UNLABELLED: Children with other extramedullary relapse of acute lymphoblastic leukemia are currently poorly characterized. We aim to assess the prevalence and the clinical, therapeutic and prognostic features of extramedullary localizations other than central nervous system or testis in children with relapse of acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) treated on a relapsed ALL protocol. PATIENTS AND METHODS: Patients with relapse of ALL and LBL, treated according to the multicentric ALL-REZ BFM trials between 1983 and 2015, were analyzed for other extramedullary relapse (OEMR) of the disease regarding clinical features, treatment and outcome. Local treatment/irradiation has been recommended on an individual basis and performed only in a minority of patients. RESULTS: A total of 132 out of 2323 (5.6%) patients with ALL relapse presented with an OEMR (combined bone marrow relapse n = 78; isolated extramedullary relapse n = 54). Compared to the non-OEMR group, patients with OEMR had a higher rate of T-immunophenotype (p < 0.001), a higher rate of LBL (p < 0.001) and a significantly different distribution of time to relapse, i.e., more very early and late relapses compared to the non-OEMR group (p = 0.01). Ten-year probabilities of event-free survival (pEFS) and overall survival (pOS) in non-OEMR vs. OEMR were 0.38 ± 0.01 and 0.32 ± 0.04 (p = 0.0204) vs. 0.45 ± 0.01 and 0.37 ± 0.04 (p = 0.0112), respectively. OEMRs have been classified into five subgroups according to the main affected compartment: lymphatic organs (n = 32, 10y-pEFS 0.50 ± 0.09), mediastinum (n = 35, 10y-pEFS 0.11 ± 0.05), bone (n = 12, 0.17 ± 0.11), skin and glands (n = 21, 0.32 ± 0.11) and other localizations (n = 32, 0.41 ± 0.09). Patients with OEMR and T-lineage ALL/LBL showed a significantly worse 10y-pEFS (0.15 ± 0.04) than those with B-Precursor-ALL (0.49 ± 0.06, p < 0.001). Stratified into standard risk (SR) and high risk (HR) groups, pEFS and pOS of OEMR subgroups were in the expected range whereas the mediastinal subgroup had a significantly worse outcome. Subsequent relapses involved more frequently the bone marrow (58.4%) than isolated extramedullary compartments (41.7%). In multivariate Cox regression, OEMR confers an independent prognostic factor for inferior pEFS and pOS. CONCLUSION: OEMR is adversely related to prognosis. However, the established risk classification can be applied for all subgroups except mediastinal relapses requiring treatment intensification. Generally, isolated OEMR of T-cell-origin needs an intensified treatment including allogeneic stem cell transplantation (HSCT) as a curative approach independent from time to relapse. Local therapy such as surgery and irradiation may be of benefit in selected cases. The indication needs to be clarified in further investigations.

Charles University 2nd Faculty of Medicine and UH Motol 5 Uvalu 84 Prague 5 15006 Czech Republic

Department of Pediatric Hematology and Oncology Charité Universitätsmedizin Berlin Augstenburger Platz 1 13353 Berlin Germany

Department of Pediatric Hematology and Oncology St Anna Children's Hospital Kinderspitalgasse 6 A 1090 Vienna Austria

Department of Pediatric Hematology and Oncology Universitätsklinikum Münster Albert Schweitzer Campus 1 Gebäude A1 48149 Münster Germany

Eleonoren Foundation Pediatric Hematology Oncology Department University Children's Hospital Zürich Steinwiesstraße 75 CH 8032 Zürich Switzerland

Zobrazit více v PubMed

Gaudichon J., Jakobczyk H., Debaize L., Cousin E., Galibert M.D., Troadec M.B., Gandemer V. Mechanisms of extramedullary relapse in acute lymphoblastic leukemia: Reconciling biological concepts and clinical issues. Blood Rev. 2019;36:40–56. doi: 10.1016/j.blre.2019.04.003. PubMed DOI

Pui C.H. Central nervous system disease in acute lymphoblastic leukemia: Prophylaxis and treatment. Hematol. Am. Soc. Hematol. Educ. Program. 2006;2006:142–146. doi: 10.1182/asheducation-2006.1.142. PubMed DOI

Wofford M.M., Smith S.D., Shuster J.J., Johnson W., Buchanan G.R., Wharam M.D., Ritchey A.K., Rosen D., Haggard M.E., Golembe B.L., et al. Treatment of occult or late overt testicular relapse in children with acute lymphoblastic leukemia: A Pediatric Oncology Group study. J. Clin. Oncol. 1992;10:624–630. doi: 10.1200/JCO.1992.10.4.624. PubMed DOI

Murray J.C., Gmoser D.J., Barnes D.A., Oshman D., Hawkins H.K., Gresik M.V., Dreyer Z.E. Isolated bone relapse during hematologic remission in childhood acute lymphoblastic leukemia: Report of a metatarsal relapse and review of the literature. Med. Pediatr. Oncol. 1994;23:153–157. doi: 10.1002/mpo.2950230217. PubMed DOI

Padmanjali K.S., Bakhshi S., Thavaraj V., Karak A.K., Arya L.S. Bone relapse in acute lymphoblastic leukemia. Indian J. Pediatr. 2004;71:555–557. doi: 10.1007/BF02724304. PubMed DOI

Curto M.L., D’Angelo P., Jankovic M., Fugardi M.G., Ziino O., Casale F. Isolated ocular relapse in childhood acute lymphoblastic leukemia during continuing complete remission. Haematologica. 1996;81:47–50. PubMed

Taylor C.W., Taylor R.E., Kinsey S.E. Leukemic infiltration of the orbit: Report of three cases and literature review. Pediatr. Hematol. Oncol. 2005;22:415–422. doi: 10.1080/08880010590964390. PubMed DOI

MacLean H., Clarke M.P., Strong N.P., Kernahan J., Ashraf S. Primary ocular relapse in acute lymphoblastic leukemia. Pt 6Eye. 1996;10:719–722. doi: 10.1038/eye.1996.167. PubMed DOI

Nadel J., Meredith T., Anthony C., Sivasubramaniam V., Jabbour A. Isolated myocardial relapse of Philadelphia-positive acute lymphoblastic leukaemia causing myocarditis: A case report. Eur. Heart J. Case Rep. 2018;2:yty104. doi: 10.1093/ehjcr/yty104. PubMed DOI PMC

Veys D., Norton A., Ainsworth J.R., Amrolia P., Lucchini G. Isolated Intraocular Relapse of Pediatric B-cell Precursor Acute Lymphoblastic Leukaemia Following Chimeric Antigen Receptor T-lymphocyte Therapy. Cureus. 2020;12:e10937. doi: 10.7759/cureus.10937. PubMed DOI PMC

Dix D.B., Anderson R.A., McFadden D.E., Wadsworth L.D. Pleural relapse during hematopoietic remission in childhood acute lymphoblastic leukemia. J. Pediatr. Hematol. Oncol. 1997;19:470–472. doi: 10.1097/00043426-199709000-00013. PubMed DOI

Esmaeli B., Medeiros L.J., Myers J., Champlin R., Singh S., Ginsberg L. Orbital mass secondary to precursor T-cell acute lymphoblastic leukemia: A rare presentation. Arch. Ophthalmol. 2001;119:443–446. doi: 10.1001/archopht.119.3.443. PubMed DOI

Hinkle A.S., Dinndorf P.A., Bulas D.I., Kapur S. Relapse of acute lymphoblastic leukemia in the inferior rectus muscle of the eye. Cancer. 1994;73:1757–1760. doi: 10.1002/1097-0142(19940315)73:6<1757::AID-CNCR2820730634>3.0.CO;2-M. PubMed DOI

Jankovic M., Conter V., Pretto G., Placa F., D’Incalci M., Masera G. Isolated bilateral anterior chamber eye relapse in a child with acute lymphoblastic leukemia. Med. Pediatr. Oncol. 1995;25:109–112. doi: 10.1002/mpo.2950250211. PubMed DOI

Kebaili K., Manel A.M., Chapelon C., Taylor P., Philippe N., Bertrand Y. Renal enlargement as presentation of isolated renal relapse in childhood leukemia. J. Pediatr. Hematol. Oncol. 2000;22:454–456. doi: 10.1097/00043426-200009000-00014. PubMed DOI

Ly-Sunnaram B., Henry C., Gandemer V., Mee F.L., Burtin F., Blayau M., Cayuela J.M., Oster M., Clech P., Rambeau M., et al. Late ovarian relapse of TEL/AML1 positive ALL confirming that TEL deletion is a secondary event in leukemogenesis. Leuk. Res. 2005;29:1089–1094. doi: 10.1016/j.leukres.2004.11.027. PubMed DOI

Mateo J., Abarzuza R., Nunez E., Cristobal J.A. Bilateral optic nerve infiltration in acute lymphoblastic leukemia in remission. Arch. Soc. Esp. Oftalmol. 2007;82:167–170. doi: 10.4321/s0365-66912007000300009. PubMed DOI

Millot F., Klossek J.M., Brizard F., Brizard A., Vandermarq P., Babin P., Guilhot F. Recurrence of childhood acute lymphoblastic leukemia presenting as a tumor of the middle ear: A case report. J. Pediatr. Hematol. Oncol. 1997;19:351–353. doi: 10.1097/00043426-199707000-00016. PubMed DOI

Qamruddin K., Hassan S., Khurshid M. Case of pelvic relapse in a child suffering from acute lymphoblastic leukemia. J. Pak. Med. Assoc. 1995;45:193–194. PubMed

Rush M., Toth B.B., Pinkel D. Clinically isolated mandibular relapse in childhood acute leukemia. Cancer. 1990;66:369–372. doi: 10.1002/1097-0142(19900715)66:2<369::AID-CNCR2820660228>3.0.CO;2-Z. PubMed DOI

Todo K., Morimoto A., Osone S., Nukina S., Ohtsuka T., Ishida H., Yoshihara T., Todo S. Isolated relapse of acute lymphoblastic leukemia in the breast of a young female. Pediatr. Hematol. Oncol. 2008;25:607–613. doi: 10.1080/08880010802258399. PubMed DOI

Tsuruchi N., Okamura J. Childhood acute lymphoblastic leukemia relapse in the uterine cervix. J. Pediatr. Hematol. Oncol. 1996;18:311–313. doi: 10.1097/00043426-199608000-00017. PubMed DOI

Uderzo C., Santamaria M., Locasciulli A., Merati I., Di Lelio A., Conter V., Masera G. Abdominal mass as manifestation of isolated extramedullary relapse in a child with acute lymphoblastic leukemia (ALL) Haematologica. 1987;72:545–547. PubMed

Gunes G., Goker H., Demiroglu H., Malkan U.Y., Buyukasik Y. Extramedullary relapses of acute leukemias after allogeneic hematopoietic stem cell transplantation: Clinical features, cumulative incidence, and risk factors. Bone Marrow Transplant. 2019;54:595–600. doi: 10.1038/s41409-018-0303-5. PubMed DOI

Bunin N.J., Pui C.H., Hustu H.O., Rivera G.K. Unusual extramedullary relapses in children with acute lymphoblastic leukemia. J. Pediatr. 1986;109:665–668. doi: 10.1016/S0022-3476(86)80238-4. PubMed DOI

Kim J.Y., Im S.A., Lee J.H., Lee J.W., Chung N.G., Cho B. Extramedullary Relapse of Acute Myeloid and Lymphoid Leukemia in Children: A Retrospective Analysis. Iran. J. Pediatr. 2016;26:e1711. doi: 10.5812/ijp.1711. PubMed DOI PMC

Bene M.C., Castoldi G., Knapp W., Ludwig W.D., Matutes E., Orfao A., van’t Veer M.B. Proposals for the immunological classification of acute leukemias. European Group for the Immunological Characterization of Leukemias (EGIL) Leukemia. 1995;9:1783–1786. PubMed

Seeger K., Adams H.P., Buchwald D., Beyermann B., Kremens B., Niemeyer C., Ritter J., Schwabe D., Harms D., Schrappe M., et al. TEL-AML1 fusion transcript in relapsed childhood acute lymphoblastic leukemia. The Berlin-Frankfurt-Munster Study Group. Blood. 1998;91:1716–1722. doi: 10.1182/blood.V91.5.1716.1716_1716_1722. PubMed DOI

Einsiedel H.G., von Stackelberg A., Hartmann R., Fengler R., Schrappe M., Janka-Schaub G., Mann G., Hahlen K., Gobel U., Klingebiel T., et al. Long-term outcome in children with relapsed ALL by risk-stratified salvage therapy: Results of trial acute lymphoblastic leukemia-relapse study of the Berlin-Frankfurt-Munster Group 87. J. Clin. Oncol. 2005;23:7942–7950. doi: 10.1200/JCO.2005.01.1031. PubMed DOI

von Stackelberg A., Hartmann R., Buhrer C., Fengler R., Janka-Schaub G., Reiter A., Mann G., Schmiegelow K., Ratei R., Klingebiel T., et al. High-dose compared with intermediate-dose methotrexate in children with a first relapse of acute lymphoblastic leukemia. Blood. 2008;111:2573–2580. doi: 10.1182/blood-2007-07-102525. PubMed DOI

Eckert C., von Stackelberg A., Seeger K., Groeneveld T.W., Peters C., Klingebiel T., Borkhardt A., Schrappe M., Escherich G., Henze G. Minimal residual disease after induction is the strongest predictor of prognosis in intermediate risk relapsed acute lymphoblastic leukaemia—Long-Term results of trial ALL-REZ BFM P95/96. Eur. J. Cancer. 2013;49:1346–1355. doi: 10.1016/j.ejca.2012.11.010. PubMed DOI

Eckert C., Henze G., Seeger K., Hagedorn N., Mann G., Panzer-Grumayer R., Peters C., Klingebiel T., Borkhardt A., Schrappe M., et al. Use of allogeneic hematopoietic stem-cell transplantation based on minimal residual disease response improves outcomes for children with relapsed acute lymphoblastic leukemia in the intermediate-risk group. J. Clin. Oncol. 2013;31:2736–2742. doi: 10.1200/JCO.2012.48.5680. PubMed DOI

Meyr F., Escherich G., Mann G., Klingebiel T., Kulozik A., Rossig C., Schrappe M., Henze G., von Stackelberg A., Hitzler J. Outcomes of treatment for relapsed acute lymphoblastic leukaemia in children with Down syndrome. Br. J. Haematol. 2013;162:98–106. doi: 10.1111/bjh.12348. PubMed DOI

Peters C., Schrappe M., von Stackelberg A., Schrauder A., Bader P., Ebell W., Lang P., Sykora K.W., Schrum J., Kremens B., et al. Stem-cell transplantation in children with acute lymphoblastic leukemia: A prospective international multicenter trial comparing sibling donors with matched unrelated donors-The ALL-SCT-BFM-2003 trial. J. Clin. Oncol. 2015;33:1265–1274. doi: 10.1200/JCO.2014.58.9747. PubMed DOI

van der Wijk A.E., Canning P., van Heijningen R.P., Vogels I.M.C., van Noorden C.J.F., Klaassen I., Schlingemann R.O. Glucocorticoids exert differential effects on the endothelium in an in vitro model of the blood-retinal barrier. Acta Ophthalmol. 2019;97:214–224. doi: 10.1111/aos.13909. PubMed DOI

Gaynon P.S., Qu R.P., Chappell R.J., Willoughby M.L., Tubergen D.G., Steinherz P.G., Trigg M.E. Survival after relapse in childhood acute lymphoblastic leukemia: Impact of site and time to first relapse--the Children’s Cancer Group Experience. Cancer. 1998;82:1387–1395. doi: 10.1002/(SICI)1097-0142(19980401)82:7<1387::AID-CNCR24>3.0.CO;2-1. PubMed DOI

Tallen G., Ratei R., Mann G., Kaspers G., Niggli F., Karachunsky A., Ebell W., Escherich G., Schrappe M., Klingebiel T., et al. Long-term outcome in children with relapsed acute lymphoblastic leukemia after time-point and site-of-relapse stratification and intensified short-course multidrug chemotherapy: Results of trial ALL-REZ BFM 90. J. Clin. Oncol. 2010;28:2339–2347. doi: 10.1200/JCO.2009.25.1983. PubMed DOI

Ninane J., Taylor D., Day S. The eye as a sanctuary in acute lymphoblastic leukaemia. Lancet. 1980;1:452–453. doi: 10.1016/S0140-6736(80)90999-X. PubMed DOI

Burkhardt B., Reiter A., Landmann E., Lang P., Lassay L., Dickerhoff R., Lakomek M., Henze G., von Stackelberg A. Poor outcome for children and adolescents with progressive disease or relapse of lymphoblastic lymphoma: A report from the berlin-frankfurt-muenster group. J. Clin. Oncol. 2009;27:3363–3369. doi: 10.1200/JCO.2008.19.3367. PubMed DOI

Burkhardt B., Taj M., Garnier N., Minard-Colin V., Hazar V., Mellgren K., Osumi T., Fedorova A., Myakova N., Verdu-Amoros J., et al. Treatment and Outcome Analysis of 639 Relapsed Non-Hodgkin Lymphomas in Children and Adolescents and Resulting Treatment Recommendations. Cancers. 2021;13:2075. doi: 10.3390/cancers13092075. PubMed DOI PMC

Khanam T., Sandmann S., Seggewiss J., Ruether C., Zimmermann M., Norvil A.B., Bartenhagen C., Randau G., Mueller S., Herbrueggen H., et al. Integrative genomic analysis of pediatric T-cell lymphoblastic lymphoma reveals candidates of clinical significance. Blood. 2021;137:2347–2359. doi: 10.1182/blood.2020005381. PubMed DOI PMC

Burkhardt B., Hermiston M.L. Lymphoblastic lymphoma in children and adolescents: Review of current challenges and future opportunities. Br. J. Haematol. 2019;185:1158–1170. doi: 10.1111/bjh.15793. PubMed DOI

Cortelazzo S., Intermesoli T., Oldani E., Ciceri F., Rossi G., Pogliani E.M., Mattei D., Romani C., Cortelezzi A., Borlenghi E., et al. Results of a lymphoblastic leukemia-like chemotherapy program with risk-adapted mediastinal irradiation and stem cell transplantation for adult patients with lymphoblastic lymphoma. Ann. Hematol. 2012;91:73–82. doi: 10.1007/s00277-011-1252-x. PubMed DOI

Dabaja B.S., Ha C.S., Thomas D.A., Wilder R.B., Gopal R., Cortes J., Bueso-Ramos C., Hess M.A., Cox J.D., Kantarjian H.M. The role of local radiation therapy for mediastinal disease in adults with T-cell lymphoblastic lymphoma. Cancer. 2002;94:2738–2744. doi: 10.1002/cncr.10552. PubMed DOI

Karrman K., Johansson B. Pediatric T-cell acute lymphoblastic leukemia. Genes Chromosomes Cancer. 2017;56:89–116. doi: 10.1002/gcc.22416. PubMed DOI

Bader P., Kreyenberg H., Henze G.H., Eckert C., Reising M., Willasch A., Barth A., Borkhardt A., Peters C., Handgretinger R., et al. Prognostic value of minimal residual disease quantification before allogeneic stem-cell transplantation in relapsed childhood acute lymphoblastic leukemia: The ALL-REZ BFM Study Group. J. Clin. Oncol. 2009;27:377–384. doi: 10.1200/JCO.2008.17.6065. PubMed DOI

Zhao J., Qiao W., Wang C., Wang T., Xing Y. Therapeutic evaluation and prognostic value of interim hybrid PET/CT with (18)F-FDG after three to four cycles of chemotherapy in non-Hodgkin’s lymphoma. Hematology. 2007;12:423–430. doi: 10.1080/10245330701393840. PubMed DOI

Eckert P., Johs A., Semrau J.D., DiSpirito A.A., Richardson J., Sarangi R., Herndon E., Gu B., Pierce E.M. Spectroscopic and computational investigations of organometallic complexation of group 12 transition metals by methanobactins from Methylocystis sp. SB2. J. Inorg. Biochem. 2021;223:111496. doi: 10.1016/j.jinorgbio.2021.111496. PubMed DOI PMC

Bride K.L., Vincent T.L., Im S.Y., Aplenc R., Barrett D.M., Carroll W.L., Carson R., Dai Y., Devidas M., Dunsmore K.P., et al. Preclinical efficacy of daratumumab in T-cell acute lymphoblastic leukemia. Blood. 2018;131:995–999. doi: 10.1182/blood-2017-07-794214. PubMed DOI PMC

Locatelli F., Zugmaier G., Rizzari C., Morris J.D., Gruhn B., Klingebiel T., Parasole R., Linderkamp C., Flotho C., Petit A., et al. Effect of Blinatumomab vs Chemotherapy on Event-Free Survival Among Children With High-risk First-Relapse B-Cell Acute Lymphoblastic Leukemia: A Randomized Clinical Trial. JAMA. 2021;325:843–854. doi: 10.1001/jama.2021.0987. PubMed DOI PMC

Bhojwani D., Sposto R., Shah N.N., Rodriguez V., Yuan C., Stetler-Stevenson M., O’Brien M.M., McNeer J.L., Quereshi A., Cabannes A., et al. Inotuzumab ozogamicin in pediatric patients with relapsed/refractory acute lymphoblastic leukemia. Leukemia. 2019;33:884–892. doi: 10.1038/s41375-018-0265-z. PubMed DOI PMC

Maude S.L., Laetsch T.W., Buechner J., Rives S., Boyer M., Bittencourt H., Bader P., Verneris M.R., Stefanski H.E., Myers G.D., et al. Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. N. Engl. J. Med. 2018;378:439–448. doi: 10.1056/NEJMoa1709866. PubMed DOI PMC

Pui C.H., Tang J.Y., Yang J.J., Chen S.J., Chen Z. International Collaboration to Save Children With Acute Lymphoblastic Leukemia. J. Glob. Oncol. 2019;5:1–2. doi: 10.1200/JGO.19.00010. PubMed DOI PMC