Factors for Sustaining Molecular Remission after Discontinuation of Tyrosine Kinase Inhibitors Therapy in Chronic Myeloid Leukemia: Results of Non-Randomized Prospective Clinical Trial

AUTOIMMUNE THROMBOCYTOPENIA ,

OA Shukhov, AN Petrova, EYu Chelysheva, AV Bykova, IS Nemchenko, AG Turkina

National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

For correspondence: Oleg Aleksandrovich Shukhov, MD, PhD, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(495)612-16-36, +7(985)287-12-69; e-mail: shuhov@list.ru

For citation: Shukhov OA, Petrova AN, Chelysheva EYu, et al. Factors for Sustaining Molecular Remission after Discontinuation of Tyrosine Kinase Inhibitors Therapy in Chronic Myeloid Leukemia: Results of Non-Randomized Prospective Clinical Trial. Clinical oncohematology. 2021;14(1):1–12. (In Russ).

DOI: 10.21320/2500-2139-2021-14-1-1-12

ABSTRACT

Aim. To study the impact of different clinical and biological factors on sustaining molecular remission after discontinuation of tyrosine kinase inhibitors (TKI) therapy in chronic myeloid leukemia (CML) patients with a stable deep molecular response (MR).

Materials & Methods. The prospective multi-center trial on molecular remission sustainability after TKIs withdrawal, held from 2015 to 2019, enrolled 98 CML patients. The trial included patients with chronic phase CML treated with TKIs at least during 3 years and having a stable deep MR (≤ МО4; BCR-ABL < 0.01 %) during at least 2 years. Molecular monitoring was carried out every month during first 6 months after TKIs withdrawal, every 2 months during 0.5–1 year, and every 3 months after 1-year follow-up. In case of the loss of major MR (BCR-ABL > 0.1 %) therapy was reinitiated.

Results. Three-year molecular relapse-free survival was 51 % (95% confidence interval 41–61 %) in all patients, 25 % in patients with the failure of prior treatment discontinuation, and 53 % in patients who discontinued TKI therapy for the first time. According to univariate analysis, the following factors proved to be significant: persistance of deep MR, duration of therapy, and depth of MR. It was shown that TKI therapy duration, but not deep MR persistance, has independent prognostic value for the Russian population of CML patients. No significant differences were identified in 3-year molecular relapse-free survival in the groups of patients treated only with imatinib (55 %) compared with patients who received 2nd generation TKI (TKI2) as first-line (70 %; p = 0.26) and second-line (39 %; p = 0.09) therapy. However, duration of therapy in patients treated with TKI2 as first-line therapy was more than twice as short as in patients treated with imatinib as first-line therapy (median 41.5 vs. 96.4 months, respectively; p < 0.0001).

Conclusion. Longer therapy duration and MR depth (≤ MО4.5) before TKI withdrawal raise the probability of sustaining off-treatment remission. The study showed that molecular relapse-free survival does not significantly increase with the use of TKI2 as first-line treatment compared to imatinib. Nevertheless, TKI2 as first-line treatment enables to halve the duration of therapy needed to achieve comparable molecular relapse-free survival, as compared with imatinib.

Keywords: chronic myeloid leukemia, tyrosine kinase inhibitors, deep molecular response, off-treatment remission.

Received: July 30, 2020

Accepted: December 1, 2020

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REFERENCES

  1. Deininger MW, Goldman JM, Melo JV. The molecular biology of chronic myeloid leukemia. Blood. 2000;96(10):3343–56.
  2. Branford S, Kim DDH, Apperley JF, et al. Laying the foundation for genomically-based risk assessment in chronic myeloid leukemia. Leukemia. 2019;33(8):1835–50. doi: 10.1038/s41375-019-0512-y.
  3. Swerdlow SH. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press; 2017.
  4. Druker BJ, Guilhot F, O’Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355(23):2408–17. doi: 10.1056/NEJMoa062867.
  5. Saussele S, Krauss MP, Hehlmann R, et al. Impact of comorbidities on overall survival in patients with chronic myeloid leukemia: results of the randomized CML study IV. Blood. 2015;126(1):42–9. doi: 10.1182/blood-2015-01-617993.
  6. Hochhaus A, Saglio G, Hughes TP, et al. Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial. Leukemia. 2016;30(5):1044–54. doi: 10.1038/leu.2016.5.
  7. Cortes JE, Saglio G, Kantarjian HM, et al. Final 5-Year Study Results of DASISION: The Dasatinib Versus Imatinib Study in Treatment-Naive Chronic Myeloid Leukemia Patients Trial. J Clin Oncol. 2016;34(20):2333–40. doi: 10.1200/JCO.2015.64.8899.
  8. Lipton JH, Chuah C, Guerci-Bresler A, et al. Ponatinib versus imatinib for newly diagnosed chronic myeloid leukaemia: an international, randomised, open-label, phase 3 trial. Lancet Oncol. 2016;17(5):612–21. doi: 10.1016/S1470-2045(16)00080-2.
  9. Hochhaus A, Larson RA, Guilhot F, et al. Long-Term Outcomes of Imatinib Treatment for Chronic Myeloid Leukemia. N Engl J Med. 2017;376(10):917–27. doi: 10.1056/NEJMoa1609324.
  10. Goldman J, Gordon M. Why do chronic myelogenous leukemia stem cells survive allogeneic stem cell transplantation or imatinib: does it really matter?. Leuk Lymphoma. 2006;47(1):1–7. doi: 10.1080/10428190500407996.
  11. Baccarani M, Castagnetti F, Gugliotta G, et al. The proportion of different BCR-ABL1 transcript types in chronic myeloid leukemia. An international overview. Leukemia. 2019;33(5):1173–83. doi: 10.1038/s41375-018-0341-4.
  12. Hughes T, Deininger M, Hochhaus A, et al. Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood. 2006;108(1):28–37. doi: 10.1182/blood-2006-01-0092.
  13. Branford S, Seymour JF, Grigg A, et al. BCR-ABL messenger RNA levels continue to decline in patients with chronic phase chronic myeloid leukemia treated with imatinib for more than 5 years and approximately half of all first-line treated patients have stable undetectable BCR-ABL using strict sensitivity criteria. Clin Cancer Res. 2007;13(23):7080–5. doi: 10.1158/1078-0432.CCR-07-0844.
  14. Branford S, Cross NC, Hochhaus A, et al. Rationale for the recommendations for harmonizing current methodology for detecting BCR-ABL transcripts in patients with chronic myeloid leukaemia. Leukemia. 2006;20(11):1925–30. doi: 10.1038/sj.leu.2404388.
  15. Cross NC, White HE, Colomer D, et al. Laboratory recommendations for scoring deep molecular responses following treatment for chronic myeloid leukemia. Leukemia. 2015;29(5):999–1003. doi: 10.1038/leu.2015.29.
  16. Hehlmann R, Muller MC, Lauseker M, et al. Deep molecular response is reached by the majority of patients treated with imatinib, predicts survival, and is achieved more quickly by optimized high-dose imatinib: results from the randomized CML-study IV. J Clin Oncol. 2014;32(5):415–23. doi: 10.1200/JCO.2013.49.9020.
  17. Rousselot P, Huguet F, Rea D, et al. Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 years. Blood. 2007;109(1):58–60. doi: 10.1182/blood-2006-03-011239.
  18. NCCN Clinical Practice Guidelines in Oncology. Chronic Myeloid Leukemia. Version 3.2020. Available from: https://www.nccn.org/professionals/physician_gls/pdf/aml_blocks.pdf. (accessed 23.10.2020).
  19. Hochhaus A, Saussele S, Rosti G, et al. Chronic myeloid leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28(Suppl 4):iv41–iv51. doi: 10.1093/annonc/mdx219.
  20. Hughes TP, Ross DM. Moving treatment-free remission into mainstream clinical practice in CML. Blood. 2016;128(1):17–23. doi: 10.1182/blood-2016-01-694265.
  21. Mahon FX, Rea D, Guilhot J, et al. Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol. 2010;11(11):1029–35. doi: 10.1016/S1470-2045(10)70233-3.
  22. Etienne G, Guilhot J, Rea D, et al. Long-Term Follow-Up of the French Stop Imatinib (STIM1) Study in Patients With Chronic Myeloid Leukemia. J Clin Oncol. 2017;35(3):298–305. doi: 10.1200/JCO.2016.68.2914.
  23. Ross DM, Branford S, Seymour JF, et al. Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER study. Blood. 2013;122(4):515–22. doi: 10.1182/blood-2013-02-483750.
  24. Ross DM, Pagani IS, Shanmuganathan N, et al. Long-term treatment-free remission of chronic myeloid leukemia with falling levels of residual leukemic cells. Leukemia. 2018;32(12):2572–9. doi: 10.1038/s41375-018-0264-0.
  25. Rousselot P, Charbonnier A, Cony-Makhoul P, et al. Loss of major molecular response as a trigger for restarting tyrosine kinase inhibitor therapy in patients with chronic-phase chronic myelogenous leukemia who have stopped imatinib after durable undetectable disease. J Clin Oncol. 2014;32(5):424–30. doi: 10.1200/JCO.2012.48.5797.
  26. Mori S, Vagge E, le Coutre P, et al. Age and dPCR can predict relapse in CML patients who discontinued imatinib: the ISAV study. Am J Hematol. 2015;90(10):910–4. doi: 10.1002/ajh.24120.
  27. Takahashi N, Tauchi T, Kitamura K, et al. Deeper molecular response is a predictive factor for treatment-free remission after imatinib discontinuation in patients with chronic phase chronic myeloid leukemia: the JALSG-STIM213 study. Int J Hematol. 2018;107(2):185–93. doi: 10.1007/s12185-017-2334-x.
  28. Clark RE, Polydoros F, Apperley JF, et al. De-escalation of tyrosine kinase inhibitor dose in patients with chronic myeloid leukaemia with stable major molecular response (DESTINY): an interim analysis of a non-randomised, phase 2 trial. Lancet Haematol. 2017;4(7):e310–e316. doi: 10.1016/S2352-3026(17)30066-
  29. Clark RE, Polydoros F, Apperley JF, et al. De-escalation of tyrosine kinase inhibitor therapy before complete treatment discontinuation in patients with chronic myeloid leukaemia (DESTINY): a non-randomised, phase 2 trial. Lancet Haematol. 2019;6(7):e375–e383. doi: 10.1016/S2352-3026(19)30094-8.
  30. Lee SE, Choi SY, Song HY, et al. Imatinib withdrawal syndrome and longer duration of imatinib have a close association with a lower molecular relapse after treatment discontinuation: the KID study. Haematologica. 2016;101(6):717–23. doi: 10.3324/haematol.2015.139899.
  31. Saussele S, Richter J, Guilhot J, et al. Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): a prespecified interim analysis of a prospective, multicentre, non-randomised, trial. Lancet Oncol. 2018;19(6):747–57. doi: 10.1016/S1470-2045(18)30192-X.
  32. Claudiani S, Apperley JF, Gale RP, et al. E14a2 BCR-ABL1 transcript is associated with a higher rate of treatment-free remission in individuals with chronic myeloid leukemia after stopping tyrosine kinase inhibitor therapy. Haematologica. 2017;102(8):e297–e299. doi: 10.3324/haematol.2017.168740.
  33. Sokal JE, Cox EB, Baccarani M, et al. Prognostic discrimination in “good-risk” chronic granulocytic leukemia. Blood. 1984;63(4):789–99. doi: 10.1182/blood.V63.4.789.789.
  34. Nicolini FE, Dulucq S, Boureau L, et al. Evaluation of Residual Disease and TKI Duration Are Critical Predictive Factors for Molecular Recurrence after Stopping Imatinib First-line in Chronic Phase CML Patients. Clin Cancer Res. 2019;25(22):6606–13. doi: 10.1158/1078-0432.CCR-18-3373.
  35. Kumagai T, Nakaseko C, Nishiwaki K, et al. Dasatinib cessation after deep molecular response exceeding 2 years and natural killer cell transition during dasatinib consolidation. Cancer Sci. 2018;109(1):182–92. doi: 10.1111/cas.13430.
  36. Takahashi N, Nishiwaki K, Nakaseko C, et al. Treatment-free remission after two-year consolidation therapy with nilotinib in patients with chronic myeloid leukemia: STAT2 trial in Japan. Haematologica. 2018;103(11):1835–42. doi: 10.3324/haematol.2018.194894.
  37. Benjamini O, Kantarjian H, Rios MB, et al. Patient-driven discontinuation of tyrosine kinase inhibitors: single institution experience. Leuk Lymphoma. 2014;55(12):2879–86. doi: 10.3109/10428194.2013.831092.
  38. Hochhaus A, Masszi T, Giles FJ, et al. Treatment-free remission following frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the ENESTfreedom study. Leukemia. 2017;31(7):1525–31. doi: 10.1038/leu.2017.63.
  39. Ross DM, Masszi T, Casares GMT, et al. Durable treatment-free remission in patients with chronic myeloid leukemia in chronic phase following frontline nilotinib: 96-week update of the ENESTfreedom study. J Cancer Res Clin Oncol. 2018;144(5):945–54. doi: 10.1007/s00432-018-2604-x.
  40. Mahon FX, Boquimpani C, Kim DW, et al. Treatment-Free Remission After Second-Line Nilotinib Treatment in Patients With Chronic Myeloid Leukemia in Chronic Phase: Results From a Single-Group, Phase 2, Open-Label Study. Ann Intern Med. 2018;168(7):461–70. doi: 10.7326/M17-1094.
  41. Kimura S, Imagawa J, Murai K, et al. Treatment-free remission after first-line dasatinib discontinuation in patients with chronic myeloid leukaemia (first-line DADI trial): a single-arm, multicentre, phase 2 trial. Lancet Haematol. 2020;7(3):e218–e225. doi: 10.1016/S2352-3026(19)30235-2.
  42. Imagawa J, Tanaka H, Okada M, et al. Discontinuation of dasatinib in patients with chronic myeloid leukaemia who have maintained deep molecular response for longer than 1 year (DADI trial): a multicentre phase 2 trial. Lancet Haematol. 2015;2(12):e528–e535. doi: 10.1016/s2352-3026(15)00196-9.
  43. Okada M, Imagawa J, Tanaka H, et al. Final 3-year Results of the Dasatinib Discontinuation Trial in Patients With Chronic Myeloid Leukemia Who Received Dasatinib as a Second-line Treatment. Clin Lymphoma Myel Leuk. 2018;18(5):353–60.e1. doi: 10.1016/j.clml.2018.03.004.
  44. Rea D, Nicolini FE, Tulliez M, et al. Discontinuation of dasatinib or nilotinib in chronic myeloid leukemia: interim analysis of the STOP 2G-TKI study. Blood. 2017;129(7):846–54. doi: 10.1182/blood-2016-09-742205.
  45. Baccarani M, Saglio G, Goldman J, et al. Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2006;108(6):1809–20. doi: 10.1182/blood-2006-02-005686.
  46. Baccarani M, Cortes J, Pane F, et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol. 2009;27(35):6041–51. doi: 10.1200/JCO.2009.25.0779.
  47. Baccarani M, Deininger MW, Rosti G, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013;122(6):872–84. doi: 10.1182/blood-2013-05-501569.
  48. Radich JP, Hochhaus A, Giles FJ, et al. Analyses of Predictors of Durable Treatment-Free Remission in Patients with Chronic Myeloid Leukemia in Chronic Phase Following Frontline or Second-Line Nilotinib. 2019;134(Suppl_1):2932. doi: 10.1182/blood-2019-129393.
  49. D’Adda M, Farina M, Schieppati F, et al. The e13a2 BCR-ABL transcript negatively affects sustained deep molecular response and the achievement of treatment-free remission in patients with chronic myeloid leukemia who receive tyrosine kinase inhibitors. Cancer. 2019;125(10):1674–82. doi: 10.1002/cncr.31977.
  50. Legros L, Nicolini FE, Etienne G, et al. Second tyrosine kinase inhibitor discontinuation attempt in patients with chronic myeloid leukemia. Cancer. 2017;123(22):4403–10. doi: 10.1002/cncr.30885.
  51. Shih YT, Cortes JE, Kantarjian HM. Treatment value of second-generation BCR-ABL1 tyrosine kinase inhibitors compared with imatinib to achieve treatment-free remission in patients with chronic myeloid leukaemia: a modelling study. Lancet Haematol. 2019;6(8):e398–e408. doi: 10.1016/S2352-3026(19)30087-0.
  52. Шуваев В.А., Абдулкадыров К.М., МартынкевичИ.С., Фоминых М.С. Выбор терапии первой линии хронического миелолейкоза: моделирование клинико-экономических факторов. Клиническая онкогематология. 2015;8(1):78–83. doi: 10.21320/2500-2139-2015-8-1-78-83.
    [Shuvaev VA, Abdulkadyrov KM, Martynkevich IS, Fominykh MS. First Line Treatment Choice for Chronic Myelogenous Leukemia: Modeling of Clinical and Economic Factors. Clinical oncohematology. 2015;8(1):78–83. doi: 10.21320/2500-2139-2015-8-1-78-83. (In Russ)]
  53. Рубрикатор клинических рекомендаций. Хронический миелолейкоз [электронный документ]. Доступно по: http://cr.rosminzdrav.ru/#!/recomend/120. Ссылка активна на 23.10.2020.
    [List of clinical guidelines. Chronic myeloid leukemia. [Internet] Available from: http://cr.rosminzdrav.ru/#!/recomend/120. (accessed 10.2020) (In Russ)]
  54. Hochhaus A, Baccarani M, Silver RT, et al. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia. 2020;34(4):966–84. doi: 10.1038/s41375-020-0776-