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47 Feasibility of Treatment Discontinuation in Chronic Myeloid Leukemia in Clinical Practice in Spain: Results from a Nationwide Series of 236 Patients

Program: Oral and Poster Abstracts
Type: Oral
Session: 632. Chronic Myeloid Leukemia: Therapy: Epidemiology, Prognosis, and Real Life Care
Hematology Disease Topics & Pathways:
Diseases, CML, Myeloid Malignancies
Saturday, December 1, 2018: 8:30 AM
Seaport Ballroom A (Manchester Grand Hyatt San Diego)

Juan Carlos Hernandez Boluda, MD, PhD1*, Arturo Pereira, MD, PhD2*, Irene Pastor-Galán, Medical Doctor3*, Alberto Alvarez-Larrán, MD, PhD4*, Alisa Savchuk5*, Jose Manuel Puerta6*, Jose M. Sanchez7,8*, Rosa Collado9*, Álvaro Díaz10*, Anna Angona, MD, PhD11*, Miguel Sagüés12*, Valentín García Gutiérrez, PhD13,14, Concepcion Boque, MD. PhD15*, Ignacio Gómez-Centurión, MD16*, Rolando Vallansot, MD17*, Luis Palomera, MD, PhD18*, Arantxa Mendizábal19*, Luis Felipe Casado, MD20*, Manuel Pérez-Encinas21*, Raul Perez Lopez22*, Francisca Ferrer Marin23*, Fermin Sanchez-Guijo, MD, PhD24*, Carmen Garcia-Hernandez, MD25*, Natalia de las Heras26*, Jose Luiz Lopez Lorenzo, MD27*, Francisco Cervantes, MD, PhD28 and Juan Luis Steegmann, MD, PhD29

1Hematology Department, Hospital Clínico Universitario, Valencia, Spain
2Hemotherapy and Hemostasis Department, Hospital Clínic, Barcelona, Spain
3Hematology, Hospital Clinico Universitario, Valencia, Spain
4Hematology, Hospital Clínic, Barcelona, Spain
5Hematology, Hospital Universitario La Princesa, Madrid, Spain
6Hospital Universitario Virgen de las Nieves, Granada, Spain
7Hematology, Hospital 12 de Octubre, Madrid, Spain
8Hospital Universitario 12 de Octubre, Madrid, Spain
9Hospital General Universitario, Valencia, Spain
10Hematology, Hospital La Fe, Valencia, Spain
11Hospital del Mar, Barcelona, Spain
12Hospital Dr Josep Trueta, Gerona, Spain
13Hematology, Hospital Universitario Ramón y Cajal, Madrid, Spain
14Servicio Hematologia y Hemoterapia, Hospital Universitario Ramon y Cajal, Madrid, Spain
15Institut Catala d'Oncologia, Hospitalet de Llobregat, Spain
16Hospital General Universitario Gregorio Marañón, Madrid, Spain
17Servei d´Hematologia, ICO-Tarragona, Hospital Universitari Joan XXIII, TARRAGONA, Spain
18Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain
19Hospital Universitario de Alava, Vitoria, Spain
20Hospital Virgen de la Salud, Toledo, Spain
21Haematology Department, Hospital Clínico, Sanatiago De Compostela, Spain
22Servicio de Hematología, Hospital Universitario Clínico Virgen de la Arrixaca, MURCIA, Spain
23Hematology and Medical Oncology Department, Hospital Morales Meseguer, IMIB, Murcia, Spain, Murcia, Spain
24Hematology Department, Hospital Clínico Universitario de Salamanca (CAUSA/IBSAL), Salamanca, Spain
25Hospital General de Alicante, Alicante, Spain
26Complejo Asistencial Universitario de León, León, Spain
27Fundación Jiménez Díaz, Madrid, Spain
28Hematology, Hospital Clinic, Barcelona, Spain
29Hospital Universitario de la Princesa, Madrid, ESP

Introduction: Over half of patients with chronic myeloid leukemia (CML) in sustained deep molecular remission do not lose the major molecular response (MMR) after stopping treatment with tyrosine kinase inhibitors (TKI). This strategy is safe in controlled clinical trials, but there is scarce information on its applicability in the real-life setting. We aimed to assess if treatment cessation was feasible in clinical practice in a large nationwide series of CML patients from Spain.
Methods: This retrospective study comprised a series of 236 patients in chronic-phase CML who discontinued TKI treatment outside of clinical trials between April 2009 and February 2018 in 33 Spanish institutions. Inclusion criteria were: a) TKI treatment duration >3 years; b) sustained MR4.5 in >4 consecutive determinations (one single point in MR4 was acceptable) during >2 years; c) molecular monitoring in a reference laboratory expressing the results on the International Scale (IS). Patients who had undergone allogeneic hematopoietic stem-cell transplantation were excluded. Molecular relapse was defined as consecutively detectable BCR-ABL1 transcripts showing a ≥1 log increase or loss of MMR in any single sample. Treatment-free remission (TFR) was estimated by the method of Kaplan-Meier and defined as the time from TKI discontinuation to the date of restarting therapy for any reason or, if treatment was not restarted, the date of last contact. Incidence of molecular relapse was calculated using the cumulative incidence function with resumption of TKI treatment in the absence of molecular relapse and death in MMR as competing events. Analysis of factors predicting molecular relapse was done by the method of Fine and Gray.
Results: Table 1 shows the main characteristics of the series. Median follow-up from treatment discontinuation was 21.5 months, and 5 patients died in MMR due to CML unrelated causes. TKI therapy was reinitiated due to molecular relapse (MMR loss: n=52, increase >1 log in BCR-ABL transcript level at two consecutive assessments without losing MMR: n=12), patient preference (n=2), and severe withdrawal syndrome (n=1). One additional patient lost MMR after 20 months from treatment cessation but decided not to be retreated, with spontaneous recovery of MMR. The probability of TFR at 4 years was 64% (95% Confidence Interval [CI]: 55%-72%)(Figure 1). The cumulative incidence of molecular recurrence was 33% (95% CI: 26%-38%) at 3 years (Figure 2). Forty-nine relapses (75% of total) occurred in the first 6 months. The latest MMR loss was detected 30 months after treatment stop. One patient restarted treatment 44 months after TKI discontinuation due to ≥1 log increase in BCR-ABL1 transcripts in two consecutive samples without losing MMR. In univariate analysis, duration of TKI treatment of less than 5 years (P=0.005) and time in RM4.5 shorter than 4 years before TKI discontinuation (P=0.003) were both significantly associated with a higher incidence of molecular recurrence.
No patient progressed to the advanced phases of CML. At the time of restarting treatment, the median BCR-ABL1 IS was 0.3%, with this value being >5% in only 7 instances. Most patients (81%) received the same TKI that they were taking before the trial of treatment cessation. Median follow-up after treatment resumption was 20 months. Among the 64 patients who restarted treatment due to molecular relapse, 46 of 52 cases regained MMR after a median time of 3 months, and 47 of 64 regained MR4.5 after a median time of 5 months. Response status at last control was: MR4.5 (n=196), MR4 (n=15), MMR (n=14), complete cytogenetic response (n=10), and other (n=1).
Fifty-one patients (22%) developed musculoskeletal or joint pain after treatment cessation. In patients stopping imatinib, a significant increase in Hb levels, leukocyte counts, total lymphocyte counts, platelet counts, and cholesterol levels was observed. At 6 months, an increase in Hb level >2 g/dL was observed in 47% of patients with anemia. By contrast, nilotinib discontinuation was not followed by any relevant change in laboratory values.
Conclusions: Our results confirm that treatment discontinuation is feasible and safe in clinical practice in Spain. Duration of TKI treatment of less than 5 years and a time in RM4.5 shorter than 4 years before TKI discontinuation were significantly associated with a higher incidence of molecular recurrence.

Disclosures: Hernandez Boluda: Incyte: Consultancy; Novartis: Consultancy. García Gutiérrez: Incyte: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Ferrer Marin: Incyte: Consultancy; Novartis: Consultancy, Research Funding. Cervantes: Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Hospital Clinic Barcelona: Employment.

*signifies non-member of ASH