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The Hi's and Lo's of Cytarabine in Acute Myeloid Leukemia

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The Hi's and Lo's of Cytarabine in Acute Myeloid Leukemia Author Manuscript Published OnlineFirst on April 13, 2020; DOI: 10.1158/1078-0432.CCR-20-0462 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. The Hi’s and Lo’s of cytarabine in acute myeloid leukemia Running title: Cytarabine dose in AML induction Authors: Justin M. Watts, MD1; Terrence Bradley, MD1 Affiliations: 1Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL Corresponding author: Justin M. Watts, MD University of Miami Sylvester Comprehensive Cancer Center 1120 NW 14th Street, Suite 610C Miami, FL 33136 USA Ph: 305-243-8986 Email: [email protected] Disclosure: J. M. Watts is a paid consultant for Takeda, Rafael Pharma, Genentech, and Jazz Pharma, and reports receiving commercial research grants from Takeda. T. Bradley reports receiving speakers bureau honoraria from Novartis and is a paid consultant/advisory board member for AbbVie. No other potential conflicts of interest were disclosed. Acknowledgment: J.M. Watts is supported by the National Institutes of Health/National Cancer Institute (5R21CA202488-02) and the Sylvester Cancer Center Support Grant 1P30CA240139- 01. 1 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 13, 2020; DOI: 10.1158/1078-0432.CCR-20-0462 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Summary: Cytarabine is the backbone of AML therapy, but the dose used during induction has remained controversial. Using an intermediate dose of cytarabine, compared to conventional dose, was shown to improve disease-free and overall survival in adult patients in China up to age 55, particularly in patients with intermediate cytogenetic risk. In this issue of Clinical Cancer Research, Wei and colleagues re-examine the important and unanswered clinical question of cytarabine dose intensity in younger patients with de novo acute myeloid leukemia (AML).1 To accomplish this, they conducted a large (591 patients) open-label, randomized trial comparing induction using conventional dose cytarabine (CDAC: 100 mg/m2/d for 7 days) and intermediate dose cytarabine (IDAC: 100mg/m2/d days 1-4 followed by 1g/m2 every 12h days 5-7), i.e., 700mg vs. 6400mg of cytarabine during the initial induction phase. Patients also received daunorubicin 40mg/m2 on days 1-3 and omacetaxine 2mg/m2 on days 1-7 (the standard induction regimen in China). In patients achieving remission, a second randomization was done prior to consolidation therapy, and half of patients received 3 cycles of high dose cytarabine (HiDAC) (3g/m2 every 12 hours for 3 days) and half received 2 cycles of IDAC (1.5g/m2 every 12h for 3 days—note this is different than the dose used during induction) combined with an anthracycline. Eligible patients could receive allogeneic hematopoietic cell transplantation (HCT). The primary endpoint was disease-free survival (DFS), and investigators and statisticians assessing outcomes were blinded to the cytarabine dose. This was a large, well-done clinical trial that adds potentially practice-changing information to the field. Notably, the investigators demonstrated superior 3-year DFS (67% vs. 54%; Hazard Ratio [HR]=0.67; p=0.005) and survival (68% vs. 59%; HR=0.72; p=0.014) with IDAC-based induction compared to conventional dose, and this advantage was maintained after multivariable analysis and censoring subjects for HCT. To us, it is undeniable that a one-third decreased risk of death or relapse (primary endpoint) with IDAC in this population is clinically meaningful. Also, of note, the second randomization done post-remission had no impact on outcomes, suggesting that the standard repeated cycles of “HiDAC” consolidation is at least equivalent to multi-drug regimens, with the added benefit that it avoids excess anthracycline exposure. Additionally, in a sub-analysis, the survival benefit with IDAC-based induction was only seen in the patients who received HiDAC consolidation. Looking more closely at the data, what is driving this survival benefit? Complete remission (CR) rates were higher with IDAC compared to CDAC (87% vs. 77%, p=0.004)—with the caveat that a small number of patients on the conventional dose arm were not treated for residual leukemia at day 14 (prior to a protocol amendment). In terms of safety, while the duration of neutropenia and thrombocytopenia were slightly longer in the IDAC group, there was no difference in induction deaths. In addition, rates of HCT between the two groups were the same. Collectively, these data suggest that IDAC-based induction provided most of its benefit early, with, numerically, a 10% better CR rate and ~10% improvement in survival. To what 2 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 13, 2020; DOI: 10.1158/1078-0432.CCR-20-0462 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. extent fewer relapses contributed to this survival difference in unclear (cumulative incidence of relapse [CIR] not given for induction cohorts). Of note, the advantage with IDAC-based induction also held true when looking at event-free survival (death, primary induction failure, and relapse). When the authors examined patients by cytogenetic subgroup, the survival advantage was only seen in patients with intermediate risk disease. However, two-thirds of all patients on study had intermediate-risk cytogenetics, and there were very few adverse risk patients, making it difficult to interpret the sub-analysis in these groups. This skew in cytogenetic distribution may be due to selection bias implicit to clinical trial enrollment, or to patient demographics in China and differences in disease biology. Regardless, the more overall favorable cytogenetic distribution, along with the younger median age (36 years), may explain the impressive 3-year OS rate of ~64% for all patients (68% for IDAC; 59% for CDAC). It is an interesting question if the molecular genetic or epigenetic profile of patients in China differs from that of the west, or other more heterogeneous populations, and whether this could confer increased sensitivity to cytarabine. Importantly, the fact that a statistically significant and meaningful survival benefit was observed despite the overall good outcome, only re-enforces the clinical significance of using IDAC-based induction in this population, although long-term follow-up still needs to be reported as the data matures. When we look at the body of literature, several studies have examined higher doses of cytarabine with induction, with varying study designs. In the late 1990s, 2 randomized studies compared HiDAC- to CDAC-based induction for de novo AML; one gave HiDAC 3g/m2 x 8 doses with daunorubicin and etoposide, and the other HiDAC 2g/m2 x 12 doses with daunorubicin. Despite no improvement in survival, both studies showed improvements in the CIR and relapse- free survival (RFS) in the HiDAC cohorts. In the mid-2000s, HOVON-SAKK compared HiDAC (2- 3g/m2) versus a more intermediate dose of cytarabine (1g/m2) for AML induction (included de novo and secondary AML).2 In this study, each group received 2 planned induction courses. The intermediate-dose group received idarubicin plus CDAC first, followed by a second induction with amsacrine plus cytarabine 1g/m2 (total cytarabine dose during induction 13.4g/m2). The high-dose group received idarubicin with cytarabine 1g/m2 first, followed by amsacrine plus cytarabine 2g/m2 (total cytarabine dose 26g/m2). Overall, this study found no significant difference in CR, relapse, EFS, or survival between the intermediate and higher dose groups. More recently, the EORTC and GIMEMA groups examined combination daunorubicin, etoposide, and cytarabine (100mg/m2 10d vs. 3g/m2 4d) induction in de novo and secondary AML patients.3 They reported statistically significant improvements in CR rate, EFS, and survival (at 6 years) for patients aged 15-45 who received HiDAC as a component of induction, as well as improved outcomes in patients with adverse cytogenetics, FLT3-ITD mutations, and secondary AML. In 2014, Wei et al conducted a meta-analysis of cytarabine dose in AML induction that assessed 6 different studies.4 Overall, there was no statistically significant difference in CR rate or survival between induction regimens containing HiDAC or CDAC; however, there was a statistically significant difference in RFS, favoring HiDAC. In a sub-group analysis, this RFS benefit was only recapitulated in favorable risk patients. Importantly, all of the 3 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 13, 2020; DOI: 10.1158/1078-0432.CCR-20-0462 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. aforementioned studies showed increased toxicity with higher doses of cytarabine, including conjunctivitis, skin reactions, and GI complications (count recovery times were comparable). The broader question this study raises is the worldwide applicability of its findings. This is a near impossible question to answer. In China, where there are more cases of AML than in the United States and European Union combined, the results of this large randomized clinical trial clearly support the use of IDAC
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