Expert Opinion on Pharmacotherapy

ISSN: 1465-6566 (Print) 1744-7666 (Online) Journal homepage: http://www.tandfonline.com/loi/ieop20

Cytarabine and daunorubicin for the treatment of acute myeloid leukemia Tracy Murphy & Karen WL Yee To cite this article: Tracy Murphy & Karen WL Yee (2017): Cytarabine and daunorubicin for the treatment of acute myeloid leukemia, Expert Opinion on Pharmacotherapy, DOI: 10.1080/14656566.2017.1391216 To link to this article: http://dx.doi.org/10.1080/14656566.2017.1391216

Accepted author version posted online: 11 Oct 2017.

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Date: 12 October 2017, At: 04:39

Cytarabine and daunorubicin for the treatment of acute myeloid leukemia

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Tracy Murphy, MB BCh BAO, FRCP, FRCPath1 and Karen WL Yee, MD2*

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Tracy Murphy, MB BCh BAO, FRCP, FRCPath Division of Medical Oncology and Hematology University Health Network – Princess Margaret Cancer Centre 700 University Avenue, 6th Floor Toronto, Ontario CANADA M5G 1Z5 Tel: 416-946-4501 ext 3052 Fax: 416-946-4563 Email: [email protected] 2

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Karen W.L. Yee, MD (*corresponding author) Division of Medical Oncology and Hematology University Health Network – Princess Margaret Cancer Centre 700 University Avenue, 6th Floor, Room 328 Toronto, Ontario CANADA M5G 1Z5 Tel: 416-946-4495 Fax: 416-946-4563 Email: [email protected]

Funding This paper was not funded

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1

Declaration of Interest

KWL Yee received research funding from Celator Pharmaceuticals, Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Abstract Introduction: Acute myeloid leukemia (AML) is the most common acute forms of leukemia in adults. It has a poor long-term survival with a high relapse rate and at relapse, is commonly

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resistant to available therapies. The current combination of daunorubicin (DNR) for three days and cytarabine (Ara-C) as a continuous infusion for seven days, more commonly known as ‘3+7’

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induction regimen internationally.

Areas covered: This paper will briefly review clinically important trials related to ‘3+7’.

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Somatic mutations in AML that are linked to chemoresistance to ‘3+7’will be discussed. Other topics covered include the novel ratiometric agent containing daunorubicin and cytarabine, CPX-

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351, and midostaurin in FLT3 mutated AML.

Expert opinion: ‘3+7’ continues to be the backbone of therapy for AML. However, genetic risk

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stratification should be used to determine patients who are unlikely to respond to standard

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intensive chemotherapy and hence, should be enrolled onto a clinical trial upfront. This will facilitate development of newer effective treatment strategies in AML. Patients with mutations that are associated with chemoresistance should be offered therapies which may circumvent or overcome these pathways.

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has remained essentially unaltered over the last forty-four years and remains the standard

Keywords: acute myeloid leukemia, anthracycline, cytarabine, CPX-351, daunorubicin, midostaurin

1. Introduction Acute myeloid leukemia (AML) is the most common malignant disease of the bone marrow in adults. It is characterized by a proliferation of immature leukemic stem cells, which fail to

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differentiate, leading to eventual bone marrow failure if untreated. While the median five year survival is 25%, there is significant variability according to disease subtype and can range from

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(APL) [1].

When considering treatment options for patients with AML, there is a triad of factors that

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should be examined - the patient, the disease and the available therapies. Patient related factors are often the most limiting as AML is an age related disease with the median age at diagnosis

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being 72 years of age, reaching a peak incidence between 80 and 84 years of age [2]. While there have been significant improvements in the overall survival (OS) for younger patients due to more

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intensive chemotherapy, transplantation and supportive care, elderly patients with leukemia continue to have an abysmal prognosis [3]. Many trials have taken place to optimize the response

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of those who are unfit for intensive induction therapy but as yet no effective therapies have been identified and clinical trial participation is considered the optimal approach [4, 5]. Our understanding of disease characteristics in AML has changed significantly in the last

decade secondary to advancement in molecular genetics. The study of leukemia stem cells and

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5-10% for patients with poor risk AML to in excess of 90% for acute promyelocytic leukemia

the recognition of pre-leukemia mutations underscore a mutational complexity that we as yet do not fully understand [6]. Furthermore, high throughput sequencing has made classification more complex and highlighted the true heterogeneity of AML as a disease entity [7]. Moreover, there

is better understanding of how these newly described genetic mutations contribute to chemoresistance in AML. In this review, the effectiveness of daunorubicin (DNR) and cytarabine (Ara-C) induction

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chemotherapy in the treatment of adult patients with AML (but not APL) who are considered suitable for intensive chemotherapy and strategies to overcome resistance or improved genetic

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midostaurin for the treatment of FLT3 mutated AML, as well as the liposomal formulation of

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Ara-C and DNR, CPX-351 will be discussed. Due to space constraints, the effect of different

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consolidation strategies and allogeneic stem cell transplant (alloSCT) on outcome will not be

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examined.

2.1. Chemistry

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2. Daunorubicin and Cytarabine: Pharmacology

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Daunorubicin (also known as daunomycin or rubidomycin) is an anthracycline cytotoxic antibiotic produced by Streptomyces cerulorubidus and Streptomyces peucetius. It has the chemical name of (1S,3S)-3-Acetyl-1,2,3,4,6,11-hexahydro-3,5,12- trihydroxy-10-methoxy6,11-dioxo-1-napthacenyl 3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranoside hydrochloride. Its molecular formula is C27H29NO10·HCl with a molecular weight of 563.99. It is a hygroscopic

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risk stratification will be reviewed. Moreover, the recently approved multikinase inhibitor

crystalline powder. The pH of a 5 mg/ml aqueous solution is 4.5 to 6.5 [8]. Cytarabine (also known as 1-beta-D-Arabinofuranosylcytosine, 4-Amino-1-beta-Darabinofuranosyl-2(1H)-pyrimidinone,

cytosine

arabinoside,

cytosine-1-beta-D-

arabinofuranoside or cytosine-β-D-arabinofuranoside) is a pyrimidine nucleoside analog. Its

molecular formula is C9H13N3O5 with a molecular weight of 243.22. It is a crystalline powder which is freely soluble in water and slightly soluble in alcohol and chloroform [9]. 2.2. Pharmacodynamics

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Daunorubicin has antimitotic and cytotoxic activity through a number of mechanisms of action.

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activity by stabilizing the DNA-topoisomerase II complex, thus preventing the relegation by

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topoisomerase II and resulting in single and double strand DNA breaks. Daunorubicin may also inhibit polymerase activity, affect regulation of gene expression and produce free radical damage

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to DNA. Although daunorubicin is maximally toxic in the S phase, the drug is not cycle-phase specific [8].

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Cytarabine is a cell phase specific cytotoxic drug, primarily during the S-phase when cells are undergoing DNA synthesis. Under certain circumstances, it can block the progression of

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cells from the G1 phase to the S phase. Its mechanism of action is not completely understood,

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but appears to inhibit DNA polymerase. A limited, but significant, incorporation of cytarabine into both DNA and RNA has been reported. Cytarabine as cause extensive chromosomal damage, including chromatoid breaks [9]. 2.3. Pharmacokinetics and metabolism

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It forms complexes with DNA by intercalating between base pairs and inhibits topoisomerase II

Following intravenous injection, plasma levels of daunorubicin rapidly decline due to tissue uptake. Thereafter, plasma levels decline slowly with a half-life of 45 minutes in the initial phase and 18.5 hours in the terminal phase. Daunorubicin is widely distributed in tissues, with the highest levels in the spleen, liver, lungs and heart. The drug binds to many cellular components,

particularly nucleic acids. Daunorubicin does not cross the blood-brain barrier, but does cross the placenta [8]. Daunorubicin is extensively metabolized in the liver and other tissues, mainly by

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cytoplasmic aldo-keto reductases, producing daunorubicinol, the major metabolite which has antineoplastic activity. Within 30 minutes of daunorubicin administration, approximately 40% of

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Daunorubicinol has a half-life of 26.7 hours. Further metabolism of daunorubicin and

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daunorubicinol via reduction cleavage of the glycosidic bond, 4-O demethylation, and

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conjugation with both sulfate and glucuronide have been demonstrated; however, in humans this is not a significant metabolic pathway. Twenty-five percent of the administered dose of

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daunorubicin and its metabolites is eliminated by urinary excretion and 40% by biliary excretion [8].

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Following intravenous administration of cytarabine, the disappearance of cytarabine from the plasma is biphasic. There is an initial distribution phase with a half-life of about 10 minutes,

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followed by a second elimination phase with a half-life of about 1 to 3 hours. After the distribution phase, more than 80% of the drug found in plasma is its inactive metabolite, 1-β-Darabinofuranosyluracil. Within 24 hours, about 80% of the administered drug can be recovered in the urine, 90% of which is 1-β-D-arabinofuranosyluracil. Cytarabine is metabolized by

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the drug is present in the plasma is daunorubicinol and increases to 60% by 4 hours.

deoxycytidine kinase and other nucleotide kinases to the nucleotide triphosphate, an effective inhibitor of DNA polymerase. It is inactivated by a pyrimidine nucleoside deaminase, which converts it to the non-toxic uracil derivative, 1-β-D-arabinofuranosyluracil [9].

Cerebrospinal fluid levels of cytarabine are low in comparison to plasma levels after a single intravenous injection. However, levels may approach 40% of the steady state plasma level 2 hours after a continuous intravenous infusion. With intrathecal administration, levels of cytarabine in the cerebrospinal fluid declined with a first order half-life of about 2 hours.

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Because cerebrospinal fluid levels of deaminase are low, little conversion to 1-β-D-

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3. Daunorubicin and Cytarabine: Clinical Efficacy

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Older individuals with AML have lower response rates and worse OS compared with younger individuals due to differences in the biology of the disease, prevalence of comorbidities,

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underlying performance status, and tolerance to intensive chemotherapy [10-12]. Even older patients with favorable tumor biology have a worse outcome than younger patients. However,

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age itself should not be the sole determinant to guide treatment decisions [13]. For both younger

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and older patients with previously untreated patients with AML, the most commonly used induction chemotherapy regimen consists of 3 days of DNR and 7 days of Ara-C, also known as ‘3+7’. While there were many preliminary studies involving the combination of Ara-C and DNR, it is the Roswell Park report from 1973 that is thought to be the seminal paper on the efficacy of induction chemotherapy with DNR and Ara-C [14] and has been confirmed in 2 larger Cancer

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arabinofuranosyluracil is observed [9].

and Leukemia Group B (CALGB) trials [15, 16]. This regimen can yield complete remission (CR) rates of 60-80% in younger patients and 45-60% in older patients (age > 60 years) [16-22]. Effects to improve outcome have focused on

intensifying therapy, developing more effective combination therapy, including those geared to specific subsets of AML, and/or minimizing toxicities associated with therapy. 3.1 Daunorubicin and cytarabine versus other regimens

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Although there is no standard induction regimen for patients with untreated AML, the most

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intravenously by continuous infusion for 7 days (Table 1). Amsacrine has been compared to

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DNR, in the context of a 3+7 strategy, with an advantage seen after stratification for age [23]. Other agents, such as alcarubicin [24] and amonafide [25] or regimens, such as FLAM

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(flavopiridol, Ara-C and mitoxantrone), have also been compared to DNR in the context of the 3+7 regimen with higher CR rates observed with alcarubicin and FLAM. Nonetheless, all

compared with 3+7.

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regimens have demonstrated similar event-free survival (EFS) and/or remission duration and OS

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Mitoxantrone 8 to 12 mg/m2 per day compared with DNR at doses of 30 to 50 mg/m2 yielded higher CR rates in some studies [26, 27] but not in others [28-30]. In one of these

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studies, DNR-50, mitoxantrone 12 mg/m2 per day, and idarubicin (IDA) 10 mg/m2 per day displayed similar activity [28]. A Cochrane systemic review of 18 randomized control trials involving 6755 patients indicated that IDA improved CR rates (p = 0.009) and OS (p = 0.0008) compared with DNR [31]. However, only 3 of these randomized studies (n=1585) have

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widely used has been DNR intravenously for 3 days and Ara-C at a dose of 100-200 mg/m2

compared DNR at a dose of > 60 mg/m2 for 3 days with IDA 12 mg/m2 for 3 days or 8 mg/m2 for 5 days in conjunction with Ara-C in adult patients with AML [32-34]. Furthermore, although 1 of these studies demonstrated an improved CR rate [33]; none showed an improved OS. A second systematic review and meta-analysis of 29 trials evaluating anthracycline-based treatment regimens in younger patients (age < 60 years) with AML indicated that superiority of IDA for

remission induction was limited to studies with a DNR/IDA dose ratio < 5 (ratio < 5: risk ratio [RR] 0.54; 95% confidence interval [CI] 0.51-0.81; p < 0.001; ratio > 5: RR 1.03; 95% CI 0.911.16; p = 0.63), suggesting that previously observed improvements with IDA represent an issue of biologic dose equivalence rather than inherent biologic advantage [35]. Similarly, a

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prospective randomized study compared induction therapy with 3+7 to TAD-HAM (6-

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and a different dose schedule of Ara-C and mitoxantrone in older patients with untreated AML

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[36]. In the 3+7 arm, less patients had secondary AML and wildtype FLT3 and NPM1 (p = 0.003 and p = 0.0455, respectively). There was no difference in CR rate, event-free survival (EFS) or

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OS between the groups. Furthermore, when most of these studies were conducted, risk stratification was performed using chromosomal analysis and not integrated genetic profiling.

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Hence, no study has systematically evaluated responses due to different molecular profiles. Therefore, DNR and Ara-C induction chemotherapy continues to be the standard against

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which most new treatments are tested; however, with the recent U.S. Food and Drug

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Administration (FDA) approval CPX-351 for the treatment of older patients with therapy-related or secondary AML or AML with myelodysplasia-related changes (see below), this drug should be considered standard of care for this group of patients [37]. 3.2 Dose of Daunorubicin

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thioguanine, Ara-C and DNR followed by high dose Ara-C and mitoxantrone) or HAM-HAM

The CALGB randomized study demonstrated comparable response rates when DNR was administered at a dose of 45 mg/m2 (DNR-45) or 30 mg/m2 (DNR-30) daily for 3 days in combination with Ara-C at a dose of 100 mg/m2 daily for 7 days (Table 2a) [16]. However, the CR rates were higher with DNR-45 than DNR-30 (72% v 59%; p < 0.03) for patients < 60 year of age. Whereas for patients > 60 years of age, the CR rate for DNR-30 was higher than for

DNR-45 (47% v 31%; p < 0.05); it is unclear whether this was related to the higher mortality observed in older patients receiving DNR-45 (41% v 54%). Based on these findings, DNR at a dose of 45 mg/m2 IV daily for 3 days became the standard when administered with Ara-C during induction chemotherapy for patients with previously untreated AML.

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Since then, several studies from large cooperative groups have demonstrated higher CR

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DNR to 90 mg/m2 (DNR-90) rather than prolonging the number of days of DNR administration

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[20-22]. In younger patients (age < 50-60 years), this was associated with a survival benefit without any increased toxicity, including cardiotoxicity [21, 22]. Subgroup analysis suggested

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that the benefit of DNR-90 was restricted to those with intermediate-risk and/or favorable-risk cytogenetics [20-22] and DNMT3A or NPM1 mutations or MLL-PTD [38]. With a longer

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follow-up of 80.1 months in the Eastern Cooperative Oncology Group (ECOG) E1900 study, DNR-90 continued to demonstrate benefit in patients < 50 years of age and those with favorable

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or intermediate risk cytogenetics [38]. Furthermore, this follow-up analysis indicated that DNR-

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90 was beneficial in patients with poor-risk cytogenetics, FLT3-ITD, DNMT3A and NPM1 mutations, as well as patients aged 50-60 years with FLT3-ITD or NPM1 mutations [38, 39]. However, during the conduct of these DNR dose intensification studies [20-22], the

majority of physicians had shifted from using DNR-45 to DNR-60 both in routine practice as

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rates can be achieved with dose intensification of DNR, in this case, by increasing the dose of

well as in clinical trials. The German AML Cooperative Group (AMLCG) demonstrated that DNR-60 yielded significantly more CRs that DNR-30 (54% v 43%, p = 0.038) with an OS at 5 years of 16% [19]. Subsequently, a small randomized trial compared DNR-45 (group A) with DNR-60 (group B) in 60 newly diagnosed AML (not APL) patients [40]. The dose of Ara-C was 100mg/m2 for 7 days in both groups. Of the 56 evaluable patients, twenty of 30 (67%) patients in

group A and 23 of 26 (88%) patients in group B (p = 0.05) achieved a CR. Fifteen (50%) patients in group A and 22 (84.6%) in group B achieved a remission after a single course of induction chemotherapy (p = 0.006). Nine patients (30%) in group A and 3 (11.5%) in group B died due to uncontrolled sepsis (p = 0.09). There was no significant difference with respect to major organ

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toxicities. However, the duration of grade 4 thrombocytopenia and admission were significantly

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unclear.

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A randomized phase 3 UK National Cancer Research Institute (NCRI) AML17 trial

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subsequently demonstrated that there was no difference in CR rates or OS between DNR-90 and DNR-60 [17]. However, DNR-90 was associated with increased 60-day mortality (10% v 5%; p

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= 0.001), leading to premature closure after a median follow-up of 14.8 months [17, 18]. Subgroup analysis performed after a median follow-up of 28 months, showed an improved

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relapse-free survival (RFS) and OS in patients with FLT3-ITD AML who received DNR-90, irrespective of allele burden or NPM1c status [18]. No other mutational analysis was performed

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to assess for other gene interactions. With the recent FDA approval of midostaurin for the treatment of FLT3 mutated AML (see below), the use of DNR-90 in this subgroup of patients may not be relevant. Therefore, current data suggests that for induction chemotherapy using the 3+7 regimen, the dose of DNR should be at least 60 mg/m2.

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greater in the DNR-45 arm (p = 0.02 and p = 0.005, respectively). The reason for this difference is

3.3 Dose of Cytarabine

Dose intensification of Ara-C either by increasing the dose from 100 mg/m2 per day to 200 mg/m2 per day [41] or 1 to 2 g/m2 twice daily [42], or extending its infusion period to 10 days (i.e. 10+3) [43] did not additionally improve the results regardless of whether the anthracycline

was DNR-30 or DNR-45 [42] (Table 3). No difference in OS was detected in

2 studies

comparing Ara-C 3 g/m2 every 12 hours on Days 1, 3, 5 and 7 (8 doses) with Ara-C 100 mg/m2 per day as continuous infusion for 7 or 10 days in combination with DNR-50 and etoposide 5075 mg/m2 intravenously per day for 5 or 7 days [44, 45]. However, on subgroup analysis, the

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European Organisation for Research and Treatment of Cancer - Gruppo Italiano Malattie

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favor of high dose Ara-C for patients < 46 years of age (51.9% v 43.3%; p = 0.003) [44]. This

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assessment has not been performed in combination with DNR-60, but has been performed with IDA at a dose of 12 mg/m2 intravenously for 3 days, which did not demonstrate any increased

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benefit [46]. Furthermore, high dose Ara-C was associated with significantly more toxicity, including neurologic toxicities, prolonged hospitalization and myelosuppression [42, 46]. No

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study has identified subsets of patients who would benefit from higher doses of Ara-C. At the current time, there is insufficient evidence to recommend administering Ara-C at doses higher

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than the standard 100-200 mg/m2 per day by continuous infusion intravenously for 7 days during

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induction chemotherapy with the 3+7 regimen. 3.4 Addition of a third drug to daunorubicin and cytarabine Most patients with AML who achieve a CR will eventually relapse or have primary refractory disease due to subpopulations of AML cells being resilient or resistant to standard chemotherapy

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Ematologiche dell' Adulto (EORTC-GIMEMA) AML-12 trial observed a survival benefit in

(e.g. DNR and Ara-C). Mechanisms of resistance have included: (a) the role of the leukemia stem cell niche and the interplay between the microenvironment and the leukemia cells, (b) drug effluxing capabilities of transporters (e.g. P-glycoprotein, ATP-binding cassette [ABC] transporters), (c) altered drug metabolism, (d) aberrant signaling pathways, (e) impaired DNA damage response (DDR) pathways, (f) the presence of subsets of quiescent leukemia cells, and

more recently, (g) genetic and epigenetic heterogeneity within the leukemia cells leading to potentially common mechanisms of regulation and action [47-53]. Attempts to overcome or prevent resistance have led to development of drugs targeting these abnormalities, either as single agents, doublet or triplet combination targeted therapies or agents administered in

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conjunction with traditional chemotherapy regimens.

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over 3+7 [43, 54] (Tables 1, 4a, 4b and 4c). Similarly, there was no additional benefit was gained

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(e.g. azacitidine and vorinostat) [57, 58] to 3+7.

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by adding an efflux inhibitors (e.g. valspodar and zosuquidar) [55, 56] or epigenetic modifiers

3.4.1 Purine Analogues

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Purine analogues, such as cladribine and fludarabine, increase cellular uptake of Ara-C and the accumulation of AraCTP in circulating blasts from patients with AML by 50-65% [59, 60], as

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well as having a direct antileukemia effect resulting from the incorporation of its metabolite into the DNA of proliferating cells [61]. Cladribine, but not fludarabine, in conjunction with DNR-60

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and Ara-C during induction increased the CR rate (67.5% v 59% v 56%; p = 0.01) and prolonged survival (OS3y 45% v 33% v 35%; p = 0.02) in younger patients with AML (age < 60 years) compared to DNR-60 and Ara-C (Table 4c) [62]. Consolidation chemotherapy included highdose Ara-C followed by stem cell transplant (SCT) or 2-year maintenance chemotherapy,

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Previous incorporation of 6-thioguanine and etoposide have not shown any improvement

determined on the basis of risk of relapse. The rates of alloSCT were comparable in the 3 treatment arms (22% v 21% v 19%). Risk stratification by cytogenetics was comparable between the groups with 25% of the patients not having karyotype available. Toxicities, including duration of cytopenias, were similar between all 3 arms. However, OS at 3 year may be slightly lower than expected for a younger population of patients with AML treated with 3+7.

Furthermore, with the advent of next generation sequencing, the question that remains with this study and all prior studies is whether integrated genetic risk stratification is comparable between the groups.

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3.4.2 Immunotherapy 3.4.2.1 Gemtuzumab ozogamicin

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that targets CD33. GO had received accelerated approval on May 17, 2000, as a single agent at a

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dose of 9 mg/m2 per day on Days 1 and 14 for older patients (age > 60 years) with CD33-

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positive AML in first relapse and who were not candidates for cytotoxic chemotherapy [63]. The Southwest Oncology Group (SWOG) study S0106 compared induction chemotherapy with

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DNR-60 and Ara-C with the administration of GO 6 mg/m2 in conjunction with DNR-45 and Ara-C in 595 younger patients (age < 60 years) with untreated AML (Table 4a) [64]. At the

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second scheduled interim analysis on August 11, 2009, given the failure to demonstrate the prespecified improvement in CR rate, RFS or OS and an increase in deaths during induction on

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the GO and DNR and Ara-C arm, the Data and Safety Monitoring Committee (DSMB) recommended early closure of the trial. Wyeth Pharmaceuticals subsequently withdrew GO from the US market in 2010. Lack of difference in efficacy may be due to the lower dose of DNR used in the GO arm. In retrospect, the induction death rate in the GO and DNR and Ara-C arm was

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Gemtuzumab ozogamicin (GO) is a humanized antibody conjugated with the toxin calicheamicin

comparable to that observed in other trials for patients of this age group; the very low death rate in the control arm accounted for the difference in the fatal induction rate for this trial. Two other trials using a single GO 3-6 mg/m2 dose in combination with DNR and Ara-C chemotherapy in patients primarily < 60 years of age also failed to show any survival benefit [65, 66]. On subgroup analysis, two studies demonstrated improved RFS and/or OS in patients with

favorable-risk AML [64, 65]. Major toxicity in the form of veno-occlusive liver disease (VOD) and more grade 3-4 hepatic toxicities (23% v 13%, respectively; p = 0.031) [66] and grade 4 or fatal nonhematologic induction toxicities (21% v 12%, respectively; p = 0.0054) [64] were observed on the GO 6 mg/m2.

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Two studies in older patients with AML demonstrated a survival benefit when GO 3

In the Acute Leukemia French Association (ALFA)-0701 study,

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cytogenetics [67, 68].

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induction. This was attributable to fewer relapses in patients with favorable- or intermediate-risk

improvement in event-free survival (EFS), RFS and OS were independent of CD33 expression

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on myeloblasts [68]. However, a criticism of the Medical Research Council (MRC) AML16 trial is that 3 additional randomizations were performed: (a) randomization between DNR and

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clofarabine v DNR and Ara-C induction therapy, (b) post-induction randomization of patients in CR or partial remission (PR) to receive 1 cycle of or no consolidation, and (c) randomization to

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maintenance therapy with azacitidine or observation only and yet, full presentation of the

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combined outcomes has not be published [69]. Therefore, it is difficult to decipher the extent of benefit with GO therapy. Despite these concerns, an individual patient data meta-analysis of these 4 studies confirmed an improved 5 year OS with GO, irrespective of patient age, due to decreased risk of relapse [70]. The benefit was observed in patients with favorable or intermediate risk karyotype, but not in adverse risk patients. Doses of 3 mg/m2 were associated

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mg/m2 was administered either as a single dose or 3 fractionated doses on days 1, 4, and 7 of

with equal efficacy and less toxicity. The FDA recently approved GO at a lower dose and different schedule in combination with chemotherapy or as monotherapy for the treatment of adults with newly diagnosed AML whose myeloblasts express CD33. 3.4.3 Tyrosine kinase inhibitors

3.4.3.1 Sorafenib Sorafenib is a multikinase inhibitor with activity against Ras/Raf, c-kit, VEGF receptor, PDGF receptor and FLT3 [71]. Two randomized trials have evaluated sorafenib administered in conjunction with induction and consolidation therapy followed by maintenance therapy in

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younger and older patients with untreated AML (Table 4b) [72, 73]. Fourteen to 17% of the

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These findings were consistent in the FLT3-ITD mutated patients, as well, albeit the small

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number of patients treated.

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3.4.3.2 Midostaurin

Midostaurin (PKC412) is a small molecule multikinase inhibitor with activity against FLT3. The

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RATIFY trial evaluated midostaurin/placebo administered with DNR-60 and Ara-C followed by 4 cycles of consolidation therapy with midostaurin/placebo and high dose Ara-C then a 1-year

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midostaurin/placebo maintenance phase in 717 patients aged 18 to 60 years with previously untreated FLT3-mutated AML (Table 4b) [74, 75]. Toxicities were comparable for the two arms,

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except for increased rash observed in the midostaurin arm (14% v 8%; p = 0.008). CR rates were comparable between the 2 arms (58.9% v 53.5%; p = 0.15), but CR rates were increased in the midostaurin arm when all CRs reported within 30 days of ending protocol therapy were considered (68% v 59%; p = 0.04). The trial met its primary end point in improving OS (74.7

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patients had a FLT3-ITD mutation. There were no differences in CR rates or OS in either study.

months v 25.6 months; hazard ratio 0.78; p = 0.009) and survival in FLT3-TKD mutated and (high and low allele burden) FLT3-ITD mutated AML, regardless of whether patients received alloSCT. Only a small proportion of patient received maintenance, therefore, the benefit of midostaurin maintenance is unclear. As of April 28, 2017, the U.S. FDA approved midostaurin for the treatment of adult patients with newly diagnosed AML who are FLT3 mutation-positive,

as detected by an FDA-approved test, in combination with standard DNR and Ara-C induction and Ara-C consolidation. 3.5 Liposomal formulations daunorubicin and/or cytarabine

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3.5.1 DaunoXome (DXR) Liposomal formulations of daunorubicin (DXR) have been evaluated in older patients in attempts

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conversion of DNR to its 13-dihydro metabolite, daunorubicinol (Table 2b). This study did not

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demonstrate an improved CR rate or OS compared with DNR-45 [76].

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There are no reported trials using liposomal cytarabine in AML.

3.5.2 CPX-351 (VYXEOS™ (cytarabine: daunorubicin) Liposome for Injection)

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Using a radio-metric approach evaluating concentration-dependent drug interactions (i.e. optimal ratios of drug combinations to ensure synergy and prevent antagonism) led to the development of

100-nm

diameter

liposomes

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within

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CPX-351. CPX-351 is a liposomal formulation of Ara-C and DNR fixed at a 5:1 molar ratio [77].

The

lipid

membrane

contains

distearylphosphatidylglycerol, disteraylphosphatidylcholine and cholesterol at a 7: 2: 1 molar ratio, which permits retention of the synergistic 5:1 ratio of Ara-C and DNR within the liposome for more than 24 hours after intravenous administration [77-79].

The simultaneous

administration of Ara-C and DNR at the 5:1 molar ratio as free drugs cannot maintain a 5:1

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to increase the dose of DNR that could be administered without increasing toxicity and to reduce

molar ratio at the tumor site (i.e. plasma and/or bone marrow) and hence, demonstrated decreased in vivo therapeutic efficacy in leukemia bearing mice compared with CPX-351 [77, 78]. One unit of CPX-351 is contains 1mg of Ara-C and 0.44 mg of DNR [80]. CPX-351

exhibits first order elimination kinetics but both encapsulated DNR and Ara-C have markedly longer half-lifes compared to ‘free form’ DNR and Ara-C [79, 81]. A dose escalating phase I study in patients with relapsed or refractory leukemia and a randomized phase II study comparing CPX-351 to physician’s treatment choice of first salvage

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therapy in patients with relapsed AML demonstrated promising results [79, 82]. Therefore, CPX-

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untreated AML were randomized 2:1 to CPX-351 or DNR and Ara-C induction therapy [83].

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Median age was 70 years (range, 60 to 77 years). A similar proportion of patients (39% v 37%) had received prior therapy with hypomethylating agents. Median time to neutrophil and platelet

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count recovery (36 days v 32 days and 37 days v 28 days) was longer in the CPX-351 arm and associated with more grades 3-4 infections (70.6% v 43.9%), but not more infection-related

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deaths (3.5% v 7.3%) or 60-day mortality (4.7% v 14.6%). There was a trend for higher ORRs in the CPX-351 arm compared to the DNR and Ara-C arm (66.7% [41 CR and 15CRi] v 51.2% [20

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CR and 1 CRi]; p = 0.07). Median remission duration was similar in both arms (8.9 months v 8.6

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months). There were higher ORRs in patients with adverse cytogenetics (77.3% v 38.5%; p = 0.03) and secondary AML (57.6% v 31.6%; p = 0.06) in favor of CPX-351. With a follow-up of 24 months, median EFS and OS for all patients were 6.5 months v 2.0 months (p = 0.36), and 14.7 months v 12.9 months (p = 0.61). There was no difference in EFS and OS in the high-risk (defined as either age > 70 years of age, secondary AML or adverse cytogenetics) patients.

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351 was evaluated in a multicenter phase 2 trial where 126 older patients with newly diagnosed

However, median OS was improved in favor of CPX-351 in patients with secondary AML (12.1 months v 6.1 months; p = 0.01). These results suggested a clinical benefit of CPX-351 in patients, especially those with secondary AML.

Based on the promising results in the two phase 2 studies, a randomized phase 3 trial assessing CPX-351 compared to DNR and Ara-C in 309 older patients (aged 60 to 75 years) with newly diagnosed high risk AML (i.e. therapy-related, secondary [preceding MDS or chronic myelomonocytic leukemia] or AML with World Health Organization (WHO)-defined MDS-

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related cytogenetic abnormalities) has been completed (Table 2b) [37]. Median age was 68

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was 47.7% after therapy with CPX-351 compared with 33.3% after DNR and Ara-C (p = 0.016)

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with CR rates of 37.3% and 25.6% in favor of CPX-351 (p = 0.04). With a minimum follow-up of 13.7 months, improved EFS (2.53 months v 1.31 months; p = 0.021) and OS (9.56 months v

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5.95 months; p = 0.005) were observed in patients treated with CPX-351 compared to those treated with DNR and Ara-C. At 24 months, 31.1% of patients enrolled in the CPX-351 arm of

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the study remained alive compared with 12.3% with DNR and Ara-C. This led to FDA approval of CPX-351 for the treatment of older patients with newly diagnosed therapy-related AML or

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AML with myelodysplasia-related changes [MRC] on August 3, 2017. Therefore, pending the

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full publication of the study, strong consideration should be given for CPX-351 to be the standard of care for older patients with therapy-related or secondary AML or AML with MRC.

4. Resistance due to epigenetic and genetic heterogeneity in AML

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years. Grade 3-5% adverse events were comparable between the 2 arms (92% v 91%). The ORR

Risk stratification for patients with AML has traditionally been based on cytogenetic abnormalities into favorable risk, intermediate risk and poor risk groups with 5-10 year OS of 55-70%, 33-38% and 11-12% for younger patients and 3-5 year OS of 19-38%, 18% and 0-5% for older patients [84-87]. However, outcomes vary considerably within groups of patients with identical karyotypes and mechanisms of drug resistance and sensitivity are unclear. The use of

high-thoroughput sequencing has permitted further insight into the molecular pathogenesis of AML, informed disease classification, refined risk classification and aided in the prediction of clinical outcome [1, 88, 89]. Research currently points to the sequential acquisition of somatic mutations in epigenetic modifiers that regulate cytosine methylation as an early occurrence in

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preleukemic cells and persist even when in remission, whereas somatic mutations in signaling

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mutations in epigenetic modifiers, such as TET2, DNMT3A and IDH1 are insufficient to

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transform cells to leukemia, it is likely that development of leukemia stems from combinatorial effects of mutations rather than individual gene mutations [48, 91]. With the increasingly

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comprehensive catalogue of leukemia genes available, Papaemmanuil et al. assessed the possibility of deriving a fully genomic classification of AML by performing cytogenetic analyses

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and sequencing 111 genes in 1540 patients with AML [7]. Over 5000 driver mutations across 76 genes or genomic regions were identified and patterns of co-mutation compartmentalized the

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cohort into 11 classes, each with distinct clinical features and outcomes. This genomic

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classification of AML may lead to improved genetic risk stratification and risk adapted therapy, including offering clinical trials to patients unlikely to respond to standard induction chemotherapy and improving the selection of patients for therapies that may circumvent or overcome the affected pathway. 4.1 DNMT3A mutations

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pathways occur as late events and lead to leukemic cell proliferation [6, 90]. Furthermore, as

DNMT3A is a gene that encodes DNA methyltransferases and is mutated in approximately 30% of cytogenetically normal AML patients [92]. DNMT3AR882 is the most common mutation identified and is associated with a poor prognosis. It is described as a founder mutation as it occurs early in AML development typically in the pre-leukemic stem cell and studies have

demonstrated that the variant allele frequency remains unaltered with therapy [93]. Inferior survival in patients with DNMT3AR882 is associated with anthracycline resistance [94]. Using mice, the authors able to demonstrate that DNMT3AR878H (the mouse equivalent of R882) increases hematopoietic stem/progenitor cells and alters differentiation in vivo and cooperates

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with FLT3-ITD and nucleophosmin 1(NPM1) to induce AML. DNR induces DNA torsional

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doses and inhibits topoisomerase II, leading to double strand breaks, at higher doses.

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DNMT3AR882 cells fail to initiate CHK1-mediated DNA damage response (DDR) to anthracyclines. DNMT3AR878H retains the ability to bind to the facilitates chromatin transcription

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(FACT) complex subunit SPT-16, a H2A/H2B dimer chaperone that is also involved in DNA

4.2. TET2 mutations

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replication and repair, but has reduced DNA binding.

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TET2 mutations are found in 10-20% of AML patients and are associated with a reduced response to chemotherapy and decreased OS [95-97]. TET2 catalyzes the 5-hydroxylation of

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methylcytosine to 5-hydroxymethylcytosine (5-hmC) leading to DNA demethylation. Similar to other epigenetic modifiers, such as DNMT3A, TET2 inactivation can contribute to leukemia initiation but is not sufficient to induce AML. TET2 loss combined with FLT3-ITD is sufficient to induce AML in vivo. Mice transplanted with conditional Vav-cre+TET-/- FLT3-ITD cells were

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stress, facilitating nucleosome turnover and chromatin remodeling and histone eviction, at lower

refractory to doxorubicin and Ara-C chemotherapy compared with other sensitive AML genotypes [91]. Furthermore, the Vav-cre+TET-/- FLT3-ITD mice treated with the FLT3 inhibitor AC220 had smaller spleens and reduced leukocyte counts, but did not reduce the burden of leukemia stem cells. Vav-cre+TET-/- and FLT3-ITD in combination, but not individually,

mediated hypermethylation and aberrant epigenetic silencing of GATA2. Restoration of GATA2 expression can restore differentiation and attenuate leukemogenesis in vivo. 4.3 EZH2 mutations

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The histone methyltransferase Enhancer of the Zeste Homolog 2 (EZH2), located on

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2-9% of patients with de novo or secondary AML [98]. Low EZH2 protein levels are associated

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with inferior survival and higher relapse rates in patients with AML [99]. Furthermore, loss of EZH2 activity induces resistance to multiple drugs, including Ara-C. An inverse correlation

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between EZH2 protein levels and Ara-C IC50 values was observed. Consistent with this, knockdown of EZH2 in AML cell lines induced Ara-C resistance, with an average of 5-fold

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increase in IC50 values as compared to controls. EZH2 protein levels are regulated by cyclindependent kinase 1 (CDK1)-dependent phosphorylation of the Thr487 on EZH2, thus targeting

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EZH2 for unbiquitation and degradation. In drug resistant cells and primary cells from relapsed AML patients, there is increased CDK1 phosphorylation of EZH2 at Thr 487 due to stabilization

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of the CDK1-EZH2 interaction by heat shock protein (HSP90), resulting in EZH2 proteasomal degradation. Reduced EZH2 protein levels led to upregulation of several HOX genes, including HOXB7 and HOXA9. Knockdown of HOXB7 and HOXA9, as well as inhibitors of HSP90, CDK1 and the proteasome in resistant cells was sufficient to restore sensitivity to tyrosine kinase

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chromosome 7q31.6, is involved in transcriptional silencing. Mutations of EZH2 are observed in

inhibitors and cytotoxic drugs. Proteasomal inhibition with bortezomib led to increased EZH2

protein levels and increased cytotoxic efficacy of the combination of Ara-C and bortezomib in primary AML samples. Two patients with relapsed/refractory AML post allogeneic transplantation whose blast cells demonstrated a response to bortezomib with increased EZH2 levels and increased sensitivity to Ara-C ex vivo were treated with a combination of bortezomib

and Ara-C. One of the patients achieved a second CR. This work not only demonstrates a novel mechanism of Ara-C resistance, but also a potential intervention for patients with low EZH2 protein levels.

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4.4 TP53 mutations

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maintenance of a normal stem cell pool and hence, tumor suppression through DNA repair, cell

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cycle arrest, differentiation, senescence, apoptosis and chemosensitivity [100, 101]. The TP53 gene is located on chromosome 17p13.1. TP53 mutations are observed in 7-15% of patients with

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de novo AML with a frequency as low as 1% in patients with favorable risk cytogenetics and as high as 60% in patients with complex karyotype AML [7, 89, 102-105]. In patients with therapy-

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related AML, TP53 mutation frequency is 30% and attributed to clonal selection of chemoresistant hematopoietic stem/progenitor cells carrying a TP53 mutation [106].

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Outcome of patients with p53 mutations with or without complex karyotypes treated with

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intensive chemotherapy, including 3+7, and/or allogeneic stem cell transplant is uniformly poor [7, 102, 107, 108]. Recent data suggests that when patients with TP53 mutated AML are treated with a 10-day cycles of decitabine, they have a higher response rate but similar outcomes after alloSCT and OS compared to patients with wild type p53 [109, 110]. However, responses are usually short lived and decitabine did not clear all leukemia-specific mutations in any patient,

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The tumor suppressor p53 transcription factor plays a key role in preserving genomic integrity,

including those who achieved a CR. Relapses were associated with the outgrowth of a preexisting subclone [109].

5. Regulatory affairs

Both DNR and Ara-C have been in medical use in the United States for the treatment of patients with AML since 1967. However, combination therapy with DNR and Ara-C was first reported in 1973 and gave rise to the current treatment schedules. Daunorubicin and Ara-C are also approved for use in patients with acute lymphocytic leukemia, chronic myeloid leukemia in blast

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crisis and non-Hodgkin’s lymphoma. As of August 3, 2017, the FDA has approved CPX-351 for

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myelodysplasia-related changes.

6. Conclusion

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Therapy of AML (not APL) has remained unchanged in the last 40-50 years with the main stay of therapy for those deemed “fit” being induction chemotherapy with an anthracycline, usually

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DNR, and ARA-C. However, the majority of patients are not cured using this strategy. The 10 years required to complete the RATIFY trial cumulated with the recent FDA approval of

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midostaurin in combination with induction and consolidation chemotherapy for FLT3 mutated

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AML and CPX-351 for older patients with higher-risk AML. Unlike other hematological malignancies (e.g. multiple myeloma or chronic lymphocytic leukemia), there is a paucity of drugs that have shown activity in AML. Since FLT3 and NPM1 mutations were first described in the early 2000s, somatic

mutations are being incorporated into integrated classification systems and risk stratification

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the treatment of older patients with newly diagnosed therapy-related AML or AML with

schemas. Nonetheless, due to cost constraints and lack of accessibility of next generation sequencing and new drugs in many clinical treatment centres, the ability to harness targeted therapy for a personalized approach at diagnosis is limited. To address these issues, the Leukemia and Lymphoma Society Beat AML Master Trial aims to perform targeted genetic

screening at diagnosis and based on the results, assign patients to receive personalized therapy on one of several sub-studies to the protocol with the goal of improving outcomes [111]. Hopefully, studies such as these will help expedite discovery of drugs that have clinical efficiency in subsets

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of younger and older patients with AML.

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When evaluating therapy in AML, one must use advances in genetic risk stratification in order to

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accurately identify treatment responders. Refinement of the risk classification systems will

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continue to occur with determination of the prognostic significance of newly discovered genetic abnormalities in AML. Furthermore, increased accuracy in predicting resistance to standard

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chemotherapy and OS can occur when this genetic profiling is incorporated into multivariable models including clinical parameters and/or treatment responses obtained from clinical trials

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and/or knowledge banks [38, 112, 113]. Unfortunately, none of these integrated classifications have evaluated the importance (or lack of importance) of proteomics, methylation profiles or

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gene expression profiles. Nonetheless, the ability to accurately predict resistance can be used to optimize treatment decisions, such as recommending standard chemotherapy or investigational therapy. Patients that are deemed unlikely to respond to standard chemotherapy should be enrolled onto a clinical trial upfront. Hence, all centres that treat patients with AML should have

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7. Expert Opinion

access to and timely reporting of somatic mutations in concert with cytogenetic (and FISH) analyses.

Increasing understanding concerning the pathophysiology of AML has emerged over the past decade with an explosion of genetic and epigenetic information. Genetic and epigenetic allelic variations follow distinct and often independent kinetics and patterns. At diagnosis,

subsets of AML demonstrated (a) high epiallele and low somatic mutation burden, (b) high somatic mutation and lower epiallele burden or (c) a mixed profile, suggesting distinct modes of tumor heterogeneity. Higher epiallele burden was linked to more aggressive disease [48]. Furthermore, as the development and progression of leukemia stems from combinatorial effects

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of mutations rather than individual gene mutations [48, 91], targeting mutant proteins that are not

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control the disease for a period of time. In addition, deciphering mechanisms for

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chemoresistance that may be associated with specific somatic mutations (e.g. DNMT3A and EZH2) may provide pathways that may be targetable. Therefore, given the clonal heterogeneity

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of AML, regimens such as 3+7 will remain a backbone onto which third “targeted” drugs are

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combined.

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present in the entire leukemia cell population is unlikely to cure the disease, although it may

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65. Burnett AK, Hills RK, Milligan D et al. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol. 2011;29:369-377. 66. Delaunay J, Recher C, Pigneux A et al. Addition of gemtuzumab ozogamycin to chemotherapy improves event-free survival but not overall survival of AML patients with intermediate cytogenetics not eligible for allogeneic transplantation. Results of the GOELAMS AML 2006 IR study. Blood. 2011;118. 67. Burnett AK, Russell NH, Hills RK et al. Addition of gemtuzumab ozogamicin to induction chemotherapy improves survival in older patients with acute myeloid leukemia. J Clin Oncol. 2012;30:3924-3931. 68. Castaigne S, Pautas C, Terre C et al. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet. 2012;379:1508-1516. 69. Neuberg DS. Reprise: gemtuzumab ozogamicin for older patients with acute myeloid leukemia. J Clin Oncol. 2012;30:3905-3906. 70. Hills RK, Castaigne S, Appelbaum FR et al. Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: a meta-analysis of individual patient data from randomised controlled trials. Lancet Oncol. 2014;15:986-996. 71. Wilhelm S, Carter C, Lynch M et al. Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov. 2006;5:835-844. 72. Rollig C, Serve H, Huttmann A et al. Addition of sorafenib versus placebo to standard therapy in patients aged 60 years or younger with newly diagnosed acute myeloid leukaemia (SORAML): a multicentre, phase 2, randomised controlled trial. Lancet Oncol. 2015;16:16911699. 73. Serve H, Krug U, Wagner R et al. Sorafenib in combination with intensive chemotherapy in elderly patients with acute myeloid leukemia: results from a randomized, placebo-controlled trial. J Clin Oncol. 2013;31:3110-3118. 74. Stone RM, Mandrekar S, Sanford BL et al. The multi-kinase inhibitor midostaurin (M) prolongs survival compared with placebo (P) in combination with daunorubicin (D)/cytarabine (C) induction (ind), high-dose C consolidation (consol), and as maintenance (maint) therapy in newly diagnosed acute myeloid leukemia (AML) patients (pts) age 18-60 with FLT3 mutations (muts): an international prospective randomized (rand) P-controlled double-blind trial (CALGB 10603/RATIFY [Alliance]). Blood. 2015;126. 75. Stone RM, Mandrekar SJ, Sanford BL et al. Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation. N Engl J Med. 2017;377:454-464. **Pivotal trial leading to approval of midostaurin with chemotherapy for the treatment of FLT3 mutated AML 76. Latagliata R, Breccia M, Fazi P et al. Liposomal daunorubicin versus standard daunorubicin: long term follow-up of the GIMEMA GSI 103 AMLE randomized trial in patients older than 60 years with acute myelogenous leukaemia. Br J Haematol. 2008;143:681-689. 77. Mayer LD, Harasym TO, Tardi PG et al. Ratiometric dosing of anticancer drug combinations: controlling drug ratios after systemic administration regulates therapeutic activity in tumor-bearing mice. Mol Cancer Ther. 2006;5:1854-1863. 78. Tardi P, Johnstone S, Harasym N et al. In vivo maintenance of synergistic cytarabine:daunorubicin ratios greatly enhances therapeutic efficacy. Leuk Res. 2009;33:129139.

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79. Feldman EJ, Lancet JE, Kolitz JE et al. First-in-man study of CPX-351: a liposomal carrier containing cytarabine and daunorubicin in a fixed 5:1 molar ratio for the treatment of relapsed and refractory acute myeloid leukemia. J Clin Oncol. 2011;29:979-985. 80. Feldman E LJ, Kolitz JE, Ritchie EK, Tracg JM, Mayer L, Louie A. Pharmacology of CPX-351: a nano-scale lipsomal fixed molar ratio cytarabine-daunorubicin for patients with advanced leukemia. Haematologica. 2009;1-694. 81. Feldman EJ, Kolitz JE, Trang JM et al. Pharmacokinetics of CPX-351; a nano-scale liposomal fixed molar ratio formulation of cytarabine:daunorubicin, in patients with advanced leukemia. Leuk Res. 2012;36:1283-1289. 82. Cortes JE, Goldberg SL, Feldman EJ et al. Phase II, multicenter, randomized trial of CPX-351 (cytarabine:daunorubicin) liposome injection versus intensive salvage therapy in adults with first relapse AML. Cancer. 2015;121:234-242. 83. Lancet JE, Cortes JE, Hogge DE et al. Phase 2 trial of CPX-351, a fixed 5:1 molar ratio of cytarabine/daunorubicin, vs cytarabine/daunorubicin in older adults with untreated AML. Blood. 2014;123:3239-3246. 84. Grimwade D, Hills RK, Moorman AV et al. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood. 2010;116:354-365. 85. Slovak ML, Kopecky KJ, Cassileth PA et al. Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood. 2000;96:4075-4083. 86. Cancer, Leukemia Group B, Farag SS et al. Pretreatment cytogenetics add to other prognostic factors predicting complete remission and long-term outcome in patients 60 years of age or older with acute myeloid leukemia: results from Cancer and Leukemia Group B 8461. Blood. 2006;108:63-73. 87. Frohling S, Schlenk RF, Kayser S et al. Cytogenetics and age are major determinants of outcome in intensively treated acute myeloid leukemia patients older than 60 years: results from AMLSG trial AML HD98-B. Blood. 2006;108:3280-3288. 88. Arber DA, Orazi A, Hasserjian R et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:23912405. 89. Cancer Genome Atlas Research N, Ley TJ, Miller C et al. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368:2059-2074. 90. Corces-Zimmerman MR, Hong WJ, Weissman IL et al. Preleukemic mutations in human acute myeloid leukemia affect epigenetic regulators and persist in remission. Proc Natl Acad Sci U S A. 2014;111:2548-2553. 91. Shih AH, Jiang Y, Meydan C et al. Mutational cooperativity linked to combinatorial epigenetic gain of function in acute myeloid leukemia. Cancer Cell. 2015;27:502-515. 92. Ley TJ, Ding L, Walter MJ et al. DNMT3A mutations in acute myeloid leukemia. N Engl J Med. 2010;363:2424-2433. 93. Klco JM, Miller CA, Griffith M et al. Association between mutation clearance after induction therapy and outcomes in acute myeloid leukemia. JAMA. 2015;314:811-822. 94. Guryanova OA, Shank K, Spitzer B et al. DNMT3A mutations promote anthracycline resistance in acute myeloid leukemia via impaired nucleosome remodeling. Nat Med. 2016;22:1488-1495.

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**Recent paper identifying the causal link for the poor prognosis of DNMT3A R882 mutations in AML to anthracycline resistance 95. Abdel-Wahab O, Mullally A, Hedvat C et al. Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies. Blood. 2009;114:144-147. 96. Delhommeau F, Dupont S, Della Valle V et al. Mutation in TET2 in myeloid cancers. N Engl J Med. 2009;360:2289-2301. 97. Metzeler KH, Maharry K, Radmacher MD et al. TET2 mutations improve the new European LeukemiaNet risk classification of acute myeloid leukemia: a Cancer and Leukemia Group B study. J Clin Oncol. 2011;29:1373-1381. 98. Lindsley RC, Mar BG, Mazzola E et al. Acute myeloid leukemia ontogeny is defined by distinct somatic mutations. Blood. 2015;125:1367-1376. 99. Gollner S, Oellerich T, Agrawal-Singh S et al. Loss of the histone methyltransferase EZH2 induces resistance to multiple drugs in acute myeloid leukemia. Nat Med. 2017;23:69-78. 100. Prokocimer M, Molchadsky A, Rotter V. Dysfunctional diversity of p53 proteins in adult acute myeloid leukemia: projections on diagnostic workup and therapy. Blood. 2017;130:699712. 101. Zhang L, McGraw KL, Sallman DA, List AF. The role of p53 in myelodysplastic syndromes and acute myeloid leukemia: molecular aspects and clinical implications. Leuk Lymphoma. 2017;58:1777-1790. 102. Hou HA, Chou WC, Kuo YY et al. TP53 mutations in de novo acute myeloid leukemia patients: longitudinal follow-ups show the mutation is stable during disease evolution. Blood Cancer J. 2015;5:e331. 103. Stirewalt DL, Kopecky KJ, Meshinchi S et al. FLT3, RAS, and TP53 mutations in elderly patients with acute myeloid leukemia. Blood. 2001;97:3589-3595. 104. Stengel A, Kern W, Haferlach T et al. The impact of TP53 mutations and TP53 deletions on survival varies between AML, ALL, MDS and CLL: an analysis of 3307 cases. Leukemia. 2017;31:705-711. 105. Rucker FG, Schlenk RF, Bullinger L et al. TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome. Blood. 2012;119:2114-2121. 106. Wong TN, Ramsingh G, Young AL et al. Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia. Nature. 2015;518:552-555. **Demonstrates that chemotherapy does not induce TP53 mutations but rather selects for chemoresistant pre-existing TP53 mutated clone(s) 107. Bowen D, Groves MJ, Burnett AK et al. TP53 gene mutation is frequent in patients with acute myeloid leukemia and complex karyotype, and is associated with very poor prognosis. Leukemia. 2009;23:203-206. 108. Middeke JM, Herold S, Rucker-Braun E et al. TP53 mutation in patients with high-risk acute myeloid leukaemia treated with allogeneic haematopoietic stem cell transplantation. Br J Haematol. 2016;172:914-922. 109. Welch JS, Petti AA, Miller CA et al. TP53 and decitabine in acute myeloid leukemia and myelodysplastic syndromes. N Engl J Med. 2016;375:2023-2036. 110. Welch JS, Petti AA, Ley TJ. Decitabine in TP53-mutated AML. N Engl J Med. 2017;376:797-798. 111. Society LL. BEAT AML Master TRial. In. 2016.

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112. Walter RB, Othus M, Paietta EM et al. Effect of genetic profiling on prediction of therapeutic resistance and survival in adult acute myeloid leukemia. Leukemia. 2015;29:21042107. 113. Gerstung M, Papaemmanuil E, Martincorena I et al. Precision oncology for acute myeloid leukemia using a knowledge bank approach. Nat Genet. 2017;49:332-340. 114. Berman E, Heller G, Santorsa J et al. Results of a randomized trial comparing idarubicin and cytosine arabinoside with daunorubicin and cytosine arabinoside in adult patients with newly diagnosed acute myelogenous leukemia. Blood. 1991;77:1666-1674. 115. Mandelli F, Petti MC, Ardia A et al. A randomised clinical trial comparing idarubicin and cytarabine to daunorubicin and cytarabine in the treatment of acute non-lymphoid leukaemia. A multicentric study from the Italian Co-operative Group GIMEMA. Eur J Cancer. 1991;27:750755. 116. Vogler WR, Velez-Garcia E, Weiner RS et al. A phase III trial comparing idarubicin and daunorubicin in combination with cytarabine in acute myelogenous leukemia: a Southeastern Cancer Study Group Study. J Clin Oncol. 1992;10:1103-1111. 117. Wiernik PH, Banks PL, Case DC, Jr. et al. Cytarabine plus idarubicin or daunorubicin as induction and consolidation therapy for previously untreated adult patients with acute myeloid leukemia. Blood. 1992;79:313-319. 118. Ohtake S, Miyawaki S, Fujita H et al. Randomized study of induction therapy comparing standard-dose idarubicin with high-dose daunorubicin in adult patients with previously untreated acute myeloid leukemia: the JALSG AML201 Study. Blood. 2011;117:2358-2365. 119. Brunnberg U, Mohr M, Noppeney R et al. Induction therapy of AML with ara-C plus daunorubicin versus ara-C plus gemtuzumab ozogamicin: a randomized phase II trial in elderly patients. Ann Oncol. 2012;23:990-996. 120. Zeidner JF, Foster MC, Blackford AL et al. Randomized multicenter phase II study of flavopiridol (alvocidib), cytarabine, and mitoxantrone (FLAM) versus cytarabine/daunorubicin (7+3) in newly diagnosed acute myeloid leukemia. Haematologica. 2015;100:1172-1179. 121. Holowiecki J, Grosicki S, Robak T et al. Addition of cladribine to daunorubicin and cytarabine increases complete remission rate after a single course of induction treatment in acute myeloid leukemia. Multicenter, phase III study. Leukemia. 2004;18:989-997. 122. Pluta A, Robak T, Wrzesien-Kus A et al. Addition of cladribine to the standard induction treatment improves outcomes in a subset of elderly acute myeloid leukemia patients. Results of a randomized Polish Adult Leukemia Group (PALG) phase II trial. Am J Hematol. 2017;92:359366.

Drug Summary Box

Drug name (generic) Phase (for indication under discussion)

ip t

an

us

cr

Route of administration Chemical structure

See Tables 1-4c

Cytarabine (Cytosar-U, Tarabine PFS; Pfizer) In medical use in the USA since 1967. In the current review, the pivotal randomized phase II and III trials are discussed. For remission induction in acute myeloid leukemia Antineoplastic anti-metabolite, synthetic pyrimidine nucleoside, which acts through direct DNA damage and incorporation into DNA. Cytotoxic activity is cell cycle phase specific, primarily killing cells undergoing DNA synthesis (Sphase) and under certain conditions blocking the progression of cells from the G1 phase to the S-phase. Intravenous

ed

Drug name (generic) Phase (for indication under discussion)

M

Pivotal trial(s)

ce pt

Indication (specific to discussion) Pharmacology description/mechanism of action

Route of administration Chemical structure

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Indication (specific to discussion) Pharmacology description/mechanism of action

Daunorubicin (Cerubidine®; Teva) In medical use in the USA since 1967. In the current review, the pivotal randomized phase II and III trials are discussed. For remission induction in acute myeloid leukemia Anthracycline antibiotic which interacts with DNA in a variety of different ways including intercalation (squeezing between the base pairs), DNA strand breakage and inhibition with the enzyme topoisomerase II. Cytotoxic activity is cell cycle phase non-specific. Intravenous

Pivotal trial(s)

See Tables 1-4c

Table 1. Selected randomized studies comparing daunorubicin and cytarabine with other regimens in patients with AML Investigator, y (reference)

Median Age (y)

N

Median F/U

Chemotherapy Regimen

CR Rate (%)

Response Disease Control

Overall Survival

Induction/ 30-day mortality (%)

60a

200

NR

MITO + Ara-C v DNR-45 + Ara-C

63 v 53

Median remission duration 8m v 6.6m

Median 10.9m v 8.2m

NR

Lowenberg 1998 EORTCHOVON [26]

68 (60-88)

489

6y

MITO + Ara-C v DNR-30 + Ara-C

46.6 v 38

Median DFS 9.1m v 9.1m ; DFS5y 8% v 8%

Median 9.1m v 8.4m; OS5y 9% v 6%

21.1 v 14.9

Anderson 2002 SWOG [29]

67-68 (56-86)

328

NR

MITO + etoposide v DNR-45 + Ara-C

34 v 43

RFS2y 16% v 18%

OS2y 11% v 19%

23 v 18

NR

IDA + Ara-C ± GMCSF v MITO + Ara-C ± GM-CSF v DNR-45 + Ara-C ± GM-CSF

67-69 (56-86)

348

M an us c

Rowe 2004 ECOG [30]

rip t

Arlin 1990 CALGB [27]

43 v 46 v 41

Median DFS 9.4m v 7.1m v 5.7m

Median 7.5m v 7.2m v 7.7m

22 v 14 v 16

51 v 50 v 48

Median EFS3y 12.4% v 15.6% v 11.4%

OS3y 22.3% v 24.7% v 22.4%

24 v 19 v 27b

80 v 58c

NR

Median 19.7m v 13.5md

NR

40.3 v 39.2

Median RFS 10m v 9.5m

Median 2.9m v 5.6m

8 v 7.2d

1147

5.6 y

DNR-60 + Ara-C v TAD-HAM or HAM-HAM v Ara-C + MITO

Berman 1991 [114]

37.5 (17-60)

120

2.5 y

IDA + Ara-C(5) v DNR-50 + Ara-C(5)

Mandelli 1991 GIMEMA [115]

62-62 (55-78)

249

NR

Vogler 1992 SWOG [116]

60-61f

218

NR

IDA + Ara-C v DNR-45+ Ara-C

71 v 58g

Remission duration 13m v 9m

Median 11m v 9m

17 v 22

Wiernik 1992 [117]

55-56h

208

NR

IDA-13 + Ara-C v DNR-45+ Ara-C

70 v 59

Remission duration 9.4m v 8.4mi

Median 12.9m v 8.7mj

22 v 19

NR

IDA + Ara-C ± GMCSF v MITO + Ara-C ± GM-CSF v DNR-45 + Ara-C ± GM-CSF

43 v 46 v 41

Median DFS 9.4m v 7.1m v 5.7m

Median 7.5m v 7.2m v 7.7m

22 v 14 v 16

d

68-69-70 (60-87)

Niederwieser 2016 AMLGC [36]

Rowe 2004 ECOG [30]

67-69 (56-86)

ep

te

Idarubicin-based

IDA + Ara-C v DNR-45 + Ara-C

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Mitoxantrone-based

348

468

49 m

IDA-12(4) + Ara-C v IDA-12(3) + Ara-C v DNR-80 + Ara-C

78 v 83 v 70k

EFS4y 22% v 21% v 12%

OS4y 34% v 32% v 23%

6v6v9

Ohtake 2011 JALSG AML201 [118]

47 (15-64)

1057

48 m

IDA + Ara-C v DNR-50(5) + Ara-C

78.2 v 77.5

RFS5y 41% v 41%

OS5y 48% v 48%

4.7 v 2.1l,m

Recher 2014 LAM-2001 [34]

47-48 (36-55)

818

7.2 y

IDA(5) + Ara-C v DNR-60 + Ara-C

87 v 86

No difference in DFS7y

OS7y 48% v 41%

NR

NRn

299

34.9 m

IDA + Ara-C v DNR-90 + Ara-C

80.5 v 74.7

RFS4y 63.5% v 74.2%; EFS4y 44.8% v 50.7%

Yates 1982 CALGB [16]

47-49 (1-84)

653

NR

DNR-30 + Ara-C v DNR-45 + Ara-C v DOX-30 + Ara-C

Hansen 1991 Danish National [24]

NRo

174

NR

ACR-50/75 + Ara-Cp v DNR-30/45 + Ara-Cq

Brunnberg 2012 [119]

69-68 (60-83)

115

33.4 m

Gemtuzumab + AraCv DNR-60 + Ara-C

Stone 2015 [25]

64 (19-84)

433

NR

Amonafide + Ara-C v DNR-45 + Ara-C

Zeidner 2015 [120]

59-60 (19-70)

165

18 m

FLAM v DNR-90 + Ara-C

te

ep

OS4y 51.1% v 54.7%

NR

55 v 58 v 50

Remission duration2y 10.7% v 11.5% v 12.6%

NR

NR

66 v 50r

Remission duration4y 37% v 33%

OS4y 29% v 20%

10 v 6d

54 v 55

Median EFS 5m v 2m

10m v 9m

19 v 5.2s

46 v 45

NR

OS1y 36% v 31%

19 v 13

65 v 45t

Median EFS 9.7m v 3.4m

OS2y 50% v 59%

5v2

d

Other Agents

M an us c

Lee 2015 [32]

rip t

60 (50-70)

Note: ACR – aclarubicin; FLAM – flavopiridol, Ara-C & mitoxantrone; HAM-HAM – high dose Ara-C & mitoxantrone x 2; MITO – mitoxantrone; NR – not reported; RFS – relapse-free survival; TAD-HAM – 6-thioguanine, Ara-C & DNR and high dose Ara-C & mitoxantrone a

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Pautas 2010 ALFA-9801 [33]

range not reported but had to > 15 y of age; b 90-day mortality; c p = 0.005; d p = 0.025; e early death; f range not reported but had to > 14 y of age; p = 0.032; h range not reported but had to > 18 y of age; i p = 0.021; j p = 0.038; k p = 0.04; l death within 60 days after start of induction therapy; m p = 0.026; n not reported but had to be < 65 y of age; o not reported but had to be between 17-65 y of age; p patients < 60 years received ACR 75 mg/m2 and patients > 60 years received ACR 50 mg/m2; q patients < 60 years received DNR 45 mg/m2 and patients > 60 years received DNR 30 mg/m2; r p = 0.043; s p = 0.021; t p = 0.003 g

Table 2a. Randomized studies comparing daunorubicin dosing during induction chemotherapy in patients with AML Median Age (y)

N

Median F/U

Chemotherapy Regimen

CR Rate (%)

Yates 1982 CALGB [16]

47-49 (1-84)

653

NR

DNR-30 + Ara-C v DNR-45 + Ara-C v DOX-30 + Ara-C

55 v 58 v 50

Remission duration2y 10.7% v 11.5% v 12.6%

Burnett 2015 UK NCRI AML17 [17, 18]

53a (16-72)

1206a

28 m

DNR-60 + Ara-C v DNR-90 + Ara-C

75 v 73

Relapse rate2y 43% v 39%

(> 65 y: 210)

NR

DNR-30 + Ara-C + 6-TG v DNR-60 + Ara-C + 6-TG

Investigator, y (reference)

Response Disease Control

Overall Survival

Induction/ 30-day mortality (%)

NR

NR

OS2y 60% v 59%

4v6

340

66 (60-83)

Lowenberg 2009 HOVONSAAK [20]

67 (60-83)

813

3.3 y

DNR-45 + Ara-C v DNR-90 + Ara-C

48g (17-60)

582

25.2 m

DNR-45 + Ara-C v DNR-90 + Ara-C

43 (15-60)

383

52.6 m

OS5y 24% v 25% ; > 65y: OS5y 5% v 14%d

31 v 20e

54 v 64f

EFS2y 17% v 21%

OS2y 26% v 31%

12 v 11

57.3 v 70.6h

NR

Median 15.7m v .7mi

4.5 v 5.5

DNR-45 + Ara-C v DNR-90 + Ara-C

EFS5y 28.4% v 40.8%k

OS5y 34.6% v 46.8%k

NR

72 v 82.5j

Note: 6-TG – 6-thioguanine; EFS – event-free survival; m – months; y - years a

rip t

DFS5y 17% v 22%

te

Lee 2011 Cooperative Study Group A for Hematology [22]

ep

Ages < 60 years Fernandez 2009 ECOG 1900 [21]

45 v 52b; > 65y: 32%v 52%c

d

Buchner 1997 AMLCG [19]

M an us c

Ages > 60 years

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All Ages

includes 6% patients with myelodysplastic syndrome (MDS); b p = 0.026; c p = 0.006;d p = 0.002; e early death p = 0.031; f p = 0.002; g n=657 patients but only 582 evaluable patients; h p < 0.001; i p = 0.001; j p = 0.014; k p = 0.030

Table 2b. Randomized studies comparing liposomal formulations of daunorubicin induction chemotherapy in patients with AML N

Median F/U

Chemotherapy Regimen

CR Rate (%)

Response Disease Control

Overall Survival

Induction/ 30-day mortality (%)

Latagliata 2008 GIMEMA GSI 103 AMLE [76]

68 (61-74.8)

301

NR

DNX-80 + Ara-C v DNR-45 + Ara-C

49.3 v 51

No difference

No difference

18.9 v 13.1

Lancet 2016 [37]

(60-75)a

309

13.7 m

CPX-351 v DNR-60 + Ara-C

47.7 v 33.3b

In favor of CPX-351c

te

d

M an us c

median age not reported;b CR + CRi; c p = 0.021; d p = 0.005; e 60-day mortality

ep

a

Ac c

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Note: DNX – DaunoXome

rip t

Median Age (y)

Investigator, y (reference)

Median 9.56m v 5.95md

13.7 v 21.2e

Table 3. Randomized studies comparing cytarabine dosing during induction chemotherapy in patients with AML Median F/U

Chemotherapy Regimen

CR Rate (%)

Response Disease Control

Overall Survival

Induction/ 30-day mortality (%)

51-54 (15-83)

326

5.2 y

DNR-30/45 + Ara-C 100a v DNR-30/45 + Ara-C 200

< 60 y: 64 v 75; > 60 y: 44 v 38

Median DFS 0.8y v 0.8y

Median 45.9wk v 38wk

NR

NR

DNR-30/45 + Ara-C v DNR-30/45 + Ara-C(10) v DNR-30/45 + Ara-C + 6TGb

52.6 v 57.3 v 56.9

Remission duration2y 22%c

OS3y 18%c

NR

< 50 y: 58 v 55 v 59e; > 50-64 y: 53 v 45d

< 50 y: RFS4y 21% v 33% v 29%e; > 50-64 y: RFS4y 9% v 21%d

Preisler 1987 CALGB [43]

NR

Weick 1996 SWOG [42]

32, 45, & 60 (15-64)

723

51 m

DNR-45 + Ara-C 200 v DNR-45 + Ara-C 2000/3000d,e

49f (17-60)

860f

5y

IDA + Ara-C 1000 ± GCSF v IDA + Ara-C 200 ± G-CSF

Lowenberg 2011 HOVONSAKK [46]

668

82 v 80

Note: 6-TG – 6-thioguanine; DFS – disease-free survival; IDA – idarubicin; wk - weeks

EFS5y 35% v 34%

< 50 y: OS4y 22% v 32% v 28%e; > 50-64 y: OS4y 11% v 13%d

NR

OS5y 42% v 40%

5v5

patients < 60 y received DNR 45 mg/m2 and patients > 60 y received DNR 30 mg/m2; b patients < 60 y received DNR 45 mg/m2 and patients > 60 y received DNR 30 mg/m2; c for all patients (RFS and OS for the different treatment arms were not reported); d DNR-45 + Ara-C 200 mg/m2 v DNR-45 + Ara-C 2000 mg/m2 ; e DNR-45 + Ara-C 200 mg/m2 v DNR-45 + Ara-C 2000 mg/m2 (all patients of age 50-64 y & patients of age < 50 y after December 1988) v DNR-45 + Ara-C 3000 mg/m2 (patients of age < 50 y until December 1988); f includes 39 patients (4.5%) with refractory anemia with excess blasts (RAEB);

ep

te

d

a

rip t

N

Ac c

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Dillman 1991 CALGB [41]

Median Age (y)

M an us c

Investigator, y (reference)

Table 4a. Selected randomized studies evaluating daunorubicin and cytarabine with gemtuzumab ozogamycin in patients with AML Median Age (y)

N

Median F/U

Chemotherapy Regimen

CR Rate (%)

Response Disease Control

Petersdorf 2013 SWOG [64]

47-48 (18-60)

595

4.1 y

DNR-60 + Ara-C v DNR-45 + Ara-C + gemtuzumab

70 v 69

RFS5y 42% v 43%

Median 61m v 41m; OS5y 50 v 46

1 v 6a

Delaunay 2011 GOELAMS [66]

50 (18-60)

238

39.3 m

DNR + Ara-C v DNR + Ara-C + gemtuzumab

86.5 v 91.6

EFS3y 33% v 51%

OS3y 46% v 53%

4.5 v 10b

33 m

DNR-50 + Ara-C ± gemtuzumab v DNR-50 + Ara-C + etoposide ± gemtuzumab v FLAG-Ida ± gemtuzumab

No GO v GO: 82 v 83d

RFS5y 35% v 39%d

OS5y 41% v 43%d

10 v 11

No GO v GO: 58 v 62e,g

RFS3y 16% v 21%e,h

OS3y 20% v 25%e,i

8 v 9e,g

72 v 73

RFS2y 22.7% v 50.3%j

OS2y 41.9% v 53.2%k

4v6

Burnett 2012 MRC AML16 [67]

67e (51-84)

1115e

30 me

DNR-50 + Ara-Cf ± gemtuzumab v DNR50 + CLO ± gemtuzumab

Castaigne 2012 ALFA-0701 [68]

66 (58-66)

278

14.8 m

DNR-60 + Ara-C v DNR-60 + Ara-C + gemtuzumab

d

477

Overall Survival

rip t

48-49c

M an us c

Burnett 2011 MRC AML15 [65]

Induction/ 30-day mortality (%)

ep

te

Note: 6-TG – 6-thioguanine; CLO – clofarabine; FLAG-Ida – fludarabine, Ara-C, G-CSF and idarubicin; GO – gemtuzumab ozogamicin a p = 0.0062; b early deaths; c range not reported but 0-71 y of age; d including patients who received FLAG-Ida and Ara-C, DNR and etoposide (ADE); e includes 10% of patients with MDS; f 771 (69%) patients received DNR + Ara-C; g patients who did not receive gemtuzumab versus patients who did receive gemtuzumab (regardless of induction chemotherapy regimen, i.e. DNR + Ara-C or DNR + CLO) with ORR (CR + CRi) 70% v 68% (p = 0.3) with no difference in 30- or 60-day mortality; h p = 0.04; i p = 0.05; j p = 0.0003; k p = 0.0368 (after adjustment for cytogenetics and FLT3-ITD status, there was no observed difference in OS, p = 0.07)

Ac c

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Investigator, y (reference)

Table 4b. Selected randomized studies evaluating daunorubicin and cytarabine with another agent in patients with AML Investigator, y (reference)

Median Age (y)

N

Median F/U

Chemotherapy Regimen

CR Rate (%)

Response Disease Control

Overall Survival

Induction/ 30-day mortality (%)

4.7 y

DNR-45 + Ara-C v DNR-35 + Ara-C + valspodar (PSC-833)

48 v 54

EFS5y 8% v 7%

OS5y 10% v 10%

15 v 16

43.4 v 46.2

PFS 2m v 3m

OS2y 23% v 20%

16.3 v 22.2b

67 (58-85)

419

Cripe 2010 ECOG 3999 [56]

69a (65-73)

433

a

50.2 m

DNR-45 + Ara-C v DNR-45 + Ara-C + zosuquidar (LY335979)

Serve 2013 SAL [73]

68 (61-80)

201

29.3 m

DNR-60 + Ara-C v DNR-60 + Ara-C + sorafenib

Rollig 2015 SAL [72]

50 (43-56)

267

36 m

DNR-60 + Ara-C v DNR-60 + Ara-C + sorafenib

47.9 (18-60.9)

717

59 m

DNR-60 + Ara-C v DNR-60 + Ara-C + midostaurin

60 v 48

Median EFS 7m v 5m

Median 15m v 13m

7 v 17c

59 v 60

Median EFS 9m v 21m; EFS3y 22% v 49%d

Median NR v NR

1v2

Median EFS 3m v 8.2me

Median 25.6m v 74.7mf OS4y 51.4% v 44.3%

NR

53.5 v 58.9

d

Stone 2015 CALGB 10603 / Alliance RATIFY [74,75]

M an us c

Kinase inhibitors

rip t

Van der Holt 2005 HOVONMRC [55]

ep

te

Note: PFS – progression-free survival a includes 3% of patients with MDS; b first 42 days of induction; c early death; d p = 0.013; e p = 0.002; f p = 0.009

Ac c

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P-glycoprotein inhibitors

Table 4c. Selected randomized studies evaluating daunorubicin and cytarabine with another agent in patients with AML Investigator, y (reference)

Median Age (y)

N

Median F/U

Chemotherapy Regimen

CR Rate (%)

Response Disease Control

Overall Survival

Induction/ 30-day mortality (%)

45 (16-60)

400

1.5 y

DNR-60 + Ara-C v DNR-60 + Ara-C + cladribine

69 v 72

LFS3y 34% v 43%

OS3y 31% v 34%

14 v 15.5a

56 v 67.5 v 59b

LFS3y 37% v 45% v 42%

47 (17-60)

652

2.8 y

DNR-60 + Ara-C v DNR-60 + Ara-C + cladribine v DNR-60 + Ara-C + fludarabine

Pluta 2017 PALG [122]

66 (60-79)

165

6.4 m

DNR-45 + Ara-C v DNR-45 + Ara-C + cladribine

209

NR

DNR-60 + Ara-C v DNR-60 + Ara-C + azacitidine

NR

DNR-90 + Ara-C v IDA + Ara-C v IDA + Ara-C + vorinostat

Median 9.1m v 8.6m

17 v 23a

52 v 48

Median EFS 6m v 6m

Median 21m v 15m

5v6

75 v 79 v 77

No difference in EFS

No difference in OS

NR

DNR-30/45 + Ara-C v DNR-30/45 + AraC(10) v DNR-30/45 + Ara-C + 6-TGe

52.6 v 57.3 v 56.9

Remission duraion2y 22%f

OS3y 18%f

NR

DNR-50 + Ara-C v DNR-50 + Ara-C + etoposide

56 v 59

Median RFS 14m v 21mh

Median OS 9m v 13m

25i

d

738

te

NRd

NR

NR

Other Agents Preisler 1987 [43]

NR

668

Bishop 1990 ALSG [54]

NRg

264

NR

ep

Garcia-Manero 2016 SWOG [58]

70 (64-74)

OS3y 33% v 45% v 35%c ; Median 14m v 24m v 16mc

29 v 35

Epigenetic modifiers Müller-Tidow 2016 SAL [57]

M an us c

Holowiecki 2012 PALG [62]

Ac c

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Holowiecki 2004 PALG [121]

rip t

Purine analogues

40 m

Note: LFS – leukemia-free survival a early death; b p = 0.01 in favor of DNR + Ara-C + cladribine; c p = 0.02 in favor of DNR + Ara-C + cladribine; d eligible if age 15-60 years; e patients < 60 y received DNR 45 mg/m2 and patients > 60 y received DNR 30 mg/m2; f for all patients (RFS and OS for the different treatment arms were not reported); g not reported but 15-70 y of age; h p = 0.02; i all patients

Cytarabine and daunorubicin for the treatment of acute myeloid leukemia.

Acute myeloid leukemia (AML) is the most common acute forms of leukemia in adults. It has a poor long-term survival with a high relapse rate and at re...
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