Update on Malignancies in HIV

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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