THALIDOMIDE - TOXICITY

 

Reduction of leukocyte count is associated with thalidomide response in treatment of multiple myeloma.
Ann Hematol. 2003 Sep;82(9):558-64.
Huang SY, Tang JL, Yao M, Ko BS, Hong RL, Tsai W, Wang CH, Tien HF, Shen MC, Chen YC.
50 patients with relapsed or refractory myeloma were treated with thalidomide, at escalating doses 100-800 mg PO qhs. Results:
  - Response rate was 44%, when including both PR (45.5%) and minor response (54.5%). No CR were seen.
  - The median tolerated dose of thalidomide was 400 mg, and only 2 patients (4%) were able to tolerate 800 mg daily
  - The median time to response was 29 days (range, 8-155 days)
Interestingly, leukopenia was a clinical predictor of response to thalidomide: 18 of the 22 (82%) responders had  a transient reduction of WBC before the the response, whereas this was seen in only 4 of the 28 (14%) non-responders (p<0.001). Leukopenia was generally transient, and it quickly resolved despite the continuation of thalidomide.

Tumor lysis syndrome in a multiple myeloma treated with thalidomide.
Fuente Ann Oncol. 2004 Mar;15(3):537.
N, Mañe JM, Barcelo R, Muñoz A, Perez-Hoyos T, Lopez-Vivanco G.

Side effects and good effects from new chemotherapeutic agents. Case 2. Thalidomide-induced interstitial pneumonitis.
J Clin Oncol. 2005 Apr 1;23(10):2425-6.
Onozawa M, Hashino S, Sogabe S, Haneda M, Horimoto H, Izumiyama K, Kondo T, Aldana LP, Hamada K, Asaka M.

 

TOXICITY - THROMBOEMBOLISM

Deep vein thrombosis in patients with multiple myeloma treated with thalidomide and chemotherapy: effects of prophylactic and therapeutic anticoagulation.
Br J Haematol. 2004 Sep;126(5):715-21.
Zangari M, Barlogie B, Anaissie E, Saghafifar F, Eddlemon P, Jacobson J, Lee CK, Thertulien R, Talamo G, Thomas T, Van Rhee F, Fassas A, Fink L, Tricot G.

Among 256 newly diagnosed myeloma patients randomized to thalidomide vs no thalidomide, DVT was observed more frequently in the thalidomide group (hazard ratio: 4.5). Low dose coumadin (1 mg/day) did not prevent venous thromboembolism, whereas LMWH (enoxaparin 40 mg SC qd) effectively prevented it.

Prophylactic low-dose aspirin is effective antithrombotic therapy for combination treatments of thalidomide or lenalidomide in myeloma.
Leuk Lymphoma. 2007 Dec;48(12):2330-7.
Niesvizky R, Martínez-Baños D, Jalbrzikowski J, Christos P, Furst J, De Sancho M, Mark T, Pearse R, Mazumdar M, Zafar F, Pekle K, Leonard J, Jayabalan D, Coleman M.
In this study, the prophylactic use of low-dose aspirin (81 mg) was effective in reducing the incidence of venous thromboembolism in patients with multiple myeloma treated with thalidomide or lenalidomide.

Hypercoagulable states in patients with multiple myeloma can affect the thalidomide-associated venous thromboembolism.
Blood Coagul Fibrinolysis. 2009 Jul;20(5):337-9.
Talamo G, Ibrahim S, Claxton D, Tricot GJ, Fink LM, Zangari M.

Arterial thrombosis in four patients treated with thalidomide.
Leuk Lymphoma. 2005 Feb;46(2):239-42.
Scarpace SL, Hahn T, Roy H, Brown K, Paplham P, Chanan-Khan A, van Besien K, McCarthy PL Jr.
This is a report of 7 cases of arterial thrombotic events during therapy with thalidomide. 3 cases occurred in patients with other risk factors.

Arterial thrombosis with immunomodulatory derivatives in the treatment of multiple myeloma: a single-center case series and review of the literature.
Clin Lymphoma Myeloma. 2009 Aug;9(4):320-3.
Martin MG, Vij R.
The authors describe 5 cases of arterial thrombosis in patients with MM treated with thalidomide.

Aspirin, Warfarin, or Enoxaparin Thromboprophylaxis in Patients With Multiple Myeloma Treated With Thalidomide: A Phase III, Open-Label, Randomized Trial.
J Clin Oncol. 2011 Mar 10;29(8):986-93.
Palumbo A, Cavo M, Bringhen S, Zamagni E, Romano A, Patriarca F, Rossi D, Gentilini F, Crippa C, Galli M, Nozzoli C, Ria R, Marasca R, Montefusco V, Baldini L, Elice F, Callea V, Pulini S, Carella AM, Zambello R, Benevolo G, Magarotto V, Tacchetti P, Pescosta N, Cellini C, Polloni C, Evangelista A, Caravita T, Morabito F, Offidani M, Tosi P, Boccadoro M.
In this study, 667 patients with myeloma treated with thalidomide were randomized into 3 groups:
  - Aspirin 100 mg/day PO
  - Warfarin fixed low-dose, 1.25 mg/day PO
  - LMWH: enoxaparin 40 mg/day SC
Treatment was continued for the first 3-6 cycles of induction therapy. Both aspirin and fixed low-dose warfarin showed similar efficacy in reducing thromboembolic complications when compared with LMWH. Rate of complications (i.e., DVT, PE, arterial thrombosis, acute cardiovascular events, and sudden death) was:
  - 5% with LMWH
  - 6% with aspirin
  - 8% with warfarin

 

TOXICITY - NEUROPATHY

Thalidomide neuropathy: clinical, electrophysiological and neuroradiological features.
Acta Neurol Scand. 2004 Mar;109(3):188-93.
Isoardo G, Bergui M, Durelli L, Barbero P, Boccadoro M, Bertola A, Ciaramitaro P, Palumbo A, Bergamasco B, Cocito D.
The authors obtained nerve conduction studies, somatosensory-evoked potentials, and MRI of cervical and dorsal spinal cord MRI in 6 patients with myeloma and thalidomide-induced polyneuropathy. The results indicated that thalidomide induces an axonal length-dependent sensory neuropathy and, less frequently, a ganglionopathy.

Severe tremors associated with use of thalidomide.
Am J Hematol. 2005 Jan;78(1):81-2.
Chiruka S, Chapman CS.

Neurological toxicity of long-term (>1 yr) thalidomide therapy in patients with multiple myeloma.
Eur J Haematol. 2005 Mar;74(3):212-6.
Tosi P, Zamagni E, Cellini C, Plasmati R, Cangini D, Tacchetti P, Perrone G, Pastorelli F, Tura S, Baccarani M, Cavo M.
40 myeloma patients treated with thalidomide for longer than 12 months were assessed for neurotoxicity. Neurotoxicity was the most important and frequent (75%) toxicity of thalidomide. Symptoms included paresthesias, tremors, and dizziness.
  - Grade 1: 15%
  - Grade 2: 32.5%
  - Grade 3: 27.5% (patients with grade 3 neurotoxicity had to interrupt the therapy)
EMG showed a symmetrical, mainly sensory peripheral neuropathy.

 

TOXICITY - SKIN

Thalidomide-induced morbilliform rash: diagnosis and continuation of therapy, premedicated with methylprednisolone.
Dermatology. 2002;204(4):365-7.
Nijsten T, Meuleman L, Schroyens W, Lambert J.
A patient with multiple myeloma who developed a morbilliform rash with thalidomide was able to continue the drug when methylprednisolone 64 mg was added.

Dermatologic side effects of thalidomide in patients with multiple myeloma.
J Am Acad Dermatol. 2003 Apr;48(4):548-52.
Hall VC, El-Azhary RA, Bouwhuis S, Rajkumar SV.
This is a report of the dermatologic side effects of thalidomide in 87 patients with multiple myeloma enrolled in a clinical trial with thalidomide either alone or in combination with dexamethasone. The prevalence of skin rash with thalidomide was high, because a minor-moderate skin rash was observed in 46% of patients (43% in patients taking thalidomide + dexamethasone). 3 patients taking thalidomide + dexamethasone developed a severe skin rash that required hospitalization and discontinuation of thalidomide.

Leukocytoclastic vasculitis due to thalidomide in multiple myeloma.
Jpn J Clin Oncol. 2007 Sep;37(9):704-7.
Yildirim ND, Ayer M, Küçükkaya RD, Alpay N, Mete O, Yenerel MN, Yavuz AS, Nalçaci M.

Desensitization to thalidomide in a patient with multiple myeloma.
Clin Lymphoma Myeloma. 2008 Jun;8(3):176-8.
Nucera E, Schiavino D, Hohaus S, Leone G, Buonomo A, Lombardo C, Patriarca G.
The authors report the case of a 65-year-old woman with multiple myeloma who developed a maculopapular rash after 2 days of thalidomide therapy, and who was successfully desensitized
. On the fifth day of an oral desensitization protocol, she could tolerate the drug.

Thalidomide-Related Eosinophilic Pneumonia: A case report and brief literature review.
Cases J. 2008 Sep 8;1(1):143.
Tilluckdharry L, Dean R, Farver C, Ahmad M.

 

 


Giampaolo Talamo, MD