Research Updates

2019 Update

One of the goals of the Silver MPN Center has been to develop research infrastructure that can be leveraged to increase the breadth and depth of MPN-related research performed at Weill Cornell Medicine. Fruits of this effort are evident in our expanding portfolio of MPN Research presented at the 2018 ASH meeting including eleven abstracts, and 27 WCM investigators, many of whom—experts in other fields—presented their first MPN related research. The clinical trials program at the center continues to expand. Two new full time post-doctoral investigators are joining the center. 

Drs. Richard T. Silver and Ghaith Abu Zheinah at the American Society of Hematology Annual Meeting

Highlights of the 2018 American Society of Hematology (ASH) Annual Meeting, San Diego, CA

Myeloproliferative Neoplasm (MPN) Driver Mutations Are Enriched during Hematopoietic Stem Cell Differentiation in Patterns That Correlate with Clinical Phenotype and Treatment Response.

Ghaith Abu-Zeinah, Silvana Di Giandomenico, Claudia Sosner, Niamh Savage, Spencer Krichevsky, Ellen K. Ritchie, Pouneh Kermani, Richard T. Silver, and Joseph Scandura

Dr. Abu-Zeinah is a talented hematology-oncology fellow at Weill Cornell Medicine (WCM) working in the laboratory of Dr Scandura. His work demonstrates for the first time that MPN clinical phenotypes are directed by the biased blood cell output of mutated MPN hematopoietic stem cell and progenitor cells (MPN HSPCs). This work provides a new method to characterize MPNs and, more importantly, a new way to monitor treatment responses. To cure MPN phenotypes, MPN-HSPCs must be controlled or eradicated. This work provides a path to develop drugs in the lab targeting MPN-HSPCs and assessing their activity in patients. This research is possible because of critical support from CR&T for data managers to consent patients for research, collect patient samples and to couple these consented samples to a robust clinical research informatics system.

Initial Therapy of Polycythemia Vera (PV) with Interferon Alfa (rIFNa) Compared to Hydroxyurea (HU) or Phlebotomy Only (PHL-O) Is Associated with a Lower Risk of Secondary Myelofibrosis.

Ghaith Abu-Zeinah, Spencer Krichevsky, Claudia Sosner, Niamh Savage, Joseph Scandura, and Richard T. Silver

Dr Silver has long advocated for the use of interferon in the treatment of PV. Center investigators have now been able to demonstrate for the first time that interferon prevents the development of myelofibrosis compared to other PV therapies. New research infrastructure developed with the generous support of CR&T was critical to the success of this retrospective study of more than 300 patients with PV treated at WCM.

Ruxolitinib Can Lead to Weight Gain in Patients with Myeloproliferative Neoplasms by Uncoupling Feeding from Central Leptin Signaling Via JAK2/STAT3.

Spencer Krichevsky, Pouneh Kermani, Nicole Molle, Richard T. Silver, Andrew I. Schafer, Ellen K. Ritchie, and Joseph Scandura

Ruxolitinib (rux) is an oral inhibitor of the JAK2 signaling protein and is FDA approved for the treatment of myelofibrosis (MF) and polycythemia vera (PV). Members of the Silver MPN Center noted that patients receiving rux often reported increased appetite with manifest weight gain. This had been reported in the original clinical trials leading to the first approval of rux for advanced myelofibrosis, but at that time weight gain was thought to be a beneficial consequence of reducing symptoms in cachexic and underweight patients. However, broader use of rux in healthier MPN patient populations suggested other explanations. Silver MPN Center investigators studied ~ 100 patients taking rux and found the vast majority (80%) gain weight (80%). The weight gains (median ~10%, up to 31% of their starting weight) were clinically relevant as many moved to a higher body mass category and had co-incident elevations in blood cholesterol. Only a small portion of the treated patients were underweight at the start of therapy. Researchers then turned to animal models to demonstrate that rux blocks leptin signaling in the brain thereby disturbing a major appetite control pathway. This work supports the hypothesis that rux blocks normal homeostatic appetite control by reducing post-prandial satiety and this, in turn, leads to overeating and weight gain. This work indicates that physicians should provide dietary counseling and guidance to patients receiving rux therapy as they are likely to experience increased appetite that unchecked can increase their risk for new cardiovascular risk due to obesity and high cholesterol.

MPN-RF Interferon Initiative Satellite Meeting.

Dr. Scandura and his team were invited to participate in an exciting international research collaboration, the MPN Interferon Initiative.  The MPN Interferon Initiative, coordinated by the MPN Research Foundation, brings together experts who will define how and why therapies that target the interferon pathway reduce the burden of mutated stem cells in MPN patients; why targeting the interferon pathway is effective for some MPN patients but not others; and why the positive effects of targeting this pathway are not permanent. Dr Scandura presented an update of the Silver MPN Center research determining the MPN cells targeted by interferon.

High Throughput Droplet Single-Cell Genotyping of Transcriptomes (GoT) Reveals the Cell Identity Dependency of the Transcriptional Output of Somatic Mutations.

Anna S Nam, Kyu-Tae Kim, Ronan Chaligne, Franco Izzo, Chelston Ang, Nathaniel Omans, Alessandro Pastore, Justin Taylor, Alicia Alonso, Wayne Tam, Ronald Hoffman, Joseph Scandura, Raul Rabadan, Omar Abdel-Wahab, Peter Smibert, and Dan A. Landau

Although the primary mutations causing MPNs have been identified, it is still not known how these mutations lead to clinical MPN diseases. This work takes the approach of identifying the genes expressed by individual cells and correlating those genes with the presence or absence of MPN mutations. Collaborating with members of the Silver MPN Center, this work identified unique transcriptional imprints of MPN driver mutations within immature hematopoietic stem and progenitor cells from patients with CALR mutated MPNs. On important finding of this work is the potential role of the unfolded protein response (UPR) in CALR mutated cells.  UPR is a targetable pathway in early drug development thus offering a new path to targeting MPNs.

A Clinical Review of the Co-Occurrence of Myeloproliferative and Lymphoproliferative Neoplasms.

Spencer Krichevsky, Erica B Bhavsar, Richard R. Furman, Ruben Niesvizky, Ellen K. Ritchie, Giorgio Inghirami and Joseph Scandura

This abstract brings together members of the MPN center with the heads of our lymphoma/myeloma programs and the head of hematopathology to report a higher than expected incidence of co-occurent MPN and lymphoid neoplasm (predominantly chronic lymphocytic leukemia and multiple myeloma).  Interestingly, about half of the patients were diagnosed with an MPN prior to the lymphoid neoplasm and half with the lymphoid malignancy first. This team is now establishing an international consortium to study the molecular causes for the co-occurrence of these two disease types and to assess responses to MPN and lymphoma treatments.

Clinical Research

Launching new clinical trials is key to the discovery of effective new treatments for these blood cancers. In 2018, seven new studies were opened to target MPNs:  four for myelofibrosis; one for polycythemia vera; two for essential thrombocythemia; and one for chronic myeloid leukemia. (For information about studies that are now seeking participants, please visit https://silvermpncenter.weill.cornell.edu/research-and-clinical-trials/myeloproliferative-clinical-trials.

These trials will be conducted in collaboration with major pharmaceutical partners. The companies have been attracted not only by the expertise of the Center’s staff, but by its strong infrastructure, which allows for highly targeted and rapid recruitment of patients who meet the study criteria.

In addition, Center investigators are opening a new investigator-initiated phase II study of a new oral TGFβ pathway inhibitor for use in anemic patients with myeloproliferative neoplasms. This study builds upon findings from the Scandura lab on the role of TGFβ signaling in normal and malignant blood cell formation. Extensive correlative science is being performed with this study to directly assess on-target activity against MPN stem and progenitor cells.

Under the leadership of the Center’s Scientific Director, Joseph M. Scandura, MD, PhD, the Center has successfully focused on increasing the number of patients who are participating in clinical trials and building resources that will accelerate the pace of clinical and translational research. The Center now boasts one of the most extensive MPN patient databases and biospecimen collections in the country, enabling investigators to access detailed clinical records and nearly 300 bone marrow and blood specimens.