Abstract
MRD detection with allele-specific oligonucleotide-quantitative polymerase chain reaction (ASO-qPCR) and using clone-specific immunoglobulin/T cell receptor rearrangements is considered as a powerful prognostic factor in acute lymphoblastic leukemia (ALL). In the present study, we evaluated an ASO-qPCR assay for MRD quantification in peripheral blood (PB) samples of adult patients with ALL. DNA was isolated from PB samples of patients with newly diagnosed ALL. They were first investigated by multiplex-PCR assay to identify V/J usage. An ASO-qPCR technique was then applied for 2.5-year monthly MRD quantification for detection of patient-specific Ig/TCR receptor rearrangements as a molecular target. From 98 patients who were diagnosed as ALL, 72 (73.5%) were enrolled in the present study for MRD detection. MRD was successfully quantified in patients with 1-month interval time. MRD level at the end of induction therapy up to day 88 was the only significant prognostic factor. Regarding MRD level, patients were categorized into two groups of low and high-risk. 2.5-year OS in all three time points (days 28, 58 and 88) were significantly lower in high-risk group (P < 0.008). The results of the 2.5-year MRD detection indicate that MRD level at the end of induction up to about 6 months after the first diagnosis was associated with clinical outcome. This study may highlight the usefulness of PB and the definitions of cut-off level for early prediction of relapse and for stratifying ALL patients. Short-interval time points and frequent PB sampling to monitor MRD level is suggested for early clinical relapse prediction and clinical management of the disease.
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References
Wartenberg DGF, Adelman AS (2008) Acute lymphoblastic leukemia: epidemiology and etiology. In: Estey EH, Faderl S, Kantarjian H (eds) Acute leukemias. Springer, Berlin
Katz AJ, Chia VM, Schoonen WM, Kelsh MA (2015) Acute lymphoblastic leukemia: an assessment of international incidence, survival, and disease burden. Cancer Causes Control 26(11):1627–1642. https://doi.org/10.1007/s10552-015-0657-6
Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH (2005) Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood 106(12):3760–3767. https://doi.org/10.1182/blood-2005-04-1623
Sive JI, Buck G, Fielding A, Lazarus HM, Litzow MR, Luger S, Marks DI, McMillan A, Moorman AV, Richards SM, Rowe JM, Tallman MS, Goldstone AH (2012) Outcomes in older adults with acute lymphoblastic leukaemia (ALL): results from the international MRC UKALL XII/ECOG2993 trial. Br J Haematol 157(4):463–471. https://doi.org/10.1111/j.1365-2141.2012.09095.x
Kolenova A, Hikkel I, Ilencikova D, Hikkelova M, Sejnova D, Kaiserova E, Cizmar A, Puskacova J, Bubanska E, Oravkinova I, Gencik M (2010) Minimal residual disease detection using real-time quantitative PCR analysis of immunoglobulin and T-cell receptor gene rearrangements in the non-MRD-based ALL IC-BFM 2002 protocol for childhood ALL: Slovak experience. Neoplasma 57(6):552–561. https://doi.org/10.4149/neo_2010_06_552
Gokbuget N, Stanze D, Beck J, Diedrich H, Horst HA, Huttmann A, Kobbe G, Kreuzer KA, Leimer L, Reichle A, Schaich M, Schwartz S, Serve H, Starck M, Stelljes M, Stuhlmann R, Viardot A, Wendelin K, Freund M, Hoelzer D (2012) Outcome of relapsed adult lymphoblastic leukemia depends on response to salvage chemotherapy, prognostic factors, and performance of stem cell transplantation. Blood 120(10):2032–2041. https://doi.org/10.1182/blood-2011-12-399287
Oriol A, Vives S, Hernandez-Rivas JM, Tormo M, Heras I, Rivas C, Bethencourt C, Moscardo F, Bueno J, Grande C, del Potro E, Guardia R, Brunet S, Bergua J, Bernal T, Moreno MJ, Calvo C, Bastida P, Feliu E, Ribera JM (2010) Outcome after relapse of acute lymphoblastic leukemia in adult patients included in four consecutive risk-adapted trials by the PETHEMA Study Group. Haematologica 95(4):589–596. https://doi.org/10.3324/haematol.2009.014274
Rowe JM (2010) Prognostic factors in adult acute lymphoblastic leukaemia. Br J Haematol 150(4):389–405. https://doi.org/10.1111/j.1365-2141.2010.08246.x
Campana D, Pui CH (1995) Detection of minimal residual disease in acute leukemia: methodologic advances and clinical significance. Blood 85(6):1416–1434
Szczepanski T, Orfao A, van der Velden VH, San Miguel JF, van Dongen JJ (2001) Minimal residual disease in leukaemia patients. Lancet Oncol 2(7):409–417. https://doi.org/10.1016/S1470-2045(00)00418-6
van Dongen JJ, Seriu T, Panzer-Grumayer ER, Biondi A, Pongers-Willemse MJ, Corral L, Stolz F, Schrappe M, Masera G, Kamps WA, Gadner H, van Wering ER, Ludwig WD, Basso G, de Bruijn MA, Cazzaniga G, Hettinger K, van der Does-van den Berg A, Hop WC, Riehm H, Bartram CR (1998) Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood. Lancet (London, England) 352(9142):1731–1738. https://doi.org/10.1016/s0140-6736(98)04058-6
Mortuza FY, Papaioannou M, Moreira IM, Coyle LA, Gameiro P, Gandini D, Prentice HG, Goldstone A, Hoffbrand AV, Foroni L (2002) Minimal residual disease tests provide an independent predictor of clinical outcome in adult acute lymphoblastic leukemia. J Clin Oncol Off J Am Soc Clin Oncol 20(4):1094–1104. https://doi.org/10.1200/jco.2002.20.4.1094
Campana D, Pui CH (2017) Minimal residual disease-guided therapy in childhood acute lymphoblastic leukemia. Blood 129(14):1913–1918. https://doi.org/10.1182/blood-2016-12-725804
Bader P, Kreyenberg H, Henze GH, Eckert C, Reising M, Willasch A, Barth A, Borkhardt A, Peters C, Handgretinger R, Sykora KW, Holter W, Kabisch H, Klingebiel T, von Stackelberg A (2009) 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 Off J Am Soc Clin Oncol 27(3):377–384. https://doi.org/10.1200/jco.2008.17.6065
Pieters R, de Groot-Kruseman H, Van der Velden V, Fiocco M, van den Berg H, de Bont E, Egeler RM, Hoogerbrugge P, Kaspers G, Van der Schoot E, De Haas V, Van Dongen J (2016) Successful therapy reduction and intensification for childhood acute lymphoblastic leukemia based on minimal residual disease monitoring: study ALL10 from the Dutch Childhood Oncology Group. J Clin Oncol Off J Am Soc Clin Oncol 34(22):2591–2601. https://doi.org/10.1200/jco.2015.64.6364
van Dongen JJ, van der Velden VH, Bruggemann M, Orfao A (2015) Minimal residual disease diagnostics in acute lymphoblastic leukemia: need for sensitive, fast, and standardized technologies. Blood 125(26):3996–4009. https://doi.org/10.1182/blood-2015-03-580027
Flohr T, Schrauder A, Cazzaniga G, Panzer-Grumayer R, van der Velden V, Fischer S, Stanulla M, Basso G, Niggli FK, Schafer BW, Sutton R, Koehler R, Zimmermann M, Valsecchi MG, Gadner H, Masera G, Schrappe M, van Dongen JJ, Biondi A, Bartram CR (2008) 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 22(4):771–782. https://doi.org/10.1038/leu.2008.5
van Dongen JJ, Langerak AW, Bruggemann M, Evans PA, Hummel M, Lavender FL, Delabesse E, Davi F, Schuuring E, Garcia-Sanz R, van Krieken JH, Droese J, Gonzalez D, Bastard C, White HE, Spaargaren M, Gonzalez M, Parreira A, Smith JL, Morgan GJ, Kneba M, Macintyre EA (2003) 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 17(12):2257–2317. https://doi.org/10.1038/sj.leu.2403202
Li AH, Forestier E, Rosenquist R, Roos G (2002) Minimal residual disease quantification in childhood acute lymphoblastic leukemia by real-time polymerase chain reaction using the SYBR green dye. Exp Hematol 30(10):1170–1177. https://doi.org/10.1016/S0301-472X(02)00892-5
Wetzler M, Dodge RK, Mrozek K, Carroll AJ, Tantravahi R, Block AW, Pettenati MJ, Le Beau MM, Frankel SR, Stewart CC, Szatrowski TP, Schiffer CA, Larson RA, Bloomfield CD (1999) Prospective karyotype analysis in adult acute lymphoblastic leukemia: the cancer and leukemia Group B experience. Blood 93(11):3983–3993
Mancini M, Scappaticci D, Cimino G, Nanni M, Derme V, Elia L, Tafuri A, Vignetti M, Vitale A, Cuneo A, Castoldi G, Saglio G, Pane F, Mecucci C, Camera A, Specchia G, Tedeschi A, Di Raimondo F, Fioritoni G, Fabbiano F, Marmont F, Ferrara F, Cascavilla N, Todeschini G, Nobile F, Kropp MG, Leoni P, Tabilio A, Luppi M, Annino L, Mandelli F, Foa R (2005) A comprehensive genetic classification of adult acute lymphoblastic leukemia (ALL): analysis of the GIMEMA 0496 protocol. Blood 105(9):3434–3441. https://doi.org/10.1182/blood-2004-07-2922
Cytogenetic abnormalities in adult acute lymphoblastic leukemia: Correlations with hematologic findings outcome. A Collaborative Study of the Group Francais de Cytogenetique Hematologique (1996). Blood 87 (8):3135–3142
Moorman AV, Harrison CJ, Buck GA, Richards SM, Secker-Walker LM, Martineau M, Vance GH, Cherry AM, Higgins RR, Fielding AK, Foroni L, Paietta E, Tallman MS, Litzow MR, Wiernik PH, Rowe JM, Goldstone AH, Dewald GW (2007) Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial. Blood 109(8):3189–3197. https://doi.org/10.1182/blood-2006-10-051912
Gokbuget N, Kneba M, Raff T, Trautmann H, Bartram CR, Arnold R, Fietkau R, Freund M, Ganser A, Ludwig WD, Maschmeyer G, Rieder H, Schwartz S, Serve H, Thiel E, Bruggemann M, Hoelzer D (2012) Adult patients with acute lymphoblastic leukemia and molecular failure display a poor prognosis and are candidates for stem cell transplantation and targeted therapies. Blood 120(9):1868–1876. https://doi.org/10.1182/blood-2011-09-377713
Ribera JM, Oriol A, Morgades M, Montesinos P, Sarra J, Gonzalez-Campos J, Brunet S, Tormo M, Fernandez-Abellan P, Guardia R, Bernal MT, Esteve J, Barba P, Moreno MJ, Bermudez A, Cladera A, Escoda L, Garcia-Boyero R, Del Potro E, Bergua J, Amigo ML, Grande C, Rabunal MJ, Hernandez-Rivas JM, Feliu E (2014) Treatment of high-risk Philadelphia chromosome-negative acute lymphoblastic leukemia in adolescents and adults according to early cytologic response and minimal residual disease after consolidation assessed by flow cytometry: final results of the PETHEMA ALL-AR-03 trial. J Clin Oncol Off J Am Soc Clin Oncol 32(15):1595–1604. https://doi.org/10.1200/jco.2013.52.2425
Bassan R, Spinelli O, Oldani E, Intermesoli T, Tosi M, Peruta B, Rossi G, Borlenghi E, Pogliani EM, Terruzzi E, Fabris P, Cassibba V, Lambertenghi-Deliliers G, Cortelezzi A, Bosi A, Gianfaldoni G, Ciceri F, Bernardi M, Gallamini A, Mattei D, Di Bona E, Romani C, Scattolin AM, Barbui T, Rambaldi A (2009) Improved risk classification for risk-specific therapy based on the molecular study of minimal residual disease (MRD) in adult acute lymphoblastic leukemia (ALL). Blood 113(18):4153–4162. https://doi.org/10.1182/blood-2008-11-185132
Dhedin N, Huynh A, Maury S, Tabrizi R, Beldjord K, Asnafi V, Thomas X, Chevallier P, Nguyen S, Coiteux V, Bourhis JH, Hichri Y, Escoffre-Barbe M, Reman O, Graux C, Chalandon Y, Blaise D, Schanz U, Lheritier V, Cahn JY, Dombret H, Ifrah N (2015) Role of allogeneic stem cell transplantation in adult patients with Ph-negative acute lymphoblastic leukemia. Blood 125(16):2486–2496; quiz 2586. https://doi.org/10.1182/blood-2014-09-599894
Campana D (2009) Role of minimal residual disease monitoring in adult and pediatric acute lymphoblastic leukemia. Hematol Oncol Clin North Am 23(5):1083–1098, vii. https://doi.org/10.1016/j.hoc.2009.07.010
Coustan-Smith E, Sancho J, Hancock ML, Boyett JM, Behm FG, Raimondi SC, Sandlund JT, Rivera GK, Rubnitz JE, Ribeiro RC, Pui CH, Campana D (2000) Clinical importance of minimal residual disease in childhood acute lymphoblastic leukemia. Blood 96(8):2691–2696
Brisco MJ, Sykes PJ, Hughes E, Dolman G, Neoh SH, Peng LM, Toogood I, Morley AA (1997) Monitoring minimal residual disease in peripheral blood in B-lineage acute lymphoblastic leukaemia. Br J Haematol 99(2):314–319. https://doi.org/10.1046/j.1365-2141.1997.3723186.x
van Rhee F, Marks DI, Lin F, Szydlo RM, Hochhaus A, Treleaven J, Delord C, Cross NC, Goldman JM (1995) Quantification of residual disease in Philadelphia-positive acute lymphoblastic leukemia: comparison of blood and bone marrow. Leukemia 9(2):329–335
van der Velden VH, Jacobs DC, Wijkhuijs AJ, Comans-Bitter WM, Willemse MJ, Hahlen K, Kamps WA, van Wering ER, van Dongen JJ (2002) Minimal residual disease levels in bone marrow and peripheral blood are comparable in children with T cell acute lymphoblastic leukemia (ALL), but not in precursor-B-ALL. Leukemia 16(8):1432–1436. https://doi.org/10.1038/sj.leu.2402636
Coustan-Smith E, Sancho J, Hancock ML, Razzouk BI, Ribeiro RC, Rivera GK, Rubnitz JE, Sandlund JT, Pui CH, Campana D (2002) Use of peripheral blood instead of bone marrow to monitor residual disease in children with acute lymphoblastic leukemia. Blood 100(7):2399–2402. https://doi.org/10.1182/blood-2002-04-1130
Zeijlemaker W, Kelder A, Oussoren-Brockhoff YJ, Scholten WJ, Snel AN, Veldhuizen D, Cloos J, Ossenkoppele GJ, Schuurhuis GJ (2016) Peripheral blood minimal residual disease may replace bone marrow minimal residual disease as an immunophenotypic biomarker for impending relapse in acute myeloid leukemia. Leukemia 30(3):708–715. https://doi.org/10.1038/leu.2015.255
Funding
This study was supported by Hematologic Malignancies Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran. (Grant numbers: 25849-36-01-93 and 25934-36-02-93).
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This study was carried out according to the Helsinki declaration. The Regional Ethics Committee of Tehran University of Medical Sciences approved the study. Informed consent was obtained from all patients included in the study.
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Shahkarami, S., Mehrasa, R., Younesian, S. et al. Minimal residual disease (MRD) detection using rearrangement of immunoglobulin/T cell receptor genes in adult patients with acute lymphoblastic leukemia (ALL). Ann Hematol 97, 585–595 (2018). https://doi.org/10.1007/s00277-018-3230-z
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DOI: https://doi.org/10.1007/s00277-018-3230-z