1. Lymphoma in the Elderly Patient Julie M. Vose, M.D. University of Nebraska Medical Center jmvose@unmc.edu

2. Issues of NHL and HL in the Elderly Incidence of NHL higher with age, HL – biomodal distribution Is the lymphoma different in older patients? Co-morbid illnesses more common Tolerance of medications and toxicities less Options more limited in older patients – due to organ changes

3. 50 40 30 20 10 0 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 Age at Diagnosis for Hodgkin’s and Non-Hodgkin’s Lymphoma (NHL) NHL ~75,000 NHL cases/yr ~7,500 HD cases/yr Cases/100,000 Hodgkin's Age at diagnosis Jemal et al. Cancer . 2004;101:3.

4. Frequency of Non-Hodgkin Lymphoma Subtypes Composite lymphomas (12%) Small lymphocytic (6%) Follicular (22%) Mantle cell (6%) N = 1403 Peripheral T-cell (6%) Marginal zone B-cell, MALT (5%) Mediastinal large B-cell (2%) Anaplastic large T/null cell (2%) Lymphoblastic (2%) Burkitt-like (2%) Diffuse large B-cell (31%) Marginal zone B-cell, nodal (1%) Lymphoplasmacytic (1%) Burkitt’s (1%) Armitage JO, et al. J Clin Oncol. 1998;16:2780–2795.

6. LDH > normal

7. PS ≥ 2

8. Ann Arbor stage III/IV

9. Extranodal involvement > 1 site**Prognostic for patients older than 60 yrs of age only. International NHL Prognosis Factors Project. N Engl J Med. 1993;329:987-994.

11. Age > 60 years

12. β2-microglobulin > ULNFederico M, et al. J Clin Oncol. 2009;27:4555-4562.

13. FLIPI2 For Follicular NHL PFS OS Federico M, et al. J ClinOncol. 2009;27:4555-4562..

15. Secondary endpoints: OS, RRCHOP ± Rituximab in DLBCL: GELA LNH-98.5 Phase III Study Coiffier B, et al. N Engl J Med. 2002;346:235-242. Feugier P, et al. J Clin Oncol. 2005;23:4117-4126.

16. CHOP ± Rituximab in DLBCL: 7-Yr Survival Results (GELA LNH-98.5 Study) OS (N = 399) 1 CHOP R-CHOP 0.8 0.6 Survival Probability 0.4 0.2 P = .0004 0 *P < .05 (multivariate analysis). 0 8 1 3 5 7 6 2 4 Yrs Coiffier B, et al. ASCO 2007. Abstract 8009.

17. CHOP-14 ± Rituximab in Elderly Patients With DLBCL (RICOVER-60 Trial) CHOP-14 × 6 (n=204) R A N D O M I Z E Patients withCD20+ DLBCL, aged 61-80 y, stages I-IV (N=1330) CHOP-14 × 8 (n=210) CHOP-14 × 6 + rituximab q2w × 8 (n=211) CHOP-14 × 8 + rituximab q2w × 8 (n=203) Primary end point: FFTF Radiotherapy was planned for patients with initial bulky disease or extranodal involvement. FFTF is defined as additional therapy, failure to achieve CR, progressive disease, relapse, or death. Pfreundschuh et al. Blood. 2005;106:9a. Abstract 13.

18. CHOP-14 ± Rituximab in Elderly PatientsWith DLBCL (RICOVER-60 Trial):OS by Cycles and Regimens 6 Cycles vs 8 Cycles CHOP-14 vs R-CHOP-14 P=0.088 P=0.284 100 80 60 40 20 0 100 80 60 40 20 0 78% 78% 77% 76% Survival (%) Survival (%) 6 × CHOP-14 ± R × 8(n=415) 8 × CHOP-14 ± R × 8(n=413) 6/8 × CHOP-14 + R × 8(n=414) 6/8 × CHOP-14(n=414) 0 5 10 15 20 25 30 35 40 45 0 5 10 15 20 25 30 35 40 45 Months Months Pfreundschuh et al. Blood. 2005;106:9a. Abstract 13.

20. Age <60 vs. 60

21. Treatment centre1080 patients; 119 sites Recruitment March 2005 - Nov 2008 Cunningham, et al: JCO 8000a, 2011

22. Overall survival 1.0 0.9 0.8 0.7 R-CHOP14 R-CHOP21 0.6 117 (22) 123 (23) Events, n (%) Probability 0.5 83% 81% 2-yr OS 0.4 p=0.70 Log-rank test 0.95 (0.74–1.23) HR (95% CI) 0.3 0.2 R-CHOP21 0.1 R-CHOP14 0.0 0 1 2 3 4 5 6 Years from randomisation Patients at Risk 1 28 120 R-CHOP21 540 474 392 234 30 242 117 1 540 R-CHOP14 476 393 Cunningham, et al: JCO 8000a, 2011

24. Secondary endpoints: response rate, OSBonnet C, et al. J Clin Oncol. 2007;25:787-792.

25. GELA: OS With CHOP ± Radiotherapy – Localized DLBCL 100 90 80 70 60 50 Probability of OS (%) 40 30 CHOPCHOP plus radiotherapy 20 P = .54 10 0 12 8 9 0 6 5 10 11 1 2 7 3 4 Yrs After Random Assignment Pts at Risk, nCHOPCHOP plus radiotherapy 277 249 226 206 178 153 131 102 75 45 22 1 299 265 243 211 187 155 123 98 68 50 30 9 Bonnet C, et al. J Clin Oncol. 2007;25:787-792.

27. R-CHOP × 3+RT

28. R-CHOP × 6-8 ± RT

30. Novel non–cross-resistant regimen ± rituximab

31. ASCT± involved field RT2

32. Clinical trial2

33. Not candidate for high-dose therapy

34. Clinical trial

35. Rituximab

36. CEPP ± Rituximab (PO and IV)

37. PEPC (PO)

39. High-dose Txwith ASCT

42. Clinical trial1. When RT is contraindicated. In patients achieving CR or PR after second-line therapy AA-IPI = age-adjusted IPI. NCCN Practice Guidelines in Oncology, v.3.2009.

43. Is NHL or HL in Elderly patients a Different Disease? For DLBLC – Increase in ABC DLBLC in patients over age 60? For HL – older patients have a higher percentage of subtypes other than nodular sclerosis Increase in inflammation and immunosuppression Endocrine changes with age

44. Diffuse Large B-Cell LymphomaHeterogeneous Molecular Pathogenesis 20% 20% Amplification TP53 mutations RELC-MYCBCL2 6% 17%-20% Somatic hypermutation IgH C-MYC 30%-40% 50% t(8;14) BCL6C-MYCPIM1PAX5RhoH/TTF BCL6 IgH BCL-2 Substituted promoter t(14;18) Lossos I. J Clin Oncol. 2005;23:6351-6357.

45. Age and risk of chemotherapy-related toxicity Short term Myelosuppression Mucositis Cardiotoxicity Neurotoxicity Long terms Acute leukemia and MDS Cardiomyopathy Dementia? Functional dependence and frailty?

46. APhenotype of Frailty Factors Defining Frailty: Weight loss Weakness Poor energy/endurance Slowness Low physical activity Prevalence of Frailty in Community Dwelling Older Adults 0 factors: Not frail 1 or 2 factors: Intermediate 3 or more factors: Frail Copyright © 2010 American Society of Clinical Oncology. All rights reserved

47. Phenotype of Frailty Predictive of 5Adverse Outcomes Incidence of Adverse Outcomes Associated with Frailty P<0.0001 Copyright © 2010 American Society of Clinical Oncology. All rights reserved

49. Cognition

50. Clotting

51. Glucose MetabolismInflammation Neuroendocrine Dysregulation Insulin –like growth factor-1 Dehydroeplandrosterone Sulfate Sex steroids Pathway to Frailty Clinical Molecular and Disease Oxidative stress Mitochondrial deletions Shortened Telomeres DNA damage Cell senescence Slowness Weakness Weight Loss Low Activity Fatigue Gene variation Inflammatory Diseases Copyright © 2010 American Society of Clinical Oncology. All rights reserved

52. Goals of Treatment Prolongation of survival Symptom Palliation Prolongation of active life expectancy Must balance toxicity with short and long term quality of life issues

53. Lymphoma and age: same treatment, same benefits Complete response All patients p < 0.001 Full-dose patients 100 100 80 80 68% 65% 64% 60% 57% 55% 60 60 52% Patients (%) 37% 40 40 20 20 0 0 < 40 40–54 55–64  65 < 40 40–54 55–64  65 Age (years) Age (years) Dixon DO, et al. J Clin Oncol. 1986;4:295-305.

54. Lymphoma and age: same treatment, same benefits Cumulative survival Overall survival (months) Lee KW, et al. Cancer. 2003;98:2651-6.

55. EORTC guidelines for G-CSF prophylaxis R-CHOP 21 associated with high risk of FN1 Patient-related factors add to risk Overall risk ≥20%

56. Elements of geriatric assessment Function Comorbidity Geriatric syndromes Polypharmacy Nutrition Social support Income

57. Cancer and aging: Activities of Daily Living (ADL)

58. Cancer and age: Instrumental Activities of Daily Living (IADL)

59. Other Benefits of Geriatric Assessment Detect reversible comorbidity Nutrition Disability and handicaps Caregiver Treatment goals Risk of chemotherapy-related toxicity

60. CGA and four-year mortality rate Four-year mortality (%) Risk score CGA = comprehensive geriatric assessment. Lee SJ, et al. JAMA. 2006;295:801-8.

61. Predictive model II Predictive risk factors for grade 3–5 chemotherapy toxicity in older adults with cancer Possible score range: 0–25 GI = gastrointestinal; GU = genitourinary; MOS = months of study. Hurria et al. J Clin Oncol. 2010;28 Suppl 15s:[abstract 9001].Data presented at ASCO 2010.

62. “High” 83% ( ≥ 12) “Mid” 53% (6–11) 92% 76% 63% “Low” 27% (0–5) 45% 31% 21% N = 39 N = 50 N = 36 N = 161 N = 64 N = 123 ROC: 0.72 100% 80% 60% Grade 3–5 toxicities (%) 40% 20% 0% ≥ 14 0–4 5 6–8 9–11 12–13 Total score Model performance:prevalence of toxicity by score ROC = receiver operating characteristic.

63. Alternative regimens for DLBCL Pre-phase treatment – prednisone, Rituximab, vincristine Shorter duration – with RT or RIT? Alternative agents – mitoxantrone, doxil, etoposide, infusional agents Dose reduction – mini CHOP Cardioprotective agents May need to add novel agents to the backbone

64. R-CEOP vs. R-CHOP for DLBCL Moccia et al, ASH 2009 abstract 408

65. R-mini CHOP Patients over 80 years Rituximab 375 mg/m2 day 1 Cyclophosphamide 400 mg/m2 day 1 Doxorubicin 25 mg/m2 day 1 Vincristine 1 mg day 1 Prednisone 40 mg/m2 days 1-5 Peyrade et al: Lancet Oncol 12: 460-68, 2011

66. R-mini CHOP Peyrade et al: Lancet Oncol 12: 460-68, 2011

67. Lymphoma in the Elderly Consider a geriatric assessment pre-treatment to identify issues Personalize therapy for the patient Clinical trials using novel therapies with standard therapy Goal to get therapy done in a shorter time Utilize support treatments to keep the therapy on time and expected doses