1. Blood Cancers in older adults Cancer and Older Adults 19 November 2015 Matthew Foster, MD Assistant Professor of Medicine Leukemia, Lymphoma and Myeloma Program

2. What is leukemia? Diverse set of blood and bone marrow cancers Can arise from any cell in the blood or bone marrow—myeloid or lymphoid

3. What is Leukemia? Can be acute (i.e. fast onset, rapidly fatal if untreated) AML, ALL Can be chronic (progresses over years, “die with it, not of it” CML, CLL Bone marrow cancers without the word “cancer” Myelodysplastic syndromes Myeloproliferative neoplasms

4. What is Lymphoma?

5. What is Multiple Myeloma?

6. Symptoms of Leukemia

9. Leukemia in older adults is an unsolved problem

10. Epidemiology—Acute Myeloid Leukemia Median age of AML/MDS at diagnosis: –65-70 years (Estey E. JCO 2007; 25(14):1908-15) Standard definition of “older” in treatment of AML is ≥ 60 y.o.

11. Older patients underrepresented in trials

12. Why the widely discrepant results in older patients?? Poor performance status (frailty) Frequent antecedent hematologic disorder (MDS/MPD) Frequent organ dysfunction –Renal dysfunction –Liver dysfuntion –Heart disease Estey E. JCO 2007; 25(14):1908-15

13. Disease variables differ in older adults, too Maslak, P. ASH Image Bank 2001;2001:100215

14. Impact of cytogenetics on prognosis Cytogenetic Profile t(15;17), t(8;21), inv(16) Normal, all others Complex (≥ 5 unrelated abnormalities) -5, -7, 3q abnormalities Complete Remission Rate 91%86%63% 5-Year survival 65%41%14% N=1612 pts Grimwade et al. Blood. 1998 Oct; 92(7): 2322-33.

15. Armstrong, S. A. et al. J Clin Oncol; 23:6306-6315 2005 Are these even the same diseases??? Adults Children

16. Standard treatment for AML…since the 1970’s “7+3”—7 days of infusional cytarabine and 3 days bolus anthracycline historically 15-30% mortality in older patients Infections, transfusions, bleeding, GI toxicity Allogeneic transplant for high risk High dose myeloablative chemotherapy unsuited for older patients

17. What should goals be if this intensive therapy seems too much for older patients? Freedom from dependence on transfusions Improved infection-related morbidity Infection prophylaxis Treatment Prevention of complications Keeping patients out of the hospital

18. Palliative-intent, low dose chemotherapy European study in 1980’s compared standard chemotherapy with low-dose therapy with palliative intent 10 week median survival advantage for induction Median days of hospitalization were equivalent: Palliative Rx: 50 Induction: 54 Lowenberg et al. JCO 7 (9): 1268. (1989)

19. Epigenetic approaches for AML and MDS Methylated genes = silenced Demethylated genes = re-expressed Egger G et al. Nature (2004) 429; 557-463.

20. Epigenetic approaches for AML and MDS Lubbert M et al. J Clin Oncol 29: 1987-1996.

21. New treatments for particular leukemias-- myelofibrosis Verstovsek S et al. N Engl J Med 2012;366:799-807.

22. New treatments for particular leukemias-- myelofibrosis Verstovsek S et al. N Engl J Med 2012;366:799-807.

23. New treatments for particular leukemias—Chronic Lymphocytic Leukemia Goede V et al. N Engl J Med 2014;370:1101-10. Patients over 65 with co-existing medical problems Tedeschi A et al. ASH Annual Abstracts 2015. Abstract no. 495

24. New treatments for particular lymphomas—Mantle Cell Lymphoma Kluin-Nelemans HC et al. N Engl J Med 2012;367:520-31.

25. What are we doing at UNC to improve on this? Clinical trials of new drugs and treatments tailored for older patients: Lenalidomide (oral immunomodulatory drug) CPX-351 (nanoparticle formulation of traditional drugs with favorable response, toxicity profile) Ibrutinib for older CLL patients Targeted drugs based on molecular profile (UNCSeq) Novel transplant approaches (umbilical cord blood and haploidentical donors) Assessments and interventions to improve frailty Comprehensive geriatric assessments Exercise program during hospitalization for leukemia treatment

26. Summary The majority of blood cancer patients are over age 60 Older patients have been under-represented in clinical trials for leukemias, lymphoma and myeloma Select older patients can be treated as aggressively as younger ones A variety of new approaches for patients that might not benefit from standard treatments are being developed Clinical trial participation is encouraged!