**Table 2.**

**159**

*What Is the Best Choice and Dose of Anthracycline for Induction Chemotherapy in Acute…*

remission as well as overall survival, compared to daunorubicin [16, 40].

neutropenia, cardiotoxicity and overall survival between the 2 drugs. The second study also showed that idarubicin was associated with improved rates of complete

A summary of the trials comparing idarubicin and high dose daunorubicin is

Mitoxantrone, an anthraquinone derivative, has been extensively used with cytarabine as part of induction chemotherapy in patients with AML. It has been shown to be equally effective, if not better, when compared to daunorubicin. Nonetheless, it has not been adapted readily into the clinical practice of upfront induction chemotherapy and is often incorporated into the treatment algorithm in the relapse and refractory setting. There are 2 randomized trials comparing mito

xantrone, idarubicin and daunorubicin which will be discussed in the subsequent

The AML-10 study was a randomized phase III study comparing daunorubicin,

2

Remission induction was not given in the traditional 7 + 3 manner and consisted of

on days 1–10, etoposide 100 mg/m

1, 3 and 5. A second round of the same regimen was given to those with a partial

There was no difference in the rate of complete remission between the 3 anthra

cyclines. Nearly a quarter of patients, in each arm, proceeded to allogeneic stem cell transplant. After a median follow-up of 5.6 years, there was no difference in median and 5-year overall survival between the 3 arms. Even after adjusting for other variables, the results remained the same. For patients without a donor, the diseasefree survival and survival from complete remission were longer in the idarubicin and mitoxantrone arm than in the daunorubicin arm. There was no difference for

with AML [42]. The study enrolled 362 patients with a median age of 67 years. A second round of the same induction was given to patients with residual disease (>5% blasts) on day 14 bone marrow biopsy. There was no statistically significant difference for the rates of complete remission between the 3 arms. Furthermore, there was no difference observed in terms of toxicity profile, disease-free survival

CPX-351 is a liposomal encapsulation of cytarabine and daunorubicin at a fixed synergistic molar ratio of 5:1. Using ratio-metric dosing, instead of the traditionally used maximum tolerated dose (MTD), potentially enhances the efficacy of drugs by maintaining the fixed drug ratio for a longer time in the blood. In the conven

tional form (MTD), the blood concentration or ratio of the drug(s), after infusion, may change immediately depending on the individual agent's pharmacokinetics, raising concern for inferior efficacy. A liposomal encapsulation, by evading first pass metabolism, may overcome this concern and lead to greater uptake by leu

kemia cells. Through this mechanism, an increased cytotoxic effect of the drugs

, idarubicin 10 mg/m

An ECOG phase III compared daunorubicin 45 mg/m

and overall survival between the 3 induction regimens.


≤60 years of age, with AML [41].

on days 1–5 and either

, idarubicin 12 mg/m

2

on days

2 and




2

2

, given with continuous cytarabine, as 7 + 3 in older adults

or mitoxantrone 12 mg/m

*DOI: http://dx.doi.org/10.5772/intechopen.94420*

**.**

idarubicin and mitoxantrone in 2157 patients,

2

2

2

presented in **Table 2**

**4. Mitoxantrone**

cytarabine 100 mg/m

patients with a donor.

mitoxantrone 12 mg/m

**5. CPX-351 (Vyxeos)**

daunorubicin 50 mg/m

remission to the first round.

section.

*Summary of trials comparing idarubicin and daunorubicin.*

#### *What Is the Best Choice and Dose of Anthracycline for Induction Chemotherapy in Acute… DOI: http://dx.doi.org/10.5772/intechopen.94420*

neutropenia, cardiotoxicity and overall survival between the 2 drugs. The second study also showed that idarubicin was associated with improved rates of complete remission as well as overall survival, compared to daunorubicin [16, 40].

A summary of the trials comparing idarubicin and high dose daunorubicin is presented in **Table 2.**

#### **4. Mitoxantrone**

*Acute Leukemias*

**158**

**Study** **NCT01145846** **JASLG AML 201**

**ALFA 9801** **GOELAMS** 

832

48

D60 vs. Ida8

7 + 3 (D60)

7 + 5 (Ida)

(17–60)

**LAM-2001**

**ALFA 9803**

**Table 2.**

*Summary of trials comparing idarubicin and daunorubicin.*

416

72

D45 vs. Ida9

7 + 4

D45 180

No significant

No significant

difference

difference

Ida 36

*D90: daunorubicin 90 mg/m2, D80: daunorubicin 80 mg/m2, D60: daunorubicin 60 mg/m2, D50: daunorubicin 50 mg/m2, D45: daunorubicin 45 mg/m2, Ida12: idarubicin 12 mg/m2, Ida8: idarubicin* 

*8 mg/m2, Ida9: idarubicin 9 mg/m2, 7 + 3: 7 days of cytarabine and 3 days of anthracycline, CR: complete remission, EFS: event-free survival, OS: overall survival.*

(65–85)

468

60

D80 vs. Ida12

7 + 3

D80 240

Ida 36

D60 180

No significant

Favors Ida

Cytogenetics:

Intermediate risk had

improved OS and EFS

with Ida

—

difference

Ida 40

(50–70)

1057

47

D50 vs. Ida12

7 + 3 (Ida)

D50 250

Ida 36

7 + 5 (D50)

(14–65)

299

49

D90 vs. Ida12

7 + 3

(15–65)

**Patients (n)**

**Age** 

**Anthracycline** 

**Induction** 

**Cumulative** 

**Complete** 

**Overall** 

**Subset analysis**

**survival**

**remission**

**anthracycline dose** 

**(mg/m2)**

D90 270

No significant

No significant

FLT3: Improved OS and

EFS with D90

—

difference

difference

No significant

No significant

difference

difference

Favors Ida

No significant

—

difference

Ida 36

**schedule**

**comparison**

**(range)**

Mitoxantrone, an anthraquinone derivative, has been extensively used with cytarabine as part of induction chemotherapy in patients with AML. It has been shown to be equally effective, if not better, when compared to daunorubicin. Nonetheless, it has not been adapted readily into the clinical practice of upfront induction chemotherapy and is often incorporated into the treatment algorithm in the relapse and refractory setting. There are 2 randomized trials comparing mitoxantrone, idarubicin and daunorubicin which will be discussed in the subsequent section.

The AML-10 study was a randomized phase III study comparing daunorubicin, idarubicin and mitoxantrone in 2157 patients, ≤60 years of age, with AML [41]. Remission induction was not given in the traditional 7 + 3 manner and consisted of cytarabine 100 mg/m2 on days 1–10, etoposide 100 mg/m<sup>2</sup> on days 1–5 and either daunorubicin 50 mg/m<sup>2</sup> , idarubicin 10 mg/m2 or mitoxantrone 12 mg/m2 on days 1, 3 and 5. A second round of the same regimen was given to those with a partial remission to the first round.

There was no difference in the rate of complete remission between the 3 anthracyclines. Nearly a quarter of patients, in each arm, proceeded to allogeneic stem cell transplant. After a median follow-up of 5.6 years, there was no difference in median and 5-year overall survival between the 3 arms. Even after adjusting for other variables, the results remained the same. For patients without a donor, the diseasefree survival and survival from complete remission were longer in the idarubicin and mitoxantrone arm than in the daunorubicin arm. There was no difference for patients with a donor.

An ECOG phase III compared daunorubicin 45 mg/m<sup>2</sup> , idarubicin 12 mg/m2 and mitoxantrone 12 mg/m2 , given with continuous cytarabine, as 7 + 3 in older adults with AML [42]. The study enrolled 362 patients with a median age of 67 years. A second round of the same induction was given to patients with residual disease (>5% blasts) on day 14 bone marrow biopsy. There was no statistically significant difference for the rates of complete remission between the 3 arms. Furthermore, there was no difference observed in terms of toxicity profile, disease-free survival and overall survival between the 3 induction regimens.

#### **5. CPX-351 (Vyxeos)**

CPX-351 is a liposomal encapsulation of cytarabine and daunorubicin at a fixed synergistic molar ratio of 5:1. Using ratio-metric dosing, instead of the traditionally used maximum tolerated dose (MTD), potentially enhances the efficacy of drugs by maintaining the fixed drug ratio for a longer time in the blood. In the conventional form (MTD), the blood concentration or ratio of the drug(s), after infusion, may change immediately depending on the individual agent's pharmacokinetics, raising concern for inferior efficacy. A liposomal encapsulation, by evading first pass metabolism, may overcome this concern and lead to greater uptake by leukemia cells. Through this mechanism, an increased cytotoxic effect of the drugs

is observed, leading to prolonged myelosuppression, in addition to apoptosis of leukemia cells [43, 44].

The liposome of daunorubin:cytarabine 44 mg/m<sup>2</sup> :100 mg/m<sup>2</sup> is FDA approved for the treatment of adults with therapy related AML or AML with myelodysplasia-related changes. A phase III study compared cytarabine + liposomal daunorubicin (CPX-351, Vyxeos) to 7 + 3 (daunorubicin 60 mg/m<sup>2</sup> ), in older patients (60–75 years) with secondary AML. The study enrolled 309 patients. CPX-351 was associated with a higher remission rate (47.7% vs. 33.3%, p = 0.016) as well as improved median overall survival (9.6 m vs. 5.9 m, HR 0.69, p = 0.003) compared to 7 + 3. There was no difference in early mortality between the two treatments. Prolonged neutropenia and thrombocytopenia were observed with CPX-351 [19].

Although the study above was limited to older patients, the FDA approved CPX-351 for all adults. The reason being that therapy related AML or AML with myelodysplasia-related changes are thought to be biologically aggressive subtypes, regardless of age. Whether CPX-351 is superior, in patients <60 years old, to 7 + 3 using either daunorubicin 90 mg/m<sup>2</sup> or idarubicin is not known. The results of ongoing studies in younger patients as well as planned clinical trials using CPX-351 in combination with targeted therapy or immunotherapy should help identify additional subsets of patients that may derive benefit from this drug.

#### **6. Conclusion**

AML is a heterogenous disease and the treatment plan for every patient is different. Both patient and disease related variables help determine the appropriate treatment option for each case. It is challenging to state the outright superiority of one anthracycline over another, but some useful conclusions can be drawn from the evidence presented above.

When choosing between 45 mg/m2 , 60 mg/m<sup>2</sup> and 90 mg/m<sup>2</sup> of daunorubicin, it is reasonable to look at patient age and cytogenetic and molecular abnormalities (if available in a timely manner), before picking one. Daunorubicin 45 mg/m<sup>2</sup> should be used for older patients >65 years of age based on the available evidence. It is probably safe and effective to use daunorubicin 60 mg/m2 in this age group, but unfortunately there is lack of randomized data to support one dose over the other. For patients younger than 65 years of age, daunorubicin 90 mg/m2 is superior to daunorubicin 45 mg/m2 . All cytogenetic risk categories and FLT3, NPM1 and DNMT3A-mutant AML seem to derive benefit from daunorubicin 90 mg/m2 . However, data is emerging to suggest that daunorubicin 60 mg/m2 can effectively replace daunorubicin 90 mg/m2 .

Idarubicin is superior to daunorubicin 45 mg/m2 , when used as 7 + 3, in younger patients. It also appears to be as safe and effective as daunorubicin 90 mg/m<sup>2</sup> , except for FLT3-mutant AML where daunorubicin 90 mg/m<sup>2</sup> may have a slight advantage. One caveat to the idarubicin vs. high dose daunorubicin studies is the small representation of older patients (>65 years). For older patients fit for intensive therapy, daunorubicin 45 mg/m2 , may still be the first choice.

Mitoxantrone is comparable to both idarubicin and daunorubicin. It's use in upfront therapy is still not as common as the other 2 available agents. CPX-351 should be the first choice in patients with secondary AML.

Whereas novel drug regimens are emerging in the treatment of AML, intensive chemotherapy still plays a significant role. Anthracyclines will serve as the backbone of AML treatment in fit patients and therefore it is important to know which type and dose to select in the appropriate setting.

**161**

**Author details**

Sravanti Rangaraju and Omer Jamy\*

Alabama at Birmingham, Birmingham, AL, USA

provided the original work is properly cited.

\*Address all correspondence to: omerjamy@gmail.com

Division of Hematology/Oncology, Department of Medicine, University of

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

*What Is the Best Choice and Dose of Anthracycline for Induction Chemotherapy in Acute…*

*DOI: http://dx.doi.org/10.5772/intechopen.94420*

The authors declare no conflict of interest.

**Conflict of interest**

*What Is the Best Choice and Dose of Anthracycline for Induction Chemotherapy in Acute… DOI: http://dx.doi.org/10.5772/intechopen.94420*
