- Email: [email protected]
Therapy of Early Chronic Phase Chronic Myeloid Leukemia (CML-CP) with Lower Dose Dasatinib
Abstracts Table 1 Safety and Response Outcomes Dasatinib
Imatinib Comorbidities
‡1 (n[192)
0 (n[66)
‡1 (n[192)
Median age, years
49
39
50
38
Median average dose, mg/day Discontinuation, %
99 39
100 38
400 36
400 39
1 (n¼193)
0 (n¼66)
1 (n¼193)
0 (n¼67)
CCyR MMR
89 77
86 74
85 67
79 54
MR4.5
46
32
36
22
0 (n[66)
Response by 5 years, %
CCyR¼complete cytogenetic response; MMR¼major molecular response (BCR-ABL1 0.1% International Scale [IS]); MR ¼BCR-ABL1 0.0032% IS. 4.5
Table 2 Frequent Treatment-related AEs by Baseline Disorder Dasatinib (n[192)
Imatinib (n[192)
Baseline CV disorder
Yes (n[43)
No (n[149)
Yes (n[43)
No (n[149)
All AEs, % Baseline DM
79 Yes (n[18)
78 No (n[174)
86 Yes (n[13)
77 No (n[179)
All AEs, % Baseline Hyperlipidemia
78 Yes (n[22)
78 No (n[170)
69 Yes (n[19)
80 No (n[173)
82
78
84
79
All AEs, %
numerically lower for patients with 0 vs 1 comorbidity. Incidence of overall AEs was comparable in the 0 and 1 comorbidity groups within both arms. Select AEs, largely grade 1/2, had a 2 times higher frequency in patients with 1 vs 0 comorbidity. PE incidence in dasatinib-treated patients appeared unrelated to baseline pulmonary comorbidity or smoking history and was most influenced by increased years of age. Treatmentrelated (Table 2) and CV AEs seemed unaffected by the presence of baseline CV disorder, DM, or hyperlipidemia. Conclusions: The superior efficacy of dasatinib over imatinib was previously demonstrated in DASISION. Although some AEs (most grade 1/ 2) occurred in patients with 1 comorbidity, these results suggest that baseline comorbidities and age did not substantially affect discontinuation rates, overall safety, or responses at 5 years in patients with CML-CP taking first-line dasatinib or imatinib. This analysis was funded by Bristol-Myers Squibb.
Abstract: CML-017 Therapy of Early Chronic Phase Chronic Myeloid Leukemia (CML-CP) with Lower Dose Dasatinib
Kiran Naqvi,1 Jorge Cortes,1 Jeffrey Skinner,1 Elias Jabbour,1 Naveen Pemmaraju,1
Gautam Borthakur,1 Zeev Estrov,1 Prithviraj Bose,1 Philip Thompson,1 Hagop Kantarjian1 1
Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA
Context: Dasatinib is a potent tyrosine kinase inhibitor (TKI) of BCR-ABL. Approved dose in the chronic phase is 100mg daily. This is however associated with notable side effects mainly myelosuppression and pleural effusion, leading to dose reductions/interruptions. Objective: To evaluate the efficacy and toxicity profile of lower dose dasatinib, at 50 mg orally daily in patients with early CML-CP. Design and Patients: All patients presenting to our institution in early CML-CP were eligible to participate. Prior TKI therapy for up to 1 month was allowed. Responses were assessed according to the European LeukemiaNet guidelines (Baccarani et al. Blood 2013 122.872:884). Results: From March 2016 to July 2017, 56 patients have been enrolled. Median age is 46 years (range 22-80). Patients categorized by Sokal risk are: low 34; intermediate 16 and high 6. Response to lower dose dasatinib is as follows: At 3 months, 93% patients had achieved early response (BCRABL PCR <10%) to therapy. Ten patients had BCR-ABL PCR < 1% (equivalent to CCyR) at 3 months but tested positive by FISH. At 6 months, 7/10 patients that were FISH positive at 3 months, achieved CCyR (FISH 0%); of these 7 patients, 6 achieved a MMR. 3/10 remaining patients that were FISH
Clinical Lymphoma, Myeloma & Leukemia October 2017
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Abstracts
No. Response/total (%)
3 months
6 months
9 months
12 months
PCR <10% [IS]
40/43 (93%)
26/27 (96%)
19/20 (95%)
9/9 (100%)
CCyR MMR
23/43 (51%) 12/43 (28%)
25/27 (93%) 19/27 (70%)
18/20 (90%) 16/20 (80%)
9/9 (100%) 9/9 (100%)
MR4.0 MR4.5
1/43 (2%) 0/43 (0%)
8/27 (30%) 2/27 (7%)
14/20 (70%) 4/20 (20%)
9/9 (100%) 3/9 (33%)
positive at 3 months, have not yet reached (NR) the 6 month follow-up. Nine patients had treatment interruption of up to 14 days in the 1st 3 months of therapy: gastrointestinal bleed 2; thrombocytopenia 3; transaminitis 2; renal dysfunction 2. None of these patients required dose modification and tolerated dasatinib once it was resumed. Seven of these 9 patients with dose interruption have achieved early response to therapy while 2 patients have not yet reached the 3 month follow-up. Therapy was discontinued in 1 patient secondary to subdural hemorrhage (traumatic), while 1 patient failed to achieve CCyR at 6 months requiring increase in dasatinib dose to 100mg daily. None of the patients have developed pleural effusion so far. Conclusion: Dasatinib at 50 mg daily dose is active and well-tolerated in newly diagnosed CML-CP. It should be further explored as a new potential dose-schedule option in CML.
Abstract: CML-019 Long-Term Outcomes of Early CP CML Patients who have Achieved CCyR but Not MMR after 24 Months on Frontline Imatinib Therapy
Sung-Eun Lee,1 Won-Sik Lee,2 Hyeong-Joon Kim,3 Jee Hyun Kong,4 Yunsuk Choi,5 Young Rok Do,6 Jae-Yong Kwak,7 Sukjoong Oh,8 Sung Hyun Kim,9 Jeong-A. Kim,10 Dae Young Zang,11 Yeung-Chul Mun,12 Young-Woong Won,13 Dong-Wook Kim1 1
Department of Hematology, Seoul St. Mary’s Hospital, The
Catholic University of Korea; 2Department of Internal Medicine, Inje University College of Medicine, Inje University Busan Paik Hospital; 3
Department of Hematology-Oncology, Chonnam National University Hwasun Hospital; 4Department of Hematology-Oncology, Wonju College of Medicine, Yonsei University; 5Department of Hematology, University of Ulsan College of Medicine, Ulsan University Hospital; 6Division of Hematology-Oncology, Keimyung University, School of Medicine, Keimyung University Hospital; 7
Division of Hematology-Oncology, Chonbuk National University
Medical School, Chonbuk National University Hospital; 8Division of Hematology-Oncology, Department of Internal Medicine, School of
S16
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Clinical Lymphoma, Myeloma & Leukemia October 2017
Medicine, Sungkyunkwan University, Kangbuk Samsung Hospital; 9
Department of Internal Medicine, Dong-A University College of
Medicine, Dong-A University Hospital; 10Department of Hematology, The Catholic University of Korea, St. Vincent’s Hospital;
11
Depart-
ment of Internal Medicine, Hallym University College of Medicine, Hallym University Hospital; 12Department of Hematology, School of Medicine, Ewha Womans University, Ehwa Womans University Hospital;
13
Division of Hematology and Oncology, Department of
Internal Medicine, Hanyang Univerysity College of Medicine, Hanyang University Guri Hospital
Context: Although failure to achieve molecular response milestones on tyrosine kinase inhibitors (TKIs) therapy for chronic phase (CP) chronic myeloid leukemia (CML) means that switching to a different TKI is needed to limit the risk of progression and death, there is insufficient data to show long-term outcomes in the patients who were in a molecular failure after 24 months. Objective: The aim of this study was to evaluate longterm survival end points and identify predictive factors for an achievement of overall major molecular response (MMR) in the patients who have achieved complete cytogenetic response (CCyR) but not MMR after 24 months on frontline IM therapy. Patients: 280 newly diagnosed CP CML patients who were in CCyR but not MMR after 24 months on frontline IM therapy were evaluated. Results: With a median follow-up of 134.2 months (range, 25.6e195.0 months), 163 (58%) patients continued IM and maintained at least a CCyR, while 117 patients permanently discontinued IM due to intolerance (n ¼ 31), warnings according to ELN 2013 recommendation with adverse events (n ¼ 43), and treatment failure (n ¼ 17), progression (n ¼ 9), death (n ¼ 1), enrollment of treatment-free remission (TFR) study (n ¼ 10), and others (n ¼ 6). Among them, 98 (84%) switched to 2G TKIs. The CI rates of MMR by 3, 4, and 5 years were 27.9 2.8%, 53.6 3.3%, and 71.8 3.0%, respectively, and the CI rates of CMR by 3, 4, and 5 years were 1.9 0.8%, 5.0 1.4%, and 10.8 2.1%, respectively on IM therapy. The 10-year FFS, PFS, and OS were 89.3 2.2%, 96.0 1.3%, and 98.5 0.9%, respectively. Transcript type of b2a2 and high Sokal risk were independent factors for failure of overall MMR on IM therapy. Conclusions: This study demonstrated long-term survival outcomes in the patients who have achieved CCyR but not MMR after 24 months on frontline IM therapy. In addition, the predictive factors may provide additional information to guide clinical decisions on selecting patients who would benefit from switching to 2G TKIs in molecular failure.
Imatinib Comorbidities
‡1 (n[192)
0 (n[66)
‡1 (n[192)
Median age, years
49
39
50
38
Median average dose, mg/day Discontinuation, %
99 39
100 38
400 36
400 39
1 (n¼193)
0 (n¼66)
1 (n¼193)
0 (n¼67)
CCyR MMR
89 77
86 74
85 67
79 54
MR4.5
46
32
36
22
0 (n[66)
Response by 5 years, %
CCyR¼complete cytogenetic response; MMR¼major molecular response (BCR-ABL1 0.1% International Scale [IS]); MR ¼BCR-ABL1 0.0032% IS. 4.5
Table 2 Frequent Treatment-related AEs by Baseline Disorder Dasatinib (n[192)
Imatinib (n[192)
Baseline CV disorder
Yes (n[43)
No (n[149)
Yes (n[43)
No (n[149)
All AEs, % Baseline DM
79 Yes (n[18)
78 No (n[174)
86 Yes (n[13)
77 No (n[179)
All AEs, % Baseline Hyperlipidemia
78 Yes (n[22)
78 No (n[170)
69 Yes (n[19)
80 No (n[173)
82
78
84
79
All AEs, %
numerically lower for patients with 0 vs 1 comorbidity. Incidence of overall AEs was comparable in the 0 and 1 comorbidity groups within both arms. Select AEs, largely grade 1/2, had a 2 times higher frequency in patients with 1 vs 0 comorbidity. PE incidence in dasatinib-treated patients appeared unrelated to baseline pulmonary comorbidity or smoking history and was most influenced by increased years of age. Treatmentrelated (Table 2) and CV AEs seemed unaffected by the presence of baseline CV disorder, DM, or hyperlipidemia. Conclusions: The superior efficacy of dasatinib over imatinib was previously demonstrated in DASISION. Although some AEs (most grade 1/ 2) occurred in patients with 1 comorbidity, these results suggest that baseline comorbidities and age did not substantially affect discontinuation rates, overall safety, or responses at 5 years in patients with CML-CP taking first-line dasatinib or imatinib. This analysis was funded by Bristol-Myers Squibb.
Abstract: CML-017 Therapy of Early Chronic Phase Chronic Myeloid Leukemia (CML-CP) with Lower Dose Dasatinib
Kiran Naqvi,1 Jorge Cortes,1 Jeffrey Skinner,1 Elias Jabbour,1 Naveen Pemmaraju,1
Gautam Borthakur,1 Zeev Estrov,1 Prithviraj Bose,1 Philip Thompson,1 Hagop Kantarjian1 1
Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA
Context: Dasatinib is a potent tyrosine kinase inhibitor (TKI) of BCR-ABL. Approved dose in the chronic phase is 100mg daily. This is however associated with notable side effects mainly myelosuppression and pleural effusion, leading to dose reductions/interruptions. Objective: To evaluate the efficacy and toxicity profile of lower dose dasatinib, at 50 mg orally daily in patients with early CML-CP. Design and Patients: All patients presenting to our institution in early CML-CP were eligible to participate. Prior TKI therapy for up to 1 month was allowed. Responses were assessed according to the European LeukemiaNet guidelines (Baccarani et al. Blood 2013 122.872:884). Results: From March 2016 to July 2017, 56 patients have been enrolled. Median age is 46 years (range 22-80). Patients categorized by Sokal risk are: low 34; intermediate 16 and high 6. Response to lower dose dasatinib is as follows: At 3 months, 93% patients had achieved early response (BCRABL PCR <10%) to therapy. Ten patients had BCR-ABL PCR < 1% (equivalent to CCyR) at 3 months but tested positive by FISH. At 6 months, 7/10 patients that were FISH positive at 3 months, achieved CCyR (FISH 0%); of these 7 patients, 6 achieved a MMR. 3/10 remaining patients that were FISH
Clinical Lymphoma, Myeloma & Leukemia October 2017
- S15
Abstracts
No. Response/total (%)
3 months
6 months
9 months
12 months
PCR <10% [IS]
40/43 (93%)
26/27 (96%)
19/20 (95%)
9/9 (100%)
CCyR MMR
23/43 (51%) 12/43 (28%)
25/27 (93%) 19/27 (70%)
18/20 (90%) 16/20 (80%)
9/9 (100%) 9/9 (100%)
MR4.0 MR4.5
1/43 (2%) 0/43 (0%)
8/27 (30%) 2/27 (7%)
14/20 (70%) 4/20 (20%)
9/9 (100%) 3/9 (33%)
positive at 3 months, have not yet reached (NR) the 6 month follow-up. Nine patients had treatment interruption of up to 14 days in the 1st 3 months of therapy: gastrointestinal bleed 2; thrombocytopenia 3; transaminitis 2; renal dysfunction 2. None of these patients required dose modification and tolerated dasatinib once it was resumed. Seven of these 9 patients with dose interruption have achieved early response to therapy while 2 patients have not yet reached the 3 month follow-up. Therapy was discontinued in 1 patient secondary to subdural hemorrhage (traumatic), while 1 patient failed to achieve CCyR at 6 months requiring increase in dasatinib dose to 100mg daily. None of the patients have developed pleural effusion so far. Conclusion: Dasatinib at 50 mg daily dose is active and well-tolerated in newly diagnosed CML-CP. It should be further explored as a new potential dose-schedule option in CML.
Abstract: CML-019 Long-Term Outcomes of Early CP CML Patients who have Achieved CCyR but Not MMR after 24 Months on Frontline Imatinib Therapy
Sung-Eun Lee,1 Won-Sik Lee,2 Hyeong-Joon Kim,3 Jee Hyun Kong,4 Yunsuk Choi,5 Young Rok Do,6 Jae-Yong Kwak,7 Sukjoong Oh,8 Sung Hyun Kim,9 Jeong-A. Kim,10 Dae Young Zang,11 Yeung-Chul Mun,12 Young-Woong Won,13 Dong-Wook Kim1 1
Department of Hematology, Seoul St. Mary’s Hospital, The
Catholic University of Korea; 2Department of Internal Medicine, Inje University College of Medicine, Inje University Busan Paik Hospital; 3
Department of Hematology-Oncology, Chonnam National University Hwasun Hospital; 4Department of Hematology-Oncology, Wonju College of Medicine, Yonsei University; 5Department of Hematology, University of Ulsan College of Medicine, Ulsan University Hospital; 6Division of Hematology-Oncology, Keimyung University, School of Medicine, Keimyung University Hospital; 7
Division of Hematology-Oncology, Chonbuk National University
Medical School, Chonbuk National University Hospital; 8Division of Hematology-Oncology, Department of Internal Medicine, School of
S16
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Clinical Lymphoma, Myeloma & Leukemia October 2017
Medicine, Sungkyunkwan University, Kangbuk Samsung Hospital; 9
Department of Internal Medicine, Dong-A University College of
Medicine, Dong-A University Hospital; 10Department of Hematology, The Catholic University of Korea, St. Vincent’s Hospital;
11
Depart-
ment of Internal Medicine, Hallym University College of Medicine, Hallym University Hospital; 12Department of Hematology, School of Medicine, Ewha Womans University, Ehwa Womans University Hospital;
13
Division of Hematology and Oncology, Department of
Internal Medicine, Hanyang Univerysity College of Medicine, Hanyang University Guri Hospital
Context: Although failure to achieve molecular response milestones on tyrosine kinase inhibitors (TKIs) therapy for chronic phase (CP) chronic myeloid leukemia (CML) means that switching to a different TKI is needed to limit the risk of progression and death, there is insufficient data to show long-term outcomes in the patients who were in a molecular failure after 24 months. Objective: The aim of this study was to evaluate longterm survival end points and identify predictive factors for an achievement of overall major molecular response (MMR) in the patients who have achieved complete cytogenetic response (CCyR) but not MMR after 24 months on frontline IM therapy. Patients: 280 newly diagnosed CP CML patients who were in CCyR but not MMR after 24 months on frontline IM therapy were evaluated. Results: With a median follow-up of 134.2 months (range, 25.6e195.0 months), 163 (58%) patients continued IM and maintained at least a CCyR, while 117 patients permanently discontinued IM due to intolerance (n ¼ 31), warnings according to ELN 2013 recommendation with adverse events (n ¼ 43), and treatment failure (n ¼ 17), progression (n ¼ 9), death (n ¼ 1), enrollment of treatment-free remission (TFR) study (n ¼ 10), and others (n ¼ 6). Among them, 98 (84%) switched to 2G TKIs. The CI rates of MMR by 3, 4, and 5 years were 27.9 2.8%, 53.6 3.3%, and 71.8 3.0%, respectively, and the CI rates of CMR by 3, 4, and 5 years were 1.9 0.8%, 5.0 1.4%, and 10.8 2.1%, respectively on IM therapy. The 10-year FFS, PFS, and OS were 89.3 2.2%, 96.0 1.3%, and 98.5 0.9%, respectively. Transcript type of b2a2 and high Sokal risk were independent factors for failure of overall MMR on IM therapy. Conclusions: This study demonstrated long-term survival outcomes in the patients who have achieved CCyR but not MMR after 24 months on frontline IM therapy. In addition, the predictive factors may provide additional information to guide clinical decisions on selecting patients who would benefit from switching to 2G TKIs in molecular failure.