Prognostic factors and survival outcomes in patients with chronic myeloid leukemia in blast phase in the tyrosine kinase inhibitor era: Cohort study of 477 patients

Abstract

Background: Outcomes in patients with chronic myeloid leukemia in blast phase (CML-BP) are historically dismal. Herein, the authors sought to analyze the characteristics, prognostic factors, and survival outcomes in patients with CML-BP in the tyrosine kinase inhibitor (TKI) era.

Methods: A total of 477 patients with CML-BP were treated with a TKI at some point during the course of their CML. Cox proportional hazard models identified characteristics that were predictive of survival. Overall survival and failure-free survival were assessed. Optimal cutoff points for specific parameters were identified using classification and regression tree (CART) analysis.

Results: The median age of the patients was 53 years (range, 16-84 years) and 64% were male. Approximately 80% of patients initially were diagnosed in the chronic phase of CML at a median of 41 months (range, 0.7-298 months) before transformation to CML-BP. De novo CML-BP occurred in 71 patients. Approximately 72% of patients received TKI therapy before CML-BP. The initial therapy for CML-BP included a TKI alone (35%), a TKI with chemotherapy (46%), and non-TKI therapies (19%). The median overall survival was 12 months and the median failure-free survival was 5 months. In multivariate analysis, myeloid immunophenotype, prior TKI, age ≥58 years, lactate dehydrogenase level ≥1227 IU/L, platelet count < 102 K/μL, no history of stem cell transplantation, transition to BP from chronic phase/accelerated phase, and the presence of chromosome 15 aberrations predicted for a significantly increased risk of death. Achievement of major hematologic response and/or complete cytogenetic response to first-line treatment was found to be predictive of better survival. The combination of a TKI with intensive chemotherapy followed by stem cell transplantation appeared to confer the best outcome.

Conclusions: Patients with CML-BP continue to pose a therapeutic challenge, have dismal outcomes, and require newer treatment approaches. Cancer 2017;123:4391-402. © 2017 American Cancer Society.

Keywords: blast phase (BP); bosutinib; chronic myeloid leukemia (CML); dasatinib; imatinib; nilotinib; ponatinib; tyrosine kinase inhibitors (TKI).

Figure-1. Survival outcome in patients with CML-BP – Overall and according to patient characteristics

A) Overall survival (OS) for all patients. The median overall survival was 12 months with 79% deaths. B) Failure free survival (FFS) for all patients. The median FFS was 5 months with 87% failing first line treatment C) Patients with de novo blast phase had better OS compared to patients who transformed from chronic/accelerated phase CML; p<0.0001 D) Survival has progressively improved after the advent of imatinib in 2000 and is significantly better in the current era; p<0.0001 E) Patients with myeloid immunophenotype of CML-BP have inferior survival compared to CML-BP with lymphoid immunophenotype (p<0.001; 5 year survival % is 15% vs 30%) F) Patients previously treated with tyrosine kinase inhibitor (TKI) had poor survival (p<0.0001; 5 year survival % is 15% vs 31%) G) Patients age ≥ 58 years had poor survival (p<0.001; 5 year survival % is 11% vs 24%). The cut off of 58 years is derived from recursive partitioning H) Patients with LDH levels ≥ 1227 IU/L had poor survival (p<0.001; 5 year survival % is 14% vs 23%). The cut off of 1227 for serum LDH is derived from recursive partitioning method

Figure-2. Overall survival (OS) in patients with CML-BP according to treatment modality

A) Patients who are treated with frontline tyrosine kinase inhibitor (TKI) in combination with chemotherapy had superior survival (p=0.005; 5 year survival % is 30% vs 14% vs 9%) compared to patients who were treated with TKI alone and non-TKI based therapies as the first line treatment for CML-BP B) Patients treated with various TKI’s are shown. Dasatinib therapy appears to have a better survival compared to other TKI’s (p=0.06; 5 year survival % with dasatinib is 29%. Too few patients to evaluate in nilotinib, ponatinib and bosutinib cohorts. C) Patients who are not treated with stem cell transplantation (SCT) after the diagnosis of CML-BP had inferior survival (p<0.001; 5 year survival % is 13% vs 43%)

Figure-3. Failure free survival (FFS) in patients with CML-BP according to treatment

A) Patients who are treated with frontline tyrosine kinase inhibitor (TKI) in combination with chemotherapy had superior FFS (p<0.001; 5 year FFS % is 20% vs 8% vs 6%) compared to patients who were treated with TKI alone and non-TKI based therapies as the first line treatment for CML-BP B) Patients treated with dasatinib therapy had better survival compared to other TKI’s, imatinib, nilotinib, ponatinib, bosutinib (p=0.06; 5 year FFS % with dasatinib is 20%. C) Patients who are not treated with stem cell transplantation (SCT) after the diagnosis of CML-BP had inferior outcome (p<0.001; 5 year FFS % is 6% vs 33%)