In a large phase III trial (IRIS) comparing imatinib versus IFN/Ara-c, imatinib demonstrated significant higher rate of major (MCyR) and complete cytogenetic response (CCyR) and improved progression free survival (PFS). However a large number of pts (n= 354) assigned to the IFN/Ara-c arm crossed-over to imatinib therapy after a median of 9 months. Thus, we performed a retrospective analysis comparing outcome of pts assigned to imatinib in the IRIS trial (

NEJM
2003
;
348
:
994
) and pts assigned to IFN/Ara-c arm included in the French multicenter (CML 91) trial before imatinib became available (
NEJM
1997
;
337
:
223
).

Methods: Pts in the IRIS trial received imatinib 400 mg daily. Pts in the CML 91 trial received IFN alpha 2b 5 MIU/m2 daily plus monthly courses of Ara-c 20 mg/m2 for 10 days. Inclusion criteria of both studies were similar: pts with Ph+ CP CML diagnosed within 6 months before randomization; hydroxyurea or anagrelide were allowed if needed. We compared pts who actually received the assigned study treatment (n=551 for IRIS and n=325 for CML91).

Results: We analyzed the results with a cut-off period of 42 months, median follow-up for alive pts being also 42 months in both groups. The imatinib treated population included more pts who were male, with high or unknown Sokal score and higher % of blasts, and with lower % of basophils at diagnosis than IFN plus Ara-c population. Evaluation included MCyR, CCyR, PFS (i.e. evolution to accelerated phase/blast crisis or death: to be consistent with the CML91 design), and overall survival. Results are summarized in the table below.

Best response (CCyR) was observed in 81% (IRIS) and 32% (CML91) of pts.

At the time of analysis 7% of all pts had never achieved confirmed MCyR but were still under study treatment in the IRIS; 8% were off treatment. These were 26% and 23% in the CML 91. Within all Sokal risk groups, imatinib was superior to IFN/Ara-c in terms of MCR, CCyR, PFS and overall survival. Using a landmark analysis, for pts who achieved MCyR at 1 year (n = 437 for IRIS and n = 125 for CML91), the survival at 36 months was similar in both groups: 95% for IRIS and 96% for CML 91.

Conclusion: This historical comparison shows that for first line therapy for newly diagnosed CP CML, imatinib is superior to prolonged therapy with IFN/Ara-c for rate of MCyR, CCyR, PFS and overall survival. Pts who do not have access to imatinib may have long PFS and overall survival with IFN/Ara-c therapy.

IRIS studyCML 91 studylogrank test**
*95% CI ; ** by 42 months 
Estimated probability of MCR at 12 months 85 (82–88)* 39 (33–45) - 
Estimated probability of MCR at 36 months 93 (91–96) 61 (55–68) p<0.0001 
Estimated probability of CCyR at 12 months 70 (66–74) 14 (10–18) - 
Estimated probability of CCyR at 36 months 87 (83–90) 42 (35–48) p<0.0001 
Progression free survival at 12 months 98 (97–99) 96 (94–98) - 
Progression free survival at 36 months 90 (87–93) 82 (77–87) p = 0.004 
Overall survival at 12 months 99 (98–100) 98 (96–100) - 
Overall survival at 36 months 92 (89–94) 84 (80–88) p<0.0001 
IRIS studyCML 91 studylogrank test**
*95% CI ; ** by 42 months 
Estimated probability of MCR at 12 months 85 (82–88)* 39 (33–45) - 
Estimated probability of MCR at 36 months 93 (91–96) 61 (55–68) p<0.0001 
Estimated probability of CCyR at 12 months 70 (66–74) 14 (10–18) - 
Estimated probability of CCyR at 36 months 87 (83–90) 42 (35–48) p<0.0001 
Progression free survival at 12 months 98 (97–99) 96 (94–98) - 
Progression free survival at 36 months 90 (87–93) 82 (77–87) p = 0.004 
Overall survival at 12 months 99 (98–100) 98 (96–100) - 
Overall survival at 36 months 92 (89–94) 84 (80–88) p<0.0001 
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Topics:
cytarabine, human leukocyte interferon, imatinib mesylate, interferons, leukemia, myelocytic, chronic, brachial plexus neuritis, immune reconstitution inflammatory syndrome, iris trial, accelerated phase, anagrelide

Author notes

Corresponding author

2005, The American Society of Hematology
2005
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