60 research outputs found
Long-term prognosis for 1-year relapse-free survivors of CD34 cell-selected allogeneic hematopoietic stem cell transplantation : a landmark analysis
Altres ajuts: This research was supported in part by National Institutes of Health award number P01 CA23766 and NIH/NCI Cancer Center Support Grant P30 CA008748. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.CD34 selection significantly improves GVHD-free survival in allogeneic hematopoietic cell transplantation (allo-HSCT). Specific information regarding long-term prognosis and risk factors for late mortality after CD34-selected allo-HSCT is lacking, however. We conducted a single-center landmark analysis in 276 patients alive without relapse 1 year after CD34-selected allo-HSCT for AML (n=164), ALL (n=33), or MDS (n=79). At 5 years' follow-up after the 1-year landmark (range 0.03-13 years), estimated RFS was 73% and OS 76%. The 5-year cumulative incidence of relapse and NRM were 11% and 16%, respectively. In multivariate analysis, HCT-CI score ≥ 3 correlated with marginally worse RFS (HR 1.78, 95% CI 0.97-3.28, p=0.06) and significantly worse OS (HR 2.53, 95% CI 1.26-5.08, p=0.004). Despite only 24% of patients with acute GVHD within 1 year, this also significantly correlated with worse RFS and OS, with increasing grades of acute GVHD associating with increasingly poorer survival on multivariate analysis (p<0.0001). Of 63 deaths after the landmark, GVHD accounted for 27% of deaths and was the most common cause of late mortality, followed by relapse and infection. While prognosis is excellent for patients alive without relapse 1 year after CD34-selected allo-HSCT, risks of late relapse and NRM persist, particularly due to GVHD
Stem and progenitor cells in myelodysplastic syndromes show aberrant stage-specific expansion and harbor genetic and epigenetic alterations
Even though hematopoietic stem cell (HSC) dysfunction is presumed in myelodysplastic syndrome (MDS), the exact nature of quantitative and qualitative alterations is unknown. We conducted a study of phenotypic and molecular alterations in highly fractionated stem and progenitor populations in a variety of MDS subtypes. We observed an expansion of the phenotypically primitive long-term HSCs (lineage ؊ /CD34 ؉ /CD38 ؊ /CD90 ؉ ) in MDS, which was most pronounced in higher-risk cases. These MDS HSCs demonstrated dysplastic clonogenic activity. Examination of progenitors revealed that lower-risk MDS i
Allogeneic Stem Cell Transplantation for Advanced Myelodysplastic Syndrome: Comparison of Outcomes between CD34+ Selected and Unmodified Hematopoietic Stem Cell Transplantation.
Feasibility of Low Dose Azacitidine Post T Cell Depleted Allogeneic Hematopoietic Stem Cell Transplants in Patients with Myeloid Malignancies At High Risk for Relapse
Recommended from our members
Hematologic Malignancies Arising in Patients with Germ Cell Tumors: Secondary Somatic Differentiation of Hematopoietic Malignancies from Germ Cell Precursors
Abstract
Genomic analyses have recently illuminated our understanding of therapy-associated myeloid neoplasms in patients receiving therapy for other cancers. One of the most intriguing relationships between solid tumors and myeloid neoplasms involves a unique clinical entity of patients with germ cell tumors (GCT) and myeloid neoplasms. One in 17 patients with primary mediastinal germ cell tumor (PMGCT) develops a hematologic malignancy (most commonly AML, MDS, or histiocytosis) and the median survival in such patients is poor at only 5 months. Intriguingly, the presence of isochromosome 12p [i(12p)], a clonal marker common to GCTs but absent in de novo myeloid neoplasms, has been demonstrated as shared across GCTs and myeloid neoplasms in such individuals. While these data suggest a clonal relationship between the two, the exact nature of the shared origin is unknown. There are two competing hypotheses to explain this: (1) an embryonic progenitor with the capacity to differentiate into germ cell and hematopoietic lineages harbors the initiating genetic alterations and drives development of both malignancies or (2) the leukemia is derived directly from GCTs with the capacity to differentiate into hematopoietic lineages. To trace the clonal evolution of these seemingly unrelated cancer types and identify recurrent genomic lesions in leukemias present in GCT patients, we applied whole exome sequencing (WES), targeted genomic analyses, and/or RNA-seq to leukemias, GCTs, and germline DNA in a series of patients with myeloid neoplasms and concurrent GCTs.
We collected 12 patients with GCT and synchronously or metachronously occurring myeloid neoplasms (8 AML, 5 MDS/CMML, 2 histiocytic sarcoma (some had >1 hematologic malignancy)) with an average of 4 months between the two diagnoses. Consistent with prior reports, all were young men (median age 26) with PMGCT and nonseminomatous histology and a 3-month median survival from leukemia diagnosis (Fig. A). In each case, at least one copy number alteration or coding mutation was shared across the GCT and hematopoietic neoplasm, demonstrating the shared origin of both lesions. For example, half of the patients (6/12) carried i(12p) in both the GCT and hematopoietic neoplasm. In the i(12p) negative cases, somatic genetic alterations identified in the GCT were also found in the leukemia. The most common genomic alterations in leukemias beyond i(12p) included mutations activating RAS-PI3K-AKT signaling (including PTEN, RAS and PI3K isoform mutations) or inactivating TP53 (Fig. B). The only exception was a testicular-only GCT patient who developed clonally distinct acute promyelocytic leukemia; however, further analysis identified this as a chemotherapy-induced neoplasm with the PML-RARa breakpoint mapped to an etoposide sensitive area and this patient was not counted amongst the 12 cases.
We next traced the evolutionary history of clonally related GCTs and leukemias based on cancer cell fraction of all coding mutations and copy number alterations using WES of DNA from each tumor type and finger nails. In each instance, we identified clonal evolution of the hematopoietic malignancies from antecedent precursors within the GCT. To illustrate this, a 19-year-old male developed successive diagnoses of histiocytic sarcoma, CMML, and AML within 18 months of GCT diagnosis. Lineage tracing by WES of each of these four individual cancers revealed that all four were clonally related, and the histiocytic sarcoma, CMML, and AML were all derived from the GCT with a common precursor giving rise to the three hematopoietic malignancies (Fig. C-D). Moreover, the histiocytic sarcoma evolved separately from CMML/AML in this patient, where the AML represented leukemic transformation from the CMML.
These data conclusively demonstrate that myeloid neoplasms developing in patients with PMGCT represent secondary somatic differentiation of a hematologic progenitor from totipotent aberrant cells that are present in the GCT. Thus, GCT-associated leukemias have a unique ontogeny from de novo and/or secondary myeloid neoplasms, which originate from progenitors within the bone marrow. As such, GCT-associated leukemias have characteristic genomic alterations hallmarked by frequent i(12p) in combination with mutations activating RAS-PI3K-AKT signaling and inactivating TP53, and these patients do poorly even when treated with aggressive contemporary chemotherapy.
Figure Figure.
Disclosures
Rampal: Jazz: Consultancy, Honoraria; Celgene: Honoraria; Constellation: Research Funding; Incyte: Honoraria, Research Funding; Stemline: Research Funding. Tallman:ADC Therapeutics: Research Funding; Orsenix: Other: Advisory board; AROG: Research Funding; Cellerant: Research Funding; AbbVie: Research Funding; Daiichi-Sankyo: Other: Advisory board; BioSight: Other: Advisory board
Eltrombopag can overcome the anti-megakaryopoietic effects of lenalidomide without increasing proliferation of the malignant myelodysplastic syndrome/acute myelogenous leukemia clone
Photobiomodulation (PBM) Provides a Prompt and Near-Resolution Response to Advanced Oral Chronic Graft-Versus-Host Disease (cGVHD) after Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT)
Impact of Omitting Post-Transplant Mini-Methotrexate Doses in Allogeneic Hematopoietic Cell Transplantation: A Single-Center Retrospective Study
Infections Are the Major Cause of Non Relapse Mortality (NRM) after T Cell Depleted (TCD) Allogeneic Hematopoietic Stem Cell Transplantation for Advanced Myelodysplastic Syndrome
Late Effects of Autologous Hematopoietic Cell Transplantation (AHCT) in Elderly Patients with Lymphoma
- …