Treatment-Free Remission in Chronic Myeloid Leukaemia: Can We Identify Prognostic Factors?

Myeloid Leukaemia ◽

Kinase Inhibitors ◽

Chronic Phase ◽

Molecular Response ◽

Predicting Success ◽

Almost All ◽

Following the development of tyrosine kinase inhibitors (TKI), the survival of patients with chronic myeloid leukaemia (CML) drastically improved. With the introduction of these agents, CML is now considered a chronic disease, for some patients. Taking into consideration the side effects, toxicity, and high cost, discontinuing TKIs became a goal for patients with chronic phase CML. Patients who achieved deep molecular response (DMR) and discontinued TKI, remained in treatment-free remission (TFR). Currently, the data from the published literature demonstrate that 40-60% of patients achieve TFR, with relapses occurring within the first six months. In addition, almost all patients who relapsed regained a molecular response upon re-treatment, indicating TKI discontinuation is safe. However, there is still a gap in the understanding the mechanisms behind TFR, and whether there are prognostic factors that can predict the best candidates who qualify for TKI discontinuation with a view to keeping them in TFR. Furthermore, the information about a second TFR attempt and the role of gradual de-escalation of TKI before complete cessation is limited. This review highlights the factors predicting success or failure of TFR. In addition, it ex-amines the feasibility of a second TFR attempt after the failure of the first one, and the current guidelines concerning TFR in clinical practice.

Treatment-Free Remission in Chronic Myeloid Leukemia: Can We Identify Prognostic Factors?

Cancers ◽

10.3390/cancers13164175 ◽

2021 ◽

Vol 13 (16) ◽

pp. 4175

Author(s):

Hilbeen Hisham Saifullah ◽

Claire Marie Lucas

Keyword(s):

Prognostic Factors ◽

Kinase Inhibitors ◽

Chronic Phase ◽

Molecular Response ◽

Predicting Success ◽

Almost All ◽

Current Guidelines ◽

Following the development of tyrosine kinase inhibitors (TKI), the survival of patients with chronic myeloid leukaemia (CML) drastically improved. With the introduction of these agents, CML is now considered a chronic disease for some patients. Taking into consideration the side effects, toxicity, and high cost, discontinuing TKI became a goal for patients with chronic phase CML. Patients who achieved deep molecular response (DMR) and discontinued TKI, remained in treatment-free remission (TFR). Currently, the data from the published literature demonstrate that 40–60% of patients achieve TFR, with relapses occurring within the first six months. In addition, almost all patients who relapsed regained a molecular response upon retreatment, indicating TKI discontinuation is safe. However, there is still a gap in understanding the mechanisms behind TFR, and whether there are prognostic factors that can predict the best candidates who qualify for TKI discontinuation with a view to keeping them in TFR. Furthermore, the information about a second TFR attempt and the role of gradual de-escalation of TKI before complete cessation is limited. This review highlights the factors predicting success or failure of TFR. In addition, it examines the feasibility of a second TFR attempt after the failure of the first one, and the current guidelines concerning TFR in clinical practice.

Incidences of Deep Molecular Responses and Treatment-Free Remission in de Novo CP-CML Patients

Cancers ◽

10.3390/cancers12092521 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2521

Author(s):

Gabriel Etienne ◽

Stéphanie Dulucq ◽

Fréderic Bauduer ◽

Didier Adiko ◽

François Lifermann ◽

...

Keyword(s):

Kinase Inhibitors ◽

De Novo ◽

Chronic Phase ◽

Risk Scores ◽

Prolonged Treatment ◽

Molecular Response ◽

First Line ◽

Background: Tyrosine Kinase Inhibitors (TKIs) discontinuation in patients who had achieved a deep molecular response (DMR) offer now the opportunity of prolonged treatment-free remission (TFR). Patients and Methods: Aims of this study were to evaluate the proportion of de novo chronic-phase chronic myeloid leukemia (CP-CML) patients who achieved a sustained DMR and to identify predictive factors of DMR and molecular recurrence-free survival (MRFS) after TKI discontinuation. Results: Over a period of 10 years, 398 CP-CML patients treated with first-line TKIs were included. Median age at diagnosis was 61 years, 291 (73%) and 107 (27%) patients were treated with frontline imatinib (IMA) or second- or third-generation TKIs (2–3G TKI), respectively. With a median follow-up of seven years (range, 0.6 to 13.8 years), 182 (46%) patients achieved a sustained DMR at least 24 months. Gender, BCR-ABL1 transcript type, and Sokal and ELTS risk scores were significantly associated with a higher probability of sustained DMR while TKI first-line (IMA vs. 2–3G TKI) was not. We estimate that 28% of CML-CP would have been an optimal candidate for TKI discontinuation according to recent recommendations. Finally, 95 (24%) patients have entered in a TFR program. MRFS rates at 12 and 48 months were 55.1% (95% CI, 44.3% to 65.9%) and 46.9% (95% CI, 34.9% to 58.9%), respectively. In multivariate analyses, first-line 2–3G TKIs compared to IMA and TKI duration were the most significant factors of MRFS. Conclusions: Our results suggest that frontline TKIs have a significant impact on TFR in patients who fulfill the selection criteria for TKI discontinuation.

Expert Opinion on the Treatment of Refractory Chronic Phase Chronic Myeloid Leukaemia

European Oncology & Haematology ◽

10.17925/eoh.2017.13.01.17 ◽

2017 ◽

Vol 13 (01) ◽

pp. 17

Author(s):

Tim Hughes ◽

Giuseppe Saglio ◽

◽

Keyword(s):

Myeloid Leukaemia ◽

Second Generation ◽

Kinase Inhibitors ◽

Chronic Phase ◽

Molecular Response ◽

Line Treatment ◽

T315i Mutation ◽

Third Line ◽

Third Line Treatment

The development and clinical availability of second-generation tyrosine kinase inhibitors (TKIs) for the treatment of patients who discontinue imatinib therapy has further improved the outlook for patients with chronic phase chronic myeloid leukaemia (CP-CML). There is, however, uncertainty surrounding how best to treat patients after failing second-generation TKIs. A three-section questionnaire was devised by chronic myeloid leukaemia experts to address questions surrounding this issue. Responses were received from 14 out of 34 experts (41.2%). Generally, a reasonable consensus was found among the responses for most issues. There was a complete consensus that ponatinib was suitable for all patients carrying the T315I mutation regardless of the molecular response to prior treatment. There was also complete consensus that allografting is appropriate in any patient who has had blast crises and is back in a second chronic phase. More recommendations for third-line treatment of CP-CML patients are necessary.

Treatment-free remission in CML: who, how, and why?

Hematology ◽

10.1182/asheducation.v2017.1.102.00014 ◽

2017 ◽

Vol 2017 (1) ◽

pp. 102-109 ◽

Cited By ~ 5

Author(s):

Francois-Xavier Mahon

Keyword(s):

Clinical Trials ◽

Myeloid Leukemia ◽

Kinase Inhibitors ◽

Chronic Phase ◽

Healthy Population ◽

Molecular Response ◽

Abstract Chronic myeloid leukemia (CML) is the best example of successful targeted therapy. Today, the overall survival of patients with CML treated by using tyrosine kinase inhibitors (TKIs) is very close to that of the healthy population. The current question is: how can we further ameliorate the clinical outcome of patients with CML? Clinical trials have shown that some patients with CML in the chronic phase who achieve sustained deep molecular responses on TKI therapy can safely suspend therapy with no evidence of relapse. The long follow-up studies and the number of eligible patients have now validated the concept of treatment-free remission (ie, the ability to maintain a molecular response after stopping therapy). It should be considered as the future criterion to evaluate the success of clinical trials, especially if we want to take into account the quality of life of patients in addition to the economic aspect. Because post-TKI discontinuation follow-ups have been increasing over time with no evidence of relapse in some patients, the next step for the coming decade will be to address the topic of CML cure.

Comparison of Response to Treatment with Imatinib Versus Nilotinib in the Initial Three Months in Chronic Myeloid Leukaemia

Journal of Evidence Based Medicine and Healthcare ◽

10.18410/jebmh/2021/376 ◽

2021 ◽

Vol 8 (24) ◽

pp. 2001-2005

Author(s):

Irom Anil Singh ◽

Aditi Jain ◽

Pukhrambam Vedanti Devi ◽

Tombing Niangneihching

Keyword(s):

Myeloid Leukaemia ◽

Kinase Inhibitors ◽

Chronic Phase ◽

Response To Treatment ◽

P Value ◽

Molecular Response ◽

Optimal Response ◽

Potent Drug

BACKGROUND Chronic myeloid leukemia (CML) accounts for 15 - 20 % of leukemia in adults worldwide. At present, the three tyrosine kinase inhibitors (TKI) imatinib, dasatinib, or nilotinib are accepted as the standard first-line treatment in chronic phase (CP). Nilotinib is a second generation TKI having faster and deeper response compared to imatinib. We wanted to see if the response achieved with nilotinib in the first three months could be translated into long term benefits when imatinib was given after 3 months. METHODS Newly diagnosed CML-CP patients were randomized into two arms. The patients on the first arm were given imatinib and in the second arm nilotinib was given for first 3 months. After three months nilotinib was switched over to imatinib. The molecular response was assessed in both arms at 3 months and 6 months. RESULTS Twenty-six patients in each arm were analysed. The optimal molecular response (QPCR <10 %) after 3 months was significantly higher in patients receiving nilotinib than imatinib (96.1 % vs 65.38 %; P < 0.0048). The optimal response after 6 months (QPCR < 1 %) was found to be more in the initial nilotinib arm than the initial imatinib arm (76.9 % vs 65.3 %; P - value = 0.35). CONCLUSIONS Patients on nilotinib arm did well even after switching to imatinib. It gives us an important platform for an economically backward country like India where the therapy with more potent drug like nilotinib is given in the initial three months or even six months. KEYWORDS Chronic Myeloid Leukaemia, Imatinib, Nilotinib, Optimal Response, Major Molecular Response

Treatment-free remission in CML: who, how, and why?

Hematology ◽

10.1182/asheducation-2017.1.102 ◽

2017 ◽

Vol 2017 (1) ◽

pp. 102-109 ◽

Cited By ~ 21

Author(s):

Francois-Xavier Mahon

Keyword(s):

Clinical Trials ◽

Myeloid Leukemia ◽

Kinase Inhibitors ◽

Chronic Phase ◽

Healthy Population ◽

Molecular Response ◽

Chronic myeloid leukemia (CML) is the best example of successful targeted therapy. Today, the overall survival of patients with CML treated by using tyrosine kinase inhibitors (TKIs) is very close to that of the healthy population. The current question is: how can we further ameliorate the clinical outcome of patients with CML? Clinical trials have shown that some patients with CML in the chronic phase who achieve sustained deep molecular responses on TKI therapy can safely suspend therapy with no evidence of relapse. The long follow-up studies and the number of eligible patients have now validated the concept of treatment-free remission (ie, the ability to maintain a molecular response after stopping therapy). It should be considered as the future criterion to evaluate the success of clinical trials, especially if we want to take into account the quality of life of patients in addition to the economic aspect. Because post-TKI discontinuation follow-ups have been increasing over time with no evidence of relapse in some patients, the next step for the coming decade will be to address the topic of CML cure.

Interruption or Discontinuation of Tyrosine Kinase Inhibitor Treatment in Chronic Myeloid Leukaemia: A Retrospective Cohort Study (SPARKLE) in Belgium

Acta Haematologica ◽

10.1159/000499329 ◽

2019 ◽

Vol 142 (4) ◽

pp. 197-207 ◽

Cited By ~ 3

Author(s):

Timothy Devos ◽

Gregor Verhoef ◽

Eva Steel ◽

Dominiek Mazure ◽

Philippe Lewalle ◽

...

Keyword(s):

Side Effects ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitor ◽

Myeloid Leukaemia ◽

Kinase Inhibitor ◽

Chronic Phase ◽

Molecular Response ◽

Tki Treatment

Objectives: To assess interruptions/discontinuations of tyrosine kinase inhibitor (TKI) treatment in Belgian patients with chronic myeloid leukaemia (CML). Methods: This retrospective study included patients with TKI interruptions/discontinuations of ≥4 continuous weeks (no clinical trial context) between May 2013 and May 2016. Data collection took place between October 2016 and February 2017. Results: All 60 participants (69 interruptions/discontinuations) had chronic-phase CML and 75% had at least a major molecular response (≥MMR) at interruption/discontinuation. Most interruptions/discontinuations occurred while on imatinib (36/69; 49%) and dasatinib (20/69; 29%). Most interruptions/discontinuations occurred due to side effects/intolerance (46/69; 67%); other reasons included a wish to conceive (6/69; 9%) and attempts to achieve treatment-free remission (TFR) (6/69; 9%). Interruptions due to side effects occurred later for imatinib- or dasatinib-treated patients than for those on nilotinib or ponatinib. Treatment was re-initiated in 62% (43/69) of cases. Most interruptions caused by side effects/intolerance were followed by treatment changes. All 4 patients with ≥MR 4.5 at interruption/discontinuation and ≥11-month follow-up who had not restarted treatment maintained the response. Conclusion: Although TKIs are used for long-term CML treatment, physicians sometimes recommend interruptions/discontinuations. In this study, interruptions/discontinuations were mainly caused by side effects or intolerance, rather than TFR attempts.

Clonal evolution and clinical implications of genetic abnormalities in blastic transformation of chronic myeloid leukaemia

Nature Communications ◽

10.1038/s41467-021-23097-w ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Yotaro Ochi ◽

Kenichi Yoshida ◽

Ying-Jung Huang ◽

Ming-Chung Kuo ◽

Yasuhito Nannya ◽

...

Keyword(s):

Myeloid Leukaemia ◽

Kinase Inhibitors ◽

Blast Crisis ◽

Clonal Evolution ◽

Chronic Phase ◽

Genetic Alterations ◽

Prognostic Impact ◽

Genetic Abnormalities ◽

Prior Use

AbstractBlast crisis (BC) predicts dismal outcomes in patients with chronic myeloid leukaemia (CML). Although additional genetic alterations play a central role in BC, the landscape and prognostic impact of these alterations remain elusive. Here, we comprehensively investigate genetic abnormalities in 136 BC and 148 chronic phase (CP) samples obtained from 216 CML patients using exome and targeted sequencing. One or more genetic abnormalities are found in 126 (92.6%) out of the 136 BC patients, including the RUNX1-ETS2 fusion and NBEAL2 mutations. The number of genetic alterations increase during the transition from CP to BC, which is markedly suppressed by tyrosine kinase inhibitors (TKIs). The lineage of the BC and prior use of TKIs correlate with distinct molecular profiles. Notably, genetic alterations, rather than clinical variables, contribute to a better prediction of BC prognosis. In conclusion, genetic abnormalities can help predict clinical outcomes and can guide clinical decisions in CML.