Stringent complete remission (CR) in acute myeloid leukemia (AML) requires the absence of both morphologic and flow cytometric evidence of disease. We have previously shown that persistent AML detected by flow cytometry (FC+) before reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (alloHCT) was associated with significantly increased relapse, shorter disease-free survival (DFS) and poorer overall survival (OS), independent of morphologic blast count. We evaluated the effect of FC status on outcomes of alloHCT for AML after either myeloablative conditioning (MAC) or RIC regimens. In 203 patients (MAC, n=80 and RIC, n=123) with no morphologic evidence of persistent AML pre-transplant on marrow biopsy. The allografts included 130 umbilical cord blood (UCB) and 73 sibling donors. We performed central review of pre-transplant standard sensitivity flow cytometry to identify detectable FC+. Twenty-five patients were FC+, including 15 (18.7%) receiving MAC and 10 (8.1%) RIC alloHCT. Among RIC patients FC+ was associated with significantly inferior relapse, disease-free survival (DFS), and overall survival (OS) [multiple regression hazard ratio (HR) 3.8, (95% confidence interval (95% CI) 1.7–8.7), p<0.01 for relapse; HR 2.9, (95% CI: 1.4–5.9), p<0.01 for DFS, and HR 3.4 (95%CI: 1.7–7), p<0.01 for OS]. In contrast, FC+ status was not associated with relapse or decreased OS after MAC. These data suggest that MAC, but not RIC, overcomes the negative effect of pretransplant FC+ following sibling or UCB alloHCT. Therefore, a deeper pre-transplant leukemia-free state is preferred for those treated with RIC.

HHV8-associated lymphomas can be clinically and pathologically heterogeneous, with features that may lead to misdiagnosis as other types of lymphoma.

Acute myeloid leukemia arising from chronic myelomonocytic leukemia is currently classified as acute myeloid leukemia with myelodysplasia-related changes, a high-risk subtype. However, the specific features of these cases have not been well described. We studied 38 patients with chronic myelomonocytic leukemia who progressed to acute myeloid leukemia. We compared the clinicopathologic and genetic features of these cases with 180 patients with de novo acute myeloid leukemia and 34 patients with acute myeloid leukemia following myelodysplastic syndromes. We also examined features associated with progression from chronic myelomonocytic leukemia to acute myeloid leukemia by comparing the progressed chronic myelomonocytic leukemia cases with a cohort of chronic myelomonocytic leukemia cases that did not transform to acute myeloid leukemia. Higher white blood cell count, marrow cellularity, karyotype risk score, and Revised International Prognostic Scoring System score were associated with more rapid progression from chronic myelomonocytic leukemia to acute myeloid leukemia. Patients with acute myeloid leukemia ex chronic myelomonocytic leukemia were older (Po0.01) and less likely to receive aggressive treatment (P ¼ 0.02) than de novo acute myeloid leukemia patients. Most cases showed monocytic differentiation and fell into the intermediate acute myeloid leukemia karyotype risk group; 55% had normal karyotype and 17% had NPM1 mutation. Median overall survival was 6 months, which was inferior to de novo acute myeloid leukemia (17 months, P ¼ 0.002) but similar to post myelodysplastic syndrome acute myeloid leukemia. On multivariate analysis of all acute myeloid leukemia patients, only age and karyotype were independent prognostic variables for overall survival. Our findings indicate that acute myeloid leukemia following chronic myelomonocytic leukemia displays aggressive behavior and support placement of these cases within the category of acute myeloid leukemia with myelodysplasia-related changes. The poor prognosis of these patients may be related to an older population and lack of favorable-prognosis karyotypes that characterize many de novo acute myeloid leukemia cases.

Double- and triple-hit lymphomas (DHL/THL) are aggressive B cell neoplasms characterized by translocation of MYC with concurrent BCL2 and/or BCL6 translocation. In this retrospective study from one institution, we report clinicopathologic features of 13 cases (9 DHL/4 THL). The median age was 59 years (range 30 to 74) and patients included 8 females and 5 males. Presentation included enlarging lymphadenopathy/masses (11 patients) and abnormal peripheral blood findings (2 patients). Features which raised the differential of an immature neoplasm included TdT positivity (4 cases, 2 THL/2 DHL); dim CD45 expression (7 cases), lack of CD20 (2 cases), or lack of surface immunoglobulin light chain (3 cases) by flow cytometry; and blastoid morphology (2 cases). We conclude that expression of TdT in a B cell lymphoma with mature features or expression of surface light chain in a case otherwise suggestive of B-lymphoblastic leukemia/lymphoma should prompt an expedited evaluation for DHL/THL.

Isolated ileal abnormalities may be detected during routine colonoscopy performed for polyp screening or surveillance. The significance of these abnormalities in asymptomatic patients without a prior diagnosis of inflammatory bowel disease is unknown. A critical clinical issue is whether isolated ileitis in asymptomatic patients is a manifestation of early Crohn disease (CD). We examined clinical, endoscopic, and pathologic data from 29 patients with isolated ileitis and no prior history of inflammatory bowel disease, and no colonic or upper gastrointestinal involvement. Only patients with at least 2 years of follow-up (range: 2.2 to 12.6 y) were included. Fifteen of 29 patients had colonoscopy for gastrointestinal symptoms whereas the remaining 14 were asymptomatic (screening colonoscopy). Seven of 15 (47%) of patients categorized as chronic active ileitis and 3 of 14 (21%) of those classified as focal active ileitis, on blinded histopathologic review, had a clinical diagnosis of CD at last follow-up. One or more features of chronicity were present in 11 of 14 (79%) of asymptomatic ileitis patients but none developed any manifestations of CD on long-term follow-up. In contrast, 8 of 10 (80%) of symptomatic patients with features of chronicity in ileal biopsies progressed to a diagnosis of CD, as did 2 of 5 (40%) symptomatic patients with focal active ileitis. Thus, the presence of symptoms seems to be the best predictor of likelihood of progression to CD in patients with isolated ileitis (P<0.001). Isolated ileitis detected in asymptomatic patients undergoing polyp screening or surveillance does not evolve into CD on follow-up, despite endoscopic and histologic overlap with findings typically seen in CD.

Monomorphic post-transplant lymphoproliferative disorder commonly resembles diffuse large B-cell lymphoma or Burkitt lymphoma, and most are Epstein-Barr virus (EBV) positive. We retrospectively identified 32 cases of monomorphic post-transplant lymphoproliferative disorder from two institutions and evaluated EBV in situ hybridization; TP53 mutation status; p53, CD30, myc, and BCL2 expression by immunohistochemistry; proliferation index by Ki67; and germinal center vs non-germinal center immunophenotype by Hans criteria. Post-transplant lymphoproliferative disorder arose after hematopoietic stem cell transplant in five and solid organ transplant in 27 patients, a median of 4 and 96 months after transplant, respectively (overall median latency 71 months, range 2-295). The most common morphology was diffuse large B-cell lymphoma (28 cases), with three cases of Burkitt lymphoma, and one case of plasmablastic lymphoma. Ten cases (31%) were EBV negative. Of those with the morphology of diffuse large B-cell lymphoma, the EBV-negative cases were more frequently TP53-mutated (P<0.001), p53 positive by immunohistochemistry (P<0.001), CD30 negative (P<0.01), and of germinal center immunophenotype (P=0.01) compared with EBV-positive cases. No statistically significant difference in overall survival was identified based on EBV, TP53 mutation status, germinal center vs non-germinal center immunophenotype, or other immunohistochemical parameters evaluated. Patients who died of post-transplant lymphoproliferative disorder were older with a longer latency from time of transplant to diagnosis (P<0.05). Our study demonstrates that diffuse large B-cell lymphoma-related immunohistochemical prognostic markers have limited relevance in the post-transplant setting and underscores differences between EBV-positive and EBV-negative post-transplant lymphoproliferative disorder in terms of immunophenotype and TP53 mutation frequency, supporting an alternative pathogenesis for EBV-negative post-transplant lymphoproliferative disorder.

Cellular immunotherapy using allogeneic natural killer (NK) cells may overcome chemotherapyrefractory acute myeloid leukemia (rAML). Our goal was to document NK cell homing/ persistence in the bone marrow following adoptive immunotherapy. Our cohort included 109 patients who received NK cell therapy for rAML following lymphodepleting conditioning +/− denileukin diftitox, +/− low-dose total body irradiation. We evaluated the NK cell density in bone marrow core biopsies performed an average of 14 days after NK cell transfer using a CD56 immunohistochemical stain. The NK cell density in core biopsies showed only moderate correlation with NK cell percentage in bone marrow aspirates evaluated by flow cytometry (r s = 0.48) suggesting that distribution of CD56 positive cells in the bone marrow niche offers unique insight into NK cell homing. Better leukemia control was associated with increased NK cell density, such that patients with <5% blasts had a higher NK cell density (p=0.01). As well, NK cell density above the median of reference group was significantly associated with morphologic remission of leukemia (p=0.01). Moreover, the NK cell density varied significantly between conditioning protocols. Our findings suggest that the use of low dose irradiation or CD25-targeting immunocytokine (denileukin diftitox, IL2DT) as part of conditioning results in increased NK cell homing/persistence in the bone marrow. These novel results will help guide future immunotherapy with NK cells.

Various cytogenetic risk scoring systems may determine prognosis for patients with myelodysplastic syndromes (MDS). We evaluated four different risk scoring systems in predicting outcome after allogeneic hematopoietic cell transplantation (alloHCT). We classified 124 patients with MDS using the International prognostic scoring system (IPSS), the revised international prognostic scoring system (R-IPSS), Armand's transplantation-specific cytogenetic grouping (TSCG), and monosomal karyotype (MK) both at the time of diagnosis and alloHCT. After adjusting for other important factors, MK at diagnosis (compared to no MK) was associated with poor 3-year disease-free survival (DFS) (27% (95% CI, 12-42%) versus 39% (95% CI, 28-50%), p=0.02) and overall survival (OS) (29% (95% CI, 14-44%) versus 47% (95% CI, 36-59%), p=0.02). OS but not DFS was affected by MK at HCT. MK frequency was uncommon in low score R-IPPS and IPSS. Although IPSS and R-IPSS discriminated good/very good groups from poor/very poor groups, patients with intermediate risk scores had the worst outcomes and therefore these scores did not show a progressive linear discriminating trend. Cytogenetic risk score change between diagnosis and alloHCT was uncommon and did not influence OS. MK cytogenetics in MDS are associated with poor survival suggesting the need for alternative or intensified approaches to their treatment.