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2835 Tyrosine Kinase Inhibitor (TKI) Discontinuation in Non-Allografted Ph+ Acute Lymphoblastic Leukemia Patients, a Campus ALL Real-Life Study

Program: Oral and Poster Abstracts
Session: 612. Acute Lymphoblastic Leukemias: Clinical and Epidemiological: Poster II
Hematology Disease Topics & Pathways:
Lymphoid Leukemias, ALL, Clinical Practice (Health Services and Quality), Diseases, Lymphoid Malignancies, Minimal Residual Disease
Sunday, December 10, 2023, 6:00 PM-8:00 PM

Matteo Dragani, MD1*, Roberta Agrippino, MD2*, Giovanna Rege Cambrin, MD, PhD3*, Matteo Leoncin, MD4*, Marco Cerrano, MD5*, Prassede Salutari, MD6*, Antonino Mulè, MD7*, Cristina Papayannidis, MD8, Marzia Defina, MD9*, Giulia Rivoli, MD10*, Elisabetta Todisco, MD, PhD11*, Elisabetta Abruzzese, MD12, Michele Cedrone, MD13*, Nicola Fracchiolla, MD14*, Fabio Guolo, MD, PhD15*, Giuseppe Lanzarone, MD16*, Robin Foà, MD17* and Sabina Chiaretti, MD, PhD18

1Hematology and Cellular Therapy Division, IRCCS Ospedale Policlinico San Martino, Genova, Italy, Genova, Italy
2Hematology, Department of Translational and Precision Medicine, Sapienza University, Rome, Italy., Rome, Italy
3Division of Internal Medicine and Hematology, San Luigi Gonzaga Hospital, Orbassano, Italy
4Hematology Unit, Azienda Ulss3 Serenissima, Ospedale dell'Angelo, Venezia-Mestre, Italy
5Hematology Unit, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza, Turin, Turin, Italy
6Department of Hematology, Ospedale Civile Spirito Santo, Pescara, Pescara, Italy
7UOC di Oncoematologia,, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy
8Istituto di Ematologia "Seràgnoli", IRCCS Azienda Ospedaliero–Universitaria di Bologna, Bologna, Italy
9Hematology, Azienda Ospedaliera Universitaria Senese, Siena, Italy
10Hematology and Cellular Therapy Division, IRCCS Ospedale Policlinico San Martino, Genova, Genova, Italy
11Onco-Hematology Division, IEO, European Institute of Oncology IRCCS, Milan, Milan, Italy
12Department of Hematology, S Eugenio Hospital, Tor Vergata University, Roma, I, Italy
13UOC Ematologia, Azienza Ospedaliera San Giovanni Addolorata, Rome, Italy
14Hematology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, Milano, Italy
15Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Genoa, Italy
16Department of Molecular Biotechnology and Health Sciences, Division of Hematology, University of Turin, Turin, Italy
17Division of Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
18Division of Hematology, Department of Translational and Precision Medicine, Division of Hematology, Rome, Italy

Introduction. Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) patients are commonly treated with tyrosine kinase inhibitors (TKI) in combination with either steroids, chemotherapy and more recently also immunotherapy. In the past, allogeneic transplant (SCT) was considered the only curative option; however, with the introduction of more potent TKIs as well as immunotherapy this milestone is nowadays debated, mostly for patients who achieve a molecular response. Moreover, as in chronic myeloid leukemia (CML), it is becoming relevant to understand if patients may over time discontinue TKI treatment. For this purpose, it is pivotal to report the outcome of Ph+ ALL patients who, for any reason, stopped TKI treatment.

Patients and Methods. Forty-seven adult Ph+ ALL patients treated since 1 January 2000, and who did not undergo a SCT, were retrospectively collected from 12 Italian centers participating to the Campus ALL network. Their treatment plan included a TKI +/- chemotherapy according to the center current practice and/or according to the ongoing national trial they were enrolled in. The median age was 63 years (20-84), 20 patients (43%) were males, 30 patients harbored a p190 transcript, 15 a p210 transcript and 2 had both transcripts. Twenty-six patients were treated within a trial, while 21 were off-protocol. For 32 patients, induction was based only on a TKI plus steroids, whereas the remaining 15 received a combination of a TKI plus chemotherapy (in 3 cases high intensity protocols such as the NILG (Northern Italian Leukemia Group) and HCVAD regimens, in 12 low dose chemotherapy). The reasons not to transplant patients were: donor unavailability (5), clinical decision, mainly due to age/unfitness (30), patient’s refusal (4), and achievement of a molecular response (i.e. at least BCR-ABL/ABL ≤0.01%) (8). The median follow-up was 60 months, with a median overall survival (OS) not reached at the last follow-up and a median disease-free survival (DFS) of 12 years. At the last follow-up, 12/47 patients had experienced a relapse. At the end of the induction (i.e. after 3 months, at a median of +82 days, from treatment initiation), 27 patients had achieved a molecular response. Overall. a molecular response was obtained in 40/46 pts (data not available for 1 case) after a median of 5 month, and was associated with a significantly lower hazard of disease recurrence (HR=0.057, 95% CI: 0.006-0.51, p=0.011) after adjusting for gender, fusion protein, association with chemotherapy, CMR at 3 months.

Results. TKI treatment was discontinued in 14 of the 47 patients evaluated. The reasons for discontinuation were either toxicity (6) or clinical/patient decision (8). Eight patients harbored a p190 transcript, 5 a p210 transcript and 1 carried both. At the time of discontinuation, the median age was 75 years (23-87) and patients had been on a TKI for a median of 57.5 months (8-160) prior to stopping treatment. For these cases, the median WBC at diagnosis were 8.6 x 109/l (2.1-306 x 109/l). In 7 patients the first TKI used was imatinib, in 3 dasatinib, in 3 ponatinib and in 1 nilotinib. All patients but 1 had achieved a molecular response before stopping treatment; the only patient who never achieved a molecular response prior to discontinuing the TKI had a rapid relapse (1 month). At the last follow-up, 9 cases were still in treatment-free remission (TFR), whereas 5 eventually relapsed after 1, 1, 4, 14 and 30 months, respectively. Re-challenge with a TKI led to a hematological and molecular response in 3 of the 5 patients. The remaining 2 patients, who had been previously heavily treated and whose TFR was of only 1 month, received salvage standard chemotherapy but eventually died from ALL progression. The median time of TFR for the entire cohort of 14 patients was 20.5 months (1-82). When considering only the 9 patients who remain off treatment, the median time of TFR was 29.5 months (7-82) (Table 1, Figure 1).

Conclusions. We report the outcome of 14 Ph+ ALL patients who discontinued TKI treatment due to various reasons. Nine of them are still on TFR after more than 2 years at the last follow-up, reinforcing the concept that a TFR is feasible in selected adult Ph+ ALL patients. Of further relevance, TKI re-challenge was successful in 3/5 patients who relapsed, similarly to what observed in CML.

Disclosures: Cerrano: Insight Novartis Servier Abbvie Janssen Jazz Astellas Italfarmaco: Honoraria. Mulè: Astellas: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; ABBVIE: Honoraria. Papayannidis: Abbvie, Astellas, Servier, Menarini/Stemline, BMS, Pfizer, Amgen, Janssen, Incyte, Novartis: Honoraria; Pfizer, Astellas, Janssen, GSK, Blueprint, Jazz Pharmaceuticals, Abbvie, Novartis, Delbert Laboratoires: Membership on an entity's Board of Directors or advisory committees. Abruzzese: Takeda: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees. Fracchiolla: Abbvie, Jazz, Pfizer, Amgen: Speakers Bureau; Abbvie, Jazz, Pfizer, Amgen: Other: travel grants. Chiaretti: Gilead: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees.

*signifies non-member of ASH