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LLA 2011 - J.M. Vose - Treatment of lymphomas in elderley patients


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LLA 2011 - J.M. Vose - Treatment of lymphomas in elderley patients

  1. 1. Lymphoma in the Elderly Patient<br />Julie M. Vose, M.D.<br />University of Nebraska Medical Center<br /><br />
  2. 2. Issues of NHL and HL in the Elderly<br />Incidence of NHL higher with age, HL – biomodal distribution<br />Is the lymphoma different in older patients?<br />Co-morbid illnesses more common<br />Tolerance of medications and toxicities less<br />Options more limited in older patients – due to organ changes<br />
  3. 3. 50<br />40<br />30<br />20<br />10<br />0<br />0<br />5<br />10<br />15<br />20<br />25<br />30<br />35<br />40<br />45<br />50<br />55<br />60<br />65<br />70<br />75<br />80<br />85<br />Age at Diagnosis for Hodgkin’s and Non-Hodgkin’s Lymphoma (NHL)<br />NHL <br />~75,000 NHL cases/yr<br /> ~7,500 HD cases/yr <br />Cases/100,000<br />Hodgkin's<br />Age at diagnosis<br />Jemal et al. Cancer . 2004;101:3.<br />
  4. 4. Frequency of Non-Hodgkin Lymphoma Subtypes<br />Composite lymphomas (12%)<br />Small lymphocytic (6%)<br />Follicular (22%)<br />Mantle cell (6%)<br />N = 1403<br />Peripheral T-cell (6%)<br />Marginal zone B-cell, MALT (5%)<br />Mediastinal large B-cell (2%)<br />Anaplastic large T/null cell (2%)<br />Lymphoblastic (2%)<br />Burkitt-like (2%)<br />Diffuse large B-cell<br /> (31%)<br />Marginal zone B-cell, nodal (1%)<br />Lymphoplasmacytic (1%)<br />Burkitt’s (1%)<br />Armitage JO, et al. J Clin Oncol. 1998;16:2780–2795.<br />
  5. 5. DLBCL: Prognostic Factors<br />Adverse risk factors correlated with response to chemotherapy and survival<br /><ul><li>Older than 60 yrs of age
  6. 6. LDH > normal
  7. 7. PS ≥ 2
  8. 8. Ann Arbor stage III/IV
  9. 9. Extranodal involvement > 1 site*</li></ul>*Prognostic for patients older than 60 yrs of age only.<br />International NHL Prognosis Factors Project. N Engl J Med. 1993;329:987-994.<br />
  10. 10. The Follicular Lymphoma International Prognostic Index 2 (FLIPI2)<br />FLIPI2 score used to predict outcomes of therapy based on adding number of risk factors (each factor = 1 point)<br />Longest diameter of largest involved node > 6 cm<br />Bone marrow involvement<br /><ul><li>Hemoglobin < 12 g/dL
  11. 11. Age > 60 years
  12. 12. β2-microglobulin > ULN</li></ul>Federico M, et al. J Clin Oncol. 2009;27:4555-4562.<br />
  13. 13. FLIPI2 For Follicular NHL<br />PFS<br />OS<br />Federico M, et al. J ClinOncol. 2009;27:4555-4562..<br />
  14. 14. Assessment<br />Stratified by risk factors (0-1 vs 2-3)<br />R-CHOPevery 3 wks for 8 cycles(n = 202)<br />Untreated elderly patients with stage II-IV DLBCL<br />(N = 399)<br />CHOPevery 3 wks for 8 cycles(n = 197)<br /><ul><li>Primary endpoint: EFS
  15. 15. Secondary endpoints: OS, RR</li></ul>CHOP ± Rituximab in DLBCL: GELA LNH-98.5 Phase III Study<br />Coiffier B, et al. N Engl J Med. 2002;346:235-242. Feugier P, et al. J Clin Oncol. 2005;23:4117-4126.<br />
  16. 16. CHOP ± Rituximab in DLBCL: 7-Yr Survival Results (GELA LNH-98.5 Study)<br />OS (N = 399)<br />1<br />CHOP<br />R-CHOP<br />0.8<br />0.6<br />Survival Probability<br />0.4<br />0.2<br />P = .0004<br />0<br />*P < .05 (multivariate analysis).<br />0<br />8<br />1<br />3<br />5<br />7<br />6<br />2<br />4<br />Yrs<br />Coiffier B, et al. ASCO 2007. Abstract 8009.<br />
  17. 17. CHOP-14 ± Rituximab in Elderly Patients With DLBCL (RICOVER-60 Trial)<br />CHOP-14 × 6<br />(n=204)<br />R<br />A<br />N<br />D<br />O<br />M<br />I<br />Z<br />E<br />Patients withCD20+ DLBCL,<br />aged 61-80 y,<br />stages I-IV<br />(N=1330)<br />CHOP-14 × 8<br />(n=210)<br />CHOP-14 × 6 + rituximab q2w × 8<br />(n=211)<br />CHOP-14 × 8 + rituximab q2w × 8<br />(n=203)<br />Primary end point: FFTF<br /> Radiotherapy was planned for patients with initial bulky disease or extranodal involvement.<br /> FFTF is defined as additional therapy, failure to achieve CR, progressive disease, relapse, or death.<br /> Pfreundschuh et al. Blood. 2005;106:9a. Abstract 13.<br />
  18. 18. CHOP-14 ± Rituximab in Elderly PatientsWith DLBCL (RICOVER-60 Trial):OS by Cycles and Regimens<br />6 Cycles vs 8 Cycles<br />CHOP-14 vs R-CHOP-14<br />P=0.088<br />P=0.284<br />100<br />80<br />60<br />40<br />20<br />0<br />100<br />80<br />60<br />40<br />20<br />0<br />78%<br />78%<br />77%<br />76%<br />Survival (%)<br />Survival (%)<br />6 × CHOP-14 ± R × 8(n=415)<br />8 × CHOP-14 ± R × 8(n=413)<br />6/8 × CHOP-14 + R × 8(n=414)<br />6/8 × CHOP-14(n=414)<br />0 5 10 15 20 25 30 35 40 45<br />0 5 10 15 20 25 30 35 40 45<br />Months<br />Months<br />Pfreundschuh et al. Blood. 2005;106:9a. Abstract 13.<br />
  19. 19. Trial design: R-CHOP14 vs. 21<br />R-CHOP21<br />CHOP21  8 cycles<br />Rituximab  8 cycles<br />n=540<br />Newly diagnosed<br />CD20+ve DLBCL<br />R<br /> R-CHOP14<br /> CHOP14  6 cycles<br /> Rituximab  8 cycles<br /> Lenograstim Day 4-12<br />n=540<br />Stratified by<br /><ul><li>IPI (0-1, 2, 3, 4-5)
  20. 20. Age <60 vs. 60
  21. 21. Treatment centre</li></ul>1080 patients; 119 sites<br />Recruitment March 2005 - Nov 2008<br />Cunningham, et al: JCO 8000a, 2011<br />
  22. 22. Overall survival<br />1.0<br />0.9<br />0.8<br />0.7<br />R-CHOP14<br />R-CHOP21<br />0.6<br />117 (22)<br />123 (23)<br />Events, n (%) <br />Probability<br />0.5<br />83%<br />81%<br />2-yr OS<br />0.4<br />p=0.70<br />Log-rank test<br />0.95 (0.74–1.23)<br />HR (95% CI)<br />0.3<br />0.2<br />R-CHOP21 <br />0.1<br />R-CHOP14 <br />0.0<br />0<br />1<br />2<br />3<br />4<br />5<br />6<br />Years from randomisation<br />Patients at Risk<br />1<br />28<br />120<br />R-CHOP21<br />540<br />474<br />392<br />234<br />30<br />242<br />117<br />1<br />540<br />R-CHOP14<br />476<br />393<br />Cunningham, et al: JCO 8000a, 2011<br />
  23. 23. GELA: CHOP ± Radiotherapy in Localized NHL <br />Stratified by treatment center and bulky disease (y vs n)<br />CHOPevery 3 wks for 4 cycles(n = 277)<br />Untreated patients aged > 60 yrs with localizedstage I/II aggressive lymphoma and no adverse prognostic indicators<br />(N = 576)<br />IFRT<br />CHOPevery 3 wks for 4 cycles(n = 299)<br /><ul><li>Primary endpoint: EFS
  24. 24. Secondary endpoints: response rate, OS</li></ul>Bonnet C, et al. J Clin Oncol. 2007;25:787-792.<br />
  25. 25. GELA: OS With CHOP ± Radiotherapy – Localized DLBCL<br />100<br />90<br />80<br />70<br />60<br />50<br />Probability of OS (%)<br />40<br />30<br />CHOPCHOP plus radiotherapy<br />20<br />P = .54<br />10<br />0<br />12<br />8<br />9<br />0<br />6<br />5<br />10<br />11<br />1<br />2<br />7<br />3<br />4<br />Yrs After Random Assignment<br />Pts at Risk, nCHOPCHOP plus radiotherapy<br />277 249 226 206 178 153 131 102 75 45 22 1<br />299 265 243 211 187 155 123 98 68 50 30 9<br />Bonnet C, et al. J Clin Oncol. 2007;25:787-792.<br />
  26. 26. DLBCL Treatment<br />Initial Therapy<br /><ul><li>Non-bulky/bulky (≥10 cm) withadverse factors
  27. 27. R-CHOP × 3+RT
  28. 28. R-CHOP × 6-8 ± RT
  29. 29. R-CHOP × 6-81</li></ul>Additional Therapy<br /><ul><li>Candidate for high-dose therapy
  30. 30. Novel non–cross-resistant regimen ± rituximab
  31. 31. ASCT± involved field RT2
  32. 32. Clinical trial2
  33. 33. Not candidate for high-dose therapy
  34. 34. Clinical trial
  35. 35. Rituximab
  36. 36. CEPP ± Rituximab (PO and IV)
  37. 37. PEPC (PO)
  38. 38. EPOCH</li></ul>PD<br /><ul><li>Continue Tx withhigher RT dose
  39. 39. High-dose Txwith ASCT
  40. 40. Clinical trial</li></ul>D <br />L<br />B<br />C<br />L<br />Stage I, II<br />PR<br />Follow-up Therapy<br />Stage III, IV + AA-IPI<br /><ul><li>Continue R-CHOP to 6-8 or
  41. 41. Clinical trial</li></ul>CR/PR<br /><ul><li>R-CHOP × 6-8
  42. 42. Clinical trial</li></ul>1. When RT is contraindicated.<br />In patients achieving CR or PR after second-line therapy<br /> AA-IPI = age-adjusted IPI.<br />NCCN Practice Guidelines in Oncology, v.3.2009.<br />
  43. 43. Is NHL or HL in Elderly patients a Different Disease?<br />For DLBLC – Increase in ABC DLBLC in patients over age 60?<br />For HL – older patients have a higher percentage of subtypes other than nodular sclerosis<br />Increase in inflammation and immunosuppression<br />Endocrine changes with age<br />
  44. 44. Diffuse Large B-Cell LymphomaHeterogeneous Molecular Pathogenesis<br />20%<br />20%<br />Amplification<br />TP53 mutations<br />RELC-MYCBCL2<br />6%<br />17%-20%<br />Somatic hypermutation<br />IgH<br />C-MYC<br />30%-40%<br />50%<br />t(8;14)<br />BCL6C-MYCPIM1PAX5RhoH/TTF<br />BCL6<br />IgH<br />BCL-2<br />Substituted promoter<br />t(14;18)<br />Lossos I. J Clin Oncol. 2005;23:6351-6357.<br />
  45. 45. Age and risk of chemotherapy-related toxicity<br />Short term<br />Myelosuppression<br />Mucositis<br />Cardiotoxicity<br />Neurotoxicity<br />Long terms<br />Acute leukemia and MDS<br />Cardiomyopathy<br />Dementia?<br />Functional dependence and frailty?<br />
  46. 46. APhenotype of Frailty<br />Factors Defining Frailty:<br />Weight loss<br />Weakness<br />Poor energy/endurance<br />Slowness<br />Low physical activity<br />Prevalence of Frailty in Community Dwelling Older Adults<br />0 factors: Not frail <br />1 or 2 factors: Intermediate<br />3 or more factors: Frail<br />Copyright © 2010 American Society of Clinical Oncology. All rights reserved <br />
  47. 47. Phenotype of Frailty Predictive of 5Adverse Outcomes<br />Incidence of Adverse Outcomes Associated with Frailty<br />P<0.0001<br />Copyright © 2010 American Society of Clinical Oncology. All rights reserved <br />
  48. 48. Impaired Physiological<br />Interleukin-6<br />Anorexia<br />Sarcopenia,<br />Osteopenia<br /><ul><li>Immune function
  49. 49. Cognition
  50. 50. Clotting
  51. 51. Glucose Metabolism</li></ul>Inflammation<br />Neuroendocrine<br /> Dysregulation<br />Insulin –like growth factor-1<br />Dehydroeplandrosterone<br />Sulfate<br />Sex steroids<br />Pathway to Frailty<br />Clinical<br />Molecular and Disease<br />Oxidative stress<br />Mitochondrial deletions<br />Shortened Telomeres<br />DNA damage<br />Cell senescence<br />Slowness<br />Weakness<br />Weight<br /> Loss<br />Low Activity<br />Fatigue<br />Gene<br />variation<br />Inflammatory <br />Diseases<br />Copyright © 2010 American Society of Clinical Oncology. All rights reserved <br />
  52. 52. Goals of Treatment<br />Prolongation of survival<br />Symptom Palliation<br />Prolongation of active life expectancy<br />Must balance toxicity with short and long term quality of life issues<br />
  53. 53. Lymphoma and age: same treatment, same benefits<br />Complete response<br />All patients<br />p < 0.001<br />Full-dose patients<br />100<br />100<br />80<br />80<br />68%<br />65%<br />64%<br />60%<br />57%<br />55%<br />60<br />60<br />52%<br />Patients (%)<br />37%<br />40<br />40<br />20<br />20<br />0<br />0<br />< 40<br />40–54<br />55–64<br /> 65<br />< 40<br />40–54<br />55–64<br /> 65<br />Age (years)<br />Age (years)<br />Dixon DO, et al. J Clin Oncol. 1986;4:295-305.<br />
  54. 54. Lymphoma and age: same treatment, same benefits<br />Cumulative survival<br />Overall survival (months)<br />Lee KW, et al. Cancer. 2003;98:2651-6.<br />
  55. 55. EORTC guidelines for G-CSF prophylaxis<br />R-CHOP 21 associated with high risk of FN1<br />Patient-related factors add to risk<br />Overall risk ≥20%<br />
  56. 56. Elements of geriatric assessment<br />Function<br />Comorbidity<br />Geriatric syndromes<br />Polypharmacy<br />Nutrition<br />Social support<br />Income<br />
  57. 57. Cancer and aging: Activities of Daily Living (ADL)<br />
  58. 58. Cancer and age: Instrumental Activities of Daily Living (IADL)<br />
  59. 59. Other Benefits of Geriatric Assessment<br />Detect reversible comorbidity<br />Nutrition<br />Disability and handicaps<br />Caregiver<br />Treatment goals<br />Risk of chemotherapy-related toxicity<br />
  60. 60. CGA and four-year mortality rate<br />Four-year mortality (%)<br />Risk score<br />CGA = comprehensive geriatric assessment.<br />Lee SJ, et al. JAMA. 2006;295:801-8.<br />
  61. 61. Predictive model II<br />Predictive risk factors for grade 3–5 chemotherapy toxicity in older adults with cancer<br />Possible score range: 0–25<br />GI = gastrointestinal; GU = genitourinary; MOS = months of study.<br />Hurria et al. J Clin Oncol. 2010;28 Suppl 15s:[abstract 9001].Data presented at ASCO 2010.<br />
  62. 62. “High” 83%<br />( ≥ 12)<br />“Mid” 53%<br />(6–11)<br />92%<br />76%<br />63%<br />“Low” 27%<br />(0–5)<br />45%<br />31%<br />21%<br />N = 39<br />N = 50<br />N = 36<br />N = 161<br />N = 64<br />N = 123<br />ROC: 0.72 <br />100%<br />80%<br />60%<br />Grade 3–5 toxicities (%)<br />40%<br />20%<br />0%<br />≥ 14<br />0–4<br />5<br />6–8<br />9–11<br />12–13<br />Total score<br />Model performance:prevalence of toxicity by score<br />ROC = receiver operating characteristic.<br />
  63. 63. Alternative regimens for DLBCL<br />Pre-phase treatment – prednisone, Rituximab, vincristine<br />Shorter duration – with RT or RIT?<br />Alternative agents – mitoxantrone, doxil, etoposide, infusional agents<br />Dose reduction – mini CHOP<br />Cardioprotective agents<br />May need to add novel agents to the backbone<br />
  64. 64. R-CEOP vs. R-CHOP for DLBCL<br />Moccia et al, ASH 2009 abstract 408<br />
  65. 65. R-mini CHOP<br />Patients over 80 years<br />Rituximab 375 mg/m2 day 1<br />Cyclophosphamide 400 mg/m2 day 1<br />Doxorubicin 25 mg/m2 day 1<br />Vincristine 1 mg day 1<br />Prednisone 40 mg/m2 days 1-5<br />Peyrade et al: Lancet Oncol 12: 460-68, 2011<br />
  66. 66. R-mini CHOP<br />Peyrade et al: Lancet Oncol 12: 460-68, 2011<br />
  67. 67. Lymphoma in the Elderly<br />Consider a geriatric assessment pre-treatment to identify issues<br />Personalize therapy for the patient<br />Clinical trials using novel therapies with standard therapy<br />Goal to get therapy done in a shorter time<br />Utilize support treatments to keep the therapy on time and expected doses<br />