The document summarizes a presentation on AIDS-related malignancies. It discusses trends seen in cancers affecting HIV/AIDS patients, including declines in AIDS-defining cancers like Kaposi's sarcoma and non-Hodgkin's lymphoma since the introduction of HAART. It also examines increases seen in certain non-AIDS defining cancers. Treatment options for Kaposi's sarcoma are reviewed, including the role of HAART and experimental approaches targeting KSHV mechanisms.
Enhancing MRD Testing in Hematologic Malignancies: When Negativity is a Posit...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This expert CME-approved slide deck, presented by Noopur Raje, MD, Director of the Center for Multiple Myeloma at Massachusetts General Cancer Center, will explore the current and emerging roles of MRD testing in hematologic malignancies. She presents the ongoing questions and latest data regarding the clinical utility of MRD testing in prognosis and treatment.
STATEMENT OF NEED
Measurable residual disease (MRD) is defined as the persistence of cancer cells at levels below morphologic detection after treatment. For patients with hematologic malignancies, MRD testing is increasingly being used to predict disease progression, monitor disease status, and evaluate treatment options (Dekker et al, 2023). Questions about current and future roles of MRD testing abound, including validation of assays, such as next-generation sequencing, machine learning, and flow cytometry; standardization of collection methods and modalities; considerations for clinical trial design and statistical analyses; and improved understanding of the roles of MRD status and depth of response across hematologic malignancies (Dekker et al, 2023; Baines et al, 2023). It is critical for members of the multidisciplinary cancer care team to stay up-to-date on the latest data regarding the clinical utility of MRD testing in prognosis and treatment. In this CME-approved activity, Noopur Raje, MD, Director of the Center for Multiple Myeloma at Massachusetts General Cancer Center, will explore the current and emerging roles of MRD testing in hematologic malignancies.
TARGET AUDIENCE
Medical oncologists, hematologists, pathologists, and other health care professionals involved in the treatment of patients with hematologic malignancies.
LEARNING OBJECTIVES
Upon completion of this activity, participants should be able to:
Distinguish the advantages and limitations of current MRD detection methods
Evaluate consensus recommendations on indications for MRD testing in hematologic malignancies
Explain the current and potential roles of MRD status and depth of response as a biomarker in clinical trials
Describe mechanisms of drug resistance/loss of response to BCMA-directed therapies
Assess the clinical utility of MRD in prognosis and treatment of selected hematologic malignancies, including acute lymphoblastic leukemia, chronic lymphocytic leukemia, and multiple myeloma
SEPSIS IS MOST FATAL DISEASE WORLD WIDE. EARLY DETECTION OR PREDICTION OF SEPSIS IS A CHALLENGE
SEPSIS BIOMARKERS ARE OUR WEAPON TO EARLY DETECT SEPSIS. WE HAVE TO UNDERSTAND IT WELL
General information about DLBCL treatment and care for internists. Not meant for hematologist, though.
Sorry for lagging of explanation but what in the slide should be sufficient.
Wesley Campbell, MD, of U.S. Navy Medicine, presents "An AIDS-Defining Illness Presenting during Acute Retroviral Syndrome: A Case Discussion and Review of the Literature" for AIDS Clinical Rounds at UC San Diego
Enhancing MRD Testing in Hematologic Malignancies: When Negativity is a Posit...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This expert CME-approved slide deck, presented by Noopur Raje, MD, Director of the Center for Multiple Myeloma at Massachusetts General Cancer Center, will explore the current and emerging roles of MRD testing in hematologic malignancies. She presents the ongoing questions and latest data regarding the clinical utility of MRD testing in prognosis and treatment.
STATEMENT OF NEED
Measurable residual disease (MRD) is defined as the persistence of cancer cells at levels below morphologic detection after treatment. For patients with hematologic malignancies, MRD testing is increasingly being used to predict disease progression, monitor disease status, and evaluate treatment options (Dekker et al, 2023). Questions about current and future roles of MRD testing abound, including validation of assays, such as next-generation sequencing, machine learning, and flow cytometry; standardization of collection methods and modalities; considerations for clinical trial design and statistical analyses; and improved understanding of the roles of MRD status and depth of response across hematologic malignancies (Dekker et al, 2023; Baines et al, 2023). It is critical for members of the multidisciplinary cancer care team to stay up-to-date on the latest data regarding the clinical utility of MRD testing in prognosis and treatment. In this CME-approved activity, Noopur Raje, MD, Director of the Center for Multiple Myeloma at Massachusetts General Cancer Center, will explore the current and emerging roles of MRD testing in hematologic malignancies.
TARGET AUDIENCE
Medical oncologists, hematologists, pathologists, and other health care professionals involved in the treatment of patients with hematologic malignancies.
LEARNING OBJECTIVES
Upon completion of this activity, participants should be able to:
Distinguish the advantages and limitations of current MRD detection methods
Evaluate consensus recommendations on indications for MRD testing in hematologic malignancies
Explain the current and potential roles of MRD status and depth of response as a biomarker in clinical trials
Describe mechanisms of drug resistance/loss of response to BCMA-directed therapies
Assess the clinical utility of MRD in prognosis and treatment of selected hematologic malignancies, including acute lymphoblastic leukemia, chronic lymphocytic leukemia, and multiple myeloma
SEPSIS IS MOST FATAL DISEASE WORLD WIDE. EARLY DETECTION OR PREDICTION OF SEPSIS IS A CHALLENGE
SEPSIS BIOMARKERS ARE OUR WEAPON TO EARLY DETECT SEPSIS. WE HAVE TO UNDERSTAND IT WELL
General information about DLBCL treatment and care for internists. Not meant for hematologist, though.
Sorry for lagging of explanation but what in the slide should be sufficient.
Wesley Campbell, MD, of U.S. Navy Medicine, presents "An AIDS-Defining Illness Presenting during Acute Retroviral Syndrome: A Case Discussion and Review of the Literature" for AIDS Clinical Rounds at UC San Diego
Introduction to Targeted Therapies in OncologyMohamed Abdulla
Describes the molecular background which represents the core for developing targeted therapies against specific biological events in malignant cellular clones.
Cancer and other noncommunicable diseases (NCDs) arenowwidely recognized as a threat to global development.The latest United Nations high-level meeting on NCDs reaffirmed thisc observation and also highlighted the slow progress in meeting the 2011 Political Declarationon the Prevention and Control of Noncommunicable Diseases and the third Sustainable Development Goal. Lack of situational analyses, priority setting,and budgeting have been identified as major obstacles in achieving these goals. All of these have incommon that they require information on the local cancer epidemiology.
The Global Burden of Disease (GBD) study is uniquely poised to provide these crucial data.
Peter Hunt, MD, of UC San Diego School of Medicine, presents "Immune Activation in Treated HIV infection," at AIDS Clinical Rounds on September 12, 2014
Evolution and Revolution: Current Issues in HIV and HCV Co-infection
Chapter 1 – HIV-Hepatitis C Virus Co-infection: An evolving epidemic
Chapter 2 - Management of HIV infection in HIV/HCV co-infected patients
Chapter 3 - Management of HCV in co-infected patients
Chapter 4 - HCV Therapy: Direct acting antiviral agents in co-infected individuals
Chapter 5 - Drug interactions with directly acting antivirals for HCV: Overview & challenges in HIV/HCV Co-infection
Chapter 6 - Complicated cases
Chapter 7 - Future trials of Hepatitis C therapy in the HIV co-infected
Chapter 8 - HCV infection in marginalized populations
Chapter 9 - HIV/HCV Co-infection: Through the eyes of a co-infected hemophiliac
Cancer Biomarkers Research, HPV and Cancer, HPV VaccineJames Lyons-Weiler
An overview of advances in cancer biomarker research strategies, the pathogenesis of HPV virus and a focus on the HPV vaccine with an analysis of evidence of type replacement.
53.Vohra P, Nimonkar S, Belkhode V, Potdar S, Bhanot R, Izna, Tiwari RVC. CD4 cells count as a prognostic marker in HIV patients with comparative analysis of various studies in Asia Pacific region. J Family Med Prim Care. 2020 May;9(5):2431-2436. doi: 10.4103/jfmpc.jfmpc_137_20. eCollection 2020 May. PubMed PMID: 32754515; PubMed Central PMCID: PMC7380754.
Fast-track the end of AIDS in the EU - practical evidence-based interventions.
Presentation by: Jens Lundgren, CHIP
In a two-day meeting under the auspices of the Maltese Presidency of the Council of the European Union (30-31 January 2017), HIV experts from across the European Union discussed how to reverse this trend and how to prepare Europe to achieve the set target of ending AIDS by 2030.
Katherine Promer Flores, MD (she/her)
Staff Physician
Division of Infectious Diseases and Global Public Health
Department of Medicine
University of California San Diego
Daniel Lee, MD
Clinical Professor of Medicine
Division of Infectious Diseases & Global Public Health
Department of Medicine
University of California, San Diego
Leandro Mena, MD, MPH
Chair and Professor of Population Health Science
Department of Population Health Science
University of Mississippi Medical Center
Maile Young Karris, MD
Associate Professor
Co-Director San Diego Center for AIDS Research Clinical Investigations Core
Divisions of Infectious Diseases & Global Public Health and Geriatrics & Gerontology
Department of Medicine
University of California San Diego
Edward Cachay, MD, MAS
Professor of Medicine
Division of Infectious Diseases & Global Public Health
Department of Medicine
University of California, San Diego
Gabriel Wagner, MD
Associate Clinical Professor
Division of Infectious Diseases & Global Public Health
Department of Medicine
University of California, San Diego
Jocelyn Keehner, MD
Infectious Disease Fellow
Division of Infectious Diseases & Global Public Health
Department of Medicine
University of California, San Diego
Richard Garfein, PhD, MPH
Professor
Herbert Wertheim School of Public Health and Human Longevity Science
Adjunct Professor
Division of Infectious Disease and Global Public Health
Department of Medicine
University of California, San Diego
Laura Bamford, MD, MSCE
Associate Professor of Medicine
Medical Director, Owen Clinic
Division of Infectious Diseases and Global Public Health
Department of Medicine
University of California, San Diego
Davey Smith, MD, MAS
Professor of Medicine
Chief, Division of Infectious Diseases and Global Public Health
Co-Director, San Diego Center for AIDS Research (CFAR)
Department of Medicine
University of California, San Diego
Elliot Welford, MD
Infectious Diseases Fellow
Division of Infectious Diseases & Global Public Health
Department of Medicine
University of California, San Diego
Darcy Wooten, MD
Assistant Professor of Medicine
Associate Program Director, Infectious Diseases Fellowship
Division of Infectious Diseases & Global Public Health
Department of Medicine
University of California, San Diego
Amutha Rajagopal, MD
Associate Physician Diplomate
Division of Infectious Diseases & Global Public Health
Department of Medicine
University of California, San Diego
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New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...
Update on Malignancies in HIV
1. 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
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 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
3. 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
4. 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
5. 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?
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 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
7. 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 incidenceover 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
8. 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
9. 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
10. 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)
11. 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)
12. 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
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 the
general population
The cancer burden attributed to each of these four
malignancies has increased over time.
SEER*Stat Database
19. 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
23. 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
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. 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
27. 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
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. 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
30. 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
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 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.
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. 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
36. 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
37. 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
38. 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
39. 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
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 both
KSHV and EBV-related malignancies
41. 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
42. 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
43. 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
44. 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
45. 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
47. 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
48. 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
49. Incidence of HL and NHL by
CD4 count at AIDS onset
•Biggar et al BLOOD 1 December 2006 Vol 108 number 12
51. Studyname Outcome Statisticsfor eachstudy Event rate and95%CI
Event Lower Upper
rate limit limit Z-Value p-Value
Spina 2002 2year OS 0.695 0.567 0.799 2.911 0.004
Calza 2002 2year OS 0.600 0.200 0.900 0.444 0.657
Gastaldi 2002 2year OS 0.944 0.495 0.997 1.947 0.052
Ribera 2002 2year OS 0.822 0.683 0.909 3.928 0.000
Gerard 2003HAART 2year OS 0.638 0.493 0.762 1.871 0.061
Hartmann 2003 2year OS 0.830 0.520 0.957 2.063 0.039
Glaser 2003 2year OS 0.640 0.553 0.718 3.125 0.002
Hentrich 2006HAART 2year OS 0.740 0.569 0.860 2.675 0.007
Tanaka 2007 2year OS 0.710 0.530 0.841 2.259 0.024
Spina 2008 2year 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
2year Overall Suvivial
MetaAnalysis(fixedeffects)
2 yr OS
Meta-analysis of Hodgkin lymphoma in HIV
52. Brentuximab Vedotin
AMC 085
Bortezomib
AMC 053
Upfront
Brentuximab Vedotin
substituted for bleomycin
in ABVD
AMC trials for Hodgkins
Relapsed/Refractory
Bortezomib + ICE
53. 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
56. 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
57. 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
58. 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).
60. 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
61. 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.
62. 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
63. Vif protects HIV against APOBEC3G
HIV replicates in
and buds from
newly infected cell
Degradation of ubiquinated
APOBEC3G by proteasome
vif
64. 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