- Email: [email protected]
Sequential flavopiridol, mitoxantrone and cytosine arabinoside for newly diagnosed poor risk acute myeloid leukemia. What to do next?
Leukemia Research 34 (2010) 856–857
Contents lists available at ScienceDirect
Leukemia Research journal homepage: www.elsevier.com/locate/leukres
Guest editorial
Sequential flavopiridol, mitoxantrone and cytosine arabinoside for newly diagnosed poor risk acute myeloid leukemia. What to do next?
Keywords: Flavopiridol Acute myeloid leukemia Timed-sequential therapy
Treatment of high risk AML has always been problematic with poor outcomes. In previous studies, few patients in this category are able to reach remission, and of those who do reach remission, very few make it to transplant. Even in the most recently published randomized trial of high dose daunorubicin in newly diagnosed patients over age 60 with AML, it is clear that increasing the dose of daunorubicin had no overall benefit for patients in the high risk category [1]. Thus, the study of a similar population of 45 patients addressed in the trial by Karp et al. in this issue [2], is necessary and timely. Many new drugs and approaches to treatment of AML begin their developmental cycle targeting the worst prognostic subgroups, even though the results of even the best prognostic groups leave much to be desired. In this study using a flavopiridol, mitoxantrone, cytosine arabinoside, and mitoxantrone (FLAM) timed sequential therapy (TST), an impressive 67% of patients achieved CR and, with a median follow-up of 22 months, median OS of all patients was 7.4 months. 12 of 30 (40%) of CR patients were able to successfully undergo a stem cell transplant with 8/12 still alive at 12.5–31 months. The addition of the transplant also undoubtedly added to the longevity of the responses seen but the combination of TST followed where possible with transplant was clearly the intent of the authors. Only four patients received a second cycle of FLAM and thus it is difficult at this time to judge how the consolidation with transplant compares with possibly one or two more cycles of FLAM. Such efficacy came with surprisingly little significant cost. 42% of patients experienced evidence of tumor lysis, despite prophylaxis with allopurinol and sevalamer. Only one patient though had clinically significant tumor lysis. Also, 30% of patients had oral mucositis, although the majority had grade 2 or less. Despite the toxicities seen, induction mortality was surprisingly low at 9%. It is interesting to note that the day 14 bone marrow demonstrated complete tumor clearance in 54% of patients. This is consistent with a rapid and effective clearance of blasts. The results of the day 14 marrow in our most recent randomized trial on treatment of adult AML was independently correlated with DFS and OS, particularly in the high risk (older patients) [3]. Similarly, we found that mitoxantrone appeared to have activity in patients not responsive to initial induction. As in the Karp study, earlier studies in CLL have also encountered high levels of tumor lysis, and 0145-2126/$ – see front matter © 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.leukres.2010.03.008
have thus incorporated a much more aggressive approach to prophylaxis and monitoring for tumor lysis by adding rasburicase to allopurinol before the first dose and also added in hourly monitoring for serum potassium during treatment [4]. Although the rapid tumor kill is perhaps desirable, the effects seen suggest that future studies of the treatment outlined in this article might benefit from more aggressive measures to monitor and prevent tumor lysis [4,5]. Clearly more studies are also required to understand the proper drug dosing and timing as well as the best patient population to select. Given this early data though, one does develop a sense of optimism that this therapy, unlike so many other leukemia studies is now demonstrating that this may well be the beginning of a novel therapy which is “first in class”, thus offering hope that it may have less in the way of cross-resistance with earlier therapies. Earlier studies have indicated that flavopiridol inhibits phosphokinases with activity on CDK-1, -2, -4, -6, and -7 and that the killing action occurs in both cycling and non-cycling cells, suggesting that the inhibition of CDKs in the control of the cell cycle may not be the only mechanism of cell killing [6]. With the advent of high throughput cancer genome analysis, it is known that there is much genomic heterogeneity that can exist within the same disease which can thus explain at least some of the differences observed in response to various kinase inhibitors [7]. A tenet worth considering thus, and as discussed [5], if further studies were to be done using the approach of Karp et al., it would be ideal if it were done using a targeted approach, using an infrastructure that can at least provide multiplex DNA sequencing of known drug-sensitizing mutations and possibly even complete genome sequencing of leukemia cell samples from patients under study [7]. This, when combined with other more obvious clinical prognostic variables, may then provide a more directed approach to explaining which population of high risk patients might best be targeted using this approach. At the very least, it may provide more information on mechanisms of sensitivity and/or resistance. The limitation of that approach however is that in order to apply personalized medicine to broader clinical practice, it would require access to the same technology, something clearly not yet available in most centers. In addition, it would be helpful if an attempt were made to combine further studies of this approach with applied pharmacogenomic testing [8]. Many single center studies have been done with what at first appears to be a promising approach. Most however, unfortunately do not pan out when applied in larger populations of patients and when properly compared to another currently considered best available “standard therapy” in a multi-center study with longer follow-up. That said, the results of this study are impressive
Guest editorial / Leukemia Research 34 (2010) 856–857
and warrant future development in larger population of similar patients. However, before doing so, the authors suggest that they are currently comparing bolus vs. hybrid bolus infusional approaches to determine which approach to use in moving forward. It is particularly notable that patients with poor risk cytogenetics appeared to benefit since 67% did achieve CR. Even in patients over age 60, 54% (13/24) achieved CR. The question then arises as to what to compare this approach to and how such development should take place. A randomized trial would be a consideration if there was a clear standard. However, there is no clear standard for this population of patients. Many others have also done studies on a similar population of patients, with highly variable response rates [9–14]. Given the lack of a standard to compare to in a traditional randomized trial, it has been hypothesized that a novel approach to developing promising new therapies is required and such approaches such as the selection design, have already been adopted by large cooperative groups such as HOVON/SAKK and the MRC [15]. A possible approach then would be to do further studies in de novo high risk patients and comparing FLAM timed sequential chemotherapy vs. high dose daunorubicin using a Bayesian approach. In addition to using the techniques referred to above and to increase our level of understanding of this novel approach, it seems timely to combine this approach with a study of the epigenetic differences in those who do and those who do not respond to drug as recently described by Figueroa et al., in which they describe that a 15 gene methylation pattern may classify the subtypes of AML and predict outcome [16]. It seems that given the tools available, there is ample opportunity and a need to refine and study this treatment strategy more carefully. We can only hope that these studies will lead to an important addition to our currently rather limited armamentarium of effective strategies to treat AML. Conflict of interest None to declare. Acknowledgements None. References [1] Löwenberg B, Ossenkoppele G, van Putten W, et al. High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med 2009;361:1235–48. [2] Karp J, Blackford B, Smith D, et al. Clinical activity of sequential flavopiridol, cytosine arabinoside, and mitoxantrone for adults with newly diagnosed, poor risk acute myelogenous leukemia. Leuk Res 2010;34(7):877–82.
857
[3] van der Jagt R et al., A multicenter randomized trial comparing responseadapted (RA), non-cross-resistant induction and consolidation with idarubicin/cytarabine (IDAC) followed by mitoxantrone/etoposide (NOVE) compared with consolidation with high dose cytarabine (HDAC) in adult patients with AML. A study by the Canadian Leukemia Studies Group (CLSG) (manuscript in preparation). [4] Byrd JC, Lin TS, Dalton JT, et al. Flavopiridol administered using a pharmacologically derived schedule is associated with marked clinical efficacy in refractory, genetically high risk chronic lymphocytic leukemia. Blood 2007;09:399–404. [5] Tariq I, Mughal A, Ejaz A, Foringer JR, Coiffier B. An integrated clinical approach for the identification, prevention, and treatment of tumor lysis syndrome. Cancer Treatment Reviews 2009;36(2):164–76. [6] Sedlacek HH. Mechanisms of action of flavopiridol. Crit Rev Oncol/Hematol 2001;38(2):139–70. [7] McDermott U, Settleman J. Personalized cancer therapy with selective kinase inhibitors: an emerging paradigm in medical oncology. J Clin Oncol 2009;27:5650–9. [8] Roumier C, Cheok MH. Pharmacogenomics in acute myeloid leukemia. Pharmacogenomics 2009;10(11):1839–51. [9] Milligan DW, Wheatley K, Littlewood T, et al. Fludarabine and cytosine are less effective than standard ADE chemotherapy in high-risk acute myeloid leukemia, and addition of G-CSF and ATRA are not beneficial: results of the MRC AML-HR randomized trial. Blood 2006;107(June (12)):4614–22. [10] Fianchi L, Pagano L, Leoni F, et al. Gemtuzumab ozogamicin, cytosine arabinoside, G-CSF combination (G-AraMy) in the treatment of elderly patients with poor-prognosis acute myeloid leukemia. Ann Oncol 2008;19(January (1)):128–34. [11] Platzbecker U, Thiede C, Fussel M, et al. Reduced intensity conditioning allows for up-front allogeneic hematopoietic stem cell transplantation after cytoreductive induction therapy in newly-diagnosed high-risk acute myeloid leukemia. Leukemia 2006;20(April (4)):707–14. [12] Ayash LJ, Ratanatharathorn V, Braun T, et al. Unrelated donor bone marrow transplantation using a chemotherapy-only preparative regimen for adults with high-risk acute myelogenous leukemia. Am J Hematol 2007;82(January (1)):6–14. [13] Auberger J, Clausen J, Willenbacher W, et al. Fludarabine/intermediate-dose cytarabine with or without allogeneic hematopoietic stem cell transplantation in poor-risk leukemia: a single center experience. Int J Hematol 2008;(May (4)):382–6. [14] Martin MG, Welch JS, Augustin K, et al. Cladribine in the treatment of acute myeloid leukemia: a single-institution experience. Clin Lymphoma Myeloma 2009;9(August (4)):298–301. [15] Estey E. AML in older patients: are we making progress? Best Prac Res Clin Haematol 2009;22(December (4)):529–36. [16] Figueroa ME, Lugthart S, Li Y, et al. DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia. Cancer Cell 2010;17(January (1)):13–27.
Richard H.C. van der Jagt ∗ Canadian Leukemia Studies Group, Ottawa Hospital, 501 Smyth Road, Otttawa, K1H 8L6, Ontario, Canada ∗ Tel.: +613 737 8804; fax: +613 739 6227. E-mail address: [email protected]
25 January 2010 Available online 7 April 2010
Contents lists available at ScienceDirect
Leukemia Research journal homepage: www.elsevier.com/locate/leukres
Guest editorial
Sequential flavopiridol, mitoxantrone and cytosine arabinoside for newly diagnosed poor risk acute myeloid leukemia. What to do next?
Keywords: Flavopiridol Acute myeloid leukemia Timed-sequential therapy
Treatment of high risk AML has always been problematic with poor outcomes. In previous studies, few patients in this category are able to reach remission, and of those who do reach remission, very few make it to transplant. Even in the most recently published randomized trial of high dose daunorubicin in newly diagnosed patients over age 60 with AML, it is clear that increasing the dose of daunorubicin had no overall benefit for patients in the high risk category [1]. Thus, the study of a similar population of 45 patients addressed in the trial by Karp et al. in this issue [2], is necessary and timely. Many new drugs and approaches to treatment of AML begin their developmental cycle targeting the worst prognostic subgroups, even though the results of even the best prognostic groups leave much to be desired. In this study using a flavopiridol, mitoxantrone, cytosine arabinoside, and mitoxantrone (FLAM) timed sequential therapy (TST), an impressive 67% of patients achieved CR and, with a median follow-up of 22 months, median OS of all patients was 7.4 months. 12 of 30 (40%) of CR patients were able to successfully undergo a stem cell transplant with 8/12 still alive at 12.5–31 months. The addition of the transplant also undoubtedly added to the longevity of the responses seen but the combination of TST followed where possible with transplant was clearly the intent of the authors. Only four patients received a second cycle of FLAM and thus it is difficult at this time to judge how the consolidation with transplant compares with possibly one or two more cycles of FLAM. Such efficacy came with surprisingly little significant cost. 42% of patients experienced evidence of tumor lysis, despite prophylaxis with allopurinol and sevalamer. Only one patient though had clinically significant tumor lysis. Also, 30% of patients had oral mucositis, although the majority had grade 2 or less. Despite the toxicities seen, induction mortality was surprisingly low at 9%. It is interesting to note that the day 14 bone marrow demonstrated complete tumor clearance in 54% of patients. This is consistent with a rapid and effective clearance of blasts. The results of the day 14 marrow in our most recent randomized trial on treatment of adult AML was independently correlated with DFS and OS, particularly in the high risk (older patients) [3]. Similarly, we found that mitoxantrone appeared to have activity in patients not responsive to initial induction. As in the Karp study, earlier studies in CLL have also encountered high levels of tumor lysis, and 0145-2126/$ – see front matter © 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.leukres.2010.03.008
have thus incorporated a much more aggressive approach to prophylaxis and monitoring for tumor lysis by adding rasburicase to allopurinol before the first dose and also added in hourly monitoring for serum potassium during treatment [4]. Although the rapid tumor kill is perhaps desirable, the effects seen suggest that future studies of the treatment outlined in this article might benefit from more aggressive measures to monitor and prevent tumor lysis [4,5]. Clearly more studies are also required to understand the proper drug dosing and timing as well as the best patient population to select. Given this early data though, one does develop a sense of optimism that this therapy, unlike so many other leukemia studies is now demonstrating that this may well be the beginning of a novel therapy which is “first in class”, thus offering hope that it may have less in the way of cross-resistance with earlier therapies. Earlier studies have indicated that flavopiridol inhibits phosphokinases with activity on CDK-1, -2, -4, -6, and -7 and that the killing action occurs in both cycling and non-cycling cells, suggesting that the inhibition of CDKs in the control of the cell cycle may not be the only mechanism of cell killing [6]. With the advent of high throughput cancer genome analysis, it is known that there is much genomic heterogeneity that can exist within the same disease which can thus explain at least some of the differences observed in response to various kinase inhibitors [7]. A tenet worth considering thus, and as discussed [5], if further studies were to be done using the approach of Karp et al., it would be ideal if it were done using a targeted approach, using an infrastructure that can at least provide multiplex DNA sequencing of known drug-sensitizing mutations and possibly even complete genome sequencing of leukemia cell samples from patients under study [7]. This, when combined with other more obvious clinical prognostic variables, may then provide a more directed approach to explaining which population of high risk patients might best be targeted using this approach. At the very least, it may provide more information on mechanisms of sensitivity and/or resistance. The limitation of that approach however is that in order to apply personalized medicine to broader clinical practice, it would require access to the same technology, something clearly not yet available in most centers. In addition, it would be helpful if an attempt were made to combine further studies of this approach with applied pharmacogenomic testing [8]. Many single center studies have been done with what at first appears to be a promising approach. Most however, unfortunately do not pan out when applied in larger populations of patients and when properly compared to another currently considered best available “standard therapy” in a multi-center study with longer follow-up. That said, the results of this study are impressive
Guest editorial / Leukemia Research 34 (2010) 856–857
and warrant future development in larger population of similar patients. However, before doing so, the authors suggest that they are currently comparing bolus vs. hybrid bolus infusional approaches to determine which approach to use in moving forward. It is particularly notable that patients with poor risk cytogenetics appeared to benefit since 67% did achieve CR. Even in patients over age 60, 54% (13/24) achieved CR. The question then arises as to what to compare this approach to and how such development should take place. A randomized trial would be a consideration if there was a clear standard. However, there is no clear standard for this population of patients. Many others have also done studies on a similar population of patients, with highly variable response rates [9–14]. Given the lack of a standard to compare to in a traditional randomized trial, it has been hypothesized that a novel approach to developing promising new therapies is required and such approaches such as the selection design, have already been adopted by large cooperative groups such as HOVON/SAKK and the MRC [15]. A possible approach then would be to do further studies in de novo high risk patients and comparing FLAM timed sequential chemotherapy vs. high dose daunorubicin using a Bayesian approach. In addition to using the techniques referred to above and to increase our level of understanding of this novel approach, it seems timely to combine this approach with a study of the epigenetic differences in those who do and those who do not respond to drug as recently described by Figueroa et al., in which they describe that a 15 gene methylation pattern may classify the subtypes of AML and predict outcome [16]. It seems that given the tools available, there is ample opportunity and a need to refine and study this treatment strategy more carefully. We can only hope that these studies will lead to an important addition to our currently rather limited armamentarium of effective strategies to treat AML. Conflict of interest None to declare. Acknowledgements None. References [1] Löwenberg B, Ossenkoppele G, van Putten W, et al. High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med 2009;361:1235–48. [2] Karp J, Blackford B, Smith D, et al. Clinical activity of sequential flavopiridol, cytosine arabinoside, and mitoxantrone for adults with newly diagnosed, poor risk acute myelogenous leukemia. Leuk Res 2010;34(7):877–82.
857
[3] van der Jagt R et al., A multicenter randomized trial comparing responseadapted (RA), non-cross-resistant induction and consolidation with idarubicin/cytarabine (IDAC) followed by mitoxantrone/etoposide (NOVE) compared with consolidation with high dose cytarabine (HDAC) in adult patients with AML. A study by the Canadian Leukemia Studies Group (CLSG) (manuscript in preparation). [4] Byrd JC, Lin TS, Dalton JT, et al. Flavopiridol administered using a pharmacologically derived schedule is associated with marked clinical efficacy in refractory, genetically high risk chronic lymphocytic leukemia. Blood 2007;09:399–404. [5] Tariq I, Mughal A, Ejaz A, Foringer JR, Coiffier B. An integrated clinical approach for the identification, prevention, and treatment of tumor lysis syndrome. Cancer Treatment Reviews 2009;36(2):164–76. [6] Sedlacek HH. Mechanisms of action of flavopiridol. Crit Rev Oncol/Hematol 2001;38(2):139–70. [7] McDermott U, Settleman J. Personalized cancer therapy with selective kinase inhibitors: an emerging paradigm in medical oncology. J Clin Oncol 2009;27:5650–9. [8] Roumier C, Cheok MH. Pharmacogenomics in acute myeloid leukemia. Pharmacogenomics 2009;10(11):1839–51. [9] Milligan DW, Wheatley K, Littlewood T, et al. Fludarabine and cytosine are less effective than standard ADE chemotherapy in high-risk acute myeloid leukemia, and addition of G-CSF and ATRA are not beneficial: results of the MRC AML-HR randomized trial. Blood 2006;107(June (12)):4614–22. [10] Fianchi L, Pagano L, Leoni F, et al. Gemtuzumab ozogamicin, cytosine arabinoside, G-CSF combination (G-AraMy) in the treatment of elderly patients with poor-prognosis acute myeloid leukemia. Ann Oncol 2008;19(January (1)):128–34. [11] Platzbecker U, Thiede C, Fussel M, et al. Reduced intensity conditioning allows for up-front allogeneic hematopoietic stem cell transplantation after cytoreductive induction therapy in newly-diagnosed high-risk acute myeloid leukemia. Leukemia 2006;20(April (4)):707–14. [12] Ayash LJ, Ratanatharathorn V, Braun T, et al. Unrelated donor bone marrow transplantation using a chemotherapy-only preparative regimen for adults with high-risk acute myelogenous leukemia. Am J Hematol 2007;82(January (1)):6–14. [13] Auberger J, Clausen J, Willenbacher W, et al. Fludarabine/intermediate-dose cytarabine with or without allogeneic hematopoietic stem cell transplantation in poor-risk leukemia: a single center experience. Int J Hematol 2008;(May (4)):382–6. [14] Martin MG, Welch JS, Augustin K, et al. Cladribine in the treatment of acute myeloid leukemia: a single-institution experience. Clin Lymphoma Myeloma 2009;9(August (4)):298–301. [15] Estey E. AML in older patients: are we making progress? Best Prac Res Clin Haematol 2009;22(December (4)):529–36. [16] Figueroa ME, Lugthart S, Li Y, et al. DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia. Cancer Cell 2010;17(January (1)):13–27.
Richard H.C. van der Jagt ∗ Canadian Leukemia Studies Group, Ottawa Hospital, 501 Smyth Road, Otttawa, K1H 8L6, Ontario, Canada ∗ Tel.: +613 737 8804; fax: +613 739 6227. E-mail address: [email protected]
25 January 2010 Available online 7 April 2010