The Depth Of ‘Complete’ Molecular Response Predicts Molecular Relapse In Chronic Myeloid Leukaemia Patients On Tyrosine Kinase Inhibitor Therapy

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5201-5201
Author(s):  
Heledd Thomas ◽  
Jane F Apperley ◽  
Richard M Szydlo ◽  
Gareth Gerrard ◽  
David Marin ◽  
...  
Keyword(s):  
Chronic Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Kinase Inhibitor ◽  
Stringent Response ◽  
Molecular Response ◽  
Control Value ◽  
Kaplan Meier ◽  
Universal Definition ◽  
Definition Of ◽  
Complete Molecular Response

Abstract Background There is currently no universal definition of complete molecular response (CMR) in chronic myeloid leukaemia (CML). This has implications for studies of TKI withdrawal as CMR is the main criterion for entry into these trials. We aimed to assess the proportion of patients in our practice who achieved CMR by a variety of definitions. We hoped to identify a definition that was predictive of sustained CMR and could therefore be recommended to predict those patients who might be able to stop treatment in the longer term. Methods We conducted a retrospective analysis of a comprehensive CML database of serial RT-qPCR results of 215 patients achieving deep molecular responses on TKI therapy. The least stringent definition of CMR was defined as BCR-ABL1 transcripts <11 and ABL1 control value (CV)>10,000. The depth of CMR was categorised according to transcript number and CV. Probability of molecular relapse according to depth of CMR at 2 and 5 years from initial CMR (ICMR) was estimated using the Kaplan Meier method. Results Patients with 6-10 transcripts (any CV) were most likely to lose CMR by 2 years (86.4%) while patients with 0 transcripts (any CV) were least likely to do so (7.6%). There was no difference in the probability of molecular relapse between patients with 1-5 transcripts (CV>32,000) and those with 0 transcripts (any CV) (RR at 2 years=1 p=0.945, RR at 5 years=3.7 p = 0.114). Conclusion Depth of CMR predicts molecular relapse at 2 and 5 years from ICMR. CMR4.5 (<6 transcripts) is the least stringent response that is required to sustain CMR. Patients with <6 transcripts (CV>32,000) are equally as likely to sustain CMR as patients with 0 transcripts up to 5 years from ICMR. These patients may be suitable for a stopping trial. Disclosures: Apperley: Ariad: Honoraria; Bristol Myers Squibb: Honoraria; Novartis: Honoraria, Research Funding; Pfizer: Honoraria. Milojkovic:BMS: Honoraria; Pfizer: Honoraria; Ariad: Honoraria; Novartis: Honoraria.

scholarly journals PF-114: A 4th Generation Tyrosine Kinase-Inhibitor for Chronic Phase Chronic Myeloid Leukaemia Including BCRABL1T315I

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1638-1638 ◽  
Author(s):  
Anna G. Turkina ◽  
Olga Vinogradova ◽  
Elza Lomaia ◽  
Evgeniya Shatokhina ◽  
Oleg A. Shukhov ◽  
...  
Keyword(s):  
Adverse Events ◽  
Chronic Myeloid Leukaemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Myeloid Leukaemia ◽  
Research Funding ◽  
Kinase Inhibitor ◽  
Molecular Response ◽  
Travel Grant ◽  
Grade 3

Background: PF-114 is a 4th-generation oral tyrosine kinase-inhibitor (TKI) active against wild-type and mutated BCR-ABL1 isoforms including BCR-ABL1T315I. We present data from a phase-1 study in patients with chronic or accelerated phase chronic myeloid leukaemia (CML) failing ≥2 TKIs or with BCR-ABL1T315I (NCT02885766) with ≥6 months therapy. Methods: 3+3 dose-escalation study to determine maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). Secondary objectives included safety and efficacy based on haematological, cytogenetic, and molecular criteria. Adverse events (AEs) were graded using NCI-CTCAE v4.03. Results: 51 patients were enrolled. Daily doses were 50 mg (n=3), 100 mg (n=3), 200 mg (n=9), 300 mg (n=11), 400 mg (n=12), 500 mg (n=3), 600 mg (n=6), 750 mg (n=4) given continuously. Median age was 50 years (range, 29-82 years). Median CML duration pre-study was 10 years (range, 0.3-23 years). All patients had baseline ECOG performance scores 0-1. Twelve patients had BCR-ABL1T315I. Patients were heavily pre-treated: 25 received ≥3 prior TKIs; 5 patients with BCR-ABL1T315I received 1 prior TKI. Interim analysis was conducted at follow-up of ≥6 months (cut-off date January 16th 2019). Therapy was ongoing in 17 patients at doses 200 mg (n=4), 300 mg (n=9), 400 mg (n=3) and 600 mg (n=1) with median duration of exposure of 7,4 (range, 4,6-26), 9,2 (range, 7,4-26), 9,2 (range, 8,3-9,2) and 9,2 months. Other patients discontinued because of progression (n=18), adverse events (n=6), consent withdrawal (n=4), participation in another study (n=3) or other reasons (n=3). The MTD was 600 mg with the grade-3 psoriasis-like skin lesions the DLT, which occurred during the first 28 days of treatment. Reversible grade-3 skin toxicity occurred in 11 patients at doses ≥400 mg. There were no other drug-related non-hematologic grade-3 toxicities except 1 grade-3 toxic hepatitis at 400 mg and there were no detectable effects on ankle-brachial index or vascular occlusive events. The best safety/efficacy dose was 300 mg/d with 6 of 11 patients achieving a major cytogenetic response (MCyR) and 4 of them - a major molecular response (MMR). Higher doses were less effective probably because of toxicity-related therapy interruptions and discontinuations. Five of 12 patients with BCR-ABL1T315I responded, 3 of which achieved a complete hematologic response and 4 achieved MCyR. Conclusion: PF-114 was safe and effective in patients with CML failing ≥2 TKIs or with BCR-ABL1T315I. The most effective dose was 300 mg/d. Five of 12 patients with BCR-ABL1T315I responded. A pivotal study is beginning. Disclosures Turkina: Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy; fusion pharma: Consultancy; Novartis: Consultancy, Speakers Bureau. Vinogradova:Novartis: Consultancy; Fusion Pharma: Consultancy. Lomaia:Novartis: Other: Travel Grant;Lecture fee; Pfizer: Other: Travel Grant. Shukhov:Pfizer: Consultancy; Novartis: Consultancy. Chelysheva:Novartis: Consultancy, Honoraria; Fusion Pharma: Consultancy. Shikhbabaeva:Novartis: Consultancy; Fusion Pharma: Consultancy. Shuvaev:Fusion Pharma: Consultancy; Novartis: Consultancy; Pfize: Honoraria; BMS: Consultancy. Cortes:Pfizer: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; Immunogen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; BiolineRx: Consultancy; Sun Pharma: Research Funding; Merus: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding. Baccarani:Novartis: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Takeda: Consultancy. Ottmann:Roche: Honoraria; Pfizer: Honoraria; Fusion Pharma: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Celgene: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Mikhailov:Fusion Pharma: Employment. Novikov:Fusion Pharma: Employment. Shulgina:Fusion Pharma: Employment. Chilov:Fusion Pharma: Consultancy.

The Majority of Chronic Myeloid Leukaemia Patients Who Cease Imatinib after Achieving a Sustained Complete Molecular Response (CMR) Remain in CMR, and Any Relapses Occur Early.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1102-1102 ◽  
Author(s):  
Davi D M Ross ◽  
Andrew Grigg ◽  
Anthony Schwarer ◽  
Christopher Arthur ◽  
Kerryn Loftus ◽  
...  
Keyword(s):  
Chronic Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Median Duration ◽  
Genomic Dna ◽  
Chronic Phase ◽  
Patient Specific ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Complete Molecular Response

Abstract After 5 years of imatinib treatment 40–50% of chronic myeloid leukaemia (CML) patients will have stable undetectable BCR-ABL by real-time quantitative RT-PCR (RQ-PCR) using strict sensitivity criteria (‘complete molecular response’, CMR). Many patients who stop imatinib in CMR will relapse, but small numbers have been reported with sustained CMR after imatinib withdrawal. We designed a non-randomised prospective Phase 2 study of imatinib withdrawal in adult chronic phase CML patients in CMR for ≥2 years (ACTRN012606000118505). Patients were treated in multiple centres around Australia, and RQ-PCR for BCR-ABL was performed centrally: monthly for the first year after imatinib withdrawal, and 2-monthly in the second year. Molecular relapse was defined as a single PCR result above the level of major molecular response (MMR) or any two consecutive positive results. Molecular relapse was treated with imatinib and patients were monitored monthly for 12 months to assess response to retreatment. Patients were enrolled in two cohorts: imatinib de novo (IM only, n=5) and imatinib after prior interferon therapy (IFN-IM, n=13). The median duration of prior IFN was 39 months. Both cohorts continue to accrue. For all 18 patients the median age at study entry was 58 years; 44% were male. The median duration of imatinib treatment was 60 months (R40-89). The Kaplan-Meier estimate of the rate of sustained CMR after 12 months off treatment was 67% (95% confidence interval 40–85%, see Figure). Ten of 13 IFN-IM patients (77%) remain in CMR, and 7 of these have been in CMR for at least 12 months without treatment (maximum 23 months). The median follow-up in the IM only patients is currently only 7 months (R1-15), and 3/5 remain in CMR. All molecular relapses in both groups have occurred within 5 months of stopping imatinib. The median duration of prior imatinib treatment was not different in the 5 patients with loss of CMR (76 months) versus those in stable CMR (60 months; p=0.59). Among the 5 patients with loss of CMR the median time to molecular relapse was 3 months (range 2–5 months). Two relapsing patients lost MMR, and 3 had detectable BCR-ABL mRNA below this level. No patient has experienced haematological relapse or developed a kinase domain mutation. At last follow-up all 5 relapsing patients had regained CMR after a median of 5 months of re-treatment with imatinib. Patient-specific DNA Q-PCR assays were developed to test whether minimal residual disease (MRD) was detectable in genomic DNA in patients in CMR defined by RQ-PCR for BCR-ABL mRNA. Results are available for 6 patients, 3 of whom have relapsed. One relapsing patient had BCR-ABL DNA detected prior to imatinib withdrawal. In the remaining 2 relapsing patients BCR-ABL DNA was detected after imatinib withdrawal, but 2–3 months prior to the detection of BCR-ABL mRNA by RQ-PCR. BCR-ABL DNA increased by at least 1-log between the time of the first positive result and the detection of molecular relapse by RQ-PCR. The 3 patients in stable CMR had no detectable BCR-ABL DNA. In conclusion, with close molecular monitoring imatinib withdrawal in stable CMR appears to be safe: currently all patients are either in stable CMR off treatment or back in CMR after re-treatment. Withdrawal of effective treatment outside the setting of a clinical trial is not recommended. Monitoring of MRD by genomic DNA Q-PCR was able to detect molecular relapse prior to mRNA RQ-PCR, and shows promise for the prospective identification of patients at high risk of relapse. There is an apparent dichotomy of response between early molecular relapse and durable CMR, at least in patients treated with imatinib after IFN. It is too early to identify clinical or laboratory factors (such as prior IFN treatment) that may influence the probability of sustained CMR without treatment. Figure Figure

scholarly journals Tyrosine Kinase Inhibitor Therapy Discontinuation for Patients with Chronic Myeloid Leukaemia in Clinical Practice

2019 ◽  
Vol 14 (6) ◽  
pp. 507-514 ◽  
Author(s):  
Richard E. Clark
Keyword(s):  
Chronic Myeloid Leukaemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Myeloid Leukaemia ◽  
Kinase Inhibitor ◽  
Molecular Response ◽  
Therapy Discontinuation ◽  
Tyrosine Kinase Inhibitor Therapy ◽  
Treatment Free Remission ◽  
Inhibitor Treatment

Abstract Purpose In chronic myeloid leukaemia, tyrosine kinase inhibitor treatment is traditionally given continuously for life. However, these drugs produce excellent responses for many patients, and this is accompanied by survival that is close to normal. This has prompted studies of whether it is possible to stop treatment, thus achieving a treatment-free remission (TFR). Recent Findings Most TFR studies have focussed on abrupt cessation in patients with long-standing deep remissions, but recent data suggest that more gradual treatment de-escalation may improve TFR success, and that it may be possible to extend TFR attempts to patients who are in stable major molecular response but not necessarily MR4. Summary Further data are badly needed on TFR for patients whose remission is less than stable MR4 and on the importance of prior interferon-alpha treatment. Funding TFR trials in a disease with such an excellent outlook is an increasing challenge.

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

2019 ◽  
Vol 142 (4) ◽  
pp. 197-207 ◽  
Author(s):  
Timothy Devos ◽  
Gregor Verhoef ◽  
Eva Steel ◽  
Dominiek Mazure ◽  
Philippe Lewalle ◽  
...  
Keyword(s):  
Side Effects ◽  
Chronic Myeloid Leukaemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Myeloid Leukaemia ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Molecular Response ◽  
Treatment Free Remission ◽  
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.

Cognitive dysfunction after withdrawal of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia

2016 ◽  
Vol 91 (11) ◽  
pp. E480-E481 ◽  
Author(s):  
Simone Claudiani ◽  
Jane F. Apperley ◽  
Simona Deplano ◽  
Jamshid Khorashad ◽  
Letizia Foroni ◽  
...  
Keyword(s):  
Chronic Myeloid Leukaemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Myeloid Leukaemia ◽  
Cognitive Dysfunction ◽  
Kinase Inhibitor ◽  
Inhibitor Therapy ◽  
Tyrosine Kinase Inhibitor Therapy

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

2021 ◽  
Author(s):  
Hilbeen Hisham Saifullah ◽  
Claire Marie Lucas
Keyword(s):  
Prognostic Factors ◽  
Chronic Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Molecular Response ◽  
Predicting Success ◽  
Treatment Free Remission ◽  
Almost All ◽  
Tki Discontinuation

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.

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