Cytogenetics and comorbidity predict outcomes in older myelodysplastic syndrome patients after allogeneic stem cell transplantation using reduced intensity conditioning.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only treatment with a curative potential for myelodysplastic syndrome (MDS) patients. Allo-HSCT has substantial risks, particularly in the elderly, and its role for older MDS patients has yet to be defined. METHODS: We analyzed 88 MDS patients aged ≥ 60 years with allo-HSCT after reduced intensity conditioning regimens over the last decade. The study cohort had high risk features; 47 of 88 (53.4%) patients were > 65 years of age, 24 (27%) patients had cytogenetic abnormalities consistent with monosomal karyotype (MKpos), 33 (38%) patients had histological subtype of RAEB-1 and RAEB-2 at diagnosis, and 45 (51%) patients had a hematopoietic cell transplantation-comorbidity index (HCT-CI) of ≥ 3. RESULTS: The 3-year incidence of progression, transplant-related mortality (TRM), and overall survival (OS) were 26% (95% confidence interval [CI], 18%-37%), 35% (95% CI, 26%-47%), and 41% (95% CI, 30%-52%), respectively. MKpos was the only prognostic factor that increased the risk of disease progression compared with good-risk cytogenetics (hazard ratio [HR] = 9.5, P = .003) as well as MKneg (HR = 3.3, P = .01). For TRM, HCT-CI ≥ 3, but not age >65 years, was associated with worse outcomes (HR = 3.1, P = .007). Cytogenetics and HCT-CI enabled us to identify prognostic groups for OS. MKpos patients had the worst 3-year OS (17%), whereas patients with good-risk cytogenetics and HCT-CI < 3 had the best OS (92%). CONCLUSION: Our results confirm that allo-HSCT can provide long-term survival in older MDS patients. Cytogenetics and HCT-CI identify prognostic risk groups and guide selection of older MDS patients who are candidates for allo-HSCT. Cancer 2017;123:2661-70. © 2017 American Cancer Society.

Infusion of CD3/CD28 costimulated umbilical cord blood T cells at the time of single umbilical cord blood transplantation may enhance engraftment.

Limited cell numbers in umbilical cord blood (UCB) grafts present a major impediment to favorable outcomes in adult transplantation, largely related to delayed or failed engraftment. The advent of UCB transplantation (UCBT) using two grafts successfully circumvents this obstacle, despite the engraftment of only one unit. Preclinical models suggested that the addition of UCB T cells at the time of transplant can enhance engraftment. We tested whether ex vivo activation by CD3/CD28 costimulation and expansion of T cells from a single UCB graft would be safe and feasible in adults with advanced hematologic malignancies, with an overall objective of optimizing engraftment in single unit UCBT. In this phase 1 study, recipients of single UCB units were eligible if the unit was stored in two adequate fractions. Dose limiting toxicity was defined as grade 3 or grade 4 GVHD within 90 days of UCBT. Four patients underwent UCBT; all were treated at the first dose level (10(5) cells/kg). At the 10(5) cells/kg dose level two subjects experienced grade 3 intestinal GVHD, thus meeting stopping criteria. For three subjects, neutrophil engraftment was early (12, 17, and 20 days), while one subject experienced primary graft failure. We observed early donor T cell trafficking and found that expanded T cells produced supraphysiologic levels of cytokines relevant to engraftment and to lymphoid differentiation and function. Taken together, these preliminary data suggest rapid engraftment in recipients of a single UCBT combined with relatively low doses of activated T cells, though potentially complicated by severe GVHD.

Decitabine versus best supportive care in older patients with refractory anemia with excess blasts in transformation (RAEBt) - results of a subgroup analysis of the randomized phase III study 06011 of the EORTC Leukemia Cooperative Group and German MDS Study Group (GMDSSG).

In the European Organisation for Research and Treatment of Cancer (EORTC)/GMDSSG phase III trial 06011, we compared decitabine (15 mg/m(2) every 8 h for 3 days) with best supportive care (BSC) in patients ≥60 years with myelodysplastic syndromes (MDS) by French-American-British (FAB) criteria. Here, we reinvestigate trial 06011 for the activity and efficacy specifically in patients with refractory anemia with excess blasts in transformation (RAEBt). Response rates in the decitabine arm (N = 40) were as follows: complete or partial remission, 15 %; hematologic improvement, 15 %; resistant disease, 30 %. RAEBt patients in the decitabine arm had longer progression-free survival (PFS; hazard ratio (HR) 0.30, 95 % confidence interval (CI) 0.18-0.51; median, 6.2 vs 2.8 months) and overall survival (OS; HR 0.68, 95 % CI 0.42-1.11; median, 8.0 vs 6.0 months) than in the BSC arm (N = 35). Censoring at allogeneic hematopoietic stem cell transplantation, the OS difference between the treatment groups increased, particularly among patients aged 60-74 years (HR 0.48, 95 % CI 0.26-0.89). After regrouping the study cohort according to World Health Organization (WHO) criteria, patients with acute myeloid leukemia (AML) (i.e., ≥20 % blasts) in the decitabine arm (N = 27) also had longer PFS than in the BSC arm (N = 23) (HR 0.46, 95 % CI 0.26-0.83; median, 6.2 vs 2.8 months). In conclusion, 3-day decitabine displays clinical activity and efficacy in MDS and/or AML with 5-30 % blood or 20-30 % marrow blasts.

Monocytic and promyelocytic myeloid-derived suppressor cells may contribute to G-CSF-induced immune tolerance in haplo-identical allogeneic hematopoietic stem cell transplantation.

We investigated the effects of granulocyte colony-stimulating factor (G-CSF) on monocytic (M), promyelocytic (P), and granulocytic (G) myeloid-derived suppressor cells (MDSCs) both in bone marrow and peripheral blood of 20 healthy donors and the association of MDSCs subgroups with acute and chronic graft-versus-host disease (aGvHD/cGvHD) in 62 patients who underwent haplo-identical allogeneic hematopoietic stem cell transplantation (allo-HSCT). Patients who received a higher absolute counts of M-MDSCs or P-MDSCs exhibited lower incidence of grade II-IV aGvHD (P = 0.001; P = 0.031) and extensive cGvHD (P = 0.011; P = 0.021). In the multivariate analysis, absolute counts of MDSCs in allografts emerged as independent factors that reduced the occurrence of grade II-IV aGvHD (M-MDSCs: HR = 0.087, 95% CI = 0.020-0.381, P = 0.001; P-MDSCs: HR = 0.357, 95% CI = 0.139-0.922, P = 0.033) and extensive cGvHD (M-MDSCs: HR = 0.196, 95% CI = 0.043-0.894, P = 0.035; P-MDSCs: HR = 0.257, 95% CI = 0.070-0.942, P = 0.04). Delayed M-MDSC reconstitution was associated with aGvHD onset. The 3-year cumulative incidence of transplant related mortality and relapse, 3-year probability of disease-free survival, and overall survival did not differ significantly between these subgroups. Our results suggested that G-CSF-induced immune tolerance may be mediated by M/P-MDSCs in allo-HSCT.

De novo acute myeloid leukemia with 20-29% blasts is less aggressive than acute myeloid leukemia with ≥30% blasts in older adults: a Bone Marrow Pathology Group study.

It is controversial whether acute myeloid leukemia (AML) patients with 20-29% bone marrow (BM) blasts, formerly referred to as refractory anemia with excess blasts in transformation (RAEBT), should be considered AML or myelodysplastic syndrome (MDS) for the purposes of treatment and prognostication. We retrospectively studied 571 de novo AML in patients aged >50 years, including 142 RAEBT and 429 with ≥30% blasts (AML30), as well as 151 patients with 10-19% BM blasts (RAEB2). RAEBT patients were older and had lower white blood count, but higher hemoglobin, platelet count, and karyotype risk scores compared to AML30, while these features were similar to RAEB2. FLT3 and NPM1 mutations and monocytic morphology occurred more commonly in AML30 than in RAEBT. RAEBT patients were treated less often with induction therapy than AML30, whereas allogeneic stem cell transplant frequency was similar. The median and 4-year OS of RAEBT patients were longer than those of AML30 patients (20.5 vs 12.0 months and 28.6% vs 20.4%, respectively, P = 0.003); this difference in OS was manifested in patients in the intermediate UKMRC karyotype risk group, whereas OS of RAEBT patients and AML30 patients in the adverse karyotype risk group were not significantly different. Multivariable analysis showed that RAEBT (P < 0.0001), hemoglobin (P = 0.005), UKMRC karyotype risk group (P = 0.002), normal BM karyotype (P = 0.004), treatment with induction therapy (P < 0.0001), and stem cell transplant (P < 0.0001) were associated with longer OS. Our findings favor considering de novo RAEBT as a favorable prognostic subgroup of AML.

Diagnosis and management of nocardiosis after bone marrow stem cell transplantation in adults: lack of lymphocyte recovery as a major contributing factor.

Hematopoietic cell transplantation (HCT) is a curative treatment for hematological malignancies. This therapeutic approach is associated with a profound immune deficiency and an increased rate of opportunistic infections. Nocardiosis is a rare bacterial infection occurring mainly in patients with deficient cell-mediated immunity, such as AIDS patients or transplant recipients. Diagnosis of nocardiosis can be challenging, as signs and symptoms are non-specific. Routine prophylaxis with trimethoprin/sulfamethoxazole (TMP/SMZ) does not prevent the risk of infection. Between May 2001 and December 2009, five cases of nocardiosis were diagnosed from the 366 allogeneic HCT recipients in our centre. Four patients developed a disseminated nocardiosis within the first year after HCT. The fifth patient presented a localized cutaneous nocardiosis. In disseminated cases, median total CD4+ T-cells were below 100 cells/µL. Naive CD4+ CD45RA+/RO- T-cells were almost undetectable. CD8(+) T-cells and NK cells were below the normal range and CD19+ B-cell reconstitution was completely deficient. In a localized case, we observed a lack of naive thymic emigrants CD4+ CD45RA+/RO- T-cells.

Outcome of children with refractory anaemia with excess of blast (RAEB) and RAEB in transformation (RAEB-T) in the Japanese MDS99 study.

We report the outcome of 16 children with refractory anaemia with excess of blasts (RAEB; n = 4) and RAEB in transformation (RAEB-T; n = 12) following induction therapy with etoposide, cytarabine and mitoxantrone (ECM) prior to haematopoietic stem cell transplantation (HSCT). The median observation period was 77 months (range 5-123). Complete remission rate was 81% following induction; no toxic deaths occurred. Eight-year event-free survival and overall survival was 50% and 56%, respectively. None of the three patients with a complex karyotype survived, suggesting karyotype is a crucial prognostic factor for survival. This study indicates the safety and high remission rate of ECM and high survival rates after HSCT for paediatric RAEB and RAEB-T.

Complex karyotype newly defined: the strongest prognostic factor in advanced childhood myelodysplastic syndrome.

To identify cytogenetic risk factors predicting outcome in children with advanced myelodysplastic syndrome, overall survival of 192 children prospectively enrolled in European Working Group of Myelodysplastic Syndrome in Childhood studies was evaluated with regard to karyotypic complexity. Structurally complex constitutes a new definition of complex karyotype characterized by more than or equal to 3 chromosomal aberrations, including at least one structural aberration. Five-year overall survival in patients with more than or equal to 3 clonal aberrations, which were not structurally complex, did not differ from that observed in patients with normal karyotype. Cox regression analysis revealed the presence of a monosomal and structurally complex karyotype to be strongly associated with poor prognosis (hazard ratio = 4.6, P < .01). Notably, a structurally complex karyotype without a monosomy was associated with a very short 2-year overall survival probability of only 14% (hazard ratio = 14.5; P < .01). The presence of a structurally complex karyotype was the strongest independent prognostic marker predicting poor outcome in children with advanced myelodysplastic syndrome.

The WHO 2016 diagnostic criteria for Acute Myeloid leukemia with myelodysplasia related changes (AML-MRC) produce a very heterogeneous entity: A retrospective analysis of the FAB subtype RAEB-T.

We studied 79 patients with AML-MRC or RAEB-T, who were later reclassified according to the WHO classification. Marrow slides were examined cytomorphologically with regard to dysplasia. Patients were followed up until March 2020. Thirty-one patients underwent allogeneic stem cell transplantation (median survival (ms) 16 months), 14 were treated with induction chemotherapy (ms 8.4 months), 18 received hypomethylating agents (ms 9.2 months), 16 received low dose chemotherapy or best supportive care (ms 2.4 months). Only 30.4 % fulfilled the morphologic WHO criteria. 46.8 % were classified as AML-MRC by an antecedent MDS, 54.4 % of the pts were classified by MDS-related chromosomal abnormalities. 5 % did not fulfill any of the criteria and were entered based on 20-29 % medullary blasts. There was no difference in ms between pts presenting with > 50 % dysplasia as compared to pts with dysplasia between 10 % and 50 % (ms 9.1 vs 9.9 months, p = n.s.) or for pts with antecedent MDS (ms 9.1 vs 8.9 months, p = n.s.). Myelodysplasia-related cytogenetic abnormalities were associated with a worse outcome (ms 8.1 vs 13.5 months, p = 0.026). AML-MRC in its current definition is a heterogenous entity. Dysplasia of ≥ 50 % in ≥ two lineages is not helpful for diagnostics and prognostication and therefore should be deleted in future classifications. We recommend utilizing the WHO guidelines for defining dysplasia (10 % or greater in ≥ 1 of the three myeloid cell lines) assisting in establishing the diagnosis of MDS.

A clinical and immunologic phase 2 trial of Wilms tumor gene product 1 (WT1) peptide vaccination in patients with AML and MDS.

This study investigated the immunogenicity of Wilms tumor gene product 1 (WT1)-peptide vaccination in WT1-expressing acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients without curative treatment option. Vaccination consisted of granulocyte-macrophage colony-stimulating factor subcutaneously days 1 to 4, and WT1.126-134 peptide and 1 mg keyhole limpet hemocyanin on day 3. The initial 9 patients received 4 vaccinations biweekly, then monthly, and the subsequent 10 patients received continual biweekly vaccination. Seventeen AML patients and 2 refractory anemia with excess blasts patients received a median of 11 vaccinations. Treatment was well tolerated. Objective responses in AML patients were 10 stable diseases (SDs) including 4 SDs with more than 50% blast reduction and 2 with hematologic improvement. An additional 4 patients had clinical benefit after initial progression, including 1 complete remission and 3 SDs. WT1 mRNA levels decreased at least 3-fold from baseline in 35% of patients. In 8 of 18 patients, WT1-tetramer(+) T cells increased in blood and in 8 of 17 patients in bone marrow, with a median frequency in bone marrow of 0.18% at baseline and 0.41% in week 18. This WT1 vaccination study provides immunologic, molecular, and preliminary evidence of potential clinical efficacy in AML patients, warranting further investigations.

Quantitation of human herpesvirus-6 (HHV-6) DNA in a cord blood transplant recipient with chromosomal integration of HHV-6.

Chromosomal integration of the human herpesvirus-6 (HHV-6) genome (CIHHV-6) is an important consideration if HHV-6 DNA is detected during the course of transplantation. A 4-year-old girl with refractory anemia with excess blasts type-2 was diagnosed with CIHHV-6 before a cord blood transplantation. HHV-6 DNA was serially quantitated by polymerase chain reaction assay in the transplant period. The possibility of HHV-6 reactivation in a transplant recipient with CIHHV-6 was suspected in our case.

[A rare case of a sclerodermoid chronic graft versus host disease. Successful treatment with extracorporeal photopheresis (ECP)]. / Ungewöhnliche chronische sklerodermiforme Graft-versus-Host-Erkrankung : Erfolgreiche Therapie mittels extrakorporaler Photopherese (ECP).

A 31-year-old woman presented with progressive deep linear induration on her lower abdomen, forearms and thighs. These symptoms developed three years after allogenic stem cell transplantation. Furthermore, the patient showed multiple hypopigmented lichenoid papules on the extensor surfaces of the forearms consistent with lichen sclerosus. Histological analysis of a biopsy specimen from her left thigh showed dermal sclerosis extending into the fascia, thus establishing the diagnosis of a rare combination of superficial and deep sclerodermoid chronic graft-versus-host disease. After 7 cycles of extracorporeal photopheresis, a marked resolution of the indurations and a reduction of the modified Rodnan skin score from 12 to 7 were noted.

[Effectiveness and safety of 5-azacitidine in three patients with myelodysplastic syndromes]. / Efectividad y seguridad de 5-azacitidina en tres pacientes con síndrome mielodisplásico.

OBJECTIVE: To assess the effectiveness and safety of using 5-azacitidine to treat myelodysplastic syndromes. METHODS: Review of medical records of patients who received 5-azacitidine 75mg/m(2) subcutaneously for during 7 days every 28 days in twelve cycles as compassionate use. We evaluated the objective response, clinical improvement and time to disease progression. We recorded adverse reactions described in the medical history. RESULTS: Six patients were candidates for treatment with 5-azacitidine. Three cases were evaluated over the study period. Most remained in partial response or better after the study, and no longer needed transfusions. In one patient, the treatment appeared to delay progression to leukaemia. CONCLUSIONS: 5-Azacitidine might be considered an effective and relatively safe drug, and may have contributed to controlling peripheral cytopenias, improving the quality of life and delaying progression to leukaemia. Additional studies with more patients are needed to support these results.

Donor lymphocyte infusions for post-transplant relapse of refractory anemia with excess blasts and monosomy 7.

An 8-year-old male relapsed with refractory anemia with excess blasts (RAEB) and monosomy 7 and mixed chimerism (MC) 21 months after HLA-matched unrelated donor bone marrow transplant (BMT). He received three donor lymphocyte infusions (DLI) using an escalating dose schedule. He developed grade II acute graft-versus-host disease (GVHD) 9 days after the third DLI, but continued to deteriorate for 2 months with decreasing marrow cellularity but persisting blasts, MC, and monosomy 7, before exhibiting a delayed but complete response which has persisted for 5 years. This case suggests that DLI and graft-versus-myelodysplasia (GVMDS) may be beneficial in post-transplant relapse of pediatric myelodysplasia.

Allogeneic haematopoietic stem cell transplant in patients with lower risk myelodysplastic syndrome: a retrospective analysis on behalf of the Chronic Malignancy Working Party of the EBMT.

We report a retrospective analysis of 246 myelodysplastic syndrome (MDS) patients in the EBMT (The European Society for Blood and Marrow Transplantation) database who were transplanted for International Prognostic Scoring System (IPSS) low or intermediate-1 disease. The majority of these patients (76%) were reclassified as intermediate or higher risk according to R-IPSS. The 3-year overall survival (OS) and PFS were 58% and 54%, respectively. In a multivariate analysis, adverse risk factors for PFS were marrow blast percentage (hazard ratio (HR): 1.77, P=0.037), donor/recipient CMV serostatus (donor-/recipient+: HR: 2.02, P=0.011) and source of stem cells (marrow and non-CR: HR: 5.72, P<0.0001, marrow and CR: HR: 3.17, P=0.027). Independent risk factors for OS were disease status at time of transplant and the use of in vivo T-cell depletion (TCD). Patients who did not receive TCD and were transplanted from an unrelated donor had worse OS (HR: 4.08, P<0.0001). In conclusion, 'lower' risk MDS patients have better outcome than those with 'higher risk' after haematopoietic stem cell transplant (HSCT). Selecting the right source of stem cells, a CMV-positive donor for CMV-positive patients and using in vivo TCD results in the best outcome in these patients. More studies are needed to evaluate the role of HSCT in these patients as compared with conventional treatment.

Antithymocyte globulin and cyclosporine A as combination therapy for low-risk non-sideroblastic myelodysplastic syndromes.

The present study evaluated the combination of antithymocyte globulin (ATG) and cyclosporine A (CsA) in patients with low-risk myelodysplastic syndromes. Twenty patients (17 with refractory anemia and 3 with refractory anemia with excess blasts) received treatment with rabbit-ATG plus CsA. The overall response rate was 30% (6/20); three of the six responders had a complete response. The responses lasted 2-58 months, with two patients still being in complete remission at 42 and 58 months. Short-lasting cytogenetic remissions were achieved in two patients. ATG was poorly tolerated in patients over 70 years of age. Four out of 20 patients progressed to acute myeloid leukemia within a year. We conclude that immunosuppressive treatment may be a therapeutic option for selected patients with myelodysplastic syndrome.

Sinusoidal obstruction syndrome of the liver after hematopoietic stem cell transplantation: decision making for orthotopic liver transplantation.

Sinusoidal obstruction syndrome (SOS) is a specific complication of hematopoietic stem cell transplantation (HSCT) that can lead to substantial morbidity and treatment-related mortality. Heparin is frequently used as prophylaxis of and defibrotide as therapy for mild to moderate SOS. In severe cases of SOS these therapies are often ineffective, and orthotopic liver trans-plantation (OLT) may be the only option. Reports in the literature about the outcome of liver transplantation for SOS are contradictory. We describe our second case of OLT after HSCT. The patient died of intracranial hemorrhage 2 weeks after liver transplantation with good initial organ function. In the first case at our center, however, the patient survived more then 8 years. The reported short- to medium-range survival rate for OLT following HSCT is approximately 50%. On the basis of the experience at our center and the findings in a review of the literature, we developed a rational approach to the selection for liver transplantation of patients with life-threatening liver dysfunction after marrow transplantation.