BCR::ABL1 transcript Type Does Not Impact Allogeneic Stem Cell Transplant Outcome in Chronic Myeloid Leukaemia
Authors: Staikdou Isidora , Claudiani Simone , Fernando Fiona R , Slade David , Khan Afzal , Hayden Chloe , Olavarria Eduardo , Pavlu Jiri , Palani Renuka , Milojkovic Dragana , Apperley Jane , Innes Andrew J 
Published: December 2024

Introduction
Chronic myeloid leukaemia (CML) is caused by the reciprocal translocation t(9;22), resulting in the BCR::ABL1 fusion protein. Depending on the breakpoints, there are multiple potential fusions, but more than 95% result in either e13a2, e14a2 or a combination of both. Studies have shown that the BCR::ABL1 transcript type impacts on disease characteristics and response to tyrosine kinase inhibitors, as well as the probability of remaining in treatment-free remission upon treatment cessation in eligible patients. However the impact of transcript type on outcome of stem cell transplantation (SCT) is unknown. This study retrospectively examines SCT outcomes in chronic phase CML patients from a single institution, focusing on the impact of different BCR::ABL1 transcript types on key post-transplant outcomes.
Methods
Chronic phase CML patients treated with SCT between 1994-2023 were included. Patients' BCR::ABL1transcript type was determined by reverse transcription polymerase chain reaction (RT-PCR), and BCR::ABL1-ABL1 ratio monitored with quantitative PCR (Q-PCR) throughout treatment. Molecular relapse was defined as a rising BCR-ABL/ABL ratio greater than 0.02% on three occasions or greater than 0.05% on two occasions, a minimum four weeks apart. The study's primary endpoints were relapse and transplant related mortality (TRM). Statistical analysis included Kaplan-Meier analysis for cumulative incidence of relapse rate and TRM, with differences assessed by log-rank test. A Cox proportional hazards regression model was used for multivariate analysis to identify independent prognostic factors affecting relapse and TRM, adjusting for variables including European Group for Blood and Marrow Transplantation score variables including age, donor type, donor-recipient sex match and time to transplant, as well as transplant conditioning, T-cell depletion, and TKI therapy prior to transplant.
Results
A total of 314 patients were identified of which 247 patients had known transcripts (e13a2 = 81, e14a2 = 140, e13a2/e14a2 = 23 other = 3, unknown=67). Of those with a known transcript (n=247), transplant condition was myeloablative in 208 (84%), and 129 (52%) received T-cell depletion. Donors were fully matched siblings in 115 (47%), with a female donor in a male recipient in 43 (17%). Fifty-four (22%) patients had received TKI pre-transplant, and transplant was performed within 12 months of diagnosis in 125 (51%). Transplant characteristics were balanced across transcript-types.
The 5-year probability of relapse for the known-transcript cohort was 65% with a median time to relapse of 17 months and no differences between the groups (e13a2, 68%, e14a2, 62%, e13a2/e14a2, 70%, other, 67%, p=0.426). The majority of relapsing patients received DLI following a standard institutional escalating dose schedule. The median number of DLI was 2, and did not differ between the groups. The 1-year TRM was low at 8%, and not significantly different between the groups (log rank p = 0.770), as were the rates of grade 2-4 acute graft versus host disease (GvHD), and extensive chronic GvHD. The 5-year overall survival (OS) was 76% and not different between the groups (log rank p = 0.171). The most common causes of death included GvHD (n=15, 6%), sepsis (n=12, 5%), relapse (n=7, 3%) and pneumonitis (n=5, 2%)
While there were expected differences in relapse, TRM and OS by conditioning intensity, donor type, donor-recipient sex match, and time to transplant, Cox regression analysis confirmed no significant differences in relapse (HR: 0.897, 95% CI: 0.630-1.278, p = 0.548), TRM (HR: 1.308, 95% CI: 0.653-2.619, p = 0.448) or OS (HR: 1.112, 95% CI 0.658- 1.879, p = 0.693) between e13a2 and e14a2 transcript groups. Equally, there were no differences for those with combined e13a2/e14a2 or rare transcripts.
Conclusion
This review of SCT outcomes in CML patients over nearly 30 years reveals no significant differences in relapse, TRM or OS between different BCR-ABL1 transcript types, suggesting that these variants are not key determinants of post-transplant prognosis.