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

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  • 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.
  • 5. DLBCL: Prognostic Factors
    Adverse risk factors correlated with response to chemotherapy and survival
    • Older than 60 yrs of age
    • 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.
  • 10. The Follicular Lymphoma International Prognostic Index 2 (FLIPI2)
    FLIPI2 score used to predict outcomes of therapy based on adding number of risk factors (each factor = 1 point)
    Longest diameter of largest involved node > 6 cm
    Bone marrow involvement
    • Hemoglobin < 12 g/dL
    • 11. Age > 60 years
    • 12. β2-microglobulin > ULN
    Federico 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..
  • 14. Assessment
    Stratified by risk factors (0-1 vs 2-3)
    R-CHOPevery 3 wks for 8 cycles(n = 202)
    Untreated elderly patients with stage II-IV DLBCL
    (N = 399)
    CHOPevery 3 wks for 8 cycles(n = 197)
    • Primary endpoint: EFS
    • 15. Secondary endpoints: OS, RR
    CHOP ± 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.
  • 19. Trial design: R-CHOP14 vs. 21
    R-CHOP21
    CHOP21  8 cycles
    Rituximab  8 cycles
    n=540
    Newly diagnosed
    CD20+ve DLBCL
    R
    R-CHOP14
    CHOP14  6 cycles
    Rituximab  8 cycles
    Lenograstim Day 4-12
    n=540
    Stratified by
    • IPI (0-1, 2, 3, 4-5)
    • 20. Age <60 vs. 60
    • 21. Treatment centre
    1080 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
  • 23. GELA: CHOP ± Radiotherapy in Localized NHL
    Stratified by treatment center and bulky disease (y vs n)
    CHOPevery 3 wks for 4 cycles(n = 277)
    Untreated patients aged > 60 yrs with localizedstage I/II aggressive lymphoma and no adverse prognostic indicators
    (N = 576)
    IFRT
    CHOPevery 3 wks for 4 cycles(n = 299)
    • Primary endpoint: EFS
    • 24. Secondary endpoints: response rate, OS
    Bonnet 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.
  • 26. DLBCL Treatment
    Initial Therapy
    • Non-bulky/bulky (≥10 cm) withadverse factors
    • 27. R-CHOP × 3+RT
    • 28. R-CHOP × 6-8 ± RT
    • 29. R-CHOP × 6-81
    Additional Therapy
    • Candidate for high-dose therapy
    • 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)
    • 38. EPOCH
    PD
    • Continue Tx withhigher RT dose
    • 39. High-dose Txwith ASCT
    • 40. Clinical trial
    D
    L
    B
    C
    L
    Stage I, II
    PR
    Follow-up Therapy
    Stage III, IV + AA-IPI
    • Continue R-CHOP to 6-8 or
    • 41. Clinical trial
    CR/PR
    • R-CHOP × 6-8
    • 42. Clinical trial
    1. 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
  • 48. Impaired Physiological
    Interleukin-6
    Anorexia
    Sarcopenia,
    Osteopenia
    Inflammation
    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