among these patients , sy-1425 in combination with azacitidine was generally well-tolerated , with no evidence of increased toxicity relative to either as a single agent , including rates of myelosuppression that were comparable to single-agent azacitidine . as of the data cut-off , of the 18 rara-positive patients that were evaluable for clinical response , the overall response rate , or orr , was 67 % , with a composite complete response rate of 61 % , with 50 % of patients achieving complete response , or cr , and 11 % achieving a complete response with incomplete blood count recovery , or cri . the median time to initial response was 1.2 months , the median duration of response was 10.8 months , and the median overall survival , or os , among patients who achieved a cr or cri was 18 months . as of the data cut-off , of the 28 rara-negative patients that were evaluable for clinical response , the 78 orr was 43 % , with a composite complete response rate of 32 % , with 25 % of patients achieving cr and 7 % achieving cri . the median time to initial response was 3.0 months , and the median duration of response was 10 . 3 months . we also presented new translational data demonstrating that most rara-positive newly diagnosed unfit aml patients have a monocytic disease phenotype that is highly correlated with resistance to upfront treatment with venetoclax and azacitidine . these data suggest that the rara biomarker not only selects for patients who are more likely to respond to treatment with sy-1425 but also for patients who are less likely to respond to treatment with venetoclax and azacitidine . approximately 18,000 patients are diagnosed with unfit aml in the united states and europe annually and we expect the overall total addressable market opportunity for aml to grow to be in excess of $ 2 billion by 2029. at ash 2020 , we also announced that sy-1425 in combination with azacitidine was generally well-tolerated in the r/r aml patient population . among the 21 r/r aml patients who were evaluable for clinical response as of the data cut-off , the orr was 19 % , and the median os was 5.9 months . in hypomethylating agent , or hma , and venetoclax naïve patients , the orr was 43 % . based on these data and our assessment of ongoing areas of high unmet need , we are advancing sy-1425 in combination with azacitidine into a registration-enabling phase 3 clinical trial in rara-positive newly diagnosed hr-mds patients . hr-mds is a hematologic malignancy that is closely related to aml , and as in aml , about 30 % of hr-mds patients are rara-positive . approximately 15,000 patients are diagnosed with hr-mds in the united states and europe annually and we expect the total addressable market opportunity for hr-mds to grow to be in excess of $ 1 billion by 2029. we plan to enroll approximately 190 rara-positive newly diagnosed hr-mds patients in the double-blind placebo-controlled trial , randomized 2:1 to receive sy-1425 in combination with azacitidine or placebo with azacitidine , respectively . the primary endpoint of the trial will be the cr rate . we opened the phase 3 clinical trial for enrollment in february 2021 and are actively screening patients . the trial , if successful , could enable us to submit to the u.s. food and drug administration , or fda , a new drug application , or nda , as early as 2024 . in addition , we plan to advance sy-1425 in combination with venetoclax and azacitidine in rara-positive newly diagnosed unfit aml patients . the trial is designed with a single-arm safety lead-in to confirm the dosing regimen of the triplet to be used in the randomized portion of the phase 2 clinical trial , which will evaluate the safety and efficacy of sy-1425 in combination with venetoclax and azacitidine compared to venetoclax and azacitidine in approximately 80 patients randomized 1:1. the primary endpoint of the trial will be the composite cr rate . the trial will also evaluate the triplet as a salvage therapy in patients who do not respond to venetoclax and azacitidine . we expect to initiate the phase 2 clinical trial in the second half of 2021 , and we expect to report initial data from the trial in 2022. sy-2101 in december 2020 , we acquired from orsenix , llc , or orsenix , a novel oral form of ato , which we refer to as sy-2101 . sy-2101 is in development for the treatment of apl , a subtype of aml defined by a fusion of the rara and promyelocytic leukemia , or pml , genes . approximately 2,000 patients are diagnosed with apl in the united states and europe annually , representing a potential total addressable market opportunity for apl of approximately $ 250 million based on current pricing estimates . an intravenously administered , or iv , formulation of ato is approved for use in combination with all-trans-retinoic-acid , or atra , in patients with newly diagnosed apl and , while curative in more than 80 % of patients , its administration requires up to 140 two- to four-hour infusions over the typical course of induction and consolidation treatment . because sy-2101 is dosed orally once daily , we believe it has the potential to become the standard-of-care frontline therapy for apl by providing comparable efficacy with a substantially more convenient option that reduces the treatment burden on patients , improving access , and lowering costs to the healthcare system . in a phase 1 clinical trial , sy-2101 demonstrated bioavailability , pharmacokinetic , or pk , exposures similar to iv ato , and a generally well-tolerated safety profile . story_separator_special_tag for collaboration arrangements within the scope of asc 808 that contain multiple elements , we first determine which elements of the collaboration are deemed to be within the scope of asc 808 and those that are more reflective of a vendor-customer relationship and therefore within the scope of asc 606. for elements of collaboration arrangements that are accounted for pursuant to asc 808 , an appropriate recognition method is determined and applied consistently , generally by analogy to asc 606. for those elements of the arrangement that are accounted for pursuant to asc 606 , we apply the five-step model described above . 83 research and development expenses expenditures relating to research and development are expensed in the period incurred . research and development expenses consist of both internal and external costs associated with the development of our gene control platform and product candidates . research and development costs include salaries and benefits , materials and supplies , external research , preclinical and clinical development expenses , stock-based compensation expense and facilities costs . facilities costs primarily include the allocation of rent , utilities , depreciation and amortization . in certain circumstances , we are required to make nonrefundable advance payments to vendors for goods or services that will be received in the future for use in research and development activities . in such circumstances , the nonrefundable advance payments are deferred and capitalized , even when there is no alternative future use for the research and development , until related goods or services are provided . we record accruals for estimated ongoing research costs . when evaluating the adequacy of the accrued liabilities , we analyze progress of the work being performed , including the phase or completion of the event , invoices received and costs . significant judgements and estimates may be made in determining the accrued balances at the end of any reporting period . actual results could differ from our estimates . we may in-license the rights to develop and commercialize product candidates . for each in-license transaction , we evaluate whether we have acquired processes or activities along with inputs that would be sufficient to constitute a “ business ” as defined under u.s. gaap . a “ business ” as defined under u.s. gaap consists of inputs and processes applied to those inputs that have the ability to create outputs . although businesses usually have outputs , outputs are not required for an integrated set of activities to qualify as a business . when we determine that we have not acquired sufficient processes or activities to constitute a business , any up-front payments , as well as milestone payments , are immediately expensed as acquired research and development in the period in which they are incurred . warrants we account for our issued warrants as either liability or equity in accordance with asc 480-10 , accounting for certain financial instruments with characteristics of both liabilities and equity , or asc 480-10 , or asc 815-40 , accounting for derivative financial instruments indexed to , and potentially settled in , a company 's own stock , or asc 815-40. under asc 480-10 , warrants are considered liability if they are mandatorily redeemable and they require settlement in cash or other assets , or a variable number of shares . if warrants do not meet liability classification under asc 480-10 , we consider the requirements of asc 815-40 to determine whether the warrants should be classified as liability or equity . under asc 815-40 , contracts that may require settlement for cash are liabilities , regardless of the probability of the occurrence of the triggering event . liability classified warrants are measured at fair value on the issuance date and at the end of each reporting period . any change in the fair value of the warrants after the issuance date is recorded in the consolidated statements of operations as a gain or loss . if warrants do not require liability classification under asc 815-40 , in order to conclude warrants should be classified as equity , the company assesses whether the warrants are indexed to its common stock and whether the warrants are classified as equity under asc 815-40 or other applicable gaap . equity classified warrants are accounted for at fair value on the issuance date with no changes in fair value recognized after the issuance date . on december 8 , 2020 , through a private placement , we issued 10,312,500 shares of our common stock and , in lieu of common stock , pre-funded warrants to purchase an aggregate of 1,000,000 shares of common stock , and , in each case , accompanying warrants to purchase an aggregate of up to 2,828,125 additional shares of common stock ( or pre-funded warrants to purchase common stock in lieu thereof ) at a price of $ 8.00 per share and accompanying warrant ( or $ 7.99 per pre-funded warrant and accompanying warrant ) . the private placement resulted in aggregate gross proceeds of $ 90.5 million , before $ 0.4 million of transaction costs . 84 in the event of certain fundamental transactions , t he holders of warrants may require us to make a payment based on a black-scholes valuation , using specified inputs . the holders of the p re - f unded w arrants issued in the december 2020 private placement do not have similar rights . therefore , we accounted for the warrants as a liabilit y , while the p re - f unded w arrants met the permanent equity criteria classification . the pre-funded w arrants are classified as a component of permanent equity because they are freestanding financial instruments that are legally detachable and separately exercisable from the shares of common stock with which they were issued , are immediately exercisable , do not embody an obligation for us to repurchase those shares , and permit the holders to receive a fixed number of shares of common

cash flows the following table provides information regarding our cash flows for the years ended december 31 , 2020 , 2019 and 2018 ( in thousands ) : replace_table_token_9_th net cash used in operating activities the use of cash in all periods presented resulted primarily from our net losses adjusted for non-cash charges and changes in components of working capital . net cash used in operating activities was $ 57.4 million during the year ended december 31 , 2020 , compared to $ 60.3 million during the year ended december 31 , 2019. the decrease in cash used in operating activities was primarily due to a $ 20.0 million collection of the advanced payment pursuant to our collaboration agreement with gbt , offset by higher operating expenses associated with our ongoing preclinical and clinical development activities and the asset acquisition of sy-2101 during the year ended december 31 , 2020. net cash used in operating activities was $ 60.3 million during the year ended december 31 , 2019 , compared to $ 40.3 million during the year ended december 31 , 2018. the increase in cash used in operating activities was primarily due to a $ 13.1 million increase in our net loss from continuing operations and proceeds received upon entry into the incyte target discovery collaboration during the year ended december 31 , 2018 that did not reoccur in 2019. net cash provided by ( used in ) investing activities net cash provided by investing activities was $ 46.7 million during the year ended december 31 , 2020 , compared to net cash used in investing activities of $ 11.7 million during the year ended december 31 , 2019. the change in net cash provided by investing activities was primarily due to our reinvestment of $ 50.0 million of our funds from marketable securities upon their maturities into cash equivalents


 Write a concise suspicious activity report of the following text delimited by triple backquotes. Return your response as a formal report which covers the key points highlighting the location,dates,entity names and account holder information in chronological order of the text.
     ```cash flows the following table provides information regarding our cash flows for the years ended december 31 , 2020 , 2019 and 2018 ( in thousands ) : replace_table_token_9_th net cash used in operating activities the use of cash in all periods presented resulted primarily from our net losses adjusted for non-cash charges and changes in components of working capital . net cash used in operating activities was $ 57.4 million during the year ended december 31 , 2020 , compared to $ 60.3 million during the year ended december 31 , 2019. the decrease in cash used in operating activities was primarily due to a $ 20.0 million collection of the advanced payment pursuant to our collaboration agreement with gbt , offset by higher operating expenses associated with our ongoing preclinical and clinical development activities and the asset acquisition of sy-2101 during the year ended december 31 , 2020. net cash used in operating activities was $ 60.3 million during the year ended december 31 , 2019 , compared to $ 40.3 million during the year ended december 31 , 2018. the increase in cash used in operating activities was primarily due to a $ 13.1 million increase in our net loss from continuing operations and proceeds received upon entry into the incyte target discovery collaboration during the year ended december 31 , 2018 that did not reoccur in 2019. net cash provided by ( used in ) investing activities net cash provided by investing activities was $ 46.7 million during the year ended december 31 , 2020 , compared to net cash used in investing activities of $ 11.7 million during the year ended december 31 , 2019. the change in net cash provided by investing activities was primarily due to our reinvestment of $ 50.0 million of our funds from marketable securities upon their maturities into cash equivalents
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 Suspicious Activity Report : among these patients , sy-1425 in combination with azacitidine was generally well-tolerated , with no evidence of increased toxicity relative to either as a single agent , including rates of myelosuppression that were comparable to single-agent azacitidine . as of the data cut-off , of the 18 rara-positive patients that were evaluable for clinical response , the overall response rate , or orr , was 67 % , with a composite complete response rate of 61 % , with 50 % of patients achieving complete response , or cr , and 11 % achieving a complete response with incomplete blood count recovery , or cri . the median time to initial response was 1.2 months , the median duration of response was 10.8 months , and the median overall survival , or os , among patients who achieved a cr or cri was 18 months . as of the data cut-off , of the 28 rara-negative patients that were evaluable for clinical response , the 78 orr was 43 % , with a composite complete response rate of 32 % , with 25 % of patients achieving cr and 7 % achieving cri . the median time to initial response was 3.0 months , and the median duration of response was 10 . 3 months . we also presented new translational data demonstrating that most rara-positive newly diagnosed unfit aml patients have a monocytic disease phenotype that is highly correlated with resistance to upfront treatment with venetoclax and azacitidine . these data suggest that the rara biomarker not only selects for patients who are more likely to respond to treatment with sy-1425 but also for patients who are less likely to respond to treatment with venetoclax and azacitidine . approximately 18,000 patients are diagnosed with unfit aml in the united states and europe annually and we expect the overall total addressable market opportunity for aml to grow to be in excess of $ 2 billion by 2029. at ash 2020 , we also announced that sy-1425 in combination with azacitidine was generally well-tolerated in the r/r aml patient population . among the 21 r/r aml patients who were evaluable for clinical response as of the data cut-off , the orr was 19 % , and the median os was 5.9 months . in hypomethylating agent , or hma , and venetoclax naïve patients , the orr was 43 % . based on these data and our assessment of ongoing areas of high unmet need , we are advancing sy-1425 in combination with azacitidine into a registration-enabling phase 3 clinical trial in rara-positive newly diagnosed hr-mds patients . hr-mds is a hematologic malignancy that is closely related to aml , and as in aml , about 30 % of hr-mds patients are rara-positive . approximately 15,000 patients are diagnosed with hr-mds in the united states and europe annually and we expect the total addressable market opportunity for hr-mds to grow to be in excess of $ 1 billion by 2029. we plan to enroll approximately 190 rara-positive newly diagnosed hr-mds patients in the double-blind placebo-controlled trial , randomized 2:1 to receive sy-1425 in combination with azacitidine or placebo with azacitidine , respectively . the primary endpoint of the trial will be the cr rate . we opened the phase 3 clinical trial for enrollment in february 2021 and are actively screening patients . the trial , if successful , could enable us to submit to the u.s. food and drug administration , or fda , a new drug application , or nda , as early as 2024 . in addition , we plan to advance sy-1425 in combination with venetoclax and azacitidine in rara-positive newly diagnosed unfit aml patients . the trial is designed with a single-arm safety lead-in to confirm the dosing regimen of the triplet to be used in the randomized portion of the phase 2 clinical trial , which will evaluate the safety and efficacy of sy-1425 in combination with venetoclax and azacitidine compared to venetoclax and azacitidine in approximately 80 patients randomized 1:1. the primary endpoint of the trial will be the composite cr rate . the trial will also evaluate the triplet as a salvage therapy in patients who do not respond to venetoclax and azacitidine . we expect to initiate the phase 2 clinical trial in the second half of 2021 , and we expect to report initial data from the trial in 2022. sy-2101 in december 2020 , we acquired from orsenix , llc , or orsenix , a novel oral form of ato , which we refer to as sy-2101 . sy-2101 is in development for the treatment of apl , a subtype of aml defined by a fusion of the rara and promyelocytic leukemia , or pml , genes . approximately 2,000 patients are diagnosed with apl in the united states and europe annually , representing a potential total addressable market opportunity for apl of approximately $ 250 million based on current pricing estimates . an intravenously administered , or iv , formulation of ato is approved for use in combination with all-trans-retinoic-acid , or atra , in patients with newly diagnosed apl and , while curative in more than 80 % of patients , its administration requires up to 140 two- to four-hour infusions over the typical course of induction and consolidation treatment . because sy-2101 is dosed orally once daily , we believe it has the potential to become the standard-of-care frontline therapy for apl by providing comparable efficacy with a substantially more convenient option that reduces the treatment burden on patients , improving access , and lowering costs to the healthcare system . in a phase 1 clinical trial , sy-2101 demonstrated bioavailability , pharmacokinetic , or pk , exposures similar to iv ato , and a generally well-tolerated safety profile . story_separator_special_tag for collaboration arrangements within the scope of asc 808 that contain multiple elements , we first determine which elements of the collaboration are deemed to be within the scope of asc 808 and those that are more reflective of a vendor-customer relationship and therefore within the scope of asc 606. for elements of collaboration arrangements that are accounted for pursuant to asc 808 , an appropriate recognition method is determined and applied consistently , generally by analogy to asc 606. for those elements of the arrangement that are accounted for pursuant to asc 606 , we apply the five-step model described above . 83 research and development expenses expenditures relating to research and development are expensed in the period incurred . research and development expenses consist of both internal and external costs associated with the development of our gene control platform and product candidates . research and development costs include salaries and benefits , materials and supplies , external research , preclinical and clinical development expenses , stock-based compensation expense and facilities costs . facilities costs primarily include the allocation of rent , utilities , depreciation and amortization . in certain circumstances , we are required to make nonrefundable advance payments to vendors for goods or services that will be received in the future for use in research and development activities . in such circumstances , the nonrefundable advance payments are deferred and capitalized , even when there is no alternative future use for the research and development , until related goods or services are provided . we record accruals for estimated ongoing research costs . when evaluating the adequacy of the accrued liabilities , we analyze progress of the work being performed , including the phase or completion of the event , invoices received and costs . significant judgements and estimates may be made in determining the accrued balances at the end of any reporting period . actual results could differ from our estimates . we may in-license the rights to develop and commercialize product candidates . for each in-license transaction , we evaluate whether we have acquired processes or activities along with inputs that would be sufficient to constitute a “ business ” as defined under u.s. gaap . a “ business ” as defined under u.s. gaap consists of inputs and processes applied to those inputs that have the ability to create outputs . although businesses usually have outputs , outputs are not required for an integrated set of activities to qualify as a business . when we determine that we have not acquired sufficient processes or activities to constitute a business , any up-front payments , as well as milestone payments , are immediately expensed as acquired research and development in the period in which they are incurred . warrants we account for our issued warrants as either liability or equity in accordance with asc 480-10 , accounting for certain financial instruments with characteristics of both liabilities and equity , or asc 480-10 , or asc 815-40 , accounting for derivative financial instruments indexed to , and potentially settled in , a company 's own stock , or asc 815-40. under asc 480-10 , warrants are considered liability if they are mandatorily redeemable and they require settlement in cash or other assets , or a variable number of shares . if warrants do not meet liability classification under asc 480-10 , we consider the requirements of asc 815-40 to determine whether the warrants should be classified as liability or equity . under asc 815-40 , contracts that may require settlement for cash are liabilities , regardless of the probability of the occurrence of the triggering event . liability classified warrants are measured at fair value on the issuance date and at the end of each reporting period . any change in the fair value of the warrants after the issuance date is recorded in the consolidated statements of operations as a gain or loss . if warrants do not require liability classification under asc 815-40 , in order to conclude warrants should be classified as equity , the company assesses whether the warrants are indexed to its common stock and whether the warrants are classified as equity under asc 815-40 or other applicable gaap . equity classified warrants are accounted for at fair value on the issuance date with no changes in fair value recognized after the issuance date . on december 8 , 2020 , through a private placement , we issued 10,312,500 shares of our common stock and , in lieu of common stock , pre-funded warrants to purchase an aggregate of 1,000,000 shares of common stock , and , in each case , accompanying warrants to purchase an aggregate of up to 2,828,125 additional shares of common stock ( or pre-funded warrants to purchase common stock in lieu thereof ) at a price of $ 8.00 per share and accompanying warrant ( or $ 7.99 per pre-funded warrant and accompanying warrant ) . the private placement resulted in aggregate gross proceeds of $ 90.5 million , before $ 0.4 million of transaction costs . 84 in the event of certain fundamental transactions , t he holders of warrants may require us to make a payment based on a black-scholes valuation , using specified inputs . the holders of the p re - f unded w arrants issued in the december 2020 private placement do not have similar rights . therefore , we accounted for the warrants as a liabilit y , while the p re - f unded w arrants met the permanent equity criteria classification . the pre-funded w arrants are classified as a component of permanent equity because they are freestanding financial instruments that are legally detachable and separately exercisable from the shares of common stock with which they were issued , are immediately exercisable , do not embody an obligation for us to repurchase those shares , and permit the holders to receive a fixed number of shares of common

