Tyrosine Kinase Inhibitor (TKI) Response in Patients with Chronic Myelogenous Leukemia (CML) and BCR-ABL 35 Base Pair Intron 8 Insertion (35INS)
Authors: Portillo Roxana A , Lee Michelle Hyunju , Tsai Harrison K. , DeAngelo Daniel J , Fathi Amir T. , Narayan Rupa , Luskin Marlise R , Hobbs Gabriela S. 
Published: December 2024

Introduction: In patients with chronic myeloid leukemia (CML), the BCR::ABL1 35 base pair intron 8 insertion (35INS) has been associated with tyrosine kinase inhibitor (TKI) resistance, particularly with imatinib. However, case series with second generation TKIs have shown mixed results. Lab based analyses (O'Hare et al., Blood 2011) indicate that this insertion does not play a role in clinical resistance and the clinical impact has not been clearly defined. Our goal was to determine the impact of the BCR::ABL1 35INS TKI treatment response for CML patients treated at our institutions.

Methods: We conducted a retrospective chart review on CML patients treated at Massachusetts General Hospital (MGH) and Dana-Farber Cancer Institute between 2012 and 2024 with a BCR::ABL1 35INS found at any time of treatment.

Results: We identified 11 patients. 3 were female, median age was 65 (42-91). 10 were diagnosed with chronic phase CML, and one with blast phase. One patient had the BCR::ABL1 35INS identified at diagnosis. The median time to BCR-ABL1 35INS identification was 1.87 years. 4 patients had extended NGS as part of their testing (n=3 at diagnosis, n=1 subsequently) and 2 were found to have the ASXL1 mutation. No other mutations were identified.

The median lines of therapy were 3 (1-4), including two patients treated with the same agent twice for intolerance. 7 patients received imatinib as 1st line therapy (64%), 4 received dasatinib (46%). Of the 11 patients, 7 (64%) switched from 1st line treatment. 5 switched from imatinib to dasatinib due to intolerance (n=2), resistance (n=2) or progression from chronic phase CML to accelerated phase (n=1). The remaining 2 patients switched from dasatinib to imatinib due to intolerance. After 2nd line therapy, 6 patients switched to 3rd or later line due to intolerance (n=4) or resistance (n=2).

The BCR::ABL1 35INS was detected in 7 patients when switching to the 2nd or 3rd line therapy. The other 4 were treated with only one line of therapy and for these the BCR::ABL1 35INS was identified as part of routine testing on treatment (n=1 at diagnosis).

Out of the 11 patients, 3 changed therapy due to resistance. 1 patient switched from imatinib to dasatinib and achieved complete molecular remission (CMR). 1 patient switched from nilotinib to asciminib and achieved CCyR. 1 patient switched from imatinib to dasatinib but did not achieve MRR, then switched to asciminib with PCR&gt;10% at last follow-up and was lost to follow-up. Two patients underwent a hematopoietic stem cell transplantation (HSCT), one due to blast crisis at diagnosis and the second due to progression to accelerated phase CML. 2 patients did not achieve CCyR, one due to intolerance to multiple TKIs and one with 1st line imatinib was lost to follow-up. For the remaining 4 patients, one switched to 3rd line therapy due to intolerance, the other three had only one line therapy; average time to CCyR was 0.86 years (0.53-1.18), to MMR was 1.83 years (0.85-2.18). All 11 patients remain alive, with an average follow-up of 4.85 years.

Discussion: We identified 11 patients with BCR::ABL1 35INS across two large medical centers over 12 years, suggesting this insertion is a rare molecular event. 2 patients were resistant to two lines of therapy and 2 required an HSCT. Over half (n=6) required a third line therapy after identification of the BCR::ABL1 35INS while receiving therapy with a 2G-TKI. Two of these patients had a concurrent ASXL1 mutation (1 underwent HSCT, the other did not respond to 1st line imatinib), confounding the attribution of resistance. The results of our series suggest that patients with the BCR::ABL1 35INS have a lower overall response rate, many of which required therapy with second and third generation TKIs to achieve a response. Additional studies are needed to further understand if there is significance to the BCR::ABL1 35INS in the management of CML patients.