CC-486 (ORAL AZACITIDINE) IN PATIENTS WITH MYELODYSPLASTIC SYNDROMES (MDS) WITH OR WITHOUT PRETREATMENT THROMBOCYTOPENIA
(Abstract release date: 05/19/16)
EHA Library. Garcia-Manero G. 06/10/16; 135162; S129
Guillermo Garcia-Manero
Contributions
Contributions
Abstract
Abstract: S129
Type: Oral Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 11:45 - 12:00
Location: Hall C14
Background
The estimated prevalence of thrombocytopenia in MDS is 40-65% (Kantarjian, Cancer, 2007). Severe thrombocytopenia (platelet count <30x109/L) is one of the worst prognostic factors for patients (pts) with MDS (Garcia-Manero, Am J Hematol, 2015). It has been suggested that pts with IPSS Low or Intermediate (Int)-1 risk MDS with severe thrombocytopenia should be considered higher-risk and receive disease-modifying therapy (DMT) at diagnosis (Gonzalez-Porras, Cancer, 2011). Like other DMTs, azacitidine (AZA) is associated with transient exacerbation of cytopenias during early treatment (Tx), which improve as Tx continues (Santini, Eur J Haematol, 2010). CC-486, the oral formulation of AZA, is in clinical development for Tx of hematologic malignancies, including MDS.
Aims
Evaluate the safety and efficacy of CC-486 monotherapy in pts with MDS with or without pretreatment thrombocytopenia.
Methods
Pts with MDS from three phase 1/2 CC-486 studies, two of which included dose-finding periods, were included in these analyses. CC-486 dosing regimens were: 120-600mg x7 days (d) (following a single SC AZA 75mg/m2 x7d/28d cycle), or (with no initial SC AZA cycle) 300mg QD or 200mg BID x14d or 21d. All dosing regimens were administered in repeated 28d cycles. Thrombocytopenia was defined as platelet count ≤75x109/L. Overall Response included complete remission (CR), partial remission (PR), hematologic improvement (HI), and transfusion independence (TI) (Cheson, Blood, 2006).
Results
In all, 137 MDS pts participated in the three studies, including 72 pts with platelet counts ≤75x109/L (LowPlt group). Median age of all pts was 72 years (range 31-91). Median platelet count at baseline in the LowPlt group was 32.5x109/L (range 2-75) and in pts with platelet counts >75x109/L (HiPlt group) was 162x109/L (78-593). At entry, pts in the LowPlt cohort were less likely to have WHO-defined refractory anemia (15% vs 42% of pts in the HiPlt group) and more likely to have higher-risk (IPSS Int-2 or high) MDS (31% vs 12%, respectively). Rate of CR+PR was 22% in the LowPlt cohort and 7% in the HiPlt cohort, and Overall Response was the same in both groups (42%, Table). In the LowPlt group, 2 pts (14%) attained platelet TI and 17 pts (24%) attained HI-P. The most frequent Grade 3-4 treatment-emergent adverse events were hematological; anemia, neutropenia, febrile neutropenia, and thrombocytopenia occurred in 17%, 13%, 18%, and 21%, respectively, of pts in the LowPlt group, and in 26%, 26%, 14%, and 14% of pts in the HiPlt group. Grade 3-4 bleeding events were infrequent (n=9, 6.6%) and did not occur more often in the LowPlt group (GI [n=2], vaginal or cerebral hemorrhage [n=1 each]) than in the HiPlt group (GI [n=4] or ear hemorrhage [n=1]). Six deaths occurred during CC-486 treatment, 4 in the LowPlt group and 2 in the HiPlt group, including a 93-yr-old HiPlt pt who died of GI hemorrhage related to a duodenal ulcer.
Conclusion
CC-486 was generally well tolerated in these MDS pts, even in the LowPlt group with median pretreatment platelet counts bordering on severe thrombocytopenia. Grade 3-4 bleeding events were uncommon overall and occurred less frequently in the LowPlt group. Death was more frequent in the LowPlt cohort, consistent with the poor prognosis associated with marked thrombocytopenia. However, more than 20% of pts in the LowPlt group attained CR during CC-486 therapy and pts were equally likely to attain HI whether in the LowPlt or HiPlt group.
Session topic: Myelodysplastic syndromes - Clinical
Keyword(s): MDS, Thrombocytopenia
Type: Oral Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 11:45 - 12:00
Location: Hall C14
Background
The estimated prevalence of thrombocytopenia in MDS is 40-65% (Kantarjian, Cancer, 2007). Severe thrombocytopenia (platelet count <30x109/L) is one of the worst prognostic factors for patients (pts) with MDS (Garcia-Manero, Am J Hematol, 2015). It has been suggested that pts with IPSS Low or Intermediate (Int)-1 risk MDS with severe thrombocytopenia should be considered higher-risk and receive disease-modifying therapy (DMT) at diagnosis (Gonzalez-Porras, Cancer, 2011). Like other DMTs, azacitidine (AZA) is associated with transient exacerbation of cytopenias during early treatment (Tx), which improve as Tx continues (Santini, Eur J Haematol, 2010). CC-486, the oral formulation of AZA, is in clinical development for Tx of hematologic malignancies, including MDS.
Aims
Evaluate the safety and efficacy of CC-486 monotherapy in pts with MDS with or without pretreatment thrombocytopenia.
Methods
Pts with MDS from three phase 1/2 CC-486 studies, two of which included dose-finding periods, were included in these analyses. CC-486 dosing regimens were: 120-600mg x7 days (d) (following a single SC AZA 75mg/m2 x7d/28d cycle), or (with no initial SC AZA cycle) 300mg QD or 200mg BID x14d or 21d. All dosing regimens were administered in repeated 28d cycles. Thrombocytopenia was defined as platelet count ≤75x109/L. Overall Response included complete remission (CR), partial remission (PR), hematologic improvement (HI), and transfusion independence (TI) (Cheson, Blood, 2006).
Results
In all, 137 MDS pts participated in the three studies, including 72 pts with platelet counts ≤75x109/L (LowPlt group). Median age of all pts was 72 years (range 31-91). Median platelet count at baseline in the LowPlt group was 32.5x109/L (range 2-75) and in pts with platelet counts >75x109/L (HiPlt group) was 162x109/L (78-593). At entry, pts in the LowPlt cohort were less likely to have WHO-defined refractory anemia (15% vs 42% of pts in the HiPlt group) and more likely to have higher-risk (IPSS Int-2 or high) MDS (31% vs 12%, respectively). Rate of CR+PR was 22% in the LowPlt cohort and 7% in the HiPlt cohort, and Overall Response was the same in both groups (42%, Table). In the LowPlt group, 2 pts (14%) attained platelet TI and 17 pts (24%) attained HI-P. The most frequent Grade 3-4 treatment-emergent adverse events were hematological; anemia, neutropenia, febrile neutropenia, and thrombocytopenia occurred in 17%, 13%, 18%, and 21%, respectively, of pts in the LowPlt group, and in 26%, 26%, 14%, and 14% of pts in the HiPlt group. Grade 3-4 bleeding events were infrequent (n=9, 6.6%) and did not occur more often in the LowPlt group (GI [n=2], vaginal or cerebral hemorrhage [n=1 each]) than in the HiPlt group (GI [n=4] or ear hemorrhage [n=1]). Six deaths occurred during CC-486 treatment, 4 in the LowPlt group and 2 in the HiPlt group, including a 93-yr-old HiPlt pt who died of GI hemorrhage related to a duodenal ulcer.
Conclusion
CC-486 was generally well tolerated in these MDS pts, even in the LowPlt group with median pretreatment platelet counts bordering on severe thrombocytopenia. Grade 3-4 bleeding events were uncommon overall and occurred less frequently in the LowPlt group. Death was more frequent in the LowPlt cohort, consistent with the poor prognosis associated with marked thrombocytopenia. However, more than 20% of pts in the LowPlt group attained CR during CC-486 therapy and pts were equally likely to attain HI whether in the LowPlt or HiPlt group.
Session topic: Myelodysplastic syndromes - Clinical
Keyword(s): MDS, Thrombocytopenia
Abstract: S129
Type: Oral Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 11:45 - 12:00
Location: Hall C14
Background
The estimated prevalence of thrombocytopenia in MDS is 40-65% (Kantarjian, Cancer, 2007). Severe thrombocytopenia (platelet count <30x109/L) is one of the worst prognostic factors for patients (pts) with MDS (Garcia-Manero, Am J Hematol, 2015). It has been suggested that pts with IPSS Low or Intermediate (Int)-1 risk MDS with severe thrombocytopenia should be considered higher-risk and receive disease-modifying therapy (DMT) at diagnosis (Gonzalez-Porras, Cancer, 2011). Like other DMTs, azacitidine (AZA) is associated with transient exacerbation of cytopenias during early treatment (Tx), which improve as Tx continues (Santini, Eur J Haematol, 2010). CC-486, the oral formulation of AZA, is in clinical development for Tx of hematologic malignancies, including MDS.
Aims
Evaluate the safety and efficacy of CC-486 monotherapy in pts with MDS with or without pretreatment thrombocytopenia.
Methods
Pts with MDS from three phase 1/2 CC-486 studies, two of which included dose-finding periods, were included in these analyses. CC-486 dosing regimens were: 120-600mg x7 days (d) (following a single SC AZA 75mg/m2 x7d/28d cycle), or (with no initial SC AZA cycle) 300mg QD or 200mg BID x14d or 21d. All dosing regimens were administered in repeated 28d cycles. Thrombocytopenia was defined as platelet count ≤75x109/L. Overall Response included complete remission (CR), partial remission (PR), hematologic improvement (HI), and transfusion independence (TI) (Cheson, Blood, 2006).
Results
In all, 137 MDS pts participated in the three studies, including 72 pts with platelet counts ≤75x109/L (LowPlt group). Median age of all pts was 72 years (range 31-91). Median platelet count at baseline in the LowPlt group was 32.5x109/L (range 2-75) and in pts with platelet counts >75x109/L (HiPlt group) was 162x109/L (78-593). At entry, pts in the LowPlt cohort were less likely to have WHO-defined refractory anemia (15% vs 42% of pts in the HiPlt group) and more likely to have higher-risk (IPSS Int-2 or high) MDS (31% vs 12%, respectively). Rate of CR+PR was 22% in the LowPlt cohort and 7% in the HiPlt cohort, and Overall Response was the same in both groups (42%, Table). In the LowPlt group, 2 pts (14%) attained platelet TI and 17 pts (24%) attained HI-P. The most frequent Grade 3-4 treatment-emergent adverse events were hematological; anemia, neutropenia, febrile neutropenia, and thrombocytopenia occurred in 17%, 13%, 18%, and 21%, respectively, of pts in the LowPlt group, and in 26%, 26%, 14%, and 14% of pts in the HiPlt group. Grade 3-4 bleeding events were infrequent (n=9, 6.6%) and did not occur more often in the LowPlt group (GI [n=2], vaginal or cerebral hemorrhage [n=1 each]) than in the HiPlt group (GI [n=4] or ear hemorrhage [n=1]). Six deaths occurred during CC-486 treatment, 4 in the LowPlt group and 2 in the HiPlt group, including a 93-yr-old HiPlt pt who died of GI hemorrhage related to a duodenal ulcer.
Conclusion
CC-486 was generally well tolerated in these MDS pts, even in the LowPlt group with median pretreatment platelet counts bordering on severe thrombocytopenia. Grade 3-4 bleeding events were uncommon overall and occurred less frequently in the LowPlt group. Death was more frequent in the LowPlt cohort, consistent with the poor prognosis associated with marked thrombocytopenia. However, more than 20% of pts in the LowPlt group attained CR during CC-486 therapy and pts were equally likely to attain HI whether in the LowPlt or HiPlt group.
Session topic: Myelodysplastic syndromes - Clinical
Keyword(s): MDS, Thrombocytopenia
Type: Oral Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 11:45 - 12:00
Location: Hall C14
Background
The estimated prevalence of thrombocytopenia in MDS is 40-65% (Kantarjian, Cancer, 2007). Severe thrombocytopenia (platelet count <30x109/L) is one of the worst prognostic factors for patients (pts) with MDS (Garcia-Manero, Am J Hematol, 2015). It has been suggested that pts with IPSS Low or Intermediate (Int)-1 risk MDS with severe thrombocytopenia should be considered higher-risk and receive disease-modifying therapy (DMT) at diagnosis (Gonzalez-Porras, Cancer, 2011). Like other DMTs, azacitidine (AZA) is associated with transient exacerbation of cytopenias during early treatment (Tx), which improve as Tx continues (Santini, Eur J Haematol, 2010). CC-486, the oral formulation of AZA, is in clinical development for Tx of hematologic malignancies, including MDS.
Aims
Evaluate the safety and efficacy of CC-486 monotherapy in pts with MDS with or without pretreatment thrombocytopenia.
Methods
Pts with MDS from three phase 1/2 CC-486 studies, two of which included dose-finding periods, were included in these analyses. CC-486 dosing regimens were: 120-600mg x7 days (d) (following a single SC AZA 75mg/m2 x7d/28d cycle), or (with no initial SC AZA cycle) 300mg QD or 200mg BID x14d or 21d. All dosing regimens were administered in repeated 28d cycles. Thrombocytopenia was defined as platelet count ≤75x109/L. Overall Response included complete remission (CR), partial remission (PR), hematologic improvement (HI), and transfusion independence (TI) (Cheson, Blood, 2006).
Results
In all, 137 MDS pts participated in the three studies, including 72 pts with platelet counts ≤75x109/L (LowPlt group). Median age of all pts was 72 years (range 31-91). Median platelet count at baseline in the LowPlt group was 32.5x109/L (range 2-75) and in pts with platelet counts >75x109/L (HiPlt group) was 162x109/L (78-593). At entry, pts in the LowPlt cohort were less likely to have WHO-defined refractory anemia (15% vs 42% of pts in the HiPlt group) and more likely to have higher-risk (IPSS Int-2 or high) MDS (31% vs 12%, respectively). Rate of CR+PR was 22% in the LowPlt cohort and 7% in the HiPlt cohort, and Overall Response was the same in both groups (42%, Table). In the LowPlt group, 2 pts (14%) attained platelet TI and 17 pts (24%) attained HI-P. The most frequent Grade 3-4 treatment-emergent adverse events were hematological; anemia, neutropenia, febrile neutropenia, and thrombocytopenia occurred in 17%, 13%, 18%, and 21%, respectively, of pts in the LowPlt group, and in 26%, 26%, 14%, and 14% of pts in the HiPlt group. Grade 3-4 bleeding events were infrequent (n=9, 6.6%) and did not occur more often in the LowPlt group (GI [n=2], vaginal or cerebral hemorrhage [n=1 each]) than in the HiPlt group (GI [n=4] or ear hemorrhage [n=1]). Six deaths occurred during CC-486 treatment, 4 in the LowPlt group and 2 in the HiPlt group, including a 93-yr-old HiPlt pt who died of GI hemorrhage related to a duodenal ulcer.
Conclusion
CC-486 was generally well tolerated in these MDS pts, even in the LowPlt group with median pretreatment platelet counts bordering on severe thrombocytopenia. Grade 3-4 bleeding events were uncommon overall and occurred less frequently in the LowPlt group. Death was more frequent in the LowPlt cohort, consistent with the poor prognosis associated with marked thrombocytopenia. However, more than 20% of pts in the LowPlt group attained CR during CC-486 therapy and pts were equally likely to attain HI whether in the LowPlt or HiPlt group.
Session topic: Myelodysplastic syndromes - Clinical
Keyword(s): MDS, Thrombocytopenia
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