Prognostic impact of minimal disseminated disease and immune response to NPM-ALK in Japanese children with ALK-positive anaplastic large cell lymphoma
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The prognostic impact of minimal disseminated disease (MDD) and anti-anaplastic lymphoma kinase (ALK) antibody titer in children with ALK-positive anaplastic large cell lymphoma (ALCL) was reported by an Italian/German group. Here, we examine their prognostic value in Japanese children with ALK-positive ALCL. We evaluated nucleophosmin (NPM)-ALK transcripts in 60 patients at diagnosis by RT-PCR and real-time PCR (qPCR). The antibody titer was assessed in 35 patients. Fifty-two percent were MDD positive by RT-PCR and 37% had more than 10 copies of NPM-ALK per 104 copies of ABL (10NCNs) by qPCR. Fifty-one percent of 35 patients had high antibody titer (> 1/750). Progression-free survival (PFS) of the patients with > 10 NCNs or low antibody titers was significantly poorer than that of patients with ≤ 10 NCNs or high antibody titers (> 1/750) (P = 0.016, 0.029), respectively, although we observed no difference in PFS associated with positive MDD on RT-PCR. On stratification using a combination of MDD and antibody titer, PFS for patients with > 10 NCNs and low antibody titer was extremely low (30.0%). Combined evaluation of MDD and anti-ALK antibody titer at diagnosis may thus be valuable for stratification of treatment for childhood ALCL.
KeywordsALCL Children MDD Anti-ALK antibody
This work was supported by Grants for Clinical Cancer Research from the Ministry of Health, Labour and Welfare of Japan; H14-Koka(Gan)-031, H15-Koka(Gan)-024, H16-GanRinsho-004, H17-GanRinsho-004, H20-GanRinsho-Ippan-017, H23-GanRinsho-Ippan-014. We thank Drs. Angelo Rosolen, Lala Mussolin and Christine Damm-Welk for teaching procedures and providing the plasmid pcDNA3 NPM-ALK and Miho Yamada for helping with sample preparing. We also would like to thank all of the children, their parents and clinicians for participating in this study.
Compliance with ethical standards
Conflict of interest
The authors declare that they had no conflict of interest.
- 1.Brugières L, Le Deley MC, Rosolen A, Williams D, Horibe K, Wrobel G, et al. Impact of the methotrexate administration dose on the need for intrathecal treatment in children and adolescents with anaplastic large-cell lymphoma: results of a randomized trial of the EICNHL Group. J Clin Oncol. 2009;27:897–903.CrossRefPubMedGoogle Scholar
- 3.Mori T, Fukano R, Saito A, Takimoto T, Sekimizu M, Nakazawa A, et al. Japanese Pediatric Leukemia/Lymphoma Study Group. Analysis of Japanese registration from the randomized international trial for childhood anaplastic large cell lymphoma (ALCL99-R1). Rinsho Ketsueki. 2014;55:526–33.PubMedGoogle Scholar
- 4.Reiter A, Schrappe M, Tiemann M, Parwaresch R, Zimmermann M, Yakisan E, et al. Successful treatment strategy for Ki-1 anaplastic large-cell lymphoma of childhood: a prospective analysis of 62 patients enrolled in three consecutive Berlin-Frankfurt-Munster group studies. J Clin Oncol. 1994;12:899–908.CrossRefPubMedGoogle Scholar
- 5.Seidemann K, Tiemann M, Schrappe M, Yakisan E, Simonitsch I, Janka-Schaub G, et al. Short-pulse B-non-Hodgkin lymphoma-type chemotherapy is efficacious treatment for pediatric anaplastic large cell lymphoma: a report of the Berlin-Frankfurt-Munster Group Trial NHL-BFM 90. Blood. 2001;97:3699–706.CrossRefPubMedGoogle Scholar
- 7.Williams DM, Hobson R, Imeson J, Gerrard M, McCarthy K, Pinkerton CR. United Kingdom Children’s Cancer Study Group. Anaplastic large cell lymphoma in childhood: analysis of 72 patients treated on The United Kingdom Children’s Cancer Study Group chemotherapy regimens. Br J Haematol. 2002;117:812–20.CrossRefPubMedGoogle Scholar
- 9.Laver JH, Kraveka JM, Hutchison RE, Chang M, Kepner J, Schwenn M, et al. Advanced-stage large-cell lymphoma in children and adolescents: results of a randomized trial incorporating intermediate-dose methotrexate and high-dose cytarabine in the maintenance phase of the APO regimen: a Pediatric Oncology Group phase III trial. J Clin Oncol. 2005;23:541–7.CrossRefPubMedGoogle Scholar
- 13.Delsol G, Falini B, Müller-Hermelink HK, Campo E, Jaffe ES, Gascoyne RD, et al. Anaplastic large cell lymphoma, ALK-positive. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW, editors. World Health Organization (WHO) Classification of tumours of haematopoietic and lymphoid tissues. Lyon: IARC Press; 2008. p. 312–6.Google Scholar
- 15.Damm-Welk C, Busch K, Burkhardt B, Schieferstein J, Viehmann S, Oschlies I, et al. Prognostic significance of circulating tumor cells in bone marrow or peripheral blood as detected by qualitative and quantitative PCR in pediatric NPM-ALK-positive anaplastic large-cell lymphoma. Blood. 2007;110:670–7.CrossRefPubMedGoogle Scholar
- 18.Ait-Tahar K, Damm-Welk C, Burkhardt B, Zimmermann M, Klapper W, Reiter A, et al. Correlation of the autoantibody response to the ALK oncoantigen in pediatric anaplastic lymphoma kinase-positive anaplastic large cell lymphoma with tumor dissemination and relapse risk. Blood. 2010;115:3314–9.CrossRefPubMedGoogle Scholar