23. HIV and Malignancy

Factors associated with better outcome in NHL

(after adjusting for age, gender, aa-IPI, baseline CD4, histology type, chemotherapy type, and use of cART): Infusional chemotherapy was superior: EPOCH: improved CR rate, EFS, and OS CDE: improved OS Concurrent cART: higher CR rate and trend towards better OS

AIDS-associated Primary CNS Lymphoma

100% EBV+ Prognosis -Dismal, pre-HAART era (2 months) -Improving now (can be cured) Treatment -Methotrexate-based chemotherapy- reconstitution with cART administered during HD-MTX correlates with long-term survival among patients with CD4 <100 -Radiation therapy ___ Before antiretrovirals was very bad Now methotrexate can be curative

Plasmablastic Lymphoma (PBL)

80% are EBV+ in HIV (vs. 50% in non-HIV) 50% have MYC translocations or amplification B-cell: usually CD20 negative Largest retrospective study: N= 369 [Castillo et al. Blood. 2015 Apr 9;125(15):2323-30] -48% involve oral cavity/jaw, 12% gastrointestinal tract, and 6% skin -PBL was the initial HIV presentation in 7% of the patients ->65% had advanced disease (ie. stage III or IV) 112 HIV-positive patients: median OS 15 months, 3-year OS 25% Preferred treatment: probably EPOCH! ___ Rare Not recognized before HIV era Oral mass, rapidly growing- can obstruct airway and die without medical care Don't do as well as diffuse B cell lymphomas, still need to make headway on this one

Role of Rituximab (anti-CD20 antibody) in HIV NHL

AMC 010: Phase III CHOP vs. rituximab (R)-CHOP for HIV-DLBCL -Infection-related deaths: 14 in 95 patients who received rituximab (15%) vs. 1 in 47 treated with CHOP alone (2%) (p=0.02). -Most deaths were due to bacterial infections and when CD4+ lymphocyte count <50. -Similar trend seen in Phase II R-EPOCH and R-CDE clinical trials Barta et al. 2013: Rituximab improved outcomes when CD4 count ≥ 50 cells/mL ___ More death in rituximab arm (mostly CD4 <50) mostly due to infection Pts with ritux and chemo do better than no retux except if CD4 <50

HIV-associated NHL Trials by the AIDS Malignancy Consortium (AMC)

AMC-075: Randomized Phase I/II rituximab-EPOCH +/- vorinostat (HDAC inhibitor) front line for HIV-associated DLBCL/NHL (recently completed) AMC-053: Phase I/II rituximab-ICE (iafosfamide, carboplatin, etoposide) + bortezomib (proteasome inhibitor) for relapsed HIV-associated EBV+ DLBCL/NHL AMC-101: Phase I/II rituximab-EPOCH + ibrutinib (Bruton's kinase inhibitor) front line for for HIV-associated DLBCL/NHL ____ Trying to improve HIV lymphoma outcomes EPOCH 053: salvage therapy - added bortexomib AMC 101- Bruton kinase inhibitor

HTLV-1 Associated Conditions

ATLL: lymphocytosis (leukemia) and cutaneous lesions (shown on right) Autoimmune/Inflammatory conditions (arthritis, dermatitis, uveitis, and HAM/TSP Opportunistic infections (PCP, strongyloides, cysticercosis, scabies) ____ Doesn't kill T cell, but persistent and lives in them and makes them live longer but they don't function properly - immunosuppressed (see many HIV related infections)

Treatment for ATL

AZT: Zidovudine Interderon alpha

Human T Lymphotropic Virus Type I (HTLV-1)

Adult T-Cell leukemia-lymphoma ___ only known retrovirus to cause cancer in humans

Clinical Features of ATLL and Subtypes: (Shimoyama Criteria)

Aggressive subtypes: -Usually high LDH -Frequent adenopathy, multi-organ involvement, hepatosplenomegaly, bone lytic lesions, ↑ Ca2+ --Acute (leukemia phase) --Lymphomatous: < 1% leukemic cells, adenopathy "Indolent" subtypes: usually progress to aggressive -Chronic: non-progressing leukemia initially --Unfavorable chronic: elevated LDH < 2x normal ---Behaves aggressive! -Smoldering: Skin involvement, often lung, <5% leukemic cells in peripheral blood

Why Increased Cancer Risk in HIV/AIDS ?

Antigen-driven stimulation, somatic hyper mutations (B-cell lymphomas) Decreased immune surveillance: due "reduced body's ability to destroy cancer cells and fight infections that may lead to cancer" (Angeletti et al. Pharmacology 2008) Opportunistic oncogenic viruses !!! -Epstein Barr Virus (EBV) -Human Herpes Virus Type 8 (HHV-8, KSHV) -Human papilloma virus (HPV) ___ B cell lymphomas -higher accumulation of mutations as B cells rearrange genes Immune system plays huge role in controlling cancer (checkpoints etc) Viruses take advantage -diseases associated with it

Epstein Barr Virus (EBV) - AIDS Cancer

B and T-Cell Lymphomas Nasopharyngeal CA Gastric cancers ___ more common (95% population infected with EBV)

Concurrent Chemotherapy and cART

Barta et al. 2013: Higher CR rate and trend towards better outcome with concurrent cART Drug interactions: Pay attention!!! -Avoid zidovudine (AZT) due to meylo-suppressive effects -CYP3A4 inhibitors: avoid ritonavir-boosted regimens (due to increased chemo drug levels) Always consult pharmacists and Infectious Disease specialist !!! ____ Antiretroviral + chemo: -was not good idea due to drug interactions -now pts tolerate regiments better, and more aware of interacitons -better survival when together

HTLV-1 associated Adult T-cell Leukemia-lymphoma (ATL)

Caused by human T-cell Lymphotrophic virus, type 1 (HTLV-1) (Poiesz et al. 1980, Hinuma et al. 1981) Develops in ~3-5% of HTLV-1 infected individuals, around 5th-6th decades "T helper" phenotype: CD4+ CD25+/-FOXP3+/-CD30+/-MUM-1/IRF+/- _____ Not necessarily associated with HIV, some pts are co-infected Only retrovirus that can cause cancer Vertical transmission Incurable- they die

Human Papilloma Virus (HPV) - AIDS Cancer

Cervical CA Anal carcinoma Genital Cancers Oropharyngeal

Hodgkin Lymphoma

Clinical presentation: often "B" symptoms (fevers, night sweats, weight loss), enlarged lymph nodes, +/- organ involvement Age peaks (two): 15-35 years, and >55 years Histologic subtypes: nodular sclerosis (most common in general population), mixed cellularity (most common in HIV), lymphocyte depleted, lymphocyte rich, nodular lymphocyte predominant (most benign type) Hodgkin "Reed Sternberg" cell: surrounded by fibrous tissue or inflammatory non-malignant cells -Expresses CD30+ ________ Associated with EBV 2 age peaks CD30+

Therapies for AIDS-PEL

Conventional Chemotherapy -CHOP or CHOP-like: an option -EPOCH: preferred Investigational -Proteasome inhibitors: AMC-053 (bortezomib-ICE) -Histone deacetylase (HDAC) inhibitors: AMC-075 (vorinostat-EPOCH) (Chair: Ramos) -Immunomodulatory drugs (IMiDs): Lenalidomide -High-dose zidovudine (AZT) combined with Interferon-a, or with high-dose methotrexate (University of Miami) -Anti-CD30 directed Ab: Brentuximab vedotin -mTOR inhibitors: Rapamycin -Mouse xenograft models: NF-kB inhibitors, BRD4 inhibitors, nutlin-3, AsO3 ______ Didn't go into detail -biologicals being investigated

Lymphotropic g-Herpesviruses

Epstein Barr Virus (EBV) Kaposi's Sarcoma Associated Virus (KSHV, HHV-8) Both encode latent and lytic proteins that contribute to oncogenesis in lymphoid and epithelial tumors ___ Lytic phase - kill cell -latency - in (episomal) extrachromosomal structures

Burkitt Lymphoma (BL)

Epstein Barr virus (EBV) Association: -Endemic African variant (~ 90-95%) --Brazilian state of Bahia (80-90%) -Sporadic and AIDS-related (~30%) Translocation involving c-myc -t(8;14) and t(2;8)

Incidence and Trends in Non-AIDS Defining Cancers

Even though not aids defining, more in AIDs population -may have to do with immune response -anal cancer has been increasing over time -also liver, prostate -breast and lung stable & HL

Viral Etiology of Lymphomas

Extra nodal NK-T cell lymphoma, nasal type -see in asia -100% time with EBV

HPV in HIV patients

HIV+ men and women are at an increased risk for: -HPV infection -Anogenital intraepithelial neoplasia (AIN) -Invasive cancer anal and cervical cancer HIV + women have a 10-fold incidence of cervical cancer

Hepatitis C - AIDS Cancer

Hepatocellular carcinoma

HPV Oncogenic Proteins

Immortalize cells, promote growth and proliferation HPV E6: Targets p53 for ubiquitin-mediated degradation thereby abrogating cell cycle control and apoptosis HPV E7: Interact with retinoblastoma protein (pRb), p107, and p130 which are negative cell-cycle regulators involved in the G1/S and G2/M transition ___ Virus makes proteins that knock out tumor suppressors E7 E6 53 and RB

Primary effusion lymphoma (PEL)

Immunocompromised patients: AIDS, post transplant, or elderly Body cavity or serous effusions -A solid variant may occur at nodal or extranodal sites 100% HHV-8 (KSHV)+ -EBV co-infection in 80% cases Prognosis: Median survival of AIDS-related PEL was 6 months after treatment with CHVp-MTX with cART. CR was seen in 25% of patients PEL Histology: anaplastic morphology to large immunoblastic or plasmablastic cells Immunophenotype: lack pan-B-cell markers, surface and cytoplasmic immunoglobulin. Usually express activation and plasma cell markers (CD30, CD38, and CD138) ___ Rare disease we sometimes see in Miami Associated with kaposi Tumors growing in fluid in cavities Huge ascites- all fluid, cells floating around 6mo survival EPOCH

Anal cancer rates in North American AIDS Cohort Collaboration

Incidence/100,000 (85% CI) HIV-infected MSM- 131 (109-157) MSW- 46 (25-77) Women-30 (17-50) ____ Anal cancer is problem in HIV population especially MSM pts

HIV+ Diffuse Large B-cell Lymphoma (HIV-DLBCL)

Incidence: The most common NHL type in HIV/AIDS Clinical presentation: more aggressive (advanced stage, high proliferation rates/Ki-67) as compared to non-HIV cases -Germinal center B-cell (GCB) type -Activated B-cell (ABC) or non-germinal B-cell (non-GCB) type EBV association: 30% of cases (higher in ABC type) Poor Prognostic features: -CD4 < 100 cell/mm3 -International prognostic index (IPI) score: --> 2 factors: stage III or IV, elevated LDH, ≥ 2 extranodal sites, ECOG performance status ≥ 2, age ≥ 60 years --Age-adjusted IPI >1 (stage, LDH, ECOG performance) -Central nervous system (CNS) involvement -ABC subtype _____ Worse prognostic feature presentation in HIV pts 2 subtypes GCB- cells become malignant when at germinal center ABC- cells express markers that are only expressed once pass germinal center 30% EBV+ Poorer outcomes: CD4<100 - despite infection or not still do poorer IPI index score helps determine risk -stage, LDH leve, extranodal, performance, age Brain= bad ABC is worse than GCB

Incidence and Trends in AIDS-associated Non-Hodgkin Lymphoma (NHL) and Kaposi's Sarcoma (KS)

KS and NHL decreased & cervical cancer (HPV)

Human Herpesvirus Type 8 (HHV-8, KSHV) - AIDS Cancer

Kaposi's Sarcoma Multicentric Castleman's Disease Primary effusion lymphoma

Oncogenic Latent EBV genes/proteins

Latent membrane protein (LMP) -LMP1: induce lymphomas in transgenic mice, mimics CD-40 and upregulates NF-kB and its targets (ie. Bcl-2) -LMP2 is essential for the survival of germinal center B cells lacking functional B-cell receptor EBV nuclear antigen-2 (EBNA-2): Transforms cells EBV-Encoded RNAs (EBERs): non-coding RNAs target innate immune signaling by blocking RNA-dependent protein kinase (PKR), which stops protein translation after viral infection ______ EBV has not captured human homologues Has oncogenic activity LMP1 mimics B cell receptor and sends signal for growth upregulating NFKP and anti apop like BCL2 LMP2 - in HL (aberrant cells that were destined to die) drop B cell receptor (destined to die) -but virus comes in and puts LMP2 that mimics B cell receptor EBNA- transforms cells; cells can become malignant EBERs- bind to molecules and target innate signaling (innate immunity)

HIV and Malignancy: Conclusions

Malignancies are more frequent behave more aggressively in HIV patients, and are often difficult to manage DLBCL, Burkitt, and Hodgkin lymphoma in HIV-AIDS can be cured upfront using standard chemotherapy. Other aggressive lymphomas (i.e. PCNSL, PBL, and HHV-8 related PEL) have poorer outcomes, but prognosis is improving in cART era Treatment should focus on preventive strategies (HIV, HPV), optimizing chemotherapy, and on development of novel therapies targeting the biology of these tumors (i.e. viruses, molecules)

Cervical CA, Anal CA, and Genital Warts Prevention

Quadrivalent HPV vaccine -Approved by the FDA for use in males females 9 to 26 years old Yearly PAP smear in all HIV + women _____ Preventable No sexual contact, no transmission Vaccine Pap smears

HIV+ Burkitt Lymphoma (HIV-BL)

Second most common NHL type in HIV patients ~1/3 of NHL cases Presents with higher CD4 (median ~ 200 cell/mm3 ) GCB type tumor CD10+, with high Ki-67 (>95%) EBV association: ~ 30-40 % of cases Treatment: Improved outcome recently !!! -AMC-048: Modified CODOX-M/IVAC (McGrath regimen): --1-year PFS was 69% -ABCVP/LNHIV91 or intensive regimens showed improved PFS in favor to dose-intense regimens (CDE, EPOCH), but no significant difference in CR rate (Barta et al. 2013) _______ C MYC Higher CD4 counts compared to other tumors More recently with antiretrovirals and intensive regiments better outcomes - highly curable now

HHV-8 (KSHV)

Seroprevalence: 0-20% in the general population (higher in central Africa and homosexual men) Viral-encoded genes/oncogenes: -Homologues of cellular genes: vIL-6, vBcl-2, vFLIP, vCyclin, and vGPCR -K-1 activates survival factors (ie. NF-kB and its targets) -LANA: inhibits p53 and Rb proteins -vIRF1 and vIRF-3: inhibits interferon signaling ______ Has captured some human genes (homologues) -pro on/ pro inflam vBcl-2- ant apop FLI P also anti apop- blocks death receptor signal Cyclins drive the cell cycle GPCR is angiogenic (promotion of vessel growth) K-1- activates NFKB- prevents cell death LANA- inhibits tumor suppressors IRF- inhibits interferon signaling (part of innate immunity)

Treatment of KS

Stage T0 (Limited KS): Skin and/or lymph nodes and/or minimal oral disease -Reversal of immunosuppression -Local treatment: intralesional chemotherapy, cryotherapy, radiation, and retinoids Stage T1 (Advanced, Systemic KS): Tumor-associated edema or ulceration, extensive oral disease and/or viscera -Chemotherapy: Liposomal doxorubicin, placlitaxel, vinca alkaloids, etoposide -Biological agents: Interferon, emerging anti-angiogenic agents and immunomodulatory drugs ______ Only 2 stages for KS -T0: skin areas etc. not organs or airways, no pain/swelling --deletions can go away with antiretrovirals -T1: higher tumor load, enlarged legs, often subcutaneous, can be ulcerated, organ involvement (lung, GI- mouth, stomach, colon) --use chemo - doesn't work well, solid tumor --some biological agents can be effective

HIV-Associated Hodgkin Lymphoma Treatment

Standard ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) + cART -2-year PFS almost 90% Current trial: AMC-085 -AVD (no bleomycin) + brentuximab (anti-CD30 drug conjugate antibody) ____ Curable disease ABVD Brentuximab targets CD30

Treatment of HIV+ DLBCL

Standard First Line Chemotherapy: Bolus regimen: Rituximab (anti-CD20 antibody)+ CHOP -Complete response (CR) rates ~58-77% -2- or 3-year progression free survival (PFS) 56-69% -May use for localized (low stage) and low risk NHL Infusional regimens: -EPOCH or CDE + rituximab --CR rates 70-91% --2- or 5-year PFS 68-70% --Probably superior for advanced stage, high IPI score, and more aggressive subtype Abbreviations: E= etoposide, P= prednisone, O= oncovin (vincristine), C= cyclophosphamide, H or D=doxorubicin ____ CHOP+ Rituximab (CD20) EPOCH or CDE + rituximab are infusional - start on drip -controversial if better than CHOP-study shown not better than CHOP -but showing better? - now is standard regiment

Kaposi's Sarcoma (KS)

The Most common AIDS-defining malignancy Association with KSHV (HHV-8) (Chang and Moore 1994) Immune-compromised KS: -HIV/AIDS -Post transplant setting -Immunosuppressive drugs Classic KS: -Mediterranean and European Jewish populations -Endemic Central African variant

Human papillomavirus (HPV)

Transmission: -Intimate contact, sexual, and fomites Oncogenic types: -15-20 including: 16, 18, 31, 33, 35, 39, 45, 51, 52, 58 -HPV 16 (54%) and HPV 18 (13%) account for majority of worldwide cervical cancer Associated cancers: -Cervical and some types of anal, penile, vaginal, vulvar, and oropharyngeal

People with HIV/AIDS and Cancer in the U.S

Was a lot of kaposi sarcoma and NHL Now pts are intervened on earlier with medications- viral control, seeing these less -seeing more cancers of regular population

Geographic Distribution of HTLV-1 Infection

Was endemic in Japan & Africa From monkeys Then brought to America - see in afro-carribean islands (like haiti, Jamaica) Eastern Brazil

People Living with HIV/AIDS in the U.S

½ a million people in USA with HIV Aging population with HIV Starting to see more cancers in advanced age with HIV