- Email: [email protected]
Comparison of the Modified Low-Dose Cytarabine with 5-Day Decitabine Therapy for Elderly AML Patients Unfit for Intensive Chemotherapy
Abstracts AML-038 Mechanisms of Resistance to Volasertib and Its Combination Effect with Azacitidine Inacute Myeloid Leukemia (AML)
Figure 2 GI50 Values of Volasertib in Resistant and Parental Cells
Yoshiya Adachi , Yuichi Ishikawa, Hitoshi Kiyoi Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Aichi, Japan
Background: Polo-like kinase1 (PLK1) plays a crucial role in many steps of mitosis. Since PLK1 is overexpressed in various cancer cells, it is thought to be a target for cancer therapy, volasertib, a selective Plk1 inhibitor, showed efficacy in clinical trials for elderly AML patients. However, its efficiency is limited in monotherapy and optimization of the combination therapies with other agents are under investigation. Purpose: We evaluated the efficacy of volasertib in mono- and combination therapy with azacitidine (AZA), which is widely used for elderly patients with high-risk myelodysplastic syndrome and AML, in a series of cell lines and primary AML cells. Subsequently, we established volasertib resistant cell lines to investigate the mechanisms of its resistance. Results: Volasertib was highly potent against several kinds of cell lines and primary AML cells in monotherapy, while its potency was not always associated with the expression and phosphorylation levels of PLK1. In the combination therapy, the effect of AZA was synergic in HEL and KG1, whereas it was antagonistic in MOLM14 and MV4;11 (Figure 1). Consistently, the effect of combination therapy varied among primary AML cells. To determine the resistant mechanism of volasertib, the volasertib-resistant MOLM14, HL60, and K562 (R-MOLM14, R-HL-60, and R-K562) were established. The GI50 values in resistant and parental cells were 149.8nM and 4.6nM, 164.0nM and 5.8nM, and 1265.8nM and 14.1nM, respectively (Figure 2). Novel missense mutations in PLK1 were identified in R-MOLM14 (p.F183L) and R-HL-60 (p.L59W), and these mutant PLK1 transduced U937 revealed resistance to volasertib. R-K562 expressed higher level of MDR1
compared to the parental cells, and its sensitivity to volasertib was restored by MDR1 inhibitors. Conclusions: Volasertib was effective in leukemia cells, but the combination effect of volasertib and AZA was different among cell lines. Further investigation is required to identify the predictive factors for the efficacy of volasertib and its combination therapy with AZA. The analysis of mutations in ATPbinding domain of PLK1 and the MDR1 expression are desired in volarsertib-resistant patient cells.
AML-047 Comparison of the Modified Low-Dose Cytarabine with 5-Day Decitabine Therapy for Elderly AML Patients Unfit for Intensive Chemotherapy Byung Sik Cho , Seung-Hwan Shin, Jae-Ho Yoon, Yun-Ho Ko, Ki-Sung Eom, Hee-Je Kimi, Woo-Sung Min Department of Hematology, Catholic Blood and Marrow Trans-
Figure 1 Combination Effect of Volasertib and Azacitidine on Myeloid Cell Lines
plantation Center, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea, Seoul, Korea, Republic of (South)
Context: Classical low-dose cytarabine (LDAC; 20 mg SQ BID for 10 days) remains a standard option for elderly acute myeloid leukemia (AML) patients unfit for intensive chemotherapy, although long-term results were unsatisfactory. Recently, hypomethylating agents, such as decitabine and azacitidine, have been proved to have better outcomes than the classical LDAC. Objective: To determine whether modification of LDAC (mLDAC) by higher dose of cytarabine for an extended duration in combination with oral etoposide could improve treatment outcomes in elderly AML, we analyzed the outcomes of patients who received mLDAC compared to those who received DAC. Patients and Main Outcome Measures: Between Sep 2002 and Dec 2015, 147 elderly AML patients received mLDAC (n¼104; cytarabine 20 mg/m2 IV BID
Clinical Lymphoma, Myeloma & Leukemia September 2016
- S23
Abstracts and etoposide 50 mg PO BID for 14 days) or DAC (n¼43; 20 mg/m2 IV for 5 days). Major outcomes, including overall response (OR), complete response (CR) and overall survival (OS), were retrospectively compared between the mLDAC and DAC groups. Results: Baseline characteristics of the mLDAC and DAC groups were comparable, except a significantly higher age in the mLDAC group (68 vs. 73 yrs). Both OR (48.1% vs. 20.9%) and CR (44.2% vs. 18.6%) rates were significantly higher in the mLDAC group. The OR duration was not significantly different between the mLDAC and DAC groups (19.4 vs. 11.3 months; P ¼ 0.60). Among 21 patients with poor cytogenetics, four (26.7%) of the mLDAC group and one (16.7%) of the DAC group achieved CR. The early ( 60 days) mortality rate of the mLDAC and DAC groups was comparable (16.3% vs. 16.3%). The estimated OS rate at 1 year was also not significantly different between the mLDAC and DAC groups (45.2% vs. 46.6%). Conclusions: These results suggest that the outcomes of classical LDAC in elderly patients with AML can be improved by modifying it, even in patients with poor cytogenetics, which is comparable to DAC. Our mLDAC regimen may become another therapeutic option with emerging novel agents for elderly patients with AML, and these should be confirmed by large randomized trials.
objectives were to determine the MTD and safety of thioguanine when given with decitabine. Key secondary objectives were to evaluate the overall response rate (ORR) and progression-free survival (PFS). Results: Twelve patients (median age 67) with de novo AML (1), transformed AML (6), relapsed/refractory AML (4), and chronic myelomonocytic leukemia (1) were treated. Dose limiting toxicities included acute renal failure requiring hemodialysis (80mg/m2), persistent grade 4 leukopenia and thrombocytopenia (120mg/m2), and grade 4 sepsis preventing continued treatment (120mg/m2). 80 mg/m2 of thioguanine was determined to be the MTD. The ORR in this poor-prognosis population was 67% (7 CR+CRi+MLFS, 1 PR). Of the eight responders, six (75%) had received prior therapy. Six patients had previously received singleagent hypomethylating therapy, and five (83%) of these patients responded, showing that TG-D can rescue prior hypomethylating agent failure. Median PFS was 8 months overall (range 1-27 months) and 10 months in the responders. Conclusions: TG-D was well-tolerated and showed promising anti-leukemic activity, especially in relapsed/refractory disease. Correlative studies including chemosensitivity screening, BH3 profiling, and DNA methylation analysis are ongoing to better understand the mechanism of synergy. A multi-center Phase II trial is being planned. This trial was partially funded by a Herbert Irving Comprehensive Cancer Center Translational Research Grant.
AML-051 A Phase I Trial of a Pharmacodynamically-Conceived Thioguanine/ Decitabine Combination in Patients with Advanced Myeloid Malignancies
AML-052
Daniel Lee ,1 Todd Rosenblat,1 Mark Heaney,1 Joseph Jurcic,1 Azra Raza,1 Katherine Harwood,1 Ryan Shelton,1 Hakim Djaballah,2 Joseph Scandura,3 Anthony Letai,4 Mark Frattini1 1
Columbia University Medical Center, New York, NY, United States; Institut Pasteur Korea, Seoul, Korea, Republic of (South); 3Weill-
2
4
Clofarabine and Cytarabine Combination in Patients with Fludarabine/ Cytarabine Refractory Acute Myeloid Leukemia
,2 Emre Tekgündüz ,1 Ali Kaya,1 Sinem Bozdag 3 1 Mehmet Dogu, Mehmet Dal, Filiz Bekdemir,1 Merih Kızıl,1 Hakan Sarı,3 Fevzi Altuntas1 1
Dr. Abdurrahman Yurtaslan Ankara Oncology Training and Research
Cornell School of Medicine, New York, NY, United States; Dana-
Hospital, Hematology and BMT Clinic, Ankara, Turkey; 2Ankara Uni-
Farber Cancer Institute, Boston, MA, United States
versity School of Medicine, Department of Hematology and BMT, Ankara, Turkey; 3Pamukkale University School of Medicine, Depart-
Context: Outcomes are poor for older patients with acute myeloid leukemia (AML), high-risk myelodysplastic syndromes (MDS), or relapsed/refractory disease, and new therapies are needed. Using a chemosensitivity screening assay, we previously demonstrated that thioguanine/decitabine (TG-D) combinations can rescue therapeutic efficacy in primary leukemia cells isolated from patients with relapsed/refractory AML. Objective: To test the safety and preliminary synergistic efficacy of TG-D in patients with advanced myeloid malignancies. Design: We utilized the 3+3 Phase I design to determine the maximum tolerated dose (MTD) of thioguanine. Patients: Patients with AML who were ineligible for standard induction, relapsed/refractory AML, and high-risk or relapsed MDS were eligible. Interventions: Two thioguanine dose levels were evaluated: 80 and 120 mg/m2/day, given on Days 1-12 of induction and Days 1-7 of maintenance. Decitabine at 20mg/m2 was administered on Days 3-12 during induction and on Days 3-7 during maintenance. Main Outcomes Measured: The primary
S24
-
Clinical Lymphoma, Myeloma & Leukemia September 2016
ment of Hematology and BMT, Denizli, Turkey
Background: The long-term outcome of patients with relapsed/ refractory acute myeloid leukemia (R/R-AML) is dismal and allogeneic hematopoietic cell transplantation (allo-HCT) seems to be the only curative treatment option for these patients. Patients who undergo allo-HCT in complete remission (CR) do benefit most from the procedure. Clofarabine in combination with cytarabine (CLARA) is an effective regimen in AML patients both in frontline and R/R settings. Here we report our multicenter, retrospective experience with CLARA in patients with fludarabine/ cytarabine (FLA) refractory AML. Patients and Methods: The study included all consecutive R/R-AML patients, who received CLARA salvage during October 2010-October 2015 period. All patients were unresponsive to FLA containing salvage chemotherapy regimens and did not undergo previous allo-HCT. CLARA regimen consisted 5 days of clofarabine (20-40 mg/m2/
Figure 2 GI50 Values of Volasertib in Resistant and Parental Cells
Yoshiya Adachi , Yuichi Ishikawa, Hitoshi Kiyoi Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Aichi, Japan
Background: Polo-like kinase1 (PLK1) plays a crucial role in many steps of mitosis. Since PLK1 is overexpressed in various cancer cells, it is thought to be a target for cancer therapy, volasertib, a selective Plk1 inhibitor, showed efficacy in clinical trials for elderly AML patients. However, its efficiency is limited in monotherapy and optimization of the combination therapies with other agents are under investigation. Purpose: We evaluated the efficacy of volasertib in mono- and combination therapy with azacitidine (AZA), which is widely used for elderly patients with high-risk myelodysplastic syndrome and AML, in a series of cell lines and primary AML cells. Subsequently, we established volasertib resistant cell lines to investigate the mechanisms of its resistance. Results: Volasertib was highly potent against several kinds of cell lines and primary AML cells in monotherapy, while its potency was not always associated with the expression and phosphorylation levels of PLK1. In the combination therapy, the effect of AZA was synergic in HEL and KG1, whereas it was antagonistic in MOLM14 and MV4;11 (Figure 1). Consistently, the effect of combination therapy varied among primary AML cells. To determine the resistant mechanism of volasertib, the volasertib-resistant MOLM14, HL60, and K562 (R-MOLM14, R-HL-60, and R-K562) were established. The GI50 values in resistant and parental cells were 149.8nM and 4.6nM, 164.0nM and 5.8nM, and 1265.8nM and 14.1nM, respectively (Figure 2). Novel missense mutations in PLK1 were identified in R-MOLM14 (p.F183L) and R-HL-60 (p.L59W), and these mutant PLK1 transduced U937 revealed resistance to volasertib. R-K562 expressed higher level of MDR1
compared to the parental cells, and its sensitivity to volasertib was restored by MDR1 inhibitors. Conclusions: Volasertib was effective in leukemia cells, but the combination effect of volasertib and AZA was different among cell lines. Further investigation is required to identify the predictive factors for the efficacy of volasertib and its combination therapy with AZA. The analysis of mutations in ATPbinding domain of PLK1 and the MDR1 expression are desired in volarsertib-resistant patient cells.
AML-047 Comparison of the Modified Low-Dose Cytarabine with 5-Day Decitabine Therapy for Elderly AML Patients Unfit for Intensive Chemotherapy Byung Sik Cho , Seung-Hwan Shin, Jae-Ho Yoon, Yun-Ho Ko, Ki-Sung Eom, Hee-Je Kimi, Woo-Sung Min Department of Hematology, Catholic Blood and Marrow Trans-
Figure 1 Combination Effect of Volasertib and Azacitidine on Myeloid Cell Lines
plantation Center, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea, Seoul, Korea, Republic of (South)
Context: Classical low-dose cytarabine (LDAC; 20 mg SQ BID for 10 days) remains a standard option for elderly acute myeloid leukemia (AML) patients unfit for intensive chemotherapy, although long-term results were unsatisfactory. Recently, hypomethylating agents, such as decitabine and azacitidine, have been proved to have better outcomes than the classical LDAC. Objective: To determine whether modification of LDAC (mLDAC) by higher dose of cytarabine for an extended duration in combination with oral etoposide could improve treatment outcomes in elderly AML, we analyzed the outcomes of patients who received mLDAC compared to those who received DAC. Patients and Main Outcome Measures: Between Sep 2002 and Dec 2015, 147 elderly AML patients received mLDAC (n¼104; cytarabine 20 mg/m2 IV BID
Clinical Lymphoma, Myeloma & Leukemia September 2016
- S23
Abstracts and etoposide 50 mg PO BID for 14 days) or DAC (n¼43; 20 mg/m2 IV for 5 days). Major outcomes, including overall response (OR), complete response (CR) and overall survival (OS), were retrospectively compared between the mLDAC and DAC groups. Results: Baseline characteristics of the mLDAC and DAC groups were comparable, except a significantly higher age in the mLDAC group (68 vs. 73 yrs). Both OR (48.1% vs. 20.9%) and CR (44.2% vs. 18.6%) rates were significantly higher in the mLDAC group. The OR duration was not significantly different between the mLDAC and DAC groups (19.4 vs. 11.3 months; P ¼ 0.60). Among 21 patients with poor cytogenetics, four (26.7%) of the mLDAC group and one (16.7%) of the DAC group achieved CR. The early ( 60 days) mortality rate of the mLDAC and DAC groups was comparable (16.3% vs. 16.3%). The estimated OS rate at 1 year was also not significantly different between the mLDAC and DAC groups (45.2% vs. 46.6%). Conclusions: These results suggest that the outcomes of classical LDAC in elderly patients with AML can be improved by modifying it, even in patients with poor cytogenetics, which is comparable to DAC. Our mLDAC regimen may become another therapeutic option with emerging novel agents for elderly patients with AML, and these should be confirmed by large randomized trials.
objectives were to determine the MTD and safety of thioguanine when given with decitabine. Key secondary objectives were to evaluate the overall response rate (ORR) and progression-free survival (PFS). Results: Twelve patients (median age 67) with de novo AML (1), transformed AML (6), relapsed/refractory AML (4), and chronic myelomonocytic leukemia (1) were treated. Dose limiting toxicities included acute renal failure requiring hemodialysis (80mg/m2), persistent grade 4 leukopenia and thrombocytopenia (120mg/m2), and grade 4 sepsis preventing continued treatment (120mg/m2). 80 mg/m2 of thioguanine was determined to be the MTD. The ORR in this poor-prognosis population was 67% (7 CR+CRi+MLFS, 1 PR). Of the eight responders, six (75%) had received prior therapy. Six patients had previously received singleagent hypomethylating therapy, and five (83%) of these patients responded, showing that TG-D can rescue prior hypomethylating agent failure. Median PFS was 8 months overall (range 1-27 months) and 10 months in the responders. Conclusions: TG-D was well-tolerated and showed promising anti-leukemic activity, especially in relapsed/refractory disease. Correlative studies including chemosensitivity screening, BH3 profiling, and DNA methylation analysis are ongoing to better understand the mechanism of synergy. A multi-center Phase II trial is being planned. This trial was partially funded by a Herbert Irving Comprehensive Cancer Center Translational Research Grant.
AML-051 A Phase I Trial of a Pharmacodynamically-Conceived Thioguanine/ Decitabine Combination in Patients with Advanced Myeloid Malignancies
AML-052
Daniel Lee ,1 Todd Rosenblat,1 Mark Heaney,1 Joseph Jurcic,1 Azra Raza,1 Katherine Harwood,1 Ryan Shelton,1 Hakim Djaballah,2 Joseph Scandura,3 Anthony Letai,4 Mark Frattini1 1
Columbia University Medical Center, New York, NY, United States; Institut Pasteur Korea, Seoul, Korea, Republic of (South); 3Weill-
2
4
Clofarabine and Cytarabine Combination in Patients with Fludarabine/ Cytarabine Refractory Acute Myeloid Leukemia
,2 Emre Tekgündüz ,1 Ali Kaya,1 Sinem Bozdag 3 1 Mehmet Dogu, Mehmet Dal, Filiz Bekdemir,1 Merih Kızıl,1 Hakan Sarı,3 Fevzi Altuntas1 1
Dr. Abdurrahman Yurtaslan Ankara Oncology Training and Research
Cornell School of Medicine, New York, NY, United States; Dana-
Hospital, Hematology and BMT Clinic, Ankara, Turkey; 2Ankara Uni-
Farber Cancer Institute, Boston, MA, United States
versity School of Medicine, Department of Hematology and BMT, Ankara, Turkey; 3Pamukkale University School of Medicine, Depart-
Context: Outcomes are poor for older patients with acute myeloid leukemia (AML), high-risk myelodysplastic syndromes (MDS), or relapsed/refractory disease, and new therapies are needed. Using a chemosensitivity screening assay, we previously demonstrated that thioguanine/decitabine (TG-D) combinations can rescue therapeutic efficacy in primary leukemia cells isolated from patients with relapsed/refractory AML. Objective: To test the safety and preliminary synergistic efficacy of TG-D in patients with advanced myeloid malignancies. Design: We utilized the 3+3 Phase I design to determine the maximum tolerated dose (MTD) of thioguanine. Patients: Patients with AML who were ineligible for standard induction, relapsed/refractory AML, and high-risk or relapsed MDS were eligible. Interventions: Two thioguanine dose levels were evaluated: 80 and 120 mg/m2/day, given on Days 1-12 of induction and Days 1-7 of maintenance. Decitabine at 20mg/m2 was administered on Days 3-12 during induction and on Days 3-7 during maintenance. Main Outcomes Measured: The primary
S24
-
Clinical Lymphoma, Myeloma & Leukemia September 2016
ment of Hematology and BMT, Denizli, Turkey
Background: The long-term outcome of patients with relapsed/ refractory acute myeloid leukemia (R/R-AML) is dismal and allogeneic hematopoietic cell transplantation (allo-HCT) seems to be the only curative treatment option for these patients. Patients who undergo allo-HCT in complete remission (CR) do benefit most from the procedure. Clofarabine in combination with cytarabine (CLARA) is an effective regimen in AML patients both in frontline and R/R settings. Here we report our multicenter, retrospective experience with CLARA in patients with fludarabine/ cytarabine (FLA) refractory AML. Patients and Methods: The study included all consecutive R/R-AML patients, who received CLARA salvage during October 2010-October 2015 period. All patients were unresponsive to FLA containing salvage chemotherapy regimens and did not undergo previous allo-HCT. CLARA regimen consisted 5 days of clofarabine (20-40 mg/m2/