Combination of Azacitidine and Lenalidomide in Myelodysplastic Syndromes or acute Myeloid Leukemia - A wise Liaison?

Leukemia

Volumn 27, Issue 9, 2013, Pages 1813-1819

  Platzbecker, U ^a,b   Germing, U ^b  

^a UNIVERSITY HOSPITAL CARL GUSTAV CARUS   (Germany)

^b UNIVERSITY HOSPITAL DÜSSELDORF   (Germany)

Author keywords

acute myeloid leukemia; azacitidine; combination therapy; higher risk; lenalidomide; myelodysplastic syndromes

Indexed keywords

AZACITIDINE; DNA METHYLTRANSFERASE; FIBROBLAST GROWTH FACTOR 2; INTERLEUKIN 12; INTERLEUKIN 1BETA; INTERLEUKIN 2; INTERLEUKIN 6; LENALIDOMIDE; PROTEIN P53; TUMOR NECROSIS FACTOR ALPHA; VASCULOTROPIN;

ACUTE GRANULOCYTIC LEUKEMIA; ANTIANGIOGENIC ACTIVITY; CELL DIFFERENTIATION; CELL MIGRATION; CYTOKINE PRODUCTION; DNA METABOLISM; DNA REPLICATION; DNA SYNTHESIS; DRUG DOSE ESCALATION; DRUG EFFICACY; DRUG MECHANISM; DRUG MEGADOSE; DRUG RESPONSE; ENDOTHELIUM CELL; GENE EXPRESSION REGULATION; HUMAN; IMMUNOMODULATION; LEUKEMIA REMISSION; LEUKOPENIA; LYMPHOCYTE PROLIFERATION; MAINTENANCE DRUG DOSE; MULTICENTER STUDY (TOPIC); MYELODYSPLASTIC SYNDROME; NEUTROPENIA; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; REPEATED DRUG DOSE; REVIEW; T LYMPHOCYTE ACTIVATION; THROMBOCYTOPENIA; TREATMENT RESPONSE;

ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; AZACITIDINE; CLINICAL TRIALS AS TOPIC; HUMANS; LEUKEMIA, MYELOID, ACUTE; MYELODYSPLASTIC SYNDROMES; THALIDOMIDE; TREATMENT OUTCOME;

EID: 84883743079     PISSN: 08876924     EISSN: 14765551     Source Type: Journal    
DOI: 10.1038/leu.2013.140     Document Type: Review

References (66)

1. Platzbecker U. Allogeneic hematopoietic cell transplantation in patients with myelodysplastic syndromes. Seminars in Hematology 2012; 49: 342-349.
2. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol 2009; 10: 223-232.
3. Kantarjian HM, Thomas XG, Dmoszynska A, Wierzbowska A, Mazur G, Mayer J et al. Randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol 2012; 30: 2670-2677.
4. Lubbert M, Suciu S, Baila L, Ruter BH, Platzbecker U, Giagounidis A et al. Low-dose decitabine versus best supportive care in elderly patients with intermediate-or high-risk myelodysplastic syndrome (mds) ineligible for intensive chemotherapy: final results of the randomized phase III study of the european organisation for research and treatment of cancer leukemia group and the german mds study group. J Clin Oncol 2011; 29: 1987-1996.
5. Giagounidis AAN. Lenalidomide for del(5q) and non-del(5q) myelodysplastic syndromes. Seminars in Hematology 2012; 49: 312-322.
6. Kuendgen A, Lauseker M, List AF, Fenaux P, Giagounidis A, Brandenburg N et al. Lenalidomide does not increase AML progression risk in RBC transfusiondependent patients with low-or intermediate-1-risk MDS with del(5q): a comparative analysis. Leukemia 2012; 27: 1072-1079.
7. Kaminskas E, Farrell A, Abraham S, Baird A, Hsieh LS, Lee SL et al. Approval summary: azacitidine for treatment of myelodysplastic syndrome subtypes. Clin Cancer Res 2005; 11: 3604-3608. (Pubitemid 40685574)
8. Lee EJ, Hogge DE, Gallagher R, Schiffer CA. Low-dose 5-azacytidine is ineffective for remission induction in patients with acute myeloid-leukemia. Leukemia 1990; 4: 835-838.
9. Daskalakis M, Nguyen TT, Nguyen C, Guldberg P, Kohler G, Wijermans P et al. Demethylation of a hypermethylated P15/INK4B gene in patients with myelodysplastic syndrome by 5-Aza-2'-deoxycytidine (decitabine) treatment. Blood 2002; 100: 2957-2964.
10. Platzbecker U, Meredyth-Stewart M, Ehninger G. The pathogenesis of myelodysplastic syndromes (MDS). Cancer Treat Rev 2007; 33: S53-S58. (Pubitemid 350056323)
11. Jiang Y, Dunbar A, Gondek LP, Mohan S, Rataul M, O'Keefe C et al. Aberrant DNA methylation is a dominant mechanism in MDS progression to AML. Blood 2009; 113: 1315-1325.
12. Egger G, Liang G, Aparicio A, Jones PA. Epigenetics in human disease and prospects for epigenetic therapy. Nature 2004; 429: 457-463. (Pubitemid 38715140)
13. Menschikowski M, Platzbecker U, Hagelgans A, Vogel M, Thiede C, Schonefeldt C et al. Aberrant methylation of the M-type phospholipase A(2) receptor gene in leukemic cells. Bmc Cancer 2012; 12: 576.
14. Flotho C, Claus R, Batz C, Schneider M, Sandrock I, Ihde S et al. The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia 2009; 23: 1019-1028.
15. Silverman LR, Demakos EP, Peterson BL, Kornblith AB, Holland JC, Odchimar-Reissig R et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol 2002; 20: 2429-2440. (Pubitemid 34525728)
16. Sudan N, Rossetti JM, Shadduck RK, Latsko J, Lech JA, Kaplan RB et al. Treatment of acute myelogenous leukemia with outpatient azacitidine. Cancer 2006; 107: 1839-1843. (Pubitemid 44582953)
17. Al Ali HK, Jaekel N, Junghanss C, Maschmeyer G, Krahl R, Cross M et al. Azacitidine in patients with acute myeloid leukemia medically unfit for or resistant to chemotherapy: a multicenter phase I/II study. Leuk Lymphoma 2012; 53: 110-117.
18. Itzykson R, Thepot S, Quesnel B, Dreyfus F, Beyne-Rauzy O, Turlure P et al. Prognostic factors for response and overall survival in 282 patients with higher-risk myelodysplastic syndromes treated with azacitidine. Blood 2011; 117: 403-411.
19. Kulasekararaj AG, Smith AE, Mian SA, Krishnamurthy P, Mohamedali AM, Lea NC et al. TP53 mutations in myelodysplastic syndrome are strongly correlated with aberrations of chromosome 5, and correlate with adverse prognosis. Br J Haematol 2013; 160: 660-672.
20. Musto P, Maurillo L, Spagnoli A, Gozzini A, Rivellini F, Lunghi M et al. Azacitidine for the treatment of lower risk myelodysplastic syndromes. Cancer 2010; 116: 1485-1494.
21. Bally C, Itzykson R, Gruson B, Francois D, Siguret V, Taksin AL et al. Azacitidine (AZA) after failure of lenalidomide (LEN) in low/int-1 risk MDS with del 5q. Blood 2011; 118: 1200-1201.
22. Kuendgen A, Bug G, Ottmann OG, Haase D, Hildebrandt B, Habersang K et al. Treatment of poor risk myelodysplastic syndromes and acute myeloid leukemia with a combination of 5-azacytidine and valproic acids. Clin Epigenetics 2011; 2: 389-399.
23. Joeckel TE, Lubbert M. Clinical results with the dna hypomethylating agent 5-Aza-2 '-deoxycytidine (decitabine) in patients with myelodysplastic syndromes: an update. Semin Hematol 2012; 49: 330-341.
24. Dredge K, Horsfall R, Robinson SP, Zhang LH, Lu L, Tang Y et al. Orally administered lenalidomide (CC-5013) is anti-angiogenic in vivo and inhibits endothelial cell migration and Akt phosphorylation in vitro. Microvasc Res 2005; 69: 56-63. (Pubitemid 40410468)
25. Corral LG, Haslett PA, Muller GW, Chen R, Wong LM, Ocampo CJ et al. Differential cytokine modulation and T cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-alpha. J Immunol 1999; 163: 380-386. (Pubitemid 29295864)
26. Schafer PH, Gandhi AK, Loveland MA, Chen RS, Man HW, Schnetkamp PP et al. Enhancement of cytokine production and AP-1 transcriptional activity in T cells by thalidomide-related immunomodulatory drugs. J Pharmacol Exp Ther 2003; 305: 1222-1232. (Pubitemid 36618002)
27. Ebert BL, Pretz J, Bosco J, Chang CY, Tamayo P, Galili N et al. Identification of RPS14 as a 5q(-) syndrome gene by RNA interference screen. Nature 2008; 451: 335-3U7.
28. Wei S, Chen XH, Rocha K, Epling-Burnette PK, Djeu JY, Liu Q et al. A critical role for phosphatase haplodeficiency in the selective suppression of deletion 5q MDS by lenalidomide. Proc Natl Acad Sci USA 2009; 106: 12974-12979.
29. Narla A, Dutt S, McAuley JR, Al Shahrour F, Hurst S, McConkey M et al. Dexamethasone and lenalidomide have distinct functional effects on erythropoiesis. Blood 2011; 118: 2296-2304.
30. Boultwood J, Pellagatti A, McKenzie ANJ, Wainscoat JS. Advances in the 5qsyndrome. Blood 2010; 116: 5803-5811.
31. List A, Kurtin S, Roe DJ, Buresh A, Mahadevan D, Fuchs D et al. Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med 2005; 352: 549-557. (Pubitemid 40204668)
32. Sekeres MA, Maciejewski JP, Giagounidis AAN, Wride K, Knight R, Raza A et al. Relationship of treatment-related cytopenias and response to lenalidomide in patients with lower-risk myelodysplastic syndromes. J ClinOncol 2008; 26: 5943-5949.
33. Tehranchi R, Woll PS, Anderson K, Buza-Vidas N, Mizukami T, Mead AJ et al. Jacobsen SEW. Persistent malignant stem cells in del(5q) myelodysplasia in remission. New Engl J Med 2010; 363: 1025-1037.
34. Verhelle D, Corral LG, Wong K, Mueller JH, Parseval LM, Jensen-Pergakes K et al. Lenalidomide and CC-4047 inhibit the proliferation of malignant B cells while expanding normal CD34(\+) progenitor cells. Cancer Res 2007; 67: 746-755. (Pubitemid 46192215)
35. Wobus M, Benath G, Ferrer RA, Wehner R, Schmitz M, Hofbauer LC et al. Impact of lenalidomide on the functional properties of human mesenchymal stromal cells. Exp Hematol 2012; 40: 867-876.
36. Raza A, Reeves JA, Feldman EJ, Dewald GW, Bennett JM, Deeg J et al. Phase 2 study of lenalidomide in transfusion-dependent, low-risk, and intermediate-1-risk myelodysplastic syndromes with karyotypes other than deletion 5q. Blood 2008; 111: 86-93.
37. List A, Dewald G, Bennett J, Giagounidis A, Raza A, Feldman E et al. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med 2006; 355: 1456-1465. (Pubitemid 44511560)
38. Fenaux P, Giagounidis A, Selleslag D, Beyne-Rauzy O, Mufti G, Mittelman M et al. A randomized phase 3 study of lenalidomide versus placebo in RBC transfusiondependent patients with Low-/Intermediate-1-risk myelodysplastic syndromes with del5q. Blood 2011; 118: 3765-3776.
39. Giagounidis AA, Haase S, Heinsch M, Gohring G, Schlegelberger B, Aul C. Lenalidomide in the context of complex karyotype or interrupted treatment: case reviews of del(5q)MDS patients with unexpected responses. Ann Hematol 2007; 86: 133-137. (Pubitemid 44964005)
40. Giagounidis AA, Germing U, Strupp C, Hildebrandt B, Heinsch M, Aul C. Prognosis of patients with del(5q) MDS and complex karyotype and the possible role of lenalidomide in this patient subgroup. Ann Hematol 2005; 84: 569-571. (Pubitemid 41194542)
41. Lancet JE, List AF, Moscinski LC. Treatment of deletion 5q acute myeloid leukemia with lenalidomide. Leukemia 2007; 21: 586-588.
42. Platzbecker U, Mohr B, Von Bonin M, Binder M, Schetelig J, Ehninger G et al. Lenalidomide as induction therapy before allogeneic stem cell transplantation in a patient with proliferative CMML-2 and del(5q) not involving the EGR1 locus. 2007Leukemia 21: 2384-2385.
43. Ades L, Boehrer S, Prebet T, Beyne-Rauzy O, Legros L, Ravoet C et al. Efficacy and safety of lenalidomide in intermediate-2 or high-risk myelodysplastic syndromes with 5q deletion: results of a phase 2 study. Blood 2009; 113: 3947-3952.
44. Jerez A, Gondek LP, Jankowska AM, Makishima H, Przychodzen B, Tiu RV et al. Topography, clinical, and genomic correlates of 5q myeloid malignancies revisited. J Clin Oncol 2012; 30: 1343-1349.
45. Haferlach C, Dicker F, Herholz H, Schnittger S, Kern W, Haferlach T. Mutations of the TP53 gene in acute myeloid leukemia are strongly associated with a complex aberrant karyotype. Leukemia 2008; 22: 1539-1541.
46. Bejar R, Levine R, Ebert BL. Unraveling the molecular pathophysiology of myelodysplastic syndromes. J Clin Oncol 2011; 29: 504-515.
47. Jadersten M, Saft L, Smith A, Kulasekararaj A, Pomplun S, Gohring G et al. TP53 mutations in low-risk myelodysplastic syndromes with del(5q) predict disease progression. J Clin Oncol 2011; 29: 1971-1979.
48. Mollgard L, Saft L, Treppendahl MB, Dybedal I, Norgaard JM, Astermark J et al. Clinical effect of increasing doses of lenalidomide in high-risk myelodysplastic syndrome and acute myeloid leukemia with chromosome 5 abnormalities. Haematologica 2011; 96: 963-971.
49. Platzbecker U, Braulke F, Kuendgen A, Gotze KS, Bug G, Shirneshan K et al. Sequential combination of azacitidine and lenalidomide in del(5q) higher-risk MDS or AML-a phase 1 study. Leukemia 2013; 120: 21.
50. Steensma DP, Stone RM. Lenalidomide in AML: del(5q) or who? Blood 2011; 118: 481-482.
51. Fehniger TA, Uy GL, Trinkaus K, Nelson AD, Demland J, Abboud CN et al. A phase 2 study of high-dose lenalidomide as initial therapy for older patients with acute myeloid leukemia. Blood 2011; 117: 1828-1833.
52. Sekeres MA, Gundacker H, Lancet J, Advani A, Petersdorf S, Liesveld J et al. A phase 2 study of lenalidomide monotherapy in patients with deletion 5q acute myeloid leukemia: Southwest Oncology Group Study S0605. Blood 2011; 118: 523-528.
53. Fehniger TA, Byrd JC, Marcucci G, Abboud CN, Kefauver C, Payton JE et al. Singleagent lenalidomide induces complete remission of acute myeloid leukemia in patients with isolated trisomy 13. Blood 2009; 113: 1002-1005.
54. Ades L, Eclache V, Gardin C, Boehrer S, Leroux G, Martiat P et al. Efficacy of lenalidomide in an sAML patient with del 5q relapsing after reduced-intensity allogeneic stem cell transplantation performed in complete remission. Bone Marrow Transplant 2010; 45: 791-792.
55. Ford CD, Asch J, Konopa K, Petersen FB. CR with lenalidomide in del(5)(q13q33) AML relapsing after allogeneic hematopoietic SCT. Bone Marrow Transplant 2010; 45: 402-403.
56. Sockel K, Bornhaeuser M, Mischak-Weissinger E, Trenschel R, Wermke M, Unzicker C et al. Lenalidomide maintenance after allogeneic HSCT seems to trigger acute graft-versus-host disease in patients with high-risk myelodysplastic syndromes or acute myeloid leukemia and del(5q): results of the LENAMAINT trial. Haematologica 2012; 97: E34-E35.
57. Sekeres MA, List AF, Cuthbertson D, Paquette R, Ganetsky R, Latham D et al. Combination trial of lenalidomide and azacitidine in patients with higher-risk myelodysplastic syndromes. J Clin Oncol 2010; 28: 2253-2258.
58. Sekeres MA, Tiu RV, Komrokji R, Lancet J, Advani AS, Afable M et al. Phase 2 study of the lenalidomide and azacitidine combination in patients with higher-risk myelodysplastic syndromes. Blood 2012; 120: 4945-4951.
59. Sekeres MA, O'Keefe C, List AF, Paulic K, Afable M, Englehaupt R et al. Demonstration of additional benefit in adding lenalidomide to azacitidine in patients with higher-risk myelodysplastic syndromes. Am J Hematol 2011; 86: 102-103.
60. Pollyea DA, Kohrt HE, Gallegos L, Figueroa ME, Abdel-Wahab O, Zhang B et al. Efficacy and biological predictors of response to sequential azacitidine and lenalidomide for elderly patients with acute myeloid leukemia. Leukemia 2012; 26: 893-901.
61. Ramsingh G, Westervelt P, Cashen A, Uy GL, Stockerl-Goldstein K, Abboud CN et al. Phase 1 study of concomitant high dose lenalidomide and 5-azacytidine induction in the treatment of acute myeloid leukemia. Leukemia 2013; 27: 725-728.
62. Pollyea DA, Kohrt HE, Gallegos L, Figueroa ME, Abdel-Wahab O, Zhang B et al. Sequential azacitidine plus lenalidomide combination for elderly patients with untreated acute myeloid leukemia. Haematologica 2013; 98: 591-596.
63. Scherman E, Malak S, Perot C, Gorin NC, Rubio MT, Isnard F. Interest of the association azacitidine-lenalidomide as frontline therapy in high-risk myelodysplasia or acute myeloid leukemia with complex karyotype. Leukemia 2012; 26: 822-824.
64. Pellagatti A, Jadersten M, Forsblom AM, Cattan H, Christensson B, Emanuelsson EK et al. Lenalidomide inhibits the malignant clone and up-regulates the SPARC gene mapping to the commonly deleted region in 5q-syndrome patients. Proc Natl Acad Sci USA 2007; 104: 11406-11411. (Pubitemid 47175153)
65. Garcia-Manero G, Daver NG, Borthakur G, Konopleva M, Ravandi F, Wierda WG et al. Study of the combination of 5-azacitidine sequentially with high-dose lenalidomide in higher-risk myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). Blood 2011; 118: 1122.
66. Bejar R, Stevenson K, Abdel-Wahab O, Galili N, Nilsson B, Garcia-Manero G et al. Clinical effect of point mutations in myelodysplastic syndromes. New Engl J Med 2011; 364: 2496-2506.