Outcomes of Accelerated and Blast Phase Chronic Myeloid Leukemia at a Tertiary Center
Authors: Mohamed Ahmed N , Zureigat Hadil , Alsabbagh Alchirazi Muaz , Dhakal Aastha , Mushtaq Ali , Rehman Naveen , Berube Bryan , Govande Sneha , Zabor Emily C. , Jain Akriti G. , Molina John C. , Balderman Sophia , Singh Abhay , Gerds Aaron T. , Advani Anjali S. , Carraway Hetty E. , Kalaycio Matt , Mukherjee Sudipto , Mustafa Ali Moaath K. 
Published: December 2024

Background:
Around 90% percent of patients with chronic myeloid leukemia (CML) present at a chronic phase (CP) (CML-CP), which is a slow-progressing disorder that responds well to treatment with tyrosine kinase inhibitors (TKI). The incidence of accelerated phase (AP) and blast phase (BP)-CML at diagnosis is 3.5% and 2.2%, respectively. Because of the rarity of CML-AP and CML-BP, less is known about their response and long-term survival.
Methods:
We conducted a single-center retrospective study to investigate the outcomes of CML-AP and CML-BP in comparison to CML-CP. Advanced CML (CML-Adv) included both CML-AP and CML-BP. Patients included were all consecutive adult patients (≥18 years) diagnosed with CML and treated at Cleveland Clinic from 7/2007-12/2022. CML phases were defined using the 2022 International Consensus Classification of Myeloid Neoplasms. We collected the following variables: demographics, Cytogenetics, comorbidities, all treatment lines and responses, and follow-up data. Responses to TKI were determined using overall survival (OS), calculated from the initiation of therapy to the time of death and response at the 12-month (mo) mark. Because response criteria to TKI varied throughout the years, we used the following criteria for 12-mo response: 1. Latest years (≥2010): rate of achieving major molecular response three or more, 2. Middle years (~2008-2010): rate of achieving a total of 3 log reductions or more in BCR:-ABL1 PCR transcript or 3, Earliest years (~2007): rate of achieving a complete cytogenetic response on bone marrow (BM) exam. The 12-mo response rate was the intention to treat, and no patients were excluded if the drug was discontinued for any reason (i.e., death less than 12 mo or intolerance...etc.). The Kaplan-Meier and log rank were used for survival analysis Multivariable regression was used to adjust outcomes for confounders.
Results:
A total of 361 patients were included in this study, of those 345/361 (95%) had CML-CP, 6/361 (1.5%) had CML-BP, and 10/361 (2.7%) had CML-AP. 13 with CML-CP evolved into CML-Adv (CML-CP or CMP-BP) at a median time of 18 mo (range 15-41). Among the CML-BP, 2 patients had a lymphoblastic crisis. The median ages for CML-CP, BP and AP were 57, 45, and 57 years, respectively. High-risk cytogenetics (i.e., + 8, i(17q), second Ph, +19, and complex karyotype) were seen in 1%, 33%, and 10% of CP, BP, and CML-AP groups, respectively. The average BM blast at diagnosis was 1%, 44.5%, and 12.5% in the CP, BP, and CML-AP groups, respectively. Allogeneic transplant was administered in 29 (8.4%), 2 (33%), and 3 (30%) of CML-CP, CML-BP, and CML-AP, respectively. Imatinib was given as the first line in 177 (51%), 1 (17%), and 3 (30%) of CML-CP, CML-BP, and CML-AP, respectively. In the CML-myeloid BP, 2 patients were treated with induction 7+3+TKI and the 2 patients with CML-lymphoblastic BP were treated with modified CALGB 19802+ TKI. The median follow-up time for the study groups was 85.22 mo (range: 0.2 - 205.9). The 2-year (yr) (95% CI) OS probability was 93% (90-96), 50% (22-100), and 90% (73-100) in CML-CP, BP, and AP, respectively (long rank P=0.015). On the multivariable Cox proportional hazards model, CML-BP was associated with higher mortality compared to CML-CP (reference) (HR: 9.68, 95%CI: 3.30, 28.4) (P&lt;0.01). In contrast, CML-AP showed no difference in OS compared to CML-CP (HR: 1.11, 95%CI: 0.76-1.81). In the CML-CP patients who evolved into CML-Adv, the 2-yr OS was 46% (95%CI 26-83) since evolution. The 12-mo intention-to-treat response rate was 13%, 0% and 10% in the CML-CP, CML-BP, and CML-AP, respectively.
When comparing CML-CP with CML-Adv (AP+BP), the 2-yr OS (95% CI) probability was 93% (90-96) and 73% (54-100) (long rank P=0.2). In subgroup analysis, the 2-yr OS (95% CI) probability among accelerated/blast type were 67%, 75%, and 73% in patients treated with imatinib, dasatinib+ nilotinib+ bosutinib, and others, respectively (P=0.9).
Conclusion: In our long-term follow-up study, we found the incidence of CML-BP and CML-AP at diagnosis and as evolution are rare. Our study showed that patients with CML-BP exhibit significantly worse OS. Patients with de-novo CML-AP had similar long-term OS compared to CML-CP, however our sample size is limited. Furthermore, patients who transform to blast/accelerated phase CML from the CML-CP demonstrated even lower OS compared to those diagnosed with blast or accelerated phase CML at baseline (i.e., de novo).