Causes of Death for Patients with Chronic Myeloid Leukemia (CML) in Chronic Phase (CP) Treated with Imatinib.

Imatinib is the current standard initial therapy for patients with CML in CP. Over 80% of patients achieve a complete cytogenetic remission (CCyR), and the projected overall survival at 7 years is 89%. This survival probability is significantly better than the historical pre-imatinib era (approximately 50% at 5 years). Understanding the causes of death among patients treated with imatinib is needed to further improve the long-term results.

To determine cause of death in patients treated with imatinib as initial therapy for CP Philadelphia-chromosome positive CML.

We reviewed the records of all patients with CML in CP treated with imatinib (standard or high-dose) as initial therapy since 2000.

A total of 281 patients were treated. The overall rate of major cytogenetic response (MCyR) was 94% and CCyR 89%. At 6 years the projected event-free survival was 83% and overall survival 91%. After a median follow-up of 5.6 years, 29 (10%) patients have died. The median age at diagnosis was 56 years (range, 20 to 84 years) and at the time of death 60 years (23 to 91 years). The median time from start of therapy to death was 3.9 years (6 months to 8 years). Initial imatinib dose was 400mg for 13 patients (out of 281, 26% treated at that dose) and 800mg for 16 patients (out of 281, 74% treated at 800mg). All patients had achieved a complete hematological response. Among those that eventually died, 24 (82%) pts achieved a MCyR with imatinib: 19 (65%) achieved CCyR and 5 (17%) partial cytogenetic response (PCyR). Two patients achieved a minor cytogenetic response and 2 had no cytogenetic response; one patient was lost to follow up soon after starting treatment. Causes of death included the following: CML (8), transplant-related complications (4), cardiac complications (3), cerebral vascular accident (2), motor vehicle accident (2), acute myeloid leukemia (1), suicide (1), sudden cardiac death (1), metastatic melanoma (1), metastatic renal cell carcinoma (1), and bowel obstruction (1). Four patients were lost to follow up and cause of death could not be determined. All eight patients that died from CML had lost their hematological response to imatinib; 7 transformed to blast phase. Three of these patients received treatment with second generation tyrosine kinase inhibitors and one achieved a transient MCyR. The four patients that died from transplant-related complications ranged in age from 20 to 48 years at diagnosis. Patients underwent transplant (2 in CP, 2 in 2^nd CP) after failing treatment with imatinib and other therapies. Three patients where in CCyR at time of death and 1 had unknown cytogenetic response. Among the other 17 pts, 9 (53%) were in CCyR at the time of death. The 3 patients that died from cardiac complications had past medical histories of heart disease and all were in CP at time of death: 2 with CCyR and 1 with PCyR. These patients died from congestive heart failure, myocardial ischemia, or arrthymia, respectively. The 2 patients that died from cerebral vascular accidents had prior histories of stroke. Both patients were in CP: 1 in CCyR and 1 with PCyR. The 2 patients who died of car accidents were in CP at the time of death: 1 in CCyR and 1 with PCyR. The patients that died of acute myeloid leukemia, suicide, sudden cardiac death, metastatic renal cell carcinoma and bowel obstruction were all in CCyR prior to death. The patient who died from metastatic melanoma had unknown cytogenetics prior to death. Among the patients that died for reasons other than CML or transplant-related complications, all except three were treated with imatinib only. Two of the 4 patients lost to follow up underwent bone marrow transplants at other facilities and status at time of death is unknown. The other 2 patients lost to follow up discontinued imatinib due to side effects long before their death.

The survival probability of CML CP patients treated with imatinib is excellent. Less than half of the deaths are related to CML or stem cell transplant. These deaths might be preventable if 2^nd generation tyrosine kinase inhibitors are more effective as initial therapy. Other deaths result from co-morbidities, with no deaths attributed to the treatment with imatinib. Close monitoring of patients with predisposing factors for these events could improve their long-term outcome.

Rios:BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau. Jabbour:Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau. Cortes:Novartis: Research Funding.