scholarly journals High-dose imatinib improves cytogenetic and molecular remissions in patients with pretreated Philadelphia-positive, BCR-ABL-positive chronic phase chronic myeloid leukemia: first results from the randomized CELSG phase III CML 11 "ISTAHIT" study

Haematologica ◽  
2010 ◽  
Vol 95 (6) ◽  
pp. 908-913 ◽  
Author(s):  
A. L. Petzer ◽  
D. Wolf ◽  
D. Fong ◽  
T. Lion ◽  
I. Dyagil ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Phase Iii ◽  
High Dose ◽  
First Results

scholarly journals Phase III, Randomized, Open-Label Study of Daily Imatinib Mesylate 400 mg Versus 800 mg in Patients With Newly Diagnosed, Previously Untreated Chronic Myeloid Leukemia in Chronic Phase Using Molecular End Points: Tyrosine Kinase Inhibitor Optimization and Selectivity Study

2010 ◽  
Vol 28 (3) ◽  
pp. 424-430 ◽  
Author(s):  
Jorge E. Cortes ◽  
Michele Baccarani ◽  
François Guilhot ◽  
Brian J. Druker ◽  
Susan Branford ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Imatinib Mesylate ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Phase Iii ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Gastrointestinal Problems

PurposeTo evaluate the safety and efficacy of initial treatment with imatinib mesylate 800 mg/d (400 mg twice daily) versus 400 mg/d in patients with newly diagnosed chronic myeloid leukemia in chronic phase.Patients and MethodsA total of 476 patients were randomly assigned 2:1 to imatinib 800 mg (n = 319) or 400 mg (n = 157) daily. The primary end point was the major molecular response (MMR) rate at 12 months.ResultsAt 12 months, differences in MMR and complete cytogenetic response (CCyR) rates were not statistically significant (MMR, 46% v 40%; P = .2035; CCyR, 70% v 66%; P = .3470). However, MMR occurred faster among patients randomly assigned to imatinib 800 mg/d, who had higher rates of MMR at 3 and 6 months compared with those in the imatinib 400-mg/d arm (P = .0035 by log-rank test). CCyR also occurred faster in the 800-mg/d arm (CCyR at 6 months, 57% v 45%; P = .0146). The most common adverse events were edema, gastrointestinal problems, and rash, and all were more common in patients in the 800-mg/d arm. Grades 3 to 4 hematologic toxicity also occurred more frequently in patients receiving imatinib 800 mg/d.ConclusionMMR rates at 1 year were similar with imatinib 800 mg/d and 400 mg/d, but MMR and CCyR occurred earlier in patients treated with 800 mg/d. Continued follow-up is needed to determine the clinical significance of earlier responses on high-dose imatinib.

Nonmyeloablative allogeneic stem cell transplantation for the treatment of chronic myeloid leukemia in first chronic phase

Blood ◽  
2003 ◽  
Vol 101 (2) ◽  
pp. 441-445 ◽  
Author(s):  
Reuven Or ◽  
Michael Y. Shapira ◽  
Igor Resnick ◽  
Avraham Amar ◽  
Aliza Ackerstein ◽  
...  
Keyword(s):  
Stem Cell ◽  
Chronic Myeloid Leukemia ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
Chronic Phase ◽  
Mixed Chimerism ◽  
High Dose ◽  
Disease Free

Reduced-intensity or nonmyeloablative stem cell transplantation (NST) is designed to induce host-versus-graft tolerance by engraftment of donor stem cells. The rationale behind NST is to induce optimal graft-versus-leukemia (GVL) effects for elimination of all malignant cells by donor alloreactive immunocompetent cells as an alternative to standard high-dose myeloablative chemoradiotherapy. NST based on the use of fludarabine, low-dose busulfan, and anti–T-lymphocyte globulin (ATG) was employed in 24 patients aged 3 to 63 years with chronic myeloid leukemia (CML) in first chronic phase (CP). Graft-versus-host disease (GVHD) prophylaxis consisted of low-dose cyclosporine (CSP), in some cases with low-dose methotrexate. Early discontinuation of CSP was attempted in cases of mixed chimerism in an attempt to amplify GVL effects. All 24 patients showed rapid 3-lineage engraftment, mostly without complete aplasia; 6 patients did not require transfusion of any blood products. NST was associated with minimal procedure-related toxicity. The incidence of acute GVHD (grade I or higher) was 54%; however, this incidence increased following CSP withdrawal. After a follow-up of up to 70 months (median, 42 months), 21 of 24 patients remained alive and disease free. The GVL effects induced by donor immunocompetent lymphocytes eradicated all host hematopoietic cells, as evidenced by molecular testing. The Kaplan-Meier probability of survival and disease-free survival at 5 years is 85% ± 8% (95% confidence interval, 70%-100%). NST may successfully replace myeloablative stem cell transplantation, providing a safer, well-tolerated therapeutic option for all patients with CML in first CP with a matched donor. However, this conclusion must be tested in a prospective randomized clinical trial.

Dasatinib Is Well-Tolerated and Efficacious in Imatinib-Intolerant Patients with Chronic-Phase Chronic Myeloid Leukemia (CP-CML).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1128-1128 ◽  
Author(s):  
Hanna Jean Khoury ◽  
Michael J. Mauro ◽  
Yousif Matloub ◽  
Tai-Tsang Chen ◽  
Erkut Bahceci ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Median Duration ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Phase Iii ◽  
Hematologic Toxicity ◽  
Molecular Response

Abstract Abstract 1128 Poster Board I-150 Imatinib (IM), a tyrosine kinase inhibitor (TKI), has been the mainstay of treatment for chronic phase chronic myeloid leukemia (CP-CML). However, IM resistance and intolerance are of considerable clinical relevance. Dasatinib (DAS), a second-line TKI, is effective in the IM-intolerant patient population. The purpose of this study was to determine baseline factors that can affect DAS response and evaluate long term efficacy in this population. Intolerance to IM was defined as ≥ Grade 3 non-hematologic toxicity and/or Grade 4 hematologic toxicity lasting > 7 days. A total of 271 Ph+ CP-CML IM-intolerant patients who received DAS were pooled from two randomized trials (Phase II-trial, CA 180013 and Phase III trial, CA 180034). DAS doses were 50 mg BID (n=43), 70 mg BID (n=141), 100 mg QD (n=43) or 140 mg QD (n=44). At baseline, the median duration of disease for the IM-intolerant patients was 24 months (range: 0.9-182.5) and the median duration of IM therapy was 9 months (range: 0.03-69.06). Of these patients, 46 (17%) had hematologic toxicity and 228 (84.1%) had non-hematologic toxicity to IM. Seventy-nine (29%) patients had prior complete cytogenetic response (CCyR) on IM and 171 (63%) patients did not. The data for prior CyR to IM was not reported for 21 (7.7%) patients. Of the 79 patients who had achieved CCyR on IM, 30 patients had maintained CCyR and 49 patients had lost this response prior to start of DAS. Of the 171 patients who did not achieve CCyR on IM, 62 (36.3%) had been on IM for 3 12 months and 109 (63.7%) for < 12 months. At 2-year follow up of the 271 patients treated with DAS, 121 (44.6%) discontinued DAS (7.4% due to hematologic toxicity and 14% due to non-hematologic toxicity). Of the patients who were intolerant of IM due to hematologic toxicity (n=46), 10 (21.7%) discontinued DAS due to hematologic toxicity, and 3 (6.5%) due to other toxicities. Of the patients with non-hematologic IM-intolerance (n=228), 10 (4.4%) discontinued DAS due to hematologic toxicity, and 35 (15.4%) due to other toxicities. The median average daily dose of DAS was 99 mg/day in the population who achieved CCyR on DAS and 71.5 mg/day in the population who did not achieve CCyR on DAS. The probability of achieving CCyR on DAS was 43.5% in patients with hematologic IM-intolerance versus 78.9% with non-hematologic IM-intolerance. The CCyR, major molecular response (MMR), progression-free survival (PFS) and overall survival (OS) at 2-year follow up for the groups classified by their CCyR status at start of DAS or IM-intolerance status are summarized in Table 1. Conclusions DAS was well-tolerated and associated with high rates of CyR in IM-intolerant patients. Patients with a prior CCyR to IM and those who switched due to non-hematologic imatinib-intolerance had the highest rates of CCyR and MMR on DAS, while patients without CCyR after more than 12 months of IM therapy or IM-intolerance due to hematologic toxicity had the lowest rates of CCyR and MMR. Disclosures Khoury: BMS: Honoraria; Wyeth: Honoraria; Novartis Pharmaceuticals: Honoraria; Chemgenex: Honoraria; Genzyme: Honoraria. Mauro:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding. Matloub:Bristol-Myers Squibb: Employment. Chen:Bristol-Myers Squibb: Employment. Bahceci:Bristol-Myers Squibb: Employment. Deininger:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Calistoga: Research Funding; Genzyme: Research Funding.

EPIC: A phase III randomized, open-label study of ponatinib versus imatinib in adult patients with newly diagnosed chronic myeloid leukemia in chronic phase.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS7129-TPS7129
Author(s):  
Jeffrey H. Lipton ◽  
Michael W. N. Deininger ◽  
Stephanie Lustgarten ◽  
Christopher D. Turner ◽  
Victor M. Rivera ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Dropout Rate ◽  
Phase Iii ◽  
Newly Diagnosed ◽  
Open Label ◽  
Phase 3 ◽  
Absolute Increase ◽  
Once Daily

TPS7129 Background: The hallmark genetic abnormality of chronic myeloid leukemia (CML), known as the Philadelphia chromosome, generates the BCR-ABL fusion gene; expression of BCR-ABL in hematopoietic stem cells gives rise to CML. Ponatinib is a potent oral pan–BCR-ABL tyrosine kinase inhibitor (TKI) that is active against native and mutated forms of BCR-ABL, including the T315I gatekeeper mutant. Results from the phase 1 and phase 2 studies of ponatinib demonstrated that ponatinib is generally well tolerated and has substantial anti-leukemic activity in patients with CML who are resistant or intolerant to prior TKI therapy, regardless of baseline mutation status. In addition, multivariate analyses suggest that ponatinib has greater activity in younger patients who are less heavily pretreated and have a shorter time since diagnosis. The phase 3 EPIC (Evaluation of Ponatinib vs Imatinib in CML) study is testing the hypothesis that ponatinib is an effective treatment for newly diagnosed chronic phase (CP) CML patients when compared with standard imatinib therapy. Methods: EPIC is a multicenter, international, phase 3, two-arm, open-label trial of ponatinib (45 mg once daily) versus imatinib (400 mg once daily) in patients with newly diagnosed CP-CML. Patients ≥18 years of age with CP-CML (diagnosed within 6 months prior to study entry) and adequate renal, hepatic, and pancreatic function are eligible for enrollment. Enrolled patients are assigned to receive ponatinib or imatinib in a 1:1 fashion, stratified by Sokal Risk score (low vs intermediate vs high). The primary efficacy endpoint for this trial is major molecular response (MMR) rate at 12 months. Secondary endpoints include MMR rate at 5 years, BCR-ABLIS<10% rate at 3 months, CCyR rate at 12 months, progression-free survival, overall survival, and safety. A sample size consisting of 480 patients will provide 90% power to detect a 15% absolute increase in MMR rate at 12 months using an unstratified Fisher exact 2-sided test at an alpha level of 0.05. Assuming a 10% dropout rate, approximately 528 patients will be enrolled. The first patient was enrolled in August 2012. Clinical trial information: NCT01650805.

Treatment-free remission (TFR) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) treated with second-line nilotinib (NIL): First results from the ENESTop study.

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. 7054-7054 ◽  
Author(s):  
Timothy P Hughes ◽  
Carla Boquimpani ◽  
Dong-Wook Kim ◽  
Noam Benyamini ◽  
Nelma Cristina D. Clementino ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Second Line ◽  
First Results ◽  
Treatment Free Remission

Frontline flumatinib versus imatinib in patients with chronic myeloid leukemia in chronic phase: Results from the China randomized phase III study.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 7004-7004
Author(s):  
Zhang Li ◽  
Li Meng ◽  
Yanli Zhang ◽  
Huanling Zhu ◽  
Jiuwei Cui ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Phase Iii ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Primary Endpoints ◽  
Study Results ◽  
Frontline Treatment ◽  
Phase Iii Study

7004 Background: Flumatinib (FM), a derivative of imatinib (IM), is a novel BCR-ABL1 tyrosine kinase inhibitor (TKI). The aim of this open-label phase III study was to validate the efficacy and safety of FM in comparison with IM as frontline treatment in Chinese patients with newly diagnosed Philadelphia chromosome–positive chronic myeloid leukemia (CML) in chronic phase (CML-CP). Methods: Randomization was stratified by Sokal score with a 1:1 allocation to each arm. Primary endpoints were major molecular response (MMR = BCR-ABL IS≤0.1%) rates at 6 and 12 months. Molecular responses were assessed at a central laboratory blinded to treatment allocations during the study. Efficacy endpoints were analyzed for the intention-to-treat populations. This study is registered with ClinicalTrials.gov, number NCT02204644. Results: 400 eligible patients were randomized and patient characteristics at baseline were similar in each arm. The full analysis set (FAS) consisted of 393 patients who received FM 600 mg (n = 196) or IM 400 mg (n = 197) tablets once daily. Compared with IM, FM resulted significantly higher induction of MMR rate (%; 95%CI) at 6 month (33.7; 27.06-40.29 vs 18.3; 12.88-23.67; P = 0.0005) and 12 month (48.5; 41.47-55.47 vs 33.0; 26.43-39.56; P = 0.0021) and also at 3 month (8.2; 4.33- 12.00 vs 2.0; 0.06-4.00; P = 0.0058). Significantly more patients in the FM than in the IM arm achieved a complete molecular response (BCR-ABL IS≤0.0032%) at 12 months. Early molecular response (BCR-ABL IS ≤ 10%) at 3 months and early CCyR at 6 months were also significantly higher with FM than IM (82.1; 76.78-87.50 vs 53.3; 46.33-60.27; P < 0.0001 and 60.71; 53.88-67.55 vs 49.75, 42.76, 56.73; P = 0.0332). FM has a safety profile similar to IM. The rates of grade 3/4 TEAEs of FM were similar to IM, 56.57% (112 of 198) vs 41.38% (87 of 196). However, the frequencies of some nonhematological and hematological adverse events were significantly lower in the FM than in the IM arm, such as rash (4.59% vs 12.63%, P = 0.0064) and eyelid edema (0.51 vs 14.65, P < 0.0001); leukopenia (30.61 vs 62.63, P < 0.0001) and neutropenia (30.10 vs 59.60, P < 0.0001). No specific TEAE was identified in each arm. Conclusions: This phase III study met its primary endpoints. Our study results suggest that FM is comparable to IM in its safety and superior in its efficacy profile at 3, 6 and 12 month time points. These results support FM as a frontline treatment option for patients with newly diagnosed CML-CP. Clinical trial information: NCT02204644.

scholarly journals Bosutinib Versus Imatinib in Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia: Results From the BELA Trial

2012 ◽  
Vol 30 (28) ◽  
pp. 3486-3492 ◽  
Author(s):  
Jorge E. Cortes ◽  
Dong-Wook Kim ◽  
Hagop M. Kantarjian ◽  
Tim H. Brümmendorf ◽  
Irina Dyagil ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Phase Iii ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Blast Phase ◽  
End Point

Purpose Bosutinib is an oral Src/Abl tyrosine kinase inhibitor. The phase III Bosutinib Efficacy and Safety in Newly Diagnosed Chronic Myeloid Leukemia (BELA) trial compared bosutinib with imatinib in newly diagnosed, chronic-phase chronic myeloid leukemia (CML). Patients and Methods A total of 502 patients were randomly assigned 1:1 to bosutinib 500 mg per day or imatinib 400 mg per day. Results The complete cytogenetic response (CCyR) rate at 12 months was not different for bosutinib (70%; 95% CI, 64% to 76%) versus imatinib (68%; 95% CI, 62% to 74%; two-sided P = .601); therefore, the study did not achieve its primary end point. The major molecular response (MMR) rate at 12 months was higher with bosutinib (41%; 95% CI, 35% to 47%) compared with imatinib (27%; 95% CI, 22% to 33%; two-sided P < .001). Time to CCyR and MMR was faster with bosutinib compared with imatinib (two-sided P < .001 for both). On-treatment transformation to accelerated/blast phase occurred in four patients (2%) on bosutinib compared with 10 patients (4%) on imatinib. A total of three CML-related deaths occurred on the bosutinib arm compared with eight on the imatinib arm. The safety profiles of bosutinib and imatinib were distinct; GI and liver-related events were more frequent with bosutinib, whereas neutropenia, musculoskeletal disorders, and edema were more frequent with imatinib. Conclusion This ongoing trial did not meet its primary end point of CCyR at 12 months, despite the observed higher MMR rate at 12 months, faster times to CCyR and MMR, fewer on-treatment transformations to accelerated/blast phase, and fewer CML-related deaths with bosutinib compared with imatinib. Each drug had a distinct safety profile.

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