Minimal residual disease and b-cell subpopulation monitoring in acute b-lymphoblastic leukaemia patients treated on rall-2016 protocol

Introduction. The Russian multicentre trial on treatment of Acute Lymphoblastic Leukaemia (ALL) in adults (RALL-2016) regulates a centralised detection of minimal residual disease (MRD) on days 70 (end of induction II), 133 (end of consolidation III) and 190 (end of consolidation V).

Aim — the assessment of tumour cell clearance and normal B-cell precursor, mature B-cell and plasma cell dynamics.

Materials and methods. The study period of December 2016 — August 2019 covered 59 B-ALL patients; the control cohort included four allogeneic blood stem cell donors. The MRD detection was performed with bone marrow samples in flow cytometry.

Results. The patient majority have reached MRD-negativity at control timepoints, 60.4, 75.6 and 91.2% on days 70, 133 and 190, respectively. No correlation was observed between MRD values and tumour cell immunophenotype. B-cell precursors were undetected in 54.4, 38.8 and 59.4% patients on days 70, 133 and 190, respectively. Mature B-cells were fewer compared to donors’ on days 133 and 190. The relative plasma cell count did not differ significantly over therapy and between patients and donors.

Conclusion. The RALL-2016 protocol facilitates MRD-negativity in the patient majority despite reduced cytostatic intensity.

1. Schuurhuis G.J., Heuser M., Freeman S., et al. Minimal/measurable residual disease in AML: A consensus document from the European LeukemiaNet MRD Working Party. Blood. 2018; 131(12): 1275–1291. DOI: 10.1182/blood-2017-09-801498.

2. 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 AIEOPBFM ALL 2000 for childhood acute lymphoblastic leukemia. Leukemia. 2008; 22(4): 771–782. DOI: 10.1038/leu.2008.5.

3. Basso G., Veltroni M., Valsecchi M.G., 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(31): 5168–5174. DOI: 10.1200/JCO.2008.20.8934.

4. Borowitz M.J., Pullen D.J., Shuster J.J., et al. Minimal residual disease detection in childhood precursor-B-cell acute lymphoblastic leukemia: Relation to other risk factors. A Children’s Oncology Group study. Leukemia. 2003; 17(8): 1566– 1572. DOI: 10.1038/sj.leu.2403001.

5. Björklund E., Mazur J., Söderhäll S., Porwit-MacDonald A. Flow cytometric follow-up of minimal residual disease in bone marrow gives prognostic information in children with acute lymphoblastic leukemia. Leukemia. 2003; 17(1): 138–148. DOI: 10.1038/sj.leu.2402736.

6. Treatment of High Risk Adult Acute Lymphoblastic Leukemia (LAL-AR/2003). ClinicalTrials.gov (database of privately and publicly funded clinical studies), 2009. https://clinicaltrials.gov/ct2/show/NCT00853008

7. Gökbuget N., Kneba M., Raff T., et al. Adult patients with acute lymphoblastic leukemia and molecular failure display a poor prognosis and are candidates for stem cell transplantation and targeted therapies. Blood. 2012; 120(9): 1868– 1876. DOI: 10.1182/blood-2011-09-377713.

8. Brüggemann M., Kotrova M. Minimal residual disease in adult ALL: Technical aspects and implications for correct clinical interpretation. Hematol Am Soc Hematol Educ Progr. 2017; 2017(1): 13–21. DOI: 10.1182/asheducation-2017.1.13.

9. Clinical trials AIEOP-BFM ALL 2009 (2007-004270-43). EU Clinical Trials Register, 2010. https://www.clinicaltrialsregister.eu/

10. Beldjord K., Chevret S., Asnafi V., et al. Oncogenetics and minimal residual disease are independent outcome predictors in adult patients with acute lymphoblastic leukemia. Blood. 2014; 123(24): 3739–3749. DOI: 10.1182/blood-2014-01-547695.

11. Parovichnikova E.N., Troitskaya V.V., Sokolov A.N., et al. Interim results of the Ph-negative acute lymphoblastic leukemia treatment in adult patients (results of Russian research group of ALL treatment (RALL)). Onkogematologiya. 2014; 3(9): 6–15. DOI: 10.17650/1818-8346-2014-9-3-6-15. (In Russian).

12. Parovichnikova E.N., Sokolov A.N., Troitskaya V.V., et al. Acute Ph-negative lymphoblastic leukemias in adults: Risk factors in the use of the ALL-2009 protocol. Terapevticheskii arkhiv. 2016; 88(7): 15–24. DOI: 10.17116/terarkh201688715-24. (In Russian).

13. Multicenter Clinical Trial for Adult Ph-negative ALL. Non-intensive But Noniterruptive Treatment. ClinicalTrials.gov (database of privately and publicly funded clinical studies), 2010. https://clinicaltrials.gov/ct2/show/NCT01193933

14. De-escalated Treatment Approach for Adult Ph-negative Acute Lymphoblastic Leukemia (ALL). ClinicalTrials.gov (database of privately and publicly funded clinical studies), 2018. https://clinicaltrials.gov/ct2/show/NCT03462095

15. Wood B.L. Principles of minimal residual disease detection for hematopoietic neoplasms by flow cytometry. Cytometry B Clin Cytom. 2016; 90(1): 47–53. DOI: 10.1002/cyto.b.21239.

16. Wood B. Multicolor immunophenotyping: human immune system hematopoiesis. Methods Cell Biol. 2004; 75: 559–576. DOI: 10.1016/S0091-679X(04)75023-2.

17. Wood B.L. Flow cytometric monitoring of residual disease in acute leukemia. In: Methods in Molecular Biology (Clifton N.J.). 2013; 999: 123–136. DOI: 10.1007/978-1-62703-357-2_8.

18. Dworzak M.N., Buldini B., Gaipa G., et al. AIEOP-BFM consensus guidelines 2016 for flow cytometric immunophenotyping of Pediatric acute lymphoblastic leukemia. Cytometry Part B. 2018; 94B: 82–93. DOI: 10.1002/cyto.b.21518.

19. Popov A.M., Verzhbitskaya T.Yu., Fechina L.G., et al. Acute leukemias: Immunophenotypic differences between blast cells and their nonneoplastic analogues in bone marrow. Klinicheskaya onkogematologiya. 2016; 9(3): 302–313. DOI: 10.21320/2500-2139-2016-9-3-302-313. (In Russian).

20. Dworzak M.N., Gaipa G., Ratei R., et al. Standardization of flow cytometric minimal residual disease evaluation in acute lymphoblastic leukemia: Multicentric assessment is feasible. Cytometry Part B. 2008; 74B: 331–340. DOI: 10.1002/cyto.b.20430.

21. Borowitz M.J., Devidas M., Hunger S.P., 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): 5477–5485. DOI: 10.1182/blood-2008-01-132837.

22. Ribera J.-M., Oriol A., Morgades M., et al. 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. 2014; 32(15): 1595–1604. DOI: 10.1200/JCO.2013.52.2425.

23. Bassan R., Spinelli O., Oldani E., et al. Improved risk classification for riskspecific therapy based on the molecular study of minimal residual disease (MRD) in adult acute lymphoblastic leukemia (ALL). Blood. 2009; 113(18): 4153–4162. DOI: 10.1182/blood-2008-11-185132.

24. Patel B., Rai L., Buck G., et al. Minimal residual disease is a significant predictor of treatment failure in non T-lineage adult acute lymphoblastic leukaemia: Final results of the international trial UKALL XII/ECOG2993. Br J Haematol. 2010; 148(1): 80–89. DOI: 10.1111/j.1365-2141.2009.07941.x.

25. Ravandi F., Jorgensen J.L., O’Brien S.M., et al. Minimal residual disease assessed by multi-parameter flow cytometry is highly prognostic in adult patients with acute lymphoblastic leukaemia. Br J Haematol. 2016; 172(3): 392–400. DOI: 10.1111/bjh.13834.

26. van Lochem E.G., Wiegers Y.M., van den Beemd R., et al. Regeneration pattern of precursor-B-cells in bone marrow of acute lymphoblastic leukemia patients depends on the type of preceding chemotherapy. Leukemia. 2000; 14(4): 688– 695. DOI: 10.1038/sj.leu.2401749.

27. van Wering E.R., van der Linden-Schrever B.E., Szczepański T., et al. Regenerating normal B-cell precursors during and after treatment of acute lymphoblastic leukaemia: Implications for monitoring of minimal residual disease. Br J Haematol. 2000; 110(1): 139–146. DOI: 10.1046/j.1365-2141.2000.02143.x.

28. Theunissen P.M.J., van den Branden A., van der Sluijs-Gelling A., et al. Understanding the reconstitution of the B-cell compartment in bone marrow and blood after treatment for B-cell precursor acute lymphoblastic leukaemia. Br J Haematol. 2017; 178(2): 267–278. DOI: 10.1111/bjh.14685.

29. Liao H., Zheng Q., Jin Y., et al. The prognostic significance of hematogones and CD34+ myeloblasts in bone marrow for adult B-cell lymphoblastic leukemia without minimal residual disease. Sci Rep. 2019; 9(1): 19722. DOI: 10.1038/s41598-019-56126-2.