Ana C. Xavier

Down Syndrome and Malignancies: A Unique Clinical Relationship: A Paper from the 2008 William Beaumont Hospital Symposium on Molecular Pathology

The patterns of malignancies in Down syndrome (DS) are unique and highlight the relationship between chromosome 21 and cancer. DS children have a approximately 10- to 20-fold higher risk for developing acute lymphoblastic leukemia and acute myeloid leukemia (AML), as compared with non-DS children, although they do not have a uniformly increased risk of developing solid tumors. DS children with acute lymphoblastic leukemia frequently experience higher levels of treatment-related toxicity and inferior event-free survival rates, as compared with non-DS children. DS children also develop AML with unique features and have a 500-fold increased risk of developing the AML subtype, acute megakaryocytic leukemia (AMkL; M7). Nearly 10% of DS newborns are diagnosed with a variant of AMkL, the transient myeloproliferative disorder, which can resolve spontaneously without treatment; event-free survival rates for DS patients with AMkL ranges from 80% to 100%, in comparison with <30% for non-DS children with AMkL. In addition, somatic mutations of the GATA1 gene have been detected in nearly all DS TMD and AMkL cases and not in leukemia cases in non-DS children. GATA1 mutations are key factors linked to both leukemogenesis and the high cure rates of DS AMkL patients. Identifying the mechanisms that account for the high event-free survival rates of DS AMkL patients may ultimately improve AML treatment as well. Examining leukemogenesis in DS children may identify factors linked to the general development of childhood leukemia and lead to potential new therapeutic strategies to fight this disease.

Diffuse Large B‐Cell Lymphoma with Primary Treatment Failure: Ultra‐high Risk Features and Benchmarking for Experimental Therapies

The outcomes of patients with DLBCL and primary treatment failure (PTF) in the rituximab era are unclear. We analyzed 331 patients with PTF, defined as primary progression while on upfront chemoimmunotherapy (PP), residual disease at the end of upfront therapy (RD) or relapse < 6 months from end of therapy (early relapse; ER). Median age was 58 years and response to salvage was 41.7%. Two‐year OS was 18.5% in PP, 30.6% in RD and 45.5% in ER. The presence of PP, intermediate‐high/high NCCN‐IPI at time of PTF or MYC translocation predicted 2‐year OS of 13.6% constituting ultra‐high risk (UHR) features. Among the 132 patients who underwent autologous hematopoietic cell transplantation, 2‐year OS was 74.3%, 59.6% and 10.7% for patients with 0,1 and 2–3 UHR features respectively. Patients with PTF and UHR features should be prioritized for clinical trials with newer agents and innovative cellular therapy.

Unique clinical and biological features of leukemia in Down syndrome children

Acute leukemias in children with Down syndrome (DS) are characterized by unique clinical and biological features. Notable among DS children with acute myeloid leukemia (AML), is the high frequency of the acute megakaryocytic leukemia (AMkL) subtype, which uniformly harbor somatic mutations in the transcription factor GATA1 gene. DS patients with AML, and in particular AMkL, have event-free survival rates of 80–100% in contrast to event-free survival rates of less than 35% for non-DS children with AMkL. DS children with acute lymphoblastic leukemia have a more heterogeneous disease, with approximately 30% of the patients having somatic JAK2 mutations, heightened methotrexate sensitivity and higher rates of treatment-related toxicities. These features highlight a striking relationship between genes localized to chromosome 21, leukemogenesis and sensitivity to leukemia chemotherapy agents.

A Unique Role of GATA1s in Down Syndrome Acute Megakaryocytic Leukemia Biology and Therapy

Background Acute megakaryocytic leukemia (AMkL) in Down syndrome (DS) children is uniformly associated with somatic GATA1 mutations, which result in the synthesis of a shorter protein (GATA1s) with altered transactivation activity compared to the wild-type GATA1. It is not fully established whether leukemogenesis and therapeutic responses in DS AMkL patients are due to loss of the wild-type GATA1 or due to a unique function of GATA1s. Methodology Stable clones of CMK cells with decreased GATA1s or Bcl-2 levels were generated by using GATA1- or BCL-2-specific lentivirus shRNAs. In vitro ara-C, daunorubicin, and VP-16 cytotoxicities of the shRNA stable clones were determined by using the Cell Titer-blue reagent. Apoptosis and cell cycle distribution were determined by flow cytometry analysis. Changes in gene transcript levels were determined by gene expression microarray and/or real-time RT-PCR. Changes in protein levels were measured by Western blotting. In vivo binding of GATA1s to IL1A promoter was determined by chromatin immunoprecipitation assays. Results Lentivirus shRNA knockdown of the GATA1 gene in the DS AMkL cell line, CMK (harbors a mutated GATA1 gene and only expresses GATA1s), resulting in lower GATA1s protein levels, promoted cell differentiation towards the megakaryocytic lineage and repressed cell proliferation. Increased basal apoptosis and sensitivities to ara-C, daunorubicin, and VP-16 accompanied by down-regulated Bcl-2 were also detected in the CMK GATA1 shRNA knockdown clones. Essentially the same results were obtained when Bcl-2 was knocked down with lentivirus shRNA in CMK cells. Besides Bcl-2, down-regulation of GATA1s also resulted in altered expression of genes (e.g., IL1A, PF4, and TUBB1) related to cell death, proliferation, and differentiation. Conclusion Our results suggest that GATA1s may facilitate leukemogenesis and potentially impact therapeutic responses in DS AMkL by promoting proliferation and survival, and by repressing megakaryocytic lineage differentiation, potentially by regulating expression of Bcl-2 protein and other relevant genes.

Changes in the use of radiation therapy for early classical Hodgkin lymphoma in adolescents and young adults: implications for survival and second malignancies.

Omission of radiation therapy (RT) in adolescents and young adults (AYA) with early classical Hodgkin lymphoma (cHL) may affect survival and risk of second malignancies (SMN). Using the Surveillance, Epidemiology and End Results database we found reduction in RT use from 60.8% among 2614 cases from 1995 to 2002 to 52.9% among 2542 cases from 2003 to 2010, p < 0.001. Survival at 5 years with and without RT was 95.1% vs. 93.3%, p = 0.013 for 1995–2002 and 97.7% vs. 96.4%, p = 0.021 for 2003–2010. Omission of RT was affected by 2003–2010 era, race-ethnicity, income and education and independently increased the risk of death (hazard ratio 1.34, p = 0.011). The cumulative risk of SMN at 150 months was 3.3% vs. 3.0% (p = 0.87) while the risk of death without SMN (competing risk) was 5.7% vs. 8.8% for RT and no-RT patients, respectively (p = 0.0009). Omission of RT for early cHL in AYA may increase mortality without reduction in SMN.

C-MYC–positive relapsed and refractory, diffuse large B-cell lymphoma: Impact of additional “hits” and outcomes with subsequent therapy

The impact of MYC proto‐oncogene, basic helix‐loop‐helix (MYC) translocations (with or without additional rearrangements involving the B‐cell lymphoma 2 [BCL2] or BCL6 genes) on the response to salvage therapy and survival in patients with diffuse large B‐cell lymphoma (DLBCL) who experience primary treatment failure is not well defined.

Gene Signature of High White Blood Cell Count in B-Precursor Acute Lymphoblastic Leukemia

In this study we sought to identify genetic factors associated with the presenting white blood cell (WBC) count in B-precursor acute lymphoblastic leukemia (BP-ALL). Using ETV6-RUNX1-positive BP-ALL patient samples, a homogeneous subtype, we identified 16 differentially expressed genes based on the presenting WBC count (< 50,000/cumm vs > 50,000). We further confirmed that IL1R1, BCAR3, KCNH2, PIR, and ZDHHC23 were differentially expressed in a larger cohort of ETV6-RUNX1-negative BP-ALL patient samples. Statistical analysis demonstrated that expression levels of these genes could accurately categorize high and low WBC count subjects using two independent patient sets, representing positive and negative ETV6-RUNX1 cases. Further studies in leukemia cell line models will better delineate the role of these genes in regulating the white blood cell count and potentially identify new therapeutic targets.

Incidence and outcomes of paediatric myelodysplastic syndrome in the United States

Cagliari, Department of Reproduction and Growth, University Hospital Sant’Anna in Ferrara, Ferrara, Haemato-Oncology Unit, Azienda Ospedaliera “Pugliese-Ciaccio”, Catanzaro, Paediatric Unit, Ospedale di Sassari, Sassari, Department of Paediatrics, University of MilanoBicocca, Monza, Dipartimento di Oncoematologia Pediatrica, IRCCS Ospedale Bambino Ges u, Rome, and Dipartimento di Scienze Pediatriche Universit a di Pavia, Italy. E-mail: giona@bce.uniroma1.it

Excess mortality among 10-year survivors of classical Hodgkin lymphoma in adolescents and young adults

Adolescents and young adults (AYA) surviving classical Hodgkin lymphoma (cHL) risk long term fatal treatment‐related toxicities. We utilized the Surveillance, Epidemiology and End Results (SEER) program to compare excess mortality rate (EMR‐observed minus expected mortality) for 10‐year survivors of AYA cHL diagnosed in 1973–1992 and 1993–2003 eras. The 15‐year EMR reduced from 4.88% to 2.19% while the 20‐year EMR reduced from 9.46% to 4.07% between eras. Survivors of stages 1–2 had lower EMR than survivors of stages 3–4 cHL in the 1993‐2003 but not in the 1973–1992 era. There was an overall decline in risk of death between 10 and 15 years from diagnosis, driven mostly by second neoplasms and cardiovascular mortality. Despite reduction in fatal second neoplasms and cardiovascular disease with more current therapy, long term survivors of AYA cHL still have a higher risk of death than the general population highlighting the need for safer therapies.

Targeted Therapies for the Treatment of Pediatric Non-Hodgkin Lymphomas: Present and Future.

Pediatric Non-Hodgkin Lymphomas (NHL) are a diverse group of malignancies and as such treatment can vary based on the different biological characteristics of each malignancy. Significant advancements are being made in the treatment and outcomes of this group of malignancies. This is in large part due to novel targeted drug therapies that are being used in combination with traditional chemotherapy. Here, we discuss several new lines of therapy that are being developed or are in current use for pediatric patients with NHL.