Posted on Authorea 26 May 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159050449.92324477 — This a preprint and has not been peer reviewed. Data may be preliminary. orsodn authors: Corresponding 4 3 2 Japan Tokyo, Affiliations: Authors neuroblastoma high-risk Hara for melphalan and Authors: thiotepa with regimen Double-conditioning Title: practice. clinical in attention special with warrants patients and in especially neuroblastoma, high-risk hzr ai .9 5 ofiec nevl=01–.6.O h 1ptet,3de eas frgmnrltdtoxicity regimen-related of because died 3 patients, 41 the Of 0.12–0.66). = interval confidence 95% rates (infection, 0.29; (OS) = survival ratio overall (hazard and for (EFS) (16.7% survival duration patients event-free follow-up neuroblastoma 60.9% 5-year median The was The patients years). point. 41.5% neuroblastoma 5.5–14.0 time anti-GD2 were = adequate underwent initiation (range the none treatment years at but from chemotherapy, 9.2 resected induction was was reviewed. multidrug patients tumor intensive were living primary autologous underwent medical 2012 The by patients the followed and immunotherapy. All neuroblastoma, regimen 2002 antibody high-risk patients. double-conditioning between for 23 the regimen rescue underwent in this cell observed who of stem neuroblastoma efficacy high-risk blood the with and peripheral patients safety mg/m the 41 800 re-evaluate of HDC To total records unique of a used. cycles Japan, widely In two is comprising established. melphalan been regimen) yet double-conditioning not has (called neuroblastoma regimen high-risk for (HDC) chemotherapy high-dose Appropriate Abstract 2020 26, May 5 4 3 2 1 Hara Junichi Yamazaki Fumito for Neuroblastoma melphalan high-risk and thiotepa with regimen Double-conditioning sk nvriyHsia,Dprmn fPdarc,Oaa Japan Osaka, Japan Pediatrics, Osaka, of Oncology, Department and Hospital, Hematology University Pediatric Osaka of Department Japan Hospital, Tokyo, General Pediatrics, City of Osaka Department Medicine, of School University Keio ainlRsac nttt o hl elhadDevelopment and Health Child Development for and Institute Health Research Medical National Child for Medicine Center of National School Graduate University Osaka Hospital Development General and City Health Osaka Child for Center National 3 iiauMatsumoto Kimikazu , n uioYamazaki Fumito ;microangiopathy, 2; = 2 n iiauMatsumoto Kimikazu and , 1 a Yamasaki Kai , 1 ainlCne o hl elhadDvlpet hlrnsCne Center, Cancer Children’s Development, and Health Child for Center National ± iiauMtuoo D PhD MD, Matsumoto, Kimikazu 1,2 1 8.8%; . a Yamasaki Kai , ± n ± 02,wihwssgicnl ueircmae to compared superior significantly was which 10.2%, ) h obecniinn eie ihtitp n epaa seetv for effective is melphalan and thiotepa with regimen double-conditioning The 1). = .%ad56.1% and 7.7% P < 0.001). 2 hkk Kiyotani Chikako , MYCN MYCN 3 hkk Kiyotani Chikako , 5 ± .% epciey h -erESof EFS 5-year The respectively. 7.8%, mlfiain oee,tedul-odtoigrgmni toxic is regimen double-conditioning the However, amplification. mlfiainwstems aoal rgotcfco o EFS for factor prognostic favorable most the was amplification 1 1 ohk Hashii Yoshiko , MYCN 1 ohk Hashii Yoshiko , apie ihrs erbatmswere neuroblastomas high-risk -amplified 2 ftitp n oa 8 mg/m 280 total and thiotepa of MYCN 4 3 ooShioda Yoko , ooShioda Yoko , MYCN nnapie high-risk -non-amplified apie high-risk -amplified 1 Junichi , 4 , 2 of Posted on Authorea 26 May 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159050449.92324477 — This a preprint and has not been peer reviewed. Data may be preliminary. fPeiti nooyErpa erbatm SOE)cnutdarnoie ra n rvdthe proved and trial randomized a the conducted of (SIOPEN) re-evaluation trials. Neuroblastoma clinical so European several immunotherapy, in Oncology ongoing antibody is Paediatric regimen anti-GD2 of HDC transplantation the by of cell safety outcomes and neuroblastoma. stem treatment efficacy high-risk of autologous for improvement with care after standard (HDC) the chemotherapy is high-dose (SCT) including treatment Intensive practice. clinical in regimen-related attention of special with warrants because patients INTRODUCTION and died in toxic 3 especially is patients, regimen neuroblastoma, 41 double-conditioning high-risk the the for effective Of is 0.12–0.66). phalan = interval confidence (infection, 95% toxicity 0.29; = ratio 41.5% were The to event-free initiation compared (16.7% 5-year treatment superior The point. significantly from was years). time which rates 5.5–14.0 10.2%, adequate = (OS) the (range survival underwent years at overall ± 9.2 none resected and was but was patients (EFS) chemotherapy, living tumor survival induction for primary multidrug duration The follow-up intensive median underwent immunotherapy. patients neu- stem antibody All high-risk blood anti-GD2 with reviewed. peripheral patients. patients were autologous 23 41 2012 by of and in followed 2002 records regimen between medical rescue double-conditioning the cell the neuroblastoma, underwent high-risk total who of for cycles roblastoma regimen two this comprising regimen) of double-conditioning efficacy (called regimen HDC mg/m unique 800 a Japan, In lished. Abstract: Abbreviation Words: Key Title: Figures: Running and Tables of Number The Counts: Word [email protected] E-mail: Setagaya-ku, +81-3-3416-2222, Okura, Fax: 2-10-1 +81-3-3416-0181, Center, Tel: Cancer Children’s Development, Japan. and 157-8535, Health Tokyo, Child for Center National .% epciey h -erESof EFS 5-year The respectively. 7.8%, ± 8.8%; 2 prpit ihds hmteay(D)frhg-iknuolsoahsntytbe estab- been yet not has neuroblastoma high-risk for (HDC) chemotherapy high-dose Appropriate ftitp n oa 8 mg/m 280 total and thiotepa of GRvr odprilresponse partial response good complete very microangiopathy thrombotic syndrome VGPR obstruction sinusoidal clearance CR creatinine TMA Criteria Response Neuroblastoma index International SOS site metastatic System Ccr Staging Neuroblastoma International INRC Neuroblastoma European Oncology transplantation MSI Paediatric cell of stem survival Society overall International INSS SIOPEN survival event-free SCT chemotherapy OS high-dose EFS HDC erbatm,titp,melphalan thiotepa, neuroblastoma, P btat25wrs antx 30words 2340 text Main words, 245 Abstract hoeaadmlhlnfrhg-ikneuroblastoma high-risk for melphalan and Thiotepa n < ;microangiopathy, 2; = 0.001). MYCN mlfiainwstems aoal rgotcfco o F (hazard EFS for factor prognostic favorable most the was amplification MYCN als iue,1Spotn nomto file Information Supporting 1 Figures, 2 Tables, 2 n 2 ) h obecniinn eie ihtitp n mel- and thiotepa with regimen double-conditioning The 1). = fmlhlni ieyue.T eeaut h aeyadthe and safety the re-evaluate To used. widely is melphalan of MYCN apie ihrs erbatm ainsws60.9% was patients neuroblastoma high-risk -amplified MYCN 2 1 apie ihrs erbatmswr observed were neuroblastomas high-risk -amplified h motneo D swl eonzd even recognized, well is HDC of importance The nnapie ihrs erbatm patients neuroblastoma high-risk -non-amplified 2 eety h nentoa Society International the Recently, MYCN mlfiain However, amplification. ± .%ad56.1% and 7.7% ± Posted on Authorea 26 May 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159050449.92324477 — This a preprint and has not been peer reviewed. Data may be preliminary. oee,teciei o eemnn h agtstsfrirdainvre rmisiuint institution. to institution from sites; varied metastatic irradiation and/or for site sites primary target the the the at determining study. tumor of for 2 residual criteria phase basis the the nationwide against the however, feasibility Japanese administered the in on was shown because therapy point was chemotherapy Radiation strategy time induction was control during adequate resection local resectability surgical delayed the tumor patients, the some of at of In regardless conducted post-HDC. HDC or was after chemotherapy insti- planned tumor induction the during primary to resection according of the feasibility cells of stem therapy. resection antibody blood GD-2 cord Surgical underwent using patients SCT no second while and/or was policy, acid (Ccr) tution’s elsewhere. retinoic clearance received reported patients creatinine are Some regimen If this of -4. details The and (mg/m dose (melphalan). -5, given formula: -11, interval following the -12, 1-week using days a on m at administered mL/min/1.73 melphalan were mg/kg/day) and 1.5 which thiotepa auto-SCT, of with regimen mg/m cycles double-conditioning 2 the underwent comprised patients chemotherapy, induction used After chemotherapeutics (INRC). induction platinum, Criteria including The Response neuroblastoma, for Neuroblastoma policy. efficacious International institution’s as alkylators. reported each previously and were to anthracycline, them of according and/or most resection, control although surgical varied, chemotherapy, local induction with for treatment radiation multimodality underwent patients 41 All also was involved, systems/compartments metastatic Treatment of number (INSS). the System on Staging based score Neuroblastoma or calculated. a International age (MSI), the any index vanil- to of site urine follows: static patients according elevated as in of performed defined 4 presence was was or the Staging neuroblastoma 4S, showing This 3, High-risk samples Japan. 2, tumor acid. Osaka, stage homovanillic of Hospital, evaluation and University histological acid of Osaka lylmandelic basis Japan; the studies. Tokyo, the previous Development, and on in and Japan; made reported Health Osaka, patients Child 19 for Hospital, included Center General cohort National the City bet- at auto-SCT Osaka 2012 with the melphalan October who and and patients thiotepa 2002 neuroblastoma comprising June high-risk regimen ween diagnosed double-conditioning newly a 41 with of HDC records underwent medical the reviewed a retrospectively We in neuroblastoma high-risk for Patients efficacy its METHODS assesses AND PATIENTS and regimen double-conditioning neuroblastoma. cohort. the multi-institutional high-risk of for cohort. safety published. regimen further was the double-conditioning of a medulloblastoma the mel- efficacy in high-risk investigated and and for regimen have feasibility neuroblastoma. regimen thiotepa double-conditioning the double-conditioning including which the reported the tumors, in of (1998) of solid centers, al. profiles various et cancer toxicity Hara for pediatric reported sche- weeks. regimen major and consecutive double-conditioning dosages 2 some the various for in at administered used regimen are widely HDC phalan is the in regimen used single conditioning broadly HDC both agent conditioning including anticancer a dules alkylating as an carboplatin is and Thiotepa etoposide, melphalan, over melphalan regimen. and busulfan of superiority 2 dy age /day; 3 15 2 < nptet gd[] er,tedsg a rnial dutdbfr n uigHDC during and before adjusted principally was dosage the years, [?]2 aged patients in er,8m/gdy n epaa ae[]2yas 0mg/m 70 years, 2 [?] (age melphalan and mg/kg/day) 8 years, 2 4 n admsettings tandem and 16–18 h epnet nuto hmteaywsasse codn othe to according assessed was chemotherapy induction to response The MYCN 2 Cr10 0 mg/m 200 x (Ccr/100) = ) 5–7 nnapie tg igoe tage at diagnosed 4 stage -non-amplified nJpn nqeHCrgmncle h double- the called regimen HDC unique a Japan, In . 3 9,11,12 14 h igoi fhg-iknuolsoawas neuroblastoma high-risk of diagnosis The 9 8 hoea(g ? er,200 years, 2 [?] (age Thiotepa . 2 dy(hoea r7 mg/m 70 or (thiotepa) /day 11 10 9 hssuyre-evaluated study This ncnrs,fwstudies few contrast, In eety ihefficacy high Recently, 8 2 19 dy age /day; kd ta.(2019) al. et Okada MYCN > 8months. 18 14 h meta- The < -amplified years, 2 2 < /day 100 13 Posted on Authorea 26 May 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159050449.92324477 — This a preprint and has not been peer reviewed. Data may be preliminary. optet ihapo eiso tts(29 -69 s 70 -9.3%; +- 37.0% compared vs. 6.9% superior significantly +- was (92.9% HDC status before remission (CR/VGPR) poor status a remission with good patients a to with patients of rate (33%) 14 patients, 41 the of HDC, Radiation Before HDC. before patients. patients 29 11 during in in patients administered performed 39 was was 4- from site tumor collected = primary primary ( were (range the the grafts peripheral of insufficient cycles for cell of Resection therapy 5 because stem patients collection. 2 median blood cell from peripheral collected in stem were of chemotherapy grafts marrow amount induction auto-bone sufficient while chemotherapy, multidrug A intensive cycles). underwent 7 patients 41 All in higher was frequency Treatment metastasis bone to The compared patients. patients patients. 31 neuroblastoma in involved high-risk were -amplified marrow bone and Bone showed tumors months). 8–75 = 1 Table 3.3.3. version package characteristics R Patient the using assessed performed were were test analyses log-rank RESULTS statistical a in All MSI (EFS) tandem model. survival metastasis, and multivariable event-free liver acid, on a retinoic univariate effects metastasis, using HDC, adverse univariate using marrow before significant using surgery showing assessed bone radiation, Factors assessed HDC, were metastasis, SCT. of factors before bone factors INRC progression Prognostic pathology, stage, prognostic as INPC amplification, INSS models. defined addition, age, was regression In event were hazard An analysis proportional cancer. Cox secondary method. multivariate Kaplan–Meier or and the death, using toxic estimated disease, was period. rate study survival the The within occurring event adverse any analysis criteria. to Statistical criteria. BMT-CTN due death Baltimore to as of to according defined 1 according was day diagnosed diagnosed death or version was was Events auto-SCT Adverse (SOS) after (TMA) for Criteria 100 syndrome Terminology microangiopathy day Common obstruction the to Sinusoidal of regimen basis double-conditioning the 4.0. on the regimen of conditioning 1 second the day from assessed was Toxicity eoeHCwr 00 -86 n 76 -80,rsetvl.Te5ya F aeo ainswt a with patients poor of a 8.0%; rate with +- EFS patients different 22.2% 5-year to significantly vs. The compared 11.0% superior respectively. not significantly +- 8.0%, was were (78.6% +- HDC status outcomes 67.6% before remission (CR/VGPR) and the status 8.6% remission results, +- good 50.0% Ccr reduction were dose their HDC needed to before patients 15 according Although melphalan 13 ( ( institutions. respectively syndrome and three 7.8%, this rates myelodysplastic thiotepa the +- (OS) During between secondary 56.1% survival of overall different and developed years). and significantly 7.7% EFS 5.5–14.0 1 +- not 5-year 41.5% = were patients, The were (range neuroblastoma. 20 initiation high-risk years treatment those for 9.2 from treatment Of was initial the patients after relapsed. living years patients all 20 of duration period, immunological follow-up expecting median cells, The poor stem with blood patients cord patients immunotherapy. (20%) using Outcome (59%) antibody 8 SCT anti-GD2 24 and underwent addition, second therapy, patients In a acid No underwent deterioration. retinoic effects. dose treatment underwent function reduced who a renal use after received (27%) of off-label response (37%) 7 because 15 requested patients, HDC patients, guardians 26 41 as Of whose Of melphalan CR/VGPR. (CR/VGPR). and showed response thiotepa HDC partial before of good resection undergo very not or did response complete showed 0.051) MYCN uprigIfrainFgr S1 Figure Information Supporting apie ihrs erbatm,11; neuroblastoma, high-risk -amplified umrzsptetcaatrsis( characteristics patient summarizes MYCN MYCN mlfiain nIP itlgclyufvrbetmrwsosre n3 patients. 35 in observed was tumor unfavorable histologically INPC An amplification. a mlfidi 3ptet,3 ainshdsae4dsae n h eann 2 remaining the and disease, 4 stage had patients 39 patients, 23 in amplified was .Te5ya F n So ainswosoe CR/VGPR/PR showed who patients of OS and EFS 5-year The ). n 1.Temda g tdanssws3 ots(range months 35 was diagnosis at age median The 41). = MYCN 4 P .04)( 0.00041) = nnapie ihrs erbatm,3; neuroblastoma, high-risk -non-amplified MYCN nnapie ihrs neuroblastoma high-risk -non-amplified iue2A Figure 21 P nadto,regimen-related addition, In 0.00019). = iue1 Figure .Smlry h -erOS 5-year the Similarly, ). .Teoutcomes The ). 20 Thrombotic 15 , MYCN MYCN P = Posted on Authorea 26 May 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159050449.92324477 — This a preprint and has not been peer reviewed. Data may be preliminary. nti study, drugs. in this HDC. these effective In tandem of especially using dose (thiotepa studies maximum combination be The some drug the could a in administer regimen intensification. of shown safely cycles treatment potent to two weeks from highly of consecutive consists benefit this 2 it to for that likely melphalan) in unique more and quite and is chemosensitive regimen more double-conditioning be might HDC. roblastoma in tandem outcomes including favorable treatment, intensive shown have studies of Some treatment the for appropriate be might neuroblastoma. regimen double-conditioning the that to compared chemotherapy though anti- considered undergo neuroblastoma. have not was studies did HDC who Comprehensive before patients rate. CR/VGPR/PR double- survival showed of superior the who prognosis a patients underwent show studies. our poor who previous of the were patients to outcome HDC Considering comparable neuroblastoma the before immunotherapy, high-risk patients antibody respectively. CR/VGPR/PR all GD2 of 50.0%, of and melphalan and rates and 41.5% EFS thiotepa comprising 5-year regimen the 2 conditioning study, drug, patient; this 1 In (TMA, patients 3 in SOS. in and pneumonia hypertension sepsis cytomegalovirus 2 DISCUSSION developed and and addition, patients injury developed one the In kidney they in of acute post-HDC. toxicity; None bronchiolitis observed regimen-related year virus patients). of also 1 grade We syncytial because hemorrhage for respectively (respiratory other). pulmonary dialysis SCT, infection the 5 required after viral grade 57 who 5 and of patient required 22 grade died patients 1 days 4 finally in on 3, which and died of (grade occurred patients patients, injury patients TMA 8 33 kidney in in acute 3). occurred observed syndrome 4 was (grade leak mucositis administration Capillary acute steroid patient). 4 intravenous 1 or 4, 3 grade grade patients; post-HDC, 32 period assessment the During analysis. Toxicity multivariable Finally, in OS analysis. for multivariate factors was in prognostic EFS Similarly, SCT for 0.12–0.66). tandem = factor significant and interval prognostic four metastasis Among strongest marrow bone the 81.8%). eliminated = selection EFS HDC, stepwise (5-year before outcomes (INRC long-term factors ( prognostic patients) good non-CR/VGPR showed in 0.019 chemotherapy = induction P patients, CR/VGPR S2 in 0.094 Figure response, = (P poor prognoses and good (CR/VGPR) with chemotherapy induction to response 11.1%; to 8.8%; compared +- superior 16.7% vs. 10.2% 8.4% +- 2B +- (60.9% ( patients SCT (32.3% neuroblastoma high-risk tandem metastasis non-amplified undergo bone didn’t without of who rate patients those to to compared compared 14.5%; prognosis EFS +- 70.0% 5-year lower vs. significantly a showed 1 Table .Smlry h -erO aeof rate OS 5-year the Similarly, ). MYCN P MYCN .01)( 0.00018) = umrzsponsi ffcsacrigt nvraeaayi.Ptet ihbn metastasis bone with Patients analysis. univariate to according effects prognostic summarizes .O note, Of ). MYCN 23,24 apie ihrs erbatm ainswssgicnl ueircmae to compared superior significantly was patients neuroblastoma high-risk -amplified apie ihrs erbatm ainssoe ihrrsos aeatrinduction after rate response higher a showed patients neuroblastoma high-risk -amplified ncnrs,i hsstudy, this in contrast, In iue2B Figure P MYCN apie ihrs erbatm ainswosoe RVP eoeHCespe- HDC before CR/VGPR showed who patients neuroblastoma high-risk -amplified MYCN .2) ih ainswoudrettne C hwdsgicnl poorer significantly showed SCT tandem underwent who patients Eight 0.021). = MYCN nnapie ihrs erbatm ains(39 -92 s 33 +- 33.3% vs. 9.2% +- (73.9% patients neuroblastoma high-risk -non-amplified 3,22 apie ihrs erbatm ainswosoe odrsos to response good showed who patients neuroblastoma high-risk -amplified MYCN .Ee hnteotoewsaaye nec ru,wihsoe good a showed which group, each in analyzed was outcome the when Even ). nnapie ihrs erbatm ains hsrsl indicated result This patients. neuroblastoma high-risk -non-amplified ti atybecause partly is It MYCN MYCN mlfiainadIR eoeHCwr locoe ssignificant as chosen also were HDC before INRC and amplification MYCN 5,6 MYCN apie ihrs erbatm ainswssignificantly was patients neuroblastoma high-risk -amplified MYCN mlfiain oemtsai,adtne C) backward SCT), tandem and metastasis, bone amplification, hsfidn ugssthat suggests finding This MYCN mlfiaina orponsi atri high-risk in factor prognostic poor a as amplification al 2 Table 5 mlfiain(aadrto=02;9%confidence 95% 0.29; = ratio (hazard amplification mlfiainwsafvrbeponsi atr al- factor, prognostic favorable a was amplification MYCN apie ihrs erbatm ainsafter patients neuroblastoma high-risk -amplified MYCN ecie h eal fmliait analysis. multivariate of details the describes apie ihrs erbatm patients neuroblastoma high-risk -amplified P .1) neetnl,te5ya EFS 5-year the Interestingly, 0.012). = apie ihrs erbatm,as neuroblastoma, high-risk -amplified MYCN MYCN apicto a associated was -amplification MYCN apie ihrs neu- high-risk -amplified P .005 ( 0.000065) = apie high-risk -amplified Supporting 8 Therefore, MYCN Figure - Posted on Authorea 26 May 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159050449.92324477 — This a preprint and has not been peer reviewed. Data may be preliminary. .Pr R risa G odnW,e l ffc fTne uooosSe elTasln sSingle vs Transplant Cell Trial. Stem Clinical Autologous Randomized Tandem A of Effect Neuroblastoma: 2019;322:746-755. High-Risk al. JAMA. With Patients et in WB, cell 2015:CD006301. Survival Event-Free London stem on Rev. SG, Transplant haematopoietic Kreissman Syst autologous JR, Database Park and Cochrane chemotherapy 2. neuroblastoma. High-dose high-risk EC. with Dalen children van for LC, rescue Kremer B, Yalcin 1. interest. REFERENCES of conflict no declare authors The INTEREST OF CONFLICT practice. espe- clinical neuroblastoma, in high-risk attention for special effective with is patients melphalan in and cially thiotepa with on regimen did potent double-conditioning based study The this was this underwent collection method, who follow-up patients data long-term in because CONCLUSIONS common complications profiles a long-term care. toxic of Therefore, considerable lack of second merit a toxicity. range treatment for of long-term entire except because report the effects, Finally, not cover prognostic records. any not medical exhibit could the only not Especially, we did Third, patients. components were of SCT. regimen treatment double-conditioning bias the However, than selection other was treatments heterogeneous. Second, there interpretation. First, careful warrants patients between limitations. rate few response the a in difference had study retrospective This trials. required. clinical are early regimen mg/m in double-conditioning 210 confirmed to been melphalan 280 with has from along regimen dose Japan induction cumulative in low approved reduced intensive was showing a therapeutic undergo with those regimen who double-conditioning in a patients as or thiotepa neuroblastoma Recently, old high-risk years to 2 applied than severe. when less therapy. still patients care was in toxicity special melphalan gastrointestinal warrants and while thiotepa function tubular year of renal renal doses 1 microangiopathy, the hemorrhage toxicity, decreasing pulmonary gastrointestinal recovery. a severe platelet toxcity from showed delayed neurological died double-conditioning tumors the and TMA solid of acidosis, 4 experience several dose-finding regimen- grade The for of developed died observed. regimen patients frequently who 2 was study, mucositis patient this Acute In 1 post-HDC. severe. and relatively toxicity, is have regimen related didn’t double-conditioning study, and the HR-NBL-1/SIOPEN of (CR/VGPR) toxicity the The status of analysis remission the good from impact. stratification as prognostic risk any such reports. for previous study, variables to as this similar extracted in were negativity, shown metastasis factors bone results. prognostic positive favorable our to Other led have might cohort our to in compared outcome poor patients. good significantly neuroblastoma a similar showed with progression also chemotherapy earlier developed induction to while response outcomes, good long-term that showed course; who reported clinical patients (2014) the neuroblastoma in risk al. dichotomy et extreme Kushner show patients prognosis. good had cially MYCN 25 25 27 MYCN h ihfeunyo chemosensitive of frequency high The kd ta.(09 eotdtescesu rvnino ea oiiyby toxicity renal of prevention successful the reported (2019) al. et Okada mlfiain oee,tedul-odtoigrgmni oi n warrants and toxic is regimen double-conditioning the However, amplification. apie ihrs erbatm ainswoddntso CR/VGPR show not did who patients neuroblastoma high-risk -amplified 8 nte td lorpre xesv atonetnltxct and toxicity gastrointestinal excessive reported also study Another . MYCN apie and -amplified 28 ute tde ocnr h ffiayo hsmodified this of efficacy the confirm to studies Further 6 2 h esblt fti oie double-conditioning modified this of feasibility The . MYCN 15,26 MYCN 9 hrfr,tedul-odtoigregimen double-conditioning the Therefore, apie and -amplified MYCN MYCN ihMI( MSI High nnapie ihrs neuroblastoma high-risk -non-amplified apie ihrs neuroblastoma high-risk -amplified apie ihrs neuroblastoma high-risk -amplified MYCN > )adodrae(?5years), ([?]5 age older and 1) MYCN nnapie high-risk -non-amplified nnapie high- -non-amplified Posted on Authorea 26 May 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159050449.92324477 — This a preprint and has not been peer reviewed. Data may be preliminary. h ramn fhg-iknuolsoa eut fapaeI ra.JCne e lnOcl 2007;133:653- in Oncol. (TCE) Clin etoposide Res Cancer and J cyclophosphamide, trial. Topotecan, phase-II in a al. of rates et Results 661. survival U, neuroblastoma. 2002;24:613-621. the Harnischmacher high-risk Oncol. of increases A, treatment Hematol chemotherapy Langler the Pediatr Intensified T, J Simon amplification. al. MYCN 18. et with H, neuroblastoma Mugishima 4 stage Y, with Tsuchida patients (JNBSG). M, Committee Kaneko treatment Neuroblastoma neuroblastoma Group high-risk 17. for Cancer 2018;23:965-973. trial Childhood II Oncol. Japan phase a Clin of the of J from burden Results Int report al. and a et Neuroblastoma pattern M, JN-H-07: International Ohira of protocol K, the Matsumoto significance from T, 2016;65:1-10. Hishiki study Prognostic A 16. Cancer. J al. neuroblastoma: Eur et 4 database. stage D, neuroblastoma Group with for Stephens Risk patients criteria WB, in international London disease the 1993;11:1466-1477. (INRG) DA, metastatic of Oncol. Group Morgenstern Revisions Clin Risk J al: 15. Neuroblastoma treatment. et to International F, response Berthold The and 2009;27:289-297. J, staging, Pritchard Oncol. diagnosis, al. GM, Clin et J Brodeur WB, report. 14. Force London Task INRG AD, J treated an Pearson Jpn neuroblastoma system: SL, high-risk classification experience. Cohn of center analysis single 13. Retrospective a conditioning: 2016;53:1-7. al. reduced-intensity Oncol. et following Hematol C, systemic transplantation Pediatr Tanaka of blood Y, end cord neuroblastoma Nakano the metastatic by K, until high-risk Yamasaki surgery with 2008;25:439-450. primary children Oncol 12. of postponed Hematol series of Pediatr case chemotherapy. consisting A high-dose strategy al. including treatment chemotherapy et novel H, a Ohta with T, treated Kusafuka 2020;67:e28012. Y, prospective Hashii Cancer. infants A 11. in Blood chemotherapy: burden Pediatr radiation high-dose Japan. minimize and to in methotrexate Strategy study J. intrathecal registry A Hara using H, medulloblastoma Sakamoto tumors: T, high-risk solid Soejima and pediatric K, Okada high-risk of K, Yamasaki for consisting 2019;66:e27953. regimen 10. rescue Double-conditioning Cancer. cell J. Blood stem Hara Pediatr autologous Y, report. with Osugi second H, 1998;22:7-12. melphalan Fujisaki Transplant. and C, Marrow thiotepa Bone Nitani K, high-dose busul- tumors. Yamasaki and solid K, melphalan pediatric Okada thiotepa, of of cell treatment 9. consisting the regimens stem for Double-conditioning with rescue al. cell chemotherapy et Bone stem high-dose H, with Ohta tandem fan Y, ANBL00P1. Osugi of study J, study Hara Group pilot 8. Oncology A Children’s al. neuroblastoma: 2013;48:947-952. et high-risk Transplant. DL, Marrow for Baker consolidation A, Transplant. as Naranjo Marrow rescue transplan- AE, Bone cell Seif study. stem NB-2004 autologous 7. SMC and chemotherapy of high-dose results Tandem neuroblastoma: 2002;20:2284- al. high-risk 2013;48:68-73. et Oncol. with SH, patients Clin Lee in J MH, triple-tandem tation Son Study. with KW, II neuroblastoma Sung Pilot high-risk 6. Chicago of the Treatment of al. results et rescue: PR, 2292. stem-cell Haut and 2006;37:271-276. failure HM, therapy Transplant. Katzenstein neuroblastoma: high-dose Marrow for M, Bone carboplatin Kletzel system. and nervous thiotepa, 5. Topotecan, central the al. et in S, relapse Modak prevent 2017;18:500-514. K, to interna- Oncol. Kramer etoposide, BH, Lancet an carboplatin, Kushner versus (HR-NBL1/SIOPEN): trial. 4. melphalan 3 neuroblastoma and phase high-risk Busulfan open-label, for multi-arm, al. chemotherapy randomised, et high-dose tional, ADJ, as Pearson melphalan U, Potschger and R, Ladenstein 3. 7 Posted on Authorea 26 May 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159050449.92324477 — This a preprint and has not been peer reviewed. Data may be preliminary. conditioning-regimen-with-thiotepa-and-melphalan-for-high-risk-neuroblastoma 2.docx Table file Hosted conditioning-regimen-with-thiotepa-and-melphalan-for-high-risk-neuroblastoma 1.docx Table partial good very file VGPR, Hosted response; complete chemotherapy. CR, high-dose Criteria; HDC, response; Response Neuroblastoma International INRC, ( amplification ( HDC before 2. FIGURE survival. overall OS, autologous 1. for FIGURE Cancer regimens high-dose lymphoma. in adult Figures or thiotepa to tumors of Legends pediatric Pharmacokinetics with patients al. 2019;84:849-860. Japanese et Pharmacol. in one. H, Chemother transplant of Goto cell price T, stem the Ikeda hematopoietic for E, transplants Kondo two conditioning adults: 28. thiotepa-melphalan (abstract). young Doble 96 and I. 2005;35:Suppl Yaniv children H, Transplant. in Gavriel Marrow transplantation J, Bone cell Kapelushnik stem Y, neuroblas- Goshen autologous MYCN-amplified IJ, of for Cohen outcome J, in Stein 2014;120:2050-2059. dichotomy Striking 27. Cancer. al. era. et contemporary K, the Kramer in 2018;65:e27363. S, toma Modak Cancer. BH, neuroblastoma: Blood Kushner metastatic Pediatr high-risk 26. of study. stratification HR-NBL-1/SIOPEN Risk the al. from et L, report Moreno A U, oncology Potschger children’s DA, Morgenstern a 2009;27:1007-1013. 25. acid: 13-cis-retinoic Oncol. neuroblastoma by high-risk Clin followed with therapy J children myeloablative for study. of results rescue group trial Long-term stem-cell randomized al. a et autologous on RC, Seeger treated with CP, Reynolds megatherapy and KK, Matthay Myeloablative 2005;6:649-658. neuroblastoma: interleukin-2, 24. Oncol. high-risk GM-CSF, al. Lancet with patients et with trial. in controlled S, treatment antibody randomised consolidation Burdach a Anti-GD2 as J, chemotherapy maintenance Boos oral al. F, versus et Berthold 2010;363:1324-1334. MF, Med. 23. J Ozkaynak Engl AL, N Gilman neuroblastoma. for AL, isotretinoin Yu committee Blood toxicity marrow network 22. Biol trials bone transplantation. clinical following transplant cell marrow stem liver 2005;11:571-575. and hematopoietic the Transplant. Blood after Marrow of al. microangiopathy et thrombotic disease S, summary: Venoocclusive Carter C, consensus Cutler al. VT, Ho et 21. WE, Beschorner KS, 1987;44:778-783. Transplantation. Lee Blood in transplantation. RJ, Pediatr strategy Jones control trial. local (JN-H-11) delayed 20. bold Group of Study study (abstract). Neuroblastoma II 3 Japan phase 2016;63:Suppl A neuroblastoma: Cancer. al. risk et high K, with Matsumoto H, children Mugishima H, Shichino 19. n F n Srtsfo a ftetetfralptet ( patients all for treatment of 1 day from rates OS and EFS F ae rmdy1o ramn o ains()wt odrmsinsau (CR/VGPR) status remission good with (A) patients for treatment of 1 day from rates EFS n 4 s orrmsinsau nnC/GR eoeHC( HDC before (non-CR/VGPR) status remission poor vs. 14) = 3 vs. 23) = vial at available at available MYCN o-mlfiain( non-amplification https://authorea.com/users/325969/articles/453903-double- https://authorea.com/users/325969/articles/453903-double- n 8 0.ES vn-resria;O,oealsurvival; overall OS, survival; event-free EFS, 20). = n 1.ES vn-resurvival; event-free EFS, 41). = n 9 n B with (B) and 29) = MYCN Posted on Authorea 26 May 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159050449.92324477 — This a preprint and has not been peer reviewed. Data may be preliminary. 9 Posted on Authorea 26 May 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159050449.92324477 — This a preprint and has not been peer reviewed. Data may be preliminary. 10