Pediatr Blood Cancer 2004;43:571–579

Toxicity and Efficacy of Intensive Chemotherapy for ChildrenWith Acute Lymphoblastic Leukemia (ALL) After First Bone

Marrow or Extramedullary Relapse

Blythe Thomson, MD,1* Julie R. Park, MD,1 Judy Felgenhauer, MD,2 Soheil Meshinchi, MD, PhD,1

John Holcenberg, MD,1 J. Russell Geyer, MD,1 Vassilios Avramis, PhD,3 James G. Douglas, MD,4

Michael R. Loken, PhD,5 and Douglas S. Hawkins, MD1

INTRODUCTION

More than 1,200 children less than 15 years of agedevelop acute lymphoblastic leukemia (ALL) in theUnited States each year [1]. With dramatic improvementsin the efficacy of chemotherapy for the treatment of ALL,approximately 70%will survive relapse-free formore than5 years [2–6]. Of those patients who relapse, the failure toachieve a second remission, toxicity, and subsequentrecurrence all contribute to unsatisfactory survival forrelapsed ALL [7–17]. The duration of initial remission isthe most significant factor predicting survival. Event-freesurvival (EFS) for patients experiencing an early relapsehas been reported to be 10–29%, compared to the EFS of31–60% for late medullary relapse [9,14,18–20]. Patientswho have relapsed <36 months from original remission,defined as an early relapse, have a 69–88% reinductionrate [9,12]. This contrasts with the patient experiencing alate relapse (>36 months from original remission), forwhom there is a 92–97% second remission rate [8,9]. Toachieve these remission rate, patients have receivedcombination chemotherapy with significant toxicity, withup to 11% toxic death rate reported in some studies [12].The secondmajor barrier to prolonged second remission isthe high risk of second recurrence. Currently, the child

with relapsed ALL remains a significant challenge for thepediatric oncologist. To address this problem, we devel-oped a prospective, limited institution pilot study to testan intensive induction and intensification regimen forrelapsed pediatric ALL.

Background. Approximately 25% of chil-dren newly diagnosed with acute lymphoblasticleukemia (ALL) will eventually experienceleukemic relapse, with bone marrow being themost common site of recurrence. The ability toachieve a durable second remission is com-plicated by toxicity and resistant disease. Wereport a novel combination of chemotherapy forrelapsed pediatric ALL. Procedure. Thirty pedia-tric patients with relapsed medullary (n¼ 18)and extra-medullary (n¼ 12) ALL were enrolledat three pediatric institutions. Following receiptof induction and the first Block A and Block B ofintensification, each patient was evaluated fortoxicity, efficacy in achieving remission, andlong-term survival. Additionally, minimal resi-dual disease (MRD) detection by multidimen-

sional flow cytometry (MDF) was performed.Results. During induction, the major non-hematopoeitic toxicities were mucositis (30%of patients) and bacteremia (50% of patients).Two patients (7%) died of toxicity duringinduction. Toxicity during intensification Block1A and 1B was markedly reduced. Eight-ninepercent of patients with marrow disease achiev-ed a remission following induction and intensi-fication. The event-free survival (EFS) for allpatients at 2 and 4 years were 60% (95%CI: 42–78%) and 49% (95% CI: 30–68%), respectively.Conclusions. This regimen for patients withrelapsed ALL was successful in achieving asecond remission for the majority of patientswith acceptable toxicity. Pediatr Blood Cancer2004;43:571–579. � 2004 Wiley-Liss, Inc.

Key words: acute lymphocytic leukemia; drug toxicity; recurrence; treatment outcome

——————1Seattle Children’s Hospital and Regional Medical Center, Seattle,

Washington

2Sacred Heart Children’s Hospital, Spokane, Washington

3Children’s Hospital Los Angeles, Los Angeles, California

4University of Washington, Seattle, Washington

5HematoLogics, Inc., Seattle, Washington

The work was performed at Seattle Children’s Hospital and Regional

Medical Center, Seattle, WA; Deaconess Hospital, Spokane, WA; and

James W. Riley Hospital for Children, Indianapolis, IN.

Grant sponsor: Orrico Foundation.

*Correspondence to: Blythe Thomson, Seattle Children’s Hospital and

Regional Medical Center, 4800 Sandpoint Way, NE, MS: 6D-1,

Seattle, WA, 98105-0371.

E-mail: blythe.thomson@seattlechildrens.org

Received 22 January 2004; Accepted 21 May 2004

� 2004 Wiley-Liss, Inc.DOI 10.1002/pbc.20128

MATERIALS AND METHODS

Eligibility Criteria

Patients with an initial relapse of ALL at Children’sHospital and Regional Medical Center, Seattle, WA;Deaconess Hospital, Spokane, WA, and James W. RileyHospital for Children, Indianapolis, IN, between May1997 and May 2001 were considered for entry onto thisprospective study. Patients were eligible with any site ofinitial relapse (including isolated or combined bonemarrow relapse, isolated or combined extramedullaryrelapse at any site) any time following initial remissionregardless of prior therapy. The initial therapy for ALLwas either Children’s Cancer Group (CCG) protocols(CCG 1882, 1891, 1922, 1942, 1952, 1961, 1962 orinstitutional standard therapy based upon the control armsof CCG studies (termed best available therapy) [21–28].Eligible patients had to be 1–21 years old and have normalcardiac function (defined by echocardiogram with afractional shortening >29% or left ventricular ejectionfraction >55% or by radionuclide cardiac cineangiogra-phy with a left ventricular ejection fraction >55%).Patients with a history of allergy to PEGasparagase, ahistory of prior pancreatitis associated with asparaginaseuse, trisomy 21, or>25%L3 lymphoblasts (mature B-cellleukemia) were excluded from the study. Informedconsent was obtained prior to study enrollment in ac-cordance with local Institutional Review Boards.

Chemotherapy Treatment Plan

The protocol consisted of three phases: one course ofInduction (5 weeks in duration), eight courses of Intensi-fication (Blocks A and B) (each 6 weeks in duration, for atotal of 16 blocks), and Maintenance for up to 1 year induration. Details of the chemotherapy are presented inFigure 1. During Induction, no dose modifications weremade for hematopoeitic toxicity. For patients with bonemarrow relapse at study entry, a bone marrow aspirationwas obtained on day 14 and 35 of Induction. Patients with>25% residual lymphoblasts (M3 response) on day 14omitted the remainder of Induction and proceeded toIntensification course 1, Block A regardless of peripheralblood counts. Patients with >5% residual lymphoblasts(M2 or M3 response) on day 35 proceeded to Intensifica-tion course 1, Block A regardless of peripheral bloodcounts. All other patients started Intensification course 1,Block A when the absolute neutrophil count (ANC) was�750/ml and platelet count was�75,000/ml. Each Intensi-fication block (either A or B) started 21 days after the startof the previous Intensification block or when theANCwas�750/ml and platelet count was �75,000/ml, which everoccurred last. For patients with an isolated CNS relapse,the use of an Ommaya reservoir during Intensificationcourses was encouraged. After the completion of Intensi-

fication course 1 Blocks A and B, patients could be takenoff study for hematopoeitic stem cell transplantation(HSCT) at the physician’s discretion. ALL patients,including those removed from protocol therapy for HSCTor other alternative therapy, were considered evaluable forEFS and overall survival.

Patients with isolated bone marrow relapse receivedcranial irradiation therapy in the first month of main-tenance: cranial dose 1,800 cGy. Patients with CNSrelapse received craniospinal irradiation therapy (CSI) inthe firstmonth ofmaintenance: cranial dose 1,800 cGy andspinal dose 600 cGy. Patientswith biopsy proven testicularrelapse received testicular irradiation therapy duringIntensification course 1, Block A: testicular dose 2,400cGy. Dose homogeneity was within 5% of the prescribedtreatment dose within the treatment volume.

Patients who proceeded to HSCT received cranial andtesticular radiotherapy at the discretion of the physician aspart of the HSCT conditioning regimen. The doses ofcranial and testicular radiation recommended dependedupon whether total body irradiation was part of the HSCTconditioning.

Supportive Care

Management of hyperuricemia, febrile neutropenia,administration of blood products, and the use of granulo-cyte-colony stimulating factor (G-CSF) were at thediscretion of the treating physician at each institution.Prophylactic fluconazole and acyclovir (for herpessimplex virus sero-positive patients) were recommendedduring Induction, although not required by study protocol.Pneumocystis carinii prophylaxis was required duringintensification.

Definitions

Risk stratification at initial diagnosis was defined asstandard risk or high risk as previously described [2].Early and late bone marrow relapse were defined asleukemia recurrence in the bone marrow<36 months and�36 months following initial remission, respectively.Bone marrow response was defined as M1: <5%, M2:<25%, and M3: �25% leukemic blasts by morphologicevaluation of bone marrow aspiration, respectively. Amarrow remission was defined as an M1 marrow. Earlyand late CNS relapse were defined as �5 WBC/ml in thespinal fluid and a cytologic evaluation demonstratingleukemic blasts, or clinical signs of cranial nerve involve-ment regardless of cell count at <36 and �36 months,respectively. CNS remission was defined as <5 WBCcells/ml regardless of cytologic evaluation. Testicularrelapse was confirmed by biopsy. Remission of testicularrelapse was defined clinically by return to normal testi-cular size. Patients were removed from protocol therapyfor failure to achieve a bone marrow remission by day 42

572 Thomson et al.

of Intensification course 1, failure to achieve CNS remis-sion by day 42 of Intensification course 1 (for patients withCNS relapse at study entry), or development of secondleukemic relapse at any site.

Minimal Residual Disease (MRD) Detection

Multidimensional flow cytometry (MDF)was perform-ed on bone marrow aspirations performed at diagnosis,

Fig. 1. Schema.

Induction: Dexamethasone 10 mg/m2/day orally on day 0–6, and day 14–20; vincristine 1.5 mg/m2/dose (2 mgmaximum single dose) IVon day 0,

7, 14, and 21; PEGaspargase 2,500 IU/m2 IMonday 2, 9, 16, 23; idarubicin 10mg/m2 over 6 hr IVon day 0, 1, and 2; intrathecal chemotherapy on day

0, 14, and 28 (additional doses given on day 7 and 21 if CNS disease at time of relapse):

Intensification: Block A, dexamethasone 10 mg/m2/day orally on day 0–4; vincristine 1.5 mg/m2/dose (2 mgmaximum single dose) IVon day 0, 7;

thioguanine 100 mg/m2/day orally on day 0–4.

Methotrexate 1 g/m2/dose IV over 36 hours on day 0, with Leucovorin 15 mg/m2/dose orally/IV at hour 48 and then every 6 hours until serum

methotrexate<0.1micromolar; Cytarabine 100mg/m2/day IVover 72 hours on days 2–4; PEGaspargase 2500 IU/m2/dose IM on day 7; Intrathecal

chemotherapy on days 0, 7, 14, 21 of course 1 only (for those with CNS disease at study entry, give on day 21 of each course); Intraventricular

Therapy on days 0, 1, 2 for those with CNS disease and an Ommaya reservoir

Intensification: Block B, etoposide 100 mg/m2/day IV for 5 days on day 21–25; ifosfamide 1,800 mg/m2/day IV for 5 days on day 21–25; MESNA

360 mg/m2/dose IVevery 3 hr for 4 doses; intraventricular therapy on day 21–24 for those with CNS disease and an Ommaya reservoir

Maintenance: Vincristine 1.5 mg/m2/dose (2 mg maximum single dose) IVon day 0, 14, 28, 42, 56, and 70; thioguanine 50 mg/m2/day orally day

0–83 (adjust dose to achieve a cumulative dose of 350 mg/m2/week; methotrexate 50 mg/m2/week IV on day 0, 14, 28, 42, 56, 70 (doses of

methotrexate escalated by 25% if the ANC>2,000/ml and platelets>75,000/ml on day 0 of any maintenance course with dose adjustments if ANC

was <750/ml).

Age (year) Cytarabine (mg) Methotrexate (mg) Hydrocortisone (mg)

1–1.99 16 8 8

2–2.99 20 10 10

�3 24 12 12

Age Cytarabine (mg) Hydrocortisone (mg)

1–1.99 10 10

2–2.99 12 12

�3 15 15

Age (year) Methotrexate (mg)

1–1.99 1

2–2.99 2

�3 2

Chemotherapy for Children With Relapsed ALL 573

day 14 and 35 of induction using methods previouslydescribed [29–31]. Cells from day 14 and 35marrowwithmatching immunophenotypic characteristics were con-sidered leukemic blasts and their percentage of totalnucleated cell population was calculated. All patientsanalyzed had a distinctive phenotype that was used tofollow the proportion of the leukemic cells. The lowerlimit of detection was estimated to be 0.2%.

Statistical Considerations

The principal goals of this study were to estimate themedullary remission induction efficacy of Induction andIntensification course 1 and to evaluate the toxicity of eachphase of treatment. For the purposes of estimating remis-sion induction efficacy, only patients with bone marrowrelapse were considered evaluable. The response rate wascalculated as the number of patients who obtained an M1marrow with recovery of peripheral blood counts (eitherby day 35 of Induction or by day 42 of Intensificationcourse 1). The toxicity of the therapywas evaluated for theInduction, each course of Intensification, and for Main-tenance. All patients enrolled were evaluated for toxicity.The CCG Toxicity Scale was used to grade toxicity.Because of the limited study size, estimation of EFSwas asecondary goal of the study. Estimates of EFSwith 95%CIwere calculated by the method of Kaplan andMeier usingSPSS version 10.0 statistical package [32]. Patients werecensored at date of last contact. EFS was measured fromthe date of initial relapse to the date of next event or date oflast contact. An event was defined as death from any causeincluding toxicity or disease relapse. All patients wereconsidered evaluable for EFS, regardless of removal fromprotocol therapy or use of HSCT. EFS was analyzed as ofAugust 31, 2003.

RESULTS

Clinical Features of Patients

Table I outlines the clinical features of patients at timeof original diagnosis and time of relapse. Of the thirtypatients, 10 experienced early bone marrow relapse (2combined with CNS), 8 experienced late bone marrowrelapse (2 combined with testicular and 1 combined withCNS), 5 experienced early isolated extramedullaryrelapse, and 7 experienced late extramedullary relapse.

Induction

The median duration of Induction (for the 28 patientswho survived to the end of Induction) was 38 days (range29–57 days) and the median days of hospitalization was19 (range 5–38 days) (Table II). As anticipated, significanthematopoietic toxicity was observed in virtually allpatients. Nine patients received G-CSF at the discretionof their physician. Of the 30 patients, 9 received total

parenteral nutrition (TPN), 11 received intravenousnarcotics, and 9 had Grade III /IV gastrointestinal toxicity(stomatitis, typhilitis, or duodenitis). Fifteen of thepatients received empiric, intravenous amphotericin, withone documented fungal infection (pulmonary aspergillus).Other Grade III/IV non-hematopoietic toxicities includedGrade III/IV hyperbilirubinemia (3 patients) and GradeIII/IV glucose or electrolyte abnormalities (4 patients).Two patients (one with late isolated bone marrow relapseand one with isolated CNS relapse) died from sepsis (oneeach with clostridium and bacillus species). Two patients(onewith isolated bonemarrow and onewith isolatedCNSrelapse) were removed from protocol therapy at physicianrecommendation (one due to pulmonary aspergillosis).Both received alternative chemotherapy and subsequentHSCT. A total of 26 patients completed therapy andproceeded to intensification.

Intensification Block 1A

Twenty-six patients received Intensification course 1,Block A (Block 1A) (Table II). The median duration ofBlock 1A was 25 days (range 16–32). The medianduration of hospitalization during Block 1Awas 10 days(range 5–21 days). The overall incidence of mucositisduring Block 1A was reduced compared to Induction(Table II). Six patients received TPN, four patientsrequired intravenous narcotics, and only three patientsexperienced Grade III/IV mucositis. There were sixpatients with Grade III/IV infections and only one patientwho received intravenous amphotericin for a suspectedbut unproven fungal infection. Six patients had Grade III/IV hepatic toxicity (either transaminitis or hyperbilirubi-nemia), all of which were reversible and did not delay oralter the planned chemotherapy. One patient was removedfrom protocol therapy after completing Block 1A toreceive HSCT.

Intensification Block 1B

Twenty-five patients received Block 1B (Table II). Themedian number of days of hospitalization was 4 days(range 0–12 days). Mucositis was uncommon, with onlyone patient receiving intravenous narcotics for Grade IIImucositis and four patients receiving TPN. Three patientsdeveloped Grade III/IV infections. One patient with T-cellbone marrow relapse died with refractory leukemiafollowing receipt of Intensification Block 1B.

Asparaginase Toxicity

Six patients had adverse reactions to PEGasparagasenecessitating discontinuation of additional doses; twopatients during Induction (one pancreatitis, and onethrombosis) and four patients during Intensification course1A (three secondary to allergic reaction and one due to

574 Thomson et al.

TABLE I. Patient Characteristics

Patient

number

Site of

relapse

Age at initial

diagnosis

(year/sex) Lineage

Risk group,

initial therapy

CR1 duration

(month)

HSCT

(donor source) Outcome (month)

Medullary: CR1 <36 months

2 BM 5/M B SR, 1942 25 HSCT (MR) Death, GVHD (35)

3 BM 1/F B HR, 1882 31 HSCT (MR) NED (60)

5 BM 9/M B SR, 1952 14 HSCT (UCB) Death, infection (6)

7 BM 9/F B SR, 1942 31 HSCT (MUD) BM relapse (23)

12 BM, CNS 0.9/M B Infant, 1883 35 None Death, infection (0.8)

13 BM 5/M B SR, 1962 16 None BM relapse (5)

15 BM 16/F T HR, BAT 27 HSCT (UCB) NED (41)

19 BM, CNS 8/F B SR, 1962 28 HSCT (MUD) NED (40)

20 BM 1/F B SR, 1952 29 HSCT (UCB) Death infection (6)

23 BM 15/M T HR, 1961 17 None Refractory leukemia (2)

Medullary: CR1 �36 months

1 BM 2/M B SR, 1891 46 HSCT (MR) BM relapse (21)

9 BM, testes 3/M B SR, 1942 42 HSCT (MMR) NED (58)

11 BM, testes 2/M B SR, 1922 47 HSCT (UCB) Death, infection (8)

17 BM 8/F B SR, 1952 38 HSCT (UCB) Death, infection (8)

21 BM, CNS 6/F B SR, 1952 42 None NED (38)

25 BM 2/M B HR, 1961 42 HSCT (Syn) BM/CNS relapse (32)

26 BM 4/F Null SR, 1922 57 None NED (34)

30 BM 9/F B HR, 1961 37 HSCT (MMR) BM relapse (12)

Isolated extramedullary: CR1 <36 months

4 CNS 4/F B HR, 1882 28 HSCT (MR) NED (50)

14 Eye 7/F B SR, BAT 35 None NED (52)

16 CNSa 7/F B SR, 1962 19 None NED (48)

24 CNS 4/M B SR, 1952 19 None CNS relapse (26)

28 CNS 6/M T HR, 1961 5 None Refractory CNS (3)

Isolated extramedullary: CR1 �36 months

6 Testes 11/M B HR, 1882 40 None NED (63)

8 CNSa 9/M B SR, 1922 42 None NED (59)

10 CNS 3/M B SR, 1922 42 HSCT (MR) NED (28)

18 Uterus 1/F B SR, BAT 46 None NED (37)

22 CNSa 2/M B SR, 1952 43 None NED (36)

27 CNS 4/M B HR, 1882 59 None Death, infection (1)

29 Testes 7/M B HR, 1961 44 None NED (31)

CR1, first complete remission; HSCT, hematopoietic stem cell transplant; CNS, central nervous system; BM, bonemarrow;M,male; F, female; SR,

standard risk; HR, high risk; BAT, best available therapy; NED, no evidence of disease; GVHD, graft versus host disease; MR, matched related

donor;MMRD,mismatched related donor;MUD,matched unrelatedmarrowor peripheral blood stem cell donor;UCB, unrelated cord blood donor;

Syn, syngeneic stem cell donor; B lineage, B cell lineage; T lineage, T cell lineage.aOmmaya reservoir placed for intraventricular therapy.

TABLE II. Toxicity

Induction

Intensification

block 1A

Intensification

block 1B

Intensification

block 2–8 (A or B)

Evaluable courses 30 26 25 137

Median hospital days (range) 19 (5–38) 10 (5–21) 4 (4–12) 5 (0–21)

Febrile neutropenia (%) 30 (100) 18 (69) 6 (24) 66 (48)

Red blood cell transfusion (%) 28 (93) 23 (88) 12 (50) 84 (61)

Platelet transfusion (%) 27 (90) 20 (77) 4 (17) 81 (59)

Bacteremia (%) 15 (50) 6 (23) 3 (12) 21 (15)

Mucositis, Grade III/IV (%) 9 (30) 3 (12) 1 (4) 7 (5)

Hepatic toxicity, Grade III/IV (%) 3 (10) 6 (23) 0 (0) 4 (3)

Pancreatitis (%) 1 (3) 1 (4) 0 (0) 0 (0)

PEGasparaginase allergy (%) 0 (0) 3 (12) 0 (0) 0 (0)

Toxic death (%) 2 (7) 0 (0) 0 (0) 0 (0)

Chemotherapy for Children With Relapsed ALL 575

pancreatitis). Details of asparaginase pharmacokineticsand L-Asparagine serum and CSF levels have beensubmitted for publication elsewhere.

Induction Response

Eighteen patients with isolated or combined bonemarrow relapse were evaluable for response to Inductionand Intensification course 1; 16 (89%) achieved a bonemarrow remission. Bone marrow remission was achievedby the end of Induction in 15 patients and by the end ofIntensification course 1, Block A in one patient whoproceeded to Intensification early due to M3 bone marrowresponse on day 14 of Induction. The two inductionfailures were due to refractory marrow disease (onepatient) or death due to sepsis (one patient). In the twelvepatients with isolated extramedullary relapse, 10 achieveda remission, with 1 induction failure due to death fromsepsis and 1 failure due to refractory CNS disease.

Therapy Following Intensification Block 1A and B

Of the 26 patients who completed Induction andreceived Intensification therapy, 10 patients continued toreceive protocol chemotherapy, 13 patients receivedHSCT. One patient was taken off study at parent requestand received alternative chemotherapy. Two patients weretake off protocol study for disease progression aftercompleting Intensification course 1: onewith second bonemarrow relapse while awaiting HSCT and one withrefractory CNS relapse (patient with T-cell ALL) despiteInduction and Intensification course 1. Ten patientscompleted Intensification Blocks 2–8 chemotherapy,resulting in 137 individual Intensification Blocks 2–8available to analyze for toxicity. The median duration ofhospitalization per block was 5 days (range 0–21 days).Therewere only seven blockswithGrade III/IVmucositis,24 blocks with Grade III/IV infections and no patientdeaths (Table II). Nine patients received maintenancetherapy with only six episodes of febrile neutropenia, noserious infections, and no Grade III/IV toxicity other thanmyelosuppression (data not shown).

Outcome

The EFS for all patients (from time of initial relapse) at2 and 4 years was 60% (95%CI: 42–78%) and 49% (95%CI: 30–68%), respectively (Fig. 2). Of the 10 patients withearly marrow relapse (less than 36 months from initialremission), the EFS was 40% (95%CI: 9–71%) at 2 yearsand 30% (95% CI: 1–59%) at 4 years. Comparatively, theEFS at 2 and 4 years from initial relapse for patients withlatemarrow relapsewas 50% (95%CI: 15–85%) and 38%(95% CI: 3–72%), respectively. Patients with isolatedextramedullary relapse had a 2 year EFS of 83% (95%CI:62–100%) and 4 year EFS of 75% (95% CI: 50–100%).

MDF

MDF analysis of marrow was performed in 17 of the30 patients enrolled. Of the 12 patients with extramedul-lary disease, data from 5 patients was analyzed. None ofthe five patients had evidence of marrow disease by MDFat relapse, confirming the morphological evaluation.

Early marrow response to induction therapy wasevaluated. Twelve of the eighteen patients with marrowdisease had MDF data available for interpretation, withbone marrow available at day 14 of induction for 10 ofthose patients and at day 35 of induction for 11 patients. Ofthe marrows evaluated at day 14 of induction, 3 of 10revealed evidence of leukemia by MDF. Two of thosepatients died of infection and one experienced a secondmarrow relapse. At day 35, only one patient had evidenceof leukemia by MDF; this patient died of graft versus hostdisease following HSCT.

DISCUSSION

The successful treatment of relapsed ALL remains asignificant challenge in pediatric oncology. The prob-ability of achieving a successful second remission isassociatedwith duration of first remission and, potentially,the re-induction therapy chosen. In this series, 89% ofpatientswithmarrow relapse achieved a second remission.These results are similar to prior reports, with inductionsuccess rates for late bone marrow relapse of 92–97%[8,9,15,20] and 69–88% [9,14,15] for early bone marrowrelapse.

The described induction regimen was developed bothto maximize efficacy and limit toxicity. Idarubicin wasselected subsequent to the data of CCG 1884, whichdemonstrated the improved 2-year EFS with idarubicincompared to daunomycin [14]. Idarubicin also has thepotential benefit of increased potency compared with

Fig. 2. Kaplan–Meier.

576 Thomson et al.

daunomycin based upon pre-clinical models and pro-longed circulation andCNSpenetration of idarubicinol, anactive metabolite [33–36]. However, the rate of infectiouscomplications was increased with higher doses ofidarubicin [14]. Idarubicin was given over the initial3 days of Induction in an attempt to prevent prolongedmyelosuppression seen with weekly dosing. PEGaspar-gasewas administeredweekly basedupon the results of thePediatric Oncology Group (POG) 9310, which demons-trated the superiority of weekly PEGaspargase comparedwith every other week PEGaspargase in the induction forrelapsed ALL [16]. Dexamethasone was used in place ofprednisone, based upon its superior CNS penetration [37]and improved efficacy in newly diagnosed ALL [38].Dexamethasone was also given in week-long pulses in anattempt to reduce the toxicity associated with prolongedexposure.

Intraventricular therapy was offered to patients whohad relapsed CNS disease to deliver chemotherapy via anOmmaya reservoir. Intraventricular therapy has severaltheoretical adavantages: more uniform distribution ofchemotherapy throughout the CSF, higher ventricularlevels than those achieved by lumbar administration, andprolonged concentration over time exposure to cell cycleactive chemotherapy [39–42].

The intensification courses in this study were closelypatterned on the R2 block of the Berlin Frankfurt Munster(BFM ALL REZ 95). This study employed intermediatedose (1 g/m2) of methotrexate over 36 hr with leucovorinrescue starting at 48 hr, as well as thioguanine anddexamethasone. Vincristine was substituted for thevindesine used in the BFM Block R2. Additionally, inlieu of the five daily doses of ifosfamide and single doseof daunorubicin used in the BFM block R2, this studyemployed a 72 hr continuous infusion of cytarabinestarting on day 2, followed by a single dose ofPEGaspargase on day 7. Prolonged infusions of cytarabinein combination with thioguanine have been used success-fully in the treatment of childrenwithALLpresentingwithlymphomatous features [43]. The efficacy of ifosfamideand etoposidewas demonstrated in a POG phase I/II studyin a heavily pretreated group of patients with relapsedALL where they demonstrated a 28% CR rate and 8% PRrate [44]. A CCG phase II study also in heavily pretreatedpatients demonstrated a 40% CR rate [45]. The role andtoxicity of these blocks in combination for repetitivecourses in continued intensification therapy for ALL hadnot been tested. Our data demonstrates the acceptabletoxicity of repetitive courses of these two blocks ofintensification and may provide an acceptable chemo-therapeutic regimen for patients awaiting transplantationor for whom a transplant is not a reasonable option.

Of the thirty evaluable patients, 50% proceeded toHSCT. In spite of the intensity of the induction therapy,there were no significant delays prior to HSCT and only

one patient relapsed while waiting for HSCT. Whichchildrenwith relapsedALL should proceed toHSCTis notaddressed in this study. Furthermore, what constitutes anacceptable HSCT donor remains controversial.

The toxicity of re-induction therapy for relapsed ALLcan be significant. Our report compares favorably withprevious intensified induction regimens. CCG 1941utilized vincristine, dexamethasone, ifosfamide, etopo-side, methotrexate, and L-asparaginase andwas associatedwith a 12% toxic death rate during the induction phase, ascompared to our 7% toxic death rate [46]. The toxicity ofidarubicin, fludarabine, and cytarabine re-induction forchildren with refractory or relapsed AML or ALL in CCG0922 was comparable, with 11.7% of the subjects dyingwith bone marrow aplasia [47]. Similarly, an 11% toxicdeath rate was also observed in adults undergoing re-induction in a phase I dose escalation study of idarubicin incombination with cytarabine for relapsed or refractoryALL [48]. A 12% regimen-related mortality rate wasobserved in children with refractory relapsed ALL treatedwith high-dose cytarabine and L-asparaginase [49]. Allstudies noted significant hematopoeitic toxicity and highincidences of mucositis with accompanying infectiouscomplications.

A recent Children’s Oncology Group study of relapsedALL (AALL02P2) used a similar induction regimen, witha lower dose of idarubicin and dexamethasone givencontinuously for 14 days. AALL02P2 was suspended dueto a high rate of infection, which may have been due todifferences in protocol therapy or to implementation of anintensive regimen in cooperative group treatment centerswith variable expertise in supportive care. Given the highrate of infection and toxicity, an intensive re-inductionregimen should be considered by large centers with signi-ficant experience in the management of these patients.

The toxicity experienced by the patients with anisolated extramedullary relapse compares with previousreports.Of the 83 patients treated onPOG9061, therewerethree patients who experienced life-threatening infections(two of which were fatal) and five patients developedsecondary malignancies [50].

Because of the small study size and the heterogeneity oftherapy after Induction and the first course of Intensifica-tion, conclusions regarding the EFS observed on this studyare limited. Within the context of the sample size, theoutcome for the current study compares favorably to theEFS reported by the BFM Group (31% at 6 years) [9] andare similar to the results reported by theMedical ResearchCouncil (46% at 5 years) [20]. Comparisons based upontiming (early or late) and site (medullary or isolatedextramedullary) of relapse are evenmore limited. TheEFSof the patients with extramedullary disease was encoura-ging and may suggest that the intensive use of PEG-aspargase within a prolonged intensification may beeffective for these patients. The outcome observed with

Chemotherapy for Children With Relapsed ALL 577

the current study are similar to the historic EFS of 10–29%, 31–60%, 24–44%, and 59–83% for early medul-lary, latemedullary, early isolated extramedullary, and lateextramedullary relapses, respectively [8,9,14,18–20].

MRD detection was performed via MDF for themajority of the patients. Our limited data suggest that forthose patients with isolated extramedullary disease, MRDmeasurements confirm morphological evaluation at timeof diagnosis. Additionally, using a sensitive measurementof MRD, for those patients with marrow disease, asignificant majority had undetectable residual leukemia inthe bone marrow, thus achieving a ‘‘deep’’ remission.However, the small number of patients in this seriesprecluded conclusive correlations of MRD with outcome.Further studies are warranted to assess if depth of remis-sion in this patient population is clinically significant.

In summary, our regimen for pediatric patients withmarrow and extramedullary relapsed ALL had acceptabletoxicity and was successful in achieving a secondremission. This study addresses the toxicity and outcomeof pediatric patients treated with an intensive inductionand intensification. Further clinical trials are necessary todefine the optimal continuation chemotherapy followingre-induction therapy and to define the role forHSCTafter asecond remission induction for relapsed pediatric ALL.

ACKNOWLEDGMENT

This study was supported in part by the OrricoFoundation through the Orrico Acute LymphoblasticLeukemia Research Fund.

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