Prediction of outcome in infants acute lymphoblastic leukemia by time to achievement of molecular remission

   Early therapy response is one of the major prognostic factors influencing an outcome of acute lymphoblastic leukemia (ALL).

   The purpose of the given work was to define a time point (TP) of fusion gene transcript (FGt) monitoring by reverse-transcriptase PCR that clearly predicts outcome in infants with MLL-rearranged ALL, enrolled onto MLL-Baby protocol.

   Molecular remission (cMR) was defined as absence of FGt at nested RT-PCR with sensitivity 1 × 10^–4 or higher confirmed with negative result in the following time point (ТP). Detection of FGt in bone marrow (BM) was performed by qualitative nested RT-PCR on 15^th , 36^th and 43^th days of therapy (TP1-TP3) and also during consolidation/intensification (ТP4-ТP9). Retrospectively, patients were divided into two groups. First group included 14 patients who achieved cMR by TP4, where two relapses occurred. The second group consisted of four MLL-AF4-positive patients, who did not achieve cMR by TP4. In this group there were 3 relapses. Number of relapses was significantly higher in the second group (odds ratio 18.00; 95 % CI: 1.19-271.47; p = 0.044). 6-years event-free survival (EFS) in the first group was 0.84 ± 0.10, in the second group — 0.25 ± 0.21 (p = 0.023). Cumulative incidence of relapse in the first group was 0.15 ± 0.01, in the second group 0.75 ± 0.08 (p = 0.022). Time of cMR achievement did not correlate with any known prognostic factors including therapy response on day 8, 15 and 36. Slow achievement of cMR corresponds to poor outcome in infant ALL with MLL rearrangements. Persistence of FGt at TP4 allows defining patients with high risk of relapse.

1. Moericke A., Reiter A., Zimmermann M. et al. Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: Treatment results of 2,169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95. Blood 2008; 111 (9): 4477–89.

2. Moghrabi A., Levy D. E., Asselin B. et al. Results of the Dana-Farber Cancer Institute ALL Consortium Protocol 95-01 for children with acute lymphoblastic leukemia. Blood 2007; 109 (3): 896–904.

3. Pui C. H., Campana D., Pei D. et al. Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med 2009; 360 (26): 2730–41.

4. Silverman L., McLean T., Gelber R. et al. Intensified therapy for infants with acute lymphoblastic leukemia: results from the Dana Farber Cancer Institute Consortium. Cancer 1997; 80: 2285–95.

5. Pieters R., Schrappe M., De Lorenzo P. et al. A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): an observational study and a multicentre randomised trial. Lancet 2007; 370 (9583): 240–50.

6. Фечина Л. Г. Новые подходы в лечении острых лейкемий у детей раннего возраста как альтернативы интенсивной программной химиотерапии в сочетании с трансплантацией гемопоэтических стволовых клеток / Л. Г. Фечина // Вестн. Уральск. мед. науки. – 2006. – (2): 38–42.

7. Fechina L., Shorikov E., Tsaur G. et al. Contribution of all-trans retinoic acid to improved early relapse-free outcome in infant acute lymphoblastic leukemia comparing to the chemotherapy alone. Blood 2008; 110 (11): 832А, Abstr 2828.

8. ISCN. Guidelines for cancer cytogenetics. In: Mitelman F., eds. Supplement to an International System for Human Cytogenetic Nomenclature. Basel, 1991; p. 1–53.

9. Borkhardt A., Repp R., Haupt E. et al. Molecular analysis of MLL/AF4 recombination in infant acute lymphoblastic leukemia. Leukemia 1994; 8 (4): 549–53.

10. Pallisgaard N., Hokland P., Riishoj D. et al. Multiplex Reverse Transcription-Polymerase Chain Reaction for Simultaneous Screening of 29 Translocations and Chromosomal Aberrations in Acute Leukemia. Blood 1998; 92 (2): 574–88.

11. Dongen van J., Macintyre E., Gabert J. et al. Standardized RT-PCR analysis of fusion gene transcripts from chromosome aberrations in acute leukemia for detection of minimal residual disease. Leukemia 1999; 13 (12): 1901–18.

12. Gabert J., Beillard E., Velden van der 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 (12): 2318–57.

13. Beillard E., Pallisgaard N., Velden van der V. et al. Evaluation of candidate control genes for diagnosis and residual disease detection in leukemic patients using ‘real-time’ quantitative reverse-transcriptase polymerase chain reaction (RQ-PCR) – А Europe Against Cancer Program. Leukemia 2003; 17 (1): 1–13.

14. Jurcic J., Nimer S., Scheinberg D. et al. Prognostic significance of minimal residual disease detection and PML/RAR-a isoform type: long-term follow-up in acute promyelocytic leukemia. Blood 2001; 98 (9): 2651–56.

15. Kaplan E. L., Meier P. Non-parametric estimation from incomplete observations. J Am Statistic Assoc 1958; 53: 457–481.

16. Riehm H., Reiter A., Schrappe M. et al. Corticosteroid-dependent reduction of leukocyte count in blood as a prognostic factor in acute lymphoblastic leukemia in childhood (therapy study ALL-BFM 83). Klin Padiatr 1987; 199 (3): 151–60.

17. 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 (4): 771–82.

18. Basso G., Veltroni M., Valsecchi M. 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 (31): 5168–74.

19. Coustan-Smith E., Sancho J., Behm F. et al. Prognostic importance of measuring early clearance of leukemic cells by flow cytometry in childhood acute lymphoblastic leukemia. Blood 2002; 100 (1): 52–8.

20. Borowitz M., Devidas M., Hunger S. et al. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children’s Oncology Group study. Blood 2008; 111 (12): 5477–85.

21. Dworzak M., Froeschl G., Printz D. et al. Prognostic significance and modalities of flow cytometric minimal residual disease detection in childhood acute lymphoblastic leukemia. Blood 2002; 99 (6): 1952–58.

22. Dongen van J., Seriu T., Panzer-Gruemayer R. et al. Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood. Lancet 1998; 352: 1731–8.

23. Velden van der V., Hochhaus A., Cazzaniga G. et al. Detection of minimal residual disease in hematologic malignancies by real-time quantitative PCR: principles, approaches, and laboratory aspects. Leukemia 2003; 17 (6): 1013–34.

24. Szczepanski T. Why and how to quantify minimal residual disease in acute lymphoblastic leukemia? Leukemia 2003; 21 (4): 622–6.

25. Pane F., Cimino G., Izzo D. et al. Significant reduction of the hybrid BCR/ABL transcripts after induction and consolidation therapy is a powerful predictor of treatment response in adult Philadelphia-positive acute lymphoblastic leukemia. Leukemia 2005; 19 (4): 628–35.

26. Popov A., Tsaur G., Ivanova A. et al. Qualitative and quantitative concordance in MRD data, assessed by flow cytometry and RT-PCR of fusion gene transcripts in infants with MLL-rearranged ALL. Hematologica 2009; 93 (Suppl. 2): 31–2.