Update on Malignancies in HIV
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Transcript of Update on Malignancies in HIV
The UC San Diego AntiViral Research Center sponsors weekly presentations by infectious disease clinicians, physicians and researchers. The goal of these presentations is to provide the most current research, clinical practices and trends in HIV, HBV, HCV, TB and other infectious diseases of global significance. The slides from the AIDS Clinical Rounds presentation that you are about to view are intended for the educational purposes of our audience. They may not be used for other purposes without the presenter’s express permission.
AIDS CLINICAL ROUNDS
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 Y
M O O R E S U C S D C A N C E R C E N T E R U C S D O W E N C L I N I C
Update on AIDS-related Malignancies
Objectives
Why is this important? What types of cancers are HIV patients getting
now? Does early HAART prevent cancer? Options for Kaposi’s sarcoma? What is different about Hodgkin Lymphoma in the
HIV patient population? New treatment options for lymphomas
Non-AIDS-related deaths on the rise
Information from Southern Alberta clinic 12/84 through 12/03
560 deaths in HIV-infected individuals
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-HIV
malignancies
20% of total deaths of HIV infected patients were cancer related
Krentz et al HIV Medicine 2005
Objectives
Why is this important? What types of cancers are HIV patients
getting now? Does early HAART prevent cancer? New treatment options for Kaposi’s sarcoma What is different about Hodgkin Lymphoma in the
HIV patient population? Should we use rituximab in HIV-related
lymphomas?
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 number of cancers per 1000 person-years) for: Kaposi's sarcoma non-Hodgkin's lymphoma
Hodgkin's 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-Infected Adults. International Collaboration on HIV and Cancer. JNCI, Vol. 92, No. 22, 1823-1830, November 15, 2000
International Collaboration on HIV and Cancer: Conclusions
AIDS-defining cancers contribute more than 90% of malignancies in HIV. NHL KS
Heterogeneity between AIDS-defining cancers in the relative decline in incidence over time Kaposi's 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: Burkitt's 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
Trends in cancer risk among people with AIDS in the United States 1980–2002
AIDS Cancer Match Study HIV/AIDS and cancer registries in six US states and five
metropolitan areas were linked using a probabilistic matching algorithm, utilizing registry data on name, social security number, sex, dates of birth and death, and race
the analysis focused on the subsequent 2-year ‘post-AIDS-onset period’ (from 4 to 27 months after registration)
HIV/AIDS Cancer Match Study Engels et. al. AIDS 2006, 20:1645–1654
Cancer Risk in AIDS patients
HIV/AIDS registries 407,740 people with AIDS diagnosed 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 for
inclusion in the study. HIV/AIDS Cancer Match Study Engels et. al. AIDS 2006, 20:1645–1654
Cancer Risk in AIDS patients 1996-2002
HIV/AIDS Cancer Match Study Engels et. al. AIDS 2006, 20:1645–1654
AIDS Defining Cancers No. cases (%) standardized incidence ratio (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)
Cancer Risk in AIDS patients 1996-2002
HIV/AIDS Cancer Match Study Engels et. al. AIDS 2006, 20:1645–1654
Non- AIDS Defining Cancers No. cases (%)
standardized incidence 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 monocytic leukemia
11 (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)
HIV/AIDS Cancer Match Study 2004-2007
During 2004–2007, 15,884 cancers occurred among HIV-infected people
in 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
AIDS-Defining Cancers by Age
AIDS NHL Cases & Incidence 1991-2005
AIDS KS Cases & Incidence 1991-2005
AIDS Cervical Cancer Cases & Incidence 1991-2005
Non-AIDS defining Cancers A. Anal B. Lung
C. Liver D. Hodgkins
E. Prostate F. Colorectal
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 the general population
The cancer burden attributed to each of these four malignancies has increased over time. SEER*Stat Database
Objectives
Why is this important? What types of cancers are HIV patients getting
now? Does early HAART prevent cancers? New treatment options for Kaposi’s sarcoma What is different about Hodgkin Lymphoma in
the HIV patient population? New treatment options for lymphomas
Copyright © 209 Wolters Kluwer.
Risk of cancers during interrupted antiretroviral 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, Donald AIDS. 21(14):1957-1963, September 2007.
Copyright © 2009 Wolters Kluwer. 3
SMART baseline characteristics
Copyright © 2009 Wolters Kluwer. 4
SMART STUDY Cancer endpoints for drug conservation and viral suppression arms
Objectives
Why is this important? What types of cancers are HIV patients getting
now? Does early HAART prevent cancers? New treatment options for Kaposi’s
sarcoma What is different about Hodgkin Lymphoma in
the HIV patient population? New treatment options for lymphomas
Kaposi’s sarcoma
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
AIDS Kaposi’s Sarcoma 25
U.S. 95%+ in homosexual/bisexual men Africa M:F=1:1 Pre-HAART 26% of HIV+ homosexual men
developed KS 3% HIV+ IV drug users develop KS HAART decreased KS >90% Sites: cutaneous, mucosa, lymph nodes, viscera Variable course: indolent to fulminent
Kaposi’s sarcoma Pathogenesis
Caused by HHV8 = KSHV Gamma herpes virus infects human B-cells and
endothelial cells Predominately latent infection
state in KS
HIV’s role in AIDS KS Tat induces growth of KS spindle
cells expression of adhesion
molecules, cytokines VEGF, IL-6
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
KS Staging
Kaposi’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
KS Staging Stebbing score and Probability of Survival
Kaposi’s Sarcoma
SCORE 6 months 1 year 2 years 5 years
0 1.0 0.99 0.99 0.98
5 0.99 0.97 0.95 0.918
10 0.93 0.83 0.74 0.63
15 0.69 0.38 0.20 0.08
Prognosis: Stebbing score
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 on
mTOR signalling) Induces VEGF expression via MAPK/SAPK pathway Induces EphrinB2 through multiple pathways - establishing arterial
vascular phenotype Required for KS cell viability
Sodhi et al. Cancer Cell. 2006 Aug;10(2):133-43.
Copyright ©2007 AlphaMed Press Wan, X. et al. Oncologist 2007;12:1007-1018
vGPCR
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
Kaposi’s sarcoma HAART +/- pegylated liposomal doxorubicin
Conclusion Role of HAART in treatment of advanced KS:
helpful but often not sufficient
Response rates at 48 weeks
Doxil + HAART
HAART alone
Total P
Intent to treat
10 (76%) 3 (20%) 13 (46%) 0.003
On-treatment
10 (91%) 3 (2%) 0.0001
Kaposi’s sarcoma treatment Addressing 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 in
angiogenesis, 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
Kaposi’s sarcoma treatment: Proteasome inhibition
Bortezomib demonstrated more cytotoxicity against PEL 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 caspase
cascade synergistic or additive cytotoxic effect in combination with other
chemotherapeutic drugs Matta 2005
Kaposi’s sarcoma treatment: Lytic activation of KSHV
HDAC inhibition AMC 038 Valproic acid: modest lytic
replication documented
Bortezomib most potent inducer of lytic activation in related gammaherpesvirus, EBV
Inhibition of NFkappaB disrupts KSHV latency and induces apoptosis in PEL
Oncolytic viral strategies
Lytic activation of viruses residing with cells causes:
Direct cell destruction (cell lysis)
Promotes expression of viral proteins that are more immunogenic
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 both
KSHV and EBV-related malignancies
Kaposi’s sarcoma Other 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
Objectives
Why is this important? What types of cancers are HIV patients getting
now? Does early HAART prevent cancer? New treatment options for Kaposi’s sarcoma What is different about Hodgkin
Lymphoma in the HIV patient population? New treatment options for lymphomas
Population-based HIV-associated Hodgkin’s disease
in the San Francisco Bay Area, 1988-98
Sally Glaser, Ph.D.
Christina Clarke, Ph.D. Northern California Cancer Center
Margaret Gulley, M.D. University of North Carolina at Chapel Hill
Fiona Craig, M.D. University of Pittsburgh
Richard Ambinder, M.D., Ph.D. Johns Hopkins University School of Medicine
Overall survival of male patients with HIV-related Hodgkin lymphoma (118) and HIV-unrelated Hodgkin lymphoma (830) who were
diagnosed during 1988–1998 in the Greater Bay Area
Glaser et. al. CANCER July 15, 2003 / Volume 98 / Number 2
Clinical Characteristics, Males HIV-Associated Hodgkin’s Disease
%
HIV-positive HIV-negative
B-symptoms*† 79 43
Extra-nodal*‡ 67 32
Stage III-IV disease* 58 19
Survival 1-year 75 92 5-year 42 80
*Significantly different from all others at p≤0.05 †Missing for n=182 ‡Missing for n=47
Tumor Characteristics, Males HIV-Associated Hodgkin’s Disease
% Histologic subtype HIV-pos HIV-neg
Nodular Sclerosis* 32 61
Mixed Cellularity* 33 19
Nod. Lymph. Predomin. - 3
Lymph. Predomin. <1 5 Lymph. Depletion* 8 2
Unspecified* 27 11
*Significantly different from all others at p≤0.05
EBV Association HIV-Associated Hodgkin’s Disease
%
HIV-pos HIV-neg
EBV-positive*† 90 33
*Significantly different from all others at p≤0.05
† Based on 519 patients
Overall survival of male patients with HIV-related Hodgkin lymphoma who were diagnosed during 1988–1995 (87 patients) and during 1996–1998 (n 31 patients) in the Greater Bay Area
Glaser et. al. CANCER July 15, 2003 / Volume 98 / Number 2
Incidence of HL and NHL by CD4 count at AIDS onset
•Biggar et al BLOOD 1 December 2006 Vol 108 number 12
Study name Outcome Statistics for each study Event rate and 95% CI
Event Lower Upper rate limit limit Z-Value p-Value Total
Spina 2002 CR 0.814 0.694 0.894 4.407 0.000 48 / 59
Calza 2002 CR 0.917 0.378 0.995 1.623 0.105 5 / 5
Gastaldi 2002 CR 0.944 0.495 0.997 1.947 0.052 8 / 8
Hartmann 2003 CR 0.962 0.597 0.998 2.232 0.026 12 / 12
Vilchez 2003 CR 0.261 0.122 0.472 -2.193 0.028 6 / 23
Hentrich 2006 HAART CR 0.647 0.476 0.787 1.689 0.091 22 / 34
Berenguer 2008 HAART CR 0.855 0.762 0.916 5.696 0.000 71 / 83
Spina 2008 CR 0.662 0.545 0.762 2.679 0.007 47 / 71
0.721 0.661 0.774 6.617 0.000
-1.00 -0.50 0.00 0.50 1.00
Complete Remission Rates
Meta Analysis (fixed effects)
CR rate
Meta-analysis of Hodgkin lymphoma in HIV
Study name Outcome Statistics for each study Event rate and 95% CI
Event Lower Upper rate limit limit Z-Value p-Value
Spina 2002 2 year OS 0.695 0.567 0.799 2.911 0.004Calza 2002 2 year OS 0.600 0.200 0.900 0.444 0.657Gastaldi 2002 2 year OS 0.944 0.495 0.997 1.947 0.052Ribera 2002 2 year OS 0.822 0.683 0.909 3.928 0.000Gerard 2003 HAART 2 year OS 0.638 0.493 0.762 1.871 0.061Hartmann 2003 2 year OS 0.830 0.520 0.957 2.063 0.039Glaser 2003 2 year OS 0.640 0.553 0.718 3.125 0.002Hentrich 2006 HAART 2 year OS 0.740 0.569 0.860 2.675 0.007Tanaka 2007 2 year OS 0.710 0.530 0.841 2.259 0.024Spina 2008 2 year OS 0.690 0.574 0.786 3.118 0.002
0.690 0.644 0.732 7.626 0.000
-1.00 -0.50 0.00 0.50 1.00
2 year Overall Suvivial
Meta Analysis (fixed effects)
2 yr OS
Meta-analysis of Hodgkin lymphoma in HIV
Brentuximab Vedotin AMC 085
Bortezomib AMC 053
Upfront Brentuximab Vedotin
substituted for bleomycin in ABVD
AMC trials for Hodgkins
Relapsed/Refractory Bortezomib + ICE
Objectives
Why is this important? What types of cancers are HIV patients getting
now? Does early HAART prevent cancer? New treatment options for Kaposi’s sarcoma What is different about Hodgkin Lymphoma in
the HIV patient population? New treatment options for lymphomas
AIDS Lymphoma
AIDS Lymphoma
NHL
DLBCL Burkitt’s Plasmablastic PEL
Hodgkin’s lymphoma
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
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
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).
Plasmablastic lymphoma OS
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 HIV patient? 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, infection
prophylaxis is important EPOCH is likely superior to CHOP for DLBCL
Use in Burkitts under study Outcomes for plasmablastic may be better than previously
reported Lytic activation of EBV/HHV8 under study
Human defense against retroviruses
APOBEC3G cytidine deaminase gene family encode proteins that are structurally and functionally
related to the C to U RNA-editing cytidine deaminase APOBEC1.
The protein encoded by this gene has been found to be a specific inhibitor of human immunodeficiency virus-1 (HIV-1) infectivity.
Human defense against retrovirus infections: ABOBEC3G
APOBEC3G hypermutates viral cDNA during reverse transcription, blocking viral replication in newly
infected cell
APOBEC3G incorporated into virion as it buds from
infected cell
No viral replication
x
Vif protects HIV against APOBEC3G
HIV replicates in and buds from
newly infected cell
Degradation of ubiquinated APOBEC3G by proteasome
vif
Proposed anti-HIV activity of bortezomib
x
HIV replication blocked in newly infected cell
Bortezomib inhibits proteasome degradation of ubiquitinated
APOBEC3G allowing its accumulation and incorporation into
budding virion
No HIV replication
vif