Sa Wang

Improved Early Outcomes Using a T Cell Replete Graft Compared with T Cell Depleted Haploidentical Hematopoietic Stem Cell Transplantation

Haploidentical stem cell transplantation (SCT) has been generally performed using a T cell depleted (TCD) graft; however, a high rate of nonrelapse mortality (NRM) has been reported, particularly in adult patients. We hypothesized that using a T cell replete (TCR) graft followed by effective posttransplantation immunosuppressive therapy would reduce NRM and improve outcomes. We analyzed 65 consecutive adult patients with hematologic malignancies who received TCR (N = 32) or TCD (N = 33) haploidentical transplants. All patients received a preparative regimen consisting of melphalan, fludarabine, and thiotepa. The TCR group received posttransplantation treatment with cyclophosphamide (Cy), tacrolimus (Tac), and mycophenolate mofetil (MMF). Patients with TCD received antithymocyte globulin followed by infusion of CD34+ selected cells with no posttransplantation immunosuppression. The majority of patients in each group had active disease at the time of transplantation. Outcomes are reported for the TCR and TCD recipients, respectively. Engraftment was achieved in 94% versus 81% (P = NS). NRM at 1 year was 16% versus 42% (P = .02). Actuarial overall survival (OS) and progression-free survival (PFS) rates at 1 year posttransplantation were 64% versus 30% (P = .02) and 50% versus 21% (P = .02). The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) was 20% versus 11% (P = .20), and chronic GVHD (cGVHD) 7% versus 18% (P = .03). Improved reconstitution of T cell subsets and a lower rate of infection were observed in the TCR group. These results indicate that a TCR graft followed by effective control of GVHD posttransplantation may lower NRM and improve survival after haploidentical SCT.

Refractory anemia with ringed sideroblasts associated with marked thrombocytosis harbors JAK2 mutation and shows overlapping myeloproliferative and myelodysplastic features

Refractory anemia with ringed sideroblasts associated with marked thrombocytosis harbors JAK2 mutation and shows overlapping myeloproliferative and myelodysplastic features

Myeloid neoplasms with isolated isochromosome 17q represent a clinicopathologic entity associated with myelodysplastic/myeloproliferative features, a high risk of leukemic transformation, and wild-type TP53.

Isolated isochromosome (17q) is a rare cytogenetic abnormality in Philadelphia chromosome‐negative myeloid neoplasms, usually myelodysplastic and/or myeloproliferative neoplasms (MDS/MPN). De novo acute myeloid leukemia (AML) with isochromosome 17q has rarely been reported. The frequency of genetic mutations is unknown.

FLT3 mutations in myelodysplastic syndrome and chronic myelomonocytic leukemia

FMS‐like tyrosine kinase III (FLT3) mutations occur in one‐third of acute myeloid leukemia (AML) patients and predict poor outcome. The incidence and impact of FLT3 in myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) is unknown. We conducted a retrospective review to identify WHO MDS and CMML patients with FLT3 mutations at diagnosis. A total of 2,119 patients with MDS and 466 patients with CMML were evaluated at MD Anderson between 1997 and 2010. Of these, FLT3 mutation analysis was performed on 1,232 (58%) MDS and 302 (65%) CMML patients. FLT3 mutations were identified in 12 (0.95%) MDS patients: 9 (75%) had FLT3‐ITD mutation and 3 had FLT3‐tyrosine kinase domain (TKD) mutation. MDS patients with FLT3 mutations were younger (P = 0.02) and presented as RAEB (P = 0.03) more frequently. Median overall survival (OS) for FLT3‐mutated MDS patients was 19.0 months versus 16.4 months for FLT3‐nonmutated MDS patients (P = 0.08). FLT3 mutations were identified in 13 (4.3%) CMML patients: 8 had FLT3‐ITD mutation and 5 had FLT3‐TKD mutation. There were no significant differences in demographic and disease characteristics among CMML patients with and without FLT3 mutations. Median OS for FLT3‐mutated CMML patients was 10.8 months versus 21.3 months for FLT3‐nonmutated CMML patients (P = 0.12). FLT3 occurs in MDS and CMML at a lower frequency than AML and does not predict poor outcome. Am. J. Hematol. 2013.

TP53 mutation characteristics in therapy-related myelodysplastic syndromes and acute myeloid leukemia is similar to de novo diseases

BackgroundTP53 mutation is more prevalent in therapy-related myeloid neoplasms (t-MN) than their de novo counterparts; however, the pattern of mutations involving TP53 gene in t-MN versus de novo diseases is largely unknown.MethodsWe collected 108 consecutive patients with therapy-related myelodysplastic syndrome (t-MDS)/acute myeloid leukemia (t-AML). Clinical, hematological, and cytogenetic data were collected by searching the electronic medical record. TP53 sequencing was performed in all patients using a clinically validated next-generation sequencing-based gene panel assay. A previously published patient cohort consisting of 428 patients with de novo MDS/AML was included for comparison.ResultsWe assessed 108 patients with t-MN, in which 40 patients (37%) had TP53 mutations. The mutation frequency was similar between t-MDS and t-AML; but significantly higher than de novo MDS/AML (62/428 patients, 14.5%) (pu2009<u20090.0001). TP53 mutations in t-MN were mainly clustered in DNA-binding domains, with an allelic frequency of 37.0% (range, 7.1 to 98.8). Most mutations involved single nucleotide changes, of which, transitions (65.9%) were more common than transversions (34.1%). Missense mutations were the most frequent, followed by frameshift and nonsense mutations. This TP53 mutation pattern was strikingly similar to that observed in de novo MDS/AML. TP53 mutations in t-MN were associated with a complex karyotype (pu2009<u20090.0001), a higher number of chromosomal abnormalities (pu2009<u20090.0001), and an inferior overall survival in affected patients (6.1 vs 14.1xa0months) by univariate (pu2009<u20090.0001) and multivariate analyses (pu2009=u20090.0020).ConclusionsOur findings support the recent notion that heterozygous TP53 mutation may be a function of normal aging and that mutated cells are subject to selection upon exposure to cytotoxic therapy. t-MN carrying TP53 mutation have an aggressive clinical course independent of other confounding factors.

Risk stratification of chromosomal abnormalities in chronic myelogenous leukemia in the era of tyrosine kinase inhibitor therapy

Clonal cytogenetic evolution with additional chromosomal abnormalities (ACAs) in chronic myelogenous leukemia (CML) is generally associated with decreased response to tyrosine kinase inhibitor (TKI) therapy and adverse survival. Although ACAs are considered as a sign of disease progression and have been used as one of the criteria for accelerated phase, the differential prognostic impact of individual ACAs in CML is unknown, and a classification system to reflect such prognostic impact is lacking. In this study, we aimed to address these questions using a large cohort of CML patients treated in the era of TKIs. We focused on cases with single chromosomal changes at the time of ACA emergence and stratified the 6 most common ACAs into 2 groups: group 1 with a relatively good prognosis including trisomy 8, -Y, and an extra copy of Philadelphia chromosome; and group 2 with a relatively poor prognosis including i(17)(q10), -7/del7q, and 3q26.2 rearrangements. Patients in group 1 showed much better treatment response and survival than patients in group 2. When compared with cases with no ACAs, ACAs in group 2 conferred a worse survival irrelevant to the emergence phase and time. In contrast, ACAs in group 1 had no adverse impact on survival when they emerged from chronic phase or at the time of CML diagnosis. The concurrent presence of 2 or more ACAs conferred an inferior survival and can be categorized into the poor prognostic group.

Application of the international prognostic scoring System-Revised in therapy-related myelodysplastic syndromes and oligoblastic acute myeloid leukemia

Application of the International Prognostic Scoring System-Revised in therapy-related myelodysplastic syndromes and oligoblastic acute myeloid leukemia

Malignancy-associated hemophagocytic lymphohistiocytosis in adults: Relation to hemophagocytosis, characteristics, and outcomes.

Malignancy‐associated hemophagocytic lymphohistiocytosis (HLH) in adults is a highly lethal disorder. Knowledge gaps have resulted in under diagnosis or delayed diagnosis.

Inhibin expression in ovarian-type stroma in mucinous cystic neoplasms of the pancreas.

Mucinous cystic neoplasms (MCNs) of the pancreas are typically found in middle-aged to elderly women and contain ovarian-type stroma in the cyst wall. Whether the resemblance of this stroma to ovarian stroma is only morphologic or has more functional similarity is still unclear. Estrogen receptors (ER) and progesterone receptors (PR) have been shown to be expressed in a wide variety of tissues and tumors, including the ovarian-type stroma of MCN. Inhibin, on the other hand, has been shown to have a more restricted expression, limited to ovarian sex cord-stromal components and placental cells, and has recently been shown to be expressed in pancreatic MCNs. However, it is still unclear whether this expression is limited to MCNs of the pancreas and whether it has any diagnostic role. Seven cases of MCN (4 mucinous cystadenoma, 2 borderline MCN, and 1 mucinous cystadenocarcinoma with microinvasion), 6 cases of intraductal papillary mucinous tumor, 1 of mucinous cystic tumor of uncertain classification, 2 of mucinous noncystic adenocarcinoma, 4 of serous cystadenoma, and 4 solid pseudopapillary neoplasms were selected for this study. Five cases with normal pancreatic tissue were included as controls. Immunohistochemical stains for α-inhibin, ER, and PR were performed on a representative section from each case on formalin-fixed, paraffin-embedded tissue sections using a standard indirect immunoperoxidase method. All cases of MCN were in female patients with an average age of 55.3 years, showing ovarian-type stroma and clusters of α-inhibin–positive luteinized theca-like cells. In all these cases, moderate to strong PR positivity was also noted in the ovarian-type stroma, including many of the α-inhibin–positive luteinized theca-like cells. ER was expressed in 2 cases. The epithelial cells of MCNs were all negative for ER, PR, and α-inhibin staining. Of the other tumors, 4 solid pseudopapillary neoplasms showed positivity for only PR in the tumor cells. The remaining tumors were negative for all markers. In conclusion, the finding of α-inhibin positivity in MCN with ovarian-type stroma further supports its similarity to true ovarian stromal tissue and may suggest a role of complex hormonal interaction in the pathogenesis. In addition, its limited expression in MCNs of the pancreas may be diagnostically useful in difficult cases.

Malignancy-associated hemophagocytic lymphohistiocytosis in adults

Malignancy‐associated hemophagocytic lymphohistiocytosis (HLH) in adults is a highly lethal disorder. Knowledge gaps have resulted in under diagnosis or delayed diagnosis.