Next-generation sequencing with a myeloid gene panel in core-binding factor AML showed KIT activation loop and TET2 mutations predictive of outcome.

Clinical outcome and mutations of 96 core-binding factor acute myeloid leukemia (AML) patients 18-60 years old were examined. Complete remission (CR) after induction was 94.6%. There was no significant difference in CR, leukemia-free-survival (LFS) and overall survival (OS) between t(8;21) (N=67) and inv(16) patients (N=29). Univariate analysis showed hematopoietic stem cell transplantation at CR1 as the only clinical parameter associated with superior LFS. Next-generation sequencing based on a myeloid gene panel was performed in 72 patients. Mutations in genes involved in cell signaling were associated with inferior LFS and OS, whereas those in genes involved in DNA methylation were associated with inferior LFS. KIT activation loop (AL) mutations occurred in 25 patients, and were associated with inferior LFS (P=0.003) and OS (P=0.001). TET2 mutations occurred in 8 patients, and were associated with significantly shorter LFS (P=0.015) but not OS. Patients negative for KIT-AL and TET2 mutations (N=41) had significantly better LFS (P<0.001) and OS (P=0.012) than those positive for both or either mutation. Multivariate analysis showed that KIT-AL and TET2 mutations were associated with inferior LFS, whereas age ⩾40 years and marrow blast ⩾70% were associated with inferior OS. These observations provide new insights that may guide better treatment for this AML subtype.

Treatment of lymphoma relapses after allogeneic hematopoietic stem cell transplantation with intensive chemotherapy followed by infusion of hematopoietic stem cell from the original donor.

Five lymphoma patients relapsed from allogeneic hematopoietic stem cell transplantation (HSCT). Three patients who received myeloablative conditioning had full donor chimerism at relapse, whereas two who received nonmyeloablative conditioning had partially or completely lost the graft. All received mini-BEAM [carmustine (BCNU), etoposide, cytarabine (AraC), melphalan], followed by infusion of HSC (four peripheral blood, one marrow) from the initial donor. Neutropenia and thrombocytopenia were brief, and full donor chimerism was established in all cases. There were four complete and one partial remissions. Graft-versus-host disease occurred in three cases, all with full donor chimerism at relapse. Two patients died subsequently of disease relapse or progression. Another two patients died from fungal infection, one of whom was still in remission at death. One patient had remained in remission 47 months after treatment. Mini-BEAM/HSC is an effective treatment for lymphoma relapses after allogeneic HSCT, but optimal strategies of remission consolidation and prevention of treatment-related complications are needed to improve outcome.

Leukaemic relapse of donor origin after allogeneic bone marrow transplantation from a donor who later developed bronchogenic carcinoma.

Donor-derived leukaemia is exceptional after allogeneic bone marrow transplantation (BMT). A woman with chronic myeloid leukaemia received an allogeneic BMT from a human leucocyte antigen-identical brother. The donor, a 50-year-old non-smoker, died of squamous cell bronchogenic carcinoma 1 year later. At 4 years post BMT, the patient became BCR/ABL positive and relapsed with acute myeloid leukaemia, which was shown to be donor-derived cytogenetically and molecularly. Retrospective analysis showed that the donor-leukaemic clone had started to evolve as early as 6 months post BMT. Sequencing of p53 ruled out Li-Fraumeni syndrome. Predisposition to malignancy might be an underlying mechanism of donor-cell leukaemia.

Natural killer cell malignancies: clinicopathologic and molecular features.

Malignancies of natural killer (NK) cells have increasingly been recognized as distinct clinicopathological entities. The tumor cells are characterized by an immunophenotype of CD2+, surface CD3-, cytoplasmic CD3epsilon+, and CD56+. The T cell receptor gene is in germline configuration, and a consistent association with Epstein-Barr virus is demonstrable. Pathologically, the tumor cells show variable cytological appearances, with frequent angioinvasion and angiocentricity associated with zonal necrosis. Clinically, most cases affect the nasal cavity or other parts of the upper aerodigestive tract, and are referred to as nasal NK cell lymphoma. A minority involve extranasal sites such as the skin, gastrointestinal tract and testis, and are often referred to as extranasal NK cell lymphoma. A particularly aggressive form presents fulminantly as disseminated disease, sometimes with a leukemic phase, and is referred to as aggressive NK cell lymphoma/leukemia. Cytogenetic and molecular analysis have shown DNA losses at chromosomes 6q, 11q, 13q and 17p to be recurrent aberrations in NK cell malignancies. Frequent DNA gains are also found in chromosomes 1p, 6p, 11q, 12q, 17q, 19p, 20q, and Xp. These regions of DNA losses and gains should be targets for further investigation in order to understand the molecular pathogenesis of this lymphoma. Finally, optimal treatment modalities need to be determined, as all subtypes of NK cell malignancies are associated with a poor prognosis.