-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

1507 Use of Ponatinib Alone or Combined with Other Therapies in Relapsed/Refractory Ph-like Acute Lymphoblastic Leukemia. a Campus ALL Real-Life Study

Program: Oral and Poster Abstracts
Session: 614. Acute Lymphoblastic Leukemias: Therapies, Excluding Transplantation and Cellular Immunotherapies: Poster I
Hematology Disease Topics & Pathways:
Lymphoid Leukemias, ALL, Biological therapies, Diseases, Therapies, Lymphoid Malignancies
Saturday, December 9, 2023, 5:30 PM-7:30 PM

Monia Lunghi, MD, PhD1*, Francesca Kaiser, MD2*, Deborah Cardinali, Bachelor in Science2*, Claudia Basilico, MD3*, Marzia Defina, MD4*, Sara Mastaglio, MD5*, Lazzarotto Davide, MD6*, Prassede Salutari, MD7*, Matteo Piccini, MD8*, Valeria Cardinali, MD9*, Antonio Pierini, MD, PhD10*, Nicola Fracchiolla, MD11*, Federica Di Biase, MD12*, Mario Annunziata, MD13*, Mariangela Di Trani, Bachelor in Science2*, Felicetto Ferrara, MD14*, Giovanni Pizzolo, MD15*, Robin Foà, MD2* and Sabina Chiaretti, MD, PhD16

1Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy
2Division of Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
3Divisione di Ematologia, Ospedale di Circolo di Varese e Fondazione Macchi, ASST Sette Laghi, Varese, Italy
4Hematology, Azienda Ospedaliera Universitaria Senese, Siena, Italy
5Hematology and Bone Marrow Transplant, Unit San Raffaele Scientific Institute, Milan, Italy
6Clinica Ematologica e Centro Trapianti, Azienda Sanitaria Universitaria Friuli Centrale, Udine, Italy
7Department of Hematology, Ospedale Civile Spirito Santo, Pescara, Pescara, Italy
8SOD Ematologia, Università di Firenze, AOU Careggi, Firenze, Italy
9Università Di Perugia, Periglia, ITA
10Department of Medicine and Surgery, Division of Hematology and Clinical Immunology, University of Perugia, Perugia, Italy
11Hematology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, Milano, Italy
12Department of Molecular Biotechnology and Health Sciences, Division of Hematology, University of Torino, Torino, Italy
13Azienda Ospedaliera Di Rilievo Nazionale Antonio Cardarelli, Napoli, ITA
14Divisione di Ematologia, Ospedale Cardarelli, Napoli, Italy
15Department of Medicine, Hematology section, University of Verona, Verona, ITA
16Division of Hematology, Department of Translational and Precision Medicine, Division of Hematology, Rome, Italy

Introduction. Ponatinib is a third-generation tyrosine kinase inhibitor (TKI) employed in relapsed/refractory (R/R) and, more recently, also in newly diagnosed Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Ph-like ALL is a genetically heterogenous subgroup that shares a common transcriptional profile, similar to that of true Ph+ ALL, though lacking the BCR::ABL1 rearrangement. Ph-like ALL is characterized by a poor prognosis, a high relapse rate and a worse overall survival if treated with standard chemotherapy. Several molecular pathways are involved, including JAK/STAT, CRLF2 and ABL-class mutations, providing a heterogeneous genetic landscape with very limited data on the subsequent clinical outcome. Few isolated cases of successful treatment of R/R Ph-like ALL with ponatinib have been reported, including also patients with lesions different from ABL-class mutations. Currently, ponatinib prescription in Italy is not allowed for Ph-like ALL.

Patients and Methods. Between January 2019 and July 2023, 17 patients were candidate to receive ponatinib on a nominate compassionate use basis; data were collected in the context of the Campus ALL network in Italy. The criteria for inclusion were a diagnosis of Ph-like ALL, with either hematological or molecular evidence of disease, and a treatment period of at least 28 consecutive days of ponatinib. The Ph-like signature was based on the BCR/ABL1 like-predictor (Chiaretti et al, BJH 2018) and, whenever possible, targeted RNA sequencing. Final data were collected for 15 patients (2 patients were excluded due to a treatment period <28 days) treated with ponatinib either as a single agent or in association with immuno and/or chemotherapy.

Results. All patients had common ALL. Eight of the 15 cases were classified as high risk or very high risk ALL at diagnosis; 10 were males, the median age was 28 years (14-66) and the median white blood count at diagnosis was 25.6 x109/l (2.7-317 x109/l). Targeted RNA sequencing was carried out in 10/15 cases: 7 presented gene fusions (ABL-class mutations in 2, JAK2 mutations in 2, and CRLF2::P2RY8, IKZF1::DDC and RB1::RCBTB2 in 1 case each); 2 additional cases had a CRLF2 rearrangement, evaluated by FISH. Copy number aberrations analysis by multiplex ligation-dependent probe amplification (MLPA) technology was performed in 12/15 cases: 5 cases had a IKZF1plus signature, 6 had a IZKF1 loss, while 1 case was IKZF1 wild type.

Ponatinib was started in first (n=2) or second (n=5) hematologic relapse in 7 patients (46%), with 3 also having an extramedullary disease; 7 additional patients (46%) were treated in first (n=5) or second (n=2) minimal residual disease (MRD) persistence/recurrence; finally, 1 patient was refractory to 3 subsequent lines of treatment. In 8/15 patients ponatinib was used as single agent or in association with steroids or intrathecal chemotherapy only, in 4 it was administered in combination with chemotherapy and in 3 with blinatumomab; 7 patients started ponatinib after having failed an allogeneic transplant (6 hematologic relapses and 1 molecular relapse). A complete hematological and molecular remission (MRD- CR) was achieved in 6 patients (40%); notably, 4 of these 6 cases carried a gene fusion (1 JAK2 rearrangement, 1 ABL-class fusion, 1 IKZF1::DDC and 1 RB1::RCBTB2); 2 further patients in hematologic relapse at the start of treatment achieved a MRD+ CR (1 patient had a ABL-class gene fusion). Thus, the overall response rate was 53%. Four patients were refractory, while 2 maintained a stable disease. After ponatinib-based treatment, 6 patients were allografted and 1 received a CAR-T cell infusion. The toxicity profile was mild: 3 patients developed a transaminitis, 1 also had a fungal pneumonia, and 1 an increase in pancreatic enzymes. At a median follow-up of 3 months (1-5), 10 patients are alive, 8 being in continuous complete remission.

Conclusions. Treatment with ponatinib showed promising results in terms of CR achievement in a heavily pre-treated population of Ph-like ALL patients, with an acceptable toxicity profile. In a pre-transplant setting, ponatinib was effective as a bridge to cellular therapies in 7 out of 8 patients as intention-to-treat (ITT), thus suggesting that this strategy may represent an effective bridge to further therapies. To our knowledge, this is the largest cohort of adult Ph-like ALL cases treated with ponatinib so far reported.

Disclosures: Pierini: Pfizer: Honoraria; Incyte: Honoraria. Fracchiolla: Abbvie, Jazz, Pfizer, Amgen: Speakers Bureau; Abbvie, Jazz, Pfizer, Amgen: Other: travel grants. Ferrara: ABBVIE: Honoraria. Chiaretti: Amgen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees.

*signifies non-member of ASH