Could (Disseminated and Residual) Minimal Disease be a useful prognostic marker in non-Hodgkin paediatric Lymphomas?

Lara Mussolin, Marta Pillon, Giuseppe Basso



Minimal Disseminated Disease (MDD) represents the small number of tumour cells in the patients' bone marrow at the time of diagnosis, whereas Minimal Residual Disease (MRD) represents the small number of tumour cells remaining in the bone marrow during treatment. Generally, MDD and MRD are measured by polymerase chain reaction, a highly sensitive technique. For a long time, bone marrow involvement has been considered an uncommon event in solid tumours. However, in recent years, several studies demonstrated that MDD and MRD could be powerful tools in paediatric non-Hodgkin lymphoma for stratifying patients in different prognostic groups. Risk stratification in future clinical trials on non-Hodgkin lymphoma based on these newly identified risk categories should be useful to improve therapies in order to increase survival for high-risk patients and decrease toxicity for low-risk patients.


Minimal residual disease; Non-Hodgkin lymphoma; Prognosis

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  • van Dongen JJ, Seriu T, Panzer-Grumayer ER, et al. Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood. Lancet 1998; 352: 1731-8;
  • Szczepanski T, Orfao A, van der Velden VH, et al. Minimal residual disease in leukaemia patients. Lancet Oncology 2001; 2: 409-7;
  • Gaipa G, Basso G, Maglia O, et al. Drug-induced immunophenotypic modulation in childhood ALL: implications for minimal residual disease detection. Leukemia 2005; 19: 49-56
  • Flohr T, Schrauder A, Cazzaniga G, et al. Minimal residual disease-directed risk stratification using real-time quantitative PCR analysis of immunoglobulin and T-cell receptor gene rearrangements in the international multicenter trial AIEOP-BFM ALL 2000 for childhood acute lymphoblastic leukemia. Leukemia 2008; 22: 771-2;
  • Campana D. Status of minimal residual disease testing in childhood haematological malignancies. Br J Haematol 2008; 143: 481-9
  • Mullighan CG, Su X, Zhang J, et al. Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med 2009; 360: 470-80;
  • Basso G, Veltroni M, Valsecchi MG, et al. Risk of relapse of childhood acute lymphoblastic leukemia is predicted by flow cytometric measurement of residual disease on day 15 bone marrow. J Clin Oncol 2009; 27: 5168-74;
  • Conter V, Bartram CR, Valsecchi MG, et al. Molecular response to treatment redefines all prognostic factors in children and adolescents with B-cell precursor acute lymphoblastic leukemia: results in 3184 patients of the AIEOP-BFM ALL 2000 study. Blood 2010; 115: 3206-14;
  • Rizzari C, Cazzaniga G, Coliva T, et al. Predictive factors of relapse and survival in childhood acute myeloid leukemia; role of minimal residual disease. Expert Rev Anticancer Ther 2011; 1391-401;
  • Conter V, Valsecchi MG, Paasole R, et al. Childhood high-risk acute lymphoblastic leukemia in first remission: results after chemotherapy or transplant from the AIEOP ALL 2000 study. Blood 2014; 123: 1470-8;
  • Mussolin L, Basso K, Pillon M, et al. Prospective analysis of minimal bone marrow infiltration in pediatric Burkitt’s lymphomas by long-distance polymerase chain reaction for t(8;14)(q24;q32). Leukemia 2003; 17: 585-9;
  • Mussolin L, Pillon M, d’Amore ES, et al. Prevalence and clinical implications of bone marrow involvement in pediatric Anaplastic Large Cell Lymphoma. Leukemia 2005; 19: 1643-7;
  • Damm-Welk C, Busch K, Burkhardt B, 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;
  • Mussolin L, Pillon M, d’Amore SG, et al. Minimal Disseminated Disease in high risk Burkitt’s Lymphoma identifies patients with different prognosis. J Clin Oncol 2011; 29: 1779-84
  • Mussolin L, Damm-Welk C, Pillon M, et al. Use of minimal disseminated disease and immunity to NPM-ALK antigen to stratify ALK-positive ALCL patients with different prognosis. Leukemia 2013; 27: 416-22;
  • Damm-Welk C, Mussolin L, Zimmermann M, et al. Early assessment of minimal residual disease identifies patients at very high relapse rish in NPM-ALK positive anaplastic large cell lymphoma. Blood 2014; 123: 334-7;
  • Murphy SB. Classification, staging and end results of treatment in childhood non Hodgkin’slymphoma: Dissimilarities from lymphomas in adults. Sem Oncol 1980; 7: 332-9
  • Patte C. Treatment of mature B-ALL and high grade B-NHL in children. Best Pract Res Clin Haematol 2002; 15: 695-711;
  • Gerrard M, Cairo MS, Weston C, et al. Excellent survival following two courses of COPAD chemotherapy in children and adolescents with resected localized B-cell non-Hodgkin’s lymphoma: results of the FAB/LMB96 international study. Br J Haematol 2008; 141: 840-7;
  • Pillon M, Di Tullio MT, Garaventa A, et al. Long-term results of the first Italian Association of Pediatric Hematology and Oncology protocol for the treatment of pediatric B-cell non-Hodgkin lymphoma (AIEOP LNH9). Cancer 2004; 101: 385-94
  • Le Deley MC, Rosolen A, Williams DM, et al. Vinblastine in children and adolescents with anaplastic large cell lymphoma: results of the randomized ALCL99-vinblastrine trial. J Clin Oncol 2010; 28: 3987-93;
  • Pillon M, Gregucci F, Lombardi A, et al. Results of AIEOP LNH-97 protocol for the treatment of anaplastic large cell lymphoma of childhood. NHL-Committee of the Italian Association of Pediatric Hematology and Oncology (AIEOP). Pediatr Blood Cancer 2012; 59: 828-33;
  • Seidemann K, Tiemann M, Schrappe M, 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-Münster Group Trial NHL-BFM 90. Blood 2001; 97: 3699-706;
  • Patte C, Kalifa C, Flamant F, et al. Results of the LMT81 protocol, a modified LSA2L2 protocol with high dose methotrexate, on 84 children with non-B-cell (lymphoblastic) lymphoma. Med Pediatr Oncol 1992; 20: 105-13;
  • Pillon M, Piglione M, Garaventa A, et al. Long-term results of AIEOP LNH-92 protocol for the treatment of pediatric lymphoblastic lymphoma: a report of the Italian Association of Pediatric Hematology and Oncology. Pediatr Blood Cancer 2009; 53: 953-9;
  • Schmidt E, Burkhardt B. Lymphoblastic lymphoma in childhood and adolescence. Pediatr Hematol Oncol 2013; 30: 484-508;
  • Reiter A. Diagnosis and treatment of childhood non- Hodgkin lymphoma. Hematology 2007; 285-96
  • Lovisa F, Mussolin L, Corral L, et al. IGH and IGK gene rearrangements as PCR targets for pediatric Burkitt’s lymphoma and mature B-ALL MRD analysis. Lab Invest 2009; 89: 1182-6;
  • Damm-Welk C, Schieferstein J, Schwalm S, et al. Flow cytometric detection of circulating tumour cells in nucleophosmin/anaplastic lymphoma kinase-positive anaplastic large cell lymphoma: comparison with quantitative polymerase chain reaction. Br J Haematol 2007; 138: 459-66;
  • Pongers-Willemse MJ, Seriu T, Stolz F, et al. Primers and protocols for standardized detection of minimal residual disease in acute lymphoblastic leukemia using immunoglobulin and T cell receptor gene rearrangements and TAL1 deletions as PCR targets: report of the BIOMED-1 CONCERTED ACTION: investigation of minimal residual disease in acute leukemia. Leukemia 1999; 13: 110-8;
  • Van Dongen JJ, Langerak AW, Bruggemann M, et al. Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: report of the BIOMED-2 Concerted Action BMH4-CT98-3936. Leukemia 2003; 17: 2257-317;
  • Gabert J, Beillard E, van der Velden V, et al. Standardization and quality control studies of ‘real-time’ quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia - a Europe Against Cancer program. Leukemia 2003; 17: 2318-57;
  • Prisco MJ, Condon J, Hughes E, et al. Outcome prediction in childhood acute lymphoblastic leukaemia by molecular quantification of residual disease at the end of induction. Lancet 1994; 343: 196-200;
  • Cavé H, van der Werff ten Bosch J, Suciu S, et al. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia. European Organization for Research and Treatment of Cancer--Childhood Leukemia Cooperative Group. N Engl J Med 1998; 339: 591-8;
  • Akasaka T, Muramatsu M, Ohno H, et al. Application of long-distance polymerase chain reaction to detection of junctional sequences created by chromosomal translocation in mature B-cell neoplasms. Blood 1996; 88: 985-94
  • Basso K, Frascella E, Zanesco L, et al. Improved long-distancepolymerase chain reaction for the detection of t(8;14) (q24;q32) in Burkitt’s lymphomas. Am J Pathol 1999; 155: 1479-85;
  • Morris SW, Kirstein MN, Valentine MB, et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma. Science 1994; 263: 1281-4;
  • Pulford K, Falini B, Banham AH, et al. Immune response to the ALK oncogenic tyrosine kinase in patients with anaplastic large-cell lymphoma. Blood 2000; 96: 1605-73
  • Bei R, Masuelli L, Moriconi E, et al. Immune response to all ErbB family receptors detectable in serum of cancer patients. Oncogene 1999; 18: 1267-75;
  • Jager E, Chen Y-T, Drijfhlout J, et al. Simultaneus humoral and cellular immune response against cance-testis antigen NY-ESO-1: definition of human histocompatibility leucocyte antigen (HLA)-A2-binding epitopes. J Exp Med 1998; 187: 265-70;
  • Coustan-Smith E, Sandlund JT, Perkins SL, et al. Minimal disseminated disease in childhood T-cell lymphoblastic lymphoma: a report from the children’s oncology group. J Clin Oncol 2009; 27: 3533-9;


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