretransplant assessment. Clinical end points (53-month median follow-up) included transplant-related mortality (TRM), relapse, relapse-free survival (RFS), and overall survival (OS). Of the 48 patients examined, 14 experienced TRM, 23 are relapse-free, and 11 relapsed, of which 7 died., Results: Using a previously described set of 10 gene regions, 42% of patients (n = 20) had mutations detectable before random assignment to reduced intensity conditioning (RIC) or myeloablative conditioning (MAC). Testing positive was associated with increased rates of relapse (3-year relapse, 40% v 11%; P = .022) and decreased OS (3-year OS, 55% v 79%, P = .045). In those testing positive, relapse rates were higher (3-year relapse, 75% v 17%; P = .003) and RFS was lower (3-year RFS, 13% v 49%; P = .003) in RIC versus MAC arms. Testing additional genes, including those associated with MDS, did not improve prognostication., Conclusion: This study provides evidence that targeted DNA sequencing in patients with MDS before transplant can identify those with highest post-transplant relapse rates. In those testing positive, random assignment to MAC lowered but did not eliminate relapse risk., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/cci/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). No potential conflicts of interest were reported., (© 2021 by American Society of Clinical Oncology.)

Acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) generally confers poor prognosis; however, the clinical outcome remains heterogeneous. We sought to further stratify this subentity of AML by performing a retrospective analysis of 179 adult patients with AML-MRC diagnosed at our institution. Based on 2016 World Health Organization diagnostic criteria, 44 (25%) patients had multilineage dysplasia alone (AML-MRC-M), 74 (41%) had history of myelodysplastic syndrome (MDS) or myelodysplastic/myeloproliferative disease (AML-MRC-H), and 61 (34%) had MDS-related cytogenetics (AML-MRC-C). AML-MRC-M and hematopoietic stem cell transplantation (HSCT) were associated with prolonged event-free survival (EFS) (P = 0.0051 and P < 0.0001, respectively) and overall survival (OS) (P = 0.0015 and P < 0.0001, respectively), whereas AML-MRC-C and age ≥60 years were associated with shorter EFS (P = 0.028 and P = 0.015, respectively) and OS (P = 0.021 and P = 0.013, respectively). Of note, NPM1 mut did not affect the patient's outcome. Multivariable analysis confirmed HSCT and AML-MRC-C as independent predictors for EFS (P < 0.0001 and P = 0.0342, respectively) and OS (P < 0.0001 and P = 0.0295, respectively). AML-MRC-M was an independent predictor for OS (P = 0.0449). When compared with a control group of 105 patients with normal karyotype AML not otherwise specified (NK-AML-NOS), patients with AML-MRC-M had similar EFS and OS (P = 0.99 and P = 0.91, respectively). However, AML-MRC-H and AML-MRC-C were associated with shorter EFS and OS (P = 0.0002 and P < 0.0001, respectively) than the same control group. In a subset of patients, next-generation sequencing analysis showed AML-MRC-M was associated with ASXL1 mutation compared with NK-AML (56% vs 6%). In conclusion, AML-MRC-M demonstrates a superior clinical outcome compared with the rest of the AML-MRC group. They have comparable outcomes to NK-AML-NOS, and these data suggest AML-MRC-M may be considered not to be classified in the same group as patients with other AML-MRC., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose of Review: Myelodysplastic syndromes (MDS) are heterogeneous diseases that principally affect older adults. Allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative therapy; however, non-relapse mortality (NRM) accounts for as many as 40% of deaths after HCT and underscores the need for careful patient selection. We review the common indications and causes of failure after HCT in MDS., Recent Findings: Appropriate patient selection is necessary to optimize HCT outcomes and maximize the life-expectancies of MDS patients. The international prognostic scoring systems (IPSS) and revised IPSS (IPSS-R) are used to identify high-risk patients and guide decision making. Neither scoring system incorporates molecular mutations, which are now recognized as important predictors of disease biology and clinical outcomes. Patient and disease characteristics including age, comorbid conditions, iron overload, blast percentage, and other features may impact post-HCT outcomes. An accurate assessment of the disease risk and patient qualities that affect NRM is necessary to optimize post-HCT outcomes. In this review, we summarize the risk factors for, and common causes of NRM, as well as markers of poor-risk disease that should lead providers to consider allogeneic HCT in MDS patients.

Purpose of Review: Myelodysplastic syndrome (MDS) is a heterogeneous hematological disorder characterized by a spectrum of clinical presentation, cytogenetic, and somatic gene mutations and the risk of transformation to acute leukemia. Management options include observation, supportive care, blood transfusion, administration of growth factors and/or hypomethylating agents, and hematopoietic cell transplant (HCT) either upfront or after disease progression., Recent Findings: Currently, HCT is the only curative therapy available for patients with MDS, with multiple factors such as donor availability, patient, and disease characteristics being involved in making the decision to proceed with transplant. In this article, we summarize (1) overall prognosis and natural history of MDS, (2) currently available non-HCT therapy with a focus on hypomethylating agents (HMA), (3) outcomes after HCT in patients with MDS, (4) factors to be considered to proceed to HCT for treatment of MDS, and (5) more recent/ongoing studies relevant to HCT decision-making processes.

Background: The optimal conditioning regimen for alloHCT in children with myeloid malignancies remains undefined., Procedure: We performed a retrospective review of children undergoing alloHCT for AML and MDS over a 10-year period (2008-2018) at our institution, comparing the outcomes of recipients of either a myeloablative busulfan- or reduced toxicity mel/thio-based conditioning regimen., Results: A total of 49 patients underwent alloHCT for AML/MDS (mel/thio, N = 21; busulfan, N = 28). Mel/thio recipients were selected due to pretransplant comorbidities. Recipients of mel/thio were more likely to have t-AML, and less likely to have MRD <0.1% at the time of alloHCT (57.1% vs 82.1%). Graft failure was more common in busulfan recipients; engraftment kinetics were similar between groups. Sinusoidal obstructive syndrome was diagnosed in 21% of busulfan and no mel/thio recipients (P = .03). One patient in each group died from TRM. Relapse incidence was comparable (mel/thio-29% vs busulfan-32%); however, relapse occurred significantly later in recipients of mel/thio conditioning (median d + 396 vs d + 137; P = .01). As a result, there was a trend toward improved OS at 1 and 3 years in mel/thio recipients (95% vs 74%, P = .06; and 75% vs 50%, P = .11; respectively)., Conclusion: In our single institution, when compared to myeloablative busulfan-based conditioning, use of a mel/thio-based reduced toxicity regimen resulted in comparable outcomes, despite higher risk patient and disease characteristics. Mel/thio recipients had both more comorbidities and higher risk disease profile, which did not translate into higher rates of either TRM or relapse., (© 2020 Wiley Periodicals, Inc.)

A 24-year-old man was diagnosed with myelodysplastic syndrome and received a haploidentical hematopoietic stem cell transplant. The patient experienced graft failure posttransplant. Analysis of specific antibodies revealed that the patient had strongly positive donor-specific antibodies; therefore, we changed the donor to the patient's mother and added a single unit of cord blood to perform the second transplant. Corresponding treatments targeting donor-specific antibodies were administered to reverse the graft rejection and to reduce the antibody load. The grafts were implanted successfully, but the patient developed an invasive fungal infection. A lung biopsy was performed, and the pathogen was confirmed to be Aspergillus terreus via gene sequencing and analysis. The combined treatment of micafungin and posaconazole had good efficacy in this case, and this patient now receives close follow-up and receives oral posaconazole for antifungal maintenance treatment.

Unrelated umbilical cord blood transplantation (UCBT) is an alternative to provide transplants in children with acute leukemia or myelodysplastic syndrome who lack a related donor. Intravenous Busulfan (Bu) combined with therapeutic drug monitoring-guided dosing has been increasingly used, with more predictable bioavailability and better outcomes comparing to oral Bu. There is still an important variation in Bu pharmacokinetic between patients that is associated with an increased risk of toxicity and graft failure. The objective of the study was to analyze the impact of first-dose pharmacokinetic adapted myeloablative conditioning regimen of intravenous Bu on the different outcomes after transplantation. Data of 36 children who underwent allogeneic HSCT with Bu plus a second alkylating agent at Sainte Justine Hospital in Montreal, Canada, between December 2000 and April 2012 were analyzed. For children with high risk myeloid malignancies receiving an UCBT, first dose Bu pharmacokinetic seems to be a significant prognostic factor, influencing neutrophil (100% vs 67.9%) and platelet recovery (95.5% vs 70.5%), non-relapse mortality (0% vs 18.6%), EFS (64% vs 28.6%) and OS (81.3% vs 37.5%) for a first-dose steady-state concentration (Css) <600ng/mL vs >600ng/mL, respectively. These data reinforce the importance of Busulfan therapeutic drug monitoring-guided dosing in pediatric HSCT patients, particularly in the context of UCBT.

Background: Next-generation sequencing has identified somatic mutations that are prognostic of cancer., Patients and Methods: We evaluated the incidence and prognostic significance of somatic mutations in 89 myelodysplastic syndrome (MDS) patients who received an allogeneic hematopoietic cell transplantation. Next-generation sequencing was performed on paraffin embedded bone marrow, which was obtained at a median of 31 days before initiating the preparative regimen., Results: The 3 most common subtypes of MDS were refractory anemia with excess blasts (RAEB)-1 (35%), RAEB-2 (29%), and refractory cytopenia with multilineage dysplasia (18%). Most patients (91%) received a myeloablative regimen of fludarabine with intravenous busulfan. Somatic mutations (> 0) were identified in 39 (44%) of analyzed samples. The 6 most commonly identified gene mutations were ASXL1 (8%), DNMT3A (8%), RUNX1 (7%), KRAS (6%), IDH2 (4%), and TP53 (4%). The low incidence of mutations in our study sample might be explained by tissue source and stringent variant-calling methodology. Moreover, we speculate that the low incidence of mutations might, perhaps, also be explained by previous azacitidine treatment in 82% of cases. Multivariate analysis identified TP53 (hazard ratio [HR], 3.82; 95% confidence interval [CI], 1.12-13.09; P = .03) and IDH2 mutations (HR, 4.74; 95% CI, 1.33-16.91; P = .02) as predictors of inferior 3-year overall survival., Conclusion: This study furthers implementation of clinical genomics in MDS and identifies TP53 and IDH2 as targets for pre- or post-transplant therapy., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Allogeneic hematopoietic stem-cell transplantation and solid-organ transplantation are associated with an increased risk of secondary neoplasms. Indeterminate cell histiocytosis (ICH) is a rare disease composed of so-called indeterminate cells, an alleged cutaneous dendritic cell subset displaying histological and some ultrastructural and immunophenotypic features of Langerhans cells but lacking Birbeck granules. We report a case of cutaneous ICH occurring after allogeneic hematopoietic stem-cell transplantation for a myelodysplastic syndrome in a 56-year-old man. Microsatellite analysis demonstrated that the neoplastic cells were derived from the donor's hematopoietic system. This case broadens the spectrum of complications after stem-cell transplantation and demonstrates that cutaneous ICH in the setting of myelodysplastic syndromes may have a nonrelated origin to dysplastic myeloid cells.

Purpose To compare a reduced-intensity conditioning regimen (RIC) with a myeloablative conditioning regimen (MAC) before allogeneic transplantation in patients with myelodysplastic syndrome (MDS) within a randomized trial. Patients and Methods Within the European Society of Blood and Marrow Transplantation, we conducted a prospective, multicenter, open-label, randomized phase III trial that compared a busulfan-based RIC with MAC in patients with MDS or secondary acute myeloid leukemia. A total of 129 patients were enrolled from 18 centers. Patients were randomly assigned in a 1:1 ratio and were stratified according to donor, age, and blast count. Results Engraftment was comparable between both groups. The CI of acute graft-versus-host disease II to IV was 32.3% after RIC and 37.5% after MAC ( P = .35). The CI of chronic graft-versus-host disease was 61.6% after RIC and 64.7% after MAC ( P = .76). The CI of nonrelapse mortality after 1 year was 17% (95% CI, 8% to 26%) after RIC and 25% (95% CI, 15% to 36%) after MAC ( P = .29). The CI of relapse at 2 years was 17% (95% CI, 8% to 26%) after RIC and 15% (95% CI, 6% to 24%) after MAC ( P = .6), which resulted in a 2-year relapse-free survival and overall survival of 62% (95% CI, 50% to 74%) and 76% (95% CI, 66% to 87%), respectively, after RIC, and 58% (95% CI, 46% to 71%) and 63% (95% CI, 51% to 75%), respectively, after MAC ( P = .58 and P = .08, respectively). Conclusion This prospective, randomized trial of the European Society of Blood and Marrow Transplantation provides evidence that RIC resulted in at least a 2-year relapse-free survival and overall survival similar to MAC in patients with MDS or secondary acute myeloid leukemia.

Objective: To investigate the clinical and laboratorial characteristics of patients with myelodysplastic syndrome (MDS) and erythroid hyperplasia. Methods: MDS patients whose bone marrow was hypercellular with erythroid lineage more than 50% and blasts account for less than 20% of non-erythroid cells were enrolled in this study. The ratio of mature erythrocytes to nucleated erythrocytes was no more than 20, namely MDS patients with erythroid hyperplasia(MDS-E). The retrospective analysis comprised 102 patients with MDS-E from the First Affiliated Hospital of Suzhou University. Clinical characteristics, karyotype, and the prognostic significance of erythroid hyperplasia were evaluated. Results: A total of 48 MDS-E patients (47.1%) presented a variety of cytogenetic abnormalities. The most frequently involved chromosomes were chromosome 8 (39.5% of all abnormal karyotypes), chromosome 7 (22.9%), followed by chromosome 5 (18.8%), chromosome 1 (16.7%) and chromosome 20 (16.7%). Hemoglobin (Hb) level affected the prognosis by survival analysis. The overall survival (OS) of MDS-E patients with Hb equal or more than 70 g/L was longer than that of patients less than 70 g/L ( P <0.001). Allogeneic hematopoietic stem cell transplantation (HSCT) significantly improved the OS compared with best supportive care ( P <0.001) and chemotherapy ( P <0.001). The extent of erythroid hyperplasia in bone marrow did not impact on prognosis ( P =0.187). Conclusions: Compared with previous reports of MDS patients, MDS-E patients have higher level of erythroid hyperplasia, more common erythroid dyshematopoiesis, more frequent 8 and 1 chromosome abnormalities. The degree of erythroid hyperplasia is not correlated with prognosis. Allogeneic hematopoietic stem cell transplantation improves the prognosis.

Infections with adenovirus (AdV) and herpesviruses can result in considerable morbidity and mortality in pediatric hematopoietic stem cell transplant (SCT) recipients. Herpes simplex virus (HSV) reactivations are usually prevented by acyclovir (ACV) prophylaxis, whereas cidofovir (CDV) has been used off indication to manage AdV infections. We report a child with myelodysplastic syndrome undergoing multiple SCT, who experienced HSV-1 disease including severe mucositis and herpetic whitlow, as well as high viral load AdV DNAemia. Both ACV and CDV were ineffective; however, viral loads were decreased with brincidofovir, resulting in viral clearance. A subsequent Epstein-Barr virus disease with relevant meningoencephalitis responded to rituximab., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The hematopoietic stem cell transplantation (HSCT) is the only curative alternative for Myelodysplastic Syndrome (MDS), but many patients are not eligible for this treatment, as there are several limiting factors, especially in the case of patients with low-risk MDS. The aim of this study is to discuss the factors that can guide the decision-making on referring or not a patient to HSCT. Three cases of MDS, two of which were submitted to HSCT are presented. We intend to report the difficulties in referring patients with MDS to transplant and the prognostic factors that contribute to define eligibility.

Disseminated infection by Hormographiella aspergillata is extremely rare and small intestine involvement has not been reported previously. A 51-year-old man with myelodysplastic syndrome developed pneumonia after cord blood cell transplantation. Fungal growth from the biopsied lung was identified as H. aspergillata by morphology and the gene analysis. Although antifungal agents including voriconazole and liposomal amphotericin B were administered, he died of disseminated H. aspergillata infection. We review the literature and discuss the treatment and prognosis., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

We present the case of a patient, with history of myelodysplastic syndrome and recent bone marrow transplant, who developed fulminant liver failure secondary to herpes simplex virus (HSV) hepatitis. His presentation was unique, as findings of liver microabscesses on computed tomography scan have not been described previously in this patient population. Despite initial treatment with acyclovir, he continued to deteriorate, and later sensitivities found the HSV strain to be resistant to acyclovir. HSV hepatitis with secondary liver failure is rare and, without appropriate treatment, its mortality is >80%. Early suspicion and immediate therapy are the keys to improve patient survival., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The impact of antithymocyte globulin (ATG) in the setting of a myeloablative conditioning transplantation remains controversial, especially when using bone marrow (BM) as the stem cell source., Methods: We therefore conducted a retrospective analysis to investigate the impact of ATG in patients with acute myeloid leukemia or myelodysplastic syndrome receiving myeloablative conditioning followed by a matched 10 of 10 unrelated donor transplant from BM or peripheral blood stem cells (PBSCs). Our study included 356 patients conditioned with cyclophosphamide associated with fractionated total body irradiation or busulfan., Results: Median follow-up was 17.6 months (range, 0-156). The ATG and PBSCs were the only variables that independently decreased the cumulative incidence (CI) of chronic graft-versus-host disease (GvHD) (hazards ratio [HR], 0.4; 95% CI, 0.21-0.73; P < 0.01; and HR, 0.53; 95% CI, 0.30-0.90; P = 0.02, respectively). The ATG had no impact on overall survival, disease-free survival, relapse, and nonrelapse mortality. In the PBSC group (n = 139), ATG was associated with a lower CI of both grades III to IV acute GvHD (HR, 0.17; 95% CI, 0.03-0.91; P = 0.04), chronic GvHD (HR, 0.31; 95% CI, 0.11-0.87; P = 0.03), and GvHD-free/relapse-free survival (HR, 0.48; 95% CI, 0.29-0.80; P < 0.01), whereas these correlations were not significant in the group of patients (n = 217) receiving BM (HR, 0.36; 95% CI, 0.11-1.93; P = 0.06 for grade III-IV acute GvHD; HR, 0.49; 95% CI, 0.22-1.06; P = 0.08 for chronic GvHD; and HR, 0.69; 95% CI, 0.46-1.01; P = 0.06 for GvHD-free/relapse-free survival)., Conclusions: Although our results confirm the recommendation for ATG to be added after PBSC transplantation, no obvious benefit was identified using this approach in the setting of BM transplantation. Only prospective studies may yield definitive answers to this question.

Background: Relapse of primary hematologic disease constitutes an important reason for failure of allogeneic hematopoietic stem cell transplantation (alloHSCT). There are very few treatment modalities for this indications. Therefore, there is a need for novel effective therapies and even more for the prevention of relapse. There are scarce data that azacitidine can be used for these purposes., Methods: At the Polish Adult Leukemia Group, we retrospectively analyzed the results of azacitidine treatment after alloHSCT. Relapsing patients, patients with minimal residual disease/mixed chimerism, and patients in complete remission with high risk of relapse were analyzed separately. There were 17 patients, 6 with myelodysplastic syndrome, 11 with acute myeloid leukemia, 8 male, and overall median age of 56 years (range, 15-78); 7 patients received donor lymphocyte infusion (DLI)., Results: Patients treated because of relapse received a median of 3 (range, 1-6) cycles of azacitidine, patients receiving preemptive treatment received a median of 4 cycles (range, 2-6), and those on maintenance received a median of 5 cycles (range, 3-5). Toxicity was considerable, especially in relapse-neutropenia (67%), anemia (67%), thrombocytopenia (100%), serious infections (78%)-and preemptive settings. Median overall survival of patients treated for relapse reached 6.8 months (95% confidence interval [CI], 0.7-∞), with better survival observed in patients with temporary disease control (7.7 vs 4.7 mo) and without previous exposure to azacitidine (7.7 vs 3.4 mo). One-year overall survival reached 75% (95% CI, 13%-96%) for preemptive and 50% (95% CI, 0%-91%) for maintenance treatment. DLI did not aggravate graft-versus-host disease., Conclusions: Effectiveness of azacitidine in relapsing patients is disappointing. Azacitidine seems to be promising in preemptive and maintenance settings. Toxicity is considerable. Further research is needed., (Copyright © 2016 Elsevier Inc. All rights reserved.)

To clarify the clinical impact of prior use of azacitidine (AZA) on outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for myelodysplastic syndrome (MDS), we retrospectively reviewed the clinical outcomes of 15 MDS patients who were treated with AZA before allo-HSCT (AZA group). We compared the outcomes of these 15 patients with 52 MDS patients who were solely given the best supportive care (BSC) before allo-HSCT (BSC group). Although patients in the AZA group were older with higher International Prognostic Scoring System (IPSS) scores compared to patients in the BSC group, no significant differences were found between the two groups in overall survival (OS), disease-free survival (DFS), cumulative incidence of relapse (CIR) or non-relapse mortality. However, in patients with a higher IPSS score (Int-2/High), pre-transplant AZA may provide better OS and DFS and lower CIR. Acute graft-versus-host disease rates were similar between the two groups. These results should be reassuring to patients with high-risk MDS receiving AZA before allo-HSCT.

Background: The prognosis of myelodysplastic syndromes (MDS) after allogeneic stem cell transplantation is critically determined by cytogenetic abnormalities, as previously defined by International Prognostic Scoring System (IPSS) cytogenetics. It has been shown that a new cytogenetic classification, included in the IPSS-R (cytogenetic-IPSS-R [C-IPSS-R]), can better predict the outcome of untreated MDS patients., Methods: In this study, we assessed the impact of the IPSS-R cytogenetic score (C-IPSS-R) on the outcome of 367 MDS patients transplanted from HLA-identical siblings or HLA allele-matched unrelated donors., Results: According to the C-IPSS-R, 178 patients (48%) fell in the good risk, 102 (28%) in the intermediate risk, 77 (21%) in the poor risk, and 10 (3%) in the very poor risk group. In multivariate analysis, after a median follow-up of 4 years, the poor and very poor-risk categories correlated with shorter overall survival (OS) (4-year OS, 32%; hazard ratio [HR], 1.59; P = 0.009 and OS, 10%; HR, 3.18; P = 0.002, respectively) and higher cumulative incidence of relapse (CIR) (CIR, 52%; HR, 1.82; P = 0.004 and CIR, 60%; HR, 2.44; P = 0.060, respectively)., Conclusions: Overall, the C-IPSS-R changed the IPSS cytogenetic risk only in 8% of cases but identified a new risk group, the very poor C-IPSS-R category, with dismal outcome after allogeneic stem cell transplantation (10% 4-year OS, 60% 4-year CIR). Posttransplantation maintenance therapy should be investigated in prospective trials for patients with high-risk C-IPSS-R karyotypes.

Background: Infective endocarditis due to Aspergillus species is an uncommon infection with a high mortality rate. It mostly occurs after the implantation of prosthetic heart valves. Parenteral nutrition, immunosuppression, broad-spectrum antibiotic regimens, and illegal intravenous drug use are the risk factors for developing infection., Case Report: We report a case of Aspergillus flavus native mitral valve endocarditis in a patient who had allogeneic stem cell transplantation in the past due to myelodysplastic syndrome., Conclusions: Although it is rare and there is limited experience available with the diagnosis and treatment, early recognition and therapeutic intervention with systemic antifungal therapy and aggressive surgical intervention are critical to prevent further complications that may eventually lead to death. In addition, better novel diagnostic tools are needed to facilitate more accurate identification of patients with invasive Aspergillus and to permit earlier initiation of antifungal treatment.

Purpose of Review: Allogeneic haematopoietic stem cell transplantation remains the only curative treatment for myelodysplastic syndrome. We highlight the various issues to consider in the pretransplant, transplant and posttransplant periods with emphasis on the management of relapse following transplant., Recent Findings: Cytogenetic and molecular characteristics are becoming more important in predicting transplant outcome. Hypomethylating agents are effective in the pretransplant setting to reduce disease burden. Haploidentical and umbilical cord blood donations may be valid transplant options for patients without human leukocyte antigen-identical sibling or match unrelated donor options. A preemptive management approach to patients at high risk of relapse is more effective. Adjusting the timing and dose of donor lymphocyte infusion reduces the risk of graft-versus-host disease without jeopardizing the graft-versus-leukaemia effect of donor lymphocyte infusion., Summary: Allogeneic haematopoietic stem cell transplantation is curative in up to 40% of myelodysplastic syndrome patients. Appropriate patient selection, modification of conditioning regimes and donor selection should be considered carefully. A preemptive approach for the management of patients at high risk of relapse should be employed following transplant, with the use of immune modulating therapies such as donor lymphocyte infusion and azacitidine.

We evaluated a maintenance, post-remission treatment with low-dose chemotherapy plus differentiating agents on poor-prognosis acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) patients ineligible to allografting. Patients had either age over 60 and/or secondary AML, therapy-related AML, previous relapse, high-risk MDS. Forty-five patients received the maintenance therapy based on two alternated schedules: (a) 6-thioguanine + 13-cis retinoic acid + dihydroxylated vitamin D3 and (b) low-dose cytarabine + 6-mercaptopurine + all-trans retinoic acid + dihydroxylated vitamin D3. We compared their outcome, at a median follow-up of 52 months, to that of a matched population of 49 patients who stopped treatments after consolidation. Maintenance group had a lower relapse incidence (70.3 vs. 86.4 % at 5 years p = 0.007) and a longer disease-free survival (median 21.2 vs. 8.7 months, p = 0.017). The relapse reduction improved overall survival: median 40.4 months (35.9 % at 5 years) for maintenance group vs. 15.8 (14.2 % at 5 years) for controls (p = 0.005). At multivariate Cox analysis, both cytogenetic and maintenance therapies resulted independent outcome predictors for overall survival. Maintenance treatment also reduced minimal residual disease (detected by WT1 and CBFβ-MYH11) in five of eight evaluable patients. The present results suggest that our strategy of maintenance therapy might improve the outcome of poor-risk AML/MDS patients.

Options to pre-emptively treat impending relapse of myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML) after allogeneic haematopoietic stem cell transplantation (allo-SCT) continuously increase. In recent years, the spectrum of diagnostic methods and parameters to perform post-transplant monitoring in patients with AML and MDS has grown. Cytomorphology, histomorphology, and chimaerism analysis are the mainstay in any panel of post-transplant monitoring. This may be individually combined with multiparameter flow cytometry (MFC) for the detection of residual cells with a leukaemia phenotype and quantitative real-time polymerase chain reaction (RQ-PCR) to assess gene expression, e.g., of WT1 or the residual mutation load (e.g., in case of an NPM1 mutation). Data evaluating the aforementioned methods alone or in combination are discussed in this review with particular emphasis on data pointing towards their suitability to steer pre-emptive post-transplant interventions such as immunotherapy, chemotherapy or therapy with demethylating agents.

Approximately one-third of patients with myelodysplastic syndrome (MDS) receiving allogeneic hematopoietic stem cell transplantation (HSCT) are cured by this treatment. Treatment failure may be due to transplant complications or relapse. To identify predictive factors for transplantation outcome, we studied 519 patients with MDS or oligoblastic acute myeloid leukemia (AML, <30% marrow blasts) who received an allogeneic HSCT and were reported to the Gruppo Italiano Trapianto di Midollo Osseo registry between 2000 and 2011. Univariate and multivariate survival analyses were performed using Cox proportional hazards regression. High-risk category, as defined by the revised International Prognostic Scoring System (IPSS-R), and monosomal karyotype were independently associated with relapse and lower overall survival after transplantation. On the other hand, older recipient age and high hematopoietic cell transplantation-comorbidity index (HCT-CI) were independent predictors of nonrelapse mortality. Accounting for various combinations of patient's age, IPSS-R category, monosomal karyotype, and HCT-CI, the 5-year probability of survival after allogeneic HSCT ranged from 0% to 94%. This study indicates that IPSS-R risk category and monosomal karyotype are important factors predicting transplantation failure both in MDS and oligoblastic AML. In addition, it reinforces the concept that allogeneic HSCT offers optimal eradication of myelodysplastic hematopoiesis when the procedure is performed before MDS patients progress to advanced disease stages.

Acute leukaemia or advanced myelodysplastic syndrome (MDS ≥ 5% blasts) in Fanconi anaemia (FA) patients is associated with a poor prognosis. We report 21 FA patients with acute leukaemia or advanced MDS who underwent haematopoietic cell transplantation (HCT) at the University of Minnesota between 1988 and 2011. Six patients had biallelic BRCA2 mutations. Eight patients received pre-transplant cytoreduction, with 3 achieving complete remission. HCT donor source included human leucocyte antigen-matched sibling (n = 2) or alternative donors (n = 19). Neutrophil engraftment was 95% for the entire cohort, and the incidence of acute graft-versus-host disease was 19%. 5-year overall survival (OS) was 33%, with a relapse rate of 24%, with similar OS in patients with biallelic BRCA2 mutations. Our study supports the use of HCT in the treatment of FA patients with acute leukaemia or advanced MDS, however, the role of chemotherapy prior to HCT remains unclear for this population. FA patients with biallelic BRCA2 are unique and may benefit from higher dose chemotherapy relative to other complementation groups., (© 2013 John Wiley & Sons Ltd.)

Pulmonary complications of hematopoietic stem cell transplantation (HSCT) are responsible for significant morbidity and mortality. There is no literature to date on the use of extracorporeal membranous oxygenation (ECMO) in patients with pulmonary manifestations of chronic graft-versus-host disease after HSCT. We describe the successful use of ECMO for refractory respiratory failure in such a patient.

Objective and Methods: We performed a single center analysis of 60 adult patients (33 males and 27 females) with myelodysplastic syndromes (MDS) or secondary acute myeloid leukemia (AML) who underwent allogeneic hematopoietic stem cell transplantation (HCT) at our institution., Results: Allogeneic stem cell in patients were transplanted between 1988 and 2010, 28 had an human leukocyte antigen (HLA)-identical sibling donor, 23 had an HLA-identical unrelated donor, and 9 had an 1 allele mismatched donor. The median age at time of HCT was 44 (range: 18-68) years. Conditioning therapy was myeloablative in 36 patients and consisted of a reduced-intensity conditioning (RIC) regimen in 24 patients. Graft-versus-host disease (GvHD) prophylaxis was performed with a combination of methotrexate and cyclosporine A in 36 patients, and cyclosporine A plus mycophenolate mofetil in 24 patients. The 10-year probability of overall survival was 46 %., Conclusion: In a multivariate analysis, we identified pretransplantation serum ferritin as the only independent adverse prognostic variable predicting survival in our patients.

The objective of is this article is to review murine xenotransplantation models for myelodysplastic syndromes (MDS). The difficulties in achieving sustained engraftment of MDS cells in immunodeficient mice may lie in innate characteristics of the MDS clones and microenvironmental factors. Engraftment of very low numbers of CD45(+) clonal MDS cells has been achieved with intravenous injection; higher rates of engraftment are obtained via the intramedullary route. Coinjection of certain stroma components with hematopoietic cells overcomes limitations of intravenous (IV) administration, allowing for engraftment of high proportions of human CD45(+) cells in mouse spleen and marrow. Expression of CD146 on stroma cells conveys an engraftment-facilitating effect. Clonal MDS cells have been propagated for periods beyond 6 months and have been transplanted successfully into secondary recipients. Engraftment of human clonal MDS cells with stem cell characteristics in immunodeficient mice is greatly facilitated by coinjection of stroma/mesenchymal cells, particularly with IV administration. CD146 expression on stroma is an essential factor; however, no model develops the laboratory and clinical features of human MDS. Additional work is needed to determine cellular and noncellular factors required for the full evolution of MDS., (Copyright © 2014 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)

Allogeneic hematopoietic stem cell transplantation (HCT) is still the only treatment modality with curative potential for patients with myelodysplastic syndromes. While early transplant-related mortality has improved during the last years, relapse risk following HCT still remains high, especially in older patients undergoing reduced-intensity conditioning. Therefore, when considering allogeneic HCT, in the absence of randomized data, emphasis should be put on patient selection and optimization of the pre-transplant and post-transplant period. In addition to a thorough comorbidity evaluation, risk stratification considering age, cytogenetics, grade of cytopenia, disease-related quality of life, as well as discussion of available treatment alternatives, are mandatory to decide when and how to perform allogeneic HCT. Since therapeutic options are often limited in patients relapsing after HCT, preventing relapse through maintenance strategies or minimal residual disease-directed therapy remains a central goal of current clinical research.

Modern treatment of myelodysplastic syndromes (MDS) with hypomethylating agents (HMAs) such as azacitidine (Vidaza) and decitabine (Dacogen) has changed the clinical landscape of these disorders. Novel drug combinations of HMAs with histone deacetylase inhibitor therapy may synergistically target different dysregulated molecular mechanisms within MDS clones. This article reviews current trial data concerning the use of the main HMAs in MDS patients where intensive chemotherapy and allogeneic stem cell transplantation is generally not an option. Collated data are presented of the clinical response outcomes, toxicity profiles and prognostic response criteria. Vidaza use in low-risk MDS cases, the selected place of allogeneic stem cell transplantation in older patients with significant comorbidity and the novel drug combination strategies for the future are discussed.

Patients with relapsed/refractory leukemias or advanced myelodysplastic syndrome (MDS) fare poorly following allogeneic hematopoietic cell transplant (HCT). We report prospective phase II study results of 29 patients given clofarabine 30 mg/m(2)/day i.v. × 5 days followed immediately by HCT conditioning while at the cytopenic nadir. A total of 15/29 patients (52%) were cytoreduced according to pre-defined criteria (cellularity <20% and blasts <10%). Marrow cellularity (P<0.0001) and blast% (P=0.03) were reduced. Toxicities were acceptable, with transient hyperbilirubinemia (48%) and gr3-4 infections (10%). In all, 28/29 proceeded to transplant; 27 received ATG or alemtuzumab. Post HCT, 180 day non-relapse mortality (NRM) was 7% (95% confidence interval (CI): 1-21), relapse was 29% (95% CI: 13-46) and OS was 71% (95% CI: 51-85), comparing favorably to published data for high-risk patients. Two-year graft vs host disease incidence was 40% (95% CI: 21-58) and 2 year OS was 31% (95% CI: 14-48). Disease at the nadir correlated with inferior OS after HCT (HR=1.22 for each 10% marrow blasts, 95% CI: 1.02-1.46). For AML/MDS patients, there was a suggestion that successful cytoreduction increased PFS (330 vs 171 days, P=0.3) and OS (375 vs 195 days, P=0.31). Clofarabine used as a bridge to HCT reduces disease burden, is well tolerated, and permits high-risk patients to undergo HCT with acceptable NRM. Late relapses are common; thus, additional strategies should be pursued. NCT-00724009.

Allogeneic stem cell transplantation (ASCT) from related or unrelated donors may cure patients with myelodysplastic syndromes (MDS), a heterogeneous group of clonal stem cell disorders. We analysed 384 elderly patients (55-69 years) with advanced MDS who received either ASCT (n=247) and were reported to The European Group for Blood and Marrow Transplantation (EBMT) or a non -transplant approach (n=137) reported to the Düsseldorf registry. Besides an attempt to answer the question of "comparison", the purpose of this work is to explain the difficulties in comparing a non-transplant with a transplant cohort, when death before transplant is likely but unknown and the selection of patients for transplant is based on assumptions. It shows which methods are almost always biased and that even the most sophisticated approaches crucially rely on clinical assumptions. Using the most appropriate model for our data, we derive an overall univariate non-significant survival disadvantage for the transplant cohort (HR: 1.29, p = 0.11). We show that such an "average" hazard ratio is however misleading due to non-proportionality of the hazards reflecting early treatment related mortality, the occurring of which is logically correlated with the interval between diagnosis and transplant creating a disproportional drop in the (reconstructed) survival curve of the transplanted patients. Also in multivariate analysis (correcting for age > 60 (HR: 1.4, p = 0.02) and abnormal cytogenetics (HR: 1.46, p = 0.01)), transplantation seems to be worse (HR: 1.39, p = 0.05) but only in the (incorrect but commonly applied) model without time varying covariates. The long term (time depending) hazard ratio is shown to be virtually 1 and overall survival is virtually identical in both groups. Nonetheless no conclusion can be reached from a clinical point of view without assumptions which are by their very nature untestable unless all patients would be followed from diagnosis.

Myelodysplastic syndromes (MDS) include a group of hematopoietic malignancies characterized by dysplastic changes, ineffective hematopoiesis and variable risk of leukemic progression. At diagnosis, 86% of MDS patients are ≥60 years. Azacitidine, the only drug that prolongs life in high-risk (HR)-MDS patients, adds a median of only 9.5 months to life. Allogeneic stem cell transplantation (alloSCT) remains the only potentially curative approach. Despite recent improvements including use of reduced intensity conditioning (RIC) that decrease transplant-related mortality, alloSCT continues to be used rarely in elderly MDS. There is paucity of data regarding outcomes of RIC alloSCT in elderly MDS patients, especially in direct comparison with azanucleosides. In this paper, the authors discuss the recent Markov decision analysis by Koreth et al. in which investigators demonstrated superior survival of patients with HR-MDS aged 60-70 years who underwent RIC alloSCT in comparison with those who were treated with azanucleosides.

Allogeneic hematopoietic cell transplantation (HCT) from human leukocyte antigen (HLA) matched related donor (MRD) and matched unrelated donors (MUD) produces similar survival for patients with acute myelogenous leukemia. Whether these results can be extended to patients with myelodysplastic syndromes (MDS) is unknown. Therefore, analysis of post-HCT outcomes for MDS was performed. Outcomes of 701 adult MDS patients who underwent HCT between 2002 and 2006 were analyzed (MRD [n = 176], 8 of 8 HLA-A, -B, -C, -DRB1 allele matched MUD [n = 413], 7 of 8 MUD [ n = 112]). Median age was 53 years (range, 22-78 years). In multivariate analyses, MRD HCT recipients had similar disease free survival (DFS) and survival rates compared with 8 of 8 MUD HCT recipients (relative risk [RR] 1.13 [95% confidence interval (CI) 0.91-1.42] and 1.24 [95% CI 0.98-1.56], respectively), and both MRD and 8 of 8 MUD had superior DFS (RR 1.47 [95% CI 1.10-1.96] and 1.29 [95% CI 1.00-1.66], respectively) and survival (RR 1.62 [95% CI 1.21-2.17] and 1.30 [95% CI 1.01-1.68], respectively) compared with 7 of 8 MUD HCT recipients. In patients with MDS, MRD remains the best stem cell source followed by 8 of 8 MUD. Transplantation from 7 of 8 MUD is associated with significantly poorer outcomes.