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1.
Sequential vs myeloablative vs reduced intensity conditioning for patients with myelodysplastic syndromes with an excess of blasts at time of allogeneic haematopoietic cell transplantation: a retrospective study by the chronic malignancies working party of the EBMT
Potter, V., Gras, L., Koster, L., Kroger, N., Sockel, K., Ganser, A., Finke, J., Labussiere-Wallet, H., Peffault de Latour, R., Koc, Y., et al
Bone marrow transplantation. 2023
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Editor's Choice
Abstract
The optimal conditioning for patients with higher risk MDS receiving potentially curative allogeneic haematopoietic stem cell transplant(allo-HCT) remains to be defined. This is particularly the case for patients with excess of blasts at time of allo-HCT. Sequential (Seq) conditioning, whereby chemotherapy is followed rapidly by transplant conditioning, offers an opportunity to decrease disease burden, potentially improving outcomes allo-HCT outcomes. Herein we present the only analysis comparing Seq to myeloablative (MAC) and reduced intensity conditioning (RIC) specifically focussed on MDS patients with excess of blasts at allo-HCT. 303 patients were identified in the EBMT registry, receiving RIC (n = 158), Seq (n = 105), and MAC (n = 40). Median follow-up was 67.2 months and median age at allo-HCT was 59.5 years (IQR 53.5-65.6). For the entire cohort, 3 y overall survival (OS) was 50% (95% CI 45-56%) and relapse free survival (RFS) 45% (95% CI 40-51%). No significant differences in OS (log-rank p = 0.13) and RFS (log-rank p = 0.18) were observed between conditioning protocols. On multivariable analysis, lower performance status, worse IPSS-R cytogenetics, sibling donor (compared to 8/8 MUD) and ≥20% blasts at allo-HCT were associated with worse outcomes. In conclusion, the Seq protocol did little to influence the outcome in this high-risk group of patients, with outcomes mostly determined by baseline disease risk and patient characteristics such as performance status.
PICO Summary
Population
Patients with myelodysplastic syndrome (MDS) with excess of blasts at allo-HCT, identified from the EBMT registry (n=303)
Intervention
Sequential conditioning, where chemotherapy is followed rapidly by transplant (Seq, n=105)
Comparison
Reduced intensity conditioning (RIC, n=158), or myeloablative conditioning (MAC, n=40).
Outcome
Median follow-up was 67.2 months and median age at allo-HCT was 59.5 years (IQR 53.5-65.6). For the entire cohort, 3 y overall survival (OS) was 50% (95% CI 45-56%) and relapse free survival (RFS) 45% (95% CI 40-51%). No significant differences in OS and RFS were observed between conditioning protocols. On multivariable analysis, lower performance status, worse IPSS-R cytogenetics, sibling donor (compared to 8/8 MUD) and ≥20% blasts at allo-HCT were associated with worse outcomes.
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2.
Progress in survival following three decades of allogeneic hematopoietic cell transplantation for myelodysplastic syndrome: a real-world registry study in Japan
Konuma, T., Itonaga, H., Ishiyama, K., Hamamura, A., Uchida, N., Ozawa, Y., Katayama, Y., Sakurai, M., Ueda, Y., Matsuoka, K. I., et al
American journal of hematology. 2023
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3.
Whole-genome sequencing identifies novel predictors for hematopoietic cell transplant outcomes for patients with myelodysplastic syndrome: a CIBMTR study
Zhang, T., Auer, P., Dong, J., Cutler, C., Dezern, A. E., Gadalla, S. M., Deeg, H. J., Nazha, A., Carlson, K. S., Spellman, S., et al
Journal of hematology & oncology. 2023;16(1):37
Abstract
Recurrent mutations in TP53, RAS pathway and JAK2 genes were shown to be highly prognostic of allogeneic hematopoietic cell transplant (alloHCT) outcomes in myelodysplastic syndromes (MDS). However, a significant proportion of MDS patients has no such mutations. Whole-genome sequencing (WGS) empowers the discovery of novel prognostic genetic alterations. We conducted WGS on pre-alloHCT whole-blood samples from 494 MDS patients. To nominate genomic candidates and subgroups that are associated with overall survival, we ran genome-wide association tests via gene-based, sliding window and cluster-based multivariate proportional hazard models. We used a random survival forest (RSF) model with build-in cross-validation to develop a prognostic model from identified genomic candidates and subgroups, patient-, disease- and HCT-related clinical factors. Twelve novel regions and three molecular signatures were identified with significant associations to overall survival. Mutations in two novel genes, CHD1 and DDX11, demonstrated a negative impact on survival in AML/MDS and lymphoid cancer data from the Cancer Genome Atlas (TCGA). From unsupervised clustering of recurrent genomic alterations, genomic subgroup with TP53/del5q is characterized with the significant association to inferior overall survival and replicated by an independent dataset. From supervised clustering of all genomic variants, more molecular signatures related to myeloid malignancies are characterized from supervised clustering, including Fc-receptor FCGRs, catenin complex CDHs and B-cell receptor regulators MTUS2/RFTN1. The RSF model with genomic candidates and subgroups, and clinical variables achieved superior performance compared to models that included only clinical variables.
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4.
Germline predisposition variants occur in myelodysplastic syndrome patients of all ages
Feurstein, S. K., Trottier, A. M., Estrada-Merly, N., Pozsgai, M. J., McNeely, K. E., Drazer, M. W., Ruhle, B., Sadera, K., Koppayi, A. L., Scott, B. L., et al
Blood. 2022
Abstract
The frequency of pathogenic/likely pathogenic (P/LP) germline variants in myelodysplastic syndrome (MDS) patients diagnosed at or younger than 40 years old is 15 to 20%. However, there are no comprehensive studies assessing the frequency of such variants across the age spectrum. We performed augmented whole exome sequencing from peripheral blood of 404 MDS patients and their related donors prior to allogeneic hematopoietic stem cell transplantation. Single nucleotide and copy number variants in 233 genes were analyzed and interpreted. Germline status was established by the presence of a variant in the patient and related donor or for those seen previously only as germline alleles. We identified P/LP germline variants in 28 out of 404 MDS patients (7%) within all age deciles. Patients with P/LP variants were more likely to develop higher-grade MDS than those without (43% vs. 25%, p=0.04). There was no statistical difference in outcome parameters between patients with and without a germline variant, but the analysis was underpowered. P/LP variants in bone marrow failure syndrome genes were found in five patients under age 40, whereas variants in DDX41 (n=4), telomere biology disorder genes (n=2), and tumor predisposition genes (n=17) were found in patients over 40. If presumed germline variants were included, the yield of P/LP variants would increase to 11% and by adding suspicious variants of unknown significance, it would rise further to 12%. The high frequency of P/LP germline variants in our study supports comprehensive germline genetic testing for all MDS patients regardless of their age at diagnosis.
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5.
Impact of in vivo T-cell depletion in patients with myelodysplastic syndromes undergoing allogeneic hematopoietic stem cell transplant: a registry study from the Chronic Malignancies Working Party of the EBMT
Forcade, E., Chevret, S., Finke, J., Ehninger, G., Ayuk, F., Beelen, D., Koster, L., Ganser, A., Volin, L., Sengeloev, H., et al
Bone marrow transplantation. 2022
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Editor's Choice
Abstract
While in vivo T-cell depletion (TCD) is widely used, its benefit in patients with MDS still remains a matter of debate. This study evaluates the impact of TCD on outcomes, and compares ATG and alemtuzumab, in patients with MDS. 1284 patients from the EBMT registry were included in this study with 470 patients in the no-TCD group and 814 in the TCD group (alemtuzumab N = 168; ATG N = 646). At 6 months, aGVHD III-IV cumulative incidences (CI) for no-TCD, ATG or alemtuzumab groups were 13% vs 14% vs 11% (ns), respectively. At 5 years, CI of chronic GVHD were 64% vs 52% vs 51% (p < 0.00017); and CI of relapse was 23% vs 25% vs 39% (p < 0.0001) for no TCD, ATG and alemtuzumab respectively; OS was 47% vs 46% vs 34% (p = 0.009) respectively; and GRFS was 21% vs 28% and 20% (p = 0.045) respectively. In multivariable analysis, ATG improved GRFS, and alemtuzumab decreased OS. Both ATG and alemtuzumab decreased risk of chronic GVHD, but the increased risk of relapse with alemtuzumab is associated with a poor GRFS and suggest to not use alemtuzumab in the setting of allo-SCT for high risk disease.
PICO Summary
Population
Patients with myelodysplastic syndromes undergoing allogeneic transplant and reported to the EBMT registry (n=1284)
Intervention
In vivo T-cell depletion (TCD, n=814: receiving alemtuzumab n=168 or ATG n=646)
Comparison
No in vivo T-cell depletion (No-TCD, n=470).
Outcome
At 6 months, aGVHD III-IV cumulative incidences (CI) for no-TCD, ATG or alemtuzumab groups were 13% vs 14% vs 11% (ns), respectively. At 5 years, CI of chronic GVHD were 64% vs 52% vs 51%; and CI of relapse was 23% vs 25% vs 39% for no TCD, ATG and alemtuzumab respectively; OS was 47% vs 46% vs 34% respectively; and GRFS was 21% vs 28% and 20% respectively. In multivariable analysis, ATG improved GRFS, and alemtuzumab decreased OS. Both ATG and alemtuzumab decreased risk of chronic GVHD, but the increased risk of relapse with alemtuzumab is associated with a poor GRFS
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6.
Myeloablative Versus Reduced-Intensity Conditioning With Fludarabine/Busulfan for Myelodysplastic Syndrome: A Propensity Score-Matched Analysis
Kurosawa, S., Shimomura, Y., Itonaga, H., Najima, Y., Kobayashi, T., Ozawa, Y., Kanda, Y., Kako, S., Kawakita, T., Matsuoka, K. I., et al
Transplantation and Cellular Therapy. 2022;28(6):323.e1-323.e9
Abstract
There are limited data comparing myeloablative conditioning with fludarabine/busulfan (Flu/Bu4) and reduced-intensity conditioning with fludarabine/busulfan (Flu/Bu2) in patients with myelodysplastic syndrome (MDS) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). We retrospectively analyzed nationwide registry data and compared the outcomes of adult patients with MDS receiving Flu/Bu4 and Flu/Bu2 by propensity score (PS) matching. Patients who met the following criteria were eligible for enrollment: (1) age ≥16 years; (2) diagnosis of de novo MDS; (3) first allo-HSCT between 2006 and 2018; (4) related bone marrow transplantation (BMT) or peripheral blood stem cell transplantation from an HLA-matched donor, unrelated BMT from an HLA-matched or HLA-1 allele-mismatched donor, or unrelated cord blood transplantation; and (5) receiving Flu/Bu4 or Flu/Bu2 as a conditioning regimen. Flu/Bu4 comprised intravenous busulfan (total dose, 12.8 mg/kg) combined with fludarabine (total dose, 125-180 mg/m(2)). Flu/Bu2 comprised intravenous busulfan (total dose, 6.4 mg/kg) combined with the same dose of fludarabine. To minimize selection bias and confounding factors, we performed a propensity score (PS)-matched analysis. The primary endpoint was overall survival (OS) after allo-HSCT. A total of 3386 patients with de novo MDS underwent their first allo-HSCT between 2006 and 2018. Among them, 202 patients were assigned each to the Flu/Bu4 and Flu/Bu2 groups after PS-matched analysis. The median age was 61 (interquartile, 57-65) years. The 3-year OS rates were 44.8% (95% confidence interval [CI], 37.1-52.1%) and 46.9% (95% CI, 39.2-54.2%) in the Flu/Bu4 and Flu/Bu2 groups, respectively (P = .67). The 3-year rates of graft-versus-host disease (GVHD)-free survival, relapse-free survival (GRFS) were 28.8% (95% CI, 22.2-35.7%) and 33.0% (95% CI, 26.2-40.0%), respectively (P = .36). The 3-year cumulative incidence rates of relapse were 28.9% (95% CI, 22.6-35.6%) and 30.0% (95% CI, 23.6-36.6%), respectively (P = .47). The 3-year cumulative incidence rates of non-relapse mortality (NRM) were 28.2% (95% CI, 21.7-35.0%) and 27.1% (95% CI, 20.6-33.9%), respectively (P = .60). The 100-day cumulative incidence rate of grade II-IV acute GVHD was significantly higher in the Flu/Bu4 group than in the Flu/Bu2 group (41.7% [95% CI, 34.8%-48.4%] versus 29.3% [95% CI, 23.2%-35.7%], P = 0.012). To identify patients who had more favorable outcomes with 1 of the 2 regimens, we compared the outcomes between the 2 groups after stratifying by age, hematopoietic cell transplantation-comorbidity index, cytogenetic risk, disease status at allo-HSCT, stem cell source, and donor type. OS, GRFS, relapse, and NRM did not differ between the 2 groups in any subgroup analyses. There were no significant interactions between the choice of conditioning regimens and any other factors. There are no differences in survival between Flu/Bu4 and Flu/Bu2, although our study population was highly selected by PS matching. Data from more patients and prospective studies are needed to determine the optimal intensity of conditioning regimens in patients with MDS.
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Haploidentical transplantation with post-transplant cyclophosphamide versus single cord blood transplantation for myelodysplastic syndrome: a retrospective study from the Adult Myelodysplastic Syndrome Working Group of the Japanese Society for Transplantation and Cellular Therapy (JSTCT)
Konuma, T., Shimomura, Y., Ishiyama, K., Ara, T., Nakamae, H., Hiramoto, N., Eto, T., Maruyama, Y., Nagafuji, K., Ishikawa, J., et al
American journal of hematology. 2022
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8.
Hematopoietic stem cell transplantation in children and adolescents with GATA2-related myelodysplastic syndrome
Bortnick, R., Wlodarski, M., de Haas, V., De Moerloose, B., Dworzak, M., Hasle, H., Masetti, R., Starý, J., Turkiewicz, D., Ussowicz, M., et al
Bone marrow transplantation. 2021
Abstract
GATA2 deficiency is a heterogeneous multi-system disorder characterized by a high risk of developing myelodysplastic syndrome (MDS) and myeloid leukemia. We analyzed the outcome of 65 patients reported to the registry of the European Working Group (EWOG) of MDS in childhood carrying a germline GATA2 mutation (GATA2(mut)) who had undergone hematopoietic stem cell transplantation (HSCT). At 5 years the probability of overall survival and disease-free survival (DFS) was 75% and 70%, respectively. Non-relapse mortality and relapse equally contributed to treatment failure. There was no evidence of increased incidence of graft-versus-host-disease or excessive rates of infections or organ toxicities. Advanced disease and monosomy 7 (-7) were associated with worse outcome. Patients with refractory cytopenia of childhood (RCC) and normal karyotype showed an excellent outcome (DFS 90%) compared to RCC and -7 (DFS 67%). Comparing outcome of GATA2(mut) with GATA2(wt) patients, there was no difference in DFS in patients with RCC and normal karyotype. The same was true for patients with -7 across morphological subtypes. We demonstrate that HSCT outcome is independent of GATA2 germline mutations in pediatric MDS suggesting the application of standard MDS algorithms and protocols. Our data support considering HSCT early in the course of GATA2 deficiency in young individuals.
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Allogeneic hematopoietic stem cell transplantation for myelodysplastic syndrome in adolescent and young adult patients
Shimomura, Y., Hara, M., Konuma, T., Itonaga, H., Doki, N., Ozawa, Y., Eto, T., Uchida, N., Aoki, J., Kato, J., et al
Bone marrow transplantation. 2021
Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curable treatment option for adolescent and young adult (AYA) patients with myelodysplastic syndrome (MDS). The study aim was to evaluate epidemiological data and identify prognostic factors for AYA patients with MDS undergoing allogeneic HSCT. Here, 645 patients were selected from patients enrolled in a multicenter prospective registry for HSCT from 2000 to 2015. The primary endpoint was 3-year overall survival (OS). Survival rates were estimated using the Kaplan-Meier method. Prognostic factors were identified using the multivariable Cox proportional hazards model. The 3-year OS was 71.2% (95% confidence interval [CI]: 67.4-74.6%). In multivariable analysis, active disease status (adjusted hazard ratio: 1.54, 95% CI: 1.09-2.18, p?=?0.016), poor cytogenetic risk (1.62, 1.12-2.36, p?=?0.011), poor performance status (2.01, 1.13-3.56, p?=?0.016), human leukocyte antigen (HLA)-matched unrelated donors (2.23, 1.39-3.59, p?0.001), HLA-mismatched unrelated donors (2.16, 1.09-4.28, p?=?0.027), and cord blood transplantation (2.44, 1.43-4.17, p?=?0.001) were significantly associated with poor 3-year OS. In conclusion, in AYA patients with MDS the 3-year OS following allogeneic HSCT was 71.2%. Active disease status, poor cytogenetic risk, poor performance status, and donor sources other than related donors were associated with poor 3-year OS.
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10.
[Allogeneic transplantation for myelodysplastic syndromes: analyses of the Japanese registry data]
Ishiyama, K.
[Rinsho Ketsueki] the Japanese Journal of Clinical Hematology. 2021;62(4):289-298
Abstract
Myelodysplastic syndrome (MDS) is characterized by its frequent appearance in elderly patients, and allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy for MDS. However, the availability of HSCT depends on various factors, and it is possible that the HSCT outcomes may differ when compared on a country-by-country basis. Comparison of nationwide registry data from the US and Japan revealed that the two countries share a common trend of increasing the number of HSCT procedures from HLA-haploidentical relatives. However, the number of cord blood transplantation (CBT) procedures in the US is decreasing, whereas the number of those in Japan appears to be increasing. The results from the studies conducted by the adult MDS Working Group of the Japan Society for Hematopoietic Cell Transplantation revealed that the HSCT outcomes for elderly patients and for patients with intermediate cytogenetic risk and CBT in Japan were slightly superior to those in the United States and Europe. Because such differences in outcomes may be attributed to differences in patient backgrounds, it is preferable to establish "evidence" in one's own country. Although it is difficult to conduct a prospective study on rare diseases such as MDS, the use of a large-scale registry can provide an answer, even for such detailed clinical questions.