IRIS
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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
- ↑ Druker BJ, et al. "Five-Year Follow-up of Patients Receiving Imatinib for Chronic Myeloid Leukemia." N Engl J Med. 2006; 355:2408-2417
- ↑ 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.
- ↑ Peggs K, Mackinnon S. "Imatinib Mesylate — The New Gold Standard for Treatment of Chronic Myeloid Leukemia." N Engl J Med 2003; 348:1048-1050