Léčba dospělých pacientů s akutní lymfoblastovou leukemií v České republice v letech 2007–2020

Česká verzia

Authors: C. Šálek ^1,2; Š. Hrabovský ³; F. Folber ³; J. M. Horáček ^4,5; Z. Kořístek ⁶; T. Szotkowski ⁷; P. Pecherková ¹; E. Froňková ⁸; M. Doubek ³; Česká leukemická skupina pro život (CELL)
Authors place of work: Ústav hematologie a krevní transfuze, Praha ¹; Ústav klinické a experimentální hematologie 1. LF UK Praha ²; Interní hematologická a onkologická klinika LF MU a FN Brno ³; IV. interní hematologická klinika LF UK a FN Hradec Králové ⁴; Katedra vojenského vnitřního lékařství a vojenské hygieny, Fakulta vojenského zdravotnictví, Univerzita obrany, Hradec Králové ⁵; Klinika hematoonkologie LF OU a FN Ostrava ⁶; Hemato-onkologická klinika LF UP a FN Olomouc ⁷; Laboratorní centrum CLIP, Klinika dětské hematologie a onkologie 2. LF UK a FN Motol, Praha ⁸
Published in the journal: Klin Onkol 2023; 36(5): 382-395
Category: Original Articles
doi: https://doi.org/10.48095/ccko2023382

Summary

Background: Pediatric-inspired protocols with prospective monitoring of minimal residual disease (MRD) are considered the standard of intensive treatment for adults with acute lymphoblastic leukemia (ALL). They have been used in the Czech Republic since 2007.

Patients and methods: Two hundred and ninety-seven patients aged 18–65 years were treated at five hematology centers between 2007–2020 according to the GMALL 07/2003 protocol. This is a retrospective analysis of their treatment outcomes.

Results: In the Ph-negative cohort, 189 (93.1%) patients achieved complete remission, 5 (2.4%) patients were refractory, and early mortality was 3.0%. Seventy (34.5%) patients experienced relapse in a median of 10.6 months. Overall survival (OS) at 3 and 5 years was 63.5% and 55.9%, disease-free survival (DFS) at 3 and 5 years was 54.5% and 49.7%, respectively. Young adults under 35 years of age (P = 0.015), patients without initial CNS infiltration (P = 0.016), with MRD negativity before consolidation treatment (P < 0.001), transplanted in the 1st complete remission (P < 0.001), and subjects treated after 2012 (P = 0.05) had significantly better overall survival. In a multivariate analysis, MRD at week 11 was the only independent factor affecting OS (HR 3.06; P = 0.006). For DFS, baseline CNS infiltration (HR 2.08; P = 0.038) and MRD at week 11 (HR 2.15; P = 0.020) were significant. In the Ph-positive cohort, 84 (89.4%) patients achieved complete remission, 1 (1.0%) patient was refractory, early mortality was 4.3%. Twenty-six (27.7%) patients relapsed in a median of 8.6 months. Survival at 3 and 5 years was 57.2% and 52.4% for OS and 50.2% and 44.9% for DFS, respectively. Transplanted patients and patients diagnosed after 2012 had statistically better overall survival (P < 0.001).

Conclusion: The introduction of pediatric-inspired protocols with treatment intensification according to MRD levels resulted in a significant improvement in the survival outcomes of adult patients with ALL.

Keywords:

acute lymphoblastic leukemia – treatment – hematopoietic stem cell transplantation – minimal residual disease – pediatric-inspired protocol

Zdroje

1. Hoelzer D, Bassan R, Dombret H et al. Acute lymphoblastic leukaemia in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2016; 27 (Suppl 5): v69–v82. doi: 10.1093/annonc/mdw025.

2. 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 (16): 3206–3214. doi: 10.1182/blood-2009-10-248146.

3. Starý J, Zimmermann M, Campbell M et al. Intensive chemotherapy for childhood acute lymphoblastic leukemia: results of the randomized intercontinental trial ALL IC-BFM 2002. J Clin Oncol 2014; 32 (3): 174–184. doi: 10.1200/JCO.2013.48.6522.

4. Bassan R, Hoelzer D. Modern therapy of acute lymphoblastic leukemia. J Clin Oncol 2011; 29 (5): 532–543. doi: 10.1200/JCO.2010.30.1382.

5. Jabbour E, O‘Brien S, Konopleva M et al. New insights into the pathophysiology and therapy of adult acute lymphoblastic leukemia. Cancer 2015; 121 (15): 2517–2528. doi: 10.1002/cncr.29383.

6. Malard F, Mohty M. Acute lymphoblastic leukaemia. Lancet 2020; 395 (10230): 1146–1162. doi: 10.1016/S0140-6736 (19) 33018-1.

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 2010; 120 (9): 1868–1876. doi: 10.1182/blood-2011-09-377713.

8. 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 (4): 604–611. doi: 10.1038/sj.leu.2404586.

9. Brüggemann M, Schrauder A, Raff T et al. Standardized MRD quantification in European ALL trials: proceedings of the second international symposium on MRD assessment in Kiel, Germany, 18–20 September 2008. Leukemia 2010; 24 (3): 521–535. doi: 10.1038/leu.2009.268.

10. Pfeifer H, Cazzaniga G, van der Velden VH et al. Standardisation and consensus guidelines for minimal residual disease assessment in Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) by real-time quantitative reverse transcriptase PCR of e1a2 BCR-ABL1. Leukemia 2019; 33 (8): 1910–1922. doi: 10.1038/s41375-019-0413-0.

11. Goldstone AH, Richards SM, Lazarus HM et al. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood 2008; 111 (4): 1827–1833. doi: 10.1182/blood-2007-10-116582.

12. Thomas DA, O‘Brien S, Faderl S et al. Chemoimmunotherapy with a modified hyper-CVAD and rituximab regimen improves outcome in de novo Philadelphia chromosome-negative precursor B-lineage acute lymphoblastic leukemia. J Clin Oncol 2010; 28 (24): 3880–3889. doi: 10.1200/JCO.2009.26.9456.

13. Huguet F, Chevret S, Leguay T et al. Intensified therapy of acute lymphoblastic leukemia in adults: report of the randomized GRAALL-2005 clinical trial. J Clin Oncol 2018; 36 (24): 2514–2523. doi: 10.1200/JCO.2017.76.8192.

14. Boissel N, Baruchel A. Acute lymphoblastic leukemia in adolescent and young adults: treat as adults or as children? Blood 2018; 132 (4): 351–361. doi: 10.1182/blood-2018-02-778530.

15. Stock W, Luger SM, Advani AS et al. A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403. Blood 2019; 133 (14): 1548–1559. doi: 10.1182/blood-2018-10-881961.

16. Dastugue N, Suciu S, Plat G et al. Hyperdiploidy with 58-66 chromosomes in childhood B-acute lymphoblastic leukemia is highly curable: 58951 CLG-EORTC results. Blood 2013; 121 (13): 2415–2423. doi: 10.1182/blood-2012-06-437681.

17. Neumann M, Bastian L, Hanzelmann S et al. Molecular subgroups of T cell acute lymphoblastic leukemia in adults treated according to GMALL protocols. Blood 2020; 136 (Suppl 1): 37–38. doi: 10.1182/blood-2020-141 921.

18. Giebel S, Marks DI, Boissel N et al. Hematopoietic stem cell transplantation for adults with Philadelphia chromosome-negative acute lymphoblastic leukemia in first remission: a position statement of the European working group for adult acute lymphoblastic leukemia (EWALL) and the Acute leukemia working party of the European society for blood and marrow transplantation (EBMT). Bone Marrow Transplant 2019; 54 (6): 798–809. doi: 10.1038/s41409-018-0373-4.

19. Maury S, Chevret S, Thomas X et al. Rituximab in B-lineage adult acute lymphoblastic leukemia. N Engl J Med 2016; 375 (11): 1044–1053. doi: 10.1056/NEJMoa1605085.

20. Šálek C, Folber F, Froňková E et al. Early MRD response as a prognostic factor in adult patients with acute lymphoblastic leukemia. Europ J Haematol 2016; 96 (3): 276–284. doi: 10.1111/ejh.12587.

21. Šálek C, Folber F, Froňková E et al. Low levels of minimal residual disease after induction chemotherapy for BCR-ABL1-negative acute lymphoblastic leukaemia in adults are clinically relevant. Br J Haematol 2022; 196 (3): 706–710. doi: 10.1111/bjh.17966.

22. 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.

23. Ribera JM, Morgades M, Montesinos P et al. A pediatric regimen for adolescents and young adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: results of the ALLRE08 PETHEMA trial. Cancer Med 2020; 9 (7): 2317–2329. doi: 10.1002/cam4.2814.

24. Bassan R, Rossi G, Pogliani EM et al. Chemotherapy-phased imatinib pulses improve long-term outcome of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: Northern Italy Leukemia Group protocol 09/00. J Clin Oncol 2010; 28 (22): 3644–3652. doi: 10.1200/JCO.2010.28.1287.

25. Chalandon Y, Thomas X, Hayette S et al. Randomized study of reduced-intensity chemotherapy combined with imatinib in adults with Ph-positive acute lymphoblastic leukemia. Blood 2015; 125 (24): 3711–3719. doi: 10.1182/blood-2015-02-627935.

26. Pfeifer H, Raum K, Markovic S et al. Genomic CDKN2A/2B deletions in adult Ph (+) ALL are adverse despite allogeneic stem cell transplantation. Blood 2018; 131 (13): 1464–1475. doi: 10.1182/blood-2017-07-796862.

27. Foà R, Bassan R, Vitale A et al. Dasatinib-blinatumomab for Ph-positive acute lymphoblastic leukemia in adults. N Engl J Med 2020; 383 (17): 1613–1623. doi: 10.1056/NEJMoa2016272.

28. Hovorková L, Žaliová M, Venn NC et al. Monitoring of childhood ALL using BCR-ABL1 genomic breakpoints identifies a subgroup with CML-like biology. Blood 2017; 129 (20): 2771–2781. doi: 10.1182/blood-2016-11-749978.

29. Dhédin N, Huynh A, Maury S et al. Role of allogeneic stem cell transplantation in adult patients with ph-negative acute lymphoblastic leukemia. Blood 2015; 125 (16): 2486–2496. doi: 10.1182/blood-2014-09-599 894.

30. Šálek C, Šponerová D, Soukupová Maaloufová J. Akutní lymfoblastická leukémie – historie a současnost. Vnitř Lék 2012; 58 (Suppl 2): 2S20–2S26.