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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 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.

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.

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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