Significance of deeper molecular responses in patients with chronic myeloid leukemia in early chronic phase treated with tyrosine kinase inhibitors
Lorenzo Falchi, Hagop M Kantarjian, Xuemei Wang, Dushyant Verma, Alfonso Quintás-Cardama, Susan O'Brien, Elias J Jabbour, Farhad Ravandi-Kashani, Gautam Borthakur, Guillermo Garcia-Manero, Srdan Verstovsek, Jan A Burger, Raja Luthra, Jorge E Cortes, Lorenzo Falchi, Hagop M Kantarjian, Xuemei Wang, Dushyant Verma, Alfonso Quintás-Cardama, Susan O'Brien, Elias J Jabbour, Farhad Ravandi-Kashani, Gautam Borthakur, Guillermo Garcia-Manero, Srdan Verstovsek, Jan A Burger, Raja Luthra, Jorge E Cortes
Abstract
Most patients with chronic myeloid leukemia (CML) in chronic phase (CP) treated with tyrosine kinase inhibitors (TKI) achieve complete cytogenetic response (CCyR). An increasing number of patients also achieve deep molecular responses (MR). We determined the frequency and significance of deep MR after TKI therapy for CML in CP. MR included: major molecular response (MMR), MR4, MR4.5, and undetectable transcripts (UND), i.e., BCR-ABL/ABL of ≤0.1, ≤0.01, ≤0.0032%, and undetectable transcripts, respectively. Four hundred eighty-three patients received imatinib 400 mg/day (IM400, 71, July 2000 to April 2001), imatinib 800 mg/day (IM800, 204, June 2001 to July 2005), nilotinib (106, July 2005 to date), or dasatinib (102, November 2005 to date). UND rates at 36 months were 18.1, 30.6, 29.2, and 28.6%, respectively. Patients achieving UND have superior transformation-free survival (TFS) and overall survival (OS) versus those obtaining ≤MMR, but not other MR levels. At the 18- and 24-month landmark analysis, patients achieving UND have no advantage in TFS and OS compared to those achieving a lesser degree of MR. Among patients achieving MR4.5, those who maintain it for ≥2 years (susMR4·5) have no additional benefit in TFS or OS. Most patients with early CP CML receiving TKI achieve MMR. BCR-ABL transcripts become undetectable in a significant fraction of them. Deeper MR at 18 or 24 months are not associated with a benefit in TFS or OS. Furthermore, achieving susMR4·5 does not appear to further reduce the risk of transformation or death.
Conflict of interest statement
Disclosure of Conflicts of Interest: H.K.M. has received research funding from Bristol-Myers Squibb, Ariad, Pfizer, and Novartis. E.J.J. has received honoraria from Pfizer, Novartis, and Bristol-Myers Squibb. F.R. has received research funding from Bristol-Myers-Squibb and has received honoraria from Bristol-Myers Squibb, Novartis, and Pfizer. J.E.C.: is consultant for Ariad, Pfizer, and Teva and has received research funding from Ariad, Bristol-Myers Squibb, Novartis, Chemgenex, and Pfizer. L.F., X.W., D.V., S.O., G.B., A.Q., G.G., S.V., and J.A.B. declare no conflicts of interest.
Copyright © 2013 Wiley Periodicals, Inc.
Figures
![Figure 1](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3849405/bin/nihms528426f1a.jpg)
![Figure 1](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3849405/bin/nihms528426f1b.jpg)
![Figure 1](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3849405/bin/nihms528426f1c.jpg)
![Figure 1](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3849405/bin/nihms528426f1d.jpg)
![Figure 2](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3849405/bin/nihms528426f2a.jpg)
Figure 2
TFS (A), and OS (B)…
Figure 2
TFS (A), and OS (B) according to different levels of molecular response in…
Figure 3
Landmark analysis at 18 and…
Figure 3
Landmark analysis at 18 and 24 months for TFS (A and B) and…
Figure 3
Landmark analysis at 18 and…
Figure 3
Landmark analysis at 18 and 24 months for TFS (A and B) and…
Figure 3
Landmark analysis at 18 and…
Figure 3
Landmark analysis at 18 and 24 months for TFS (A and B) and…
Figure 3
Landmark analysis at 18 and…
Figure 3
Landmark analysis at 18 and 24 months for TFS (A and B) and…
Figure 4
TFS (A) and OS (B)…
Figure 4
TFS (A) and OS (B) of patients with susMR4.5 compared to those with…
Figure 4
TFS (A) and OS (B)…
Figure 4
TFS (A) and OS (B) of patients with susMR4.5 compared to those with…
- BCR-ABL1 transcript at 3 months predicts long-term outcomes following second generation tyrosine kinase inhibitor therapy in the patients with chronic myeloid leukaemia in chronic phase who failed Imatinib.Kim DD, Lee H, Kamel-Reid S, Lipton JH. Kim DD, et al. Br J Haematol. 2013 Mar;160(5):630-9. doi: 10.1111/bjh.12187. Epub 2012 Dec 24. Br J Haematol. 2013. PMID: 23278256
- Frequency of ABL gene mutations in chronic myeloid leukemia patients resistant to imatinib and results of treatment switch to second-generation tyrosine kinase inhibitors.Marcé S, Zamora L, Cabezón M, Xicoy B, Boqué C, Fernández C, Grau J, Navarro JT, Fernández de Sevilla A, Ribera JM, Feliu E, Millá F; Grupo ICO de estudio de mutaciones de ABL en pacientes afectos de LMC. Marcé S, et al. Med Clin (Barc). 2013 Aug 4;141(3):95-9. doi: 10.1016/j.medcli.2012.10.028. Epub 2013 Feb 22. Med Clin (Barc). 2013. PMID: 23433665
- Efficacy and safety of dasatinib versus imatinib in Japanese patients with newly diagnosed chronic-phase chronic myeloid leukemia (CML-CP): Subset analysis of the DASISION trial with 2-year follow-up.Fujisawa S, Nakamae H, Ogura M, Ishizawa K, Taniwaki M, Utsunomiya A, Matsue K, Takamatsu Y, Usuki K, Tanimoto M, Ishida Y, Akiyama H, Onishi S. Fujisawa S, et al. Int J Hematol. 2014 Feb;99(2):141-53. doi: 10.1007/s12185-013-1470-1. Epub 2013 Dec 20. Int J Hematol. 2014. PMID: 24357015 Clinical Trial.
- Dasatinib-associated major molecular responses in patients with chronic myeloid leukemia in chronic phase following imatinib failure: response dynamics and predictive value.Hochhaus A, Müller MC, Radich J, Branford S, Kantarjian HM, Hanfstein B, Rousselot P, Kim DW, Lipton JH, Bleickardt E, Lambert A, Hughes TP. Hochhaus A, et al. Leukemia. 2009 Sep;23(9):1628-33. doi: 10.1038/leu.2009.156. Epub 2009 Jul 30. Leukemia. 2009. PMID: 19641527
- Response dynamics in chronic-phase chronic myeloid leukemia.Mauro MJ. Mauro MJ. Clin Lymphoma Myeloma. 2009 Jun;9(3):217-22. doi: 10.3816/CLM.2009.n.043. Clin Lymphoma Myeloma. 2009. PMID: 19525190 Review.
- Asciminib monotherapy in patients with CML-CP without BCR::ABL1 T315I mutations treated with at least two prior TKIs: 4-year phase 1 safety and efficacy results.Mauro MJ, Hughes TP, Kim DW, Rea D, Cortes JE, Hochhaus A, Sasaki K, Breccia M, Talpaz M, Ottmann O, Minami H, Goh YT, DeAngelo DJ, Heinrich MC, Gómez-García de Soria V, le Coutre P, Mahon FX, Janssen JJWM, Deininger M, Shanmuganathan N, Geyer MB, Cacciatore S, Polydoros F, Agrawal N, Hoch M, Lang F. Mauro MJ, et al. Leukemia. 2023 Mar 22. doi: 10.1038/s41375-023-01860-w. Online ahead of print. Leukemia. 2023. PMID: 36949155
- Leukemia Stem Cells as a Potential Target to Achieve Therapy-Free Remission in Chronic Myeloid Leukemia.Ito K, Ito K. Ito K, et al. Cancers (Basel). 2021 Nov 20;13(22):5822. doi: 10.3390/cancers13225822. Cancers (Basel). 2021. PMID: 34830976 Free PMC article. Review.
- Treatment-Free Remission in Chronic Myeloid Leukemia: Can We Identify Prognostic Factors?Saifullah HH, Lucas CM. Saifullah HH, et al. Cancers (Basel). 2021 Aug 19;13(16):4175. doi: 10.3390/cancers13164175. Cancers (Basel). 2021. PMID: 34439327 Free PMC article. Review.
- Targeting Leukemic Stem Cells in Chronic Myeloid Leukemia: Is It Worth the Effort?Soverini S, De Santis S, Monaldi C, Bruno S, Mancini M. Soverini S, et al. Int J Mol Sci. 2021 Jun 30;22(13):7093. doi: 10.3390/ijms22137093. Int J Mol Sci. 2021. PMID: 34209376 Free PMC article. Review.
- Treatment-free remission in patients with chronic myeloid leukaemia.Ross DM, Hughes TP. Ross DM, et al. Nat Rev Clin Oncol. 2020 Aug;17(8):493-503. doi: 10.1038/s41571-020-0367-1. Epub 2020 May 6. Nat Rev Clin Oncol. 2020. PMID: 32377005 Review.
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Antineoplastic Agents / pharmacology
- Antineoplastic Agents / therapeutic use*
- Benzamides / pharmacology
- Benzamides / therapeutic use
- Biomarkers, Tumor
- Dasatinib
- Disease-Free Survival
- Female
- Fusion Proteins, bcr-abl / antagonists & inhibitors*
- Fusion Proteins, bcr-abl / blood
- Fusion Proteins, bcr-abl / genetics
- Humans
- Imatinib Mesylate
- Leukemia, Myeloid, Chronic-Phase / blood
- Leukemia, Myeloid, Chronic-Phase / drug therapy*
- Leukemia, Myeloid, Chronic-Phase / genetics
- Male
- Middle Aged
- Neoplasm Proteins / antagonists & inhibitors*
- Neoplasm Proteins / blood
- Neoplasm Proteins / genetics
- Piperazines / pharmacology
- Piperazines / therapeutic use
- Protein Kinase Inhibitors / pharmacology
- Protein Kinase Inhibitors / therapeutic use*
- Pyrimidines / pharmacology
- Pyrimidines / therapeutic use
- RNA, Messenger / blood
- RNA, Neoplasm / blood
- Real-Time Polymerase Chain Reaction
- Survival Analysis
- Thiazoles / pharmacology
- Thiazoles / therapeutic use
- Treatment Outcome
- Young Adult
- Antineoplastic Agents
- BCR-ABL1 fusion protein, human
- Benzamides
- Biomarkers, Tumor
- Neoplasm Proteins
- Piperazines
- Protein Kinase Inhibitors
- Pyrimidines
- RNA, Messenger
- RNA, Neoplasm
- Thiazoles
- Imatinib Mesylate
- Fusion Proteins, bcr-abl
- nilotinib
- Dasatinib
- Full Text Sources
- Other Literature Sources
- Medical
- Miscellaneous
![Figure 2](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3849405/bin/nihms528426f2b.jpg)
Figure 3
Landmark analysis at 18 and…
Figure 3
Landmark analysis at 18 and 24 months for TFS (A and B) and…
Figure 3
Landmark analysis at 18 and…
Figure 3
Landmark analysis at 18 and 24 months for TFS (A and B) and…
Figure 3
Landmark analysis at 18 and…
Figure 3
Landmark analysis at 18 and 24 months for TFS (A and B) and…
Figure 3
Landmark analysis at 18 and…
Figure 3
Landmark analysis at 18 and 24 months for TFS (A and B) and…
Figure 4
TFS (A) and OS (B)…
Figure 4
TFS (A) and OS (B) of patients with susMR4.5 compared to those with…
Figure 4
TFS (A) and OS (B)…
Figure 4
TFS (A) and OS (B) of patients with susMR4.5 compared to those with…
![Figure 3](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3849405/bin/nihms528426f3a.jpg)
![Figure 3](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3849405/bin/nihms528426f3b.jpg)
![Figure 3](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3849405/bin/nihms528426f3c.jpg)
![Figure 3](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3849405/bin/nihms528426f3d.jpg)
![Figure 4](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3849405/bin/nihms528426f4a.jpg)
![Figure 4](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3849405/bin/nihms528426f4b.jpg)
Source: PubMed