Purpose of Review
Secondary AML (s-AML) encompasses a distinct subgroup of AML with either therapy-related AML or AML arising from preexisting myeloid neoplasms. Despite recent advances in the treatment armamentarium of AML, outcomes remain poor in s-AML. The purpose of this review is to highlight distinct characteristics, prognostic factors, and treatment options for patients with s-AML. Further, we focus on a distinctly poor-risk subgroup of s-AML with previous exposure to hypomethylating agents (HMAs) and describe ongoing clinical trials in this patient population.
CPX-351 (liposomal daunorubicin and cytarabine) is the first drug approved for s-AML and represents an advancement in the management of fit patients with this subtype of AML. Despite incremental improvement in remission rates and survival, long-term survival remains poor. Patients who have received prior HMAs for antecedent MDS rarely benefit from CPX-351 or other cytotoxic chemotherapy regimens. The approval of venetoclax in combination with azacitidine has led to a paradigm shift in the management of newly diagnosed older unfit AML patients; however, patients with s-AML and prior HMA therapy were excluded from the landmark randomized phase 3 study. Several early phase clinical trials with both low- and high-intensity therapies are ongoing for s-AML patients, though prior HMA exposure limits inclusion in many of these studies that include HMAs.
Patients with s-AML previously treated with an HMA have dismal outcomes with standard therapeutic options and are under-represented in clinical trials. Trials investigating novel therapeutic options in this population are critically needed.
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Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391–405.
Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129(4):424–47.
Papaemmanuil E, Gerstung M, Bullinger L, Gaidzik VI, Paschka P, Roberts ND, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374(23):2209–21.
Zeidner JF, Foster MC, Blackford AL, Litzow MR, Morris LE, Strickland SA, et al. Randomized multicenter phase II study of flavopiridol (alvocidib), cytarabine, and mitoxantrone (FLAM) versus cytarabine/daunorubicin (7+3) in newly diagnosed acute myeloid leukemia. Haematologica. 2015;100(9):1172–9.
Lindsley RC, Mar BG, Mazzola E, Grauman PV, Shareef S, Allen SL, et al. Acute myeloid leukemia ontogeny is defined by distinct somatic mutations. Blood. 2015;125(9):1367–76 This analysis is the first to specifically define secondary AML by the presence of specific molecular mutations.
Higgins A, Shah MV. Genetic and genomic landscape of secondary and therapy-related acute myeloid leukemia. Genes (Basel). 2020;11(7):749.
Borthakur G, Lin E, Jain N, Estey EE, Cortes JE, O’Brien S, et al. Survival is poorer in patients with secondary core-binding factor acute myelogenous leukemia compared with de novo core-binding factor leukemia. Cancer. 2009;115(14):3217–21.
Boddu P, Kantarjian HM, Garcia-Manero G, Ravandi F, Verstovsek S, Jabbour E, et al. Treated secondary acute myeloid leukemia: a distinct high-risk subset of AML with adverse prognosis. Blood Adv. 2017;1(17):1312–23.
Kennedy JA, Atenafu EG, Messner HA, Craddock KJ, Brandwein JM, Lipton JH, et al. Treatment outcomes following leukemic transformation in Philadelphia-negative myeloproliferative neoplasms. Blood. 2013;121(14):2725–33.
Boddu PC, Kantarjian HM, Ravandi F, Garcia-Manero G, Verstovsek S, Jabbour EJ, et al. Characteristics and outcomes of older patients with secondary acute myeloid leukemia according to treatment approach. Cancer. 2017;123(16):3050–60.
Stone RM, Mazzola E, Neuberg D, Allen SL, Pigneux A, Stuart RK, et al. Phase III open-label randomized study of cytarabine in combination with amonafide L-malate or daunorubicin as induction therapy for patients with secondary acute myeloid leukemia. J Clin Oncol. 2015;33(11):1252–7 This is the first randomized phase 3 study specifically done in a secondary AML patient population. Ultimately, there was no significant difference in outcomes between cytarabine + amonafide versus cytarabine + daunorubicin in newly diagnosed secondary AML.
Lancet JE, Cortes JE, Hogge DE, Tallman MS, Kovacsovics TJ, Damon LE, et al. Phase 2 trial of CPX-351, a fixed 5:1 molar ratio of cytarabine/daunorubicin, vs cytarabine/daunorubicin in older adults with untreated AML. Blood. 2014;123(21):3239–46.
Lancet JE, Uy GL, Cortes JE, Newell LF, Lin TL, Ritchie EK, et al. CPX-351 (cytarabine and daunorubicin) liposome for injection versus conventional cytarabine plus daunorubicin in older patients with newly diagnosed secondary acute myeloid leukemia. J Clin Oncol. 2018;36(26):2684–92 This landmark randomized phase 3 study revealed that CPX-351 led to significantly improved overall survival and clinical outcomes compared with 7+3 in newly diagnosed older adults with secondary AML or AML with MDS-Related Changes rednering CPX-351 a new standard-of-care for this patient population.
Becker PS, Medeiros BC, Stein AS, Othus M, Appelbaum FR, Forman SJ, et al. G-CSF priming, clofarabine, and high dose cytarabine (GCLAC) for upfront treatment of acute myeloid leukemia, advanced myelodysplastic syndrome or advanced myeloproliferative neoplasm. Am J Hematol. 2015;90(4):295–300.
Rizzieri DA, O'Brien JA, Broadwater G, Decastro CM, Dev P, Diehl L, et al. Outcomes of patients who undergo aggressive induction therapy for secondary acute myeloid leukemia. Cancer. 2009;115(13):2922–9.
Hulegårdh E, Nilsson C, Lazarevic V, Garelius H, Antunovic P, Rangert Derolf Å, et al. Characterization and prognostic features of secondary acute myeloid leukemia in a population-based setting: a report from the Swedish Acute Leukemia Registry. Am J Hematol. 2015;90(3):208–14.
Granfeldt Østgård LS, Medeiros BC, Sengeløv H, Nørgaard M, Andersen MK, Dufva IH, et al. Epidemiology and clinical significance of secondary and therapy-related acute myeloid leukemia: a national population-based cohort study. J Clin Oncol. 2015;33(31):3641–9.
Kantarjian H, O'Brien S, Cortes J, Giles F, Faderl S, Jabbour E, et al. Results of intensive chemotherapy in 998 patients age 65 years or older with acute myeloid leukemia or high-risk myelodysplastic syndrome: predictive prognostic models for outcome. Cancer. 2006;106(5):1090–8.
Borate U, Norris BA, Statler A, Fu R, Bucy T, Sekeres MA. Representation of therapy-related myelodysplastic syndrome in clinical trials over the past 20 years. Blood Adv. 2019;3(18):2738–47 This important analysis revealed the underrepresentation of therapy-related MDS on prospective clinical trials reinforcing the importance of inclusion of this patient population and the lack of generalizability of our treatments for this patient population.
Burnett AK, Milligan D, Prentice AG, Goldstone AH, McMullin MF, Hills RK, et al. A comparison of low-dose cytarabine and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment. Cancer. 2007;109(6):1114–24.
Kantarjian HM, Thomas XG, Dmoszynska A, Wierzbowska A, Mazur G, Mayer J, et al. Multicenter, 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(21):2670–7.
Dombret H, Seymour JF, Butrym A, Wierzbowska A, Selleslag D, Jang JH, et al. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood. 2015;126(3):291–9.
Kantarjian HM, Roboz GJ, Kropf PL, Yee KWL, O’Connell CL, Tibes R, et al. Guadecitabine (SGI-110) in treatment-naive patients with acute myeloid leukaemia: phase 2 results from a multicentre, randomised, phase 1/2 trial. Lancet Oncol. 2017;18(10):1317–26.
Fenaux P, Gobbi M, Kropf PL, Mayer J, Roboz GJ, Döhner H, et al. S879 Results of ASTRAL-1 study, a phase 3 randomized trial of guadecitabine (G) vs treatment choice (TC) in treatment naïve acute myeloid leukemia (TN-AML) not eligible for intensive chemotherapy (IC). HemaSphere. 2019;3(S1):394–5.
Amadori S, Suciu S, Selleslag D, Aversa F, Gaidano G, Musso M, et al. Gemtuzumab ozogamicin versus best supportive care in older patients with newly diagnosed acute myeloid leukemia unsuitable for intensive chemotherapy: results of the randomized phase III EORTC-GIMEMA AML-19 trial. J Clin Oncol. 2016;34(9):972–9.
Roboz GJ, DiNardo CD, Stein EM, de Botton S, Mims AS, Prince GT, et al. Ivosidenib induces deep durable remissions in patients with newly diagnosed IDH1-mutant acute myeloid leukemia. Blood. 2020;135(7):463–71.
Pollyea DA, Tallman MS, de Botton S, Kantarjian HM, Collins R, Stein AS, et al. Enasidenib, an inhibitor of mutant IDH2 proteins, induces durable remissions in older patients with newly diagnosed acute myeloid leukemia. Leukemia. 2019;33(11):2575–84.
Cortes JE, Heidel FH, Hellmann A, Fiedler W, Smith BD, Robak T, et al. Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome. Leukemia. 2019;33(2):379–89.
Wei AH, Montesinos P, Ivanov V, CD DN, Novak J, Laribi K, et al. Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: a phase 3 randomized placebo-controlled trial. Blood. 2020;135(24):2137–45 This randomized phase 3 study compared LDAC + venetoclax versus LDAC + placebo in newly diagnosed older or unfit AML patients who are not candidates for intensive chemotherapy. Although response rates were higher with LDAC + venetoclax vs. LDAC + placebo, overall survival improvements were more modest and not statistically significant. Further, those with prior HMAs had dismal outcomes with LDAC + venetoclax.
CD DN, Jonas BA, Pullarkat V, Thirman MJ, Garcia JS, Wei AH, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383(7):617–29 This landmark randomized phase 3 study established azacitidine + venetoclax as a new standard-of-care in newly diagnosed older or unfit AML patients who are not candidates for intensive chemotherapy. Azacitidine + venetoclax led to significant improvement in overall survival and clinical outcomes compared with azacitidine + placebo. However, patients previously treated with HMAs for MDS or other myeloid malignancies were excluded on this study; thus, these results are not generalizable to secondary AML with prior HMA treatment.
DiNardo CD, Maiti A, Rausch CR, Pemmaraju N, Naqvi K, Daver NG, et al. 10-day decitabine with venetoclax for newly diagnosed intensive chemotherapy ineligible, and relapsed or refractory acute myeloid leukaemia: a single-centre, phase 2 trial. Lancet Haematol. 2020;7(10):e724–e36.
Fenaux P, Mufti GJ, Hellström-Lindberg E, Santini V, Gattermann N, Germing U, et al. Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol. 2010;28(4):562–9.
DiNardo CD, Stein EM, de Botton S, Roboz GJ, Altman JK, Mims AS, et al. Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N Engl J Med. 2018;378(25):2386–98.
Heuser M, Robak T, Montesinos P, Leber B, Fiedler WM, Pollyea DA, et al. Glasdegib (GLAS) plus low-dose cytarabine (LDAC) in AML or MDS: BRIGHT AML 1003 final report and four-year overall survival (OS) follow-up. J Clin Oncol. 2020;38(15_suppl):7509.
Konopleva M, Pollyea DA, Potluri J, Chyla B, Hogdal L, Busman T, et al. Efficacy and biological correlates of response in a phase ii study of venetoclax monotherapy in patients with acute myelogenous leukemia. Cancer Discov. 2016;6(10):1106–17.
Konopleva M, Letai A. BCL-2 inhibition in AML: an unexpected bonus? Blood. 2018;132(10):1007–12.
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(10):2429–40.
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(3):223–32.
Kantarjian H, Issa JP, Rosenfeld CS, Bennett JM, Albitar M, DiPersio J, et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer. 2006;106(8):1794–803.
Lübbert M, Suciu S, Baila L, Rüter 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(15):1987–96.
Bello C, Yu D, Komrokji RS, Zhu W, Wetzstein GA, List AF, et al. Outcomes after induction chemotherapy in patients with acute myeloid leukemia arising from myelodysplastic syndrome. Cancer. 2011;117(7):1463–9.
Talati C, Goldberg AD, Przespolewski A, Chan O, Ali NA, Kim J, et al. Comparison of induction strategies and responses for acute myeloid leukemia patients after resistance to hypomethylating agents for antecedent myeloid malignancy. Leuk Res. 2020;93:106367.
Jaglal MV, Duong VH, Bello CM, Al Ali NH, Padron E, Fernandez HF, et al. Cladribine, cytarabine, filgrastim, and mitoxantrone (CLAG-M) compared to standard induction in acute myeloid leukemia from myelodysplastic syndrome after azanucleoside failure. Leuk Res. 2014;38(4):443–6.
Menssen AJ, Walter MJ. Genetics of progression from MDS to secondary leukemia. Blood. 2020;136(1):50–60.
Yokoyama K, Shimizu E, Yokoyama N, Nakamura S, Kasajima R, Ogawa M, et al. Cell-lineage level-targeted sequencing to identify acute myeloid leukemia with myelodysplasia-related changes. Blood Adv. 2018;2(19):2513–21.
Tefferi A, Mudireddy M, Mannelli F, Begna KH, Patnaik MM, Hanson CA, et al. Blast phase myeloproliferative neoplasm: Mayo-AGIMM study of 410 patients from two separate cohorts. Leukemia. 2018;32(5):1200–10.
Grinfeld J, Nangalia J, Baxter EJ, Wedge DC, Angelopoulos N, Cantrill R, et al. Classification and personalized prognosis in myeloproliferative neoplasms. N Engl J Med. 2018;379(15):1416–30.
Tefferi A, Guglielmelli P, Lasho TL, Gangat N, Ketterling RP, Pardanani A, et al. MIPSS70+ Version 2.0: mutation and karyotype-enhanced international prognostic scoring system for primary myelofibrosis. J Clin Oncol. 2018;36(17):1769–70.
Tefferi A, Guglielmelli P, Nicolosi M, Mannelli F, Mudireddy M, Bartalucci N, et al. GIPSS: genetically inspired prognostic scoring system for primary myelofibrosis. Leukemia. 2018;32(7):1631–42.
Mascarenhas JO, Rampal RK, Kosiorek HE, Bhave R, Hexner E, Wang ES, et al. Phase 2 study of ruxolitinib and decitabine in patients with myeloproliferative neoplasm in accelerated and blast phase. Blood Adv. 2020;4(20):5246–56.
McKenney AS, Lau AN, Somasundara AVH, Spitzer B, Intlekofer AM, Ahn J, et al. JAK2/IDH-mutant-driven myeloproliferative neoplasm is sensitive to combined targeted inhibition. J Clin Invest. 2018;128(2):789–804.
Cahill K, Patel AA, Liu H, Gurbuxani S, Thirman M, Kosuri S, et al. Outcomes of IDH-mutated advanced phase Ph-negative myeloproliferative neoplasms treated with idh inhibitors. Blood, 2019;134(Supplement_1):4176.
Pratz KW, Rudek MA, Gojo I, Litzow MR, McDevitt MA, Ji J, et al. A phase I study of topotecan, carboplatin and the PARP inhibitor veliparib in acute leukemias, aggressive myeloproliferative neoplasms, and chronic myelomonocytic leukemia. Clin Cancer Res. 2017;23(4):899–907.
Seiler M, Yoshimi A, Darman R, Chan B, Keaney G, Thomas M, et al. H3B-8800, an orally available small-molecule splicing modulator, induces lethality in spliceosome-mutant cancers. Nat Med. 2018;24(4):497–504.
Steensma DP, Wermke M, Klimek VM, Greenberg PL, Font P, Komrokji RS, et al. Results of a clinical trial of H3B-8800, a splicing modulator, in patients with myelodysplastic syndromes (MDS), acute myeloid leukemia (AML) or chronic myelomonocytic leukemia (CMML). Blood, 2019;134(Supplement_1):673.
Sallman D A A A, Kambhampati S, Al Malki MM, Zeidner JF, Donnellan W, et al. The first-in-class anti-CD47 antibody magrolimab combined with azacitidine is well-tolerated and effective in AML patients: phase 1b results. Blood. 2020.
Sallman DA, DeZern AE, Garcia-Manero G, Steensma DP, Roboz GJ, Sekeres MA, et al. Phase 2 results of APR-246 and azacitidine (AZA) in patients with TP53 mutant myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia (AML). Blood. 2019;134(Supplement_1):676.
Uy GL, Duncavage EJ, Chang GS, Jacoby MA, Miller CA, Shao J, et al. Dynamic changes in the clonal structure of MDS and AML in response to epigenetic therapy. Leukemia. 2017;31(4):872–81.
Jacoby MA, Duncavage EJ, Chang GS, Miller CA, Shao J, Elliott K, et al. Subclones dominate at MDS progression following allogeneic hematopoietic cell transplant. JCI Insight. 2018;3(5).
Qin T, Jelinek J, Si J, Shu J, Issa JP. Mechanisms of resistance to 5-aza-2'-deoxycytidine in human cancer cell lines. Blood. 2009;113(3):659–67.
Kantharidis P, El-Osta A. deSilva M, Wall DM, Hu XF, Slater A, et al. Altered methylation of the human MDR1 promoter is associated with acquired multidrug resistance. Clin Cancer Res. 1997;3(11):2025–32.
Yang H, Bueso-Ramos C, DiNardo C, Estecio MR, Davanlou M, Geng QR, et al. Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents. Leukemia. 2014;28(6):1280–8.
Conflicts of interest
MCF has served as a consultant for Daiichi-Sankyo and Macrogenics and has received institutional research funding from Bellicum Pharmaceuticals and Macrogenics.
JFZ has received honoraria from Agios, Bristol-Myers Squibb/Celgene, Daiichi-Sankyo, Genentech, Pfizer, and Takeda; has served as a consultant for AbbVie, AsystBio Laboratories, Celgene, and Takeda; and has received institutional research funding from AROG, Forty Seven, Merck, Sumitomo Dainippon Pharma, and Takeda.
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Richardson, D.R., Green, S.D., Foster, M.C. et al. Secondary AML Emerging After Therapy with Hypomethylating Agents: Outcomes, Prognostic Factors, and Treatment Options. Curr Hematol Malig Rep (2021). https://doi.org/10.1007/s11899-021-00608-6
- Acute myeloid leukemia
- Secondary AML
- Hypomethylating agents
- Clinical trials