Blood Res.  2025;60:4. 10.1007/s44313-024-00050-6.

Efficacy of bortezomib combined with Hyper‑CVAD in adults with relapsed acute lymphoblastic leukemia or positive measurable residual disease; effect of bortezomib in leukemia

• Peñafiel C
• Sámano D
• Rodríguez A
• Palacio C
• Carrillo I
• Murillo C
• Lampón G
• García
• Tovar A

• KMID: 2564325
• DOI: http://doi.org/10.1007/s44313-024-00050-6

Abstract

Purpose
Despite advances in the treatment of adult acute lymphoblastic leukemia (ALL), relapse remains the most significant challenge in improving prognosis. Measurable residual disease (MRD) assessment can predict bone marrow relapse based on MRD positivity. As access to innovative therapies remains limited because of the high cost, chemotherapy is the widely utilized treatment option. The efficacy of a combination of bortezomib and Hyper-CVAD has been reported in patients with multiple myeloma; however, its efficacy has not yet been confirmed in patients with ALL.
Methods
This prospective cohort study involved patients with ALL who presented with MRD-positive results or relapse and received treatment with a combination of bortezomib and Hyper-CVAD at two reference centers in Mexico City.
Results
Of the 20 patients with positive MRD included in this study, 60% (n = 12) exhibited MRD negative results after combination treatment, 30% (n = 6) persisted positive MRD results, and 10% (n = 2) passed away. Of the 23 patients with bone marrow relapse, 43.5% (n = 10) achieved a second complete remission (2CR), 34.8% (n = 6) exhibited refractory status, and 21.7% (n = 5) passed away. To achieve a 2CR, 20% (n = 2) patients required less than four cycles of treatment, 50% (n = 5) required four cycles (two A and B cycles each), and 30% (n = 3) required six cycles.
Conclusion
The combination of bortezomib and Hyper-CVAD treatment exhibited better results in achieving MRD negative results, indicating its potential as a promising first-line treatment strategy for ALL.

Keyword

Bortezomib; Chemotherapy; Acute Lymphoblastic Leukemia; Relapse; Measurable Residual Disease

Figure

• 

  Fig. 1 Survival rate among patients with MRD positivity and relapse

• 

  Fig. 2 Survival rate among patients according to the response to the combination treatment with Hyper-CVAD and bortezomib

Reference

1. Paietta E, Roberts KG, Wang V, Gu Z, Buck GAN, Pei D, et al. 2021; Molecular classification improves risk assessment in adult BCR-ABL1-negative B-ALL. Blood. 138(11):948–58. Available from: https://doi.org/10.1182/blood.2020010144. DOI: 10.1182/blood.2020010144. PMID: 33895809. PMCID: PMC9069478.

2. Li J, Dai Y, Wu L, Zhang M, Ouyang W, Huang J, et al. 2021; Emerging molecular subtypes and therapeutic targets in B-cell precursor acute lymphoblastic leukemia. Front Med. 15(3):347–71. Available from: https://doi.org/10.1007/s11684-020-0821-6. DOI: 10.1007/s11684-020-0821-6. PMID: 33400146.

3. Kruse A, Abdel-Azim N, Kim HN, Ruan Y, Phan V, Ogana H, et al. 2020; Minimal residual disease detection in acute lymphoblastic leukemia. Int J Mol Sci. 21(3):1054. Available from: https://doi.org/10.3390/ijms21031054. DOI: 10.3390/ijms21031054. PMID: 32033444. PMCID: PMC7037356.

4. Correia RP, Bento LC, de Sousa FA, Barroso R de S, Campregher PV, Bacal NS. 2021; How I investigate minimal residual disease in acute lymphoblastic leukemia. Int J Lab Hematol. 43(3):354–63. Available from: https://doi.org/10.1111/ijlh.13463. DOI: 10.1111/ijlh.13463. PMID: 33423385.

5. Mocquot P, Mossazadeh Y, Lapierre L, Pineau F, Despas F. 2022; The pharmacology of blinatumomab: state of the art on pharmacodynamics, pharmacokinetics, adverse drug reactions and evaluation in clinical trials. J Clin Pharm Ther. 47(9):1337–51. Available from: https://doi.org/10.1111/jcpt.13741. DOI: 10.1111/jcpt.13741. PMID: 35906791. PMCID: PMC9796714.

6. Gökbuget N, Dombret H, Bonifacio M, Reichle A, Graux C, Faul C, et al. 2018; Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia. Blood. 131(14):1522–31. Available from: https://doi.org/10.1182/blood-2017-08-798322. DOI: 10.1182/blood-2017-08-798322. PMID: 29358182. PMCID: PMC6027091.

7. Kantarjian H, Stein A, Gökbuget N, Fielding AK, Schuh AC, Ribera J-M, et al. 2017; Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 376(9):836–47. Available from: https://doi.org/10.1056/NEJMoa1609783. DOI: 10.1056/NEJMoa1609783. PMID: 28249141. PMCID: PMC5881572.

8. Specchia G, Pastore D, Carluccio P, Liso A, Mestice A, Rizzi R, et al. 2005; FLAGIDA in the treatment of refractory/relapsed adult acute lymphoblastic leukemia. Ann Hematol. 84(12):792–5. Available from: https://doi.org/10.1007/s00277-005-1090-9. DOI: 10.1007/s00277-005-1090-9. PMID: 16047203.

9. Hashmi KU, Khan B, Ahmed P, Raza S, Hussain I, Mahmood A, et al. 2005; FLAGIDA in the treatment of refractory/relapsed acute leukaemias: single centre study. J Pak Med Assoc. 55(6):234–8.

10. Cengiz Seval G, Beksac M. 2018; The safety of bortezomib for the treatment of multiple myeloma. Expert Opin Drug Saf. 17(9):1–10. Available from: https://doi.org/10.1080/14740338.2018.1513487. DOI: 10.1080/14740338.2018.1513487. PMID: 30118610.

11. Tarockoff M, Gonzalez T, Ivanov S, Sandoval-Sus J. 2022; Mantle cell lymphoma: The role of risk-adapted therapy and treatment of relapsed disease. Curr Oncol Rep. 24(10):1313–26. Available from: https://doi.org/10.1007/s11912-022-01297-x. DOI: 10.1007/s11912-022-01297-x. PMID: 35639332.

12. Du X, Tong J, Lu H, He C, Du S, Jia P, et al. 2017; Combination of bortezomib and daunorubicin in the induction of apoptosis in T-cell acute lymphoblastic leukemia. Mol Med Rep. 16(1):101–8. Available from: https://doi.org/10.3892/mmr.2017.6554. DOI: 10.3892/mmr.2017.6554. PMID: 28487980. PMCID: PMC5482122.

13. Cheung LC, de Kraa R, Oommen J, Chua G-A, Singh S, Hughes AM, et al. 2021; Preclinical evaluation of carfilzomib for infant KMT2A-rearranged acute lymphoblastic leukemia. Front Oncol. 11:631594. Available from: https://doi.org/10.3389/fonc.2021.631594. DOI: 10.3389/fonc.2021.631594. PMID: 33937032. PMCID: PMC8082024.

14. Horton TM, Whitlock JA, Lu X, O'Brien MM, Borowitz MJ, Devidas M, et al. 2019; Bortezomib reinduction chemotherapy in high-risk ALL in first relapse: a report from the Children's Oncology Group. Br J Haematol. 186(2):274–85. Available from: https://doi.org/10.1111/bjh.15919. DOI: 10.1111/bjh.15919. PMID: 30957229. PMCID: PMC6606340.

15. Saraceni MM, Scott E, Maziarz RT, Siegel MB, Bassale S, Jiing S, et al. 2018; Modified HyperCVAD versus bortezomib-HyperCAD in patients with relapsed/refractory multiple myeloma. Clin Lymphoma Myeloma Leuk. 18(1):e77–84. Available from: https://doi.org/10.1016/j.clml.2017.10.008. DOI: 10.1016/j.clml.2017.10.008. PMID: 29169873.

16. Nih. 2006. Common terminology criteria for adverse events V3.0 (ctcae). Handydex;Available from: https://www.eortc.be/services/doc/ctc/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf. cited June 8, 2023.

17. Frey NV, Luger SM. 2015; How I treat adults with relapsed or refractory Philadelphia chromosome-negative acute lymphoblastic leukemia. Blood. 126(5):589–96. Available from: https://doi.org/10.1182/blood-2014-09-551937. DOI: 10.1182/blood-2014-09-551937. PMID: 25966988.

18. Forman SJ, Rowe JM. 2013; The myth of the second remission of acute leukemia in the adult. Blood. 121(7):1077–82. Available from: https://doi.org/10.1182/blood-2012-08-234492. DOI: 10.1182/blood-2012-08-234492. PMID: 23243288. PMCID: PMC3575753.

19. DuVall AS, Sheade J, Anderson D, Yates SJ, Stock W. 2022; Updates in the management of relapsed and refractory acute lymphoblastic leukemia: An urgent plea for new treatments is being answered! JCO Oncol Pract. 18(7):479–87. Available from: https://doi.org/10.1200/OP.21.00843. DOI: 10.1200/OP.21.00843. PMID: 35380890.

20. Guru Murthy GS, Atallah E. 2022; Relapsed/refractory acute lymphoblastic leukemia in adults: Progress and challenges. JCO Oncol Pract. 18(7):489–90. Available from: https://doi.org/10.1200/OP.22.00237. DOI: 10.1200/OP.22.00237. PMID: 35588183.

21. Visani G, Tosi P, Zinzani PL, Manfroi S, Ottaviani E, Cenacchi A, et al. 1996; FLAG (fludarabine, cytarabine, G-CSF) as a second line therapy for acute lymphoblastic leukemia with myeloid antigen expression: in vitro and in vivo effects. Eur J Haematol. 56(5):308–12. Available from: https://doi.org/10.1111/j.1600-0609.1996.tb00720.x. DOI: 10.1111/j.1600-0609.1996.tb00720.x. PMID: 8641405.

22. Clavio M, Carrara P, Miglino M, Pierri I, Canepa L, Balleari E, et al. 1996; High efficacy of fludarabine-containing therapy (FLAG-FLANG) in poor risk acute myeloid leukemia. Haematologica. 81(6):513–20.

23. Montillo M, Tedeschi A, Centurioni R, Leoni P. 1997; Treatment of relapsed adult acute lymphoblastic leukemia with fludarabine and cytosine arabinoside followed by granulocyte colony-stimulating factor (FLAG-GCSF). Leuk Lymphoma. 25(5-6):579–83. Available from: https://doi.org/10.3109/10428199709039047. DOI: 10.3109/10428199709039047. PMID: 9250830.

24. Yavuz S, Paydas S, Disel U, Sahin B. 2006; IDA-FLAG regimen for the therapy of primary refractory and relapse acute leukemia: a single-center experience. Am J Ther. 13(5):389–93. Available from: https://doi.org/10.1097/01.mjt.0000181690.21601.09. DOI: 10.1097/01.mjt.0000181690.21601.09. PMID: 16988532.

25. McGregor BA, Brown AW, Osswald MB, Savona MR. 2009; The use of higher dose clofarabine in adults with relapsed acute lymphoblastic leukemia. Am J Hematol. 84(4):228–30. Available from: https://doi.org/10.1002/ajh.21365. DOI: 10.1002/ajh.21365. PMID: 19260120.

26. Barba P, Sampol A, Calbacho M, Gonzalez J, Serrano J, Martínez-Sánchez P, et al. 2012; Clofarabine-based chemotherapy for relapsed/refractory adult acute lymphoblastic leukemia and lymphoblastic lymphoma. The Spanish experience. Am J Hematol. 87(6):631–4. Available from: https://doi.org/10.1002/ajh.23167. DOI: 10.1002/ajh.23167. PMID: 22431002.

27. Faderl S, Thomas DA, O'Brien S, Ravandi F, Garcia-Manero G, Borthakur G, et al. 2011; Augmented hyper-CVAD based on dose-intensified vincristine, dexamethasone, and asparaginase in adult acute lymphoblastic leukemia salvage therapy. Clin Lymphoma Myeloma Leuk. 11(1):54–9. Available from: https://doi.org/10.3816/CLML.2011.n.007. DOI: 10.3816/CLML.2011.n.007. PMID: 21454191.

28. Liedtke M, Dunn T, Dinner S, Coutré SE, Berube C, Gotlib J, et al. 2014; Salvage therapy with mitoxantrone, etoposide and cytarabine in relapsed or refractory acute lymphoblastic leukemia. Leuk Res. 38(12):1441–5. Available from: https://doi.org/10.1016/j.leukres.2014.09.018. DOI: 10.1016/j.leukres.2014.09.018. PMID: 25449689.

29. Ahn J-S, Yang D-H, Jung S-H, Lee J-J, Kim I, Park S, et al. 2015; Clinical efficacy of mitoxantrone and Ara-C with or without etoposide salvage chemotherapy in adult patients with relapsed or refractory acute lymphoblastic leukemia: retrospective multicenter study of the Korean Adult ALL Working Party. Acta Haematol. 133(1):91–7. Available from: https://doi.org/10.1159/000362261. DOI: 10.1159/000362261. PMID: 25171064.

30. Berry DA, Zhou S, Higley H, Mukundan L, Fu S, Reaman GH, et al. 2017; Association of minimal residual disease with clinical outcome in pediatric and adult acute lymphoblastic leukemia: A meta-analysis. JAMA Oncol. 3(7):e170580. Available from: https://doi.org/10.1001/jamaoncol.2017.0580. DOI: 10.1001/jamaoncol.2017.0580. PMID: 28494052. PMCID: PMC5824235.

31. Hein K, Short N, Jabbour E, Yilmaz M. 2022; Clinical value of measurable residual disease in acute lymphoblastic leukemia. Blood Lymphat Cancer. 12:7–16. Available from: https://doi.org/10.2147/BLCTT.S270134. DOI: 10.2147/BLCTT.S270134. PMID: 35340663. PMCID: PMC8943430.

32. Ferrari LC, Rivas MM, Navickas AB, Dick H, Mela Osorio MJ, Agamennoni L, et al. 2023; PH negative acute lymphoblastic leukemia in adolescents and young adults treated according a MRD adapted BFM ALL IC 2009 protocol: Argentine real-world data on 171 patients. Ann Hematol. 102(5):1087–97. Available from: https://doi.org/10.1007/s00277-023-05151-3. DOI: 10.1007/s00277-023-05151-3. PMID: 36892593.

33. Curran E, Stock W. 2019; Taking a "BiTE out of ALL": blinatumomab approval for MRD-positive ALL. Blood. 133(16):1715–9. Available from: https://doi.org/10.1182/blood-2018-12-852376. DOI: 10.1182/blood-2018-12-852376. PMID: 30796026. PMCID: PMC6634959.

34. Basquiera AL, Seiwald MC, Best Aguilera CR, Enciso L, Fernandez I, Jansen AM, et al. 2023; Expert recommendations for the diagnosis, treatment, and management of adult B-cell acute lymphoblastic leukemia in Latin America. JCO Glob Oncol. 9:e2200292. Available from: https://doi.org/10.1200/GO.22.00292. DOI: 10.1200/GO.22.00292. PMID: 37167576. PMCID: PMC10497277.

35. Zahid MF. 2016; The role of bortezomib in the treatment of acute lymphoblastic leukemia. Future Oncol. 12(16):1861–4. Available from: https://doi.org/10.2217/fon-2016-0126. DOI: 10.2217/fon-2016-0126. PMID: 27173950.

36. Lato MW, Przysucha A, Grosman S, Zawitkowska J, Lejman M. 2021; The new therapeutic strategies in pediatric T-cell acute lymphoblastic leukemia. Int J Mol Sci. 22(9):Available from: https://doi.org/10.3390/ijms22094502. DOI: 10.3390/ijms22094502. PMID: 33925883. PMCID: PMC8123476.

37. August KJ, Guest EM, Lewing K, Hays JA, Gamis AS. 2020; Treatment of children with relapsed and refractory acute lymphoblastic leukemia with mitoxantrone, vincristine, pegaspargase, dexamethasone, and bortezomib. Pediatr Blood Cancer. 67(3):e28062. Available from: https://doi.org/10.1002/pbc.28062. DOI: 10.1002/pbc.28062. PMID: 31724803.

38. Nachmias B, Shaulov A, Gatt ME, Shapira M, Gural A. 2018; A bortezomib-based protocol induces a high rate of complete remission with minor toxicity in adult patients with relapsed/refractory acute lymphoblastic leukemia. Acta Haematol. 140(4):209–14. Available from: https://doi.org/10.1159/000493252. DOI: 10.1159/000493252. PMID: 30343286.

39. Jonas BA, Fisch SC, Rosenberg AS, Hoeg RT, Tuscano JM, Abedi M. 2021; Phase I study of escalating doses of carfilzomib with HyperCVAD in patients with newly diagnosed acute lymphoblastic leukemia. Am J Hematol. 96(4):E114–7. Available from: https://doi.org/10.1002/ajh.26105. DOI: 10.1002/ajh.26105.

40. Jain H, Sengar M, Goli VB, Thorat J, Tembhare P, Shetty D, et al. 2021; Bortezomib and rituximab in de novo adolescent/adult CD20-positive, Ph-negative pre-B-cell acute lymphoblastic leukemia. Blood Adv. 5(17):3436–44. Available from: https://doi.org/10.1182/bloodadvances.2020003368. DOI: 10.1182/bloodadvances.2020003368. PMID: 34461632. PMCID: PMC8525225.