The Hi S and Lo S of Cytarabine in Acute Myeloid Leukemia

Published OnlineFirst April 13, 2020; DOI: 10.1158/1078-0432.CCR-20-0462

CLINICAL CANCER RESEARCH | CCR TRANSLATIONS

The Hi0s and Lo0s of Cytarabine in Acute Myeloid Leukemia Justin M. Watts and Terrence Bradley

SUMMARY ◥ Cytarabine is the backbone of AML therapy, but the dose used patients in China up to age 55, particularly in patients with during induction has remained controversial. Using an interme- intermediate cytogenetic risk. diate dose of cytarabine, compared with conventional dose, was See related article by Wei et al., p. xxx shown to improve disease-free and overall survival in adult

In this issue of Clinical Cancer Research, Wei and colleagues re- Looking more closely at the data, what is driving this survival examine the important and unanswered clinical question of cytarabine benefit? Complete remission (CR) rates were higher with IDAC dose intensity in younger patients with de novo acute myeloid leukemia compared with CDAC (87% vs. 77%, P ¼ 0.004), with the caveat that (AML; ref. 1). To accomplish this, they conducted a large (591 patients) a small number of patients on the conventional dose arm were not open-label, randomized trial comparing induction using conventional treated for residual leukemia at day 14 (prior to a protocol amend- dose cytarabine (CDAC: 100 mg/m2/day for 7 days) and intermediate ment). In terms of safety, while the duration of neutropenia and dose cytarabine (IDAC: 100 mg/m2/day days 1–4 followed by 1 g/m2 thrombocytopenia were slightly longer in the IDAC group, there was every 12 hours, days 5–7), that is, 700 mg versus 6,400 mg of cytarabine no difference in induction deaths. In addition, rates of HCT between during the initial induction phase. Patients also received daunorubicin the two groups were the same. Collectively, these data suggest that 40 mg/m2 on days 1–3 and omacetaxine 2 mg/m2 on days 1–7 (the IDAC-based induction provided most of its benefit early, with, standard induction regimen in China). In patients achieving remis- numerically, a 10% better CR rate and 10% improvement in survival. sion, a second randomization was done prior to consolidation therapy, To what extent fewer relapses contributed to this survival difference in and half of patients received 3 cycles of high-dose cytarabine (HiDAC; unclear [cumulative incidence of relapse (CIR) not given for induction 3 g/m2 every 12 hours for 3 days) and half received two cycles of IDAC cohorts]. Of note, the advantage with IDAC-based induction also held (1.5 g/m2 every 12 hours for 3 days—note this is different than the dose true when looking at event-free survival (death, primary induction used during induction) combined with an anthracycline. Eligible failure, and relapse). patients could receive allogeneic hematopoietic cell transplantation When the authors examined patients by cytogenetic subgroup, the (HCT). The primary endpoint was disease-free survival (DFS), and survival advantage was only seen in patients with intermediate risk investigators and statisticians assessing outcomes were blinded to the disease. However, two-thirds of all patients on study had intermediate- cytarabine dose. risk cytogenetics, and there were very few adverse risk patients, making This was a large, well-done clinical trial that adds potentially it difficult to interpret the sub-analysis in these groups. This skew in practice-changing information to the field. Notably, the investigators cytogenetic distribution may be due to selection bias implicit to clinical demonstrated superior 3-year DFS [67% vs. 54%; HR ¼ 0.67; P ¼ trial enrollment, or to patient demographics in China and differences 0.005] and survival (68% vs. 59%; HR ¼ 0.72; P ¼ 0.014) with IDAC- in disease biology. Regardless, the more overall favorable cytogenetic based induction compared with conventional dose, and this advantage distribution, along with the younger median age (36 years), may was maintained after multivariable analysis and censoring subjects for explain the impressive 3-year OS rate of approximately 64% for all HCT. To us, it is undeniable that a one-third decreased risk of death or patients (68% for IDAC; 59% for CDAC). It is an interesting question if relapse (primary endpoint) with IDAC in this population is clinically the molecular genetic or epigenetic profile of patients in China differs meaningful. Also, of note, the second randomization done postremis- from that of the west, or other more heterogeneous populations, and sion had no impact on outcomes, suggesting that the standard repeated whether this could confer increased sensitivity to cytarabine. Impor- cycles of “HiDAC” consolidation is at least equivalent to multidrug tantly, the fact that a statistically significant and meaningful survival regimens, with the added benefit that it avoids excess anthracycline benefit was observed despite the overall good outcome, only reenforces exposure. In addition, in a subanalysis, the survival benefit with IDAC- the clinical significance of using IDAC-based induction in this pop- based induction was only seen in the patients who received HiDAC ulation, although long-term follow-up still needs to be reported as the consolidation. 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, two randomized studies compared de novo Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida. HiDAC-based to CDAC-based induction for AML; one gave HiDAC 3 g/m2 8 doses with daunorubicin and etoposide, and the Corresponding Author: Justin M. Watts, University of Miami, Sylvester Com- 2 prehensive Cancer Center, 1120 NW 14th Street, Suite 610C, Miami, FL 33136. other HiDAC 2 g/m 12 doses with daunorubicin. Despite no Phone: 305-243-8986; Fax: 3305-243-9161; E-mail: [email protected] improvement in survival, both studies showed improvements in the CIR and relapse-free survival (RFS) in the HiDAC cohorts. In the mid- Clin Cancer Res 2020;26:1–4 2000s, HOVON-SAKK compared HiDAC (2–3 g/m2) versus a more doi: 10.1158/1078-0432.CCR-20-0462 intermediate dose of cytarabine (1 g/m2) for AML induction (included 2020 American Association for Cancer Research. de novo and secondary AML) (2). In this study, each group received

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Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2020 American Association for Cancer Research. OF2 lnCne e;2(3 uy1 2020 1, July 26(13) Res; Cancer Clin at n Bradley and Watts Table 1. Summary of randomized trials comparing cytarabine dose during induction in acute myeloid leukemia.

Downloaded from Cumulative cytarabine dose Study in planned Authors subjects Eligibility criteria Induction cycles Induction regimens induction(s) Consolidation Outcomes

Bishop et al, 301 De novo AML, ages 1 cycle if CR, up to 3 DNR 50 mg/m2 D1-3 þ VP16 700 mg/m2 2 cycles of DNR 50 mg/m2 D1–2 þ Improved CIR, RFS – 2 – þ 2 – þ 1996 15 60 identical induction 75 mg/m D1 7 cytarabine VP16 75 mg/m D1 5 cytarabine Published OnlineFirstApril13,2020;DOI:10.1158/1078-0432.CCR-20-0462 cycles 100 mg/m2 D1–7 100 mg/m2 D1–5 clincancerres.aacrjournals.org DNR 50 mg/m2 D1–3 þ VP16 24 g/m2 75 mg/m2 D1–7 þ cytarabine 3 g/m2 q12h D1, 3, 5, and 7 Weick et al, 723 De novo or 1 cycle DNR 45 mg/m2 D5–7 þ 1.4 mg/m2 CR: Randomized to 2 cycles of DNR Improved CIR, RFS 1996a secondary AML, cytarabine 200 mg/m2 xD1–7 24 g/m2 45 mg/m2 D6–7 þ cytarabine ages 15–64 DNR 45 mg/m2 D7–9 þ 200 mg/m2 D1–7 vs. 1 cycle of DNR cytarabine 2 g/m2 q12h D1–6 45 mg/m2 D6–7þ cytarabine 2 g/ m2 q12h D1–5 CR: Nonrandomly assigned to DNR 45 mg/m2 D6–7 þ cytarabine 2 g/ m2 D1–5 Cancer Research. Buchner et al, 1,770 De novo or 2 cycles C1: DNR 60 mg/m2 D3–5 þ TG 18.8 g/m2 CR: 1 course of DNR 60 mg/m2 D3–5 No significant difference 2006b secondary AML, 100 mg/m2 q12h D3–9 þ þ TG 100 mg/m2 q12h D3–9 þ on September 24, 2021. © 2020American Association for ages 16–85 cytarabine 100 mg/m2 D1–8; cytarabine 100 mg/m2 D1–8 (median 60) C2: MTZ 10 mg/m2 D3-5 þ After consolidation chemotherapy, cytarabine 3 g/m2 q12h D1–3 randomized to maintenance or C1: MTZ 10 mg/m2 D3–5 þ 36 g/m2 autoSCT cytarabine 3 g/m2 q12h D1–3; C2: MTZ 10 mg/m2 D3–5 þ cytarabine 3 g/m2 q12h D1–3 Note: For patients ≥60, higher dose cytarabine was dosed at 1g/m2 q12h D1–3 Buchner et al, 725 De novo AML, ages 2 cycles C1: DNR 60 mg/m2 D3–5 þ TG 1.6 g/m2 CR: 1 course of DNR 60 mg/m2 D3–5 No significant difference 1999b 16–60 (median 100 mg/m2 q12h D3–9 þ 18.8 g/m2 þ TG 100 mg/m2 q12h D3–9 þ Subgroup analysis poor-risk 44) cytarabine 100 mg/m2 D1–8 cytarabine 100 mg/m2 D1-8 (>40% residual blasts, C2: C1: DNR 60 mg/m2 D3–5 þ TG Consolidation followed by adverse cytogenetics, 100 mg/m2 q12h D3–9 þ maintenance elevated LDH): Improved cytarabine 100 mg/m2 D1-8 AlloSCT if <50 w/sibling donor CR, EFS, and OS LNCLCNE RESEARCH CANCER CLINICAL C1: DNR 60 mg/m2 D3–5 þ TG 100 mg/m2 q12h D3–9 þ cytarabine 100 mg/m2 D1–8; C2: MTZ 10 mg/m2 D3–5 þ cytarabine 3 g/m2 q12h D1–3 (Continued on the following page) AACRJournals.org Downloaded from Table 1. Summary of randomized trials comparing cytarabine dose during induction in acute myeloid leukemia. (Cont'd ) Cumulative cytarabine dose Study in planned Authors subjects Eligibility criteria Induction cycles Induction regimens induction(s) Consolidation Outcomes Published OnlineFirstApril13,2020;DOI:10.1158/1078-0432.CCR-20-0462 Buchner et al, 1,284 De novo AML, ages 2 cycles C1: DNR 60 mg/m2 D3–5 þ TG 18.8 g/m2 CR: 1 course of DNR 60 mg/m2 D3–5 No significant difference clincancerres.aacrjournals.org 2009 16–85 100 mg/m2 q12h D3–9 þ 36 g/m2 þ TG 100 mg/m2 q12h D3–9 þ cytarabine 100 mg/m2 D1–8; cytarabine 100 mg/m2 D1–8 C2: MTZ 10 mg/m2 D3–5 þ Random assignment to autoSCT or cytarabine 3 g/m2 q12h D1–3 maintenance C1: MTZ 10 mg/m2 D3–5 þ cytarabine 3 g/m2 q12h D1–3; C2: MTZ 10 mg/m2 D3–5 þ cytarabine 3 g/m2 q12h D1–3 Note: For patients ≥60, higher dose cytarabine was dosed at 2 –

Cancer Research. 1g/m q12h D1 3 Lowenberg 858 De novo AML or 2 cycles C1: IDA 12 mg/m2 D5–7 þ 13.4 g/m2 If CR after 2nd induction, risk adapted No signiﬁcant difference et al, 2011 RAEB (IPSS≥1.5), cytarabine 200 mg/m2 D1–7; 26 g/m2 strategy of HiDAC vs. alloSCT vs. on September 24, 2021. © 2020American Association for ages 18–60 C2:amsacrine 120 mg/m2 D3, 5, autoSCT (median 49) 7 þ cytarabine 1 g/m2 q12h D1–6 C1: IDA 12 mg/m2 D5–7 þ cytarabine 1 g/m2 q12h D1–5; C2: amsacrine 120 mg/m2 D3, 5, 7 þ cytarabine 2 g/m2 q12h D1, 2, 4, 6 Willemze et 1,942 De novo or 1 cycle if CR, 2nd identical DNR 50 mg/m2 D1, 3, 5 þ VP16 1g/m2 If CR, one cycle of DNR 50 mg/m2 Improved CR, EFS, and OS al, 2013 secondary AML, induction if PR 50 mg/m2 D1–5 þ cytarabine 18 g/m2 D4–6 þ cytarabine 500 mg/m2 (ages <46) ages 15–60 100 mg/m2 D1–10 q12h D1–5 (median 45) DNR 50 mg/m2 D1, 3, 5 þ VP16 AlloSCT if suitable donor, otherwise 50 mg/m2 D1–5 þ cytarabine autoSCT 3 g/m2 q12h D1, 3, 5 Wei et al, 591 De novo AML, ages Up to 2 induction cycles in DNR 40 mg/m2 D1–3 þ 700 mg/m2 If CR, randomized to 1st consolidation Improved CR, DFS, EFS, OS

lnCne e;2(3 uy1 2020 1, July 26(13) Res; Cancer Clin 2 2 2 2020 15–55 (median conventional cytarabine omacetaxine 2 mg/m D1–7 þ 6 g/m with DNR 40 mg/m D1–3 þ Induction AML in Dose Cytarabine 36) arm if CR not cytarabine 100 mg/m2 D1–7 cytarabine 3 g/m2 q12h D1–3 vs. accomplished after C1 DNR 40 mg/m2 D1–3 þ DNR 40 mg/m2 D1–3 þ cytarabine omacetaxine 2 mg/m2 D1–7 þ 1.5 mg/m2 q12h D1–3 cytarabine 1 g/m2 q12h D5–7 C2: MTZ 6 mg/m2 D1–3

aInitially HiDAC was dosed 3 g/m2 in induction and consolidation for patients <50; however, this was reduced to 2 g/m2 in 1988 (DMC). In all consolidation arms, DNR was reduced to 30 mg/m2 for ages 50–64. bMaintenance therapy after consolidation consisting of monthly cytarabine 100 mg/m2 q12h SQ D1–5 paired with alternating DNR 45 mg/m2 D3–4, TG 100 mg/m2 q12h D1–5, and cyclophosphamide 1 g/m2 D3 for 3-year duration. OF3 Published OnlineFirst April 13, 2020; DOI: 10.1158/1078-0432.CCR-20-0462

Watts and Bradley

two planned induction courses. The intermediate-dose group received Cytarabine has served as the backbone of AML therapy for decades. idarubicin plus CDAC first, followed by a second induction with The use of HiDAC during consolidation has established DFS and OS amsacrine plus cytarabine 1 g/m2 (total cytarabine dose during benefit versus CDAC in younger patients and is standard of care (5). induction 13.4 g/m2). The high-dose group received idarubicin with Subsequent efforts to demonstrate further survival benefitbyusing cytarabine 1 g/m2 first, followed by amsacrine plus cytarabine 2 g/m2 higher doses of cytarabine during induction have shown mixed (total cytarabine dose 26 g/m2). Overall, this study found no significant results. One problem is that it is nearly impossible to compare difference in CR, relapse, EFS, or survival between the intermediate studies, as the dose of cytarabine, induction drug partner(s), and higher dose groups. More recently, the EORTC and GIMEMA number of planned inductions, consolidation strategy, and patient groups examined combination daunorubicin, etoposide, and cytara- eligibility factors (such as age and de novo vs. secondary AML) vary bine (100 mg/m2 10 days vs. 3 g/m2 4 days) induction in de novo and considerably. This study and others also raise the question of secondary AML patients (3). They reported statistically significant population differences in AML biology that may affect treat- improvements in CR rate, EFS, and survival (at 6 years) for patients ment-specific outcomes, and how to compare studies across diverse aged 15–45 who received HiDAC as a component of induction, as well groups. Regardless of these considerations, Wei and colleagues have as improved outcomes in patients with adverse cytogenetics, FLT3- reminded us that cytarabine is the most active drug we have in AML ITD mutations, and secondary AML. In 2014, Wei and colleagues therapy, and that the dose matters, even during induction. This is conducted a meta-analysis of cytarabine dose in AML induction that the first study to show a survival benefit with cytarabine intensi- assessed 6 different studies (4). Overall, there was no statistically fication during induction in adult patients ages 15–55. Only one significant difference in CR rate or survival between induction regi- other study has shown a survival benefitinadultAML,butwith mens containing HiDAC or CDAC; however, there was a statistically higherdosesofcytarabineandonlyforages15–45 (3). Wei and significant difference in RFS, favoring HiDAC. In a subgroup analysis, colleagues have importantly demonstrated that using an interme- this RFS benefit was only recapitulated in favorable risk patients. diate dose of cytarabine in the 6-gram range (not HiDAC, Importantly, all of the aforementioned studies showed increased see Table 1), is sufficient to achieve a significant survival advantage toxicity with higher doses of cytarabine, including conjunctivitis, skin compared with CDAC. On the basis of this, an intermediate-dose reactions, and gastrointestinal complications (count recovery times level of cytarabine with induction should be considered in younger were comparable). adults, particularly intermediate risk, FLT3-negative patients. Given The broader question this study raises is the worldwide applicability that this study enrolled mostly intermediate risk patients, it is of its findings. This is a near impossible question to answer. In China, harder to assess the impact of IDAC on favorable or adverse risk where there are more cases of AML than in the United States and disease. Although a meta-analysis has shown RFS benefitwith European Union combined, the results of this large randomized HiDAC-based induction in favorable risk patients, one has to clinical trial clearly support the use of IDAC with induction for consider whether this outweighs the benefitofaddingGOto younger patients with de novo AML, particularly those with interme- standard 7þ3. Adverse risk AML is a more complicated topic and diate risk. Potential confounders that may limit generalizability ideally would be treated on a clinical trial, and the existing evidence include the use of omacetaxine and a daunorubicin dose of 40 mg/ appears less convincing for using higher doses of cytarabine with m2 during induction. In many countries, higher doses of daunorubicin induction in these patients. Finally, there was also an important are used, and 90 mg/m2 vs. 45 mg/m2 has known survival benefit when negative finding on this study: deviating from standard HiDAC given with CDAC. Another point to consider is that patients on the consolidation therapy was not supported. CDAC arm were allowed to receive a second induction based on the D14 bone marrow biopsy (although sensitivity analysis showed no Disclosure of Potential Conflicts of Interest difference in outcomes). The following questions could be raised and J.M. Watts is a paid consultant for Takeda, Rafael Pharma, Genentech, and Jazz have not been (and may never be) answered: if cytarabine dose Pharma, and reports receiving commercial research grants from Takeda. T. Bradley intensification were delayed until reinduction (if needed), would reports receiving speakers bureau honoraria from Novartis and is a paid consultant/ fl outcomes be any different than using IDAC upfront (and could advisory board member for AbbVie. No other potential con icts of interest were disclosed. such sequencing minimize potential excess toxicity in patients already sensitive to CDAC)? Along those lines, what is the role of Acknowledgments HiDAC-based salvage if IDAC is used during induction? Finally, as J.M. Watts is supported by the NIH/NCI (5R21CA202488-02) and the Sylvester these are largely intermediate risk patients, some of who had a Cancer Center Support Grant 1P30CA240139-01. FLT3-ITD mutation (11%), what is the role of midostaurin if IDAC is used, both in terms of efficacy and safety? What about gemtu- Received March 3, 2020; revised March 26, 2020; accepted April 8, 2020; zumab ozogamicin? published first April 13, 2020.

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OF4 Clin Cancer Res; 26(13) July 1, 2020 CLINICAL CANCER RESEARCH

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

Justin M. Watts and Terrence Bradley

Clin Cancer Res Published OnlineFirst April 13, 2020.

Updated version Access the most recent version of this article at: doi:10.1158/1078-0432.CCR-20-0462

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