Effectiveness of Second-Line (2L) Tyrosine Kinase Inhibitor (TKI) Therapy after Resistance or Intolerance to a Prior TKI in Patients with Philadelphia Chromosome-Positive Chronic Myeloid Leukemia in Chronic Phase (Ph+ CML-CP)
Authors: Mukherjee Sudipto , Cao Xiting , Sadek Islam , Maegawa Rodrigo , Latremouille-Viau Dominick , Pivneva Irina , Guérin Annie , Smith B. Douglas 
Published: February 2021

Introduction: Second-generation (2G) TKIs have shown better efficacy than first-generation (1G) TKI in patients (pts) with Ph+ CML-CP. However, real-world evidence for 2G TKIs as 2L therapy following resistance or intolerance to prior therapy is limited. BCR-ABL1 mutations have different sensitivities to TKIs, highlighting the need to consider the mutational status of pts when selecting the next best TKI in pts who are resistant to prior CML therapy. This study reports real-world treatment effectiveness of 2G TKIs as 2L therapy in the US among pts with Ph+ CML-CP following resistance, intolerance, or other reasons for termination of 1L TKI.
Methods: From 6/21/2019-8/30/2019, data were retrospectively collected from pt clinical charts via an online case report form completed by US oncologists/hematologists from an existing panel of physicians. Eligible charts were those of adult pts diagnosed with Ph+ CML-CP who were initiated on a 2G TKI (dasatinib, nilotinib, or bosutinib) as 2L therapy between 01/2013-06/2017 outside of a clinical trial. Molecular response (MR; MR2 = BCR-ABL ≤ 1%/2-log reduction, MMR/MR3 = BCR-ABL ≤ 0.1%/3-log reduction, MR4 = BCR-ABL ≤ 0.01%/4-log reduction) achieved during the course of 2L therapy was assessed using Kaplan-Meier (KM) analyses and reported for the overall cohort and for the following subgroups: (1) 1G TKI as 1L therapy, (2) 2G TKI as 1L therapy, (3) treatment with a 2L TKI that is not recommended based on the mutation profile (per National Comprehensive Cancer Network [NCCN] practice guidelines), (4) 1L TKI termination due to intolerance/management of adverse events (AEs), and (5) 1L TKI termination due to resistance/lack of efficacy.
Results: A total of 111 physicians (academic-based practices: 45%; community: 55%) abstracted data for 539 pts. Approximately half of physicians had access to qPCR test with a sensitivity of detection of at least MR4.5 (53%); 27% had access to a level of detection of MR4 and 20% of MR3.
For the overall cohort, the mean age was 56 years and 56% were male. At the time of diagnosis, 60% of pts had an intermediate and 10% had a high Sokal risk score. A total of 61% of pts were treated with 1G TKI and 39% were treated with 2G TKI in 1L therapy; pts treated with dasatinib in 1L were observed to be older with a higher comorbidity burden than those using 1G TKI. The most common reasons for terminating 1L TKI therapy were lack of efficacy (46%), resistance (28%), intolerance/management of AEs (22%), and pt preference (15%; not mutually exclusive). At 2L TKI therapy initiation, 15% of pts did not undergo a mutation test, 34% had no mutations, and the most prevalent BCR-ABL1 mutation was T315I (16%); 26% received a TKI as 2L therapy that was not recommended based on their mutation profile.
In 2L TKI therapy, 41% of pts received nilotinib, 19% dasatinib, and 40% bosutinib; median 2L TKI duration was 37 months. KM response rates on 2L TKI for MR2 at 12 months, MR3 at 12 months and MR4 at 24 months (time points influencing treatment decision in clinical practice based on NCCN and European LeukemiaNet [ELN] guideline recommendations) were 71%, 55%, and 46%, respectively. The lowest MR rates at these key time points were observed in the subgroup of pts for whom the TKI is not recommended based on the mutation profile (rates of MR2 at 12 months of 59%, MR3 at 12 months of 40%, and MR4 at 24 months of 22%) and those with 1L TKI termination due to resistance/lack of efficacy (rate of MR4 at 24 months of 43%; stratifications by subgroup are shown in Figures 1A-C).
Conclusions: This study highlights the treatment challenges for 2L TKI therapy in Ph+ CML-CP and provides insights into the opportunities to refine 2L treatment options to improve outcomes for many pts. Although 2G TKIs have higher efficacy and lower progression rates in 1L vs 1G TKI, a substantial proportion of pts still do not achieve the important treatment response milestones; almost 50% did not achieve MMR within 12 months of 2L TKI therapy. This study also suggests that TKI switching from 1L to 2L uninformed by mutational testing adversely impacts treatment response. There appears to be a need for more effective communication to highlight the relevance and timing of mutation testing, access to adequate sensitive tools mandated by practice guidelines (e.g., NCCN, ELN) to monitor MR, and new effective treatment options for pts with CML-CP resistant or intolerant to prior therapy, particularly among pts presenting with mutations.

Disclosures
Mukherjee: EUSA Pharma: Consultancy; Aplastic Anemia and MDS International Foundation: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squib: Honoraria; Celgene/Acceleron: Membership on an entity's Board of Directors or advisory committees; Partnership for Health Analytic Research, LLC (PHAR, LLC): Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cao:Novartis: Current Employment, Current equity holder in publicly-traded company. Sadek:Novartis: Current Employment, Current equity holder in publicly-traded company. Maegawa:Novartis Pharmaceutical Corporation: Current Employment, Current equity holder in publicly-traded company. Latremouille-Viau:Novartis Pharmaceutical Corporation: Consultancy, Other: Dominique Latremouille-Viau is an employee of Analysis Group, Inc. which received consultancy fees from Novartis.; Sanofi Genzyme: Consultancy, Other: Dominique Latremouille-Viau is an employee of Analysis Group, Inc. which received consultancy fees from Sanofi Genzyme.. Pivneva:Novartis: Consultancy, Other: Irina Pivneva is an employee of Analysis Group, Inc which received consultancy fees from Novartis.. Guérin:Novartis: Consultancy, Other: Annie Guérin is an employee of Analysis Group, Inc which received consultancy fees from Novartis.. Smith:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.