Identifying familial myelodysplastic/acute leukemia predisposition syndromes through hematopoietic stem cell transplantation donors with thrombocytopenia

Churpek, Jane E.; Nickels, Eric; Márquez, Rafael; Rojek, Katarzyna; Liu, Bohao; Lorenz, Rachelle; Lepore, Janet B.; Madžo, Jozef; Wickrema, Amittha; Artz, Andrew S.; Besien, Koen van; Godley, Lucy A.

doi:10.1182/blood-2012-09-457945

Cited by 21 publications

(16 citation statements)

References 6 publications

(4 reference statements)

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“…The first was a 63-year-old donor with mild thrombocytopenia (platelet count, 136 K/μL) and macrocytosis (MCV, 107.8 fL) whom we had reported previously with a novel deleterious germline TERT mutation (c.2908A>G; p.M970V; 48% allelic ratio), identified in the recipient’s leukemia as well [1]. Mutations in TERT are known to cause an inherited autosomal dominant telomere biology disorder [4], and we demonstrated that all lymphocyte subsets from the donor had short or very short telomeres by flow fluorescein in situ hybridization [1]. …”

Section: Resultsmentioning

confidence: 99%

“…However, genetic factors contributing to donors who mobilize PBSC poorly, and how this affects transplantation outcomes, are not well understood. Previously, our laboratory identified a case of germline predisposition to myeloid malignancies by studying related allogeneic stem cell donors who had baseline unexplained thrombocytopenia as a marker for identifying familial myelodysplastic syndrome (MDS)/acute leukemia predisposition syndromes [1]. Because poor mobilization has been observed in individuals with other heritable hematopoietic disorders [2], we hypothesized that we could identify additional individuals and families at high risk for having a germline predisposition allele by examining related allogeneic HSC donors who mobilized low numbers of PBSCs.…”

Section: Introductionmentioning

confidence: 99%

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Identifying Inherited and Acquired Genetic Factors Involved in Poor Stem Cell Mobilization and Donor-Derived Malignancy

Rojek

Nickels

Neistadt

et al. 2016

Biology of Blood and Marrow Transplantation

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Analysis of the clinical characteristics of hematopoietic stem cell transplant (HSCT) donors has proven beneficial for identifying cases of heritable hematopoietic disorders. This study examines poor peripheral blood hematopoietic stem cell mobilization after granulocyte colony–stimulating factor administration among 328 donors as a potential marker for suspected familial predisposition to myeloid malignancies. Here, we present data comparing the clinical characteristics of poor-mobilizing versus nonpoor-mobilizing donors and the results of panel-based sequencing of hematopoietic genes in poor-mobilizing donors. From this analysis, we identified a novel case of a donor-derived myelodysplastic syndrome in an HSCT recipient that is consistent with clonal evolution of TET2-mutated clonal hematopoiesis of indeterminate potential (CHIP) within the donor. This study demonstrates the potential risk of using hematopoietic stem cells from a donor with CHIP and raises the question of whether there should be increased screening measures to identify such donors.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Identifying Inherited and Acquired Genetic Factors Involved in Poor Stem Cell Mobilization and Donor-Derived Malignancy

Rojek

Nickels

Neistadt

et al. 2016

Biology of Blood and Marrow Transplantation

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“…Among the 28 poor mobilizers sequenced using MarrowSeq (The University of Washington Medical Center Genetics and Solid Tumor Diagnostic Laboratory), clearly damaging mutations were identified in 2 individuals (7%). The first was a 63-year-old donor with mild thrombocytopenia (platelet count, 136 K/μL) and macrocytosis (MCV, 107.8 fL) whom we had reported previously with a novel deleterious germline TERT mutation (c.2908A>G; p.M970V; 48% allelic ratio), identified in the recipient's leukemia as well [1]. Mutations in TERT are known to cause an inherited autosomal dominant telomere biology disorder [4], and we demonstrated that all lymphocyte subsets from the donor had short or very short telomeres by flow fluorescein in situ hybridization [1].…”

Section: Resultsmentioning

confidence: 99%

Identifying Inherited and Acquired Genetic Factors Involved in Poor Stem Cell Mobilization and Donor-Derived Malignancy

Rojek

Nickels

Niestadt

et al. 2015

Blood

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Background Mobilized peripheral blood (PB) stem cells (PBSC) are the most frequent source of hematopoietic stem cells (HSC) used for allogeneic HSC transplantation (HSCT). However, genetic factors contributing to donors who mobilize PBSC poorly are not well understood. We previously identified an undetected case of a familial myelodysplastic syndrome/acute leukemia (MDS/AL) predisposition syndrome in a donor with mild pre-donation thrombocytopenia who mobilized very poorly. Familial MDS/AL predisposition syndromes were identified in two other donors found to have hypocellular bone marrows after poor PBSC mobilization. Thus, we hypothesized that we could identify germline MDS/AL predisposition among poor mobilizing donors using a genomic screen of key hematopoietic genes. Patients and Methods Among 331 HLA-matched related HSC donors who underwent PBSC mobilization at The University of Chicago from 2001 to 2011, we defined those whose PB CD34+ cells/μl on day 5 post G-CSF administration fell within the lowest quartile as poor mobilizers (PM). Genomic DNA was available for 23 consented PM. This study was approved by The University of Chicago Institutional Review Board. Genomic DNAs isolated from donors' mobilized PBSC product were screened utilizing MarrowSeq, an next generation sequencing (NGS) assay targeting 142 genes involved in inherited and acquired bone marrow failure syndromes and hematologic malignancies. Potentially damaging variants were confirmed by Sanger sequencing. Clinical NGS panel testing was used to identify additional acquired mutations in one donor/recipient pair. Results Among the 23 PM sequenced using MarrowSeq, deleterious mutations were identified in 2 (9%). The first, a 63 year old male donor with mild thrombocytopenia (platelet count 136 K/μL) and macrocytosis (MCV 107.8 fL) was previously reported by our group to have a deleterious germline TERT mutation (c.2908A>G; p.M970V; 48% allelic ratio), which was also identified in the recipient's leukemia. This donor required bone marrow harvest after two failed PBSC mobilization attempts and the recipient died 5 months post-HSCT due to complications of poor engraftment. The second was a 67 year old mildly thrombocytopenic male donor (platelet count 139 K/μl) with a deleterious TET2 mutation (c.3765C>G; p.Y1255*; 48% allelic ratio), which was not present in the recipient's skin fibroblasts, most consistent with the presence of clonal hematopoiesis of indeterminate potential (CHIP) in the donor. Follow-up of this donor six years after collection of these TET2-mutated PBSCs demonstrated persistent mild thrombocytopenia (platelet count 121 K/μl), but otherwise normal blood counts. The recipient achieved remission after reinduction chemotherapy for relapsed AML followed by matched-related HSCT. Post-HSCT, the recipient demonstrated persistent mild thrombocytopenia. Six years later, she developed transfusion-dependent anemia and refractory anemia with excess blasts-2. Karyotype and microsatellite marker analysis of the bone marrow were consistent with an MDS of male donor origin. NGS sequencing from the bone marrow demonstrated the same TET2 mutation found in the mobilized PBSC product used in the transplant and an additional acquired RUNX1 mutation (c.585del; p.T196Qfs*15). Additional data from NGS sequencing of donor and recipient samples over time will be presented. Conclusions We demonstrate that both inherited and acquired genetic factors in PBSC from apparently healthy donors can contribute to poor mobilization and donor-derived malignancy post-HSCT. To the best of our knowledge, this is the first example of clonal evolution of TET2-mutated CHIP within a donor resulting in a donor-derived leukemia within the HSCT recipient. Replicative stress to reconstitute hematopoiesis in the recipient and/or the recipient's damaged bone marrow microenvironment may be contributing factors to the development of this donor-derived leukemia while the donor remains well. This study suggests that PM with thrombocytopenia may carry inherited or acquired mutations in hematopoietic genes, and alternative donor options should be considered. Our study also raises concerns about whether we need to screen for CHIP in healthy donors with unexplained cytopenias, especially as donors of increasing age are utilized. This research was supported by the American Society of Hematology through the ASH HONORS Award. Disclosures van Besien: Miltenyi Biotec: Research Funding. Godley:Onconova: Research Funding.

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“…The recommendation proposed to allow donors with mild anemia (defined as 2 g/dL below anemia thresholds), mild neutropenia (defined as <1 Â 10 9 neutrophils/L), mild lymphopenia (defined as <.5 Â 10 9 lymphocytes/L), or mild thrombocytopenia (defined as between 100 and 130 Â 10 9 /L) absent a contraindication requires further comment. We and others have found that it is among this group of donors that workup will have the highest likelihood of finding unsuspected inherited hematopoietic malignancy syndromes [1]. Thus, we propose that without specific mention of when and how to evaluate potential donors for inherited susceptibility, the above recommendation may lead to increased risks for both donor and recipient and fall short of the outlined principles of donor/recipient safety in your consensus statement.…”

Section: To the Editormentioning

confidence: 96%

Correspondence Regarding the Consensus Statement from the Worldwide Network for Blood and Marrow Transplantation Standing Committee on Donor Issues

Churpek

Artz

Bishop

et al. 2016

Biology of Blood and Marrow Transplantation

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Identifying familial myelodysplastic/acute leukemia predisposition syndromes through hematopoietic stem cell transplantation donors with thrombocytopenia

Cited by 21 publications

References 6 publications

Identifying Inherited and Acquired Genetic Factors Involved in Poor Stem Cell Mobilization and Donor-Derived Malignancy

Identifying Inherited and Acquired Genetic Factors Involved in Poor Stem Cell Mobilization and Donor-Derived Malignancy

Identifying Inherited and Acquired Genetic Factors Involved in Poor Stem Cell Mobilization and Donor-Derived Malignancy

Correspondence Regarding the Consensus Statement from the Worldwide Network for Blood and Marrow Transplantation Standing Committee on Donor Issues

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