Outcomes of Adolescents and Young Adult Patients with Chronic Myeloid Leukemia in the Era of Second-Generation TKIs and Treatment-Free Remission

Background: While chronic myeloid leukemia (CML) is most often diagnosed in older adults, it is frequently diagnosed in adolescents and young adults (AYA). Defined by the NCI as individuals between the ages of 15-39 years old, AYA CML patients have been understudied by comparison to their older counterparts, with little known about their outcomes in the United States (US) in the era of second-generation tyrosine kinase inhibitors (TKIs) and treatment-free remission (TFR). We sought to determine the clinical outcomes of AYA patients with CML at our institution, a CML specialty center.

Methods: We performed a single-center, retrospective cohort study of patients with CML who were diagnosed between the ages of 15-39 years old and seen in our adult hematology clinic between January 2012 and December 2022. Patients were identified by ICD-9 and ICD-10 codes from the electronic medical record and chart review. Descriptive statistics were used to summarize the data. Outcomes evaluating second-generation TKIs (2G-TKIs) started with patients diagnosed in June 2010. Outcomes evaluating molecular response included BCR-ABL1 PCR testing conducted after implementation of the International Scale (IS) in 2012. Molecular treatment milestones were defined per the 2023 NCCN guidelines for CML.

Results: Of 396 CML patients evaluated at our institution, 136 (34.3%) were diagnosed as AYA at a median age of 31 years (range 15-39). The majority were male (62.5%; n=85/136) and English speaking (94.1%; n=128/136). The most frequently cited race/ethnicities were Caucasian (40.4%; n=55/136), Asian (20.6%; n=28/136), and Hispanic (19.1%; n=26/136). At time of diagnosis, 91.2% (n=124/136) were in chronic phase (CP), followed by 4.4% (n=6/136) in accelerated phase (AP) and 4.4% (n=6/136) in blast phase (BP). Of those diagnosed in advanced phase, 91.7% (n=11/12) were male and 66.7% (n=8/12) were Asian or Hispanic. Of CP patients evaluated, 75.8% (n=94/124) started treatment in the 2G-TKI era. Most CP patients were first prescribed dasatinib (61.7%; n=58/94), followed by imatinib (28.7%; n=27/94), and nilotinib (8.5%; n=8/94).

Of 62 patients in CP with available molecular data after 2012, 64.5% (n=40/62) met a transcript level <10% at 3-months and 80.6% (n=50/62) met a transcript level <1% at 12-months. Major molecular response (MMR) was achieved and maintained in 59.7% (n=37/62) of these patients, with 25.8% (n=16/62) losing MMR and 14.5% (n=9/62) never achieving MMR. Reasons for loss of MMR included TFR attempts (31.3%; n=5/16), non-adherence from side effects (25%; n=4/16), lack of health insurance/inability to afford medication (18.8%; n=3/16), lack of response (18.8%; n=3/16), and pregnancy attempts (6.3%; n=1/16). Fertility was a notable issue for AYA patients, with 16 females (31.4%; n=16/51) and 18 patients overall (13.2%; n=18/136) interrupting or delaying start of TKI because of pregnancy/fertility. For patients who attempted TFR, 48.1% (n=13/27) remained off TKI in MMR at time of last follow-up.

Of 130 AYA patients with CP or AP CML at diagnosis, 7.7% (n=10/130) experienced disease transformation, including 3.2% (n=3/94) of CP patients in the 2G-TKI era. Of 14 patients who presented or transformed into BP, 42.8% (n=6/14) underwent allogeneic stem cell transplantation and 64.3% (n=9/14) died. Of the entire cohort, 9.56% (n=13/136) patients died at a median age of 35 years old, including 5.4% who presented in CP (n=7/124) and 50% (n=6/12) of those who presented in AP/BP. Of the 13 who died, 11 (84.6%) died from CML-related complications.

Conclusions: This represents the largest analysis of NCI-defined AYA CML patients in the US in the 2G-TKI era. Molecular response, progression and successful TFR rates in AYA CP CML patients appear to approximate those reported in prior large clinical trials that compared 2G-TKIs with imatinib. AYA patients can experience unique challenges that impact their management, including pregnancy/fertility and adherence, which can affect clinical outcomes. Patients may also present with aggressive advanced phase disease leading to mortality despite transplantation. Further study is warranted to better support the needs of this patient population. Evaluation of CML patients ≥ 40 years old at diagnosis at our institution is ongoing. A formal comparison between these groups will be presented.