Mitoxantrone, etoposide, and cytarabine versus mitoxantrone and high-dose cytarabine for R/R AML

A consensus has yet to be reached regarding the optimal salvage regimen for patients with relapsed/refractory (R/R) acute myeloid leukemia (AML). Current salvage choices are typically based on patient age, performance status, prior treatments, patient preference, disease burden, and clinician or institute preferences.

The combinations of mitoxantrone, etoposide, and intermediate-dose cytarabine (Ara-C, MEC) and mitoxantrone with high-dose Ara-C (Ara-C couplets) have been used in various single-center trials with differing degrees of success. Additionally, it is unknown how such regimens perform in a real-world population compared with patients enrolled in these clinical trials.

To compare these salvage regimens, Sonia Christian et al.¹ conducted a retrospective, multi-institutional study comparing the use of MEC to Ara-C couplets in a racially diverse population of patients with R/R AML.

Study design

• Retrospective analysis of 155 patients treated at three academic institutions between 1998–2017
• Induction therapy was delivered in the inpatient setting, as described below:
  • MEC (n = 87) administered on Days 1­–5, as follows:  
    • Mitoxantrone: 8 mg/m² intravenously (IV)
    • Etoposide: 100 mg/m² IV
    • Ara-C: 1 g/m² IV
  • Ara-C couplets (n = 68) administered on Day 1 and Day 5, as follows:
    • Mitoxantrone: 30 mg/m² IV
    • Ara-C: 3 g/m² IV (reduced to 2 g/m² for patients > 60 years old)

• • Following induction, additional therapy was given based on the remission status, clinical condition, and availability of allogeneic stem cell transplant (allo-SCT) donor
• Primary endpoint: Overall response (OR)
• Secondary endpoints: Progression-free survival (PFS), overall survival (OS), duration of hospitalization, hematologic and non-hematologic toxicities, and proportion of patients proceeding to allo-SCT

Baseline characteristics

• As shown in Table 1, baseline characteristics between patients receiving MEC and Ara-C couplets were mainly comparable
• Significant differences (p < 0.01) were noted in relation to
  • year of treatment (more patients in the MEC group were treated more recently)
  • performance status prior to initiation
  • use of initial 7 + 3 induction therapy
  • number of salvage therapies received (more patients receiving Ara-C couplets had received ≥ 1 prior line of salvage regimen)
• There were significantly more non-Hispanic White males treated with MEC (72.4%) compared with the Ara-C couplets cohort (52.9%; p = 0.01)
• Additionally, there was a trend towards a higher rate of comorbidities in the cohort receiving Ara-C couplets (MEC vs Ara-C couplets):  33% vs 48.5%; p = 0.07

Table 1. Baseline characteristics¹

Ara-C couplets, mitoxantrone + high-dose cytarabine; IQR, interquartile range; MEC, mitoxantrone + etoposide + intermediate-dose cytarabine; R/R, relapsed/refractory
Characteristic	MEC n = 87	Ara-C couplets n = 68
Median age (range), years	52 (20–75)	54 (22–75)
Age ≥ 50 years at relapse, %	50.6	64.7
Race, % White Black Hispanic Other	72.4 13.8 8.0 5.7	52.9 22.1 13.2 11.8
High Charlson comorbidity index (≥ 4), %	33.3	48.5
Performance status prior to initiation, % 0 1 2 3 4 Unknown	32.2 44.8 11.5 2.3 1.1 8.0	20.6 23.5 1.5 0 0 54.4
Initial 7 + 3 induction therapy, %	90.8	51.5
Unfavorable cytogenetics, %	36.8	32.4
Number of salvage therapies, % 0 1 ≥ 2	80.5 16.1 3.4	55.9 35.3 8.8
Median time from initial diagnosis to R/R disease, days (IQR)	303 (180–445)	285 (188–505)

 Efficacy

• There were no significant differences in median PFS, OS, mortality rates, and duration of hospital stays between regimens. There was a non-significant (p = 0.10) trend to better OR in patients receiving Ara-C couplets (Table 2)
• In the Ara-C couplets cohort, all 37 responders proceeded to allo-SCT, while 27 out of 38 responders in the MEC cohort progressed to allo-SCT
• Count recovery was significantly faster in the MEC cohort than the Ara-C couplets cohort (p = 0.01 for absolute neutrophil count and p < 0.01 for platelets)

Table 2. Key efficacy data¹

Allo-SCT, allogeneic stem cell transplant; Ara-C couplets, mitoxantrone + high-dose cytarabine; CR, complete remission; CRi complete remission with incomplete hematologic recovery; CRp, complete remission with residual thrombocytopenia; MEC, mitoxantrone + etoposide + intermediate-dose cytarabine; MLFS, morphologic leukemia-free state; OR, overall response; OS, overall survival; PFS, progression-free survival
Efficacy data	MEC n = 87	Ara-C couplets n = 68	p value
OR, %	43.7	54.4	0.10
Responses, % CR CRi (CRp) MLFS Refractory	37.9 2.3 3.4 56.3	38.2 8.8 8.8 44.1	—
Median PFS, days	66	107.5	0.71
Median OS, months	5.3	6.5	0.35
60-day mortality, %	23.0	11.8	—
Proceeded to allo-SCT, %	31.0	54.4	0.003

Multivariable analysis

Multivariable analysis (adjusted for age, race, Charlson comorbidity index, and cytogenetic risk) found no significant differences in risk of overall mortality between regimens (HR, 1.00; 95% CI, 0.48–2.09; p = 0.99).

Safety

• Ara-C couplets led to significantly lower rates of febrile neutropenia and Grade 3/4 gastrointestinal toxicity compared with MEC (Table 3)
• There were no significant differences between the regimens in relation to other Grade 3/4 toxicities including pulmonary, cardiac, liver, renal, neurologic, or endocrine

Table 3. Safety summary of MEC versus Ara-C couplets¹

Ara-C couplets, mitoxantrone + high-dose cytarabine; GI, gastrointestinal; MEC, mitoxantrone + etoposide + intermediate-dose cytarabine
	MEC	Ara-C couplets	p value
Febrile neutropenia, %	94	72	< 0.001
Grade 3/4 GI toxicities, %	17.2	2.94	0.005

Limitations

The following limitations should be considered:

• Institutional practice and physician preference may have dictated which patients proceeded to allo-SCT
  • Of the three institutes, one exclusively used Ara-C couplets, one exclusively used MEC, and one used both regimens
  • In the institute where both regimens were used, there was no difference in patients proceeding to allo-SCT, though the sample size was small, limiting conclusions
• This was a retrospective study of non-randomized treatment regimens

Conclusion

Whilst there were no significant differences in OR between MEC and Ara-C couplets, Ara-C couplets led to a reduction in toxicities, such as febrile neutropenia and Grade 3/4 gastrointestinal toxicities, suggesting that this salvage regimen may represent a suitable option for patients with R/R disease.

In the Ara-C couplets cohort, all responding patients proceeded to allo-SCT, indicating Ara-C couplets may have a valuable role as a chemotherapy backbone, whereby more targeted epigenetic therapies could be added to improve responses without increasing toxicity.

Further reading

To read more salvage regimens in combination with, or without, allo-SCT in patients who have failed to respond to induction, click here.