Thalidomide New Uses of an Old Drug - PowerPoint PPT Presentation

ThalidomideNew Uses of an Old Drug

Jeri Benton Johnson, MD

Internal Medicine Resident

Grand Rounds

February 13, 2001

• 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?

Behcet’s syndrome

Crohn’s disease

Lupus Erythematosus

Prurigo nodularis

Multiple myeloma

Wasting syndrome

Aphthous ulcers

Esophageal ulcers

Rheumatoid Arthritis

GVHD

Kaposi’s sarcoma

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

• 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

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

W.G.McBride

• Withdrawn in December of 1961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

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

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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• Aphthous ulcers
• Wasting syndrome
• Esophageal ulcers
• Kaposi’s sarcoma
• Diarrhea

• 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

• 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

• 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

• 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.

• Methods
• double-blind,randomized,placebo controlled study
• 29 randomized to receive 200mg of thalidomide for 4 weeks
• 28 randomized to placebo

• Outcomes measured
• resolution of ulcers
• quality of life
• evidence of toxicity
• plasma TNF-a levels
• soluble TNF-a receptors
• HIV RNA

• 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

• 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

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.

• 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.

• 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

• 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

• 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)

• Side effects: Rash(80%), somnolence, diarrhea, dizziness, anorexia, nausea; neuropathy was observed in 1 patient from each group.

• 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

• 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

• Exclusion criteria
• Peripheral neuropathy
• pregnancy
• Corticosteroid therapy
• Antiretroviral therapy was held constant 4 weeks prior to study entry

• 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

• Outcomes
• resolution of IEU by EGD at week 4
• quality of life
• TNF-a levels
• soluble TNF-a receptor levels
• HIV RNA

• 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)

• 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

• 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

• 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

• 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

• 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

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

• 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

• 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)

• 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)

• 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

• 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

• 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

• 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

• 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

• 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

• 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)

• 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

• 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

• 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

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

• 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

• 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

• 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

• 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.