Abboud, Camille N

Abboud, Ramzi

Cashen, Amanda F

DiPersio, John F

Duncavage, Eric J

Han, Se Young

Shirai, Cara Lunn

Welch, John S

English

Digital Commons@Becker

Washington University School of MedicineDigital Commons@BeckerOpen Access Publications2019Serendipity: Decitabine monotherapy inducedcomplete molecular response in a 77-year-oldpatient with acute promyelocytic leukemiaRamzi AbboudWashington University School of Medicine in St. LouisSe Young HanUniversity of Minnesota - Twin CitiesEric J. DuncavageWashington University School of Medicine in St. LouisAmanda F. CashenWashington University School of Medicine in St. LouisCara Lunn ShiraiWashington University School of Medicine in St. LouisSee next page for additional authorsFollow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubsThis Open Access Publication is brought to you for free and open access by Digital Commons@Becker. It has been accepted for inclusion in OpenAccess Publications by an authorized administrator of Digital Commons@Becker. For more information, please contact engeszer@wustl.edu.Recommended CitationAbboud, Ramzi; Han, Se Young; Duncavage, Eric J.; Cashen, Amanda F.; Shirai, Cara Lunn; Welch, John S.; DiPersio, John F.; andAbboud, Camille N., ,"Serendipity: Decitabine monotherapy induced complete molecular response in a 77-year-old patient with acutepromyelocytic leukemia." Haematologica.,. . (2019).https://digitalcommons.wustl.edu/open_access_pubs/8070AuthorsRamzi Abboud, Se Young Han, Eric J. Duncavage, Amanda F. Cashen, Cara Lunn Shirai, John S. Welch, JohnF. DiPersio, and Camille N. AbboudThis open access publication is available at Digital Commons@Becker: https://digitalcommons.wustl.edu/open_access_pubs/8070Serendipity: decitabine monotherapy induced com-plete molecular response in a 77-year-old patientwith acute promyelocytic leukemiaAcute promyelocytic leukemia (APL) is an uncommonbut very aggressive subtype of acute myeloid leukemia(AML), accounting for 10-15% of adult AML with 600-800 new cases per year in the United States.1,2 Over 95%of cases involve translocation t(15;17)(q22;q21), whichresults in the promyelocytic leukemia retinoic acid recep-tor alpha (PML-RARa) rearrangement and fusionprotein.3Most of the remaining APL cases harbor a fusionprotein involving RARa and another partner.4 The PML-RARa fusion gene initiates APL by blocking differ-entiation and increasing self-renewal and proliferation ofleukemic progenitor cells. In the 1970s, outcomes in APL were dismal.Anthracycline-based regimens were used, producinglong-term survival rates of 15-25%.1 This changed drasti-cally with the introduction of all-trans retinoic acid(ATRA) and arsenic trioxide (ATO) which both target thePML-RARa fusion. With modern ATRA and ATO thera-py, long-term survival rates approach 95%, in many caseswithout cytotoxic therapy.5Herein, we present a case of an APL patient with thetypical PML-RARa fusion, but atypical morphology andimmunophenotype, who unexpectedly achieved mor-phological and molecular remission after treatment withsingle agent decitabine.A 77-year-old female with atrial fibrillation and hyper-tension presented with two months of progressivefatigue and oral ulcers. Family history was significant fora brain tumor (classification unknown) in her mother,and breast cancer in two of her daughters. She consumedhaematologica 2019; 104:e170CASE REPORTSFigure 1. Diagnosis marrow morphologic evaluation andflow cytometry. Panel A: The bone marrow was hypercellu-lar with >90% cellularity and 63% blasts. There was a pre-dominance of atypical mononuclear cells with monocytoidfeatures and some atypical promyelocytes. Top left: aspiratewith Wright Stain 100x original magnification. Top right:aspirate with myeloperoxidase stain 100x original magnifi-cation. Panel B: Characteristic microgranular/hypogranularAPL flow cytometry phenotype of the patient. Flow cytometryof the patient’s bone marrow aspirate at diagnosis is depict-ed. The blasts had moderate CD45 expression and reducedside scatter, shown in a “blast” gate (upper left panel) andencompassing 79% of total cellular events. The blasts werepositive for CD33 (bright), CD34 (82%, blue), CD117, CD2(dim), CD13, and CD64 (dim). The blasts were negative forHLA-DR and CD11b. The blasts were also negative for CD14,CD123, CD19, and CD56 (not shown).ABalcohol socially, never smoked, and had no history ofillicit drug use. Physical exam including vital signs werenormal on presentation, and the patient had no bruises,petechiae, or lymphadenopathy.Complete blood counts revealed WBC 5600/mL, 69%blasts, hemoglobin 9.3 g/dL, and platelets 24000/mL.Coagulation panel revealed elevated PT (14.2 seconds)and INR (1.31), and normal PTT (24.6 seconds) and fib-rinogen (200 mg/dL). Comprehensive metabolic panelwas normal. Serum LDH was 258 units/L and uric acidwas 6.3 mg/dL. Peripheral smear morphology revealed alarge blast population with no promyelocytes or Auerrods. Bone marrow biopsy revealed AML with matura-tion (Figure 1A). Flow cytometry identified 79% blastscharacterized by co-expression of CD33, CD34, CD117,CD13, CD2 (dim), CD64 (dim) and negative expressionof HLA-DR, CD14, CD11b, CD19, CD56, and CD123(Figure 1B). Cytogenetics revealed a t(15;17) rearrange-ment which was subsequently confirmed by fluorescencein situ hybridization (FISH) as a PML-RARa fusion in91.5% of cells and 100% of transcripts by quantitativereverse transcriptase polymerase chain reaction (RT-PCR). FLT3-ITD testing was positive by standard meth-ods. While the laboratory‘s protocol is to perform upfrontFISH for 7 probes (including PML-RARa) on all suspectedcases of AML, only routine cytogenetics was initiallyrequested in this case.  As the morphology and flow cyto-metric findings were not typical for APL, it was originallyreported as AML with maturation.  Cytogenetic studiesdemonstrating a t(15;17) and confirmatory FISH/RT-PCRwere reported in the electronic medical record approxi-mately one week after the initial diagnosis of AML withmaturation was reported, but did not come to immediateclinical attention.  Given the patient’s advanced age and presumed diag-nosis of AML, she was treated with a 10-day course ofdecitabine. Her leukocyte count did not increase duringtreatment, as might be typical of differentiation syn-drome. She developed mild coagulopathy evidenced byelevated INR (peak 1.70), but she had no evidence ofbleeding and the fibrinogen and D-Dimer remained nor-mal throughout. Her hospital course was complicated bymultifocal embolic infarcts attributed to atrial fibrillation,resulting in expressive aphasia and gait abnormalities.The patient was discharged to inpatient rehabilitation onhospital day 22, and two subsequent cycles of 5-daydecitabine consolidation were administered by her localoncologist. At her first follow-up appointment at our institution,the pre-treatment cytogenetics were reviewed and herdiagnosis was amended to APL. A restaging bone mar-row biopsy at that time confirmed achievement of com-plete molecular remission (Figure 2) with cytogeneticremission and negative RT-PCR.Given her complete remission, the patient was treatedwith four cycles of ATRA and ATO consolidation perLoCocco protocol.5 She has experienced significant neu-rological recovery with mild right facial weakness,haematologica 2019; 104:e171CASE REPORTSFigure 2. Day 30 marrow morphologic evaluation. D30 Marrow morphologic evaluation. The bone marrow was normocellular for age and showed trilineagehematopoiesis with an erythroid predominance and no increased blasts. Top left: core 2x original magnification. Top right: core 10x original magnification,Bottom row: bone marrow aspirate 40x original magnification. expressive aphasia, and wide-based gait. She remainsindependent for ADLs and IADLs. She is now 1,035 daysfrom diagnosis in both morphologic and molecular com-plete remission with undetectable PML-RARa and FLT3-ITD.Bone marrow morphology was consistent with micro-granular variant of APL which lacks the Auer rods andthe CD34/HLA-DR negative phenotype typically seen inAPL (Figure 1A). Microgranular APL frequently has FLT3-ITDs, however it does not itself predict for a worseprognosis compared with classic APL.6Flow cytometry was consistent withmicrogranular/hypogranular variant of APL.2 The APLblasts identified (79% total cells) were characterized byco-expression of CD33, CD34, CD117, CD13, CD2(dim), CD64 (dim), and were negative for expression ofHLA-DR, CD14, CD11b, CD19, CD56, and CD123(Figure 1B). Cytogenetics revealed a t(15;17) rearrangement whichwas subsequently confirmed by FISH as a PML-RARafusion in 91.5% of cells and 100% of transcripts by quan-titative RT-PCR. A Next generation hematologic malig-nancy panel was negative for mutations in ABL1, ASXL1,ATM, BCOR, BIRC3, BRAF, CALR, CBL, CEBPA, CREBBP,CSF1R, CSF3R, DNMT3A, EP300, ETV6, EZH2, FBXW7,FGFR4, FLT3, GATA1, GATA2, GATA3, IDH1, IDH2,IL7R, JAK2, JAK3, KDM6A, KIT, KMT2A, KRAS, MPL,NF1, NOTCH1, NOTCH2, NPM1, NRAS, NSD1, PAX5,PDGFRA, PDGFRB, PTPN11, RUNX1, SETBP1, SF3B1,SRSF2, STAG2, TERT, TET1, TET2, TP53, TSLP, U2AF1and ZRSR2.4Our patient is a unique example of APL who fortu-itously achieved complete molecular remission withdecitabine monotherapy. She was misdiagnosed withnon-APL AML due, in part, to the lack of up-front FISHtesting for PML-RARa, nonstandard APL morphology,and communication issues in reporting the positive cyto-genetic findings.  Cases of microgranular variant, whilerare, have been described and highlight the importance ofcytogenetic analysis.6,7 As a result of this case, we nowhave an institutional policy that all PML-RARa resultsmust be communicated by voice to the treating attendingphysician.Several groups have sought the role of DNA methyla-tion in APL. DNA methyltransferase (DNMT) is the keyenzyme in DNA methylation, a process that plays amajor role in leukemogenesis.8 Di Croce et al., have sug-gested that the PML-RARa fusion protein interacts withDNMT1 and DNMT3A, leading to hyper-methylationand subsequent silencing of downstream pathwaysinvolved in hematopoietic cell differentiation - such asRARa.8 Furthermore, overexpression of DNMT3A, in col-laboration with PML-RARa, promotes APL leukemogen-esis in vivo. While ATRA can make changes in posttrans-lational modification such as histone acetylation, it doesnot affect DNA methylation in APL cells.9 Therefore,there may be a role for hypomethylating agents in com-bination with ATRA and ATO to improve therapeuticoutcomes of APL through activity in an additional path-way.Decitabine is a well-tolerated hypomethylating agentthat alters gene expression resulting in severalantileukemic effects. Forkhead box (FOX) genes are impor-tant in hematopoietic cell differentiation. FOXC1 tran-scription levels are low in APL, in contrast to AML.10Interestingly, in APL cell lines, decitabine upregulatesFOXC1 transcription to normal levels throughhypomethylation of the promoter,10,11 which may pro-mote differentiation. Furthermore, decitabine can acti-vate the TRAIL pathway in APL cells, thus inducingleukemic cell apoptosis.12 Finally, decitabine has beenshown to induce apoptosis in the ATRA resistant APL cellline NB4-R213 as well as HL-60 acute myeloid leukemiacells.14Further support of the role of hypomethylating agentsis provided by a case of refractory APL with varianttranslocation STAT5B/RARA where decitabine was usedin combination with alternating cycles ofidarubicin/cytarabine and aclacinomycin/cytarabineinducing a complete and durable response.15 Although this patient presented with a low WBC CTand low-risk APL clinical features, she harbored theFLT3-ITD mutation which some view as an added riskfactor in acute myeloid leukemia. Her robust molecularresponse after decitabine single agent therapy is remark-able. She continues in complete remission 24 monthsafter standard consolidation with ATRA and ATO. Thiscase has prompted us to consider the addition ofdecitabine to ATRA and ATO induction as an attractivealternative to anthracyclines in high-risk APL. Our elderly patient with low-risk APL achieved com-plete morphologic and molecular remission after singleagent treatment with decitabine. In cases of high-risk APL, where many centers usecytotoxic chemotherapy, decitabine may be an effica-cious and more tolerable alternative to anthracyclinetherapy.Our case is the first to demonstrate the potential effica-cy of front-line single-agent decitabine in a patient withde novo APL, with the potential caveated that the APL didnot have a classic morphology and expressed CD34.Ramzi Abboud,1 Se Young Han,2 Eric J. Duncavage,1Amanda F. Cashen,1 Cara Lunn Shirai,1 John S. Welch,1John F. DiPersio1 and Camille N. Abboud11BMT and Leukemia Program, Department of Medicine,Washington University School of Medicine, Saint Louis, MO and2Hematology, Oncology, and Transplantation Division, Department ofMedicine, University of Minneapolis, MN, USAFunding: RA was supported by the National Cancer Institute of theNational Institutes of Health under Award Number R25CA190190.Correspondence: CAMILLE N. ABBOUD. cabboud@wustl.edudoi:10.3324/haematol.2018.209478Information on authorship, contributions, and financial & other disclo-sures was provided by the authors and is available with the online versionof this article at www.haematologica.org.References1. Chen Y, Kantarjian H, Wang H, Cortes J, Ravandi F. Acute promye-locytic leukemia: A population-based study on incidence and sur-vival in the United States, 1975-2008. Cancer. 2012;118(23):5811-5818.2. Wiernik PH, Gallagher RE, Tallman MS. Acute promyelocyticleukemia. In: Wiernik PH, Goldman JM, Dutcher JP, Kyle RA, editors.Neoplastic Diseases of the Blood, Sixth Edition 2018. New York, NY:Springer International Publishing AG; p409-463.3. Yan W, Zhang G. Molecular characteristics and clinical significance of12 fusion genes in acute promyelocytic leukemia: A systematicreview. Acta Haematol. 2016;136(1):1-15.4. Madan V, Shyamsunder P, Han L, et al. Comprehensive mutationalanalysis of primary and relapse acute promyelocytic leukemia.Leukemia. 2016;30(8):1672–1681.5. Lo-Coco F, Avvisati G, Vignetti M, et al. Retinoic acid and arsenic tri-oxide for acute promyelocytic leukemia. N Engl J Med. 2013;369(2):111-121.6. Tallman MS, Kim HT, Montesinos P, et al. Does microgranular vari-ant morphology of acute promyelocytic leukemia independentlypredict a less favorable outcome compared with classical M3 APL? Ahaematologica 2019; 104:e172CASE REPORTSjoint study of the North American Intergroup and the PETHEMAGroup. Blood. 2010;116(25):5650-5659.7. McDonnell MH, Smith ET, Lipford EH, Gerber JM, Grunwald MR.Microgranular acute promyelocytic leukemia presenting withleukopenia and an unusual immunophenotype. Hematol OncolStem Cell Ther. 2017;10(1):35-38.8. Di Croce L, Raker VA, Corsaro M, et al. Methyltransferase recruit-ment and DNA hypermethylation of target promoters by an onco-genic transcription factor. Science. 2002;295(5557):1079-1082.9. Martens JHA, Brinkman AB, Simmer F, et al. PML-RARa/RXR altersthe epigenetic landscape in acute promyelocytic leukemia. CancerCell. 2010;17(2):173-185.10. Fabiani E, Falconi G, Noguera NI, et al. The forkhead box C1(FOXC1) transcription factor is downregulated in acute promyelo-cytic leukemia. Oncotarget. 2017;8(48):84074-84085.11. Seo S, Singh HP, Lacal PM, et al. Forkhead box transcription factorFoxC1 preserves corneal transparency by regulating vascular growth.Proc Natl Acad Sci U S A. 2012;109(6):2015-2020.12. Soncini M, Santoro F, Gutierrez A, et al. The DNA demethylatingagent decitabine activates the TRAIL pathway and induces apoptosisin acute myeloid leukemia. Biochim Biophys Acta. 2013;1832(1):114-120.13. Xiong M-J, Xiao R-Z, Chen Y, et al. [Decitabine inhibits cell prolifer-ation and induces apoptosis of all-trans retinoid acid-resistant acutepromyelocytic leukemia NB4-R2 cell line]. Zhongguo Shi Yan Xue YeXue Za Zhi. 2012;20(1):48-52.14. Zhu Z, Lu X, Jiang L, et al. STAT3 signaling pathway is involved indecitabine induced biological phenotype regulation of acute myeloidleukemia cells. Am J Transl Res. 2015;7(10):1896-1907.15. Wang A, Cai X, Qiang P, Duan Q. Successful treatment of a patientwith acute promyelocytic leukemia with a STAT5B / RARA fusiongene using decitabine. Leuk Lymphoma. 2018;59(3):763-765.haematologica 2019; 104:e173CASE REPORTS

Serendipity: Decitabine monotherapy induced complete molecular response in a 77-year-old patient with acute promyelocytic leukemia

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Serendipity: Decitabine monotherapy induced complete molecular response in a 77-year-old patient with acute promyelocytic leukemia

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