Phase 2 clinical trial of 5-azacitidine, valproic acid, and all-trans retinoic acid in patients with high-risk acute myeloid leukemia or myelodysplastic syndrome

Emmanuel Raffoux, Audrey Cras, Christian Recher, Pierre-Yves Boëlle, Adrienne de Labarthe, Pascal Turlure, Jean-Pierre Marolleau, Oumedaly Reman, Claude Gardin, Maud Victor, Sébastien Maury, Philippe Rousselot, Jean-Valère Malfuson, Odile Maarek, Marie-Thérèse Daniel, Pierre Fenaux, Laurent Degos, Christine Chomienne, Sylvie Chevret, Hervé Dombret, Emmanuel Raffoux, Audrey Cras, Christian Recher, Pierre-Yves Boëlle, Adrienne de Labarthe, Pascal Turlure, Jean-Pierre Marolleau, Oumedaly Reman, Claude Gardin, Maud Victor, Sébastien Maury, Philippe Rousselot, Jean-Valère Malfuson, Odile Maarek, Marie-Thérèse Daniel, Pierre Fenaux, Laurent Degos, Christine Chomienne, Sylvie Chevret, Hervé Dombret

Abstract

In this Phase 2 study, we evaluated the efficacy of combination of 5-azacitidine (AZA), valproic acid (VPA), and all-trans retinoic acid (ATRA) in patients with high-risk acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Treatment consisted of six cycles of AZA and VPA for 7 days, followed by ATRA for 21 days. Sixty-five patients were enrolled (median age, 72 years; 55 AML including 13 relapsed/refractory patients, 10 MDS; 30 unfavorable karyotypes). Best responses included 14 CR and 3 PR (26%), 75% of the responders and 36% of the non-responders achieving an erythroid response. Median overall survival (OS) was 12.4 months. Untreated patients had a longer OS than relapsed/refractory patients. In patients who fulfilled the 6 planned cycles, OS did not appear to depend on CR/PR achievement, suggesting that stable disease while on-treatment would be a surrogate for survival with this approach. During therapy, early platelet response and demethylation of the FZD9, ALOX12, HPN, and CALCA genes were associated with clinical response. Finally, there was no evidence for the restoration of an ATRA-induced differentiation during therapy. Epigenetic modulation deserves prospective comparisons to conventional care in patients with high-risk AML, at least in those presenting previously untreated disease and low blast count.

Figures

Fig. 1
Fig. 1
Kinetics of peripheral blood neutrophil count, platelet count, and hemoglobin level during the treatment period. The evolution of peripheral blood neutrophil count (/mm3), platelet count (/mm3), and hemoglobin level (g/dL) is shown in the 34 patients who may receive the planned 6 treatment cycles, according to the response (15 CR + PR patients versus 19 non-responding patients).
Fig. 2. Overall survival
Fig. 2. Overall survival
(A) OS from study inclusion according to the three eligibility subsets. OS was significantly shorter in patients relapsing after prior intensive chemotherapy (subset 2) than in naïve patients with either AML (subset 1) or high-risk MDS (subset 3) (P= 0.0024). (B) OS following the 6-month evaluation according to the response observed at 6 months. In the 34 patients who received the 6 planned cycles, OS after the 6-month evaluation was not significantly different between responding (N= 15) and non-responding (N= 19) patients.

References

    1. Herman JG, Baylin SB. Mechanisms of disease: gene silencing in cancer in association with promoter hypermethylation. N Engl J Med. 2003;349:2042–2054.
    1. Silverman LR, Demakos EP, Peterson BL, Kornblith AB, Holland JC, Odchimar-Reissig R, Stone RM, Nelson D, Powell BL, DeCastro CM, Ellerton J, Larson RA, Schiffer CA, Holland JF. 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.
    1. Sudan N, Rossetti JM, Shadduck RK, Latsko J, Lech JA, Kaplan RB, Kennedy M, Gryn JF, Faroun Y, Lister J. Treatment of acute myelogenous leukemia with outpatient azacitidine. Cancer. 2006;107:1839–1843.
    1. Cashen AF, Schiller GJ, O'Donnell MR, Larsen JS, Baranwal A, DiPersio JF. Preliminary results of a multicenter Phase II trial of 5-day decitabine as front-line therapy for elderly patients with acute myeloid leukemia. Blood. 2008;112:560. ASH Meeting Abstracts.
    1. Lübbert M, Schmid M, Rüter B, Germing U, Rethwisch V, Ganser A, Platzbecker U, Galm O, Brugger W, Wijermans PW, Schmoor C, Döhner H. Continued treatment with an outpatient maintenance schedule of decitabine in older AML patients ineligible for induction chemotherapy: results of the 00331 Phase II multicenter trial. Blood. 2008;112:2965. ASH Meeting Abstracts.
    1. Blum W, Klisovic R, Liu S, Garzon R, Kefauver C, Liu Z, Mickle J, Devine H, Devine S, Grever MR, Chan K, Villalona-Calero M, Byrd JC, Marcucci G. Preliminary results of a Phase II study of low dose decitabine as a single agent in older patients (age≥60) with previously untreated acute myeloid leukemia. Blood. 2008;112:2957. ASH Meeting Abstracts.
    1. Al-Hali HK. The safety and efficacy of azacitidine in patients with newly-diagnosed and refractory/relapsed AML not eligible for or resistant to chemotherapy: a multicenter Phase I/II study of the East German Haematology and Oncology Study Group (OSHO) Haematologica. 2009;94:343. EHA Meeting Abstracts.
    1. Fenaux P, Mufti GJ, Hellstrom - Lindberg E, Santini V, Finelli C, Giagounidis A, Schoch R, Gattermann N, Sanz G, List A, Gore SD, Seymour JF, Bennett JM, Byrd J, Backstrom J, Zimmerman L, McKenzie D, Beach C, Silverman LR. International Vidaza High-Risk MDS Survival Study Group. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes : a randomized open-label Phase III study. Lancet Oncol. 2009;10:223–232.
    1. Fenaux P, Mufti GJ, Hellström-Lindberg E, Santini V, Gattermann N, Germing U, Sanz G, List AF, Gore S, Seymour JF, Dombret H, Backstrom J, Zimmerman L, McKenzie D, Beach CL, Silverman LR. Azacitidine improves overall survival in WHO acute myeloid leukemia in elderly patients with low bone marrow blast count. J Clin Oncol. 2010;28:562–569.
    1. Kitaruma K, Hoshi S, Koike M, Kiyoi H, Saito H, Naoe T. Histone deacetylase inhibitor but not arsenic trioxide differentiates acute promyelocytic leukaemia cells with t(11;17) in combination with all-trans retinoic acid. Br J Haematol. 2000;108:696–702.
    1. Warrell RP, Jr, He LZ, Richon V, Calleja E, Pandolfi PP. Therapeutic targeting of transcription in acute promyelocytic leukemia by use of an inhibitor of histone deacetylase. J Nat Cancer Inst. 1998;90:1621–1625.
    1. Phiel CJ, Zhang F, Huang EY, Guenther MG, Lazar MA, Klein PS. Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J Biol Chem. 2001;276:36734–36741.
    1. Kuendgen A, Strupp C, Aivado M, Bernhardt A, Hildebrandt B, Haas R, Germing U, Gattermann N. Treatment of myelodysplastic syndromes with valproic acid alone or in combination with all-trans retinoic acid. Blood. 2004;104:1266–1269.
    1. Raffoux E, Chaibi P, Dombret H, Degos L. Valproic acid and all-trans retinoic acid for the treatment of elderly patients with acute myeloid leukemia. Haematologica. 2005;90:986–988.
    1. Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, Vallespi T, Hamblin T, Oscier D, Ohyashiki K, Toyama K, Aul C, Mufti G, Bennett J. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997;89:2079–2088.
    1. Cheson BD, Bennett JM, Kopecky KJ, Bûchner T, William CL, Estey EH, Schiffer CA, Doehner H, Tallman MS, Lister TA, Lo-Coco F, Willemze R, Biondi A, Hiddemann W, Larson RA, Löwenberg B, Sanz MA, Head DR, Ohno R, Bloomfield CD. Revised recommendations of the International Working Group for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia. J Clin Oncol. 2003;21:4642–4649.
    1. Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, Pinto A, Beran M, de Witte TM, Stone RM, Mittelman M, Sanz GF, Gore SD, Schiffer CA, Kantarjian H. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood. 2006;108:419–425.
    1. Soriano AO, Yang H, Faderl S, Estrov Z, Giles F, Ravandi F, Cortes J, Wierda WG, Ouzounian S, Quezada A, Pierce S, Estey EH, Issa JP, Kantarjian HM, Garcia-Manero G. Safety and clinical activity of the combination of 5-azacitidine, valproic acid, and all-trans retinoic acid in patients with acute myeloid leukemia and myelodysplastic syndrome. Blood. 2007;110:2302–2308.
    1. Craddock C, Goardon N, Griffiths M, Siddique S, Cavenagh J, Vyas P. 5' azacitidine in combination with valproic acid induces complete remissions in patients with high risk acute myeloid leukaemia but does not eradicate clonal leukaemic stem/progenitor cells. Haematologica. 2009;94:429. EHA Meeting Abstracts.
    1. Garcia-Manero G, Kantarjian HM, Sanchez-Gonzalez B, Yang H, Rosner G, Verstovsek S, Rytting M, Wierda WG, Ravandi F, Koller C, Xiao L, Faderl S, Estrov Z, Cortes J, O'brien S, Estey E, Bueso-Ramos C, Fiorentino J, Jabbour E, Issa JP. Phase 1/2 study of the combination of 5-aza-2'-deoxycytidine with valproic acid in patients with leukemia. Blood. 2006;108:3271–3279.
    1. Yang H, Hoshino K, Sanchez-Gonzalez B, Kantarjian H, Garcia-Manero G. Antileukemia activity of the combination of 5-aza-2'-deoxycytidine with valproic acid. Leukemia Research. 2005;29:739–748.
    1. Issa JP, Castoro R, Ravandi-Kashani F, Faderl S, Huang X, Estey E, Borthakur G, Morris G, Garcia-Manero G, Kantarjian H. Randomized Phase II study of combined epigenetic therapy: decitabine vs. decitabine and valproic acid in MDS and AML. Blood. 2008;112:228. ASH Annual Meeting Abstracts.
    1. Silverman LR, Verma A, Odchimar-Reissig R, LeBlanc A, Najfeld V, Gabrilove J, Isola L, Espinoza_Delgado I, Zwiebel J. A phase I trial of epigenetic modulators vorinostat, in combination with azacitidine (azaC) in patients with the myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML): a study of the New York Cancer Consortium. Blood. 2008;112:3656. ASH Annual Meeting Abstracts.
    1. Fandy TE, Herman JG, Kerns P, Jiemjit A, Sugar EA, Choi SH, Yang AS, Aucott T, Dauses T, Odchimar-Reissig R, Licht J, McConnell MJ, Nasrallah C, Kim MK, Zhang W, Sun Y, Murgo A, Espinoza-Delgado I, Oteiza K, Owoeye I, Silverman LR, Gore SD, Carraway HE. Early epigenetic changes and DNA damage do not predict clinical response in an overlapping schedule of 5-azacitidine and entinostat in patients with myeloid malignancies. Blood. 2009;114:3448–3458.
    1. Jiang Y, Dunbar A, Gondek L.P, Mohan S, Rataul M, O'Keefe C, Sekeres M, Saunthararajah Y, Maciejewski JP. Aberrant DNA methylation is a dominant mechanism in MDS progression to AML. Blood. 2009;113:1315–1325.

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