Toward individualized therapy in acute myeloid leukemia a contemporary review

JAMA Oncology

Volumn 1, Issue 6, 2015, Pages 820-828

  Kadia, Tapan M ^a   Ravandi, Farhad ^a   Cortes, Jorge ^a   Kantarjian, Hagop ^a  

^a UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

TUMOR MARKER;

GENETIC EPIGENESIS; GENETIC PREDISPOSITION; GENETIC SCREENING; GENETICS; HUMAN; LEUKEMIA, MYELOID, ACUTE; MOLECULARLY TARGETED THERAPY; MUTATION; PATIENT SELECTION; PERSONALIZED MEDICINE; PHENOTYPE; PREDICTIVE VALUE; PROCEDURES; RISK ASSESSMENT; RISK FACTOR; TREATMENT OUTCOME;

BIOMARKERS, TUMOR; EPIGENESIS, GENETIC; GENETIC PREDISPOSITION TO DISEASE; GENETIC TESTING; HUMANS; LEUKEMIA, MYELOID, ACUTE; MOLECULAR TARGETED THERAPY; MUTATION; PATIENT SELECTION; PHENOTYPE; PRECISION MEDICINE; PREDICTIVE VALUE OF TESTS; RISK ASSESSMENT; RISK FACTORS; TREATMENT OUTCOME;

EID: 85010219668     PISSN: 23742437     EISSN: 23742445     Source Type: Journal    
DOI: 10.1001/jamaoncol.2015.0617     Document Type: Review

References (92)

1. Byrd JC, Mrózek K, Dodge RK, et al; Cancer and Leukemia Group B (CALGB 8461). Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). Blood. 2002;100 (13):4325-4336.
2. Döhner H, Estey EH, Amadori S, et al; European LeukemiaNet. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. 2010;115(3):453-474.
3. Grimwade D, Hills RK, Moorman AV, et al; National Cancer Research Institute Adult Leukaemia Working Group. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood. 2010;116(3):354-365.
4. Pastore F, Dufour A, Benthaus T, et al. Combined molecular and clinical prognostic index for relapse and survival in cytogenetically normal acute myeloid leukemia. J Clin Oncol. 2014;32(15): 1586-1594.
5. Mrózek K, Marcucci G, Paschka P, Whitman SP, Bloomfield CD. Clinical relevance of mutations and gene-expression changes in adult acute myeloid leukemia with normal cytogenetics: are we ready for a prognostically prioritized molecular classification? Blood. 2007;109(2):431-448.
6. Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013; 368(22):2059-2074.
7. Lindsley RC, Ebert BL. The biology and clinical impact of genetic lesions in myeloid malignancies. Blood. 2013;122(23):3741-3748.
8. Schlenk RF, Döhner K, Krauter J, et al; German-Austrian Acute Myeloid Leukemia Study Group. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008;358(18):1909-1918.
9. Patel JP, Gönen M, Figueroa ME, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 2012;366 (12):1079-1089.
10. Raelson JV, Nervi C, Rosenauer A, et al. The PML/RAR alpha oncoprotein is a direct molecular target of retinoic acid in acute promyelocytic leukemia cells. Blood. 1996;88(8): 2826-2832.
11. Niu C, Yan H, Yu T, et al. Studies on treatment of acute promyelocytic leukemia with arsenic trioxide: remission induction, follow-up, and molecular monitoring in 11 newly diagnosed and 47 relapsed acute promyelocytic leukemia patients. Blood. 1999;94(10):3315-3324.
12. Shen ZX, Chen GQ, Ni JH, et al. Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL), II: clinical efficacy and pharmacokinetics in relapsed patients. Blood. 1997;89(9):3354-3360.
13. Wang ZY, Chen Z. Acute promyelocytic leukemia: from highly fatal to highly curable. Blood. 2008;111(5):2505-2515.
14. Takeshita A, Shinjo K, Naito K, et al. Efficacy of gemtuzumab ozogamicin on ATRA-and arsenic-resistant acute promyelocytic leukemia (APL) cells. Leukemia. 2005;19(8):1306-1311.
15. Ghavamzadeh A, Alimoghaddam K, Rostami S, et al. Phase II study of single-agent arsenic trioxide for the front-line therapy of acute promyelocytic leukemia. J Clin Oncol. 2011;29(20):2753-2757.
16. Mathews V, George B, Lakshmi KM, et al. Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: durable remissions with minimal toxicity. Blood. 2006;107(7):2627-2632.
17. Shen ZX, Shi ZZ, Fang J, et al. All-trans retinoic acid/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci USA. 2004;101(15):5328-5335.
18. Ravandi F, Estey E, Jones D, et al. Effective treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin. J Clin Oncol. 2009;27(4): 504-510.
19. Lo-Coco F, Avvisati G, Vignetti M, et al; Gruppo Italiano Malattie Ematologiche dell'Adulto; German-Austrian Acute Myeloid Leukemia Study Group; Study Alliance Leukemia. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013;369(2):111-121.
20. Park JH, Qiao B, Panageas KS, et al. Early death rate in acute promyelocytic leukemia remains high despite all-trans retinoic acid. Blood. 2011;118(5): 1248-1254.
21. Rego EM, Kim HT, Ruiz-Argüelles GJ, et al. Improving acute promyelocytic leukemia (APL) outcome in developing countries through networking, results of the International Consortium on APL. Blood. 2013;121(11):1935-1943.
22. Byrd JC, Ruppert AS, Mrózek K, et al. Repetitive cycles of high-dose cytarabine benefit patients with acute myeloid leukemia and inv(16)(p13q22) or t(16;16)(p13;q22): results from CALGB 8461. J Clin Oncol. 2004;22(6):1087-1094.
23. Borthakur G, Cortes JE, Ravandi F, et al. Replacing gemtuzumab ozogamicin with idarubicin in frontline fludarabine, cytarabine and G-CSF based regimen does not compromise outcome in core binding factor acute myelogenous leukemia. https://ash.confex.com/ash/2013/webprogram/Paper60181.html. Accessed March 16, 2015.
24. Bradstock KF, Matthews JP, Lowenthal RM, et al; Australasian Leukaemia and Lymphoma Group. A randomized trial of high-versus conventional-dose cytarabine in consolidation chemotherapy for adult de novo acute myeloid leukemia in first remission after induction therapy containing high-dose cytarabine. Blood. 2005;105 (2):481-488.
25. Burnett A, Hills RK, Russell N, et al. Reasons for survival improvement in core binding factor AML: a 25 year analysis of the UK MRC/NCRI AML trials. http://www.bloodjournal.org/content/122/21/358. Accessed March 13, 2015.
26. Burnett AK, Hills RK, Milligan D, et al. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol. 2011;29(4):369-377.
27. Hills RK, Petersdorf S, Estey EH, et al. The addition of gemtuzumab ozogamicin (GO) to induction chemotherapy reduces relapse and improves survival in patients without adverse risk karyotype: results of an individual patient meta-analysis of the five randomised trials. http://www.bloodjournal.org/content/122/21/356. Accessed March 13, 2015.
28. Petersdorf SH, Kopecky KJ, Slovak M, et al. A phase 3 study of gemtuzumab ozogamicin during induction and postconsolidation therapy in younger patients with acute myeloid leukemia. Blood. 2013; 121(24):4854-4860.
29. Borthakur G, Cortes JE, Estey EE, et al. Gemtuzumab ozogamicin with fludarabine, cytarabine, and granulocyte colony stimulating factor (FLAG-GO) as front-line regimen in patients with core binding factor acute myelogenous leukemia. Am J Hematol. 2014;89(10):964-968.
30. Burnett AK, Russell NH, Hills RK, et al. Optimization of chemotherapy for younger patients with acute myeloid leukemia: results of the medical research council AML15 trial. J Clin Oncol. 2013;31 (27):3360-3368.
31. Kung Sutherland MS, Walter RB, Jeffrey SC, et al. SGN-CD33A: a novel CD33-targeting antibody-drug conjugate using a pyrrolobenzodiazepine dimer is active in models of drug-resistant AML. Blood. 2013;122(8):1455-1463.
32. Stein EM, Stein A, Walter RB, et al. Interim analysis of a phase 1 trial of SGN-CD33A in patients with CD33-positive acute myeloid leukemia (AML). ASH Annual Meeting Abstracts. 2014;124(21):623.
33. Jurcic J, Ravandi F, Pagel JM, et al. Phase i trial of the targeted alpha-particle nano-generator Actinium-225 (225Ac)-lintuzumab (anti-cd33) in combination with low-dose cytarabine (LDAC) for older patients with untreated acute myeloid leukemia (AML). ASH Annual Meeting Abstracts. 2013;122(21):1460.
34. Topp MS, Gökbuget N, Zugmaier G, et al. Phase II trial of the anti-CD19 bispecific T cell-engager blinatumomab shows hematologic and molecular remissions in patients with relapsed or refractory B-precursor acute lymphoblastic leukemia. J Clin Oncol. 2014;32(36):4134-4140.
35. Park SH, Chi HS, Min SK, Park BG, Jang S, Park CJ. Prognostic impact of c-KIT mutations in core binding factor acute myeloid leukemia. Leuk Res. 2011;35(10):1376-1383.
36. Paschka P, Marcucci G, Ruppert AS, et al; Cancer and Leukemia Group B. Adverse prognostic significance of KIT mutations in adult acute myeloid leukemia with inv(16) and t(8;21): a Cancer and Leukemia Group B Study. J Clin Oncol. 2006;24 (24):3904-3911.
37. Yin JA, O'Brien MA, Hills RK, Daly SB, Wheatley K, Burnett AK. Minimal residual disease monitoring by quantitative RT-PCR in core binding factor AML allows risk stratification and predicts relapse: results of the United Kingdom MRC AML-15 trial. Blood. 2012;120(14):2826-2835.
38. Marcucci G, Geyer S, Zhao W, et al. Adding KIT inhibitor dasatinib (DAS) to chemotherapy overcomes the negative impact of KIT mutation/over-expression in core binding factor (CBF) acute myeloid leukemia (AML): results from CALGB 10801 (Alliance). ASH Annual Meeting Abstracts. 2014;124(21):8.
39. Zhu H, Zhang X-h, Qin Y, et al. Risk-stratification treatment directed by minimal residual disease improves the outcome of acute myeloid leukemia with t(8;21) in first complete remission: results of the AML05 multicentre trial. ASH Annual Meeting Abstracts. 2012;120(21):139.
40. Wang Y, Wu DP, Liu QF, et al. RUNX1/RUNX1T1-based MRD-monitoring early after allogeneic transplantation rather than c-KIT mutations in adult t(8;21) AML allows further risk stratification. http://www.bloodjournal.org/content/124/12/1880?sso-checked=true. Accessed March 16, 2015.
41. Döhner K, Schlenk RF, Habdank M, et al. Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations. Blood. 2005;106(12): 3740-3746.
42. Schnittger S, Schoch C, Kern W, et al. Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype. Blood. 2005;106(12): 3733-3739.
43. Thiede C, Koch S, Creutzig E, et al. Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia (AML). Blood. 2006;107(10):4011-4020.
44. Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009;114(5):937-951.
45. Fröhling S, Schlenk RF, Stolze I, et al. CEBPA mutations in younger adults with acute myeloid leukemia and normal cytogenetics: prognostic relevance and analysis of cooperating mutations. J Clin Oncol. 2004;22(4):624-633.
46. Wouters BJ, Löwenberg B, Erpelinck-Verschueren CA, van Putten WL, Valk PJ, Delwel R. Double CEBPA mutations, but not single CEBPA mutations, define a subgroup of acute myeloid leukemia with a distinctive gene expression profile that is uniquely associated with a favorable outcome. Blood. 2009;113(13):3088-3091.
47. Green CL, Koo KK, Hills RK, Burnett AK, Linch DC, Gale RE. Prognostic significance of CEBPA mutations in a large cohort of younger adult patients with acute myeloid leukemia: impact of double CEBPA mutations and the interaction with FLT3 and NPM1 mutations. J Clin Oncol. 2010;28 (16):2739-2747.
48. Moore AS, Faisal A, Gonzalez de Castro D, et al. Selective FLT3 inhibition of FLT3-ITD+ acute myeloid leukaemia resulting in secondary D835Y mutation: a model for emerging clinical resistance patterns. Leukemia. 2012;26(7):1462-1470.
49. Yanada M, Matsuo K, Suzuki T, Kiyoi H, Naoe T. Prognostic significance of FLT3 internal tandem duplication and tyrosine kinase domain mutations for acute myeloid leukemia: a meta-analysis. Leukemia. 2005;19(8):1345-1349.
50. Smith CC, Wang Q, Chin CS, et al. Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia. Nature. 2012;485 (7397):260-263.
51. Gale RE, Green C, Allen C, et al; Medical Research Council Adult Leukaemia Working Party. The impact of FLT3 internal tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia. Blood. 2008; 111(5):2776-2784.
52. Thiede C, Steudel C, Mohr B, et al. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood. 2002;99(12):4326-4335.
53. Pratz KW, Sato T, Murphy KM, Stine A, Rajkhowa T, Levis M. FLT3-mutant allelic burden and clinical status are predictive of response to FLT3 inhibitors in AML. Blood. 2010;115(7):1425-1432.
54. Ravandi F, Arana Yi C, Cortes JE, et al. Final report of phase II study of sorafenib, cytarabine and idarubicin for initial therapy in younger patients with acute myeloid leukemia. Leukemia. 2014;28 (7):1543-1545.
55. Ravandi F, Cortes JE, Jones D, et al. Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with acute myeloid leukemia. J Clin Oncol. 2010;28(11): 1856-1862.
56. Stone RM, Fischer T, Paquette R, et al. Phase IB study of the FLT3 kinase inhibitor midostaurin with chemotherapy in younger newly diagnosed adult patients with acute myeloid leukemia. Leukemia. 2012;26(9):2061-2068.
57. Röllig C, Müller-Tidow C, Hüttmann A, et al. Sorafenib vs placebo in addition to standard therapy in younger patients with newly diagnosed acute myeloid leukemia: results from 267 patients treated in the randomized placebo-controlled SAL-Soraml Trial. ASH Annual Meeting Abstracts. 2014;124(21):6.
58. Serve H, Krug U, Wagner R, et al. Sorafenib in combination with intensive chemotherapy in elderly patients with acute myeloid leukemia: results from a randomized, placebo-controlled trial. J Clin Oncol. 2013;31(25):3110-3118.
59. Ravandi F, Alattar ML, Grunwald MR, et al. Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. Blood. 2013; 121(23):4655-4662.
60. Cortes JE, Kantarjian H, Foran JM, et al. Phase I study of quizartinib administered daily to patients with relapsed or refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase 3-internal tandem duplication status. J Clin Oncol. 2013;31 (29):3681-3687.
61. Borthakur G, Kantarjian HM, O'Brien S, et al. The combination of quizartinib with azacitidine or low dose cytarabine is highly active in patients (pts) with FLT3-ITD mutated myeloid leukemias: interim report of a phase I/II trial. ASH Annual Meeting Abstracts. 2014;124(21):388.
62. Randhawa JK, Kantarjian HM, Borthakur G, et al. Results of a phase II study of crenolanib in relapsed/refractory acute myeloid leukemia patients (pts) with activating FLT3 mutations. ASH Annual Meeting Abstracts. 2014;124(21):389.
63. Badar T, Kantarjian HM, Borthakur G, et al. Improvement in clinical outcome of FLT3 mutated AML patients over the last one and a half decade. ASH Annual Meeting Abstracts. 2014;124(21):949.
64. Kadia TM, Kantarjian H, Kornblau S, et al. Clinical and proteomic characterization of acute myeloid leukemia with mutated RAS. Cancer. 2012; 118(22):5550-5559.
65. Neubauer A, Maharry K, Mrózek K, et al. Patients with acute myeloid leukemia and RAS mutations benefit most from postremission high-dose cytarabine: a Cancer and Leukemia Group B study. J Clin Oncol. 2008;26(28): 4603-4609.
66. Borthakur G, Popplewell L, Boyiadzis M, et al. Phase I/II trial of the MEK1/2 inhibitor trametinib (GSK1120212) in relapsed/refractory myeloid malignancies: evidence of activity in patients with RAS mutation-positive disease. ASH Annual Meeting Abstracts. 2012;120(21):677.
67. Gröschel S, Sanders MA, Hoogenboezem R, et al. Mutational spectrum of myeloid malignancies with inv(3)/t(3;3) reveals a predominant involvement of RAS/RTK signaling pathways. Blood. 2015;125(1):133-139.
68. Fenaux P, Mufti GJ, Hellström-Lindberg E, 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):562-569.
69. Dombret H. Results of a phase 3, multicenter, randomized, open-label study of azacytidine vs conventional care regimens in older patients with newly diagnosed acute myeloid leukemia. EHA Annual Meeting Abstracts. 2014;LB6212.
70. Kantarjian HM, Thomas XG, Dmoszynska A, 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):2670-2677.
71. Ley TJ, Ding L, Walter MJ, et al. DNMT3A mutations in acute myeloid leukemia. N Engl J Med. 2010;363(25):2424-2433.
72. Thol F, Damm F, Lüdeking A, et al. Incidence and prognostic influence of DNMT3A mutations in acute myeloid leukemia. J Clin Oncol. 2011;29(21): 2889-2896.
73. Metzeler KH, Walker A, Geyer S, et al. DNMT3A mutations and response to the hypomethylating agent decitabine in acute myeloid leukemia. Leukemia. 2012;26(5):1106-1107.
74. Iyer LM, Tahiliani M, Rao A, Aravind L. Prediction of novel families of enzymes involved in oxidative and other complex modifications of bases in nucleic acids. Cell Cycle. 2009;8(11):1698-1710.
75. Tahiliani M, Koh KP, Shen Y, et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science. 2009;324(5929):930-935.
76. Itzykson R, Kosmider O, Cluzeau T, et al; Groupe Francophone des Myelodysplasies (GFM). Impact of TET2 mutations on response rate to azacitidine in myelodysplastic syndromes and low blast count acute myeloid leukemias. Leukemia. 2011;25(7):1147-1152.
77. Losman JA, Looper RE, Koivunen P, et al. (R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible. Science. 2013;339(6127):1621-1625.
78. Ward PS, Patel J, Wise DR, et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell. 2010;17(3):225-234.
79. Xu W, Yang H, Liu Y, et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell. 2011;19(1):17-30.
80. Stein EM, Altman JK, Collins R, et al. AG-221, an oral, selective, first-in-class, potent inhibitor of the IDH2 mutant metabolic enzyme, induces durable remissions in a phase I study in patients with IDH2mutation positive advanced hematologic malignancies. ASH Annual Meeting Abstracts. 2014; 124(21):115.
81. Agios Pharmaceuticals Inc. Clinical safety and activity in a phase I trial of AG-120, a first in class, selective, potent inhibitor of the IDH1-mutant protein, in patients with IDH1 mutant positive advanced hematologic malignancies. EORTC-NCI-AACR Meeting Abstracts. 2014;1LBA.
82. Chan SM, Medeiros BC, Majeti R. BCL-2 inhibition as a synthetic lethal approach to target isocitrate dehydrogenase mutations in acute myeloid leukemia stem cells. ASH Annual Meeting Abstracts. 2013;122(21):885.
83. Konopleva M, Pollyea DA, Potluri J, et al. A phase 2 study of ABT-199 (GDC-0199) in patients with acute myelogenous leukemia (AML). ASH Annual Meeting Abstracts. 2014;124(21):118.
84. Sinha S, Thomas D, Yu L, et al. Mutant WT1 is associated with DNA hypermethylation of PRC2 targets in AML and responds to EZH2 inhibition. Blood. 2015;125(2):316-326.
85. Daigle SR, Olhava EJ, Therkelsen CA, et al. Potent inhibition of DOT1L as treatment of MLL-fusion leukemia. Blood. 2013;122(6):1017-1025.
86. Stein EM, Garcia-Manero G, Rizzieri DA, et al. The DOT1L inhibitor EPZ-5676: safety and activity in relapsed/refractory patients with MLL-rearranged leukemia. ASH Annual Meeting Abstracts. 2014;124 (21):387.
87. Ernst T, Chase AJ, Score J, et al. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nat Genet. 2010;42(8): 722-726.
88. Zuber J, Shi J, Wang E, et al. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature. 2011;478(7370):524-528.
89. Valent P, Zuber J. BRD4: a BET(ter) target for the treatment of AML? Cell Cycle. 2014;13(5): 689-690.
90. Herrmann H, Blatt K, Shi J, et al. Small-molecule inhibition of BRD4 as a new potent approach to eliminate leukemic stem and progenitor cells in acute myeloid leukemia AML. Oncotarget. 2012;3(12):1588-1599.
91. Dawson MA, Gudgin EJ, Horton SJ, et al. Recurrent mutations, including NPM1c, activate a BRD4-dependent core transcriptional program in acute myeloid leukemia. Leukemia. 2014;28(2): 311-320.
92. Herait P, Berthon C, Thieblemont C, et al. BET-bromodomain inhibitor OTX015 shows clinically meaningful activity at nontoxic doses: interim results of an ongoing phase I trial in hematologic malignancies. AACR Annual Meeting Abstracts. 2014;CT231.