The evaluation of minimal residual disease (MRD) in acute myeloid leukemia (AML) is an important strategy to identify patients at high risk of relapse. There is no standardized MRD assay. This study compared 8-color flow to detect aberrant antigen expression of blasts with cytogenetic/molecular test at diagnosis (day 0) and postinduction (day 30). A total of 85 AML patients were included, 71 with abnormal cytogenetic/molecular results at diagnosis at day 0 and cytogenetic/molecular results at day 30, 11 with no complete cytogenetic/molecular data, and 3 with normal cytogenetic/molecular test. Flow MRD is positive if ≥ 2 aberrant antigen expressions are present both at day 0 and at day 30 at the blast level of 0.1-5%; suspicious if 1, and negative if 0. At initial diagnosis, flow detected aberrant antigen expression in 100% cases, with CD34 (76%), HLA-DR (47%) and CD7 the most common (35%). Seventy-five percent of patients have ≥ 3 aberrant antigens at diagnosis. Eighty-seven percent (62/71) of patients are positive or negative for MRD by flow, and 13% (9/71) patients are suspicious. Of 62 patients, 39% (24/62) patients are positive, and 61% (38/62) patients negative for MRD by flow, while 34% (21/62) of patients are positive, and 66% (41/62) of patients negative by cytogenetic/molecular test. Flow is accordant with cytogenetic/molecular results in 89% (55/62), and discordant in 11% (7/62) of patients. Among the 9 patients suspicious for MRD by flow, 44% (4/9) patients are positive, and 56% (5/9) patients negative by cytogenetic/molecular test. In conclusion, for cases with ≥ 2 aberrant antigens both at day 0 and day 30, flow is more sensitive than cytogenetic/molecular test for MRD detection. For cases with 1 aberrant antigen at day 30, 44% (4/9) patients are positive for MRD by cytogenetic/molecular test. Fifty-six percent (5/9) of patients are negative by cytogenetic/molecular test, which is mostly due to low percentage of blast population, which is below the limitation of the cytogenetic test (< 0.5%), and/or sampling issue.
Background: Both impaired immune reconstitution (IR) of selected cellular subsets and abnormally high lymphocyte expression of activation markers, such as HLA-DR, CD25, and CD69, have been observed in recipients of HCT experiencing graft-versus-host disease (GVHD). Whether such alterations in cell subsets and expression of activation markers occurs normally in long term survivors of allogeneic HCT, including those without any prior GVHD, has not been well described. Patients and methods: 122 consecutive adult allogeneic HCT survivors who were at least 2 years beyond HCT and returning for long-term follow up were included if they had an immune reconstitution panel drawn between 9-14-11 (date of current panel antibody choice and gating strategy) and 9-5-13. Sixty-four were male, 52 underwent reduced intensity conditioning, 69 received grafts from matched unrelated donors (MUD), 60 received GVHD prophylaxis that included prednisone, 74 had prior acute GVHD, and 111 had chronic GVHD. Transplant factors considered in analyzing differences in IR and lymphocyte activation included age, sex, conditioning intensity, donor, GVHD prophylaxis, prior acute GVHD, and prior chronic GVHD. IR parameters analyzed included the absolute neutrophil, lymphocyte, monocyte, and eosinophil counts (ANC, ALC, AMC, AEC), platelet counts, and percentages of the following lymphocyte phenotypes: CD3+, CD3+/4+, CD3+/8+, double negative CD3, double positive CD4, naïve T, NK, NKT-like (CD3+56+), total B, naïve B, marginal zone-like B, switched memory B, CD4/8 ratio, and lymphocytes expressing activation markers, including CD3+HLA-DR+, CD4+25+, CD4+25bright+, CD8+CD69+. Results: CD4/8 ratio was <1 in 54 patients (44%) in this cohort of long-term survivors. Several determinants of IR showed variability with respect to different transplant-related factors. Total CD4% and CD4%CD25bright+% but not absolute counts were increased in those receiving myeloablative conditioning. CD4% was also increased in those receiving grafts from HLA-matched siblings compared to MUD. Prednisone-based GVHD prophylaxis was associated with a decreased percentage of naïve B cells compared to others. Absolute monocyte count was increased in those with a history of acute GVHD. CD3+HLA-DR+% was increased in those with chronic GVHD. As dichotomized variables below or above the normal range, increases in NKT-like cells were observed in 63% of patients (median 3.1%, IQR 1.3 – 6.8%, typically 1-2% in healthy controls) and increased T cell subsets expressing activation markers, (e.g. increased CD25 in 43% and CD69 in 25% of patients), could be observed in even in those who had never experienced GVHD. B cells were negatively correlated (r= -0.44, p<0.001) and CD69-expressing CD8+ T cells positively correlated (r=0.33, p=0.005) with NKT-like cells. History of acute GVHD was associated with increased CD4+25bright+ T cells during long term follow up (increased in 10% of patients with a history of acute GVHD, compared to 1.6% of those without a history of acute GVHD, p=0.046), otherwise no significant differences in those who had acute or chronic GVHD versus those who never had GVHD were identified. Conclusions: Over half of long-term allogeneic HCT survivors have an increased percentage of circulating NKT-like cells. In addition, many survivors, including those who have never had GVHD, have abnormally high expression of T cell activation markers. Despite most of this cohort exhibiting clinical tolerance with treated chronic GVHD, subclinical abnormalities in lymphocyte activation remained detectable. Further longitudinal studies are needed to determine whether these abnormalities predict future flares of chronic GVHD, susceptibility to infections, or other post-HCT complications. Disclosures No relevant conflicts of interest to declare.
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