1. Center for Hematologic Malignancies
Ross L. Levine, M.D.
Human Oncology and Pathogenesis Program
Leukemia Service, Department of Medicine
Center for Epigenetics Research
Center for Hematologic Malignancies
Memorial Sloan Kettering Cancer Center

2. Blood Cancers Lymphomas Multiple Myeloma Leukemias
growth of lymphocytes in lymph node and bone marrow
Hodgkin, non-Hodgkin lymphoma with >100 subtypes
Multiple Myeloma
excess plasma cells in blood and bone marrow
Bone lesions, kidney disease
Leukemias
Proliferation of circulating blood, bone marrow cells
Acute (ALL, AML) and chronic (CLL, CML, MPN)

3. Blood Cancers
171,500 people in the US will be diagnosed with a blood cancer this year: 81,000 lymphoma, 60,000 leukemia, and 30,000 myeloma new cases each year
>10% of all new cancer cases
1.2 million people are living with, or have been treated for, a blood cancer
58,000 deaths each year from blood cancers
Some of the greatest successes in the history of the war on cancer
First cure of any cancer (pediatric ALL)
Development of stem cell transplant
First molecularly targeted therapy (Imatinib/Gleevec for CML)
Many seminal discoveries in the blood cancer field

4. Heme Malignancies at MSKCC
World leaders in clinical/laboratory efforts in:
- Leukemia, lymphoma, myeloma, transplant
- Immunotherapy, targeted therapies, epigenetics
Clinical Trials:
- Numerous investigator-initiated/registration trials
HemeOnc Tissue Bank:
- An expanding resource for research
- More then 100,000 vials banked and counting…
Funding:
- Many grants from NIH/NCI, Stand up to Cancer, LLS

5. Success Stories in Blood Cancers at MSKCC
First trials of CAR-T cells for leukemia patients
Leader in development of novel approaches to stem cell transplantation
Have led the development of leukemia drugs which are now part of clinical practice – research to improve the standard of care worldwide
Developed the first drugs for cutaneous T-cell lymphoma, providing the first good therapeutic options for patients with these rare lymphomas
Recruited and supported >10 lab-based investigators who are world leaders in blood cancer research

6. Build on Our Strength: Gaols for MSK Heme Malignancies
Recruit laboratory-based investigators in lymphoid malignancies (lymphoma, CLL, myeloma)
Increase ability to attract collaborative grants
State of the art computational infrastructure
Ensure access to patient samples for translational/basic research
Support for pilot projects/translational efforts encourage high risk, high reward research

7. New MSK Center for Hematoligic Malignancies
Director: Ross Levine
Administrator: Eder Paraiso, Sharon Sobel
Translational Project Manager: Minal Patel
Irene Phillip
Chris Famulare
Associate Director: Elli Papaemmanuil, PhD
(Bioinformatics, analysis, genomics, operations, strategy)
Bioinformatics: Franck Rapaport, PhD
Pipeline manager
Database Support
Analysts
Grants Support: Shane Mayack, PhD

8. Heme Malignancies – Translational Team
Tremendous wealth of samples in HOTB - allow people to find and use our rich sample collection

9. External Funding
Given our national/international leadership we are competitive for grants from NIH, LLS, other foundations
Key to fund our research and to further extend our international leadership position in blood cancers
Integrate across diseases and across different aspects of expertise (immunotherapy, targeted therapy)
We will provide leadership/assistance with
Assembling teams/proposals
Integrate clinical investigators with less grant-writing experience into collaborative grant efforts
Allows Society support to be a multiplier->your investment will allow us to obtain additional, long-term/renewable external funding
Engelman

10. Bioinformatics
Increasing use of state-of-the-art profiling technologies to study patients with blood cancer (and all cancers)
We have assembled and continue to grow a team of bioinformatics experts who can provide expertise with data analysis, especially around big data
By having these experts in the center, we develop computational researchers with expertise, interest, and focus on blood cancers
Engelman

11. Future of Blood Cancer Research
Most patients currently are treated with chemotherapy, transplant, radiation therapy
Effective, but highly toxic, risk of short and long term side effects
When patients fail these therapies, there are few options which offer the chance for cure
The labs at MSK have been at the vanguard of laboratory studies which have identified the molecular events which drive blood cancers
How can we translate this to clinical benefit?
Engelman

12. AML Still Associated with Poor Overall Survival
Note from NCCN: changed -> into arrow symbol ().
Even with intensive induction chemotherapy/transplantation most patients die of their disease new insights are needed
Only 2 classes of agents approved for AML in 3 decates (hypomethylating agents, gemtuzumab)
Issa, Kantarjian et al, Cancer 2008

13. IDH2 mutations in AML
Genome sequencing and metabolism studies (Thompson, Levine labs) led to identification of IDH2 mutations in acute myeloid leukemia
The overall incidence of IDH1/2 mutations is 15-30%, most common in older patients
How do these mutations contribute to leukemia development?
Is IDH2 a therapeutic target?
Ward et al. Cancer Cell 2010
Marcucci et al JCO 2010
Gross et al. J Ex Med 2010

14. AML in IDH2 mutant mice
Resistant to chemotherapy, similar to AML patients with same mutations
What are the key pathways which drive AML-> genome-wide DNA methylation profiling

15. Epigenetic Silencing in IDH-mutant AML
TET2-mutant AML
Normal stem cells
GATA2, master regulator of hematopoiesis, is silenced in IDH-mutant AML
What happens when you restore Gata2 in AML cells?

16. Rexpression of GATA2 abrogates in vivo transformation of FLT3/TET2-mutant AML cells
Adding back a single silenced gene can make the leukemias go away over time

17. In Vivo efficacy of IDH2 Inhibition with AG221
In vitro and in vivo assays show significant efficacy
See evidence of differentiation in vivo with reduced blasts, expansion of mature myeloid cells
Clinical trials of AG-221, IDH2-specific inhibitor in relapsed/refractory IDH2-mutant AML (Eytan Stein, PI)

18. AG-221 in Relapsed/Refractory IDH2-mutant AML
Significant clinical activity in AML patients with IDH2 mutations (required for enrollment
Evidence of differentiation in vivo with neutrophil expansion followed by clinical response
Stein et al. ASH 2015

19. AG-221 in Relapsed/Refractory IDH2-mutant AML
CR: 6/7 patients have neutrophils with IDH2 mutations (and all other mutations) present at diagnosis (3-18 months)

20. Center for Hematologic Malignancies
An innovative effort to accelerate discovery and clinical translation in blood cancers
Allows us to serve as a leader for laboratory/clinical research, adult/pediatric blood cancer efforts, and links between basic science and clinical translation
Serve as the catalyst to increase research and to shorten the path from discovery to clinical application
Will allow us to continue to lead the world in blood cancer research and clinical care and to attract the best talent to blood cancer efforts at MSK

21. Blood Cancer Research at MSK!
Acknowledgements
Elodie Pronier
Olga Guryanova
Sophie McKenney
Hiro Kunimoto
Gila Spitzer
Andrew Dunbar
Bobby Bowman
NCI, LLS, NIDDK