UChicago scientists present latest blood cancer discoveries

ASH 2016

The 58th American Society of Hematology Annual Meeting and Exposition was held December 2-6 in San Diego. The conference, with more than 20,000 attendees, served as a platform for scientists and physicians from across the U.S. and worldwide to share the most recent scientific advances in the prevention, diagnosis and treatment of adult and pediatric hematological malignancies, or blood cancers, including leukemia, lymphoma, and multiple myeloma. Many University of Chicago Medicine Comprehensive Cancer Center researchers showcased their findings and played leadership roles in the conference. The following are representative highlights from UChicago faculty, trainees and research staff.

Inherited Hematological Malignancies

For the first time, a ‘Friday Scientific Workshop’ before the official start of the meeting was dedicated to the rapidly evolving field of inherited blood cancers. These diseases occur in families because of DNA mutations in the germline – that is, in the lineage of germ cells (sperm and eggs) and passed from parent to offspring. Organized and chaired by Lucy Godley, MD, PhD, the workshop focused on the current understanding of the genes that are mutated in these familial syndromes and the mechanisms of cancer development in individuals and families with germline mutations.

Hematology/Oncology fellow Michael Drazer, MD, described his work with Godley and Jane Churpek, MD, identifying families with a specific inherited disorder (i.e., familial platelet disorder with propensity to acute myeloid leukemia) and how malignancies develop in individuals with germline RUNX1 mutations. RUNX1 is a protein that normally controls the development of hematopoietic stem cells into mature blood cells, and its mutation is known to be associated with several types of leukemia.

At a presentation later in the conference, a multicenter, collaborative study involving Godley and Churpek showed that careful tracking of skin disorders with a family history of blood cancers may assist in identifying RUNX1-mutant families, and that other mutations in other known genes associated with blood cancer can modify the presentation of RUNX1-mutant disease.

The importance of this emerging field is highlighted by the fact that germline predisposition to hematological malignancies debuted in the 2016 World Health Organization classification of myeloid neoplasms and acute leukemia co-authored by UChicago faculty Daniel Arber, MD, Michelle Le Beau, PhD, and James Vardiman, MD, among others.

ASH 2016

Leukemia Clinical Trials and Correlate Studies

The results of three leukemia clinical trials led by Hongtao Liu, MD, PhD, were presented at the conference.

In the first, resident Amy Wang, MD, mentored by Liu, was selected to give an oral presentation on the results of a phase I dose-escalation trial using a combination of selinexor (a drug that controls the export of proteins from cell nuclei) with high-dose chemotherapy (cytarabine and mitoxantrone) for remission induction in acute myeloid leukemia (AML). The study of 20 patients, thus far, showed that this regimen is both feasible and tolerable. Based on these findings, a phase II trial is planned. Other UChicago investigators involved in the study included Godley, Churpek, Richard Larson, MD, Olatoyosi Odenike, MD, Andrew Artz, MD, Michael Thirman, MD, Emily Curran, MD, Kristen Pettit, MD, and Wendy Stock, MD.

Liu also presented preliminary results from the REMAIN trial, a randomized phase II study to test nivolumab (an immunotherapy called a checkpoint inhibitor) as a single agent to eliminate minimal residual disease and maintain remission in AML patients after chemotherapy. A current challenge in immunotherapy is the lack of genomic biomarkers to help predict a patient’s response to therapy. Liu led a research team to ask whether the variety of T cell receptors proteins the body produces could serve as such biomarkers. His team, which included Yusuke Nakamura, MD, Jae-Hyun Park, PhD, Odenike and Stock, found that assessing the repertoire of T cell receptors by DNA sequencing is feasible and that certain types of T cell receptor clones were dramatically enriched in bone marrow samples after nivolumab treatment.

Liu also presented the results of a small, randomized pilot study that used an immunotherapy vaccine against the WT-1 protein abnormally expressed in leukemia. The research team, which included Park, Nakamura, Larson, Odenike and Thomas Gajewski, MD, PhD, found that the vaccine was able to induce a specific immune response and T cell receptor clonal enrichment to control minimal residual disease in patients with myeloid leukemia. Future work will explore the effectiveness of combining this vaccine with checkpoint blockade immunotherapy.

A poster presented by bioinformatician Sabah Kadri, PhD, Y. Lynn Wang, PhD, and colleagues described their efforts to identify risk factors and biomarkers for relapse in chronic lymphocytic leukemia (CLL) patients treated with ibrutinib, a first-in-class Bruton’s tyrosine kinase (BTK) inhibitor. BTK is important for CLL development and ibrutinib is an effective CLL therapy, although drug resistance can occur. The team compared recurrent molecular and cytogenetic abnormalities among pre-treatment and relapsed patients. They also identified mutations, including in BTK itself, and clonal evolution patterns associated with disease progression on ibrutinib. Other Comprehensive Cancer Center faculty collaborators included Thirman, Sonali Smith, MD, and Jeremy Segal, MD, PhD.

ASH 2016

Biology of Myelodysplastic Syndromes and Leukemia

Le Beau, director of the Comprehensive Cancer Center, is a leader in dissecting the molecular mechanisms that drive the development of myelodysplastic syndromes (MDS) and subsequent AML, including in the setting of therapy-related MDS and AML.

In an oral presentation, Angela Stoddart, PhD, from Le Beau’s group, described the role of the Wnt signaling protein beta-catenin in MDS development. Stoddart used a mouse model that mimics many features of human MDS in which the long arm of chromosome 5 has been deleted or del(5q). She showed that Wnt signaling in the bone marrow niche promotes MDS, while pyrvinium, a drug that inhibits the Wnt pathway, prevents MDS and prolongs survival. The results of this study, also involving Jason Cheng, MD, PhD, suggest that inhibiting the Wnt pathway may be an effective MDS therapeutic approach.

Cheng gave two oral presentations on molecular mechanisms that control therapeutic responses in leukemia. In a ‘Friday Scientific Workshop on Myeloid Development’, he described the role of RNA modifying enzymes, such as those responsible for tagging RNA with a specific mark called 5-methylcytosine, and RNA binding proteins, including heterogeneous nuclear ribonucleoprotein (hnRNP) K, in leukemia.

A poster presentation by Pathology resident Adam Cloe, MD, PhD, under the mentorship of Cheng and involving Liu, identified specific hnRNPs as novel therapeutic targets and indicators of how AML patients respond to the drug selinexor. In a second talk, Cheng described mechanisms that contribute to acquired resistance to a class of drugs used to treat MDS and AML called DNA methyltransferase inhibitors. He found that a set of proteins – bromodomain and extra-terminal motif (BET) proteins – mediate resistance to these drugs, including 5-azacytidine, in leukemia cells. They do so by altering the three-dimensional DNA structure and subsequent gene expression. These data suggest that such DNA structural changes could be used as predictors of therapy response and may be targeted to overcome 5-azacytidine resistance.

ASH 2016

Multiple Myeloma

UChicago researchers and physicians are leading advancements in the treatment of multiple myeloma, a cancer of plasma cells –  white blood cells in the bone marrow that produce antibodies to fight infection.

Todd Zimmerman, MD, presented the final results of a phase II trial in newly diagnosed multiple myeloma involving multiple centers and other Comprehensive Cancer Center faculty Sandeep Gurbuxani, MD, and Andrzej Jakubowiak, MD, PhD. The team found that extended treatment with a three-drug regimen referred to as Krd – carfilzomib (a proteasome inhibitor), lenalidomide (a drug with multiple mechanisms of action) and dexamethasone (a steroid) – with autologous stem cell transplantation produced high rates of response and improvements in progression-free survival and overall survival. These data set the stage for ongoing and planned, larger randomized trials.

Resistance to currently available therapies, such as carilzomib, is a significant challenge in myeloma. In a high-profile oral presentation, Jakubowiak presented the final results from a phase I Multiple Myeloma Research Consortium trial of selinexor, carfilzomib, and dexamethasone in relapsed/refractory multiple myeloma. Other Comprehensive Cancer Center authors on the study included Zimmerman and Theodore Karrison, PhD. Data from this small, multicenter trial demonstrated that this protocol was safe and tolerable overall, and that the addition of selinexor to the regimen showed promising activity in heavily pretreated patients, with 64 percent of patients showing a partial response or better.

Jakubowiak also presented a poster describing an economic evaluation of two treatment regimens in relapsed or refractory multiple myeloma, namely carfilzomib and dexamethasone (Kd) vs. bortezomib (another proteasome inhibitor) and dexamethasome (Vd). These regimens are being compared in the ENDEAVOR phase III trial, and the current work assessed their cost-effectiveness using data from the trial. Their model predicted that Kd provided 1.85 additional life years and is more cost-effective than the Vd regimen for both patients and payers.

Sonali Smith ASH 2016


International leader in lymphoma research and clinical care Sonali Smith, MD, led a “How I Treat: Bringing Science to Clinical Dilemmas” session on biological insights in follicular lymphoma. She also presented in a major scientific session on lymphoid neoplasia, chaired by Stock. Smith discussed the importance of developing reliable predictors of outcomes in follicular lymphoma patients, given that currently available tools, such as pathology, clinical factors and gene expression profiling, are imperfect. In addition, she described current therapeutic efforts aimed at molecular events, such as activation of the PI3K/mTOR signaling pathway, driving tumor initiation or progression. Smith was an author on eight other lymphoma studies presented at the meeting.

Justin Kline, MD, presented final findings from a phase II trial of the drugs temsirolimus (an inhibitor of the mTOR pathway) and lenalidomide in patients with relapsed/refractory lymphomas conducted through the UChicago Phase II Consortium. This work, in collaboration with Smith, Karrison, Kenneth Cohen, MD, Walter Stadler, MD, builds off a UChicago-led temsirolimus trial and phase I study of these agents together showing tolerability and evidence of clinical activity. Here, Kline showed that the most significant activity was observed in patients with relapsed/refractory Hodgkin lymphoma, with an 80 percent response rate.

Other notable highlights of the ASH Annual Meeting included:

  • Artz co-chaired a ‘Friday Scientific Workshop on Hematology and Aging,’ and presented his work on biologic vs. physiologic age in bone marrow transplant candidates;
  • Gajewski presented his research on innate immune sensing in antitumor immunity and cancer immunotherapy in a major scientific session;
  • Stock discussed acute lymphoblastic leukemia in adolescents and young adults in a ‘How I Treat: Bringing Science to Clinical Dilemmas’ session;
  • Megan McNerney, MD, PhD, presented data on molecular mechanisms dictating dosage of the haploinsuffcient transcription factor, CUX1;
  • Tara Henderson, MD, presented her work with Rena Conti, PhD, on an approach and the feasibility of patient-reported outcomes in a phase III trial for advanced-stage classical Hodgkin lymphoma in children and adolescents; and
  • Hematology/Oncology fellow Michael Tallarico, MD, was honored with an Abstract Achievement Award for his oral presentation on toxicities and related outcomes of elderly patients with hematologic malignancies in the contemporary era.
About Kathleen Goss (30 Articles)
Kathleen Goss, PhD, is the Director for Strategic Partnerships and senior science writer at the University of Chicago Medicine Comprehensive Cancer Center.
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