The effect of body mass index on efficacy and safety of bosutinib or imatinib in patients with newly diagnosed chronic myeloid leukemia.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7037-7037
Author(s):  
Tim H. Brümmendorf ◽  
Jorge E. Cortes ◽  
Lambert Busque ◽  
Carlo Gambacorti-Passerini ◽  
Leif Stenke ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Chronic Myeloid Leukemia ◽  
Body Mass ◽  
Myeloid Leukemia ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Dose Intensity ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Efficacy And Safety

7037 Background: Bosutinib (BOS) is approved for the treatment (Tx) of Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia (CML) resistant/intolerant to prior therapy and newly diagnosed Ph+ chronic phase (CP) CML. Body mass index (BMI) was shown to influence Tx response with front-line dasatinib vs imatinib (IMA). We report the efficacy and safety of BOS and IMA by BMI in patients (pts) with newly diagnosed CP CML. Methods: In the open-label BFORE trial, pts were randomized to receive 400 mg once daily BOS or IMA. Outcomes were assessed according to baseline BMI ≥25 or = 25 kg/m2. This post hoc analysis was based on the final 5-y analysis (database lock: June 12, 2020). Results: In the BOS and IMA arms, respectively, 149 (56.4%) vs 115 (43.6%) pts and 145 (54.3%) vs 122 (45.7%) pts had BMI ≥25 vs = 25. In both the BOS and IMA arms, median Tx duration and time on study was 55 mo for pts with BMI ≥25 or = 25; respective median dose intensity was 394 vs 393 mg/d and 400 vs 400 mg/d. Molecular response (MR) rates are shown in the table. Cumulative incidence of major MR was similar in pts with ≥25 vs = 25 receiving BOS (HR 0.99; 95% CI 0.74−1.31) or IMA (HR 1.09; 95% CI 0.81−1.47). Event-free survival (EFS) and overall survival (OS) rates at 60 mo are shown in the table. Most common reasons for Tx discontinuation were adverse events (AEs) (BOS 28.2 vs 20.0%; IMA 13.3 vs 10.7%) and lack of efficacy (BOS 5.4 vs 5.2%; IMA 16.1 vs 19.8%). In pts with BMI ≥25 vs = 25, dose reductions and interruptions due to Tx-emergent AEs (TEAEs) occurred in 43.6 % vs 46.2% and 66.4% vs 69.7% of pts with BOS and 24.5% vs 24.6% and 40.6% vs 50.8% with IMA. Any grade TEAEs in ≥30% of pts with BMI ≥25 vs = 25 were diarrhea (73.8 vs 73.1%), nausea (40.9 vs 31.9%), thrombocytopenia (30.9 vs 41.2%), increased alanine (37.6 vs 28.6%) and aspartate aminotransferase (30.2 vs 20.2%) with BOS and diarrhea (49.0 vs 29.5%), nausea (46.2 vs 37.7%), muscle spasms (33.6 vs 26.2%), neutropenia (14.7 vs 32.0%) and thrombocytopenia (10.5% vs 30.3%) with IMA. Conclusions: Efficacy of BOS was consistent in pts with BMI ≥25 or = 25; however, with IMA a low (vs high) BMI appeared to be associated with worse survival outcomes. Differences in certain TEAEs were observed between BMI subgroups in both treatment arms. Clinical trial information: NCT02130557. [Table: see text]

Clinical Efficacy and Safety Of Dasatinib For Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase In Japan

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1493-1493
Author(s):  
Kohei Yamaguchi ◽  
Kazunori Murai ◽  
Shigeki Ito ◽  
Tomoaki Akagi ◽  
Kazuei Ogawa ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Efficacy And Safety ◽  
Major Molecular Response ◽  
Once Daily

Abstract Background Dasatinib is a second-generation BCR-ABL inhibitor that has a 325-fold higher potency than imatinib and a 16-fold higher potency than nilotinib in vitro. The previous report from the global DASISION trial showed dasatinib resulted in significantly higher and faster rates of complete cytogenetic response (CCyR) and major molecular response (MMR) compared with imatinib. We conducted a phase II study to evaluate the efficacy and safety of dasatinib in patients with newly diagnosed chronic-phase chronic myeloid leukemia (CML-CP) in Japan. Methods Eighty newly diagnosed CML-CP patients were include in this study. Patients received dasatinib 100mg once daily. Treatment was continued until disease progression or unacceptable toxicity. Primary end point was the rate of major molecular response (MMR) by 12 months. MMR defined as a BCR-ABL transcript level of 0.1% or lower on the International scale by means of a real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) in peripheral blood. Secondary end points were the rate of complete cytogenetic response (CCyR) by 12 months, the rate of MR4.5 (either (i) detectable disease with <0.0032% BCR-ABL1 IS or (ii) undetectable disease in cDNA with >32,000 ABL1 transcripts in the same volume of cDNA used to test for BCR-ABL1) by 12 months and adverse events of dasatinib (UMIN #000006358). Results Eighty newly diagnosed CML-CP patients were included in this study. All except one patient administered dasatinib 100 mg once daily. One patient was withdrawal before administration of dasatinib. So far, there were 71 patients with 6 months follow-up and 51 patients with 12 months follow-up. The estimated MMR rates were 69.5 % (95%CI, 58.7-80.3 %) by 6 months and 82.7% (95%CI, 73.0-92.4 %) by 12 months. The estimated MR4.5 rates were 27.1 % (95%CI, 16.7-37.5 %) by 6 months and 48.9% (95%CI, 36.0-61.7 %) by 12 months. Only 6 patients were withdrawal because of adverse event (5 patients) and ineffectiveness (1 patient). Conclusion Dasatinib treatment results in higher rates of molecular responses in newly diagnosed CML-CP patients in Japan. Dasatinib as the first-line agent might be acceptable for CML-CP patients because of better clinical efficacy and less toxicity. Disclosures: No relevant conflicts of interest to declare.

Velocity of Early BCR-ABL Transcript Elimination As an Optimized Predictor of Deep Molecular Response in Chronic Myeloid Leukemia Patients in Chronic Phase on Treatment with Dasatinib

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4052-4052
Author(s):  
Kazunori Murai ◽  
Kohei Yamaguchi ◽  
Shigeki Ito ◽  
Tomoaki Akagi ◽  
Kazuei Ogawa ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Roc Analysis ◽  
Chronic Phase ◽  
Molecular Response ◽  
Similar Data ◽  
Newly Diagnosed ◽  
Efficacy And Safety ◽  
Once Daily ◽  
Deep Molecular Response

Abstract Background: We conducted a phase II study to evaluate the efficacy and safety of dasatinib in patients with newly diagnosed chronic-phase chronic myeloid leukemia (CML-CP) in Japan (IMIDAS PART2 study; UMIN000006358). Several groups reported that some of CML patients who achieved stable deep molecular response (DMR) level or deeper could stop Tyrosine Kinase Inhibitor (TKI) and approximately 40% of these patients could keep therapy free survival by cessation of TKI. Discontinuation of TKI has emerged as a new goal of treatment in CML. Achievement of DMR is necessary for discontinuation of TKI. The aim of the present study was to analyze the prognostic significance of (i) BCR-ABL transcript International Scale (BCR-ABL IS) levels, (ii) the halving time and (iii) velocity of BCR-ABL transcript elimination using an optimized cutoff according to receiver operating characteristic (ROC) analysis. Methods: Eighty newly diagnosed CML-CP patients were included in this study. Patients received dasatinib 100mg once daily. Treatment has continued until disease progression or unacceptable toxicity. Clinical efficacy and safety was partially reported in 55th ASH Meeting. We sought to investigate the impacts of above 3 parameters within the initial 1 or 3 months of therapy. Halving time was calculated by the method, described by Branford et al. Velocity of BCR-ABL transcript elimination at 1 or 3 months (V-BCR-ABL1m or 3m respectively) was calculated as BCR-ABL IS at 1 or 3 months (BCR-ABL IS1m or 3m respectively) divided by that at diagnosis. Results: One patient was withdrawal before administration of dasatinib. Seventy-nine patients administered dasatinib 100 mg once daily. The estimated MMR and DMR rates were 92.1 % (95%CI, 76.8-97.3 %) and 60.9% (95%CI; 42.3-73.4 %) by 12 months respectively. The patients who had already achieved DMR at 3 months were excluded from landmark analysis. The cut off values for prediction of DMR at 12 months were obtained by ROC analysis. Those of BCR-ABL IS1m and BCR-ABL IS3m were 11.7% and 0.284% respectively. Those of halving times on 0-1 month and 0-3months (halving time1m and 3m) were 17.8 and 13.6 days respectively. Those of V-BCR-ABL1m and V-BCR-ABL3m were 0.321 and 0.018 respectively. The estimated DMR at 12 months, 95% CI and probability (P), obtained by Kaplan-Myer analysis, were shown in Figure 1. Odd' ratio, obtained by Chi-square test, was shown in Table 1. The patients with less than 0.321 at V-BCR-ABL1m showed the highest DMR at 12 months (80%), the least probability (P=0.009) and the least odd' ratio (0.175). At 3 months, there were similar data in these parameters among BCR-ABL IS3m, halving time3m and V-BCR-ABL3m. Figure 1 showed the cumulative DMR rate according to the cutoff values in V-BCR-ABL1m and V-BCR-ABL3m. V-BCR-ABL1m 0.321 and V-BCR-ABL3m 0.018 separated best. Conclusion: These data strongly suggested that V-BCR-ABL1m,3m would be a significant landmark to predict DMR at 12 months as well as BCR-ABL IS1m,3m, halving time1m,3m. Among them, less than 0.321 in V-BCR-ABL1m was identified as an optimized predictive cutoff value of DMR at 12 months. Disclosures Ishida: Bristol-Myers Squibb: Honoraria.

scholarly journals The Comparison of Dasatinib 70 Mg/Day to 100 Mg/Day in Newly Diagnosed Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP): A Multicenter, Prospective, Randomized Controlled Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3615-3615
Author(s):  
Dan Yu ◽  
Zhuangzhi Yang ◽  
Hui Cheng ◽  
Rui Jiang ◽  
Jingming Guo ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Standard Dose ◽  
Chronic Phase ◽  
Controlled Study ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Efficacy And Safety ◽  
Best Response ◽  
Significant Difference

Abstract Background: The purpose of this study is to compare efficacy and safety of patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with frontline dasatinib 70 mg/day with those who received standard-dose dasatinib 100 mg/day. Method: From July 2019 to July 2021, 81 patients with newly diagnosed CML-CP were enrolled across 11 centers. All of the patients were randomly treated with dasatinib 70 mg/day (N=43) or standard-dose dasatinib 100 mg/day (N=38). Results: Among 81 enrolled patients, 16 patients were off study at different times for different reasons.All patients achieved hematological remission after 3 months of treatment, and the best response rates were 84.00% (21/25) and 88.89% (24/27) for 70mg/d and 100mg/d groups (P&gt;0.05).At 6 months, the best response, complete cytogenetic response (CCyR) and major molecular response (MMR) rate were 94.44% vs 92.86% (P &gt; 0.05), 94.44% vs 92.86% (P &gt; 0.05) and 55.56% vs 71.43% (P &gt; 0.05), respectively.At 9 months, the rates of CCyR and MMR were 90.91% vs 88.89% (P &gt; 0.05) and 66.67% vs 72.73% (P &gt; 0.05);CCyR and MMR by 12 months, respectively, were 90.91% vs 100.00% (P &gt; 0.05), 81.82% vs 80.00% (P &gt; 0.05).The adverse events (AEs) of the two groups were mild, and there was no significant difference (P &gt; 0.05).The most common grade ≥3 hematological AEs in 70 mg/d group were leukopenia (1/43), neutropenia (1/43) and anemia (2/43), and In 100mg/d group were leukopenia (4/38), neutropenia (6/38), anemia (3/38) and thrombocytopenia (3/38). Conclusions: Our study suggests that patients with newly diagnosed CML-CP treated with dasatinib 70 mg/day or 100 mg/day, there is no significant difference in efficacy and safety. Decreasing the dose of dasatinib can ensure the efficacy of patients, while reducing the economic burden of patients and increasing patient compliance. Disclosures No relevant conflicts of interest to declare.

scholarly journals High-Dose Imatinib in Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia: High Rates of Rapid Cytogenetic and Molecular Responses

2009 ◽  
Vol 27 (28) ◽  
pp. 4754-4759 ◽  
Author(s):  
Jorge E. Cortes ◽  
Hagop M. Kantarjian ◽  
Stuart L. Goldberg ◽  
Bayard L. Powell ◽  
Francis J. Giles ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Adverse Events ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Dose Intensity ◽  
Musculoskeletal Symptoms ◽  
High Dose ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Rapid Reduction

Purpose Long-term clinical outcome data have established imatinib 400 mg/d as standard front-line treatment for newly diagnosed patients with chronic myeloid leukemia (CML). Patients and Methods The Rationale and Insight for Gleevec High-Dose Therapy (RIGHT) trial is a multicenter study of imatinib 400 mg twice a day as initial therapy in 115 patients (70% Sokal low risk) with newly diagnosed CML in chronic phase who were observed for both molecular and cytogenetic responses for up to 18 months. Eighty-three patients (72%) completed the study, 10 patients (9%) discontinued the study because of adverse events, and six patients (5%) discontinued because of unsatisfactory therapeutic effect. Results Polymerase chain reaction analysis demonstrated rapid kinetics of major molecular response (MMR), with 48% of patients achieving MMR by 6 months, 54% by 12 months, and 63% by 18 months. Corresponding complete molecular response rates were 39%, 44%, and 55%, respectively. Median dose-intensity was 98%. Overall, 79% of patients who received at least 90% dose-intensity achieved MMR. The most frequent adverse events included myelosuppression, rash, fatigue, and musculoskeletal symptoms. Conclusion This study suggests that imatinib 400 mg twice a day results in more rapid reduction in tumor burden than imatinib 400 mg/d with minimal added toxicity.

Efficacy of Frontline Nilotinib Therapy in Patients (Pts) with Newly Diagnosed Philadelphia Chromosome (Ph)-Positive Chronic Myeloid Leukemia in Early Chronic Phase (CML-CP)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 454-454 ◽  
Author(s):  
Alfonso Quintás-Cardama ◽  
Hagop M Kantarjian ◽  
Rajyalakshmi Luthra ◽  
Susan o'Brien ◽  
Elias Jabbour ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Adverse Events ◽  
Myeloid Leukemia ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Grade 3 ◽  
Elevated Transaminases

Abstract Abstract 454 Efficacy of Frontline Nilotinib Therapy in Patients (Pts) with Newly Diagnosed Philadelphia Chromosome (Ph)-Positive Chronic Myeloid Leukemia in Early Chronic Phase (CML-CP) Alfonso Quintás-Cardama, Hagop Kantarjian, Raja Luthra, Susan O'Brien, Elias Jabbour, Gautam Borthakur, Farhad Ravandi, Guillermo Garcia-Manero, Stefan Faderl, Marina Konopleva, William Wierda, Elizabeth Burton, Jorge Cortes 1MD Anderson Cancer Center, University of Texas, Houston, TX Background: In 2005, we initiated a phase II study of nilotinib as 1st line therapy in pts with newly diagnosed CML-CP to investigate the efficacy and safety of nilotinib as frontline therapy for pts with CML-CP. Methods: The primary objective was to estimate the proportion of pts attaining major molecular response (MMR) at 12 months (mo). Pts with untreated CML-CP within 6 mo from diagnosis were eligible and received nilotinib 400 mg twice daily. Results: 100 pts (41% female) have received for a median of 24 mo (range 1 to 72mos). Median age was 49 years (range 17–86). Median WBC, PB blasts, PB basophils, hemoglobin, and platelet count was 42.6, 0%, 2.5%, 12.3, 307, respectively. Five pts (5%) had a variant Philadelphia chromosome and 1 (1%) had deletion of derivative chromosome 9. Seventy-two (72%), 20 (20%), and 8 (8%) pts had low, intermediate, and high Sokal risk score. Among the 102 CP pts who were not in CHR at the start, 100 (98%) achieved CHR (one discontinued after 2 weeks without adverse events). Among 73 CP pts followed for at least 12 mo, 69 (95%) achieved a complete cytogenetic response (CCyR). MMR at 18 mo has been achieved in 51 (89%) pts, including 30 (52%) with a complete molecular response (CMR)(Table 1). The median time to achieve CCyR, MMR was 6 mo each. Grade 3–4 thrombocytopenia, neutropenia, and anemia occurred in 9%, 12%, and 6% pts. The most frequent non-hematologic toxicities were rash (62%), pain (57%), and elevated transaminases (45%) and bilirubin (42%). However, grade 3–4 non-hematologic adverse events (possible, probable or suspected relationship only) were rare, including: pain and increased bilirubin (4% each), elevated lipase, fatigue, and elevated transaminases (2% each), and hyperglycemia (1%). One (1%) pt experienced QTc prolongation (grade 2; QTc prolonged from 444msec to 483msec), not associated with arrhythmias and resolved after a brief treatment interruption. Forty-five (45%) pts had transient treatment interruptions (median days off-nilotinib 7 [range 1–68]) and 27 (27%) had dose reductions. Of the patients that were dose reduced, their current or last known dose was either 200mg daily (n=7), 200mg twice daily (n=14), or 400mg daily (n=6). Nineteen (19%) pts terminated nilotinib therapy due to toxicity (n=7), personal reasons or loss to follow-up (n=7), loss of MCyR (n=2), progression to BP (n=2), or death (n=1). Of the pts who discontinued therapy, 3 were tested for BCR-ABL1 mutations; 2 were found to have mutations (F359C and Y253H). The 48 mo probability of EFS (event= loss of CHR, loss of MCyR, AP/BP, or death) is 88%. The annual rate of events during the first 48 mo of follow-up was 4%, 0%, 2%, 5%, and 0% and the rate of transformation 2%, 0%, 0%, and 0%, respectively. The best response achieved on nilotinib by the 2 pts that transformed to BP was CCyR and PCyR, respectively. The overall survival at 48 mos is 96%. One pt died due to stroke, unrelated to nilotinib. No other vascular events have been observed to date. Conclusion: Nilotinib 400 mg twice daily induces CCyR in 78% of pts as early as 3 mo and MMR in 86% at 12 mo after the start of therapy, with very low rates of progression to AP/BP and a mild toxicity profile. Disclosures: No relevant conflicts of interest to declare.

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.

Sign in / Sign up

Export Citation Format

Share Document