Chronic disseminated intravascular coagulation (DIC) markers in a patient with multiple angiomatosis during treatment with antiangiogenics: interferon α, thalidomide and lenalidomide

Česká verzia

Authors: Z. Adam ¹; L. Pour ¹; M. Matýšková ¹; M. Krejčí ¹; M. Tomíška ¹; P. Szturz ¹; Z. Řehák ²; R. Koukalová ²; L. Křikavová ³; T. Nebeský ³; Č. Neuman ⁴; M. Navrátil ¹; R. Hájek ¹; Z. Král ¹; J. Mayer ¹
Authors place of work: Interní hematoonkologická klinika Lékařské fakulty MU a FN Brno, pracoviště Bohunice, přednosta prof. MUDr. Jiří Mayer, CSc. ¹; PET CT oddělení Masarykova onkologického ústavu Brno, přednosta prim. MUDr. Karol Bolčák ²; Radiologická klinika Lékařské fakulty MU a FN Brno, pracoviště Bohunice, přednosta prof. MUDr. Jiří A. Válek, CSc., MBA ³; Chirurgická klinika Lékařské fakulty MU a FN Brno, pracoviště Bohunice, přednosta prof. MUDr. Zdeněk Kala, Ph. D. ⁴
Published in the journal: Vnitř Lék 2012; 58(2): 145-153
Category: Case Reports

Summary

Background:
Multiple angiomatosis is a rare disease with angiomatous formations in multiple organs and tissues and associated with a risk of fatal bleeding.

Case description:
In this patient, the bones, pleural and peritoneal cavities and digestive tract were involved. The patient had long-term been administered zoledronate that provided relief from bone pain as early as after the second dose. The effect of antiangiogenics was evaluated on CT and MRI. Since angiomatous proliferation is associated with chronic disseminated intravascular coagulation (DIC) and anaemisation, blood count and fibrinogen as well as D-dimer and soluble fibrin monomer concentrations are also used to assess treatment response.

Results:
Before treatment, D-dimer levels were in excess of 20 μg/mL, fibrinogen 1.4 g/L and soluble fibrin monomers were at measurable levels. During treatment with interferon α at a dose of 6 million units 3 times a week with the dose reduction after 10 month, the median fibrinogen concentration increased to 1.5 (1.2–2.0) g/L, the median D-dimer levels declined to 17.2 (13.4–20.0) μg/mL and fibrin monomers were still detectable. Thalidomide therapy (100 mg/day) provided reduction in the median D-dimer levels to 6.07 (4.71–10.21) μg/ml and increase in median fibrinogen concentration to 1.9 g/L; soluble fibrin monomers were unidentifiable. CT imaging suggested significant reduction of angiomatous mass. Progressing neuropathy required dose reduction of thalidomide to 50 mg/day, leading to D-dimer increase. Lenalidomide 10 mg/day provided an increase in median D-dimer concentration to 10.8 (10.8–17.35) and decline in the level of haemoglobin to a median of 124 (135–117) g/L. Soluble fibrin monomers became detectable again. Therefore, a low dose of lenalidomide 10 mg/day was combined with thalidomide 100 mg and, subsequently, 50 mg/day. Treatment with lenalidomide 10 mg and thalidomide 50 mg provided median D-dimer levels of 9.32 and the disease has remained stable for 9 months.

Conclusion:
Thalidomide 100 mg/day stabilized multiple angiomatosis better than interferon alfa. Thalidomide 50 mg/day was insufficient to maintain disease stability. Lenalidomide at a dose of 10 mg was tolerated really well but this dose was insufficient to maintain low D-dimer levels and normal haemoglobin concentrations. The combination of lenalidomide 10 mg and thalidomide 50 mg daily stabilized the disease for 9 months.

Key words:
hemangiomatosis – angiomatosis – thalidomide – lenalidomide – D-dimers – chronic disseminated intravascular coagulation – PET-CT imaging

Zdroje

1. Adam Z, Křikavová L, Krejčí M et al. Léčba mnohočetné angiomatózy postihující skelet, břišní i hrudní dutinu interferonem α, thalidomidem a zoledronatem. Vnitř Lék 2008; 54: 553–664.

2. Adam Z, Pour L, Krejčí M et al. Úspěšná léčba angiomatózy thalidomidem a interferonem α. Popis pěti případů a přehled léčby angiomatózy a proliferujících hemangiomů. Vnitř Lék 2010; 56: 810–824.

3. Heidt J, Langers AMJ, van der Meer et al. Thalidomide as treatment for digestive angiodysplasias. Neth J Med 2006; 64: 425–428.

4. Crane E, List A. Immunomodulatory drugs. Cancer Invest 2005; 23: 625–634.

5. De Sanctis JB, Mijares M, Suárez A et al. Pharmacological properties of thalidomide and its analogues. Recent Pat Inflamm Allergy Drug Discov 2010; 4: 144–148.

6. Dreicer R. Lenalidomide: immunomodulatory, antiangiogenic, and clinical activity in solid tumors. Curr Oncol Rep 2007; 9: 120–123.

7. Elice F, Jacoub J, Rickles FR et al. Hemostatic complications of angiogenesis inhibitors in cancer patients. Am J Hematol 2008; 83: 862–870.

8. Knight R. IMiDs: a novel class of immunomodulators. Semin Oncol 2005; 32 (Suppl 5): S24–S30.

9. Kotla V, Goel S, Nischal S et al. Mechanism of action of lenalidomide in hematological malignancies. J Hematol Oncol 2009; 2: 36–40.

10. Teo SK. Properties of thalidomide and its analogues: implications for anticancer therapy. AAPS J 2005; 7: E14–E19.

11. Lu L, Payvandi F, Wu L et al. The anti-cancer drug lenalidomide inhibits angiogenesis and metastasis via multiple inhibitory effects on endothelial cell function in normoxic and hypoxic conditions. Microvasc Res 2009; 77: 78–86.

12. Elice F, Rodeghiero F. Bleeding complications of antiangiogenic therapy: Pathogenetic mechanisms and clinical impact. Thromb Res 2010; 125 (Suppl 2): S55–S57.

13. Zangari M, Fink LM, Elice F et al. Thrombotic events in patients with cancer receiving antiangiogenesis agents. J Clin Oncol 2009; 27: 4865–4873.

14. Hájek R, Maisnar R, Adam Z et al. Mnohočetný myelom, diagnostika a léčba. Doporučení pro diagnostiku a léčbu České myelomové skupiny. Transfuze Hematol dnes 2009; 15: (Suppl 2): 2–80.

15. Awan FT, Johnson AJ, Lapalombella R et al. Thalidomide and lenalidomide as new therapeutics for the treatment of chronic lymphocytic leukemia. Leuk Lymphoma 2010; 51: 27–38.

16. Dasanu CA, Reale MA, Bauer F. Mantle cell lymphoma arising in a multiple myeloma patient responding to lenalidomide. Leuk Res 2010; 34: 178–180.

17. Fine HA, Kim L, Albert PS et al. A phase I trial of lenalidomide in patients with recurrent primary central nervous system tumors. Clin Cancer Res 2007; 13: 7101–7106.

18. Mandac I, Kolonic SO. Lenalidomide induced good clinical response in a patient with multiple relapsed and refractory Hodgkin’s lymphoma. J Hematol Oncol 2010; 3: 20–25.

19. Sher T, Miller KC, Lawrence D et al. Efficacy of lenalidomide in patients with chronic lymphocytic leukemia with high-risk cytogenetics. Leuk Lymphoma 2010; 51: 85–88.

20. Böll B, Borchmann P, Topp MS et al. Lenalidomide in patients with refractory or multiple relapsed Hodgkin lymphoma. Br J Haematol 2010; 148: 480–482.

21. Habermann TM, Lossos IS, Justice G et al. Lenalidomide oral monotherapy produces a high response rate in patients with relapsed or refractory mantle cell lymphoma. Br J Haematol 2009; 145: 344–339.

22. Galustian C, Dalgleish A. Lenalidomide: a novel anticancer drug with multiple modalities. Expert Opin Pharmacother 2009; 10: 125–133.

23. Tempescul A, Ianotto JC, Morel F et al. Lenalidomide, as a single agent, induces complete remission in a refractory mantle cell lymphoma. Ann Hematol 2009; 88: 921–922.

24. Wiernik PH, Lossos IS, Tuscano JM et al. Lenalidomide monotherapy in relapsed or refractory aggressive non-Hodgkin’s lymphoma. J Clin Oncol 2008; 26: 4952–4957.

25. Chanan-Khan AA, Cheson BD. Lenalidomide for the treatment of B-cell malignancies. J Clin Oncol 2008; 26: 1544–1552.

26. Darabi K, Kantamnei S, Wiernik PH. Lenalidomide-induced warm autoimmune hemolytic anemia. J Clin Oncol 2006; 24: e59.

27. Bowcock SJ, Patrick HE. Lenalidomide to control gastrointestinal bleeding in hereditary haemorrhagic telangiectasia: potential implications for angiodysplasias? Br J Haematol 2009; 146: 220–222.

28. Sumrall A, Fredericks R, Berthold A et al. Lenalidomide stops progression of multifocal epitheloid hemangioendothelioma including intracranial disease. J Neurooncol 2010; 97: 275–277.

29. Ščudla V, Heřman M, Minařík J et al. Přínos celotělové magnetické rezonance pro diagnostiku monoklonální gammapatie nejistého významu, mnohočetného myelomu a stanovení klinického stadia dle Durie-Salmon Plus stážovacího systému. Vnitř Lék 2011; 57: 52–60.

30. Mysliveček M, Bačovský J, Ščudla V et al. 18F-FDG PET/CT v diagnostice mnohočetného myelomu a monoklonální gamapatie nejistého významu: srovnání s 99mTc-MIBI scintigrafií. Klin Onkol 2010; 23: 325–331.