PF409 DURABILITY AND IMPACT ON QUALITY OF LIFE OF TREATMENT‐FREE REMISSION (TFR) IN PATIENTS WITH CHRONIC MYELOID LEUKEMIA (CML) AFTER STOPPING FRONTLINE (1L) NILOTINIB: ENESTFREEDOM 192‐WK RESULTS
Authors: Ross D.M. , Masszi T. , Gómez Casares M.T. , Hellmann A. , Stentoft J. , Conneally E. , García Gutierrez V. , Gattermann N. , Le Coutre P.D. , Martino B. , Saussele S. , Giles F.J. , Radich J.P. , Saglio G. , Sondhi M. , Acharyya S. , Aimone P. , Hochhaus A. 
Published: June 2019

Background:

ENESTfreedom (NCT01784068) is a single‐arm, open‐label, phase 2 study evaluating TFR in patients with CML in chronic phase who achieved a sustained deep molecular response (DMR) with 1L nilotinib. In the primary analysis, 51.6% of patients remained in TFR 48 wks after stopping nilotinib. Analyses at 144 wks showed durability of TFR.

Aims:

To assess longer‐term maintenance and safety of TFR after 192 wks of follow‐up.

Methods:

Eligible patients had been treated with ≥2 y of 1L nilotinib and achieved MR4.5 (BCR‐ABL1
IS ≤0.0032%). After 1 y of consolidation treatment, patients with sustained DMR could attempt TFR. Nilotinib was resumed upon loss of major molecular response (MMR; BCR‐ABL1
IS ≤0.1%). As of 17 Sep 2018 (data cut‐off), all patients had either completed ≥192 wks of TFR, resumed nilotinib, or discontinued the study.

Results:

Of 190 patients who had entered TFR, 87 remained in TFR, 91 had resumed nilotinib and 12 had discontinued the study by the data cut‐off. At 192 wks, the TFR rate was 44.2% (84/190, 95% CI: 37.0–51.6%). Of patients in TFR at 144 wks, 5/89 were not evaluable for TFR at 192 wks as 2 had discontinued by 192 wks due to patient/physician decision, and 3 who were previously in MR4.5 did not have 192‐wk PCR data. A total of 90/91 (98.9%) and 84/91 (92.3%) patients who resumed nilotinib regained MMR and MR4.5, respectively. At 48 wks after regaining MMR or MR4.5, 75/90 and 73/84 patients, respectively, had stable responses. There were no disease progressions or deaths due to CML. A total of 10 deaths were reported in the 144‐wk analysis, with no new deaths reported subsequently. The treatment‐free survival rate at 192 wks was 48.7% (95% CI 41.4–55.6%; Figure). Rates of all‐grade AEs were 84.3% during consolidation and 77.5%, 70.8%, 48.3% and 52.8% during each subsequent 48‐wk period of TFR, respectively, among the 89 patients who remained in TFR for >144 wks (including 87 patients for >192 wks). Rates of musculoskeletal pain AEs (all‐grade) were 15.7% during consolidation, then increased during the first 48 wks of TFR (40.4%) and subsequently decreased during TFR to below levels seen during consolidation (9.0%, 3.4% and 3.4%, respectively). Rates of cardiovascular events were low across all periods (3.4%, 2.2%, 1.1%, 2.2% and 0%). Among the 91 patients who resumed nilotinib, the most common AEs were nasopharyngitis (18.7%) as well as pruritus, fatigue and increased lipase (14.3% each); the majority of AEs were grade 1/2. To further explore AEs that may affect quality of life, incidences of AEs grouped by category (rate >10% on treatment) were analyzed during consolidation and the 1st, 2nd, 3rd, and 4th 48‐wk periods of TFR, respectively: gastrointestinal disorders, 29.2%, 28.1%, 16.9%, 6.7% and 3.4%; infections and infestations, 39.3%, 34.8%, 24.7%, 19.1% and 20.2%; musculoskeletal and connective tissue disorders: 27.0%, 50.6%, 22.5%, 7.9% and 10.1%; and general disorders and administration site conditions (eg, asthenia, pyrexia): 14.6%, 11.2%, 10.1%, 6.7% and 4.5%. In these AE categories, similar trends toward decreasing incidences during TFR compared with consolidation were observed.

Summary/Conclusion:

These results demonstrate the long‐term durability and safety of TFR following 1L nilotinib. There were no disease progressions or CML‐related deaths, and musculoskeletal pain AEs were transient. AEs that may adversely affect patients’ quality of life tended to decrease in frequency during TFR vs during consolidation. Patients should continue to be regularly monitored during TFR.

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