scholarly journals Imatinib discontinuation in chronic phase myeloid leukaemia patients in sustained complete molecular response: A randomised trial of the Dutch–Belgian Cooperative Trial for Haemato-Oncology (HOVON)

2013 ◽  
Vol 49 (15) ◽  
pp. 3242-3246 ◽  
Author(s):  
Noortje Thielen ◽  
Bronno van der Holt ◽  
Jan J. Cornelissen ◽  
Gregor E.G. Verhoef ◽  
Titia Gussinklo ◽  
...  
Keyword(s):  
Myeloid Leukaemia ◽  
Randomised Trial ◽  
Chronic Phase ◽  
Molecular Response ◽  
Cooperative Trial ◽  
Complete Molecular Response

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 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.

Increasing Frequency and Marked Stability of Complete Molecular Response Is Observed in Imatinib-Treated CML Patients with Long-Term Follow Up.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 430-430 ◽  
Author(s):  
Susan Branford ◽  
John Francis Seymour ◽  
Andrew Grigg ◽  
Chris Arthur ◽  
Kevin Lynch ◽  
...  
Keyword(s):  
Chronic Phase ◽  
Leukemic Cells ◽  
Molecular Response ◽  
Second Line ◽  
First Line ◽  
Important Indicator ◽  
Complete Molecular Response ◽  
Time Point ◽  
Marked Stability

Abstract The degree of reduction of BCR-ABL in imatinib-treated patients with chronic phase CML is an important indicator of prognosis. The IRIS trial established that with first-line therapy patients with a major molecular response (MMR, 3 log reduction from a standardized baseline value for untreated patients) have a significantly more favorable progression free survival. Although 40% achieved a MMR by 12 months, very few had undetectable BCR-ABL according to strict PCR sensitivity criteria. We measured peripheral blood BCR-ABL levels by quantitative PCR at 3 to 6 month intervals in 155 patients with chronic phase CML enrolled in clinical trials of imatinib for up to 6 years. We aimed to (i) determine if BCR-ABL levels continued to decline over time, and (ii) evaluate the stability and significance of undetectable BCR-ABL. The patients included the Australasian subset of IRIS trial patients treated with 400mg of imatinib; 29 first-line patients evaluated for a median of 69 months (25th to 75th percentile range (pr) 58–72) and 24 second-line patients for a median of 54 months of imatinib (pr 38–60). 102 de-novo patients enrolled in the TIDEL trial of 600mg imatinib were evaluated for a median of 39 months (pr 30–42). Complete molecular response (CMR) was defined as undetectable BCR-ABL at a PCR sensitivity of at least 4.5 logs below the standardized baseline value confirmed on subsequent analysis after at least 3 months. The BCR control transcript level determined sensitivity and was dependent on RNA quality and reverse transcription efficiency. Of note CMR may not indicate eradication of leukemic cells, rather a reduction of BCR-ABL below the detection limit. CMR occurred in 34 patients who had 178 analyses after achieving CMR (median 4 tests per patient) and a median follow up of 15 months (pr 9–24). Very low level BCR-ABL was detected in 3 patients, the remaining 31 had undetectable BCR-ABL on every subsequent assay. Of the IRIS trial patients treated with first-line imatinib, 41% achieved a CMR by 69 months, a frequency significantly higher than occurred in these patients at 24 months (7%, p=0.006). The rate of CMR appeared to increase substantially beyond the 3 year time point (7%, 24% and 34% at 3, 4 and 5 years). 75 patients achieved MMR but not CMR and were followed for a median of 24 months after achieving MMR (pr 17–33). Six of 75 patients (8%) lost MMR as defined by >2-fold rise in BCR-ABL and loss of MMR on 2 consecutive analyses. The median fold rise was 18-fold (4 to 1900-fold), of whom 1 went on to blast crisis. Four of the 6 patients had BCR-ABL mutations detected at the time of the rise and 1 of the remaining patients had duplicate Ph. MMR was lost in these 6 patients within 18 months of its achievement. The overall rate of CMR and MMR (including patients with CMR) did not differ significantly between the 3 treatment groups at the 3 year time point (CMR 7%, 8% and 18%; MMR 66%, 71% and 70% for first-line 400mg, second-line 400mg and first-line 600mg respectively). In conclusion at a median follow-up of 5.75 years of 400mg first-line imatinib, CMR was achieved in 41% of patients. Importantly, of all patients who achieved a CMR in this study using strict criteria to define the sensitivity of analysis, none have lost MMR and 91% have maintained CMR. The slow acquistion and marked stability of CMR favour the notion that the leukemic stem cell pool is steadily declining with prolonged exposure to imatinib.

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

2017 ◽  
Vol 13 (01) ◽  
pp. 17
Author(s):  
Tim Hughes ◽  
Giuseppe Saglio ◽  
◽  
Keyword(s):  
Chronic Myeloid Leukaemia ◽  
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.

scholarly journals Efficacy of nilotinib in a patient in non-optimal response after imatinib treatment but in reduced compliance to the new drug

2015 ◽  
Vol 5 (5S) ◽  
pp. 15-19
Author(s):  
Francesca Sassolini
Keyword(s):  
Myeloid Leukemia ◽  
Standard Dose ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Major Molecular Response ◽  
Optimal Response ◽  
Future Pregnancy ◽  
Complete Molecular Response

We report a case of a patient with chronic myeloid leukemia in chronic phase who was treated with imatinib at standard dose from diagnosis to 18 months end point. He rapidly achieved a stable complete cytogenetic response (CCyR), but not a major molecular response (MMolR). According to European LeukemiaNet (ELN) recommendations, he was classified as a suboptimal patient. Since the treatment was fully tolerated by the patient, we tried an imatinib dose escalation in order to improve this result, obtaining only a transitory MMolR: BCR-ABL trascript level waved from 0,23 to 0,3% (BCR-ABL/ABL%). Therefore, we proposed a change of therapy. Due to his optimal compliance to imatinib and his wish of a future pregnancy, he refused the proposal. Unfortunately the pregnancy remained a desire, therefore, after 1 year of stable results (“near” MMolR), the patient switched to nilotinib at 400 mg/BID. After 3 months of treatment he achieved MMolR and after 6 months we could also document a complete molecular response (CMolR).

Responses to Dasatinib as a Second- and Third-Line Tyrosine Kinase Inhibitor in Chronic Phase Chronic Myeloid Leukaemia Patients

2019 ◽  
Vol 142 (2) ◽  
pp. 79-86 ◽  
Author(s):  
Jiaqi Tan ◽  
Mengxing Xue ◽  
Jinlan Pan ◽  
Jiannong Cen ◽  
Xiaomei Qi ◽  
...  
Keyword(s):  
Chronic Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Chronic Phase ◽  
Molecular Response ◽  
Second Line ◽  
Second Line Therapy ◽  
Line Therapy ◽  
Third Line Therapy ◽  
Third Line ◽  
Dasatinib Treatment

We retrospectively evaluated the efficacy and safety of dasatinib among 48 Chinese patients with chronic phase chronic myeloid leukaemia. The proportions of patients achieving the optimal molecular responses at 3, 6, and 12 months, a major molecular response (MMR) rate and a complete cytogenetic response (CCyR) rate were 87.0, 87.0, 72.2, 45.8, and 72.7% for patients with dasatinib as second-line therapy, and 34.8, 34.8, 33.3, 20.8, and 46.2% as third-line therapy, respectively. A BCR-ABL1 transcript level on the International Scale (BCR-ABL1IS) of ≤10% at the initiation of ­dasatinib treatment was found to be associated with a higher probability of achieving MMR. Among patients with a ­BCR-ABL1IS higher than 10% at initiation of dasatinib treatment, dasatinib showed better performance as a second-line therapy than as a third-line therapy. The patients who achieved an optimal molecular response at 3 months had a superior cumulative incidence of MMR and CCyR compared with patients who failed to achieve such a response. Dasatinib induced considerable responses as a second-line treatment, especially in patients with a BCR-ABL1IS ≤10% at initiation of treatment, whereas the efficacy was limited in patients receiving third-line therapy with a BCR-ABL1IS >10% at the initiation of treatment.

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