The benefit of high dose mitoxantrone-based (“5 + 1”) induction chemotherapy in elderly patients with newly diagnosed acute myeloid leukemia

The standard induction therapy for patients with newly diagnosed acute myeloid leukemia (AML) who are under the age of 60 years, and otherwise medically fit, is a “7 + 3” regimen, comprising 7 days continuous infusion cytarabine with 3 days of a short infusion of an anthracycline. The most commonly used anthracycline is daunorubicin, but others can be used, such as idarubicin or mitoxantrone. However, in the elderly, the concept of dose intensifications has not historically led to improved outcomes due to increased treatment related mortality (TRM).

The study by Neeraj Y. Saini, UMASS Memorial Medical Center, Massachusetts, and MD Anderson Cancer Center, Texas, and colleagues, presented the outcome of 101 patients with newly diagnosed AML treated with an intensive “5 + 1” regimen. The regimen consisted of high dose cytarabine (HiDAC) and high dose mitoxantrone (HDM). The results focussed on elderly patients since overall survival (OS) rates in this population have been reported as less than 6 months, with 8-week mortality approaching 36%, due to an increase in treatment related mortality. Therefore, there is an unmet need for new treatments in the elderly group.^1,2

Patient population and study design

• N = 101
• Patients with newly diagnosed AML
• Median age: 65 (18–90)
• Stratified according to 2017 European Leukemia Net-AML criteria (ELN-AML):³
  • Favourable vs intermediate vs adverse: 15.8% (16) vs 39.6% (40) vs 40.5% (41)
• Intermediate/adverse risk cytogenetics: 85%
  • Complex karyotype: 20.7% (n = 21)
• One-third of patients had secondary or treatment-related AML
• Score >3 on the hematopoeitic cell transplant comorbidity index (HCT-CI) score: 50%⁴
• Regimen: “5 + 1”:
  • Days 1–5: Bolus HiDAC: 3000 mg/m² once/day over 3 hours
  • Day 2: HDM: 80 mg/m² immediately after HiDAC infusion
• Due to comorbidities, 12 patients received 60 mg/m² of mitoxantrone

Key Findings

Response rates

• Overall response evaluated as complete response (CR) + CR with incomplete hematologic recovery (CRi): 76.2% (77/101)
• Primary refractory or partial responses: 22% (23/101)
• Complete response:
  • Age (<60 vs 60–69 vs ≥70 years old): 80% (24/30) vs 74.2% (26/35) vs 77.1% (27/35)
  • ELN-AML category (favourable and intermediate vs adverse): 85.2% (46/54) vs 65.8% (28/42) (P = 0.03)
  • AML status (de novo vs secondary): 83.5% (56/67) vs 63.6% (21/33) (P = 0.04)

Post-treatment therapy

• Of the 77 patients with a response (CR/CRi):
  • 21 (27%) patients received conventional chemotherapy alone:
    • Hypomethylating agents: n = 13
    • HiDAC: n = 8
  • 47 (61%) proceeded to transplantation:
    • Allogeneic stem cell transplant (allo-SCT): n = 34
    • Autologous stem cell transplant (auto-SCT): n = 13
  • No further treatment due to decline in status, early relapse or transfer: n = 9
• Out of the whole cohort, 86 patients received further treatment after induction chemotherapy

Relapse

• Total: 28% relapses (n = 29)
• Relapse following CR (n = 77): 29% (n = 22)
  • Median time to relapse: 7 months (2–21 months)
• Relapse in allo-SCT vs no allo-SCT: 14.7% (5/34) vs 39.5% (17/43)
• Non-relapse mortality (NRM): 1 year vs 3 year: 29% vs 45%

Overall Survival and HCT-CI

• Median follow-up of survivors: 62 months (1–109)
  • Alive at last follow-up: 37.4% (n = 38)
• Median event-free survival: 8 months
• Median OS: 25 months
  • Two-year OS: 45%
  • Five-year OS: 37%
• Median OS by age (<60 vs 60–69 vs ≥70 years old): 56 vs 31 vs 9 months (P = 0.02)
• Median OS by ELN-AML categories (favourable and intermediate vs adverse): 43 vs 11 months (P = 0.12)
  • Significant factors with a negative impact on OS included: high white blood cell count, elevated creatinine, age, history of acquired heart disease, previous chemotherapy for another malignancy and complex karyotype
• HCT-CI score as a predictor of OS and 8-week mortality:
  • Median OS (HCT-CI score ≤3 vs ≥ 4): 87 vs 11.5 months (P = 0.0046)
  • Overall mortality in patients with HCT-CI score ≥ 4: HR 1.793 (P = 0.023, 95% CI, 1.083–2.971)
  • HR for 8-week mortality was not statistically significant

Transplant outcomes

• During consolidation, 60 patients underwent transplant (allo-SCT vs auto-SCT): 46.5% (n = 47) vs 12.8% (n = 13)
  • In the allo-SCT group: 2 year vs 5 year OS were 70% and 54%
• Of the 84 patients (excluding any lost to follow-up), in the intermediate/adverse risk group (ENL/AML criteria): 51.7% proceeded to allo-SCT
  • By age (<60 vs 60–69 vs ≥70 years old): 75% (18/24) vs 60.7% (17/28) vs 31.2% (10/32)

Induction mortality and toxicity:

• Four-week induction mortality: 2.9% (3/101)
  • By age (<60 vs 60–69 vs ≥70 years old): 0% (0/30) vs 2.8% (1/35) vs 5.5% (2/36)
• Eight-week induction mortality: 7% (7/99)
  • By age (<60 vs 60–69 vs ≥70 years old): 0% (0/29) vs 5.8% (2/34) vs 13.8% (5/36)
• Regimen relatively well-tolerated
• Myelosuppression Grade 4: 100%
• Neurotoxicity: cytarabine infusion had to be stopped on 2 occasions
• Cardiotoxicity: 19% had decline in ejection fraction < 40%

In conclusion, high CR rates were achieved with HDM-based induction chemotherapy. This was especially promising given that there was a high proportion of high-risk patients in the study. The regimen was well tolerated and allowed patients to progress to postremission therapies such as stem cell transplants, which may be curative.  The authors related the high response rates in the elderly age group to improvements in supportive care in the last years, indicating that elderly patients should now be more frequently considered for induction chemotherapy. The retrospective cohort design was one of the limitations of the study and therefore further studies are warranted to identify the optimal regimen for older patients with AML.