Donor-derived Myelodysplastic Syndrome Research Articles

Donor Derived Myelodysplastic Syndrome after Sex Matched Haploidentical Allograft for AML with Monosomy 7 in Both Diseases: Importance of Donor Chimerism Assessment By Two Independent Techniques

Donor-derived leukaemia is a rare outcome in patients following allogeneic hematopoietic cell transplant (HCT) accounting for ~ 0.1-5% of relapsed cases although the true incidence is likely underestimated. A 39-year-old male patient with a history of ulcerative colitis treated with mercaptopurine was subsequently diagnosed with therapy related acute myeloid leukaemia (AML) and karyotype showed 45,XY,-7. The patient achieved remission after two cycles of treatment and proceeded to a paternal haploidentical HCT. Complete remission with no detectable disease by flow cytometry and fluorescent in-situ hybridisation (FISH) was achieved by day 40 of transplantation with whole blood and T-cell chimerism of 97% as assessed by routine short tandem repeat (STR) chimerism analysis. With withdrawal of immunosuppression this increased to 100% in both fractions. At 11 months post-transplant evidence of low-level cytogenetic relapse emerged with monosomy 7 seen by FISH in 15/200 interphase cells. Chimerism remained stable at 99% with aspirate findings indicating 2-3% blasts and some trilineage dysplasia. Two subsequent marrows showed persistence of monosomy 7 by FISH with full donor STR chimerism. Although a possibility of donor derived myelodysplastic syndrome (DD-MDS) was considered, due to the monosomy 7, donor lymphocyte infusion (DLI) therapy was administered at 16 and 19 months post-transplant. Monosomy 7 persisted on FISH and standard cytogenetic analysis. To confirm validity of STR chimerism and to distinguish between DD-MDS and relapse of original disease, HLA typing by next generation sequencing (NGS) to exclude HLA loss related relapse and potentially guide rescue decisions was performed alongside NGS chimerism assessment. NGS chimerism utilises genetic markers with population independent discriminative power distributed across 17 chromosomes and further selected to allow sensitive detection combined with accurate and precise quantification of mixed chimerism. NGS chimerism is demonstrated to be sensitive enough to detect a minor DNA contributor comprising down to 0.5% of the sample, detection of low level mixed chimerism and therefore clinical utility in better predicting relapse compared to conventional techniques. Original stored donor cells were tested and showed no evidence of monosomy 7 by FISH. After confirming DD-MDS a second HCT was considered. Originally unsuccessful unrelated donor search was re-opened and wide family donor search initiated. With azacytidine therapy the patient achieved a short lived cytogenetic remission, but subsequently relapsed and progressed to AML with karyotype of 45,XY,-7,der(16)t(11;16)(q13;p13.1)[9]/46,XY[1] and died 33 months after HCT prior to initiation of a second HCT. This case was complicated by the presence of monosomy 7 detected by karyotyping in both the initial diagnostic t-AML and in the DD MDS. Monosomy 7 is the most common abnormality found in DD-MDS but a review of the literature available does not seem to indicate any cases where it was also present in the patient's initial diagnostic sample as a separate disease entity. The pathogenesis of DD-MDS remains unclear. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

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

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.

Outcomes of Cord Blood Transplantation as Salvage Therapy after Graft Failure or Relapse after Prior Allogeneic Transplantation

For patients with disease relapse or graft failure after allogeneic hematopoietic cell transplantation (HCT), there are few treatment options and survival rates are exceedingly low. Because of the unacceptably high risk of transplantation-related mortality, second allogeneic HCTs are often not considered. Herein, we report the outcomes of 23 patients (median age, 33years) undergoing a second allogeneic transplantation with unrelated cord blood donor grafts between 2006 and 2013. Indications for second HCT were relapse (n=19), graft failure (n=3), and donor-derived myelodysplastic syndrome (n=1). Ten patients received reduced-intensity conditioning and 13 patients received either myeloablative (MAC) or middle-intensity (MIDI) conditioning. Twenty patients received a double cord blood transplantation. All patients engrafted at a median of 22days (range, day 6 to 49). Death before day 100 occurred in 5 patients. Overall disease-free survival (DFS), treatment-related mortality, and relapse at 2years were 31%, 33%, and 35%, respectively. Two-year DFS in the 13 patients receiving MAC or MIDI conditioning was slightly higher at 46%. Our results demonstrate that second allogeneic HCT using cord blood as the graft source should be considered in patients who have relapsed or experience graft failure after an allogeneic HCT.

An unusual case of donor‐derived myelodysplastic syndrome following double‐unit umbilical cord blood transplantation in acute lymphoblastic leukemia

Umbilical cord-blood transplantation is considered an effective treatment strategy for acute lymphoblastic leukemia (ALL) when a human leukocyte antigen (HLA)-matched donor is unavailable. The use of a second unit helps ensure engraftment in larger adults and those with comorbidities, even though only one unit engrafts in most patients. Herein, we present the clinical and laboratory characteristics of a patient who developed donor-derived myelodysplastic syndrome (ddMDS) after double umbilical cord-blood transplantation (dUCB HSCT). To our knowledge, no cases of ddMDS have been described in a patient with a history of ALL in molecular remission after receiving a dUCB HSCT. Current molecular techniques, including analysis of short tandem repeats (STR) and fluorescence in situ hybridization (FISH) allowed us to firmly establish donor origin.

Recurrence of monoclonal gammopathy associated with donor-derived myelodysplastic syndrome after cord blood stem cell transplantation

Myelodysplastic syndrome (MDS) is known to be associated with functional abnormalities of B cells, including hypergammaglobulinemia and monoclonal gammopathy (MG). However, the pathogenesis of these immunological disorders has not been clarified. We report a patient who developed donor-derived MDS followed by leukemic transformation after cord blood transplantation for MDS with MG. Interestingly, MG reappeared before development of donor-derived MDS. We analyzed the immunoglobulin allotype gene polymorphisms to determine whether the MG after cord blood transplantation was of recipient origin or donor origin. Results of genetic analysis and enzyme-linked immunosorbent assay of IgG1 allotype revealed that the MG after cord blood transplantation was of donor origin. Although the mechanism of donor-derived MG remains unclear, the persistent presence of recipient's antigen presenting cells might have induced the abnormal immunoglobulin production.

Donor-Derived Myelodysplastic Syndrome and Acute Leukemia After Allogeneic Hematopoietic Stem Cell Transplantation (HSCT): Incidence, Natural History and Treatment Response

AbstractAbstract 1306Donor-derived myelodysplastic syndrome (DD-MDS) and acute leukemia (DD-AL) are rare complications of allogeneic HSCT with approximately 40 cases identified in the literature. While the estimated incidence of DD-MDS/AL is between 0.12–5% for recipients of allogeneic HSCTs, more precise estimates by HSCT source have been impaired by differences in follow-up and changes in diagnostic tools over time. To this end, we evaluated all allogeneic transplants performed at the University of Minnesota between 1992 and 2009 in whom molecular assays for chimerism were performed. Patients transplanted for malignancy also had routine marrow examinations for evidence of recurrent disease. During this interval, there were 226 related donor transplants (47 marrow, 164 peripheral blood, 3 marrow and peripheral blood, 12 umbilical cord blood [UCB]), and 1254 unrelated donor transplants (436 marrow, 16 peripheral blood, 802 UCB). Of the entire cohort, 73% had a malignant and 27% had a non-malignant disease with 60% male, and 57% aged >18 years. The median follow-up among survivors was 3.5 years (range, 0.5 to 15.1). Eight cases of DD-MDS/AL were identified with the event diagnosed between 3 months and 15 years (median 33 months) after transplant. At 5 years, the incidence of DD-MDS/AL by donor type was 3.4% after matched sibling donor, 0% after unrelated marrow/peripheral blood donor and 0.4% after unrelated UCB donor transplant. Main characteristics of the 8 cases are described in Table 1. Four patients had CMV reactivation during their post-transplant course requiring antiviral therapy; three had poor hematopoietic recovery with prolonged courses of hematopoietic growth factor therapy. Five had monosomy 7, including all 4 UCB cases. Time to DD-MDS/AL varied by HSCT source: 22 months for UCB and 50 months for MSD cases. Underlying mechanisms are not yet known but have been postulated to include inherited or chemotherapy-induced marrow stroma and microenvironment abnormalities, bystander injury due to residual low-level chemotherapy and radiation damage, impaired tumor surveillance, chronic antigenic stimulation, premature aging of donor cells, transfer of oncogenic material from host to donor cells and the presence of preleukemic clones found rarely in UCB samples. Interestingly, one patient with DD-MDS had a sustained complete remission and loss of the cytogenetic clone by removing GCSF. The patient with DD-acute lymphocyte leukemia completed Children's Cancer Group protocol 1961 and remains disease-free currently out 43 months from DD-AL occurrence. Two of the DD-acute myeloid leukemia cases were treated with high dose Ara-C containing regimens and one patient went on to a second HSCT. Two of the DD-MDS cases were treated with a second HSCT, while one was given decitabine. These 8 cases illustrate the rarity of the event and potentially provide more accurate estimates of the risk of this complication by HSCT source for counseling patients. Furthermore, therapeutic interventions are limited but removal of hematopoietic growth factor may alone be effective in some cases. Disclosures:No relevant conflicts of interest to declare.