AIDSAssociated Malignancies Lee Ratner, 3628836, LRATNERIM'WUSTL'EDU

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AIDS-Associated MalignanciesLee Ratner,
362-8836, LRATNER_at_IM.WUSTL.EDU

• Cancers
• Kaposis Sarcoma
• Lymphomas Systemic and CNS NHL, HD
• Anogenital Carcinomas
• Other Malignancies
• Epidemiology, Biology, Clinical, Treatment,
  Protocols

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Viruses Associated with Human Cancer

• Viruses are major contributory factors for at
  least 20 of human cancers
• Most common cancers worldwide are caused by
  viruses
• Other micro-organisms associated with cancer
  (e.g. H pylori)

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How do we know if a virus is causally associated
with a specific type of cancer?
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What are the mechanisms of virus-induced cancer?
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Human viruses associated with cancer
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Cancer Incidence among AIDS Cases in HAART Era
compared to Pre-HAART Era

• UCSF, 8th Internatl Conf on Malignancies in AIDS,
  2004
• RR KS 0.6
• RR NHL 0.5
• RR anal cancer 4.0
• RR lung cancer 1.0
• RR Hodgkins disease 1.6

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Benefits of HAART for AIDS Malignancies

• Lower incidence of development of HIV-associated
  malignancies, esp primary CNS-lymphoma and
  Kaposis sarcoma
• Onset of malignancies at a higher level of CD4
• Improved tolerance of full dose chemotherapy,
  improved response rates and duration of responses
• Improved survival during treatment of their
  malignancy
• Metabolism and clearance of several
  chemotherapeutic agents is not affected by HAART,
  but caution recommended when high doses of
  chemotherapy are utilized, for example, during
  stem cell transplantation studies.
• Avoid nucleoside analog ZDV excessive
  neutropenia and anemia.
• Caution in the use of antiretrovirals associated
  with neurotoxicity (e.g. didanosine, stavudine,
  dideoxcytidine) together with chemotherapy
  regimens including vinca alkaloids, esp in
  individuals with pre-existing HIV-associated
  neuropathy

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Case 1
43 yo, Admitted in 4/04 with 1 wk history of
hemoptysis and dyspnea without pain, fever,
chills, sweats. HIV dxed in 5/03 when zoster
and pigmented skin lesions noted Exam also showed
diffuse adenopathy (up to 4 cm) HIV RNA 1290, CD4
356 Pleural fluid blood Node Bx showed
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Case 1
Node Bx showed Started on doxil, then
taxol, followed by valproic acid with no toxicity
and stable disease Treated with vinorelbine for
progressive disease and died from sepsis in 8/06
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Case 2

• 64 yo man
• 12/03 Fever, Wt loss, Forgetfulness, Decreased R
  visual acuity
• FH pos for brother with HIV NHL
• HIV RNA 1160, CD4 355
• Started on AZT/3TC/EFV, septra
• PE loss of R pupil reflex and visual acuity,
  hemorrhagic lesions in R retina, short and long
  term memory deficit
• Brain MRI Infarct, periventricular changes, Ring
  enhancing lesion in L hypothalamus, R nasopharynx
  mass (PET)

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Case 3

• 40 yo man
• 8/96 PCP 8/96 neurosyphilis, 9/96 perirectal
  herpes
• 9/96 enlarged R cervical nodes

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Case 4
32 yo HIV Nigerian male with headache
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Case 5
43 yo man Complications of HIV includes PCP
(3/95, 4/95), thrush (10/95), zoster (10/97,
4/03), anal HSV lesion (1/01) PMH Bactrim rash,
PPD (8/00, treated 6 mos with INH) 2/02 8 cm R
ing node and anal mass
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KS Epidemiology

• 20-30 of AIDS patients prior to HAART
• KS in HIV neg Africa, transplant, Mediterranean
• Incidence 50,000-fold higher than HIV neg men in
  N America
• Almost exclusively in homosexual men Why?

KS Biology

• Diploid, Oligo- or polyclonal Significance?
• Derived from lymphatic endothelium VEGFR3,
  podoplanin, PDGFR
• KS cell lines
• Upregulation of VEGF, Akt Significance?
• How would you determine the mechanism?

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HHV-8

• HHV-8 identified by RDA in KS
• HHV-8 also found in PEL
• Seropositivity higher in KS risk groups
• Seropositivity precedes KS
• Homologs of cellular proteins

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HHV8 Proteins that Interact with Rb-p53 Pathway
Pathways Inhibited by Specific KSHV Immune
Evasion Proteins
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 Effects of the signal modulatory proteins EBV
LMP2A and KSHV K15  
Transforming proteins of 1st ORF of EBV and KSHV  
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KS Treatment

• Prevention
• Good Risk KS
• A) HAART alone
• B) Local Therapy XRT, cryo, laser, intralesion
  chemo
• C) Systemic IFN, retinoids, thalidomide
• D) Investigational
• AMC038 A pilot trial of valproic acid closed
• AMC042 A pilot trial of imatinib - closed
• AMC 051 A Phase I/II Trial of Rapamycin in
  Patients with HIV-related Kaposis Sarcoma
• AMC 059 A Phase I/II Trial of PTC299 in
  Patients with HIV-related Kaposis Sarcoma
• AMC 049 Phase II Study Of Sunitinib (SU11248) In
  Patients With Kaposis Sarcoma In East Africa
• AMC 063 Single-arm, dose-finding pilot trial of
  single-agent bortezomib in patients with
  relapsed/refractory AIDS-associated Kaposi
  sarcoma with correlative assessments of KSHV and
  HIV
• Phase I/II Study of Lenalidomide in Patients with
  AIDS-associated Kaposi's sarcoma
• Poor Risk KS (CD4lt150, edema, B sx, pulmonary/gi
  disease, progressive disease)
• A) Doxil, Taxol, Etoposide, or Vinorelbine

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Epidemiology of HIV-NHL

• Incidence 200-fold higher than HIV-neg
• 10 of AIDS patients
• Incidence decreased with HAART

Biology of HIV-NHL

• B cell
• Large cell (DLBCL) or small non-cleaved (BL)
• Primary effusive lymphoma associated with HHV8
• EBV in 30 of DLBCL BL
• C-myc rearranged and p53 mutated in BL
• Other viral associations Virus Discovery
  Project What methods would you use?

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Burkitts Lymphoma
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Primary Effusion Lymphoma

• 4 of HIV NHL
• Pleural, peritoneal, or pericardial effusions
• Plasmacytoid features
• CD20-, CD22-, CD25-, CD45-, CD38/syndecan-1
• HHV8 and usually EBV

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Hodgkins Disease
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Brain CT Scans
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PCNSL in HIV-neg and pos Patients
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Activities of Selected EpsteinBarr Virus (EBV)
Proteins That Are Important for Latent Viral
Infection or Evasion of Host Immune Responses
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Bortezomib-induced enzyme targeted radiotherapy
in herpesvirus-associated tumors
Ambinder and colleagues, Nat Med, 2008
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HAART Chemo for HIV-NHL

• 40 patients with mCHOP (CYC, DOX, VCR, PRED) and
  25 pts with CHOP/
• G-CSF plus HAART (3TC, D4T, Indinavir)
• CR 30 and 48, respectively
• Similar toxicity (25 and 13 grade 3 neutropenia,
  respectively)
• Adverse prognosis
• Small-cell histology, mCHOP vs full-dose
• Not significant (in this trial) CD4, prior OI,
  PS, age, BM involvement, stage, LDH, response to
  HAART, extranodal disease
• Virus load 29,000-gt lt400
• No change in CD4 PCP prophylaxis

From Ratner, Tan et al, JCO 192171, 2001
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Conclusions HAART Chemo for HIV NHL

• Pharmacokinetics
• Cyclophosphamide clearance 41, 46 mL/min/m2 vs
  control 70
• Doxorubicin clearance 594, 607 mL/min/m2 vs
  control 500
• Indinavir clearance 28, 25 µM/h vs control 32
• HAART ameliorates chemotherapy induced
  myelosuppression
• Avoid AZT, PI, ATZ?
• G-CSF safe and effective

From Ratner, Tan et al, JCO 192171, 2001
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HIV-Lymphoma Treatment

• Initial Systemic DLBCL
• A) CHOP/HAART/G-CSF -/ rituximab
• B) AMC 047 A Phase II Trial Of Doxil, Rituximab,
  Cyclophosphamide, Vincristine, and Prednisone
  (DR-COP) in patients with newly diagnosed
  AIDS-Associated B-Cell Non-Hodgkins Lymphoma
• Intial Systemic Burkitt Lymphoma
• A) R-HyperCVAD, Cortes et al. Cancer 2001
• B) AMC 048 Prospective Phase II Study of a High
  Dose, Short Course Regimen (R-CODOX-M/IVAC)
  including CNS Penetration and Intensive IT
  Prophylaxis in HIV-Associated Burkitts And
  Burkitts-Like Lymphoma
• Relapsed Systemic NHL
• A) Other Chemo ESHAP, ICE, DHAP, Topo/Dox
• B) Autologous peripheral blood stem cell
  transplantation for patients with relapsed
  AIDS-related lymphoma
• C) AMC 053 Safety And Efficacy Trial Of The
  Anti-Viral And Anti-Tumor Activity Of Velcade
  Combined With (R) ICE In Subjects With
  Relapsed/Refractory AIDS-Associated Non-Hodgkin's
  Lymphoma
• CNS NHL
• A) XRT/HAART
• B) HD MTX/VCR/PROC, XRT, ARA C with HAART
• Hodgkins Disease
• A) ABVD/HAART/G-CSF

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HPV
E1
Rb
Non-kertainizing, Keratinizing, Basaloid large
cell
E7
E2
E5b
L1
p53
E6
E4
E5a
0 1000 2000 3000 4000 5000
6000 7000 7912
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Woodman et al. Nature Reviews Cancer 7, 1122
(January 2007) doi10.1038/nrc2050
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HIV neg vs pos Anal Cancer, JCO 08

• 81 vs 40 pts
• 62 vs 48 yo
• 96 vs 92 CR
• Grade 3/4 skin toxicity 17 vs 35
• Grade 3/4 hematologic toxicity 12 vs 33

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Treatment of HIV-associated Anal Carcinoma
Dysplasia

• Prevention L1 vaccines
• AMC 051A Single-Arm, Open-Label Trial Of The
  Safety And Immunogenicity Of A Quadrivalent Human
  Papillomavirus Vaccine In HIV-1-Infected Men
• Dysplasia Experimental - E6 or E7 vaccines
• AMC 046 A Phase II Trial of Cidofovir in
  HIV-Infected Patients with High-Grade Perianal
  Dysplasia
• Carcinoma - FU/XRT - ? Omit MMC, ? Substitute
  CDDP
• AMC 045 Phase II Trial of Combined Modality
  Therapy plus Cetuximab in HIV-Associated Anal
  Carcinoma

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Other HIV-Associated Malignancies

• Lung and testicular cancers
• Hepatocellular carcinoma
• Plasma cell disorders

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Conclusions

• Increased frequency of cancers in AIDS, esp KS,
  NHL, Anal Carcinoma
• Altered pathogenic and clinical features of
  cancers associated with AIDS compared to
  non-immunosuppressed individuals
• High frequency of virus-associated cancers
• Treatment based on viral and immune status
• Improvements in antiretroviral therapy result in
  HIV cancers and treatments that more closely
  resemble those in uninfected individuals