Real-World Data Analysis of the Molecular Response Kinetics within the Two First Years of the RELMC-NOVA Study in Newly Diagnosed Spanish CML-CP Patients Treated with Tirosin Kinasa Inhibitors (TKIs) in First Line

Introduction: The RELMC-Nova study analyses first line treatments in patients with chronic myeloid leukemia (CML) in chronic phase (CP) in standard clinical practice in two cohorts, before (retrospective) and after (prospective) the introduction of generic imatinib in 25 hospitals throughout Spain with special emphasis on the molecular kinetics of the initial response (studied as halving time [HT] and with logarithmic reduction [log red] between 2 times).

METHODS: 311 patients were registered (171 in the retrospective cohort and 140 in the prospective cohort), all of them treated with TKIs according to standard clinical practice. Molecular Response (MR) was analyzed at 3, 6, 12, 18 and 24 months of treatment in local laboratories according to local clinical practice. HT and log red were calculated between diagnosis and molecular response at 1, 2, 3 and 6 months.

RESULTS:

Clinical characteristics at diagnosis: total (retrospective (R)/prospective(P)) were the following: Median age 56 years (55/61), Body mass index 24.2 (24.2/24.2), Male-Female 58%-42% (56%-44%/60%-40%), Sokal Index (L-I-H) 44%-43%-13% (50%-37%-13%/37%-51%-12%) and ELTS (L-I-H) 57%-33%-10% (63%-30%-7%/50%-37%-13%). First line TKI: Imatinib (GlivecÒ): 35% (65%/0%), generic Imatinib: 34% (0%/75%), 2^nd generation (2^nd G) TKIs 30.3% (35%-25%): Nilotinib 20% (22%/17%), Dasatinib 10% (13%/7%), Ponatinib 0.3% (0%/1%). In the retrospective cohort 26.3% of Low o Intermediate Sokal Index patients were treated with 2^nd GTKIs versus only 18.2% in the prospective cohort.

Overall response rate, total (R/P): See table 1. A statistically significance difference in major molecular response (MMR) between the retrospective and prospective cohorts was only seen at 3 months.

Deep molecular response (>MR4), total (R/P): See table 1. No statistically significant differences were observed between cohorts at any time point.

Overall response rate, total (Imatinib/2^nd GTKIs): See table 1. A statistically significance difference in MMR between imatinib and 2^nd GTKIs was only seen at 3 months.

Deep molecular response (>MR4), total (Imatinib/2^nd GTKIs): See table 1. No statistically significant differences were observed between cohorts at any time point.

Only 1 patient (0.32%) showed progression to accelerated phase.

Response kinetics: See table 1. Halving time at 3 and 6 months was lower in patients treated with 2^nd GTKIs, but without statistical significance.

Patients with deep molecular response at 24 months showed a lower HT being statistically significant only at 6 months.

Log red: No significant differences were found between patients treated with imatinib and 2^nd GTKIs, although results were initially higher in patients treated with 2^nd GTKIs.

Patients with a deep molecular response at 24 months showed statistically significant differences in log reduction at 3 and 6 months.

CONCLUSIONS:

1. Generic imatinib has cornered 1st line treatment increasing from 65% to 75% in the retrospective and prospective cohorts respectively, relegating 2^ndGTIKs to high-risk patients.
2. The responses obtained in the first months were higher and faster with the 2^nd GTKIs but evened out after 12 months and remained similar at 2 years.
3. Molecular response kinetics (HT or log red) can predict future response and should be assessed in patients with poor early responses.
4. A rapid decline (HR or log red) at the start of treatment guarantees a deep response at 2 years.
5. 2^nd GTKIs produce faster molecular response kinetics but final outcomes were similar to that obtained with imatinib.