Successful of Chemo-Free Treatment with Dasatinib and Blinatumomab in a Pediatric EBF1-PDGFRβ Positive Acute Lymphoblastic Leukemia
Authors: Petruzziello Fara , Giagnuolo Giovanna , Cazzaniga Giovanni , Beneduce Giuliana , Locatelli Franco , Stellato Pio , Fazio Grazia , Mirabelli Giuseppe , Menna Giuseppe , Parasole Rosanna 
Published: October 2019

Abstract
Recently, a novel subgroup of B Cell Precursor (BCP) Acute Lymphoblastic Leukemia (ALL), called Philadelphia-like (Ph-like) ALL, has been described. This high-risk group, despite the absence of BCR-ABL1 rearrangement, shows genomic abnormalities that result in aberrant expression of cytokine receptors genes or tyrosine-kinase-activating signaling. These patients are poor responder to conventional chemotherapy but potentially sensitive to Tyrosine-Kinase Inhibitors (TKIs).
Herein we report the case of a 10 year-old girl who received diagnosis of precursor B-ALL on February 2018. She started therapy according to observational protocol ALL 2017 of the Italian Association of Pediatric Hemato-Oncology (AIEOP). After pre-phase, the patient resulted prednisone poor responder and continued induction therapy, including daunorubicin, vincristine, PEG-L-Asparaginase, prednisone and intrathecal methotrexate. Bone marrow evaluation showed persistence of disease on day 15 (88% of lymphoblasts) and 33 (60% of blasts) in flow cytometry. At the end of IA induction phase, Minimal Residual Disease (MRD) in RT-PCR showed high positivity (marker 1 = 7.2x10-1, marker 2= 8.11x10-1). At this time, further molecular studies, using RNA targeted next generation sequencing (PanCancer, Illumina), revealed the presence of EBF1-PDGFRβ gene fusion.
Since the patient was resistant to conventional therapy and literature's evidences demonstrated potential sensitivity of EBF1-PDGFRβ to TKIs therapy, we decided to add dasatinib, a second generation TKI, to IB induction, with cyclophosphamide, cytarabine and 6-mercapthopurine. After one week of therapy, clinical course was complicated by Klebsiella Pneumoniae sepsis, followed by digestive hemorrhage. Since we retained that the hemorrhagic event could be related to dasatinib, the drug was temporarily discontinued. However, bone marrow evaluation, after only 10 days of dasatinib administration, showed hematologic remission (3% of lymphoblast) and MRD reduction >1 logarithm (markers 1=1-10-2 e markers 2= 9.9 x 10-3).
Given the resistance to chemotherapy alone and the excellent response to dasatinib but its related toxicity in combination, we decided to start immunotherapy with blinatumomab, a bi-specific CD3-CD19 monoclonal antibody, alternated to dasatinib, in order to achieve MRD negativity before to proceed with allogeneic hematopoietic stem cell transplantation (HSCT) from HLA-identical sibling. The patient received 2 courses of blinatumomab for 28 days continuous infusion (15 mcg/mq days 1-28), interspersed by 15 days of dasatinib (60 mg/mq/day). After the first cycle the patient achieved complete hematological remission and MRD negativity. MRD negativity was confirmed after first course of dasatinib, second course of blinatumomab and second course of dasatinib. Dasatinib, given alone, was well tolerated and no serious adverse event were reported. Actually, the patient is undergoing HSCT by HLA-identical sister.
To our knowledge, only few cases of EBF1-PDGFRβ ALL, treated with TKIs, are described in literature and this is the first in which MRD negativity was obtained with a sequential combination of dasatinib and blinatumumomab, a chemo-free approach, showing efficacy and good tolerability. This case highlights also that screening for targetable lesions at diagnosis or in case of resistance to induction phase is mandatory to identify patients who might benefit from alternative therapies as TKIs, immunotherapy or their combination. A longer follow-up is required to definitively establish the long-term efficacy of this biological approach in our patient. Nevertheless, it is interesting to speculate that alternative treatment with TKIs or immunotherapy could avoid, in the future, an intensive chemotherapy, or probably a transplant approach in selected patients, in order to achieve a durable cure in these Ph-like patients.

Disclosures
Locatelli: Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Parasole:Baxalta: Membership on an entity's Board of Directors or advisory committees; behring: Consultancy; jazz: Honoraria, Speakers Bureau.