PROGNOSIS STUDY OF HIV-RELATEDLYMPHOMACHUN CHAO, PH.D.,DEPARTMENT OF RESEARCH AND EVALUATIONKAISER PERMANENTE SOUTHERN CAL...
HIV-INFECTION AND NON-HODGKIN LYMPHOMA (NHL) • HIV-infected persons are at increased risk of   developing NHL compared to ...
HIV INFECTION AND RISK OF NHL (CONT.)     • However, HIV-infected persons are still at       increase risk of NHL in the H...
NHL IN HIV-INFECTED PATIENTS Not only are HIV+ persons at significantly  elevated risk of NHL, they also tend to have  a ...
CHANGE IN TREATMENT PARADIGM FOR HIV+ NHL Before HAART, NHL mortality approaches  100%, and most standard treatment is hi...
SURVIVAL OF HIV+ NHL PATIENTS IN THE PRE-AND POST-HAART ERA    Graph source: Lim et al, J Clin Oncol 2005;23:8477-8482.   ...
SURVIVAL IN NHL PATIENTS More than half (59%) of the HIV+ NHL died within 2  years, compared to 29% in HIV-uninfected cas...
INCREASED MORTALITY IN HIV+ NHL PATIENTS –MULTIVARIABLE ANALYSES  Table source: Chao et al. AIDS. 2010; 24(11): 1765–1770 ...
PROGNOSTIC FACTORS IN HIV+ NHL PATIENTS In the pre-HAART era, only CD4 cell count,  but not lymphoma characteristics, app...
BACKGROUND – HIV+ DIFFUSE LARGE B-CELL LYMPHOMA   Diffuse large B-cell lymphoma (DLBCL) is the    most common subtype of ...
 Objective:  To determine the prognostic significance of novel   viral/molecular markers in HIV-related DLBCL in the HAA...
STUDY METHODS Study Design: Cohort study. Study population: HIV+ DLBCL cases diagnosed between 1996-2007 at KP Souther...
ANALYSIS OF TISSUE SPECIMENSPathology review: Selection of appropriate tissue specimen. Diagnosis confirmation and DLBCL...
ANALYSIS OF TISSUE SPECIMENS (CONT.) Archived FFPE tumor blocks. Tissue microarray and immunohistochemistry. EBV infect...
IMAGE OF TMA CORES                     15
STUDY METHODS (CONT.) Outcome of interest:  Overall survival and progression-free survival. Follow-up:  Up to 5 years ...
STUDY POPULATION                   17
STUDY POPULATION FOR TUMOR MARKER ANALYSIS  Of 194 HIV+ DLBCL cases identified; 80 had   sufficient tissue for study incl...
BASELINE CHARACTERISTICS                KP Northern      KP Southern                                      California      ...
FINDINGS OF TUMOR MARKER EXPRESSION We found that Ki-67, PKC-beta 2, CD44, and  survivin were expressed (i.e., 2+) in the...
CLUSTER EXAMINATION OF TUMOR MARKERS We examined the pair-wise Pearson’s  correlation coefficient between the  expression...
MARKER EXPRESSION & HAZARD RATIO (HR)OF MARKER POSITIVITY ON 2-YEAR MORTALITYAdjusted HR adjusted for stage, presence of B...
HIV+ DLBCL PROGNOSTIC TUMOR MARKERS   In the crude analysis, cMYC, EBV and BLIMP1 positivity    was associated with great...
2-YEAR OVERALL SURVIVAL BY CD4 AND MARKER LEVELS Red: high CD4/low marker; Blue: high CD4/high marker Green: low CD4/low m...
SUMMARY OF IMMUNODECIFENCY ANDPROGNOSTIC TUMOR MARKER ANALYSIS Cases with low CD4 and high levels of EBV or  cMYC had wor...
FUTURE STEPS Future analysis will incorporate Progression-free survival. Validation using bootstrapping. Examination o...
ACKNOWLEDGEMENTSHIV-related DLBCL study investigator team:Kaiser Permanente Southern California: Drs. Chun Chao  (PI), Rei...
THANK YOU FOR YOUR ATTENTION        Questions?                               28
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Identification of Prognostic Tumor Markers in HIV Diffuse Large B cell Lymphoma CHAO

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Identification of Prognostic Tumor Markers in HIV Diffuse Large B cell Lymphoma CHAO

  1. 1. PROGNOSIS STUDY OF HIV-RELATEDLYMPHOMACHUN CHAO, PH.D.,DEPARTMENT OF RESEARCH AND EVALUATIONKAISER PERMANENTE SOUTHERN CALIFORNIA 1
  2. 2. HIV-INFECTION AND NON-HODGKIN LYMPHOMA (NHL) • HIV-infected persons are at increased risk of developing NHL compared to the general population.  AIDS defining cancer. • Use of highly active antiretroviral therapy (HAART) has significantly decreased the occurrence of NHL in HIV+ persons. 2
  3. 3. HIV INFECTION AND RISK OF NHL (CONT.) • However, HIV-infected persons are still at increase risk of NHL in the HAART era.1 crude rate per 100,000 person-years2 Rate ratios from Poisson regression models included terms for HIV status, age, sex, calendar period, andrace/ethnicity. Standard multiple imputation methods were used with imputation for missingrace/ethnicity.Table source: Silverberg et al. AIDS 2009, 23(17): 2337-2345. 3
  4. 4. NHL IN HIV-INFECTED PATIENTS Not only are HIV+ persons at significantly elevated risk of NHL, they also tend to have a more aggressive course of disease.  Diagnosed at advanced stage  Extranodal involvement  CNS lymphoma  B symptoms Graph source: http://diseaseminutely.com/diseases/infectious- diseases/hiv-and-aids/ 4
  5. 5. CHANGE IN TREATMENT PARADIGM FOR HIV+ NHL Before HAART, NHL mortality approaches 100%, and most standard treatment is highly toxic. In the HAART era, CHOP appear to be tolerably by HIV+ patients diagnosed with NHL. The safety of rituximab use in HIV+ patients has been controversial. Time to evaluate care standard for HIV+ patients with NHL, and to investigate novel treatment approaches. 5
  6. 6. SURVIVAL OF HIV+ NHL PATIENTS IN THE PRE-AND POST-HAART ERA Graph source: Lim et al, J Clin Oncol 2005;23:8477-8482. 6
  7. 7. SURVIVAL IN NHL PATIENTS More than half (59%) of the HIV+ NHL died within 2 years, compared to 29% in HIV-uninfected cases. 2-year overall mortality 2-year lymphoma-specific mortality 7
  8. 8. INCREASED MORTALITY IN HIV+ NHL PATIENTS –MULTIVARIABLE ANALYSES Table source: Chao et al. AIDS. 2010; 24(11): 1765–1770 8
  9. 9. PROGNOSTIC FACTORS IN HIV+ NHL PATIENTS In the pre-HAART era, only CD4 cell count, but not lymphoma characteristics, appeared to predict survival. In the HAART era, lymphoma characteristics, such as stage, have been reported to predict survival in HIV+ NHL. We are interested in identifying tumor markers that explain the aggressiveness and heterogeneity of HIV+ lymphoma. 9
  10. 10. BACKGROUND – HIV+ DIFFUSE LARGE B-CELL LYMPHOMA  Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of HIV+ NHL.  HIV-related DLBCL is no longer invariably fatal and is heterogeneous in clinical outcomes.  Despite the availability of potentially effective regimens for DLBCL treatment, more than 50% of HIV+ patients continue to succumb to the disease. 10
  11. 11.  Objective:  To determine the prognostic significance of novel viral/molecular markers in HIV-related DLBCL in the HAART era. Rationale:  Clinical prognostic factors, such as International Prognostic Index (IPI), do not always accurately predict patient survival.  A predictive equation combining clinical prognostic markers and tumor markers may further enhance patient risk stratification.  Our results may help to identify new molecular therapeutic targets for resistant tumors. 11
  12. 12. STUDY METHODS Study Design: Cohort study. Study population: HIV+ DLBCL cases diagnosed between 1996-2007 at KP Southern and Northern California. Data collection on outcomes and covariates: Kaiser Permanente’s electronic medical records. Medical chart abstraction.  Relevant clinical symptoms: e.g., B symptoms.  Earliest date of known HIV infection.  Clinical disease progression: e.g., relapse, progression. 12
  13. 13. ANALYSIS OF TISSUE SPECIMENSPathology review: Selection of appropriate tissue specimen. Diagnosis confirmation and DLBCL subtyping. Two study pathologists independent conducted the assessment. Discrepancy resolved by consensus. 13
  14. 14. ANALYSIS OF TISSUE SPECIMENS (CONT.) Archived FFPE tumor blocks. Tissue microarray and immunohistochemistry. EBV infection was determined by in situ hybridization of EBV- encoded RNA (EBER). Tumor expression of selected B-cell oncogenic markers in the following categories:  Viral factor: EBV, HHV8.  Cell cycle promoters: cyclin D2, cyclin E, cMYC, p27, SKP2.  B-cell activators: BCL6, FOXP1, PKC-beta 2 and CD21.  Apoptotic regulators: BCL2, p53, survivin, BAX, GAL3, and BLIMP1.  Others: CD10, MUM1, Ki-67, CD44, CD30, CD43, LMO2, and MMP9. 14
  15. 15. IMAGE OF TMA CORES 15
  16. 16. STUDY METHODS (CONT.) Outcome of interest:  Overall survival and progression-free survival. Follow-up:  Up to 5 years after DLBCL diagnosis (minimum 3 yrs). Statistical analysis:  Multivariable Cox model.  Propensity score used for adjusting for potential confounding.  Bootstrapping for validation. 16
  17. 17. STUDY POPULATION 17
  18. 18. STUDY POPULATION FOR TUMOR MARKER ANALYSIS  Of 194 HIV+ DLBCL cases identified; 80 had sufficient tissue for study inclusion.  We compared the demographic, HIV disease factors, DLBCL characteristics, and co- morbidity history among those who did vs. did not have an adequate tumor specimen.  No important difference was found between those who were included vs. those who were not. 18
  19. 19. BASELINE CHARACTERISTICS KP Northern KP Southern California California Total (N=131) (N=63) (N=194)   Mean (SD)/Percent Age, yr 47 (10) 48 (10) 47 (10) Male gender 97% 90% 95% White Race 66% 49% 60% Stage           I (Localized) 26% 19% 24%     II (Regional) 17% 16% 16%     III (Distant) 54% 49% 53% Extranodal involvement           Stage I: 10, 11, 12 27% 22% 25%     Stage II: 20, 21, 22, 23 16% 14% 15%     Stage III: 30, 31, 32, 33 15% 16% 15% Stage IV: 88 Disseminated 40% 44% 42% B symptoms           No B symptoms 47% 46% 47%     Any B symptoms 32% 43% 36%     Unknown 21% 10% 17% HIV risk group           Heterosexual 11% 22% 15%     IDU 8% 0% 5%     MSM 61% 30% 51%     OTH/UNK 20% 48% 29% Prior AIDS diagnosis 42% 63% 49% Prior use of HAART 59% 71% 63% CD4 cell count at DLBCL dx 204.3 (181.08) 187.4 (159.82) 198.5 (173.84) 19     Mean (SD), cells/mm 3
  20. 20. FINDINGS OF TUMOR MARKER EXPRESSION We found that Ki-67, PKC-beta 2, CD44, and survivin were expressed (i.e., 2+) in the majority of these HIV-related DLBCL cases. On the other hand, expression of HHV8, CD21, cyclin D2, SKP2, and BLMIP1 was uncommon. 31% of cases were positive for EBV; 4% positive for HHV8. We did not find universal CD20 expression in these cases, suggesting that CD20 might be lost in some HIV+ DLBCL. 20
  21. 21. CLUSTER EXAMINATION OF TUMOR MARKERS We examined the pair-wise Pearson’s correlation coefficient between the expressions of all markers. The correlation coefficient was generally low (i.e., <0.25). Notably, EBV and HHV8 infection status was associated with the expression of several markers. 21
  22. 22. MARKER EXPRESSION & HAZARD RATIO (HR)OF MARKER POSITIVITY ON 2-YEAR MORTALITYAdjusted HR adjusted for stage, presence of B symptom, Germinal Center phenotype, prior AIDSand CD4 cell count. 22
  23. 23. HIV+ DLBCL PROGNOSTIC TUMOR MARKERS In the crude analysis, cMYC, EBV and BLIMP1 positivity was associated with greater 2-yr overall mortality.Red : cMYC+, Blue: cMYC - Red : EBV+, Blue: EBV - 23
  24. 24. 2-YEAR OVERALL SURVIVAL BY CD4 AND MARKER LEVELS Red: high CD4/low marker; Blue: high CD4/high marker Green: low CD4/low marker; Black: low CD4/high marker 24
  25. 25. SUMMARY OF IMMUNODECIFENCY ANDPROGNOSTIC TUMOR MARKER ANALYSIS Cases with low CD4 and high levels of EBV or cMYC had worse survival. Risk stratification may consider both CD4 and tumor marker expression, although confirmation is needed in larger studies. 25
  26. 26. FUTURE STEPS Future analysis will incorporate Progression-free survival. Validation using bootstrapping. Examination of trend in treatment pattern for HIV+ DLBCL. Effects of antiretroviral medication discontinuation on lymphoma outcome. Tumor marker expression comparison by HIV infection status. 26
  27. 27. ACKNOWLEDGEMENTSHIV-related DLBCL study investigator team:Kaiser Permanente Southern California: Drs. Chun Chao (PI), Reina Haque, and Daniel H Zha.Kaiser Permanente Northern California: Drs. Michael Silverberg (site PI) and Laurel Habel.University of California, Los Angeles: Drs. Jonathan Said (Site PI) and Otoniel Martínez-Maza.University of California, San Francisco: Dr. Donald Abrams (Site PI).Funding: R01CA134234-01 from the NCI (Chao), K01AI071725 from the NIAID (Silverberg). 27
  28. 28. THANK YOU FOR YOUR ATTENTION Questions? 28

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