IRIS

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O'Brien SG, et al. "Imatinib Compared with Interferon and Low-Dose Cytarabine for Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia". The New England Journal of Medicine. 2003. 384(11):994-1004.
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Clinical Question

Among patients with Philadelphia chromosome-positive CML, does imatinib delay disease progression compared to IFNα/cytarabine?

Bottom Line

In patients with Philadelphia chromosome-positive CML, imatinib (STI571) delays disease progression compared to IFNα/cytarabine.

Major Points

The Philadelphia chromosome (Ph) results from a t(9;22) translocation that produces the BCR-ABL protein, a tyrosine kinase responsible for cell proliferation that drives CML. Imatinib (STI571) is a selective inhibitor of the BCR-ABL tyrosine kinase that has been shown to delay disease progression among individuals in the chronic phase of CML.

The International Randomized Study of Interferon and STI571 (IRIS) randomized 1,106 patients with chronic-phase CML to receive either imatinib or IFNα/cytarabine. At a mean follow-up of 18 months, those treated with imatinib had a higher rate of progression-free survival (92.1% vs. 73.5%), with a NNT of 6, and a greater proportion were free of accelerated-phase or blast-phase CML (96.7% vs. 91.5%), with a NNT of 19. At 5 years of follow-up, a complete cytogenetic response was seen in 87% and overall survival was 89% among patients treated with imatinib.[1]

Guidelines

NCCN CML (2013):[2]

  • Discuss treatment options with patients with Ph or BRC-ABL positive chronic phase CML with a TKI, HCST, or a clinical trial (category 2A)
  • Initial treatment with imatinib, nilotinib, or dasatinib in above patients as appropriate (category 2A)

Design

  • Multicenter, open-label, parallel group, randomized, controlled trial
  • N=1,106 patients
    • Imatinib (n=553)
    • IFNα/cytarabine (n=553)
  • Setting: 177 centers in 16 countries
  • Enrollment: 2000-2001
  • Median follow-up: 19 months
  • Primary outcome: Disease progression
  • Analysis: Intention-to-treat and per-protocol

Population

Inclusion Criteria

  • Age 18-70 years
  • Chronic-phase, Ph-positive CML diagnosed in the prior 6 months

Exclusion Criteria

  • Prior treatment of CML except for hydroxurea and/or anagrelide
  • Prior chemotherapy or investigational therapy
  • Extramedullary disease (other than hepatosplenomegaly or thrombocytopenia)
  • Liver aminotransferases, bilirubin, and creatinine >1.5x ULN
  • Breast-feeding, pregnancy, child-bearing potential without negative pregnancy test
  • ECOG status 3-4
  • Hematopoietic-cell transplant
  • Major surgery in prior 4 weeks
  • HIV infection
  • Cancer diagnosis in the prior 5 years other than BCC or cervical CIS

Baseline Characteristics

  • Age: 51 years (21.9% ≥60 years)
  • Male: 58.9%
  • Interval since diagnosis: ~2 mos
  • ECOG status: 0 (75.5%), 1 (21.4%), 2 (1.7%)
  • Splenomegaly: 25%
  • WBC: 19,000/mm3
  • Hgb: 12.9 g/dL
  • Plt: 338,000/mm3
  • Peripheral blasts: 0%
  • Peripheral basophils: 3%
  • Chromosomal abnormalities in addition to Ph: 12.1% vs. 7.6% (P=0.015)

Interventions

Comparisons are imatinib vs. IFNα/cytarabine.

  • Randomized to imatinib 400mg daily or IFNα titrated to 5 million units/m2 as tolerated and cytarabine 20-40 mg/m2 for 10 days/month until patient derived no further benefit
  • Hydroxyurea added as needed

Outcomes

Comparisons are imatinib vs. IFNα/cytarabine.

Primary Outcome

Progression-free survival at 18 months
92.1% vs. 73.5% (P<0.001; NNT=6)

Secondary Outcomes

Absence of accelerated-phase or blast-phase CML at 18 months
96.7% vs. 91.5% (P<0.001)
Survival at 18 months
97.2% vs. 95.1% (P=0.16)
Complete hematologic response
Defined as WBC <10,000/mm3, Plt <450,000/mm3, <5% myelocytes plus metamyeloctyes, <20% basophils, absence of blasts and promyelocytes, absence of extramedullary involvement
95.3% vs. 55.5% (P<0.001; NNT=3)
Major cytogenetic response
Defined as 0-35% of Ph-positive cells in metaphase
85.2% vs. 22.1% (P<0.001; NNT=2)

Adverse Events

Imatinib had higher rates of superficial edema, muscle cramps, rash, abdominal pain, nasopharyngitis, dyspepsia, pharyngolaryngeal pain, URIs, weight gain. It was generally well-tolerated.

Crossover

Continued initial treatment
85.7% vs. 10.8%
Discontinued initial treatment
12.3% vs. 31.6%
Crossed over to alternative treatment
2.0% vs. 57.5%

Criticisms

Does not demonstrate superior overall survival of imatinib treatment, although this arose out of the study's crossover design[3]

Funding

Novartis

Further Reading

  1. Druker BJ, et al. "Five-Year Follow-up of Patients Receiving Imatinib for Chronic Myeloid Leukemia." N Engl J Med. 2006; 355:2408-2417
  2. O'Brien S et al. "NCCN clinical practice guidelines in oncology: Chronic Myelogenous Leukemia." E-published at NCCN.org. Version 4.2013. Accessed 2013-08-07.
  3. Peggs K, Mackinnon S. "Imatinib Mesylate — The New Gold Standard for Treatment of Chronic Myeloid Leukemia." N Engl J Med 2003; 348:1048-1050