Adra, Nabil

Einhorn, Lawrence H.

Sayar, Hamid

Nabil Adra

Hamid Sayar

Lawrence H. Einhorn

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JAMA Oncology

Chemotherapy-Related Chronic Myelogenous Leukemia

IUPUIScholarWorks

Chemotherapy-Related Chronic Myelogenous Leukemia: A Case Series of Patients With Germ Cell Tumor

Copyright 2016 American Medical Association. All rights reserved.decrease the likelihoodofdiscoveringunknowntoxiceffects inlargerpopulationsandcostlyphase2and3studies.That (2)pro-spectivelydelineatingtherapeutic intentwithprespecifiedclini-cal endpoints shouldbeadoptedbecause itmay facilitateearlyidentificationofefficacyandimprove insurancecoverageofandpatient access to early-phase trials.2 The ability to directly at-tribute late toxic effects to specific drug radiation combina-tions is complicated by early patient mortality and confound-ing treatments.However,because investigatorsareobligated totheir patients and peers to evaluate toxic effects from investi-gational treatments, we propose that (3) assessment and re-porting of late toxic effects be included in phase 1 trials.Limitations of this study include the time period evalu-ated, that it is a single database query, and that it only includespublished trials and toxic effects.ClinicalTrials.govwasnot in-cluded because trial registration is not mandated as a condi-tionofpublication forphase 1 trials.6However, thesedata iden-tify3 importantmeasures,which if addressed,will improve thequality, availability, and interpretability of phase 1 trials.Hyun Kim, MDTu D. Dan, MDJoshua D. Palmer, MDBenjamin E. Leiby, PhDYaacov R. Lawrence, MRCPAdam P. Dicker, MD, PhDAuthor Affiliations:Department of Radiation Oncology, Sidney KimmelMedical College, Thomas Jefferson University, Philadelphia, Pennsylvania (Kim,Dan, Palmer, Dicker); Division of Biostatistics, Department of Pharmacology andExperimental Therapeutics, Sidney Kimmel Medical College, Thomas JeffersonUniversity, Philadelphia, Pennsylvania (Leiby); Department of RadiationOncology, ShebaMedical Center, Tel HaShomer, Israel (Lawrence).Corresponding Author:Hyun Kim, MD, Department of Radiation Oncology,Sidney Kimmel Medical College and Cancer Center, Thomas JeffersonUniversity, 111 S 11th St, Philadelphia, PA 19107 (hyun.kim@jefferson.edu).Published Online:December 17, 2015. doi:10.1001/jamaoncol.2015.4833.Author Contributions:Dr Kim had full access to all of the data in the study andtakes responsibility for the integrity of the data and the accuracy of the dataanalysis.Study concept and design: Kim, Dan, Palmer, Lawrence, Dicker.Acquisition, analysis, or interpretation of data: Kim, Dan, Palmer, Leiby, Dicker.Drafting of the manuscript: Kim, Dan.Critical revision of the manuscript for important intellectual content: All authors.Statistical analysis:Dan, Leiby, Lawrence.Administrative, technical, or material support: Kim, Dicker.Study supervision: Kim, Palmer.Conflict of Interest Disclosures:None reported.Funding/Support:Dr Leiby is supported in part by award No. P30 CA056036-16 from the National Cancer Institute (NCI). Dr Lawrence is supported in part byEU FP7Marie-Curie funding (CIG PCIG10-GA-2011-303795).Role of the Funder/Sponsor: The NCI andMarie-Curie funding had no role inthe design and conduct of the study; collection, management, analysis, andinterpretation of the data; preparation, review, or approval of themanuscript;and decision to submit themanuscript for publication.Previous Presentation:Data were presented in part at the AmericanAssociation for Cancer Research Radiation Oncology Think Tank, InauguralMeeting; January 11-13, 2015; Fort Myers, Florida.1. Shaw AT, Kim D-W, Mehra R, et al. Ceritinib in ALK-rearranged non-small-celllung cancer.N Engl J Med. 2014;370(13):1189-1197. doi:10.1056/NEJMoa1311107.2. Weber JS, Levit LA, Adamson PC, et al American society of clinical oncologypolicy statement update: the critical role of phase i trials in cancer research andtreatment. J Clin Oncol. 2014 ;33(3):278-284.doi:10.1200/JCO.2014.58.2635.3. Paller CJ, Bradbury PA, Ivy SP, et al. Design of phase I combination trials:recommendations of the Clinical Trial Design Task Force of the NCIInvestigational Drug Steering Committee. Clin Cancer Res. 2014;20(16):4210-4217.doi:10.1158/1078-0432.CCR-14-0521.4. Darby SC, Ewertz M, McGale P, et al. Risk of ischemic heart disease in womenafter radiotherapy for breast cancer.N Engl J Med. 2013;368(11):987-998. doi:10.1056/NEJMoa1209825.5. Elliott AC, Hynan LSA. A SAS(®) macro implementation of a multiplecomparison post hoc test for a Kruskal-Wallis analysis. Comput MethodsPrograms Biomed. 2011;102(1):75-80. doi:10.1016/j.cmpb.2010.11.002.6. AndersonML, Chiswell K, Peterson ED, Tasneem A, Topping J, Califf RM.Compliance with results reporting at ClinicalTrials.gov. N Engl J Med. 2015;372(11):1031-1039. doi:10.1056/NEJMsa1409364.Chemotherapy-Related ChronicMyelogenous Leukemia: A Case Seriesof PatientsWith GermCell TumorGermcell tumors (GCTs) are themost commoncancer inyoungmen ages 15 to 35 years and are uniquely responsive to che-motherapy,with cure rates approaching80%.Late adverse ef-fects of treatment can manifest throughout the lifetime of acured patientwhowill be at increased risk of solid and hema-tologicmalignant neoplasms.1,2 Etoposidehas becomeoneofthe cornerstones of platinum-containing regimens for GCT.Treatment with etoposide entails a known risk of secondaryleukemia that typically exhibits a short latencyperiod, a chro-mosomal translocation (11q23 and 21q22), and rearrange-ment of the mixed-lineage leukemia gene.Methods | We observed 3 patients with Philadelphia chromo-some-positive chronic myelogenous leukemia (CML) follow-ing therapy for GCT.Results | Case 1. In 1999, a man in his mid-30s with nonsemi-nomatous GCT (NSGCT) was treated with orchiectomy fol-lowed by 4 courses of bleomycin, etoposide, and cisplatin. InSeptember 2011, hewasnoted tohave awhite blood cell count(WBC) of 111 700/μL (111.7 × 109/L). Bone marrow examina-tion showedmorphologic findings of chronic-phaseCML, anda t(9;22)(q34;q11) was identified. The patient started treat-mentwith imatinib andachieveda completemolecular remis-sion. Unfortunately, in 2014, he developed malignant trans-formationof teratoma to anundifferentiatedneuroendocrinecarcinoma with unresectable hepatic metastases and died ofhis disease.Case 2. In 2006, a man in his early 30s had orchiectomy forclinical stage I NSGCT and elected to receive a single cycle ofBEP. In November 2006, the disease relapsed, and he wastreated with 3 cycles of etoposide, ifosfamide, and cisplatin(VIP). In 2007, the patient experienced a second relapse andwas treatedwith 2 cycles of high-dose carboplatin and etopo-side followedbyperipheral blood stemcell rescue. In 2011, hewas found to have leukocytosis (WBC, 91 700/μL [91.7 × 109/L]). Bonemarrowexamination confirmed chronic-phaseCMLwith t(9;22)(q34;q11). The patient was treated with dasatiniband achieved amolecular remission . Todate, he continues tobe in remission for his CML and recurrent GCT.Lettersjamaoncology.com (Reprinted) JAMAOncology March 2016 Volume 2, Number 3 391Downloaded From: http://jamanetwork.com/pdfaccess.ashx?url=/data/journals/oncology/935080/ by a Indiana University School of Medicine User  on 02/08/2017Copyright 2016 American Medical Association. All rights reserved.Case 3. In 2012, a young adult manwith history of Klinefeltersyndrome presented with intermittent chest pain and wasfound to have a 15-cm primary mediastinal NSGCT. He wastreated with 4 cycles of VIP followed by resection of residualmediastinal mass, which revealed teratoma. In 2014, he wasfound to have leukocytosis (WBC, 44000/μL [44.0 × 109/L]). Bone marrow examination confirmed chronic-phaseCML by morphologic characteristics, and a t(9;22)(q34;q11)was identified by chromosome analysis. The patient startedtreatment with dasatinib and achieved a hematologicresponse. To date, his BCR/ABL transcript declined appropri-ately from 55% to 9%. He continues to be in remission for hisGCT.Discussion | There have been reports of chemotherapy-relatedPhiladelphia-chromosome leukemias in patients with ante-cedent malignant neoplasms.3 Past treatments for GCT withcisplatin-etoposide–containing regimens or HDCT with car-boplatin-etoposidehavebeen linkedtoan increasedriskof sec-ondary acute leukemia1,4 and solid tumors.5 A review of theliterature reveals 7 cases of GCT with subsequent develop-ment of CML.1,3,6 In this series, we present 3 cases of patientswithGCTwhoachievedremissionwithchemotherapyandlaterdeveloped BCR/ABL-positive CML. These findings raise thequestion of a causal relationship between etoposide and/orplatinum-containing chemotherapy and the development ofCML with t(9;22)(q34;q11).Etoposide-basedchemotherapy inpatientswithGCTis leu-kemogenic. It is not clear whether combination chemo-therapy with cisplatin and bleomycin contribute to this re-sult. While its association with AML is well established,questions regarding theconnectionof etoposideandcisplatin-containingcombinationchemotherapyandsecondaryCMLareposed herein. The relatively low risk of secondary leukemiainpatients treatedwithpotentially curative combination che-motherapy forGCTcontinues tobe reassuring.1However, phy-sicians should be aware of possible late toxic effects of thesetreatment regimensandtheneedfordiligent follow-up in thesepatients.Nabil Adra, MDHamid Sayar, MDLawrence H. Einhorn, MDAuthor Affiliations: Indiana University, Indianapolis, Melvin & Bren SimonCancer Center, Division of Hematology/Oncology, Indiana University School ofMedicine, Indianapolis.Corresponding Author:Nabil Adra, MD, Indiana University, 535 Barnhill Dr, RT400, Indianapolis, IN 46202 (nadra@iu.edu).Published Online:December 3, 2015. doi:10.1001/jamaoncol.2015.4837.Author Contributions:Dr Adra had full access to all the data in the study andtake responsibility for the integrity of the data and the accuracy of the dataanalysis.Study concept and design: All authors.Acquisition, analysis, or interpretation of data: All authors.Drafting of the manuscript: Adra, Einhorn.Critical revision of the manuscript for important intellectual content: All authors.Administrative, technical, or material support: Adra.Study supervision: Sayar.Conflict of Interest Disclosures:None reported.Funding/Support:Dr Einhorn supported in part by the National CancerInstitute (NCI) (1 RO1 CA157823-)1A1.Role of the Funder/Sponsor: The NCI had no role in the design and conduct ofthe study; collection, management, analysis, and interpretation of the data;preparation, review, or approval of themanuscript; and decision to submit themanuscript for publication.Additional Contributions:We thank the patients for granting permission topublish this information.1. Travis LB, AnderssonM, Gospodarowicz M, et al. Treatment-associatedleukemia following testicular cancer. J Natl Cancer Inst. 2000;92(14):1165-1171.2. Travis LB, Fosså SD, Schonfeld SJ, et al. Second cancers among 40,576testicular cancer patients: focus on long-term survivors. J Natl Cancer Inst.2005;97(18):1354-1365.3. Pedersen-Bjergaard J, Brøndum-Nielsen K, Karle H, Johansson B.Chemotherapy-related - late occurring - Philadelphia chromosome in AML, ALLand CML: similar events related to treatment with DNA topoisomerase IIinhibitors? Leukemia. 1997;11(9):1571-1574.4. HouckW, Abonour R, Vance G, Einhorn LH. Secondary leukemias inrefractory germ cell tumor patients undergoing autologous stem-celltransplantation using high-dose etoposide. J Clin Oncol. 2004;22(11):2155-2158.5. Fung C, Fossa SD, MilanoMT, Oldenburg J, Travis LB. Solid tumors afterchemotherapy or surgery for testicular nonseminoma: a population-basedstudy. J Clin Oncol. 2013;31(30):3807-3814.6. Iurlo A, Foa P, Maiolo AT, Polli EE. Chronic myelogenous leukemia followingradiation therapy for testicular seminoma. Blut. 1989;59(6):503-504.Disease-Specific Hashtags for OnlineCommunication About Cancer CareIncreasingly, patients, caregivers, andhealth care profession-als (HCPs) go online to learn about and discuss cancer care.1However, finding other people or organizations with similarinterests can be difficult without some structure.Hashtagsareuser-generated tags that canorganizeandag-gregate content on social networks. In July 2011, 2 patient ad-vocates started a breast cancer chat on Twitter using the tag#bcsm (breast cancer social media); one of us (D.J.A.) joinedas a comoderator. This same model but with hashtag #btsmwas used to discuss brain tumors in January 2012. Both tagsare now regularly usedonTwitter bypatients, caregivers, andHCPs.Dedicated hashtags may make it easier to engage in rel-evant conversations online for other types of cancer. In thisstudy,wedescribe away tousedisease-specifichashtags simi-lar to #bcsm and #btsm to organize and increase online dis-cussion of cancer care.Methods | Based on the models using the #bcsm and #btsmhashtags, 2 of us (M.S.K. and P.F.A.) developed a set of 23 newcancer-specific tags that met the following criteria: diseasespecific, short, unique orminimally used on Twitter, and end-ing in “sm” for “social media” (as a prompt that online use ispublic). We selected this design to balance practical use withthe ability to organize content. Initially proposed in July 2013,this cancer tag ontology (CTO) was posted on Symplur inNovember 2013 after public commentary and engagement(Table).2We analyzed the number of tweets and users of the tagsquarterly from April 2011 through June 2015 using SymplurLetters392 JAMAOncology March 2016 Volume 2, Number 3 (Reprinted) jamaoncology.comDownloaded From: http://jamanetwork.com/pdfaccess.ashx?url=/data/journals/oncology/935080/ by a Indiana University School of Medicine User  on 02/08/2017

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Chemotherapy-Related Chronic Myelogenous Leukemia: A Case Series of Patients With Germ Cell Tumor

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