Pediatric patients with lymphoblastic lymphoma are generally treated using the Berlin-Frankfurt-Munster (BFM) 90 protocol, which is the standard treatment strategy for pediatric acute lymphoblastic leukemia, and have a favorable outcome. However, this intense regimen includes high total doses of anthracycline and alkylating agents, and is known to cause late complications. We therefore planned a clinical trial to examine the efficacy and safety of a modified BFM regimen. We expect that this phase II, nationwide multicenter trial will help to establish an effective and safer standard therapy for stage I/II pediatric lymphoblastic lymphoma

Fujimoto, Junichiro

Horibe, Keizo

Sekimizu, Masahiro

Sunami, Shosuke

Takimoto, Tetsuya

Tsurusawa, Masahito

Okayama University Digital Information Repository

Phase II Clinical Trial for Newly Diagnosed Children and Adolescents with Localized Lymphoblastic Lymphoma (Japanese Leukemia/Lymphoma Study Group Trial LLB-NHL03) : Study Protocol for Nationwide Multicenter Trial

Okayama University Scientific Achievement Repository

P ediatric lymphoblastic lymphoma (LBL) consists of precursor B-cell and precursor T-cell LBL.  Pediatric patients with LBL are usually treated using the standard treatment strategy for pediatric acute lympho-blastic leukemia (ALL),  since the two diseases are bio-logically similar; children treated with this approach have a favorable outcome [1-3].  The exact same proto-col [1-4] is used for both conditions — namely,  chemo-therapy consisting mainly of prednisolone,  vincristine,  and L-asparaginase.  The protocol involves a 4-week remission-induction phase with an anthracycline drug and an alkylating agent.  Drugs not used for remission- induction are then added to an early intensive phase.  After a central nervous system (CNS) prophylaxis phase (high-dose methotrexate 3 × 3 g/m2),  patients are tran-sitioned to a maintenance phase.  The therapeutic regi-men adopted for the current trial uses this ALL-type basic framework.  Although the standard treatment described above is generally used for pediatric patients with localized LBL,  the optimum treatment remains to be determined due to the small number of patients.  Nonetheless,  it is apparent that adequate therapy for patients with stage I/II pediatric LBL is an ALL-type therapy with a certain level of therapeutic intensity lower than that required for stage III/IV disease.  In previous clinical trials [1 , 5],  patients with limited stage LBL have received treatment Acta Med.  Okayama,  2018Vol.  72,  No.  4,  pp.  427-430CopyrightⒸ 2018 by Okayama University Medical School.http ://escholarship.lib.okayama-u.ac.jp/amo/Clinical Study ProtocolPhase II Clinical Trial for Newly Diagnosed Children and Adolescents with Localized Lymphoblastic Lymphoma  (Japanese Leukemia/Lymphoma Study Group Trial LLB-NHL03):  Study Protocol for Nationwide Multicenter TrialMasahiro Sekimizua＊,  Junichiro Fujimotob,  Tetsuya Takimotoc,  Masahito Tsurusawad,   Keizo Horibee, and Shosuke Sunami faDepartment of Pediatrics,  eClinical Research Center,  Nagoya Medical Center,  Nagoya 460-0001,  Japan,   bDepartment of Pathology,  National Center for Child Health and Development,  Tokyo 157-8535,  Japan,   cCenter for Clinical Research and Development,  National Center for Child Health and Development,  Tokyo 157-8535,  Japan,   dAdvanced Medical Research Center,  Aichi Medical University,  Nagoya 480-1195,  Japan,   fDepartment of Pediatric Hematology Oncology,  Japanese Red Cross Narita Hospital,  Chiba 286-8523,  JapanPediatric patients with lymphoblastic lymphoma are generally treated using the Berlin-Frankfurt-Munster (BFM) 90 protocol,  which is the standard treatment strategy for pediatric acute lymphoblastic leukemia,  and have a favorable outcome.  However,  this intense regimen includes high total doses of anthracycline and alkylating agents,  and is known to cause late complications.  We therefore planned a clinical trial to examine the efficacy and safety of a modified BFM regimen.  We expect that this phase II,  nationwide multicenter trial will help to establish an effective and safer standard therapy for stage I/II pediatric lymphoblastic lymphoma.  Key words:  pediatrics,  limited stage,  lymphoblastic lymphoma,  efficacy,  safetyReceived December 25, 2017 ; accepted April 9, 2018.＊Corresponding author. Phone : +81-52-951-1111; Fax : +81-52-963-5503E-mail : masahiro.sekimizu@nnh.go.jp (M. Sekimizu)Conflict of Interest Disclosures: No potential conflict of interest relevant to this article was reported.of the same intensity as patients with advanced stage LBL.  It is presumed that the intensity of chemotherapy for limited stage LBL can be attenuated,  since event-free survival was obtained in all cases of limited stage LBL in the literature.Although the Berlin-Frankfurt-Munster (BFM) 90 protocol [5] has been considered as a standard therapy,  it has a number of problems when treating patients with stage I/II pediatric LBL.  Specifically,  even though the protocol achieves a good prognosis for children with limited stage disease,  the regimen is too intense and the cumulative doses of both anthracycline and alkylating agents — known to cause late complications — are high.  To resolve these problems,  we planned a clinical trial to examine the efficacy and safety of a modified BFM reg-imen.EndpointsPrimary endpoint. The primary outcome is the 3-year event-free survival (EFS) rate.Secondary endpoints. The secondary endpoints are (1) occurrence rates of adverse events of grade 3 or higher,  according to the National Cancer Institute’s Common Toxicity Criteria; and (2) the 3-year overall survival rate.  Eligibility CriteriaInclusion criteria. The inclusion criteria for the trial are as follows.  (1) Newly diagnosed with stage I/II non-Hodgkin’s lymphoma — either precursor T-cell LBL or precursor B-cell LBL — based on the World Health Organization’s categorization [6]; (2) Younger than 18 years old at the time of diagnosis; (3) Untreated at the time of trial registration; (4) Able to be followed up for at least 3 years after initiating therapy; (5) Provision of written informed consent to participate in the trial,  obtained from a legal representative.Exclusion criteria. The exclusion criteria for the trial are as follows.  (1) Down syndrome; (2) History of malignant tumor,  hematopoietic stem-cell transplanta-tion or organ transplantation; (3) History of congenital or acquired immunodeficiency; (4) Assessed by the attending physician as being unsuitable for the trial.  MethodsStudy design. This is a phase IIb,  multicenter trial.  The subjects are patients categorized as having stage I/II pediatric LBL according to the Murphy stag-ing system [7].  Fig. 1 provides an overview of the treat-ment protocol.  This study has been registered in the Clinical Trial Registry (University Hospital Medical Information Network Clinical Trials Registry [UMIN-CTR]) under no.  UMIN000002213).Treatment methods. A schema of the treatment regimen is shown in Fig. 2.  The following modifications were made to the standard therapy (the BFM90 proto-col) for stage I/II [5]:(1) In the remission-induction phase,  daunorubicin will be administered only twice (reduced from 4 times); this drug will be administered again in the re-induction phase.  Because this population428 Sekimizu et al. Acta Med.  Okayama　Vol.  72,  No.  42 years Remission-induction phase Early consolidation phase CNS-prophylaxis phase Re-induction phase Maintenance phase Response evaluation Fig. 1　 Overview of the study treatment.  After enrolling subjects in this study,  we will perform a 2-year modiﬁed BFM-type multidrug combination chemotherapy.has a favorable prognosis,  the dau-norubicin administrations were divided to effectively create a re-in-duction phase without increasing the total anthracycline dose given.(2)  In the remission-induction phase,  cyclophosphamide was moved to day 1.  The cyclophosphamide doses usually given on days 36 and 64 were reduced to 500 mg/m2 and will be given on days 29 and 43.  This will allow mainte-nance of the total cyclophospha-mide dose so as to maintain ther-apeutic intensity,  and so that patients can proceed directly to the early intensive phase,  without an interval.(3)  In the remission-induction phase,  the dosage of L-asparaginase was changed from 10,000 U/m2 ×  8 times to 6,000 U/m2 × 9 times.  This will avoid the administration of L-asparaginase and vincristine on the same day.(4)  The number of total cytarabine administrations was reduced,  from 16 to 12 times.  This will reduce the duration of neutrope-nia.(5)  In the CNS-prophylaxis phase the dose per administration of high-dose methotrexate was reduced from 5 g/m2 to 3 g/m2,  and the number of doses was reduced from 4 to 3.  This will shorten the CNS-prophylaxis phase,  as the standard 2-month period was considered too long [8 , 9].August 2018  LLB-NHL03 429PSL 60mg/m2(capped at 80mg)VCR 1.5mg/m2(capped at 2mg)CPA 1.0g/m2DNR 30mg/m2(capped at 45mg)L-ASP 6,000U/m2DIT MTX＋HDCPSL 60mg/m2CPA 1.0g/m2Ara-C 75mg/m26-MP 60mg/m2DIT MTX＋HDCHD-MTX 3.0g/m2DIT MTX＋HDCPSL 60mg/m2(capped at 80mg)VCR 1.5mg/m2(capped at 2mg)CPA 1.0g/m2DNR 30mg/m2(capped at 45mg)L-ASP 6,000U/m2DIT MTX＋HDCMTX 20mg/m26-MP 60mg/m2Fig. 2　 Schema of the treatment regimen.  The treat-ment regimen consists of a basic backbone of BFM-type ALL treatment and contains a re-introduction phase.  A 4-week remission induction phase consisting of PSL,  VCR,  CPA,  DNR and L-ASP,  an early consolidation phase consisting of 6-MP,  CPA and Ara-C,  a CNS prophylactic phase with high-dose MTX,  a 2-week re-induction phase,  and maintenance therapy by oral administration of 6-MP and MTX will be carried out.(6)  A re-induction phase was newly introduced.  The re-induction phase will consist of 5 drugs: pred-nisolone,  vincristine,  cyclophosphamide,  dauno-rubicin,  and L-asparaginase.  This phase will address the treatment of patients with large tumors.(7)  In regard to the number of intrathecal injections and drugs,  instead of 9 solitary intraspinal injections of methotrexate,  7 intraspinal injections comprising 2 drugs (methotrexate and cytarabine) will be given.(8)  In the maintenance phase,  patients will receive daily mercaptopurine (starting at 60 mg/m2 and adjust-ing based on the white blood cell (WBC) count) and weekly methotrexate (starting at 20 mg/m2 and adjusting based on the WBC count).Statistical ConsiderationsSample size. Although studies from Japan and overseas have indicated that patients with stage I/II pediatric LBL have favorable prognosis,  an EFS rate that could serve as a clear criterion has not been published due to the small number of cases in these studies.  Therefore,  in this trial we set an expected efficacy rate of 95% and a threshold efficacy rate of 80% for 3-year EFS.  Because this is a single arm trial,  if the type-1 error is set to 0.05 and the type-2 error is set to 0.2,  the number of cases needed is 42.  Assuming that 10% of cases will be disqualified,  48 cases are needed.  Eight cases are expected to be registered in Japan per year,  so a 6-year registration period is required to obtain the necessary number of cases to examine the aforemen-tioned statistical hypothesis.Statistical analysis. The primary endpoint (3-year EFS rate) will be evaluated using the Kaplan-Meier method.  We will calculate 3-year EFS rate point estimates and 95% confidence intervals using Greenwood’s formula.  If the upper limit of the 95% confidence interval does not reach the expected efficacy rate (95%),  therapy with the protocol regimen will be considered ineffective.  In principle,  the occurrence rate of adverse events will be calculated using a binomial distribution for point estimates and 95% confidence intervals,  assessed for the items requiring regular mon-itoring.  The Kaplan-Meier method will be used to eval-uate the 3-year overall survival rate.DiscussionIt is expected that this trial will help to establish an effective and safer standard therapy for patients with stage I/II pediatric LBL in Japan.  If this trial confirms the protocol’s efficacy and safety,  its results can be used to establish an optimal therapy with less toxicity.Acknowledgments.　This work was supported by a Health Labour Sciences Research Grant.References 1. Yumura K,  Hara J and Kurahashi H: Immunological phenotype and prognosis of T-lineage malignancy in children.  The Japanese Journal of Pediatric Hematology (1993) 7: 41-46. 2. Reiter A,  Schrappe M,  Parwaresch R,  Henze G,  Muller-Weihrich S,  Sauter S,  Sykora KW,  Ludwig WD,  Gadner H and Riehm H: Non-Hodgkinʼs lymphomas of childhood and adolescence: Result of a treatment stratiﬁed for biologic subtypes and stage-A report of the Berlin-Frankfurt-Munster Group.  J Clin Oncol (1995) 13: 359-372. 3. Lauer SJ,  Camitta BM,  Leventhal BG,  Mahoney DH,  Shuster JJ,  Adair S,  Casper JT,  Civin CI,  Graham M,  Kiefer G,  Pullen J,  Steuber CP and Kamen B: Intensive alternating drug pairs for treatment of high-risk childhood acute lymphoblastic leukemia.  A Pediatric Oncology Group pilot study.  Cancer (1993) 71: 2854-2861. 4. Patte C,  Kalifa C,  Flamant F,  Hartmann O,  Brugières L,  Valteau-Couanet D,  Bayle C,  Caillaud JM and Lemerle J: Results of the LMT81 protocol,  a modiﬁed LSA2-L2 protocol with high dose meth-otrexate,  on 84 children with non-B-cell (lymphoblastic) lymphoma.  Med Pediatr Oncol (1992) 20: 105-113. 5. Reiter A,  Schrappe M,  Ludwig W-D,  Tiemann M,  Parwaresch R,  Zimmermann M,  Schirg E,  Henze G,  Schellong G,  Gadner H and Riehm H: Intensive ALL-type therapy without local radiotherapy provides a 90% event-free survival for children with T-cell lympho-blastic lymphoma: a BFM group report.  Blood (2000) 95; 416-421. 6. Jaﬀe ES,  Harris NL,  Stein H and Vardiman JW: Pathology and genetics of tumors of haematopoietic and lymphoid tissues; in WHO classiﬁcation of tumors,  3rd Ed,  Vol 3,  IARC Press,  Lyon (2001).   7. Murphy SB: Classiﬁcation,  staging,  and end results of treatment of childhood non-Hodgkinʼs lymphomas: Dissimilarities from lym-phomas in adults.  Semin Oncol (1980) 7: 332–339. 8. Barredo JC,  Synold TW,  Laver J,  Relling MV,  Pui CH,  Priest DG and Evans WE: Diﬀerences in constitutive and post-methotrexate folylpolyglutamate synthetase in B-lineage and T-lineage leukemia.  Blood (1994) 84: 564-569. 9. Matherly LH,  Taub JW,  Wong SC,  Simpson PM,  Ekizian R,  Buck S,  Williamson M,  Amylon M,  Pullen J,  Camitta B and Ravindranath Y:  Increased frequency of elevated dihydrofolate reductase in T-cell versus B-precursor acute lymphoblastic leukemia in children.  Blood (1997) 90: 578-589.430 Sekimizu et al. Acta Med.  Okayama　Vol.  72,  No.  4

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Phase II Clinical Trial for Newly Diagnosed Children and Adolescents with Localized Lymphoblastic Lymphoma (Japanese Leukemia/Lymphoma Study Group Trial LLB-NHL03) : Study Protocol for Nationwide Multicenter Trial

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