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Thalidomide New Uses of an Old Drug . Jeri Benton Johnson, MD Internal Medicine Resident Grand Rounds February 13, 2001. Case presentation.

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thalidomide new uses of an old drug

ThalidomideNew Uses of an Old Drug

Jeri Benton Johnson, MD

Internal Medicine Resident

Grand Rounds

February 13, 2001

case presentation
Case presentation
  • J.F. is a 42 year old HIV infected male with a CD4 T cell count of 240cells/mm3 who presents to ID clinic with recurrence of an esophageal ulcer. Patient was treated 2 months earlier with steroids. Patient is experiencing weight loss and dysphagia. He is compliant with his meds and has not been in the hospital for16 months. He now feels is quality of life is declining. What do you have to offer him at this point?
what is the role of thalidomide in today s medicine
Erythema nodosum leprosum

Behcet’s syndrome

Crohn’s disease

Lupus Erythematosus

Prurigo nodularis

Multiple myeloma

Wasting syndrome

Aphthous ulcers

Esophageal ulcers

Rheumatoid Arthritis

GVHD

Kaposi’s sarcoma

What is the role of Thalidomide in today’s medicine?
overall goals
History of thalidomide

Reintroduction of thalidomide for ENL

Mechanisms of action

anti-inflammatory

immunomodulatory

anti-angiogenic

Thalidomide’s effect on HIV

RCT on thalidomide

aphthous ulcers

esophageal ulcers

wasting syndrome

Adverse reactions

Future of thalidomide

S.T.E.P.S.

Conclusion

Overall Goals
introduction of thalidomide
Introduction of Thalidomide
  • Synthesized by W. Kunz and others in 1956
  • Distributed in Europe, Australia, and Canada
  • Marketed as safe, potent, non-barbiturate sedative and antiemetic
  • Not approved by the FDA for use in the US
the lancet december 16 1961
Sir, Congenital abnormalities are present in approximately 1.5% of babies. In recent months I have observed that the incidence of multiple severe abnormalities in babies delivered of women who were given the drug thalidomide during pregnancy, as an antiemetic or as a sedative, to be almost 20%. These abnormalities are present in structures developed from mesenchyme-i.e., the bones and musculature of the gut. Bony development seems to be affected in a very striking manner, resulting in polydactyly, syndactyly, and failure of long bones.

Have any of your readers seen similar abnormalities in babies delivered of women who have taken this drug during pregnancy?

W.G.McBride

The Lancet, December 16,1961
withdrawn from the world market
Withdrawn from the world market
  • Withdrawn in December of 1961
  • Exposure from day 21 through day 40 of gestation
  • 10,000 cases of birth defects worldwide
  • Only 17 infants in the USA
    • 10 from investigative use
    • 7 from exposure to sources outside US
birth defects
Amelia

phocomelia

hypoplasticity of the bones

absence of bones

external ear abnormalities

facial palsy

Eye abnormalities (anophthalmos, microphthalmos)

Congenital heart defects

Alimentary, urinary, and genital malformations

Birth Defects
reintroduction of thalidomide
Dr. Jacob Sheskin an Israeli physician in 1965

Treating ENL, Erythema nodosum leprosy

Again used for its sedative properties

ENL

painful vasculitic rash

fever

muscle and joint pain

malaise

weight loss

insomnia

peripheral neuritis

Reintroduction of Thalidomide
treating enl
Treating ENL
  • Dr Sheskin treated 6 cases of acute, severe leprosy reactions with resolutions of symptoms.
  • In 1965, Sheskin performed a series of placebo controlled trials which revealed resolution of symptoms associated with ENL
  • Sheskin surveyed data in 1980 from 4522 cases around the world and found 99% response rate
  • Thalidomide was shown not to have effect against Mycobacterium leprae
approval of thalidomide for enl
Approval of Thalidomide for ENL
  • In a double-blind study in 1967 performed by World Health Organization helped confirm the drug’s efficacy
  • FDA approved the use of Thalidomide for erythema nodosum leprosum in July 16, 1998
  • Thalidomide is now first line of tx for ENL
pharmokinetics
Pharmokinetics
  • Metabolic route is not known in humans
  • Undergoes non-enzymatic hydrolysis in plasma
  • Renal clearance of 1.15mL/minute
  • Mean half-life ranges from 5 to 7 hours
  • No significant dose changes in those with HIV, renal or hepatic disease
immunomodulatory and anti inflammatory properties
Immunomodulatory and Anti-inflammatory properties
  • Inhibits leukocyte chemotaxis in site of inflammation
  • Alters density of TNF-a induced adhesion molecules on leukocytes
  • Reduces phagocytosis by PMN leukocytes
  • Enhances mononuclear cell production of IL-4 and-5; inhibits interferon gamma production
  • Inhibits IL-12
  • Inhibits production of TNF-alpha by monocytes and macrophages by reducing half-life of mRNA
anti angiogenic properties
Anti-angiogenic properties
  • Thalidomide inhibits fibroblast growth factor
  • Thalidomide inhibits vascular endothelial growth factor
  • Plasma levels of angiogenic cytokines are often elevated in diseases such as multiple myeloma
  • Postulated thalidomide has a role in solid tumors
tnf a role in hiv
TNF-a Role in HIV
  • Serum TNF- a and soluble TNF- a receptor levels are elevated in those with HIV
  • TNF- a enhances replication of HIV-1
  • TNF- a enhances a nuclear transcriptional factor used by the virus
  • HIV-1 induces TNF- a mRNA
makonkawkeyoon et al
Makonkawkeyoon et al.
  • A study to evaluate the inhibitory effects of thalidomide on HIV-1
  • A human monocytoid cell line was latently infected with HIV-1 and exposed to TNF-a
  • Fivefold increase in reverse transcriptase activity was noted after exposure to TNF-a
makonkawkeyoon et al continued
Makonkawkeyoon et al continued
  • Addition of thalidomide to the cultures resulted in a decrease in the production of HIV-1
  • Decrease of production of HIV was in a dose dependent manner
  • Associated with a decrease in TNF- a mRNA
thalidomide s role in hiv
Thalidomide’s role in HIV
  • Aphthous ulcers
  • Wasting syndrome
  • Esophageal ulcers
  • Kaposi’s sarcoma
  • Diarrhea
aphthous and esophageal ulcers
Aphthous and Esophageal Ulcers
  • 50% of ulcers in HIV-infected patients idiopathic
  • painful necrotic lesions
  • lead to weight loss and wasting syndrome
  • Relapse often common after treatment with corticosteroids
current treatment for ulcers
Current Treatment for Ulcers
  • Oral corticosteroids
  • IV corticosteroids
  • Intralesional injection by endoscopy
  • Relapse is common after 2 months of successful oral therapy
  • Need for alternatives to corticosteroids for those ulcers which are refractory
jacobson et al 1997 aphthous ulcers
Jacobson, et al 1997Aphthous Ulcers
  • Study population: 29 patients with oral aphthous ulceration of at least 2 week duration; biopsy confirmed no infectious, neoplastic or other specific diagnosis. Surface diameter was at least 5mm for the largest ulcer. Hgb >8g per deciliter, and ANC >500 per cubic millimeter . Antiretroviral tx was held constant 4 week prior to study.
  • Exclusion criteria: neuropathy, pregnancy, tx for opportunistic infections, or anti-neoplastic alkylating agents
jacobson et al continued
Jacobson, et al continued
  • Stringent precautions were taken to prevent and detect pregnancy in women of childbearing potential including pregnancy testing prior to study entry, weekly while on the study, and 4 weeks after discontinuation of the drug. Patients were required to use 2 forms of birth control.
jacobson et al continued25
Jacobson, et al continued
  • Methods
    • double-blind,randomized,placebo controlled study
    • 29 randomized to receive 200mg of thalidomide for 4 weeks
    • 28 randomized to placebo
jacobson et al continued26
Jacobson, et al continued
  • Outcomes measured
    • resolution of ulcers
    • quality of life
    • evidence of toxicity
    • plasma TNF-a levels
    • soluble TNF-a receptors
    • HIV RNA
jacobson et al continued27
Jacobson, et al continued
  • Results
    • 55% response to therapy at week 4 versus 7% response in placebo group (OR of 15; 95% CI 1.8-499)
    • 90% response at week 4 if you combine partial and complete response in thalidomide group versus 25% in placebo (OR 24;95% CI 5.2-162)
    • median time for survival is 3.5 weeks
jacobson et al continued28
Jacobson et al continued
  • Results
    • TNF-a level increased in thalidomide group vs placebo group at week 4 (p=0.090)
    • TNF-a receptor increased in thalidomide group vs placebo group at week 4 (p=0.007)
    • HIV RNA median increase 0.42 log10 copies per milliliter at 4 weeks of therapy with thalidomide
jacobson et al continued side effects
Most common > rash

7/29 had new or worsened peripheral neuropathy

fever

confusion

headaches

nausea

Syncope

lethargy

elevated AST/ALT

Estimated probability of remaining in the study without dose reduction was 52% in the thalidomide group.

Jacobson, et al continuedSide effects
jacobson et al conclusion
Jacobson et alConclusion
  • Thalidomide is effective in healing aphthous ulcers in those with HIV
  • No significant difference in adverse outcomes in either group
  • Caution is urged for prolonged treatment with thalidomide because of the elevated HIV RNA.
ramirez amador et al 1999 aphthous ulcers
Ramirez-Amador, et al 1999Aphthous Ulcers
  • Study population
    • sixteen HIV infected patients with aphthous ulcers were enrolled from AIDs clinic in Mexico City
    • Biopsy from aphthous ulcers ruled out infectious or neoplastic conditions
ramirez amador et al
Ramirez-Amador, et al
  • Methods
    • double-blind, randomized placebo-controlled clinical trials
    • 10 patients received 400mg a day for 1 week followed by 200 mg a day for 7 weeks of thalidomide
    • 6 patients received placebo
ramirez amador et al33
Ramirez-Amador, et al
  • Outcomes
    • complete absence of ulcers at 8 weeks
    • no new lesions after 8 weeks
  • Results
    • 9 of 10 patients (90%) responded in the thalidomide group versus 2 of 6 patients (33%) responded in the placebo group (p=.03)
ramirez amador et al continued
Ramirez-Amador, et al continued
  • Side effects: Rash(80%), somnolence, diarrhea, dizziness, anorexia, nausea; neuropathy was observed in 1 patient from each group.
ramirez amador et al conclusions
Ramirez-Amador et alConclusions
  • Thalidomide heals aphthous ulcers in those infected with HIV
  • Side effects are common although transient and mild
  • Obvious limitation is due to the small study size
jacobson et al esophageal ulcers
Jacobson, et alEsophageal ulcers
  • Study population
    • 24 HIV infected patients with esophageal ulcer > 5mm
    • Biopsy ruled out infectious or neoplastic condition
    • CD4 T cell count < 200
    • Dysphagia or odonyphagia for > 2 weeks
jacobson et al esophageal ulcers37
Jacobson, et al Esophageal ulcers
  • Exclusion criteria
    • Peripheral neuropathy
    • pregnancy
    • Corticosteroid therapy
  • Antiretroviral therapy was held constant 4 weeks prior to study entry
jacobson et al esophageal ulcers38
Jacobson, et alEsophageal Ulcers
  • Methods
    • multi-center,double-blind, randomized placebo-controlled trial
    • 11 patients were randomized to receive 200mg of thalidomide for 4 weeks
    • 13 patients were randomized to placebo
jacobson et al esophageal ulcers39
Jacobson, et alEsophageal Ulcers
  • Outcomes
    • resolution of IEU by EGD at week 4
    • quality of life
    • TNF-a levels
    • soluble TNF-a receptor levels
    • HIV RNA
jacobson et al esophageal ulcers40
Jacobson, et alEsophageal Ulcers
  • Results
    • 8 of the 11 patients (73%) responded to therapy versus 3 of the 13 patients (23%) in placebo group had resolution of IEU (OR13;CI 1.2-823;p=0.03)
    • 9 of the11 patients (82%) responded if partial and complete response are combined versus 4 of 13 patients(31%) in placebo group ( OR 11;CI 1.16-195;p=0.033)
jacobson et al esophageal ulcers41
Jacobson, et al Esophageal Ulcers
  • Results
    • TNF-a levels and TNF-a receptor levels were elevated in thalidomide group compared to placebo group
    • No changes in CD4 or CD8 T cell count in either group
    • HIV RNA elevated in the thalidomide group although not statistically significant
jacobson et al esophageal ulcers42
Jacobson, et alEsophageal Ulcers
  • Side effects
    • 5 of 11 patients (45%) randomized to placebo group discontinued the study drug
    • 3 developed peripheral sensory neuropathy
    • other SE included rash, somnolence, fever, nausea, dehydration, and seizures
jacobson et al esophageal ulcers43
Jacobson, et alEsophageal Ulcers
  • Conclusions
    • Thalidomide heals IEU in HIV patients
    • Concern for the high incidence of peripheral neuropathy in such a small group
    • Thalidomide did not prove to be a systemic TNF-a inhibitor
    • Modest increase in HIV RNA which contradicts studies in vitro
wasting syndrome in hiv
Wasting Syndrome in HIV
  • Pathogenesis is multifactorial
  • Cytokines like TNF-a are implicated
  • Wasting syndrome
    • opportunistic infections
    • chronic progressive weight loss from the virus
  • Proposed thalidomide might play a role
    • few studies
    • one RCT
gustavo et al 1996 wasting syndrome
Gustavo, et al 1996Wasting Syndrome
  • Study population:
    • 28 adults with advanced HIV being treated with antiretroviral therapy at least 12 weeks prior to study
    • progressive loss of >10% of usual body weight in 6 months
    • patients did not have an active opportunistic infection
    • CD4 T cell count < 500cells/mm3
gustavo et al continued exclusion criteria
diarrhea

immunosuppressors

opportunistic infection

Kaposi’s sarcoma

hemoglobin <9.5g/dl

Platlet count<75,000

Creatinine >2mg/dl

AST >3times normal

Total granulocyte <1000 cells/mm3

Gustavo, et al continuedExclusion Criteria
gustavo et al continued
Gustavo, et al continued
  • Methods
    • Randomized,double-blind placebo controlled trial to evaluate thalidomide’s role on wasting syndrome
    • 14 of 28 patients received 100mg Q.I.D.
    • 14 of 28 patients received placebo Q.I.D.
  • Outcomes
    • Weight gain , CD4 T cell count, HIV load
gustavo et al continued48
Gustavo, et al continued
  • Results
    • median weight change in placebo group was -1.30kg
    • median weight change in thalidomide group was + 4.05kg (p=0.0001)
    • median calculated muscle mass in placebo group was -1.10kg
    • median calculated muscle mass in thalidomide group was +1.00kg (p=0.0001)
gustavo et al continued49
Gustavo, et al continued
  • Secondary endpoints
    • CD 4 T+ cell counts and viral burden did not change in either group
  • Adverse Outcomes
    • transient somnolence in 11 of 14 in tx group vs 5 of 14 in placebo (p=0.02)
    • skin rash in 11 of 14 in tx group vs 3 of 14 in placebo (p=0.017)
adverse reactions to thalidomide in hiv
Adverse Reactions to Thalidomide in HIV
  • Haslett, et al performed 3 prospective studies to evaluate the tolerance and SE of thalidomide in HIV population.
    • 56 patients were treated with 200-300mg of thalidomide for 14-21 days
    • 24(43%)of 56 did not complete course
    • CD4 T cell counts in 20 pts and HIV RNA titers in 16 pts were followed
thalidomide s side effects
Thalidomide’s Side Effects
  • Sedation in 13%
  • Cutaneous and febrile reactions in 36%
  • Constipation in 9%
  • Neuropathic signs in 4%
  • Mood changes in 4%
  • CD4 T cell counts and HIV RNA burden did not change significantly
antitumor activity of thalidomide
Antitumor activity of thalidomide
  • Angiogenesis leads to proliferation and metastases in many solid tumors
    • without angiogenesis tumors do not grow beyond 1 to 2mm
    • increased angiogenesis is an adverse prognostic indicator in several solid tumors
    • increased bone marrow angiogenesis in myeloma correlates with worse prognosis
anti angiogenesis role of thalidomide
Anti-angiogenesis role of thalidomide
  • Inhibits fibroblast growth factor
  • Inhibits vascular endothelial growth factor
  • Both of these angiogenic growth factors are elevated in multiple myeloma
  • It is hypothesized that elevated angiogenic cytokines lead to increased microvascular density of the BM leading to relapse in MM
antitumor activity of thalidomide54
Antitumor activity of thalidomide
  • Singhal et al, 1999 enrolled 84 patients with refractory multiple myeloma
    • 76 received 1 cycle of high dose chemo with autologous hematopoietic stem-cell support
    • 58 received 2 or more cycles of intensive chemo
    • starting dose of 200mg which was increased by 200mg every 2 weeks for max dose of 800mg
antitumor activity of thalidomide55
Antitumor activity of thalidomide
  • Assessment of response was a reduction of paraprotein in the serum or urine by at least 25%, 50%,75%,or 90% on 2 occasions 6 weeks apart
  • Results
    • 90% response in 8 patients
    • 75% response in 6 patients
    • 50% response in 7 patients
    • 25% response in 6 patients
antitumor activity of thalidomide56
Antitumor activity of thalidomide
  • Total response of 32% at the end of the trial
  • After 12 months, event free survival is 22% and overall survival is 58%
  • At least one-third had SE of constipation, fatigue, somnolence, and weakness
  • As of June 1999, 36 patients had died (30 without a response and 6 with response)
antitumor activity of thalidomide conclusion
Antitumor activity of thalidomideConclusion
  • Thalidomide does have some antitumor activity against refractory multiple myeloma
  • 10% of patients had nearly complete or complete response in this study
  • Randomized controlled trials are needed to evaluated the antiangiogenesis properties of thalidomide against other solid tumors
s t e p s
S.T.E.P.S.
  • STEPS: System for Thalidomide Education and Prescribing Safety
    • Prescribers contact Celgene corporation
    • Register with the STEPS program
    • Prescribers are required to wait for confirmation of a registration prior to prescribe thalidomide
prescribing to a female
Prescribing to a Female
  • Counseled about severity of birth defects and side effects
  • If a patient is postmenopausal for 24 months or has had a TAH then no contraceptive counseling is required
  • If capable of childbearing then patient must have 2 forms of BC
  • Given 5 yes/no quiz to asses their understanding
pregnancy testing in s t e p s
Pregnancy testing 24 hours prior to tx

Tested initially every wk for the first 4 wks

Tested every 4 wks thereafter if menses are regular

Tested every 2 wks thereafter if menses are irregular

If pregnancy test is positive, FDA is notified; pt is referred to OBGYN for reproductive toxicity

Pregnancy testing in S.T.E.P.S.
prescribing to a male
Prescribing to a male
  • Counseled about birth defects and other side effects
  • Unknown if thalidomide is in semen or sperm
  • Males must were a condom even if they have had a vasectomy
  • Asked 5 yes/no quiz to assess their understanding
pharmacist role
Pharmacist role
  • Register with Celgene corporation
  • Must have patient’s informed consent
  • Refilled only every 4 week
  • Must have script filled with 7 days
  • Recommended that female patients of childbearing ability receive no more than 1 wk supply for the first 4 wks
conclusion take home points
Conclusion: Take home points
  • Thalidomide is effective as TNF-a inhibitor
  • Effective in treating aphthous ulcers, esophageal ulcers and wasting syndrome in HIV infected individuals
  • Unsure of thalidomide’s effect on HIV RNA
  • Role for thalidomide in treating solid tumors
conclusion
Conclusion
  • Therapeutic agents which regulate TNF-production are likely to be very important in the future in the treatment of autoimmune diseases, malignancies and many infections, including AIDS.