A Predictive Score for Outcomes of Tyrosine Kinase-Inhibitor Therapy in Persons with Chronic Myeloid Leukaemia Presenting in Accelerated Phase
Authors: Yang Sen , Zhang Xiaoshuai , Huang Xiaojun , Gale Robert Peter , Jiang Qian 
Published: November 2021

Abstract
Background Chronic myeloid leukaemia (CML) presenting in accelerated phase (AP) is uncommon and there are few data on predictive co-variates for outcomes of tyrosine kinase-inhibitor (TKI)-therapy. Moreover, it is unknown which outcomes of TKI-therapy in these persons correlate with European LeukemiaNet (ELN) definitions of warning and failure which were developed in people in chronic phase or whether imatinib and 2 nd generation tyrosine kinase-inhibitors (TKIs) are equally effective.
Objective Identify co-variates correlated with outcomes of TKI-therapy in persons with CML presenting in AP diagnosed by MD Anderson or World Health Organization (WHO) criteria and develop a predictive score. Determine which outcomes correlate with ELN criteria of warning and failure. Compare outcomes of initial therapy with imatinib versus 2 nd-generation TKIs.
Methods We interrogated data from 312 and 334 consecutive subjects with CML presenting in AP and receiving imatinib or a 2 nd-generation TKI as initial therapy. Diagnosis of AP was based on widely-accepted MD Anderson or WHO criteria. Demographic, clinical and laboratory co-variates significantly correlated with outcomes were analyzed in a Cox multi-variable regression model. Propensity score matching was done to compare outcomes of initial therapy with imatinib versus a 2 nd generation TKIs.
Results In the cohort defined by MD Anderson criteria there were 197 males (63%) with a median age of 41 years (Interquartile Range [IQR], 30 - 54 years). 106 subjects (34%) had ≥ 1 co-morbidities. Median haemoglobin concentration was 99 g/L (range, 40-176 g/L), WBC concentration, 138 x 10E+9/L (range, 3-797 x10E+9/L), platelet concentration, 450 x 10E+9/L (range, 11-4094 x10E+9/L) and percentage blood or bone marrow blasts (whichever was higher), 4% (range, 0-27%). Non-mutually exclusive criteria for classifying subjects as AP included: (1) 15-29% blasts (n = 22, 7%); (2) blood basophils ≥ 20% (n = 184, 59%); (3) platelets &lt; 100 × 10E+9/L unrelated to therapy (n = 31, 10%); (4) clonal evolution (n = 45, 15%); (5) ≥ 2 features (n = 30, 10%). Co-variates associated with failure-free survival (FFS) were haemoglobin concentration &lt; 100 g/L (HR = 1.9; 95% Confidence Interval [CI], 1.1, 3.1; p = 0.014) and blasts &gt; 4.5% (HR = 1.8 [1.1 - 2.9]; p = 0.013). Co-variates associated with progression-free survival (PFS) were platelets &lt; 230 × 10E+9/L (HR = 3.3 [1.7, 6.5]; p &lt; 0.001), blasts &gt; 4.5% (HR = 2.4 [1.3, 4.6]; p = 0.007) and ≥ 1 co-morbidities (HR = 2.4 [1.2, 4.7]; p = 0.010). Co-variates associated with survival were haemoglobin concentration &lt; 100 g/L (HR = 3.3 [1.1, 10.2]; p = 0.04), platelets &lt; 230 × 10E+9/L (HR = 11.4 [3.9, 33.3]; p &lt; 0.001) and ≥ 1 co-morbidities (HR = 6.7 [2.3, 19.5]; p &lt; 0.001). Next, we divided subjects into 4 cohorts: (1) low-risk (no adverse co-variate; n = 49); (2) intermediate-1 risk (1 adverse co-variate; n = 116); (3) intermediate-2 risk (2 adverse co-variates; n = 92); and (4) high-risk (≥ 3 adverse co-variates; n = 47) with significant different probabilities of FFS, PFS and survival (all p-values &lt; 0.001). Using the 2020 ELN criteria for w arning at 3 months was significantly-associated with worse FFS (HR = 3.1 [1.7, 5.7]; p &lt; 0.001). Failure at 3 months was significantly associated with worse PFS (HR = 9.3 [4.3, 18.8]; p &lt; 0.001) and survival (HR = 6.2 [2.0, 19.2]; p = 0.002). In propensity score matching analyses subjects receiving initial therapy with imatinib had lower probabilities of complete cytogenetic response (CCyR; HR = 1.3 [1.0, 1.8]; p = 0.079), major molecular response (MMR; HR = 1.2 [0.8, 1.7; p = 0.386) and molecular response 4.5 (.5; HR = 1.8 [1.1, 3.1]; p = 0.019). However, other endpoints including FFS, PFS and survival were similar for both interventions. Similar results in the subjects diagnosed as AP using the WHO criteria.
Conclusions We identify co-variates associated with several outcomes of TKI-therapy in persons presenting in AP CML and used these to develop a prognostic score. We show the 2020 ELN criteria for warning and failure to TKI-therapy developed in persons in chronic phase also operate in subjects diagnosed in AP. Lastly, using propensity score matching we show that whilst some landmarks are achieved more rapidly in persons initially treated with a 2 nd generation TKI, FFS, PFS and survival are similar to those in persons initially treated with imatinib. Our data should help inform physicians treating person with CML presenting in AP.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.