European experience and risk factor analysis of donor cell-derived leukaemias/MDS following haematopoietic cell transplantation

Engel, Nicole; Rovó, Alicia; Badoglio, Manuela; Labopin, Myriam; Basak, Grzegorz W.; Béguin, Yves; Guyotat, Denis; Ljungman, Per; Nagler, Arnon; Schattenberg, A.V.M.B.; Schroeder, Thomas; Schroyens, Wilfried; Tischer, Johanna; Socié, Gérard; Kolb, Hans‐Jochem; Thewis, André; Salooja, Nina; Duarte, Rafael F.

doi:10.1038/s41375-018-0218-6

Cited by 50 publications

(54 citation statements)

References 31 publications

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“…[14][15][16] DCL represents a relatively rare complication that affects 0.1% of those who undergo transplantion. 17,18 In addition, it has been shown that five of six recipients with unexplained cytopenias received allografts from donors with DNMT3A mutation. 19 Nonmalignant outcome consequences of donor CHIP, such as graft function and/or immunologic impairment, may be more common than DCL and may thereby contribute to HSCT outcome.…”

Section: Introductionmentioning

confidence: 99%

Role of Donor Clonal Hematopoiesis in Allogeneic Hematopoietic Stem-Cell Transplantation

Frick

Chan

Arends

et al. 2019

JCO

193

139

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Purpose Clonal hematopoiesis of indeterminate potential (CHIP) occurs in the blood of approximately 20% of older persons. CHIP is linked to an increased risk of hematologic malignancies and of all-cause mortality; thus, the eligibility of stem-cell donors with CHIP is questionable. We comprehensively investigated how donor CHIP affects outcome of allogeneic hematopoietic stem-cell transplantation (HSCT). Methods We collected blood samples from 500 healthy, related HSCT donors (age ≥ 55 years) at the time of stem-cell donation for targeted sequencing with a 66-gene panel. The effect of donor CHIP was assessed on recipient outcomes, including graft-versus-host disease (GVHD), cumulative incidence of relapse/progression (CIR/P), and overall survival (OS). Results A total of 92 clonal mutations with a median variant allele frequency of 5.9% were identified in 80 (16.0%) of 500 donors. CHIP prevalence was higher in donors related to patients with myeloid compared with lymphoid malignancies (19.2% v 6.3%; P ≤ .001). In recipients allografted with donor CHIP, we found a high cumulative incidence of chronic GVHD (cGVHD; hazard ratio [HR], 1.73; 95% CI, 1.21 to 2.49; P = .003) and lower CIR/P (univariate: HR, 0.62; 95% CI, 0.40 to 0.97; P = .027; multivariate: HR, 0.63; 95% CI, 0.41 to 0.98; P = .042) but no effect on nonrelapse mortality. Serial quantification of 25 mutations showed engraftment of 24 of 25 clones and disproportionate expansion in half of them. Donor-cell leukemia was observed in two recipients. OS was not affected by donor CHIP status (HR, 0.88; 95% CI, 0.65 to 1.321; P = .434). Conclusion Allogeneic HSCT from donors with CHIP seems safe and results in similar survival in the setting of older, related donors. Future studies in younger and unrelated donors are warranted to extend these results. Confirmatory studies and mechanistic experiments are warranted to challenge the hypothesis that donor CHIP might foster cGVHD development and reduce relapse/progression risk.

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Section: Introductionmentioning

confidence: 99%

Role of Donor Clonal Hematopoiesis in Allogeneic Hematopoietic Stem-Cell Transplantation

Frick

Chan

Arends

et al. 2019

JCO

193

139

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“…The incidence of DCL has been estimated to range from less than 1 to 6.6% of all transplantations (2-10), and the frequency of DCL is increasing due to the increase in the number of SCTs (15). Dietz et al (9) reported that the risk of DCL was similar between stem cell sources.…”

Section: Discussionmentioning

confidence: 99%

“…Previous cases of DCL have been reported with all stem cell sources, including peripheral blood stem cells (2,9,10), bone marrow (2,9,11), and umbilical cord blood (5,9,(12)(13)(14). Umbilical cord blood is recognized as an alternative stem cell source for transplantation, and since 2005, some cases of DCL after cord blood transplantation (CBT) have been reported to have poor prognoses (12)(13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

Jumping translocations of 1q in donor cell‑derived myelodysplastic syndrome after cord blood transplantation: Case report and review of the literature

et al. 2020

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Donor cell-derived leukemia and myelodysplastic syndrome (DCL) is a rare complication in patients after allogenic stem cell transplantation (SCT). Since 1971, numerous cases of DCL have been reported, but the detailed mechanisms of DCL are still unclear. A patient with jumping translocations (JTs) of 1q in umbilical cord blood donor cell-derived myelodysplastic syndrome (MDS), which likely occurred due to genetic alterations of TET2 and ASXL1 after cord blood transplantation (CBT), was examined in this study. Previously reported DCL cases after CBT that focused on the cytogenetic and molecular characteristics of these patients and patient outcome were reviewed. A total of 30 cases of DCL after CBT were identified between 2005 and 2018. The median time from CBT to the development of DCL was 16 months. The number of patients with DCL who were diagnosed with acute myeloid leukemia (AML) and MDS was 19 and 8, respectively. JTs were frequently observed in 5 of 27 DCL patients who had cytogenetic abnormalities, including our patient. Molecular abnormalities were described in 7 of the cases, and the most frequent abnormality was an NPM1 mutation. Other gene mutations that were usually found in de novo MDS or AML were observed in JT-DCL after CBT. From these results, chromosomal abnormalities such as JTs that occur subsequent to genetic alterations were seemed an important mechanisms underlying DCL onset in patients after CBT. Further molecular analyses regarding the genetic alterations of JTs are required to understand the pathogenesis of umbilical cord blood-derived JT-DCL.

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“…Development of DCL especially after haploHSCT is a poorly reported phenomenon. Just recently, a multi-center survey of the European Society for Blood and Marrow Transplantation (EBMT) estimated a frequency of 80.5 DCLs per 100,000 alloHSCTs [3]. Since proof of DCL is generally difficult to obtain, the real prevalence is probably significantly higher.…”

Section: Dear Editormentioning

confidence: 99%

Donor-cell leukemia with novel genetic features 2 years after sex-mismatched T cell-depleted haploidentical stem cell transplantation

et al. 2020

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Dear Editor,The mechanisms leading to the appearance of acute myeloid leukemia (AML) in the donor cells after allogeneic hematopoietic stem cell transplantation (alloHSCT) are barely understood [1,2]. This phenomenon is associated with a poor prognosis. However, it has to be assumed that only a fraction of cases get detected and reported, making every case in its uniqueness a valuable and worthwhile to report information. While the detection of the chromosomal gender of the donor in leukemic blasts leads with certainty to the diagnosis, detection of donor cell leukemia (DCL) following sex-matched transplantation can be challenging. Here we report a welldocumented case of DCL after haploidentical HSCT (haploHSCT) for secondary AML.A 56-year-old male patient with secondary AML (karyotype 46,XY; no partial tandem duplication [PTD] of the KMT2A [MLL] gene) following myelodysplastic syndrome (MDS) was referred to our center for induction therapy and alloHSCT in 2010. After standard "7+3" induction chemotherapy with cytarabine and daunorubicin, the patient received conditioning with fludarabine, busulfane, and anti-thymocyte globuline (ATG) and proceeded to alloHSCT using bone marrow from a male HLA-mismatched unrelated donor. C y c l o s p o r i n e a n d m e t h o t r e x a t e w e r e u s e d a s immunosuppression.The absence of leukocyte recovery prompted us to perform bone marrow punctures at day +20 and +32 confirming primary graft-failure of unknown origin. In this life-threatening situation, it was decided to perform a rescue haploHSCT from the patient's daughter. After reconditioning with fludarabine, cyclophosphamide, ATG, and total body irradiation (TBI), the patient received a CD34-selected peripheral blood stem cell graft. Neutrophil engraftment appeared on day +17 followed by platelet engraftment on day +50.The post-transplant period was unspectacular showing stable hematopoiesis, donor-chimerism > 99 % in granulocytes, and between 12 and 75% in T cells and no detectable cells from the first donor.More than 2 years later, the patient presented with persistent fever of unknown origin. Peripheral blood count detected about 5% immature white cells so that bone marrow puncture was performed revealing 30% blasts. However, donor chimerism in peripheral blood remained almost complete with 97% and > 99% in the myeloid cells. Selected CD34 + cells showed also a complete donor chimerism. Moreover, FACS analysis revealed a new blastic phenotype and coinciding with this cytogenetic and molecular analysis documented novel aberrations including trisomy 8, trisomy 11, and KMT2A-PTD, not present at primary diagnosis of the leukemia. Chromosome

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European experience and risk factor analysis of donor cell-derived leukaemias/MDS following haematopoietic cell transplantation

Cited by 50 publications

References 31 publications

Role of Donor Clonal Hematopoiesis in Allogeneic Hematopoietic Stem-Cell Transplantation

Role of Donor Clonal Hematopoiesis in Allogeneic Hematopoietic Stem-Cell Transplantation

Jumping translocations of 1q in donor cell‑derived myelodysplastic syndrome after cord blood transplantation: Case report and review of the literature

Donor-cell leukemia with novel genetic features 2 years after sex-mismatched T cell-depleted haploidentical stem cell transplantation

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