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A feasibility study of simultaneous administration of gemtuzumab ozogamicin with intensive chemotherapy in induction and consolidation in younger patients with acute myeloid leukemia

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A feasibility study of simultaneous administration of gemtuzumab ozogamicin with intensive chemotherapy in induction and consolidation in younger patients with acute myeloid leukemia
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  doi:10.1182/blood-2003-05-1620Prepublished online August 21, 2003;2003 102: 4277-4283Dominic Culligan, Ann Hunter, Archie G. Prentice and Donald W. MilliganWilliam J. Kell, Alan K. Burnett, Raj Chopra, John A. L. Yin, Richard E. Clark, Ama Rohatiner, in younger patients with acute myeloid leukemiaozogamicin with intensive chemotherapy in induction and consolidationA feasibility study of simultaneous administration of gemtuzumab   http://bloodjournal.hematologylibrary.org/content/102/13/4277.full.html Updated information and services can be found at: (4212 articles)Neoplasia  (3770 articles)Clinical Trials and Observations  Articles on similar topics can be found in the following Blood collections  http://bloodjournal.hematologylibrary.org/site/misc/rights.xhtml#repub_requests Information about reproducing this article in parts or in its entirety may be found onlineat:  http://bloodjournal.hematologylibrary.org/site/misc/rights.xhtml#reprints Information about ordering reprints may be found online at:  http://bloodjournal.hematologylibrary.org/site/subscriptions/index.xhtml Information about subscriptions and ASH membership may be found online at: Copyright 2011 by The American Society of Hematology; all rights reserved.Washington DC 20036.by the American Society of Hematology, 2021 L St, NW, Suite 900,Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly  For personal use only.by guest on October 5, 2013. bloodjournal.hematologylibrary.orgFrom For personal use only.by guest on October 5, 2013. bloodjournal.hematologylibrary.orgFrom For personal use only.by guest on October 5, 2013. bloodjournal.hematologylibrary.orgFrom For personal use only.by guest on October 5, 2013. bloodjournal.hematologylibrary.orgFrom For personal use only.by guest on October 5, 2013. bloodjournal.hematologylibrary.orgFrom For personal use only.by guest on October 5, 2013. bloodjournal.hematologylibrary.orgFrom For personal use only.by guest on October 5, 2013. bloodjournal.hematologylibrary.orgFrom For personal use only.by guest on October 5, 2013. bloodjournal.hematologylibrary.orgFrom   CLINICALOBSERVATIONS, INTERVENTIONS,AND THERAPEUTIC TRIALS Afeasibilitystudyofsimultaneousadministrationofgemtuzumabozogamicinwithintensivechemotherapyininductionandconsolidationinyoungerpatientswithacutemyeloidleukemia William J. Kell, Alan K. Burnett, Raj Chopra, JohnA. L. Yin, Richard E. Clark, Ama Rohatiner, Dominic Culligan,Ann Hunter, Archie G. Prentice, and Donald W. Milligan The feasibility of combining gemtuzumabozogamicin (GO) with intensive chemo-therapy as first-line treatment of acutemyeloid leukemia (AML) was assessed in72 patients, aged 17 to 59 years, as aprelude to the United Kingdom MedicalResearch Council (MRC) AML15 trial.Sixty-fourpatientsreceivedinductionche-motherapy (DAT [daunorubicin, ara-C,thioguanine], DA [daunorubicin, ara-C],or FLAG-Ida [fludarabine, ara-C, G-CSF,idarubicin]) with GO on day 1. It waspossible to give GO 3 mg/m 2 with course1, but 6 mg/m 2 with course 1 or GO in adoseof3mg/m 2 withconsecutivecourseswas not feasible because of hepatotoxic-ity and delayed hematopoietic recovery.Thirty-one patients who were treated inconsolidation with MACE (amsacrine,ara-C,etoposide)orHidAC(HidAC)andGO(3mg/m 2 ),and23ininductionandconsolida-tion, tolerated GO (3 mg/m 2 ) well. Grade 4livertoxicityandsinusoidalobstructivesyn-drome was more common in thioguanine-containingschedules( P  ؍ .007).Remissionwith course 1 was seen in 86% of patients.DA or FLAG-Ida with GO in inductionachieved complete remission in 91% of pa-tients and 78% of these patients are incontinuouscompleteremissionat8months.GO given with induction (DA or FLAG-Ida)and consolidation (MACE or HidAC) waswell tolerated. These schedules are nowbeing compared in the MRC AML15 trial inpatientsyoungerthan60years.(Blood.2003;102:4277-4283) © 2003 by TheAmerican Society of Hematology Introduction Although evidence indicates that intensification of chemotherapy usedin the treatment of acute myeloid leukemia (AML) has, in recent years,improved survival in younger patients, 1-6 further intensification 5,7,8 islimited by toxicity and compromised by reduced compliance. Stem celltransplantation studies, both allograft and autograft, have demonstratedthat, although it is not always possible to improve overall survival, therate of relapse can be reduced. 2-4,9,10 This supports the contention thatmore antileukemic treatment can reduce the risk of relapse. Oneapproach to this problem is to target treatment using immunologicallydirected treatment either with antibody alone or antibody-directedchemotherapyorradiationtherapy.The immunotoxin gemtuzumab ozogamicin (GO [Mylotarg;Wyeth Pharmaceuticals, Collegeville, PA]) is a humanized IgG4monoclonal antibody directed against the CD33 epitope, which ischemically linked to calicheamicin, a highly potent antitumorantibiotic. 11 As a single agent it has been shown to be an effectiveagent in the treatment of relapsedAMLwith a tolerable toxicity profilecompared to what is expected using intensive chemotherapy. 12-14 OnestrategyforexpandingitsplaceinthetreatmentofAMListoadministerit simultaneously with chemotherapy in situations where intensificationhas been shown to be effective, specifically, in younger patients.Wherethis has been attempted in patients with advanced disease and incombination with various chemotherapy schedules in older patients,liver toxicity was the limiting toxicity, 15 and the potential for unaccept-ablyprolongedmyelosuppressionisnotknown.The United Kingdom Medical Research Council (MRC) AML15trial has been designed to evaluate the effect of adding GO to eachcourse of intensive induction or consolidation chemotherapy in patientsyounger than 60 years as first-line treatment. It was srcinally intendedthatpatientswouldreceive2coursesofinductionchemotherapywithorwithout GO in each course and would then be assigned to receive 2consolidationcourseswithorwithoutGOineachcourse.GOwastobegiven on day 1 of each treatment course. No studies are available toassess the safety of such a strategy, so to assess the feasibility of thisapproach, we conducted a pilot trial in which the antibody-directedchemotherapy was added to each chemotherapy component course of theproposedAML15trialtoevaluatesafetyandfeasibility. Patients, materials, and methods Induction treatment plan It was intended to recruit patients to sequential cohorts of each componentof the proposed AML15 trial treatment. The GO doses were planned to be From the Department of Haematology, University of Wales College ofMedicine, Heath Park, Cardiff; CRC Department of Medical Oncology, ChristieHospital National Health Service (NHS) Trust, Manchester, United Kingdom;Department of Haematology, Manchester Royal Infirmary, Manchester, UnitedKingdom; Department of Haematology, Leicester Royal Infirmary, Leicester,United Kingdom; Department of Haematology, St Bartholomew’s Hospital, London,UnitedKingdom;DepartmentofHaematology,AberdeenRoyalInfirmary,Aberdeen,United Kingdom; University Department of Haematology, Royal Liverpool Hospital,Liverpool, United Kingdom; Department of Haematology, Derriford Hospital,Plymouth, United Kingdom; and Department of Haematology, BirminghamHeartlandsHospital,Birmingham,UnitedKingdom.Submitted May 29, 2003; accepted July 26, 2003. Prepublished online as Blood  First Edition Paper,August 21, 2003; DOI 10.1182/blood-2003-05-1620.Supported by a grant form the United Kingdom Leukaemia Research Fund andJohn Wyeth, Inc. Reprints: Alan K. Burnett, Department of Haematology, University of WalesCollege of Medicine, Heath Park, Cardiff, CF14 4XN, Wales; e-mail:burnettak@cardiff.ac.uk.The publication costs of this article were defrayed in part by page chargepayment. Therefore, and solely to indicate this fact, this article is herebymarked ‘‘advertisement’’in accordance with 18 U.S.C. section 1734. © 2003 by TheAmerican Society of Hematology4277BLOOD, 15 DECEMBER 2003 ⅐ VOLUME 102, NUMBER 13  escalated from 3 mg/m 2 to 6 mg/m 2 and to 9 mg/m 2 expressed as protein, insuccessive cohorts of patients treated with each chemotherapy course. GO wasadministered on day 1 of each course. Escalation of the GO dose to the 6 mg/m 2 and9mg/m 2 cohortscouldoccuronlyifsafetycriteriaweremetinatleast3of4patientsineachcohort.Ifmorethan25%ofcasesexperiencedgrade4toxicityoragrade3nonhematologictoxicitythatdidnotrecoverbyday28,thecohortwasexpandedto8patientstoassesstoxicitybeforeprogressiontothenextdoselevelortreatmentcourse.Ifthesafetycriteriawerethennotmet,thatis,morethan25%grade 3 or 4 toxicity was seen, in the expanded cohort, the previous dose levelwasacceptedasthestudydose.Oncethestudydosewasestablishedwithcourse1, patients were to be recruited into subsequent cohorts to receive course 1 withGO at the study dose and course 2 with dose escalations of GO. Patients whoreceivedinductioncourses1and2thenreceivedconsolidationcourse3(MACE[amsacrine,ara-C,etoposide]orHidAC[HidAC])and4(MidAC[mitoxantroneara-C] or HidAC) without GO, to determine whether GO treatment in inductionpredisposed patients to excess toxicity with the consolidation chemotherapyalone. During the course of the study 9 patients were treated with stem celltransplantationasconsolidation. Consolidation treatment Patients who were treated with induction chemotherapy courses 1 and 2without GO were recruited into cohorts that combined the proposedconsolidation chemotherapy (MACE and MidAC or 2 courses of HidAC)with GO starting at 3 mg/m 2 . A similar approach to dose escalation of GOwas planned, as in the induction plan. Induction and consolidation After a study dose had been separately established for induction andconsolidation, cohorts of patients were recruited to receive the inductionand consolidation chemotherapy with GO in both phases, where the dose of GO was the previously established study dose.The requirement to expand cohorts due to toxicity in the initial patients ineach cohort or the need to expand the fi nal study cohort, or to recruit additionalpatientstofeedtheconsolidationcohortsexplainswhythe fi nalnumbersineachcohortaredifferentasshowninTables5and6andFigure1. Chemotherapy The induction treatments used were those planned for courses 1 and 2 in theAML15 trial: H-DAT 3 ϩ 10 followed by H-DAT 3 ϩ 8 or S-DAT 3 ϩ 10followed by S-DAT 3 ϩ 8 or FLAG-Ida ( fl udarabine, ara-C, G-CSF,idarubicin) followed by FLAG-Ida. During the study, thioguanine becameunavailable in the United Kingdom so a cohort of 8 patients received S-DA3 ϩ 10 followed by S-DA 3 ϩ 8. The consolidation chemotherapy com-prised MACE and MidAC or 2 courses of HidAC. Treatment details aregiven in Table 1. Toxicity assessment and treatment dose escalation Toxicity was assessed using the National Cancer Institute common toxicitycriteria. 16 Each patient was scored on the basis of the highest grade seen inthe period between starting the study course and either day 28 or the day of starting the subsequent treatment course.AGO dose increase was permittedif 25% or less of cases experienced grade 4 toxicity or a grade 3 toxicity thatdid not resolve by day 28.The initial size of each cohort was 4 patients, so if 3 patients avoided toxicity this was accepted as the study dose or enabledescalation of the GO dose for the next cohort.The main feasibility assessments focused on hepatic or hematologictoxicity (Tables 2 and 3). The grades are summarized in Table 2 where theupper limit of normal was that of each investigator ’ s own institution.Sinusoidal obstruction syndrome (SOS) was de fi ned clinically as thesyndromeofweightgainofmorethan10%ofbaseline,rightupperquadrantpainor tender hepatomegaly, jaundice, and edema or ascites. 17 Ultrasonic imaging of hepatic vein blood fl ow was not required but was used to support a diagnosis of SOSintheclinicalsetting.Liverbiopsywasnotroutinelyundertaken.Because grades 3 and 4 hematologic toxicity was expected in all casesand delayed hematopoietic recovery was a relevant end point, hematopoi-etic recovery criteria were developed for each treatment course based on anhistorical group of 1000 patients in the MRC AML12 trial who receivedH-DAT chemotherapy. For each course, dose-limiting hematologic toxicitywas de fi ned as recovery of absolute neutrophil counts (ANCs) to 1.0 ϫ 10 9  /Land platelet counts to 100 ϫ 10 9  /L, delayed beyond that expected for 97.5%of historical controls who received the same treatment course. The valuesfor each course are shown in Table 3. If more than 25% of patients exceedthese recovery times dose escalation could not take place.By aiming to test each component of the proposed phase 3 trial it wasexpected to conclude if a combination of chemotherapy with GO was feasible,and what dose level of GO was acceptable.To be acceptable for prospective usethe hematologic and hepatotoxicity criteria set out above had to be achieved in agroup of at least 8 patients. This approach followed the standard phase 1 doseescalationapproachwithatraditionalFibonaccidesign. 18 Response assessment Complete remission (CR) was de fi ned as less than 5% blasts on a bonemarrow aspirate of adequate cellularity showing evidence of trilineage Figure 1. Study treatment plan by cohort. The treatment planned for each of the 9cohorts is shown. Cohorts were recruited sequentially, that is, when enough patientsentered a cohort and were assessed a new cohort was opened. Cohort 7 and 8included patients who had different induction chemotherapy schedules without GO.In cohort 7, 3 patients received H-DAT, 8 received S-DAT, 4 received DA, and 3received FLAG-Ida. In cohort 8, 7 patients received FLAG-Ida, 4 received DA, and 2received S-DAT. In cohort 9, 7 patients received DA, 10 received FLAG-Ida, and 6received S-DAT as induction with GO 3 mg/m 2 . Of these 23 patients, 13 receivedMACE with GO and 10 received HidAC with GO as course 3. Table 1. Chemotherapy schedules Induction chemotherapy H-DAT scheduleCourse 1 (DAT 3 ϩ 10) Daunorubicin 50 mg/m 2 daily IV, d 1, 3, and 5Cytosine arabinoside 200 mg/m 2 twice a day,d 1-10Thioguanine 100 mg/m 2 twice a day, d 1-10Course 2 (DAT 3 ϩ 8) Daunorubicin 50 mg/m 2 daily IV, d 1, 3, and 5Cytosine arabinoside 200 mg/m 2 twice a day,d 1-8Thioguanine 100 mg/m 2 twice a day, d 1-8FLAG-Ida scheduleCourses 1 and 2 Fludarabine 30 mg/m 2 IV, d 2-6Cytosine arabinoside 2 g/m 2 d 2-6G-CSF 263 ␮ g SC, d 1-7Idarubicin 10 mg/m 2 IV, d 4-6 Consolidation chemotherapy Course 3 (MACE) Amsacrine 100 mg/m 2 IV, d 1-5Cytosine arabinoside 200 mg/m 2 CI, d 1-5Etoposide 100 mg/m 2 IV, d 1-5Course 4 (MidAC) Mitoxantrone 10 mg/m 2 d 1-5Cytosine arabinoside 1 g/m 2 twice a day, d 1-3Courses 3 and 4 (HidAC) Cytosine arabinoside 3 g/m 2 twice a day,d 1, 3, and 5S-DAT was identical to H-DAT except the cytosine arabinoside dose was 100mg/m 2 twice a day; DAwas identical to S-DATwith the exclusion of thioguanine.IV indicates intravenously; G-CSF, granulocyte colony-stimulating factor; SC,subcutaneously; and CI, continuous infusion. 4278 KELLet al BLOOD, 15 DECEMBER 2003 ⅐ VOLUME 102, NUMBER 13  regeneration with a peripheral ANC to 1.0 ϫ 10 9  /L and platelet count to100 ϫ 10 9  /L. Partial remission (PR) was de fi ned as 5% to 15% blasts in abone marrow of adequate cellularity with evidence of trilineage regenera-tion.Bonemarrowassessmentwasundertaken18to23daysaftertheendof course 1 and repeated after course 2 if patients were not in CR. Centralreview was provided by an experienced hematologist who was not involvedin the study and who examined the marrow smears in a blinded manner.The study was approved at the national level by the Wales MulticentreResearch Ethics Committee and by each participating institution ’ s localresearch ethics committee. All patients received written information andprovided written consent before entry to the study. Patients Seventy-twopatientswithuntreatedAMLwererecruitedandtreatedin9centersin the United Kingdom. Patients were eligible if they were 16 to 59 years oldinclusive,andhadAML(denovoorsecondary)diagnosedbyFrench-American-Britishcriteriaonbonemarrowaspirateortrephinebiopsytogetherwithrelevantimmunophenotyping or cytochemistry as required. The European CooperativeOncology Group (ECOG) performance score was required to be 2 or less withnormalliverfunction(aspartateaminotransferase/alanineaminotransferase[AST/ ALT], alkaline phosphatase [ALP], and bilirubin), a negative pregnancy testwhere relevant, and no previous chemotherapy or other experimental agentwithin30days.CD33positivityonleukemicblastcellswasde fi nedasmorethan20% positive blast cells but was not a requirement for study entry. Patients withacute promyelocytic leukemia or blast transformation of chronic myeloidleukemiawerenoteligible.Sixty-four patients were recruited to the induction phase of the study. Of these, 23 were treated in the combined induction and consolidation phase.Eight patients were recruited to the consolidation courses with GO. Thesepatients had received courses 1 and 2 of chemotherapy without GO. Thecharacteristics of all patients are shown in Table 4. Nine patients in thestudy underwent stem cell transplantation in consolidation (6 allogeneic,including 2 nonmyeloablative transplants, and 3 autografts).The median patient age was 46.5 years; 13 were good cytogenetic risk,47 were standard, 7 were unfavorable, and 5 were undetermined cytoge-netic risk by the MRC criteria. 19 Sixty cases were CD33 ϩ , 5 were CD33 Ϫ ( Ͻ 20%), and CD33 status was unknown in 7.Patients received prophylaxis with 500 to 1000 mg/m 2 paracetamol(acetaminophen) and 50 mg diphenhydramine orally or 50 mg methylpred-nisolone intravenously 1 hour prior to receiving GO. Standard antiemeticschedules were given and itraconazole or other antifungal prophylaxis waswithheld until day 5 following GO because of concern about a possiblecontribution to hepatotoxicity. All other medications that were clinicallyindicated were permitted with the exception of immunosuppressive orcytotoxic chemotherapy except as provided in the chemotherapy schedules.Growth factors were not routinely used except in the FLAG-Ida regimen.GO was given as 3 mg/m 2 or 6 mg/m 2 (expressed as dose equivalentprotein) over 2 hours via intravenous pump infusion and allowing a 2-hourgap between chemotherapy. GO was light protected throughout preparationand infusion. Full blood count and biochemical data were collected at leastthrice weekly and reported to a central database.Remission status was assessed 18 to 23 days after course 1 induction byexamination of the bone marrow and hematopoietic recovery. CR requirednormalization of the peripheral blood counts with less than 5% blasts in thebone marrow. Results In summary, the fi rst cohort with 3 mg/m 2 GO and H-DATful fi lled theGO dose escalation criteria so a dose of 6 mg/m 2 with course 1 (DAT)wasevaluated.Thisresultedinexcesshepatictoxicityandsomedelayinhematopoietic recovery so it was concluded after an expanded cohortthat 6 mg/m 2 was not possible and that the study dose with course 1should be 3 mg/m 2 . Patients were then recruited to receive GO (3mg/m 2 ) with course 1 and course 2. This was found not to be feasiblebecauseofhepaticandhematologictoxicityinthesecondcourse.Itwas,therefore, decided to limit the induction combination to GO (3 mg/m 2 )with course 1 only, and cohorts were recruited to S-DAT or FLAG-Idainduction chemotherapy each with GO (3 mg/m 2 ). At this stage of thestudy, thioguanine became unavailable in the United Kingdom so acohortofpatientsreceivedS-DAwithGO(3mg/m 2 ).Forconsolidationevaluation 2 cohorts of patients, who had received 2 courses of DATwithout GO in induction, received MACE or HidAC, respectively, ascourse 3 with GO (3 mg/m 2 ). In view of the induction experience at the6-mg/m 2 dose,aGOdosebeyond3mg/m 2 wasnotattempted,norwasasequential course 4 with GO. The 3-mg/m 2 dose ful fi lled the studycriteriasosubsequentpatientswhohadreceivedinductioncourse1withGO 3 mg/m 2 were recruited to the fi nal phase of testing where GO wasgiven with course 1 and course 3 each at the 3-mg/m 2 dose.The resultsare presented for the fi nal total of patients who contributed to thedifferent cohorts, which are shown in Table 5. No other signi fi canttoxicitywasreported. Induction cohorts Cohort 1: H-DAT with GO 3 mg/m  2  . Twenty-two patients in totalreceived H-DAT with GO (3 mg/m 2 ) as course 1. They had amedian age of 39 years (range, 19-56 years). Six patients experi-enced grade 3 or 4 hepatotoxicity of at least one liver parameter,which was more than that seen in a group of patients treated withH-DAT without GO (Figure 2A-B). Four patients recovered andprogressed to receive the remaining chemotherapy courses withoutfurther toxicity. Two patients died, one with toxic megacolon and Table 2. Liver toxicity criteria Liver criteria Grade 0 Grade 1 Grade 2 Grade 3 Grade 4 Bilirubin WNL WNL ULN to 1.5 ϫ ULN Ͼ 1.5-3.0 ϫ ULN Ͼ 3.0 ϫ ULNAST WNL ULN to 2.5 ϫ ULN Ͼ 2.5-5.0 ϫ ULN 5.0-20.0 ϫ ULN Ͼ 20.0 ϫ ULNALT WNL ULN to 2.5 ϫ ULN Ͼ 2.5-5.0 ϫ ULN 5.0-20.0 ϫ ULN Ͼ 20.0 ϫ ULNWNLindicates within normal limits; ULN, upper limit of normal. Table 3. Hematopoietic toxicity criteria Hematopoietic criteria Course 1 Course 2 Course 3 ANC to 1.0 ϫ 10 9  /L* 39 36 41Platelets to 100 ϫ 10 9  /L* 40 42 60*These data represent the recovery times from the end of treatment for 97.5% ofhistorical control patients treated on the H-DATschedule. Table 4. Patient demographics Induction Consolidation No. 64 31*Age, y (range) 46.5 (18-59) 46 (17-58)Sex, M/F 37/27 17/14De novo/secondary 61/3 30/1Presenting WBC count, ϫ 10 9  /L (range) 9.5 (0.54-305.8) 9.19 (0-305.8)Cytogenetic risk group, 19 favorable/ standard/unfavorable/not available13/39/7/5 5/20/4/2WBC indicates white blood cell.*Atotal of 23 patients were also treated with GO induction. GEMTUZUMAB WITH INTENSIVE CHEMOTHERAPYINAML 4279BLOOD, 15 DECEMBER 2003 ⅐ VOLUME 102, NUMBER 13  sepsis and another from sepsis after having developed diffusepulmonary hemorrhage 5 days after GO therapy to which it wasthought to be possibly related. Twenty (91%) of the 22 patientsachieved CR with one treatment course. Nineteen of the 20 patientsful fi lled the hematopoietic recovery targets (Table 5). Cohort 2: H-DAT with GO 6 mg/m  2  . Because the fi rst 4recipientsofGO(3mg/m 2 )withcourse1ful fi lledtheescalationcriteria,cohort 2 recruited patients to receive H-DAT with 6 mg/m 2 GO. Thisgroup was eventually expanded to 9 patients. Five patients developedgrade 3 or 4 hepatotoxicity, 2 of whom had grade 3 bilirubinemia only(Figure 2C). No patients developed SOS. Hematopoietic recovery wasdelayed in platelet recovery in 4 patients, one of whom also failed torecover neutrophils by the target. Eight patients (89%) achieved CR.One patient died of sepsis and intracerebral hemorrhage. This cohorttherefore did not achieve the protocol requirements for the study dosebasedonlivertoxicity. Cohort 3: H-DAT with GO 3 mg/m  2 with courses 1 and 2. Fifteen patients who entered cohort 1 were also treated with GO (3mg/m 2 ) in course 2 of H-DAT. Five patients experienced grade 3 or4 liver toxicity, all of whom had clinical or ultrasonic features of SOS (Figure 2D). Complete hematopoietic recovery was notachieved within the target time in 13 patients, although with longerfollow up 7 achieved recovery. It was therefore concluded that itwas not possible to give GO, even at 3 mg/m 2 , on consecutivecourses of H-DAT therapy in view of combined hematopoietic andliver toxicity. Cohort 4: S-DAT with GO 3 mg/m  2  . It had become clear fromouranalysisoftheMRCAML12trial,whichcomparedthedailydoseof ara-C (H-DAT400 mg/m 2 ara-C versus S-DAT200 mg/m 2 ara-C), thatthere was no difference in ef  fi cacy between the schedules. 20 Conse-quently a cohort of patients was treated with S-DAT, that is, with thelower ara-C dose level, aiming to determine if less toxicity occurredwhen combined with GO. Ten patients were treated, 4 of whomdevelopedgrade3or4hepatotoxicityincluding2withSOS(Figure2E).Hematopoietic recovery occurred by the target date. Two patients died,onefromSOSandtheotherfromacerebralbleedandsepsis. Cohort 5: S-DA with GO 3 mg/m  2  . Serendipitously, thiogua-nine became unavailable in the United Kingdom as interest wasdeveloping about its potential contribution to liver toxicity. Conse-quentially, 8 patients were treated with S-DA and GO 3 mg/m 2 .Hematopoietic recovery was satisfactory. Two patients developedgrade 3 toxicity only. No patients developed grade 4 toxicity or Table 5. Outcome of induction cohorts Cohort Treatment No.ANC to 1.0 ؋ 10 9 /L,d median (range)Platelets to 100 ؋ 10 9 /L,d median (range)Grade 3 or 4hepatotoxicity DeathsCR course 1,N (%) 1 H-DAT ϩ 3 mg/m 2 GO 22 30.5 (23-41) 35 (26-48) 6 2 20 (91)2 H-DAT ϩ 6 mg/m 2 GO9 24 (22-43) 36 (30-43) 5 1 8 (89)3 H-DAT ϩ 3 mg/m 2 GO andH-DAT ϩ 3 mg/m 2 GO15 33 (23-50)* 50 (35-68)* † 5* 5* NA4 S-DAT ϩ 3 mg/m 2 GO 10 26 (21-54) 27 (22-34) 4 ‡ 2 6 (60)5 S-DA ϩ 3 mg/m 2 GO 8 28 (19-35) 25 (21-41) 2 0 8 (100)6 FLAG-Ida ϩ 3 mg/m 2 GO 15 24 (22-38) 26 (21-60) 3 1 13 (87)NAindicates not applicable.*After course 2. † Five cases of SOS. ‡ Two cases of SOS. Figure 2. Assessment of liver toxicity in induction. Panels demonstrate the maximum liver toxicity gradeseen for each induction cohort. (A) Historical group ofpatientsreceivingH-DATtreatmentalone;(B)H-DATwithGO (3 mg/m 2 ) in 22 patients; (C) H-DAT with GO (6mg/m 2 ) in 9 patients; (D) DAT with GO in 2 coursesshowing the toxicity after course 2 in 15 patients; (E)S-DATwith GO (3 mg/m 2 ) in 10 patients; (F) after DAandGO (3 mg/m 2 ) in 8 patients; and (G) after FLAG-Ida andGO (3 mg/m 2 ) in 15 patients. 4280 KELLet al BLOOD, 15 DECEMBER 2003 ⅐ VOLUME 102, NUMBER 13
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