Update on Malignancies in HIV

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Erin G. Reid, MD, of UC San Diego Moores Cancer Center, presents "Update on Malignancies in HIV"

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Update on Malignancies in HIV

  1. 1. The UC San Diego AntiViral Research Center sponsors weeklypresentations by infectious disease clinicians, physicians andresearchers. The goal of these presentations is to provide the mostcurrent research, clinical practices and trends in HIV, HBV, HCV, TBand other infectious diseases of global significance.The slides from the AIDS Clinical Rounds presentation that you areabout to view are intended for the educational purposes of ouraudience. They may not be used for other purposes without thepresenter’s express permission.AIDS CLINICAL ROUNDS
  2. 2. E R I N G O U R L E Y R E I D , M . D .A S S O C I A T E C L I N I C A L P R O F E S S O R , H E M A T O L O G YM O O R E S U C S D C A N C E R C E N T E RU C S D O W E N C L I N I CUpdate on AIDS-relatedMalignancies
  3. 3. Objectives Why is this important? What types of cancers are HIV patients gettingnow? Does early HAART prevent cancer? Options for Kaposi’s sarcoma? What is different about Hodgkin Lymphoma in theHIV patient population? New treatment options for lymphomas
  4. 4. Non-AIDS-related deaths on the riseInformation from Southern Albertaclinic 12/84 through 12/03560 deaths in HIV-infectedindividuals 124 in the HAART era 67% AIDS-related Of these 14% cancer related 7% Kaposi’s sarcoma 7% NHL 32% Non-AIDS Related 19% of these non-HIVmalignancies 20% of total deaths of HIVinfected patients werecancer relatedKrentz et al HIV Medicine 2005
  5. 5. Objectives Why is this important? What types of cancers are HIV patientsgetting now? Does early HAART prevent cancer? New treatment options for Kaposi’s sarcoma What is different about Hodgkin Lymphoma in theHIV patient population? Should we use rituximab in HIV-relatedlymphomas?
  6. 6. In the year 2000:International Collaboration on HIV and Cancer Cancer incidence data from 23 prospective studies 47,936 HIV-seropositive individuals North America, Europe, and Australia Calculated adjusted incidence rates (expressed as numberof cancers per 1000 person-years) for: Kaposis sarcoma non-Hodgkins lymphoma Hodgkins disease cervical cancer 20 other cancer types or sites Rate ratios were estimated comparing incidence rates from 1997 - 1999 with rates from 1992 -1996 Adjusted for study, age, sex, and HIV transmission group.Highly Active Antiretroviral Therapy and Incidence of Cancer in Human Immunodeficiency Virus-InfectedAdults. International Collaboration on HIV and Cancer. JNCI, Vol. 92, No. 22, 1823-1830, November 15, 2000
  7. 7. International Collaboration on HIV and Cancer:Conclusions AIDS-defining cancers contribute more than 90% ofmalignancies in HIV. NHL KS Heterogeneity between AIDS-defining cancers in therelative decline in incidenceover time Kaposis sarcoma shows the greatest decline (rate ratio = 0.32) Also decreased: Cerebral lymphoma (rate ratio = 0.42) Immunoblastic lymphoma (rate ratio = 0.57). Stable rates: Burkitts lymphoma (rate ratio = 1.18) cervical cancer (rate ratio = 1.87)Highly Active Antiretroviral Therapy and Incidence of Cancer in Human Immunodeficiency Virus-Infected Adults.International Collaboration on HIV and Cancer. JNCI, Vol. 92, No. 22, 1823-1830, November 15, 2000
  8. 8. Trends in cancer risk among people with AIDS in theUnited States 1980–2002 AIDS Cancer Match Study HIV/AIDS and cancer registries in six US states and fivemetropolitan areas were linked using a probabilisticmatching algorithm, utilizing registry data on name,social security number, sex, dates of birth and death, andrace the analysis focused on the subsequent 2-year ‘post-AIDS-onset period’ (from 4 to 27 months afterregistration)HIV/AIDS Cancer Match Study Engels et. al. AIDS 2006, 20:1645–1654
  9. 9. Cancer Risk in AIDS patientsHIV/AIDS registries 407,740 people with AIDSdiagnosed in 1977–2004 Excluded Those with AIDS diagnosed before 1980 (18) not complete overlap of two registries (26 635) children aged 0–14 years (5154) 375,933 adult and adolescent individuals forinclusion in the study.HIV/AIDS Cancer Match Study Engels et. al. AIDS 2006, 20:1645–1654
  10. 10. Cancer Risk in AIDS patients1996-2002HIV/AIDS Cancer Match Study Engels et. al. AIDS 2006, 20:1645–1654AIDS Defining Cancers No. cases (%) standardizedincidenceratio (SIR)Kaposi sarcoma 494 (30.0) 3640 (3330–3980)Non-Hodgkin lymphoma 560 (34.0) 22.6 (20.8–24.6)Diffuse large B-cell NHL 266 (16.2) 29.6 (26.1-33.3)CNS NHL 115 (7.0) 1020 (838-1220)Cervical cancer 30 (1.8) 5.3 (3.6-7.6)
  11. 11. Cancer Risk in AIDS patients1996-2002HIV/AIDS Cancer Match Study Engels et. al. AIDS 2006, 20:1645–1654Non- AIDS Defining Cancers No. cases(%)standardizedincidence ratio(SIR)Anal cancer 43 (2.6) 19.6 (14.2-26.4)Larynx 16 (1.0) 2.7 (1.6-4.4)Lung 111 (6.7) 2.6 (2.1-3.1)Liver 20 (1.2) 3.3 (2.0-5.1)Myeloid and monocyticleukemia11 (0.7) 2.2 (1.1-4.0)Hodgkin Lymphoma 72 (4.4) 13.6 (10.6-17.1)Total Non-AIDS defining ca 563 (34.2) 1.7 (1.6-1.9)
  12. 12. HIV/AIDS Cancer Match Study2004-2007 During 2004–2007, 15,884 cancers occurred among HIV-infected peoplein 34 US states 7869 (49.5%) were AIDS-defining cancers 7563 (47.6%) were non-AIDS-defining cancers. 2191 (29.0%) occurred in the non-AIDS HIV-only population. Lung cancer comprised 19.7% of the cancer burden (n = 454) Other common cancers in people with HIV-only: female breast cancer (n = 166 cancers) prostate cancer (n = 147 cancers) anal cancer (n = 154 cancers), Hodgkin lymphoma (n = 150 cancers)Shields 2011
  13. 13. AIDS-Defining Cancers by Age
  14. 14. AIDS NHL Cases & Incidence 1991-2005
  15. 15. AIDS KS Cases & Incidence 1991-2005
  16. 16. AIDS Cervical Cancer Cases & Incidence 1991-2005
  17. 17. Non-AIDSdefiningCancersA. Anal B. LungC. Liver D. HodgkinsE. Prostate F. Colorectal
  18. 18. The BIG 4 NADC In the US 1991–2005 50% of NADC were comprised of Lung cancer (3x) Anal cancer (29x) Liver cancer (5x) Hodgkin (11x) These accounted for only 16% of cancers in thegeneral population The cancer burden attributed to each of these fourmalignancies has increased over time.SEER*Stat Database
  19. 19. Objectives Why is this important? What types of cancers are HIV patients gettingnow? Does early HAART prevent cancers? New treatment options for Kaposi’s sarcoma What is different about Hodgkin Lymphoma inthe HIV patient population? New treatment options for lymphomas
  20. 20. Copyright © 209 Wolters Kluwer.Risk of cancers during interruptedantiretroviral therapy in the SMART study.Silverberg, Michael; Neuhaus, Jacqueline; Bower, Mark; Gey, Daniela;Hatzakis, Angelos; Henry, Keith; Hidalgo, Jose; Lourtau, Leonardo; Neaton,James; Tambussi, Giuseppe; Abrams, DonaldAIDS. 21(14):1957-1963, September 2007.
  21. 21. Copyright © 2009 Wolters Kluwer. 3SMART baseline characteristics
  22. 22. Copyright © 2009 Wolters Kluwer. 4SMART STUDYCancer endpoints for drug conservation and viral suppression arms
  23. 23. Objectives Why is this important? What types of cancers are HIV patients gettingnow? Does early HAART prevent cancers? New treatment options for Kaposi’ssarcoma What is different about Hodgkin Lymphoma inthe HIV patient population? New treatment options for lymphomas
  24. 24. Kaposi’s sarcoma
  25. 25. Kaposi’s sarcoma“look-alikes” Bacillary angiomatosis Bartonella species Pyogenic granuloma Extrapulmonary Pneumocystis carinii Occurs even in absence of lung infection Chronic venous stasis mimicking plaque KS
  26. 26. AIDS Kaposi’s Sarcoma25 U.S. 95%+ in homosexual/bisexual men Africa M:F=1:1 Pre-HAART 26% of HIV+ homosexual mendeveloped KS 3% HIV+ IV drug users develop KS HAART decreased KS >90% Sites: cutaneous, mucosa, lymph nodes, viscera Variable course: indolent to fulminent
  27. 27. Kaposi’s sarcomaPathogenesis Caused by HHV8 = KSHV Gamma herpes virus infects human B-cells andendothelial cells Predominately latent infectionstate in KS HIV’s role in AIDS KS Tat induces growth of KS spindlecells expression of adhesionmolecules, cytokines VEGF, IL-6
  28. 28. Evaluation Thorough exam Labs CD4, HIV viral load Chem/LFTs --> if abnl, consider imaging CXR If abnl --> CT chest Fecal occult blood If abnl --> endoscopy
  29. 29. KS StagingKaposi’s Sarcoma Criteria evolving: pre vs post HAART Pre-HAART Localized/disseminated, CD4 count, systemic illness Post-HAART Stebbing et al Lancet 367:1495 (2006) Score 0-15, starting at 10 Negative points: AIDS-defining KS, CD4 Positive points: age >50, 2nd AIDS-assoc illness Stebbing et al JCO 25:2230 (2007) CD8 count: 5% improvement/100 cells
  30. 30. KS StagingStebbing score and Probability of SurvivalKaposi’s SarcomaSCORE 6 months 1 year 2 years 5 years0 1.0 0.99 0.99 0.985 0.99 0.97 0.95 0.91810 0.93 0.83 0.74 0.6315 0.69 0.38 0.20 0.08
  31. 31. Prognosis: Stebbing score
  32. 32. Role of KSHV vGPCR vGPCR (lytic gene) 1st KSHV gene identified with transforming capacity in KS Homologue of CXC α-chemokine receptor Related to IL-8R HIV Tat induces expression of vGPCR Functions Endothelial cell transformation Auto- and paracrine Akt activation in infected endothelial cells Akt = kinase, activates mTOR via inactivation of TSC 1/2 (a break onmTOR signalling) Induces VEGF expression via MAPK/SAPK pathway Induces EphrinB2 through multiple pathways - establishing arterialvascular phenotype Required for KS cell viabilitySodhi et al. Cancer Cell. 2006 Aug;10(2):133-43.
  33. 33. Copyright ©2007 AlphaMed Press Wan, X. et al. Oncologist 2007;12:1007-1018vGPCR
  34. 34. Kaposi’s sarcoma treatment Limited HAART alone Local injection (Vinblastine) Radiation Visceral or advanced cutaneous: HAART+ Doxil (pegylated doxorubicin) Taxol Gemcitabine, navelbine ABV Treatment philosophy Not curable, manage as a chronic disease
  35. 35. Kaposi’s sarcomaHAART +/- pegylated liposomal doxorubicinConclusionRole of HAART in treatment of advanced KS:helpful but often not sufficientResponserates at 48weeksDoxil +HAARTHAARTaloneTotal PIntent totreat10 (76%) 3 (20%) 13 (46%) 0.003On-treatment10 (91%) 3 (2%) 0.0001
  36. 36. Kaposi’s sarcoma treatmentAddressing oncogenic mechanisms of KSHV LANA LANA inhibits tumor suppressors: p53 impaired apoptosis von Hippel-Lindau (VHL) increased HIF-1alpha levels which in turn activates genes involved inangiogenesis, cell proliferation and survival Mechanism of inhibition: proteasomal degradation via LANA’s ubiquitin E3 ligase activity (Cai 2006) Role for proteasome inhibition (bortezomib) in KS
  37. 37. Kaposi’s sarcoma treatment:Proteasome inhibition Bortezomib demonstrated more cytotoxicity againstPEL cell lines than against myeloma lines Demonstrated: inhibition of classical and alternative NF-kappaB pathways upregulation of p53, p21 and p27 and activation of the caspasecascade synergistic or additive cytotoxic effect in combination with otherchemotherapeutic drugs Matta 2005
  38. 38. Kaposi’s sarcoma treatment: Lytic activation of KSHV HDAC inhibitionAMC 038 Valproic acid: modest lyticreplication documented Bortezomib most potent inducer of lyticactivation in related gammaherpesvirus, EBV Inhibition of NFkappaB disrupts KSHVlatency and induces apoptosis in PEL
  39. 39. Oncolytic viral strategiesLytic activation of virusesresiding with cells causes: Direct cell destruction (celllysis) Promotes expression ofviral proteins that are moreimmunogenic
  40. 40. Kaposi’s sarcoma treatment:Summary of strategies addressing KSHV mTOR inhibition Pilot oral rapamycin trial underway (AMC 051) Unblocking tumor suppressors Inducing Lytic activation of KSHV HDAC inhibition AMC 038 valproic acid (Lechowicz ASH 2007) Modest lytic activation demonstrated Minor clinical responses Limitations: weak HDAC inhibitor, short exposure Proteasome inhibition AMC 053/063: Bortezomib trials in development within AMC for bothKSHV and EBV-related malignancies
  41. 41. Kaposi’s sarcomaOther future directions VEGF inhibition Thalidomide and lenolidomide Inhibit angiogenesis induced by bFGF Tyrosine kinase inhibitors Gleevec (AMC 042) Immune modulation Thalidomide and lenolidomide Inhibit IL-1b, IL-6 and bFGF IL-6, bFGF drive angiogenesis Increase IL-2 Promotes NK cell cytotoxicity and antibody-dependent cell-mediated cytotoxicity (ADCC) Increase IL-12 defective IL-12 responses is felt to play a role in progressive immune deficiency in HIV AMC 063: Proteasome inhibition Blocking angiogenesis AMC 061: PTC299 AMC 070: lenalidomide Concept: EphB2 inhibition
  42. 42. Objectives Why is this important? What types of cancers are HIV patients gettingnow? Does early HAART prevent cancer? New treatment options for Kaposi’s sarcoma What is different about HodgkinLymphoma in the HIV patient population? New treatment options for lymphomas
  43. 43. Population-based HIV-associatedHodgkin’s diseasein the San Francisco Bay Area,1988-98Sally Glaser, Ph.D.Christina Clarke, Ph.D.Northern California Cancer CenterMargaret Gulley, M.D.University of North Carolina at Chapel HillFiona Craig, M.D.University of PittsburghRichard Ambinder, M.D., Ph.D.Johns Hopkins University School of Medicine
  44. 44. Overall survival of male patients with HIV-related Hodgkin lymphoma(118) and HIV-unrelated Hodgkin lymphoma (830) who werediagnosed during 1988–1998 in the Greater Bay AreaGlaser et. al. CANCER July 15, 2003 / Volume 98 / Number 2
  45. 45. Clinical Characteristics, MalesHIV-Associated Hodgkin’s Disease%HIV-positive HIV-negativeB-symptoms*† 79 43Extra-nodal*‡ 67 32Stage III-IV disease* 58 19Survival1-year 75 925-year 42 80*Significantly different from all others at p≤0.05†Missing for n=182‡Missing for n=47
  46. 46. Tumor Characteristics, MalesHIV-Associated Hodgkin’s Disease%Histologic subtype HIV-pos HIV-negNodular Sclerosis* 32 61Mixed Cellularity* 33 19Nod. Lymph. Predomin. - 3Lymph. Predomin. <1 5Lymph. Depletion* 8 2Unspecified* 27 11*Significantly different from all others at p≤0.05
  47. 47. EBV AssociationHIV-Associated Hodgkin’s Disease%HIV-pos HIV-negEBV-positive*† 90 33*Significantly different from all others at p≤0.05† Based on 519 patients
  48. 48. Overall survival of male patients with HIV-related Hodgkinlymphoma who were diagnosed during 1988–1995 (87 patients)and during 1996–1998 (n 31 patients) in the Greater Bay AreaGlaser et. al. CANCER July 15, 2003 / Volume 98 / Number 2
  49. 49. Incidence of HL and NHL byCD4 count at AIDS onset•Biggar et al BLOOD 1 December 2006 Vol 108 number 12
  50. 50. Studyname Outcome Statisticsfor eachstudy Eventrateand95%CIEvent Lower Upperrate limit limit Z-Value p-Value TotalSpina 2002 CR 0.814 0.694 0.894 4.407 0.000 48/59Calza 2002 CR 0.917 0.378 0.995 1.623 0.105 5/5Gastaldi 2002 CR 0.944 0.495 0.997 1.947 0.052 8/8Hartmann 2003 CR 0.962 0.597 0.998 2.232 0.026 12/12Vilchez 2003 CR 0.261 0.122 0.472 -2.193 0.028 6/23Hentrich 2006HAART CR 0.647 0.476 0.787 1.689 0.091 22/34Berenguer 2008HAART CR 0.855 0.762 0.916 5.696 0.000 71/83Spina 2008 CR 0.662 0.545 0.762 2.679 0.007 47/710.721 0.661 0.774 6.617 0.000-1.00 -0.50 0.00 0.50 1.00CompleteRemissionRatesMetaAnalysis(fixedeffects)CR rateMeta-analysis of Hodgkin lymphoma in HIV
  51. 51. Studyname Outcome Statisticsfor eachstudy Event rate and95%CIEvent Lower Upperrate limit limit Z-Value p-ValueSpina 2002 2year OS 0.695 0.567 0.799 2.911 0.004Calza 2002 2year OS 0.600 0.200 0.900 0.444 0.657Gastaldi 2002 2year OS 0.944 0.495 0.997 1.947 0.052Ribera 2002 2year OS 0.822 0.683 0.909 3.928 0.000Gerard 2003HAART 2year OS 0.638 0.493 0.762 1.871 0.061Hartmann 2003 2year OS 0.830 0.520 0.957 2.063 0.039Glaser 2003 2year OS 0.640 0.553 0.718 3.125 0.002Hentrich 2006HAART 2year OS 0.740 0.569 0.860 2.675 0.007Tanaka 2007 2year OS 0.710 0.530 0.841 2.259 0.024Spina 2008 2year OS 0.690 0.574 0.786 3.118 0.0020.690 0.644 0.732 7.626 0.000-1.00 -0.50 0.00 0.50 1.002year Overall SuvivialMetaAnalysis(fixedeffects)2 yr OSMeta-analysis of Hodgkin lymphoma in HIV
  52. 52. Brentuximab VedotinAMC 085BortezomibAMC 053 Upfront Brentuximab Vedotinsubstituted for bleomycinin ABVDAMC trials for Hodgkins Relapsed/Refractory Bortezomib + ICE
  53. 53. Objectives Why is this important? What types of cancers are HIV patients gettingnow? Does early HAART prevent cancer? New treatment options for Kaposi’s sarcoma What is different about Hodgkin Lymphoma inthe HIV patient population? New treatment options for lymphomas
  54. 54. AIDS LymphomaAIDSLymphomaNHLDLBCL Burkitt’s Plasmablastic PELHodgkin’slymphoma
  55. 55. AMC trials for non-Hodgkin lymphoma Relapsed/Refractory Velcade + ICE +/- rituximab (final cohort enrolling) Hematopoietic stem cell transplant Auto and allo protocols (enrolling) Burkitt’s or Burkitt’s-like Modified McGrath Regimen (in follow-up) REPOCH (starting enrollment) Upfront NHL Adding vorinostat (enrolling) RCHOP – early stage + favorable prognosis REPOCH – advanced stage or unfavorable prognosis
  56. 56. AMC S003: Retrospective Plasmablastic NHL 19/40 cases confirmed on central review 17/19 patients were HIV positive. 29% on HAART at the time of lymphoma diagnosis First line chemo/immuno therapy given for 17 pts(89%) 6 were Primary refractory 1 relapse
  57. 57. Plasmablastic lymphoma Outcome At last follow-up, 9 alive, 9 died and 1 lost to follow-up Median follow-up for survivors 49 wks (range, 24-165) weeks. Median Survival 7 years (95% CI, 0.9-9 years) 1 yr OS 62.7% (SE, 11.2).
  58. 58. Plasmablastic lymphoma OS
  59. 59.  Why is this important? People with HIV are living longer ->more cancer related deaths What types of cancers are HIV patients getting now? HIV related and Non-HIV related Does early HAART prevent cancer? AIDS-related lower with early HAART New treatment options for Kaposi’s sarcoma? no curative therapy MULTIPLE strategies under study What is different about Hodgkin Lymphoma in the HIVpatient? EBV positive, significantly poorer prognosis pre-HAART,different subtype profile, decreases with lower CD4 count HAART era seeing improved response rates and OS What is new for HIV-related lymphomas? Rituximab shows benefit for remission rates, infectionprophylaxis is important EPOCH is likely superior to CHOP for DLBCL Use in Burkitts under study Outcomes for plasmablastic may be better than previouslyreported Lytic activation of EBV/HHV8 under study
  60. 60. Human defense against retrovirusesAPOBEC3G cytidine deaminase gene family encode proteins that are structurally and functionallyrelated to the C to U RNA-editing cytidine deaminaseAPOBEC1. The protein encoded by this gene has been found to be aspecific inhibitor of human immunodeficiency virus-1 (HIV-1) infectivity.
  61. 61. Human defense against retrovirusinfections: ABOBEC3GAPOBEC3G hypermutates viralcDNA during reverse transcription,blocking viral replication in newlyinfected cellAPOBEC3G incorporated intovirion as it buds frominfected cellNo viralreplicationx
  62. 62. Vif protects HIV against APOBEC3GHIV replicates inand buds fromnewly infected cellDegradation of ubiquinatedAPOBEC3G by proteasomevif
  63. 63. Proposed anti-HIV activity of bortezomibxHIV replication blockedin newly infected cellBortezomib inhibits proteasomedegradation of ubiquitinatedAPOBEC3G allowing itsaccumulation and incorporation intobudding virionNo HIVreplicationvif

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