scholarly journals Shorter halving time of BCR-ABL1 transcripts is a novel predictor for achievement of molecular responses in newly diagnosed chronic-phase chronic myeloid leukemia treated with dasatinib: Results of the D-first study of Kanto CML study group

2015 ◽  
Vol 90 (4) ◽  
pp. 282-287 ◽  
Author(s):  
Noriyoshi Iriyama ◽  
Shin Fujisawa ◽  
Chikashi Yoshida ◽  
Hisashi Wakita ◽  
Shigeru Chiba ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Study Group ◽  
Newly Diagnosed ◽  
Molecular Responses

Impact of early dose intensity on cytogenetic and molecular responses in chronic- phase CML patients receiving 600 mg/day of imatinib as initial therapy

Blood ◽  
2008 ◽  
Vol 112 (10) ◽  
pp. 3965-3973 ◽  
Author(s):  
Timothy P. Hughes ◽  
Susan Branford ◽  
Deborah L. White ◽  
John Reynolds ◽  
Rachel Koelmeyer ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Dose Escalation ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Dose Intensity ◽  
Cytogenetic Response ◽  
Initial Therapy ◽  
Newly Diagnosed ◽  
Molecular Responses ◽  
Daily Average

Abstract We conducted a trial in 103 patients with newly diagnosed chronic phase chronic myeloid leukemia (CP-CML) using imatinib 600 mg/day, with dose escalation to 800 mg/day for suboptimal response. The estimated cumulative incidences of complete cytogenetic response (CCR) by 12 and 24 months were 88% and 90%, and major molecular responses (MMRs) were 47% and 73%. In patients who maintained a daily average of 600 mg of imatinib for the first 6 months (n = 60), MMR rates by 12 and 24 months were 55% and 77% compared with 32% and 53% in patients averaging less than 600 mg (P = .037 and .016, respectively). Dose escalation was indicated for 17 patients before 12 months for failure to achieve, or maintain, major cytogenetic response at 6 months or CCR at 9 months but was only possible in 8 patients (47%). Dose escalation was indicated for 73 patients after 12 months because their BCR-ABL level remained more than 0.01% (international scale) and was possible in 45 of 73 (62%). Superior responses achieved in patients able to tolerate imatinib at 600 mg suggests that early dose intensity may be critical to optimize response in CP-CML. The trial was registered at www.ANZCTR.org.au as #ACTRN12607000614493.

scholarly journals Prognostic Value of Multi-Drug Resistance 1 Gene (MDR1) Expression in Newly Diagnosed Patients with Chronic Myeloid Leukemia on Nilotinib Treatment—a Subanalysis of the ENEST1st Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3144-3144 ◽  
Author(s):  
Christian Dietz ◽  
Michael Lauseker ◽  
Benjamin Hanfstein ◽  
Philippe Rousselot ◽  
Thoralf Lange ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Phase ◽  
Multi Drug Resistance ◽  
Newly Diagnosed ◽  
First Line ◽  
Molecular Responses ◽  
Expression Levels ◽  
Mdr1 Expression

Abstract Introduction MDR1 gene expression has recently been reported to be associated with clinical outcome in imatinib-resistant patients with chronic myeloid leukemia (CML) on second-line nilotinib treatment (Agrawal et al., Leukemia 2014). High MDR1 expression was predictive for achieving deeper cytogenetic and molecular responses as well as duration of chronic phase. We thus prospectively evaluated the value of MDR1 expression analysis in the first-line situation within a large European, multicenter trial of CML patients under treatment with nilotinib. Methods 305 patients enrolled on the ENEST1st study (Evaluating Nilotinib Efficacy and Safety in clinical Trials as First-Line Treatment, NCT01061177) consented to participate in this substudy. Of these, 225 patients were evaluable due to sample availability and presence of typical e14a2 and/or e13a2 BCR-ABL1 transcripts. The median age was 52 (range 18-83), 39% were female. Prior to therapy, the expression of MDR1, BCR-ABL1, and GUSB were determined using a serial dilution of a plasmid constructs harboring MDR1 and GUSB and BCR-ABL1 and GUSB sequences. Ratios MDR1/GUSB and BCR-ABL1/GUSB were calculated. ROC curves were established using initial MDR1 and BCR-ABL1 expression levels aiming to achieve the primary endpoint of MR4 (defined as BCR-ABL1 ≤ 0.01% on the International Scale [BCR-ABL1IS] or undetectable BCR-ABL1 in cDNA with ≥ 10,000 ABL1 transcripts) at 18 months or to achieve a MMR (≤ 0.1% BCR-ABL1IS) at 9 months. Mann-Whitney tests have been applied using a significance level of 0.05. Results At 9 months, 161 patients (72%) achieved MMR and at 18 months 111 patients (49%) a MR4. The median ratio MDR1/GUSB among all evaluable patients was 11.4% (range, 0.6-318.1), the median ratio BCR-ABL1/GUSB was 22.2% (range 0.09-198.7). Initial BCR-ABL1/GUSB levels did not predict MMR or MR4 at 9 or 18 months. However, initial ratios MDR1/GUSB were predictive for the achievement of MMR at 9 months (best cut-off 3.8%, sensitivity 88.8%, specificity 26.6%, AUC 0.598, p=0.022) and for reaching MR4 at 18 months (best cut-off 7.90%, sensitivity 72.1%, specificity 51.8%, AUC 0.624, p=0.001). Conclusions High MDR1 expression levels in newly diagnosed CML patients appear to be associated with deeper molecular responses within the first 18 months of nilotinib treatment. These data merit further exploration and if validated would justify the investigation of frontline CML therapy guided by baseline MDR1 expression levels. Disclosures Dietz: Novartis: Research Funding. Hanfstein:Bristol-Myers Squibb: Honoraria; Novartis: Research Funding. Rousselot:Novartis: Research Funding. Lange:Novartis: Consultancy, Honoraria, Research Funding. Maier:Novartis: Research Funding. Foroni:Novartis: Research Funding. Gerrard:Novartis: Research Funding. Talmaci:Novartis: Research Funding. Janssen:Novartis: Research Funding. Frank:Novartis: Employment. Saussele:Pfizer: Honoraria, Travel, Travel Other; Bristol-Myers Squibb: Honoraria, Research Funding, Travel, Travel Other; Novartis: Honoraria, Research Funding, Travel Other. Giles:Novartis: Honoraria, Research Funding. Hochhaus:Novartis: Research Funding. Müller:Novartis: Honoraria, Research Funding.

scholarly journals Long-term outcomes with frontline nilotinib versus imatinib in newly diagnosed chronic myeloid leukemia in chronic phase: ENESTnd 10-year analysis

Leukemia ◽  
2021 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Timothy P. Hughes ◽  
Richard A. Larson ◽  
Dong-Wook Kim ◽  
Surapol Issaragrisil ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Survival Rates ◽  
Chronic Phase ◽  
Individual Treatment ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Long Term Outcomes ◽  
Treatment Free Remission

AbstractIn the ENESTnd study, with ≥10 years follow-up in patients with newly diagnosed chronic myeloid leukemia (CML) in chronic phase, nilotinib demonstrated higher cumulative molecular response rates, lower rates of disease progression and CML-related death, and increased eligibility for treatment-free remission (TFR). Cumulative 10-year rates of MMR and MR4.5 were higher with nilotinib (300 mg twice daily [BID], 77.7% and 61.0%, respectively; 400 mg BID, 79.7% and 61.2%, respectively) than with imatinib (400 mg once daily [QD], 62.5% and 39.2%, respectively). Cumulative rates of TFR eligibility at 10 years were higher with nilotinib (300 mg BID, 48.6%; 400 mg BID, 47.3%) vs imatinib (29.7%). Estimated 10-year overall survival rates in nilotinib and imatinib arms were 87.6%, 90.3%, and 88.3%, respectively. Overall frequency of adverse events was similar with nilotinib and imatinib. By 10 years, higher cumulative rates of cardiovascular events were reported with nilotinib (300 mg BID, 16.5%; 400 mg BID, 23.5%) vs imatinib (3.6%), including in Framingham low-risk patients. Overall efficacy and safety results support the use of nilotinib 300 mg BID as frontline therapy for optimal long-term outcomes, especially in patients aiming for TFR. The benefit-risk profile in context of individual treatment goals should be carefully assessed.

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