Assessment of extramedullary leukemic infiltration in childhood acute lymphoblastic leukemia and its clinical use. Review and original data

Authors: J. Volejníková 1;  E. Mejstříková 1;  L. Slámová 1;  V. Mihál 2;  J. Štěrba 3;  Y. Jabali 4;  D. Procházková 5;  B. Blažek 6;  J. Hak 7;  Z. Černá 8;  O. Hrušák 1;  J. Starý 1;  J. Trka 1;  E. Froňková 1
Authors‘ workplace: Klinika dětské hematologie a onkologie, 2. LF UK a FN Motol, Praha 1;  Dětská klinika UP a FN Olomouc 2;  Klinika dětské onkologie LF MU a FN Brno 3;  Dětská klinika Nemocnice České Budějovice 4;  Dětská klinika Masarykovy nemocnice v Ústí nad Labem 5;  Oddělení dětské hematologie a hematoonkologie Kliniky dětského lékařství FN Ostrava 6;  Dětská klinika LF UK HK a FN Hradec Králové 7;  Dětská klinika LF UK Plzeň a FN Plzeň 8
Published in: Transfuze Hematol. dnes,18, 2012, No. 3, p. 124-129.
Category: Comprehensive Reports, Original Papers, Case Reports


Minimal residual disease (MRD) has become a crucial criterion for the risk stratification within modern protocols for the treatment of both childhood and adult acute lymphoblastic leukemia (ALL). The most data obtained so far apply to the bone marrow and studies on extramedullary MRD are scarce. According to the published data, levels of MRD in peripheral blood and bone marrow correlate well in T-ALL, whereas in B-cell precursor ALL the correlation is weak and MRD in blood is mostly more than one log lower than in the bone marrow. Despite this fact, MRD in peripheral blood during the induction therapy is predictive of prognosis, as shown by our results for day 15 of the ALL IC-BFM 2002 protocol. There is still lack of information on the benefit of cerebrospinal fluid examination by PCR and flow cytometry at initial diagnosis in patients with ALL. Flow cytometry presumably reveals more positive results than “classical” microscopy. Both PCR and flow cytometry are suitable for the examination of leukemic involvement at the time of CNS relapse, but their informative value during the treatment of relapse is questionable due to insufficient DNA quality for the purpose of PCR and due to fast sample degradation for the purpose of flow cytometry. An unambiguous benefit of PCR lies in the assessment of simultaneous bone marrow infiltration at diagnosis of isolated extramedullary relapse, which, if present, confers inferior prognosis.

Key words:
acute lymphoblastic leukemia (ALL), minimal residual disease (MRD), peripheral blood, extramedullary relapse


1. Cave 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: 591-598.

2. Coustan Smith E, Sancho J, Hancock ML, et al. Clinical importance of minimal residual disease in childhood acute lymphoblastic leukemia. Blood 2000; 96: 2691-2696.

3. 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: 1731-1738.

4. 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: 771-782.

5. Pui CH, Relling MV, Sandlund JT, et al. Rationale and design of Total Therapy Study XV for newly diagnosed childhood acute lymphoblastic leukemia. Ann Hematol 2004; 83(Suppl 1): S124-126.

6. Schultz KR, Pullen DJ, Sather HN, et al. Risk- and response-based classification of childhood B-precursor acute lymphoblastic leukemia: a combined analysis of prognostic markers from the Pediatric Oncology Group (POG) and Children’s Cancer Group (CCG). Blood 2007; 109: 926-935.

7. Zhou J, Goldwasser MA, Li A, et al. Quantitative analysis of minimal residual disease predicts relapse in children with B-lineage acute lymphoblastic leukemia in DFCI ALL Consortium Protocol 95-01. Blood 2007; 110: 1607-1611.

8. 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: 3206-3214.

9. 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: 110-118.

10. 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: 2257-2317.

11. van der Velden VH, Cazzaniga G, Schrauder A, et al. Analysis of minimal residual disease by Ig/TCR gene rearrangements: guidelines for interpretation of real-time quantitative PCR data. Leukemia 2007; 21: 604-611.

12. Fronkova E, Muzikova K, Mejstrikova E, et al. B-cell reconstitution after allogeneic SCT impairs minimal residual disease monitoring in children with ALL. Bone Marrow Transplant 2008; 42: 187-196.

13. Brisco MJ, Sykes PJ, Hughes E, et al. Monitoring minimal residual disease in peripheral blood in B-lineage acute lymphoblastic leukaemia. Br J Haematol 1997; 99: 314-319.

14. Coustan-Smith E, Sancho J, Hancock ML, et al. Use of peripheral blood instead of bone marrow to monitor residual disease in children with acute lymphoblastic leukemia. Blood 2002; 100: 2399-2402.

15. van der Velden VH, Jacobs DC, Wijkhuijs AJ, et al. 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 2002; 16: 1432-1436.

16. Volejnikova J, Mejstrikova E, Valova T, et al. Minimal residual disease in peripheral blood at day 15 identifies a subgroup of childhood B-cell precursor acute lymphoblastic leukemia with superior prognosis. Haematologica 2011; 96: 1815-1821.

17. Schrappe M. Evolution of BFM trials for childhood ALL. Ann Hematol 2004; 83(Suppl 1): S121-123.

18. 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: 5168-5174.

19. Burger B, Zimmermann M, Mann G, et al. Diagnostic cerebrospinal fluid examination in children with acute lymphoblastic leukemia: significance of low leukocyte counts with blasts or traumatic lumbar puncture. J Clin Oncol 2003; 21: 184-188.

20. Mahmoud HH, Rivera GK, Hancock ML, et al. Low leukocyte counts with blast cells in cerebrospinal fluid of children with newly diagnosed acute lymphoblastic leukemia. N Engl J Med 1993; 329: 314-319.

21. Pui CH, Campana D, Pei D, et al. Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med 2009; 360: 2730-2741.

22. te Loo DM, Kamps WA, van der Does-van den Berg A, et al. Prognostic significance of blasts in the cerebrospinal fluid without pleiocytosis or a traumatic lumbar puncture in children with acute lymphoblastic leukemia: experience of the Dutch Childhood Oncology Group. J Clin Oncol 2006; 24: 2332-2336.

23. Marwaha RK, Kulkarni KP, Bansal D, et al. Central nervous system involvement at presentation in childhood acute lymphoblastic leukemia: management experience and lessons. Leuk Lymphoma 2010; 51: 261-268.

24. Gajjar A, Harrison PL, Sandlund JT, et al. Traumatic lumbar puncture at diagnosis adversely affects outcome in childhood acute lymphoblastic leukemia. Blood 2000; 96: 3381-3384.

25. Howard SC, Gajjar AJ, Cheng C, et al. Risk factors for traumatic and bloody lumbar puncture in children with acute lymphoblastic leukemia. JAMA 2002; 288: 2001-2007.

26. Biojone E, Queiroz Rde P, Valera ET, et al. Minimal residual disease in cerebrospinal fluid at diagnosis: a more intensive treatment protocol was able to eliminate the adverse prognosis in children with acute lymphoblastic leukemia. Leuk Lymphoma 2012; 53: 89-95.

27. Hagedorn N, Acquaviva C, Fronkova E, et al. Submicroscopic bone marrow involvement in isolated extramedullary relapses in childhood acute lymphoblastic leukemia: a more precise definition of “isolated” and its possible clinical implications, a collaborative study of the Resistant Disease Committee of the International BFM study group. Blood 2007; 110: 4022-4029.

Haematology Internal medicine Clinical oncology
Forgotten password

Don‘t have an account?  Create new account

Forgotten password

Enter the email address that you registered with. We will send you instructions on how to set a new password.


Don‘t have an account?  Create new account