Death from Blast Crisis Is Preventable: Impact of Compliance and Social Determinants of Health on the Risk of Blast Crisis in CML

Introduction: With the introduction of tyrosine kinase inhibitors (TKI) in the early 2000's most CML patients achieve hematologic remission, and many achieve a deep molecular response. Overall, the prognosis has dramatically improved, but some patients still develop blast crisis (BC) despite access to TKI. Once a patient develops BC, the prognosis is in general poor. Some studies have noted worse outcomes for BC patients who have taken TKI's in the past, (as compared with de-novo BC; Jain P et al, 2017). Adherence to TKI's is important and noted to be effective at near 100% adherence with poorer outcomes if adherence drops to just 90% (Obeng-Kusi M et al, 2021). Even though the molecular features of CML-BC are well described and TKIs are universally available we wondered what the risk factors are to develop BC. The aim of our study is to investigate how compliance, drug abuse and social determinants of health affect outcomes with a focus on mortality.

Materials and Methods: Institutional Review Board approval was obtained to perform a retrospective analysis of patients diagnosed with blast phase CML at our institution between 2014 to 2024 using CoPath, Sunrise electronic medical records (EMR) and Epic EMR. Noncompliance was operationally defined as stopping TKIs for more than three months without a valid reason or “noncompliance” listed in medical records repeatedly or not showing up to appointments for more than six months. Drug use was defined as consistent use of illicit drugs or being on opioid substitution for previous drug use. The diagnosis of BC was made when > 20% blasts were identified in blood or bone marrow. The social deprivation index was calculated according to the neighborhood atlas of the University of Wisconsin with higher scores indicating more disadvantaged groups (Kind AJH et al, NEJM, 2018). Data was analyzed using SAS v9.4 (SAS, Cary, NC, USA). The significance level for all statistical tests is α = 0.05. Fisher's Exact test was used for categorical variables and t-tests for continuous variables.

Results We identified 20 patients with CML-BC. 13 patients (65%) were male and seven (35%) were female. 16 patients were Caucasian, 2 Hispanic, 1 Black and 2 of unknown race. 12 patients developed a myeloid BC, 6 a lymphoid BC and in 2 patients the type of BC was unknown. Seven patients were deemed compliant and 13 were non-compliant. The use of illicit drugs was frequent in non-compliant patients (7/13; 53.8%) versus none in compliant patients (p< 0.001). The compliant patients were found to have a significantly higher age at diagnosis (P=0.009) and higher age at first BC (P=0.041). We found no significant difference when we stratified compliance by type of BC, index of deprivation, gender and race. 16 patients in BC were treated with a combination of chemotherapy and TKI, 2 received only TKI and 2 did not receive treatment because of poor performance status. Three patients underwent allogeneic transplantation (15%). The median survival after first BC was poor in both groups (14 months in the non-compliant versus 13 months in the compliant group; NS). After adjusting for the deprivation index, the difference in survival remains non-significant (P=0.304). One compliant patient with de-novo BC and treated only with TKI is a long-term survivor (134+ months). A preliminary analysis of compliant and non-compliant patient shows no difference in their chronic phase biologic characteristics.

Conclusions: In our single institution study, the survival of CML BC remains universally poor. Only a minority of patients could be rescued with TKIs, chemotherapy or stem cell transplant. The majority of patients with BC have a history of non-compliance. Non-compliance is associated with younger age and a history of drug abuse. In conclusion, non-compliance may be a more important risk factor than extra chromosomes or mutations of the TKI binding domain. Non-compliance may be a modifiable risk factor. We found little difference in the Index of Deprivation between the compliant and noncompliant groups and no significant effect on our primary endpoint of death, indicating that socioeconomic status may play less of a role in medication adherence than we originally hypothesized. We plan to expand our study to other academic centers in the United States who may have a different patient population and investigate how compliance can be modified.

Munker:Incyte: Current equity holder in publicly-traded company; Gilead Sciences: Current equity holder in publicly-traded company; Novartis: Research Funding; Lilly Pharmaceutical: Research Funding; Ono Pharmaceutical: Research Funding; Merck: Research Funding.