Lo-Coco 2013

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Lo-Coco F, et al. "Retinoic acid and arsenic trioxide for acute promyelocytic leukemia". The New England Journal of Medicine. 2013. 369(2):111-21.
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Clinical Question

Among patients with low/intermediate-risk acute promyelocytic leukemia, how does combination ATRA plus arsenic trioxide compare to conventional therapy with ATRA plus chemotherapy?

Bottom Line

Among patients with low/intermediate-risk acute promyelocytic leukemia (APL), combination ATRA plus arsenic trioxide (ATO) was at least non-inferior and possibly superior to conventional ATRA plus chemotherapy. Two-year event-free survival among patients receiving ATRA-ATO was 97%.

Major Points

Acute promyelocytic leukemia (APL) accounts for about 10% of acute myeloid leukemia (AML) cases and is associated with severe DIC and early death. Traditionally, it had been treated with chemotherapy, similar to other cases of AML. Advances in the molecular understanding of APL identified the t(15;17) translocation as the sine qua non of APL. This translocation results in the PML-RARA fusion product, leading to the arrest of myeloid differentiation and the clinical phenotype of APL. In the 1980s, studies demonstrated that all-trans retinoic acid (ATRA) could reverse this maturation block and clinical investigations demonstrated that single-agent ATRA was associated with hematologic complete responses (CR) in 85% of patients with APL. The finding that arsenic trioxide (ATO) induces apoptosis in APL blasts prompted the development of chemotherapy-free regimens including ATRA-ATO, which delivered CR in >90% of patients in initial studies. Additionally, it was hypothesized that ATRA-ATO may be associated with less treatment-related toxicity. This landmark study was carried out to compare ATRA-ATO and ATRA-chemotherapy, and determine whether patients with APL could be cured without chemotherapy.

Lo-Coco and colleagues randomized 156 patients with low- or intermediate-risk APL to either ATRA-ATO or ATRA-chemotherapy. Low or intermediate risk was defined as WBC ≤10,000. Patients in the ATRA-ATO group received induction and consolidation with ATRA and ATO. Those in the ATRA-chemotherapy group received induction with ATRA plus idarubicin; consolidation with ATRA, idarubicin, and mitoxantrone; and maintenance with ATRA, methotrexate, and 6-mercaptopurine. The primary endpoint was event-free survival at 2 years, and ATRA-ATO was at least non-inferior and perhaps superior to ATRA-chemotherapy (97% vs. 86%). ATRA-ATO was associated with higher rates of hematologic CR (100% vs. 95%; P=0.12), overall survival at 2 years (99% vs. 91%; P=0.02), and disease-free survival at 2 years (97% vs. 90%; P=0.11). Relapses were uncommon in both groups, but were less frequent with ATRA-ATO (1% vs. 6%; P=0.24). ATRA-ATO was associated with higher rates of grade 3-4 hepatotoxicity and QTc prolongation, but a lower incidence of infection or FUO.

As a result, many leukemia centers prefer ATRA-ATO as first-line therapy and forgo chemotherapy altogether for low- or intermediate-risk APL.

Guidelines

NCCN AML Guidelines (2.2014, adapted)[1]

Induction:

  • ATRA-ATO as per Lo-Coco 2013
  • ATRA, daunorubicin, and cytarabine
  • ATRA plus idarubicin

Consolidation:

  • ATRA-ATO as per Lo-Coco 2013
  • ATRA, ATO, daunorubicin
  • ATRA, idarubicin

Maintenance:

  • None after ATRA-ATO induction/consolidation
  • ATRA-chemotherapy with other regimens

Design

  • Multicenter, randomized, non-inferiority trial
  • N=156 patients with low- or intermediate- risk APL
    • ATRA-ATO (n=77)
    • ATRA-chemotherapy (n=79)
  • Setting: 40 European centers
  • Enrollment: 2007-2010
  • Median follow-up: 34.4 months
  • Analysis: Non-inferiority, intention-to-treat
  • Primary outcome: Event-free survival at 2 years

Population

Inclusion Criteria

  • Age 18-71 years
  • Low- to intermediate-risk APL (WBC <10k at diagnosis)
  • Initial diagnosis of APL based on morphologic features followed by genetic confirmation with conventional cytogenetics, FISH, PCR
  • WHO performance status 0-2
  • Creatinine ≤3.0 mg/dL (≤265 μmol/L)
  • Bilirubin ≤3.0 mg/dL (≤51 μmol/L)

Exclusion Criteria

Not specified in the manuscript.

Baseline Characteristics

  • Median age: 45 years
  • Female 51%
  • WBC: 1.55k
  • Platelets: 29k
  • Risk: low 39%, intermediate 61%
  • PML-RARA isoform: long 59%
  • FLT3-ITD mutation: 23%

Interventions

Participants were randomized to either ATRA-ATO or ATRA-chemotherapy and treated as follows:

ATRA-ATO

Induction:

  • ATRA 45 mg/m2/day PO divided BID
  • ATO 0.15 mg/kg/day
Continue until complete remission, up to 60 days.

Consolidation (at the time of count recovery):

  • ATRA 45 mg/m2/day PO divided BID during weeks 1-2 of each 4-week cycle for 7 cycles
  • ATO 0.15 mg/kg/day 5 days per week during weeks 1-4 of each 8-week cycle for 4 cycles

ATRA-chemotherapy

Induction:

  • ATRA 45 mg/m2/day PO divided BID
  • Idarubicin 12 mg/m2 IV on days 2, 4, 6, and 8
Continue until complete remission, up to 60 days.

Consolidation:

  • ATRA 45 mg/m2/day PO divided BID days 1-15
  • Idarubicin 5 mg/m2 IV days 1-4 of consolidation cycle #1
  • Mitoxantrone 10 mg/m2 IV days 1-5 of consolidation cycle #2
  • Idarubicin 12 mg/m2 IV on day 1 of consolidation cycle #3
Repeat cycles every 3 months for 3 cycles.

Maintenance:

  • ATRA 45 mg/m2/day PO divided BID days 1-15
  • Methotrexate 15 mg/m2 PO or IV weekly (except during days 1-15)
  • 6-Mercaptopurine 50 mg/m2 PO daily (except during days 1-15)
Repeat cycles every 3 months for 2 years.

Supportive Care

Differentiation syndrome prophylaxis
Prednisone 0.5 mg/kg PO daily until complete remission
Differentiation syndrome treatment
Dexamethasone 10 mg twice daily until symptom resolution, at which point the prior dose of prednisone was resumed
Leukocytosis management
For patients who developed leukocytosis during treatment.
For WBC 10-50k, hydroxyurea 500 mg PO QID
For WBC >50k, hydroxyurea 1000 mg PO QID
Hydroxyurea was discontinued when WBC <10k

Outcomes

Comparisons are ATRA-ATO vs. ATRA-chemotherapy.

Primary Outcome

Event-free survival at 2 years
97% vs. 86% (diff 11%; 95% CI 2-22%; P<0.001 for noninferiority, P=0.02 for superiority; NNT 9)

Secondary Outcomes

Overall survival at 2 years
99% vs. 91% (P=0.02; NNT 13)
Disease-free survival at 2 years
97% vs. 90% (P=0.11)
Relapse at 2 years
1% vs. 6% (P=0.24)
Hematologic complete remission
100% vs. 95% (P=0.12)
Median time to CR
32 vs. 35 days (P=0.61)
Leukocytosis (WBC >10k)
47% vs. 24% (P=0.007)

Adverse Events

Differentiation syndrome
19% vs. 16% (P=0.62)
Severe differentiation syndrome
6% in each group (P=0.99), fatal in 2 ATRA-chemotherapy patients
Infection or FUO
26 vs. 59 episodes (P<0.001)
Grade 3-4 hepatotoxicity
63% vs. 6% (P<0.001)
All cases resolved with temporary discontinuation of ATO, ATRA, and/or chemotherapy
QTc prolongation
16% vs. 0% (P<0.001)
1 patient required permanent ATO discontinuation.

Funding

Supported by non-industry grants.

Further Reading

  1. O'Donnell MR, et al. NCCN Clinical Practice Guidelines in Oncology: Acute Myeloid Leukemia." E-published at NCCN.org. Version 2.2014.