Virus, Lymphoma, and Worms, Oh My Complications and Treatment of HTLV1

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Virus, Lymphoma, and Worms, Oh My!Complications
and Treatment of HTLV1

• Boone Goodgame, MD

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Case

• HPI 69 year-old Japanese American woman
  presented with weakness, vomiting, and abdominal
  pain.Had one month of progressive abdominal
  discomfort and distension and had lost 8 lbs.
• No fevers, chills, NS, dysphagia, cough,
  dysuria, SOB, or neuro symptoms.
• PMH no medical problems, no h/o blood
  transfusion.
• MEDICATIONS None
• FHX mother gastric cancer, father throat
  cancer.
• SOCIAL HX Moved from Okinawa to Illinois at age
  26. Last visit to Japan was 5 years ago. No
  alcohol or tobacco use.

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PHYSICAL EXAM

• GENERAL No acute distress.
• VITAL SIGNS 88/43, P 92, RR 16.
• HEENT dry mucous membranes
• NECK Supple. No adenopathy or thyromegaly.
• LYMPH No supraclavicular, infraclavicular,
  axillary, or inguinal adenopathy.
• CHEST lungs clear, no wheezing or rales.
• CARDIOVASCULAR RRR, no S3 or S4.
• ABDOMEN Mildly diffusely tender, distended,
  tympanic. No masses or hepatosplenomegaly.

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LABS

• WBC 48,000, NEUT 48, LYMPH 51
• HGB 12, MCV 94
• Na 130, K 3.2, Cr 0.5, Albumin 2.5

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ABDOMINAL CT

• The duodenum and proximal small bowel are
  diffusely dilated and filled with dense contrast
  material. There is diffuse thickening of the wall
  of the entire colon with mild pericolonic fat
  stranding. Findings consistent with proximal
  partial small bowel obstruction, possibly
  secondary to a pancolitis.

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• FLOW CYTOMETRY OF PERIPHERAL BLOOD
• Flow cytometry shows 52 T-cells. Cells
  express CD2, CD4, and CD5. No expression of
  CD25 seen
• The morphologic and immunophenotypic features
  are most consistent with adult T-cell
  leukemia/lymphoma. Lack of expression of CD25 is
  atypical.
• SEROLOGY HTLV 1 Antibody positive

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EGD

• Multiple non-bleeding erosions in the gastric
  antrum and duodenum. Diffuse inflammation of the
  duodenum and proximal jejunum.

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PATHOLOGY

• SMALL INTESTINE, DUODENUM, BIOPSYAcute and
  chronic duodenitis with abundant strongyloides
  stercoralis organisms
• STOMACH, BIOPSYAcute and chronic gastritis with
  abundant strongyloides stercoralis organisms
• STOOL OP abundant strongyloides stercoralis.

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Questions relevant to this case

• How does HTLV1 infection lead to
  immunosuppression and is there a predisposition
  for parasitic infections?
• How does HTLV1 lead to Adult T-Cell
  leukemia/lymphoma (ATLL) and does infection play
  a role in transformation?
• How is HTLV1 associated ATLL treated?

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Overview

• HTLV1 epidemiology and associated diseases.
• HTLV1 related immunosuppression and associated
  infections.
• Mechanisms of development of adult T-cell
  leukemia/lymphoma.
• Treatment of HTLV1 associated leukemia/lymphoma.

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Global Prevalence of HTLV1

• Brown 1 - 5. Tan less than 1,

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Global Epidemiology

• About 1520 millions persons live with
  HTLVinfection worldwide.
• Highes rates are in southwestern Japan (up to
  37), the Caribbean Jamaica and Trinidad (up to
  6), and several African countries Benin,
  Cameroon and Guinea-Bissau (up to 5)
• Lower prevalence rates are found in South America
  (Argentina, Brazil, Colombia and Peru).
• Transmission is parenteral breastfeeding, sexual
  intercourse, needles, and blood transfusions, and
  requires live, infected cells, not virions.

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HTLV1 associated diseases

• Malignant Adult T-cell leukemia/ lymphoma (ATLL)
• Myelopathy HTLV1 associated myelopathy (HAM/TSP)
• Other inflammatory disease uveitis,
  polymyositis, synovitis, thyroiditis,
  pneumonitis.
• Opportunistic infections

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Opportunistic Infections in HTLV1

• In the setting of acute ATLL PCP,
  aspergillosis, CMV, zoster, MAI, and
  strongyloides hyperinfection.
• In chronic HTLV1 infection without ATLL
  strongyloidiasis is the most commonly reported
  OI.
• Scabies, disseminated molluscum, extra-pulmonary
  histoplasmosis, and staph/strep dermatitis are
  also reported.

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Strongyloides Life Cycle

• Image courtesy of LAsinerie, Bocage France

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Strongyloides Life Cycle
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Strongyloides Life Cycle
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Strongyloides clinical features

• Endemic in most tropical and subtropical areas,
  as well as in the southern United States.
• Infection is usually asymptomatic, can have
  non-specific GI symptoms diarrhea, abdominal
  cramping.
• Chronic infestation occurs through
  auto-infection, when larvae invade the colonic
  mucosa, allowing them to mature to adults in the
  small intestine.

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Hyperinfection

• With immunosuppression, disseminated
  strongyloidiasis (or hyperinfection) can occur
  when the burden of auto-infection is accelerated.
• Hyperinfection begins with inflammatory diarrhea,
  duodenitis, and gastritis, and often paralytic
  ileus.
• Death can come from pan-colitis, respiratory
  failure, bacteremia, and meningitis.

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Risk factors for hyperinfection

• any immunosuppressing condition
• Corticosteroids
• hematologic malignancies
• HTLV1
• HIV
• diabetes, chronic renal failure, alcoholism.

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Immune suppression due to HTLV1

• HTLV1 is a retrovirus that infects T-cells.
• The viral protein, Tax regulates viral gene
  expression.
• Tax also increases T cell growth and
  proliferation by stimulating the expression of
  IL-2, IL-15, GM-CSF, and IL-2 receptor.
• HTLV1 infected T cells activate un-infected
  T-cells, potentiating the Th1 response,
  characterized by high production of IFN-g.
• Th1 cytokines down-regulate Th2 cells.
• The inhibited Th2 response (IL-4, IL-5, IgE)
  prevents parasite killing.

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HTLV1 and strongyloides stercoralis

• Parasite Immunology, 2004, 26, 487497

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HTLV1 and adult T-cell leukemia

• Occurs mostly in adults, at least 20-30 years
  after HTLV1 infection.
• Almost exclusively associated with virus
  acquisition through breast feeding.
• 6 of male 2 of female HTLV1 carriers develop
  ATL.
• Tends to present in the fifth decade of life
• Risk factors for ATL high anti-HTLV1 titer, low
  anti-Tax reactivity, vertical infection, and
  strongyloides infestation.

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Four sub-types of ATLL

• Smoldering 1-5 peripheral blood lymphocytes, or
  limited skin lesions.
• Chronic lymphocytosis, skin lesions,
  hepatosplenomegaly, liver or lymph node
  involvement.
• Lymphomatous non-Hodgkins lymphoma, often with
  blood, skin, bone involvement.
• Leukemic (Acute) lymphocytosis, hypercalcemia,
  lytic bone lesions, lymphadenopathy, visceral
  involvement, opportunistic infections.
• Acute comprises 55-75 and rapidly progresses
  with pulmonary complications, opportunistic
  infections, and sepsis.

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Mechanism of malignant transformation
Oncogene (2005) 24, 60476057
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Mechanism of malignant transformation

• Tax increases the number of HTLV-I-infected cells
  by promoting proliferation and inhibiting
  apoptosis.
• Tax also evokes the host immune response,
  triggering cytotoxic T cells to kill infected
  cells.
• Accumulation of genetic changes in clonally
  proliferating cells leads to Tax independent
  proliferation and loss of Tax (66 of ATLL).
• p53 and p16 mutations as well as DNA methylation
  have been identified.
• Loss of FasL has been demonstrated in ATL cells,
  enabling them to avoid apoptosis.

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Does strongyloides infection predispose to the
development of ATLL?

• Several studies have associated the presence of
  strongyloides with a higher frequency of ATLL but
  they have not been well controlled.
• Other studies have found that co-infection with
  Strongyloides stercoralis was associated with a
  better prognosis in ATLL.
• Strongyloides antigen induces IL-2 and therefore
  may induce polyclonal expansion of HTLV1 infected
  cells.
• Patients with ATLL have the highest levels of
  type 1 cytokines, which decreases defenses
  against strongyloides and is the most likely
  reason for the association.

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ATL Treatment

• Median survival is less than 1 year and has not
  significantly improved significantly in the past
  two decades.
• Multiple therapies have been studied
• Conventional lymphoma chemotherapyNucleoside
  analoguesTopoisomerase inhibitorsInterferon-aZi
  dovudineArsenicMonoclonal antibodies
  (anti-CD25, anti-CD52)

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• Oncogene (2005) 24, 60476057

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• Oncogene (2005) 24, 60476057

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• Oncogene (2005) 24, 60476057

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• Oncogene (2005) 24, 60476057

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Conventional chemotherapy regimens

• CHOP is most commonly used therapy with median
  survival 6 8 months.
• Best reported outcome is with seven cycles of
  VCAP (vincristine, cyclophosphamide, doxorubicin,
  and prednisone), AMP (doxorubicin, ranimustine,
  and prednisone), and VECP (vindesine, etoposide,
  carboplatin, and prednisone).
• Grade 4 haematological toxicity in the majority
  of patients, but a median survival of 13
  months.(2001). Br. J. Haematol., 113, 375382.

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Addition of zidovudine (AZT) and interferon

• Reverse transcriptase inhibitors are effective in
  controlling replication of HTLV1.
• Addition of interferon-a improves the response
  rate in ATLL.
• Survival has been prolonged in some studies which
  followed conventional chemotherapy with
  zidovudine and interferon (11-18 months).

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AMC 033 Phase II Trial of Induction Therapy with
EPOCH Chemotherapy and Maintenance Therapy with
Combivir/Interferon for HTLV-1 Associated T-cell
non-Hodgkins Lymphoma

• RationaleInduction with a regimen active in
  refractory lymphomas (up to 6 cycles).
• More intensive anti-retroviral therapy for one
  year.

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Monoclonal Antibodies

• Most ATLL cells express CD25 (IL-2 receptor)
• Anti-CD25 therapies have shown pre-clinical
  efficacy.
• Studies are enrolling of
• denileukin difitox (Ontak) fusion protein of
  diphtheria toxin and anti-CD25
• dacluzimab (Zenapax) humanized anti-Tac (IL-2R
  alpha)

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Allogenic stem cell transplant

• Graft versus ATLL effect is active, relapses
  respond to withdrawal of immunosuppression.
• Most recent case series is of 40 patients with
  33 3 year DFS.Leukemia. 2005 May19(5)829-34.

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SUMMARY

• Immigrants from HTLV1 endemic areas may be
  susceptible to opportunistic infections.
• Less than 10 of HTLV1 carriers develop ATL which
  worsens immunosuppression.
• Combinations of chemotherapy and anti-retrovirals
  are currently the most effective treatment.
• Better therapies are needed to prolong survival
  more than 1 year.

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Tax Oncoprotein Activites

• Transcriptional Activities Serum-response
  factor cAMP-response factor Activation of
  viral promoter Nuclear factor ?B Activation
  of cytokines, anti-apoptosis genes, cell
  proliferation genes, and angiogenesis
  Post-Transcriptional Activities Proliferation
  Inhibition of p16 cell cycle inhibitor,
  Activation of cyclin-dependent kinase 4 and
  Cyclin 2 Apoptosis Inactivation of p53
  Genetic Instability Defect in G2/M checkpoint due
  to binding mitotic arrest defect 1 protein, Cdc20
  anaphase-promoting complex, and checkpoint
  kinases Chk1 and 2