Timed sequential induction chemotherapy in AML: Time for reflection
2
Timed sequential induction chemotherapy in AML: Time for reflection Richard Stone* Experts in leukemia frankly admit that induction therapy for acute myeloid leukemia has changed little in the past 30 years. An anthracycline for 3 days plus 7 days of cytara- bine was used in 1980 [1] and is still used today. There have been many attempts to improve upon this famous ‘3 1 7’ backbone. Such efforts have included altering the anthracycline [2] (e.g., idarubicin instead of daunorubicin), substituting [3] or adding [4] high dose ara-C, adding etopo- side [5], and adding 6-thioguanine [6]. Although some of these additions or changes have resulted in possible improvements based on Phase II studies, Phase III studies have not demonstrated significant effects on long-time sur- vival rates. A more recent approach uses myeloid growth factors to ‘‘prime’’ the leukemic stem cell toward cell divi- sion and thereby potentially become more sensitive to S- phase specific chemotherapeutic agents like cytarabine [7]. Although most studies have not shown this priming approach to be of value, at least one study in younger adults with AML suggested that there was a disease-free (but again, no overall survival) advantage to priming with G-CSF [8]. Most of the clinical research in younger adults with AML of late has pertained to refining or improving post-remission therapy; especially in regard to high dose ara-C [9] and allogeneic stem cell transplant [10]. One important additional strategy for improving induction chemotherapy is so-called timed sequential therapy. On the basis of the historical development of ‘3 1 7’, patients receive the initial 7 days of chemotherapy and then undergo bone marrow examination on Day 14–21 to deter- mine if aplasia and a sufficient degree of blast reduction has been achieved. If not, then either the 3 1 7 is repeated or a shorter version (2 1 5) is given as a reinduction attempt. However, it is recognized that those who require a second induction generally do not fare as well in the long term; another problem is interpreting the Day 14 marrows (are the blasts coming or going?). In contrast, timed se- quential therapy delivers a second course of therapy rela- tively close to the first therapy without regard to the status of the marrow, taking advantage of the fact that the stem cells would be in cycle and more sensitive to chemother- apy, analogous to the priming strategy. The article by inves- tigators at the Cleveland Clinic published in this issue of the American Journal of Hematology is a Phase II trial in which timed sequential therapy was used to induce patients under age 60 with newly diagnosed AML. They employed a regimen in which mitoxantrone was given by IV bolus for 3 days, cytarabine was given by IV continuous infusion for the first 72 hr and etoposide and cytarabine were given by IV infusion for 72 hr on Days 8–10 to take advantage of the cycling effect. To further promote cells to proliferate, the investigators also gave G-CSF at a dose of 10 ll/kg/ll sub- cutaneously on Day 4 until count recovery was achieved. No second course of chemotherapy was administered. In this small trial the results were somewhat disappointing. Despite a high complete remission rate (83%), the five-year overall survival of 38% was really no different from that seen in trials with standard induction chemotherapy. The effect of induction therapy could be outweighed by post- remission therapy, which in this case was autologous or allogeneic stem cell transplant (depending on donor avail- ability) for all patients without an inversion of chromosome 16 or t(8;21). It was hoped that a superior induction ther- apy, by achieving remission at a lower level of disease burden, might make any post-remission therapy more effective. This study should not be considered as the death-knell for timed sequential therapy in all its various forms. For example, the Children’s Oncology Group showed that young patients with AML seem to fare better with DCTER- repetitive induction courses compared with standard timed induction therapy [11]. The German Acute Leukemia group has shown that repetitive cycles of high dose ara-C and mitoxantrone can be given safely and potentially effectively [12] in induction. In adults, the biggest problem is the large subgroup of patients with high risk disease on the basis of adverse chromosomal abnormalities. This very intrinsically resistant group has not responded well to intensive chemo- therapy. This is true in the upfront setting based on the German approach, as well as the post-remission setting. For example, CALGB high dose ara-C which, while benefi- cial in the aggregate, [9] provides no apparent benefit for those with nonfavorable cytogenetics and certainly is espe- cially unhelpful for those with poor risk cytogenetics [13]. As pointed out by the Cleveland Clinic investigators, we need to be more clever about risk-adapted therapy in the future. Certainly intensive chemotherapy in the post-remis- sion setting is beneficial for patients who have core-binding factor leukemias [13]. For those with the type of adverse cytogenetics similar to that seen after alkylating agent ther- apy for other cancers or in MDS, currently an immunologi- cal approach (allogeneic transplant) seems the only way to yield a reasonable number of long-term disease-free survi- vors. In the normal cytogenetics group there is a high degree of molecular heterogeneity. The 30% of patients in this category with an activating mutation of FLT3 (poor prognosis) could benefit from FLT3 inhibitors or transplant [14]. In the subset of patients who do not have a FLT3 mutation but who have an NPM1 mutation, intensive chemotherapy may be as good as it is in those with a core binding factor leukemias [14]. The non-FLT3 mutant patients who also do not have a NPM1 mutation may be Conflict of interest: Nothing to report. *Correspondence to: Dr. Richard Stone, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115. E-mail: [email protected] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts Received for publication 4 September 2008; Accepted 5 September 2008 Am. J. Hematol. 83:829–830, 2008. Published online 11 September 2008 in Wiley InterScience (www.interscience. wiley.com). DOI: 10.1002/ajh.21288 Commentary V V C 2008 Wiley-Liss, Inc. American Journal of Hematology 829 http://www3.interscience.wiley.com/cgi-bin/jhome/35105
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Transcript of Timed sequential induction chemotherapy in AML: Time for reflection
Timed sequential induction chemotherapy in AML: Time for reflection
Richard Stone*
Experts in leukemia frankly admit that induction therapyfor acute myeloid leukemia has changed little in the past30 years. An anthracycline for 3 days plus 7 days of cytara-bine was used in 1980 [1] and is still used today. Therehave been many attempts to improve upon this famous ‘31 7’ backbone. Such efforts have included altering theanthracycline [2] (e.g., idarubicin instead of daunorubicin),substituting [3] or adding [4] high dose ara-C, adding etopo-side [5], and adding 6-thioguanine [6]. Although some ofthese additions or changes have resulted in possibleimprovements based on Phase II studies, Phase III studieshave not demonstrated significant effects on long-time sur-vival rates. A more recent approach uses myeloid growthfactors to ‘‘prime’’ the leukemic stem cell toward cell divi-sion and thereby potentially become more sensitive to S-phase specific chemotherapeutic agents like cytarabine [7].Although most studies have not shown this primingapproach to be of value, at least one study in youngeradults with AML suggested that there was a disease-free(but again, no overall survival) advantage to priming withG-CSF [8]. Most of the clinical research in younger adultswith AML of late has pertained to refining or improvingpost-remission therapy; especially in regard to high doseara-C [9] and allogeneic stem cell transplant [10].One important additional strategy for improving induction
chemotherapy is so-called timed sequential therapy. On thebasis of the historical development of ‘3 1 7’, patientsreceive the initial 7 days of chemotherapy and thenundergo bone marrow examination on Day 14–21 to deter-mine if aplasia and a sufficient degree of blast reductionhas been achieved. If not, then either the 3 1 7 is repeatedor a shorter version (2 1 5) is given as a reinductionattempt. However, it is recognized that those who require asecond induction generally do not fare as well in the longterm; another problem is interpreting the Day 14 marrows(are the blasts coming or going?). In contrast, timed se-quential therapy delivers a second course of therapy rela-tively close to the first therapy without regard to the statusof the marrow, taking advantage of the fact that the stemcells would be in cycle and more sensitive to chemother-apy, analogous to the priming strategy. The article by inves-tigators at the Cleveland Clinic published in this issue ofthe American Journal of Hematology is a Phase II trial inwhich timed sequential therapy was used to induce patientsunder age 60 with newly diagnosed AML. They employed aregimen in which mitoxantrone was given by IV bolus for3 days, cytarabine was given by IV continuous infusion forthe first 72 hr and etoposide and cytarabine were given byIV infusion for 72 hr on Days 8–10 to take advantage of thecycling effect. To further promote cells to proliferate, theinvestigators also gave G-CSF at a dose of 10 ll/kg/ll sub-cutaneously on Day 4 until count recovery was achieved.No second course of chemotherapy was administered. Inthis small trial the results were somewhat disappointing.Despite a high complete remission rate (83%), the five-yearoverall survival of 38% was really no different from that
seen in trials with standard induction chemotherapy. Theeffect of induction therapy could be outweighed by post-remission therapy, which in this case was autologous orallogeneic stem cell transplant (depending on donor avail-ability) for all patients without an inversion of chromosome16 or t(8;21). It was hoped that a superior induction ther-apy, by achieving remission at a lower level of diseaseburden, might make any post-remission therapy moreeffective.This study should not be considered as the death-knell
for timed sequential therapy in all its various forms. Forexample, the Children’s Oncology Group showed thatyoung patients with AML seem to fare better with DCTER-repetitive induction courses compared with standard timedinduction therapy [11]. The German Acute Leukemia grouphas shown that repetitive cycles of high dose ara-C andmitoxantrone can be given safely and potentially effectively[12] in induction. In adults, the biggest problem is the largesubgroup of patients with high risk disease on the basis ofadverse chromosomal abnormalities. This very intrinsicallyresistant group has not responded well to intensive chemo-therapy. This is true in the upfront setting based on theGerman approach, as well as the post-remission setting.For example, CALGB high dose ara-C which, while benefi-cial in the aggregate, [9] provides no apparent benefit forthose with nonfavorable cytogenetics and certainly is espe-cially unhelpful for those with poor risk cytogenetics [13].As pointed out by the Cleveland Clinic investigators, we
need to be more clever about risk-adapted therapy in thefuture. Certainly intensive chemotherapy in the post-remis-sion setting is beneficial for patients who have core-bindingfactor leukemias [13]. For those with the type of adversecytogenetics similar to that seen after alkylating agent ther-apy for other cancers or in MDS, currently an immunologi-cal approach (allogeneic transplant) seems the only way toyield a reasonable number of long-term disease-free survi-vors. In the normal cytogenetics group there is a highdegree of molecular heterogeneity. The 30% of patients inthis category with an activating mutation of FLT3 (poorprognosis) could benefit from FLT3 inhibitors or transplant[14]. In the subset of patients who do not have a FLT3mutation but who have an NPM1 mutation, intensivechemotherapy may be as good as it is in those with a corebinding factor leukemias [14]. The non-FLT3 mutantpatients who also do not have a NPM1 mutation may be
Conflict of interest: Nothing to report.
*Correspondence to: Dr. Richard Stone, Dana-Farber Cancer Institute,44 Binney Street, Boston, MA 02115. E-mail: [email protected]
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston,Massachusetts
Received for publication 4 September 2008; Accepted 5 September 2008
Am. J. Hematol. 83:829–830, 2008.
Published online 11 September 2008 in Wiley InterScience (www.interscience.wiley.com).DOI: 10.1002/ajh.21288
Commentary
VVC 2008 Wiley-Liss, Inc.
American Journal of Hematology 829 http://www3.interscience.wiley.com/cgi-bin/jhome/35105
best served by a post-remission allogeneic transplant [14].Unfortunately, beyond the use of all trans retinoic acid andanthracyclines in induction for those with a t(15;17), wehave not truly scratched the surface of risk-adapted induc-tion therapy. The timed sequential therapy in the article byKalaycio et al. [15] was a reasonable attempt to maximallyprime leukemic stem cells and increase sensitivity to thechemotherapy given on Day 8–10. Unfortunately, the pleo-tropic mechanisms of resistance displayed by AML cells(particularly in the high-risk subset) is beyond the reach ofa purely cytokinetic approach.
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830 American Journal of Hematology
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