Significance of Minimal Residual Disease in Chronic Lymphocytic Leukemia

Česká verzia

Authors: M. Doubek
Authors place of work: Interní hematologická a onkologická klinika LF MU a FN BrnoCEITEC – Středoevropský technologický institut, MU, Brno
Published in the journal: Klin Onkol 2015; 28(Supplementum 3): 16-21
doi: https://doi.org/10.14735/amko20153S16

S příchodem nových a vysoce účinných léčebných postupů do terapie chronické lymfocytární leukemie nabývá na významu analýza minimální reziduální nemoci. Minimální reziduální nemoc získává u chronické lymfocytární leukemie význam jako prediktivní faktor, nicméně její důležitost je v mnoha klinických situacích stále nejasná. Roli minimální reziduální nemoci ovlivňují především tyto faktory: metoda použitá k detekci minimální reziduální nemoci, léčebný režim, vyšetření z periferní krve vs. kostní dřeně nebo časový bod, kdy byl proveden odběr vzorku na analýzu minimální reziduální nemoci.

Summary

Newly introduced highly effective treatment options increase the importance of minimal residual disease measurement in chronic lymphocytic leukemia. Minimal residual disease is gaining interest mainly as a predictive marker; however, clinical significance of minimal residual disease in chronic lymphocytic leukemia in many different situations remains unresolved. Factors with a possible impact on the clinical significance of minimal residual disease are as follows: technique for minimal residual disease quantification, treatment regimen, peripheral blood vs. bone marrow analysis or time‑ point for sampling. Highly sensitive methods now available to evaluate minimal residual disease can detect a single chronic lymphocytic leukemia cell in 10^–4– 10^–5 leukocytes using either allele‑ specific oligonucleotide polymerase chain reaction or multicolor flow cytometry. Minimal residual disease quantification as a surrogate marker to assess treatment efficacy in routine hematological practice has to be further evaluated.

Key words:
chronic lymphocytic leukemia – minimal residual disease – prognostic factors – flow cytometry – progression‑free survival

The author declare he has no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.

Submitted:
29. 7. 2015

Accepted:
4. 8. 2015

Zdroje

1. Krejčí M, Doubek M, Brychtová Y et al. Fludarabine with cytarabine followed by reduced‑ intensity conditioning and allogeneic hematopoietic stem cell transplantation in patients with poor‑ risk chronic lymphocytic leukemia. Ann Hematol 2013; 92(2): 249– 254. doi: 10.1007/ s00277‑ 012‑ 1579‑ y.

2. Gallagher RE, Yeap BY, Bi W et al. Quantitative real‑ time RT‑PCR analysis of PML‑RAR alpha mRNA in acute promyelocytic leukemia: assessment of prognostic significance in adult patients from intergroup protocol 0129. Blood 2003; 101(7): 2521– 2528.

3. Diverio D, Rossi V, Avvisati G et al. Early detection of relapse by prospective reverse transcriptase‑ polymerase chain reaction analysis of the PML/ RARalpha fusion gene in patients with acute promyelocytic leukemia enrolled in the GIMEMA‑ AIEOP multicenter „AIDA“ trial. GIMEMA‑ AIEOP Multicenter „AIDA“ Trial. Blood 1998; 92(3): 784– 789.

4. 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(5): 1607– 1611.

5. Šálek C, Folber F, Froňková E et al. Early MRD response as a prognostic factor in adult patients with acute lymphoblastic leukemia. Eur J Haematol. In press 2015. doi: 10.1111/ ejh.12587.

6. Doubek M, Palasek I, Pospisil Z et al. Detection and treatment of molecular relapse in acute myeloid leukemia with RUNX1 (AML1), CBFB, or MLL gene translocations: frequent quantitative monitoring of molecular markers in different compartments and correlation with WT1 gene expression. Exp Hematol 2009; 37(6): 659– 672. doi: 10.1016/ j.exphem.2009.03.004.

7. Hochhaus A, Reiter A, Saussele S et al. Molecular heterogeneity in complete cytogenetic responders after interferon‑alpha therapy for chronic myelogenous leukemia: low levels of minimal residual disease are associated with continuing remission. German CML Study Group and the UK MRC CML Study Group. Blood 2000; 95(1): 62– 66.

8. Bosch F, Ferrer A, López‑ Guillermo A et al. Fludarabine, cyclophosphamide and mitoxantrone in the treatment of resistant or relapsed chronic lymphocytic leukaemia. Br J Haematol 2002; 119(4): 976– 984.

9. Rawstron AC, Kennedy B, Evans PA et al. Quantitation of minimal disease levels in chronic lymphocytic leukemia using a sensitive flow cytometric assay improves the prediction of outcome and can be used to optimize therapy. Blood 2001; 98(1): 29– 35.

10. Moreton P, Kennedy B, Lucas G et al. Eradication of minimal residual disease in B‑ cell chronic lymphocytic leukemia after alemtuzumab therapy is associated with prolonged survival. J Clin Oncol 2005; 23(13): 2971– 2979.

11. Wierda W, O‘Brien S, Wen S et al. Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab for relapsed and refractory chronic lymphocytic leukemia. J Clin Oncol 2005; 23(18): 4070– 4078.

12. Skuhrová Francová H, Tichý B, Malinová K et al. Stanovení minimální zbytkové nemoci u B-buněčné chronické lymfocytární leukemie: možnosti a vývoj metodických přístupů založených na PCR a RQ-PCR. Transfuze Hematol Dnes 2009; 15: 197–203.

13. Bezdíčková L, Špaček M, Peková S Kozák T. Minimální reziduální nemoc u chronické lymfocytární leukemie: metody stanovení a klinický význam. Transfuze Hematol dnes 2010; 16 (Suppl 1): 97– 101.

14. Rawstron AC, Kennedy B, Evans PA et al. Quantitation of minimal disease levels in chronic lymphocytic leukemia using a sensitive flow cytometric assay improves the prediction of outcome and can be used to optimize therapy. Blood 2001; 98(1): 29– 35.

15. Böttcher S, Ritgen M, Pott C et al. Comparative analysis of minimal residual disease detection using four‑ color flow cytometry, consensus IgH‑PCR, and quantitative IgH PCR in CLL after allogeneic and autologous stem cell transplantation. Leukemia 2004; 18(10): 1637– 1645.

16. Rawstron AC, Villamor N, Ritgen M et al. International standardized approach for flow cytometric residual disease monitoring in chronic lymphocytic leukaemia. Leukemia 2007; 21(5): 956– 964.

17. Rawstron AC, Böttcher S, Letestu R et al. Improving efficiency and sensitivity: European Research Initiative in CLL (ERIC) update on the international harmonised approach for flow cytometric residual disease monitoring in CLL. Leukemia 2013; 27(1): 142– 149. doi: 10.1038/ leu.2012.216.

18. Stehlíková O, Chovancová J, Tichý B et al. Detecting minimal residual disease in patients with chronic lymphocytic leukemia using 8- color flow cytometry protocol in routine hematological practice. Int J Lab Hematol 2014; 36(2): 165– 171. doi: 10.1111/ ijlh.12149.

19. Vuillier F, Claisse JF, Vandenvelde C et al. Evaluation of residual disease in B‑ cell chronic lymphocytic leukemia patients in clinical and bone‑ marrow remission using CD5– CD19 markers and PCR study of gene rearrangements. Leuk Lymphoma 1992; 7(3): 195– 204.

20. Peková S, Bezdíčková L, Smolej L et al. Quantitation of minimal residual disease in patients with chronic lymphocytic leukemia using locked nucleic acid‑ modified, fluorescently labeled hybridization probes and real‑ time PCR technology. Mol Diagn Ther 2007; 11(5): 325– 335.

21. Karkare S, Bhatnagar D. Promising nucleic acid analogs and mimics: characteristic features and applications of PNA, LNA, and morpholino. Appl Microbiol Biotechnol 2006; 71(5): 575– 586.

22. O‘Brien SM, Kantarjian HM, Thomas DA et al. Alemtuzumab as treatment for residual disease after chemotherapy in patients with chronic lymphocytic leukemia. Cancer 2003; 98(12): 2657– 2663.

23. Wendtner CM, Ritgen M, Schweighofer CD et al. German CLL Study Group (GCLLSG). Consolidation with alemtuzumab in patients with chronic lymphocytic leukemia (CLL) in first remission – experience on safety and efficacy within a randomized multicenter phase III trial of the German CLL Study Group (GCLLSG). Leukemia 2004; 18(6): 1093– 1101.

24. Montillo M, Tedeschi A, Miqueleiz S et al. Alemtuzumab as consolidation after a response to fludarabine is effective in purging residual disease in patients with chronic lymphocytic leukemia. J Clin Oncol 2006; 24(15): 2337– 2342.

25. Del Poeta G, Del Principe MI, Consalvo MA et al. The addition of rituximab to fludarabine improves clinical outcome in untreated patients with ZAP‑ 70- negative chronic lymphocytic leukemia. Cancer 2005; 104(12): 2743– 2752.

26. Del Poeta G, Del Principe MI, Buccisano F et al. Consolidation and maintenance immunotherapy with rituximab improve clinical outcome in patients with B‑ cell chronic lymphocytic leukemia. Cancer 2008; 112(1): 119– 128.

27. Böttcher S, Ritgen M, Fischer K et al. Minimal residual disease quantification is an independent predictor of progression‑free and overall survival in chronic lymphocytic leukemia: a multivariate analysis from the randomized GCLLSG CLL8 trial. J Clin Oncol 2012; 30(9): 980– 988. doi: 10.1200/ JCO.2011.36.9348.

28. Fischer K, Cramer P, Busch R et al. Bendamustine in combination with rituximab for previously untreated patients with chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol 2012; 30(26): 3209– 3216. doi: 10.1200/ JCO.2011.39.2688.

29. Goede V, Fischer K, Busch R et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med 2014; 370(12): 1101– 1110. doi: 10.1056/ NEJMoa1313984.

30. Hillmen P, Robak T, Janssens A et al. Chlorambucil plus ofatumumab versus chlorambucil alone in previously untreated patients with chronic lymphocytic leukaemia (COMPLEMENT 1): a randomised, multicentre, open‑ label phase 3 trial. Lancet 2015; 385(9980): 1873– 1883. doi: 10.1016/ S0140‑ 6736(15)60027‑ 7.

31. Hillmen P, Skotnicki AB, Robak T et al. Alemtuzumab compared with chlorambucil as first‑line therapy for chronic lymphocytic leukemia. J Clin Oncol 2007; 25(35): 5616– 5623.

32. Doubek M, Brychtova Y, Panovska A et al. Ofatumumab added to dexamethasone in patients with relapsed or refractory chronic lymphocytic leukemia: results from a phase II study. Am J Hematol 2015; 90(5): 417– 421. doi: 10.1002/ ajh.23964.

33. Burger JA, Keating MJ, Wierda WG et al. Safety and activity of ibrutinib plus rituximab for patients with high‑risk chronic lymphocytic leukaemia: a single‑arm, phase 2 study. Lancet Oncol 2014; 15(10): 1090– 1099. doi: 10.1016/ S1470‑ 2045(14)70335‑ 3.

34. Byrd JC, Brown JR, O‘Brien S et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med 2014; 371(3): 213– 223. doi: 10.1056/ NEJMoa1400376.

35. Esteve J, Villamor N, Colomer D et al. Stem cell transplantation for chronic lymphocytic leukemia: different outcome after autologous and allogeneic transplantation and correlation with minimal residual disease status. Leukemia 2001; 15(3): 445– 451.

36. Ritgen M, Stilgenbauer S, von Neuhoff N et al. Graft‑ versus‑ leukemia activity may overcome therapeutic resistance of chronic lymphocytic leukemia with unmutated immunoglobulin variable heavy‑chain gene status: implications of minimal residual disease measurement with quantitative PCR. Blood 2004; 104(8):2600– 2602.

37. Moreno C, Villamor N, Colomer D et al. Clinical significance of minimal residual disease, as assessed by different techniques, after stem cell transplantation for chronic lymphocytic leukemia. Blood 2006; 107(11): 4563– 4569.

38. Smolej L, Doubek M, Špaček M et al. Doporučení pro diagnostiku a léčbu chronické lymfocytární leukémie (CLL). Transf Hematol dnes 2013; 19: 61– 68.

39. Doubek M, Mayer J (eds). Postupy diagnostiky a léčby leukemií a jejich infekčních komplikací u dospělých pacientů. Doporučení České leukemické skupiny – pro život (CELL). 2. vyd. Brno: Česká leukemická skupina – pro život: 162.

40. Hallek M, Cheson BD, Catovsky D et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) updating the National Cancer Institute‑ Working Group (NCI‑ WG) 1996 guidelines. Blood 2008; 111(12): 5446– 5456. doi: 10.1182/ blood‑ 2007‑ 06‑ 093906.

41. Panovská A, Smolej L, Lysák D et al. The outcome of chronic lymphocytic leukemia patients who relapsed after fludarabine, cyclophosphamide, and rituximab. Eur J Haematol 2013; 90(6): 479– 485. doi: 10.1111/ ejh.12106.

42. Furman RR, Sharman JP, Coutre SE et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med 2014; 370(11): 997– 1007. doi: 10.1056/ NEJMoa1315226.