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Clonal Hematopoiesis in Related Allogeneic Transplant Donors: Implications for Screening and Management

2020; Elsevier BV; Volume: 26; Issue: 6 Linguagem: Inglês

10.1016/j.bbmt.2020.02.022

1523-6536

Matthew D. Seftel, Michelle Kuxhausen, Linda J. Burns, Pintip Chitphakdithai, Dennis L. Confer, Deirdre Kiefer, Stephanie J. Lee, Brent R. Logan, Paul V. O’Donnell, Michael A. Pulsipher, Nirali N. Shah, Galen E. Switzer, Bronwen E. Shaw,

Hemoglobinopathies and Related Disorders

Disorders of clonal hematopoiesis may be subclinical findings in asymptomatic individuals. Examples include monoclonal B-cell lymphocytosis (MBL) and or acquired somatic mutations detected by gene sequencing. These findings are more common in older individuals and in relatives of patients with hematologic malignancies [1Shim Y.K. Rachel J.M. Ghia P. et al.Monoclonal B-cell lymphocytosis in healthy blood donors: an unexpectedly common finding.Blood. 2014; 123: 1319-1326Crossref PubMed Scopus (48) Google Scholar, 2Jaiswal S. Fontanillas P. Flannick J. et al.Age-related clonal hematopoiesis associated with adverse outcomes.N Engl J Med. 2014; 371: 2488-2498Crossref PubMed Scopus (2278) Google Scholar, 3Del Giudice I. Mauro F.R. De Propris M.S. et al.Identification of monoclonal B-cell lymphocytosis among sibling transplant donors for chronic lymphocytic leukemia patients.Blood. 2009; 114: 2848-2849Crossref PubMed Scopus (20) Google Scholar]. In hematopoietic cell transplantation (HCT), clonal hematopoiesis in the donor may result in reduced capacity for stem cell mobilization or transmission of a clonal disorder to the recipient [3Del Giudice I. Mauro F.R. De Propris M.S. et al.Identification of monoclonal B-cell lymphocytosis among sibling transplant donors for chronic lymphocytic leukemia patients.Blood. 2009; 114: 2848-2849Crossref PubMed Scopus (20) Google Scholar,4Rojek K. Nickels E. Neistadt B. et al.Identifying inherited and acquired genetic factors involved in poor stem cell mobilization and donor-derived malignancy.Biol Blood Marrow Transplant. 2016; 22: 2100-2103Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar]. It is also possible that hematopoietic growth factors administered to donors, or the proliferative stimulus experienced by donor cells during reconstitution in the recipient, may act as an additional driver of mutagenesis [4Rojek K. Nickels E. Neistadt B. et al.Identifying inherited and acquired genetic factors involved in poor stem cell mobilization and donor-derived malignancy.Biol Blood Marrow Transplant. 2016; 22: 2100-2103Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar,5Avalos B.R. Lazaryan A. Copelan E.A. Can G-CSF cause leukemia in hematopoietic stem cell donors?.Biol Blood Marrow Transplant. 2011; 17: 1739-1746Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar]. There have been suggestions to screen donors for clonal hematopoiesis [3Del Giudice I. Mauro F.R. De Propris M.S. et al.Identification of monoclonal B-cell lymphocytosis among sibling transplant donors for chronic lymphocytic leukemia patients.Blood. 2009; 114: 2848-2849Crossref PubMed Scopus (20) Google Scholar,4Rojek K. Nickels E. Neistadt B. et al.Identifying inherited and acquired genetic factors involved in poor stem cell mobilization and donor-derived malignancy.Biol Blood Marrow Transplant. 2016; 22: 2100-2103Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar,6Kiss T.L. Chang H. Daly A. et al.Bone marrow aspirates as part of routine donor assessment for allogeneic blood and marrow transplantation can reveal presence of occult hematological malignancies in otherwise asymptomatic individuals.Bone Marrow Transplant. 2004; 33: 855-858Crossref PubMed Scopus (20) Google Scholar,7Frick M. Chan W. Arends C.M. et al.Role of donor clonal hematopoiesis in allogeneic hematopoietic stem-cell transplantation.J Clin Oncol. 2019; 37: 375-385Crossref PubMed Scopus (107) Google Scholar]. The extent to which HCT centers have made systematic efforts to screen for these conditions, and if found, how donors are managed, is unknown. The purpose of this survey was to understand the process HCT centers use to identify related donors with clonal hematopoiesis, whether such donors would be excluded from donation, and what other management steps that programs provide. In July 2017, we sent a survey to all HCT centers registered with the Center for International Blood and Marrow Transplant Research (CIBMTR) that evaluated related donors (http://www.SurveyGizmo.com). The survey consisted of 10 categorical (yes/no) or qualitative, open-ended questions regarding otherwise healthy related donors with normal peripheral blood counts (Appendix 1). Out of a total of 609 requests, there were 280 complete responses (response rate, 46%). Two-thirds of the responding centers were either Foundation for the Accreditation of Cellular Therapy (FACT)- or Joint Accreditation Committee of ISCT-EBMT (JACIE)-accredited. In comparison to nonresponding centers, a greater proportion of responding centers were from North America and from higher-volume HCT centers. We found that an appreciable number of HCT centers routinely screen related donors for clonal hematopoiesis (Table 1). Peripheral blood screening is conducted for monoclonal gammopathy of undetermined significance (MGUS) (18.9% of centers), MBL (5.0%), and gene sequencing for somatic mutations (3.6%). Respondents recalled detecting 1 or more cases of MGUS (17.8%), MBL (9.9%), or clonal cytogenetic abnormalities (7.7%). Donor deferral was recommended in 62% of respondents for MGUS, in 60.4% for MBL, in 74% for cytogenetic abnormalities, and in 62.8% for somatic mutations. Some centers felt that they could still proceed with donor collection, especially in cases of MBL (7.5%) and MGUS (8.9%), provided that myeloid growth factors were avoided in favor of an unstimulated bone marrow harvest. Although extensive studies of normal donors found no evidence of increased risk of acute myelogenous leukemia/myelodysplastic syndrome transformation after granulocyte colony-stimulating factor mobilization [8Pulsipher M.A. Chitphakdithai P. Logan B.R. et al.Lower risk for serious adverse events and no increased risk for cancer after PBSC vs BM donation.Blood. 2014; 123: 3655-3663Crossref PubMed Scopus (81) Google Scholar], this risk may differ in the small subset of donors with preexisting clonal hematopoiesis.Table 1Summary of Responses Regarding Types of Peripheral Blood Testing Performed in Related DonorsConditionYes, n (%)No, n (%)Uncertain, n (%)Not answered, n (%)During your assessment of otherwise healthy related donors with a normal complete blood count and differential, which of the following conditions do you routinely test for in the peripheral blood?MBL by flow cytometry14 (5.0)242 (86.1)6 (2.1)19 (6.8)Paroxysmal nocturnal hemoglobinuria screen by flow cytometry12 (4.3)246 (87.5)4 (1.4)19 (6.8)Monoclonal gammopathy by protein electrophoresis53 (18.9)202 (71.9)8 (2.9)18 (6.4)Jak-2 mutation8 (2.9)252 (89.7)4 (1.4)15 (5.4)BCR-ABL mutation8 (2.9)252 (89.7)4 (1.4)17 (6.1)Gene sequencing for somatic mutations associated with hematologic neoplasms10 (3.6)245 (87.2)7 (2.5)19 (6.8)Other13 (4.6)150 (53.4)14 (5.0)104 (37.0) Open table in a new tab We also found that 6% of centers perform routine bone marrow biopsies, and an additional 6.7% of centers perform bone marrow biopsies in subgroups, especially in donors of advanced age or whose recipients have a hematologic disorder that is possibly familial (eg, chronic lymphoblastic leukemia). One publication outlined the rationale for the use of this procedure during donor workup [6Kiss T.L. Chang H. Daly A. et al.Bone marrow aspirates as part of routine donor assessment for allogeneic blood and marrow transplantation can reveal presence of occult hematological malignancies in otherwise asymptomatic individuals.Bone Marrow Transplant. 2004; 33: 855-858Crossref PubMed Scopus (20) Google Scholar]. The requirement for a bone marrow biopsy may decrease relatives' willingness to donate; however, modern diagnostic techniques readily allow for detection of clonality from peripheral blood, without the need for an invasive procedure. Given that marrow biopsy is unlikely to helpful in the great majority of donors, it is important to redefine meaningful criteria for the use of this test. This survey adds to the emerging concerns about the transmissibility of noninfectious diseases from donor to recipient. This is especially relevant in an era where the age of HCT recipients and their related (matched or haploidentical) donors is increasing [9D'Souza A, Fretham C. Current uses and outcomes of hematopoietic cell transplantation (HCT): CIBMTR summary slides, 2018. Available at: http://www.cibmtr.org. Accessed March 31 2020.Google Scholar]. The increased use of older donors is likely to increase the likelihood of finding age-related hematopoietic disorders. FACT/JACIE standards require that centers evaluating related donors should have either questionnaires or laboratory tests to "identify persons at risk of transmitting a hematological or immunological disease" [10FACT/JACIEinternational standards for hematopoietic cellular therapy: product collection, processing, and administration. 7th ed. Available at: https://www.ebmt.org/sites/default/files/2018-06/FACT-JACIE%207th%20Edition%20Standards.pdf. Accessed March 31 2020.Google Scholar]. These standards call for specific attention to donors at extremes of age. However, there are no explicit requirements or guidelines about screening for clonal hematopoietic disorders. Detection of clonal hematopoiesis in a donor also requires disclosure of that finding, with attendant risk of distress in the knowledge of a premalignant finding or cardiovascular risk factor of unclear clinical significance [2Jaiswal S. Fontanillas P. Flannick J. et al.Age-related clonal hematopoiesis associated with adverse outcomes.N Engl J Med. 2014; 371: 2488-2498Crossref PubMed Scopus (2278) Google Scholar]. Consent from a potential donor to undergo evaluation for clonal hematopoiesis may require more than a procedural consent form, given the risk of discovering a disease predisposition. Inherent to surveys is the challenge of nonresponders. However, we did not appreciate differences between the responding (46%) and nonresponding sites that would alter the results. The survey was acquired from both North American (47%) and other (53%) HCT centers from a mix of small (53%) and medium to large HCT sites (47%), with both pediatric and adult HCT respondents. Another limitation is that we asked respondents to recall ever having identified a clonal disorder of hematopoiesis during a related donor workup; this question may be subject to recall bias. However, because this finding is likely to have been uncommon and clinically significant, the risk of recall bias would be low. In conclusion, a proportion of HCT centers routinely screen related donors for clonal hematopoietic disorders in peripheral blood or bone marrow specimens. Centers differ in their approach to detection of these disorders and as to whether they represent grounds for donor exclusion. We recommend the development of guidelines and standardization regarding how and when to test for clonal hematopoietic conditions in donors. Such an approach must incorporate a medical and ethical framework to minimize harm to both donors and recipients. The authors thank the staff of the CIBMTR and National Marrow Donor Program (NMDP) provided administrative personnel, statistical analyses, and software support for this study. Financial disclosure: Funding for this study was provided by the CIBMTR and NMDP. Final analysis and interpretation of the data, as well as manuscript completion, were the responsibility of the primary investigator and the co-authors. Conflict of interest statement: The authors declare no competing financial interests in relation to this study. 1.What is your transplant center's name? Please refrain from using abbreviations.2.For what related donor age groups does your program collect donors for allogeneic hematopoietic cell transplants?a.Adult donors onlyb.Pediatric donors onlyc.Both of the above3.What types of related donor collections are offered at your program?a.Peripheral blood stem cellsb.Bone marrow harvestc.Both of the above4.Is your program accredited for related donor assessment and collections by either FACT or JACIE?a.Yesb.Noc.Applied, accreditation pending5.During your assessment of otherwise healthy related donors with a normal complete blood count and differential (CBC and diff), which of the following conditions do you routinely test for in the peripheral blood? If any tests are performed only in special sub-groups of donors (e.g. donors > age 60 years) please indicate this in the comments section. (Yes, no, uncertain, space for comments).a.Monoclonal B-cell lymphocytosis (MBL) by flow cytometryb.Paroxysmal nocturnal hemoglobinuria (PNH) screen by flow cytometryc.Monoclonal gammopathy by protein electropheresisd.JAK-2 mutatione.BCR-ABL mutationf.Gene sequencing for somatic mutations associated with hematological neoplasmsg.Other6.During your assessment of otherwise healthy related donors with a normal complete blood count and differential (CBC and diff), some centres may perform bone marrow aspirate and/or biopsy. Please comment on your center's approach. If these tests are performed in only special sub-groups of donors (e.g. donors > age 60 years), please indicate this in the comments section.a.Routine bone marrow aspirates and/or biopsies are not performed in otherwise healthy related donors.b.Routine bone marrow aspirates and/or biopsies are performed in otherwise healthy related donors.c.Routine bone marrow aspirates and/or biopsies are performed in sub-groups of otherwise healthy related donors. (if yes, please comment on which sub-group, below)7.If routine bone marrow aspirates and/or biopsies are performed in all or subgroups of otherwise healthy related donors with a normal complete blood count and differential (CBC and diff), which of the following conditions do you test for? Please select all that apply. If tests are performed only in sub-groups (e.g. donors > age 60 years), please indicate this in the comments section. (yes, no, uncertain, space for comments)a.Morphological assessment of bone marrow (e.g. for myelodysplasia or other hematologic neoplasm)b.Monoclonal B-call lymphocytosis (MBL) by flow cytometryc.Clonal cytogenetic abnormalitiesd.JAK-2 mutatione.BCR-ABL mutationf.Somatic mutations associated with hematological neoplasms detected by gene sequencingg.Other (please describe)8.To your knowledge, has your center ever identified by screening tests any of the following conditions in an otherwise healthy related donor with a normal complete blood count and differential (CBC and diff)? (yes, no, uncertain, space for comments)a.Myelodysplasia, or other hematological neoplasm noted by morphological assessmentb.Paroxysmal nocturnal hemoglobinuria (PNH)c.Monoclonal B-cell lymphocytosis (MBL)d.Monoclonal gammopathye.Clonal cytogenetic abnormalityf.JAK-2g.BCR-ABL9.Which of the following disorders found in an otherwise healthy related donor with a normal complete blood count and differential (CBC and diff) would lead to donor deferral? Please add comments if required. (yes, no, uncertain, space for comments).a.Paroxysmal nocturnal hemoglobinuria (PNH)b.Monoclonal B-cell lymphocytosis (MBL)c.Monoclonal gammopathyd.Clonal cytogenetic abnormalitye.JAK-2 mutationf.BCR-ABL mutationg.Somatic mutations associated with hematological neoplasms detected by gene sequencingh.Other abnormalities (please describe)10.Which of the following conditions would still be permissible for donation provided that myeloid growth factors (e.g. GCSF) were avoided in favor of an unstimulated bone marrow harvest? Please add comments as required. (yes, no, uncertain, space for comments)a.Paroxysmal nocturnal hemoglobinuria (PNH)b.Monoclonal B-cell lymphocytosis (MBL)c.Monoclonal gammopathyd.Clonal cytogenetic abnormalitye.JAK-2 mutationf.BCR-ABL mutationg.Somatic mutations associated with hematological neoplasms detected by gene sequencingh.Other abnormalities (please describe)