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Safety and Tolerability of
Thalidomide
Over all thalidomide as a single agent or in combination is well tolerated.
The tolerability of the therapy with this agent is dependant on the starting
dose of therapy, the maximal target dose, the cumulative dose and more
importantly especially for the hyper-coagulation events that are noted in those
patients the type of agents thalidomide is combined with and the intensity of
the schedule for those agents.
Deep Venous Thrombosis
The most critical side effect is the increased incidence of deep venous
thrombosis that is noted. Plasma cell dyscrasia appears to be associated with
high incidence of thrombotic events 1. Hyper-coagulation state appears to be
inherent to plasma cell dyscrasia as noted by the increase of incidence of
thrombotic events in patients with monoclonal gammopathy who are not receiving
any active therapy. The incidence of deep venous thrombosis in MGUS (7.5%) was
not statistically significant than what is noted in multiple myeloma patients
(9.8%). Of interest is the absence of any significant increase in the incidence
of those events with the use of thalidomide in combination with dexamethasone
when the latter used in a less intense schedule as compared to the more frequent
intense steroid timetable 1-3. When used in combination with chemotherapy
especially anthracyclines the incidence of deep venous thrombosis is
significantly increased and could be reduced to baseline by the use of low dose
aspirin or low molecular weight heparin 4;5. In summary when thalidomide is used
a single agent or in combination with non intense steroid schedule (dexamethasone
at 40mg a day for 4 days with 10 days off) prophylactic anti-coagulation does
not seem to be warranted. When used in combination with anthracycline based
regimens low dose aspirin prevents deep venous thrombosis with no side effects.
Other Side Effects
Other toxicities related to the use of thalidomide are a critical issue that
more often than not results in premature discontinuation of an effective
therapy. Form our experience, and that of others it does appear that the drug is
not well tolerated when used in patients with poor performance status, or the
dose escalated in a rapid fashion.
Somnolence and Dizziness
The most common adverse effects are dose-dependent somnolence and dizziness 6 To
minimize these complications, thalidomide should be administered as a once-daily
dose in the evening, initiated at low doses (50 mg a day) and the dose escalated
at 50 mg a week to the maximum dose specified according to the disease or the
protocol followed. Tolerance to the sedative properties usually develops over
time. Relative to the dizziness, which appears to be related to the hypotensive
effect of the drug, a special care should be directed to increasing the fluid
intake of the patient. This is particularly important in diseases such as
multiple myeloma, where dehydration and low hemoglobin from different factors
are common events. Patients also should be advised to sit upright for a few
minutes before standing from a recumbent position.
Constipation
Constipation is a common side effect experienced by 3% to 30% of patients.
Narcotics, decreased mobility as well as electrolyte imbalances worsen the
symptom. In our experience, initiating all patients on two Senokot-S a day and
up to eight tablets to be titrated according to their symptoms have eliminated
this side effect.
Neuropathy
Chronic thalidomide therapy can produce peripheral neuropathy. The neuropathy
results from axonal degeneration without demyelination in the sensory fibers of
the lower and occasionally upper extremities. Risk of peripheral neuropathy
appears to rise with patient age and cumulative dose of thalidomide, resulting
in an incidence of approximately 25% in non-lepromatous patients on chronic
thalidomide therapy 7. We have shown that 15% of patients with plasma cell
dyscrasia have functional vitamin B12 deficiency which could reach as high as
25% 8. Detecting, and treating this deficiency will probably result in the drug
being better tolerated.
Rashes
Thalidomide-induced erythematous macular rash, usually involving the
trunk and back, has been reported. This rash is less likely to be pruritic 7 and
does not progress with the continuation of therapy. The rash usually occurs
within 2 to 13 days after initiation and reverses after discontinuation with or
without the use of antihistamines 7. Because severe, life-threatening epidermal
damage has been reported 9, our policy is to observe the patients carefully, and
discontinue the drug only if the rash worsens and or pruritic symptoms develop.
Low White Blood Count
A rare side effect of the use of thalidomide is leukopenia that has been
reported to occur in less than 10% of the cases 10;11. Its occurrence is usually
transient and could signify evidence of early response to therapy 12. In our
experience this is a rare event that is asymptomatic and with our policy of
using steroids for maintenance therapy 13 the leukopenia usually resolves.
Birth Defects
Teratogenicity from the use of thalidomide has been carefully addressed by a
careful program that is designed to enforce the use of the agent in patients who
are well instructed and educated to different contraceptives measures 14.
Reference List
1. Srkalovic G, Cameron MG, Rybicki L et al. Monoclonal gammopathy of
undetermined significance and multiple myeloma are associated with an increased
incidence of venothromboembolic disease. Cancer 2004;101:558-566.
2. Rajkumar SV, Hayman S, Gertz MA et al. Combination Therapy With Thalidomide
Plus Dexamethasone for Newly Diagnosed Myeloma. J Clin Oncol 2002;20:4319-4323.
3. Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R. Thalidomide Alone or
With Dexamethasone for Previously Untreated Multiple Myeloma. J Clin Oncol
2003;21:16-19.
4. Agrawal, N. Pegylated Doxorubicin (D), Vincristine(V), Reduced Frequency
Dexamethasone(D) and Thalidomide(T) (DVd-T) In Newly Diagnosed (Nmm) and
Relapsed/Refractory (Rmm) Multiple Myeloma Patients. 2003.
Ref Type: Generic
5. Zangari M, Barlogie B, Anaissie E et al. Deep vein thrombosis in patients
with multiple myeloma treated with thalidomide and chemotherapy: effects of
prophylactic and therapeutic anticoagulation. Br.J.Haematol. 2004;126:715-721.
6. Tseng S, Pak G, Washenik K, Pomeranz MK, Shupack JL. Rediscovering
thalidomide: a review of its mechanism of action, side effects, and potential
uses. J.Am.Acad.Dermatol. 1996;35:969-979.
7. Hussein MA. Research on thalidomide in solid tumors, hematologic
malignancies, and supportive care. Oncology (Huntingt) 2000;14:9-15.
8. Baz R, Alemany C, Green R, Hussein MA. Prevalence of vitamin B12 deficiency
in patients with plasma cell dyscrasias: a retrospective review. Cancer
2004;101:790-795.
9. Hall VC, El-Azhary RA, Bouwhuis S, Rajkumar SV. Dermatologic side effects of
thalidomide in patients with multiple myeloma. J.Am.Acad.Dermatol.
2003;48:548-552.
10. Huang SY, Tang JL, Yao M et al. Reduction of leukocyte count is associated
with thalidomide response in treatment of multiple myeloma. Ann.Hematol.
2003;82:558-564.
11. Tosi P, Zamagni E, Cellini C et al. Salvage therapy with thalidomide in
patients with advanced relapsed/refractory multiple myeloma. Haematologica
2002;87:408-414.
12. Huang SY, Tang JL, Yao M et al. Reduction of leukocyte count is associated
with thalidomide response in treatment of multiple myeloma. Ann.Hematol.
2003;82:558-564.
13. Berenson JR, Crowley JJ, Grogan TM et al. Maintenance therapy with
alternate-day prednisone improves survival in multiple myeloma patients. Blood
2002;99:3163-3168.
14. Zeldis JB, Williams BA, Thomas SD, Elsayed ME. S.T.E.P.S.: a comprehensive
program for controlling and monitoring access to thalidomide. Clin.Ther.
1999;21:319-330.
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