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1035 Prospective Evaluation of a Continuation Therapy with Midostaurin in Adult Patients with Core-Binding Factor Leukemia and Integrated Genetic Analysis: A Multi Center Phase II Study. Preliminary Results

Program: Oral and Poster Abstracts
Session: 615. Acute Myeloid Leukemia: Commercially Available Therapy, excluding Transplantation: Poster I
Hematology Disease Topics & Pathways:
AML, Non-Biological, Diseases, Therapies, chemotherapy, Myeloid Malignancies, Clinically relevant
Saturday, December 5, 2020, 7:00 AM-3:30 PM

Roberto Cairoli1*, Mauro Krampera, MD, PhD2, Patrizia Zappasodi, MD3*, Elisabetta Todisco, MD PhD4*, Erika Borlenghi, MD5*, Alfredo Molteni, MD6*, Monica Fumagalli, MD7*, Marta Ubezio8*, Massimo Bernardi, MD9*, Rosa Greco, MD1*, Erika Ravelli, MD1*, Valentina Mancini, MD1*, Giovanni Grillo, MD10*, Marta Riva11*, Beatrice De Marco12*, Adriana Cassaro, PhD13*, Bruno Brando, MD14*, Arianna Gatti14*, Silvio Marco Veronese15* and Alessandro Beghini13*

1Department of Hematology, ASST Grande Ospedale Metropolitano Niguarda, Milano, Italy
2Section of Hematology and Bone Marrow Transplant Unit, Department of Medicine, University of Verona, Verona, Italy
3Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
4European Institute of Oncology, Milano, Italy
5Department of Hematology, ASST Spedali Civili di Brescia, Brescia, Italy
6ASST Cremona, Cremona, Italy
7Ospedale San Gerardo, Monza, Italy
8Cancer Center, IRCCS Humanitas Research Hospital & Humanitas University, Rozzano (Milan), ITA
9Hematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milano, Italy
10Department of Hematology, ASST Grande Ospedale Metropolitano Niguarda, Milano, Italy, Italy
11Department of Hematology, ASST Grande Ospedale Metropolitano Niguarda, Milano, MI, Italy
12University of Verona, Verona, Italy
13Department of Health Sciences, University of Milan, Milan, Italy
14ASST Ovest Milanese, Legnano, Italy
15Azienda Ospedaliera Ospedale Niguarda Ca' Granda, Milano, Italy

Genetic and Clinical Background

The clinical outcome of Core Binding Factor Leukemia (CBFL) seems influenced by the mutational status of KIT. In fact, several retrospective studies, in addition to our own, as well as a systematic review, indicate that KIT mutations have a negative prognostic impact in AML with t(8;21) or, to a lesser extent, with inv(16)/t(16;16).

In addition, gene expression studies found KIT to be highly expressed in CBFL regardless of its mutational status. Furthermore, recent studies have identified novel recurrent somatic mutations co-occurring with KITmut.

In-vitro studies revealed that Midostaurin (Mido) is effective in inhibiting both wild type (WT) and a range of KIT mutants. In addition, it is proven to be effective in KIT–positive malignancies such as Aggressive Systemic Mastocytosis (ASM), Mast Cell Leukemia (MCL), and SM with Associated Hematological Neoplasm (SM-AHN).

With this background, we designed a Phase II trial to evaluate the safety and efficacy of Mido in association with Intensive Chemotherapy (IC), in CBFL regardless of KIT mutational status.


The inclusion criteria were the following: age 18 to 60 years, diagnosis of de-novo CBFL, adequate organ function, signed informed consent. The exclusion criteria were: central nervous system involvement, uncontrolled infections, other active malignancies, a Qtc value greater than 470 ms (according to Bazett formula) at the electrocardiogram, significant uncontrolled or active cardiovascular diseases.

Patients received standard induction therapy with an anthracycline containing regimen (“7+3”-like) + Mido, three cycles of post-remission consolidation chemotherapy with high-dose cytarabine + Mido, and 12 months of Mido as Maintenance.

The Mido dosage was: 50 mg orally twice a day, on days 8-21, in association with IC, and 50 mg orally twice a day as single agent maintenance.

In order to attain a reduction in 2 years Relapse Incidence (RI), from the historical value of 48% to 28% (Primary Objective of the Study), we plan to enrol 39 patients (power 82%, alpha error 4,6%). At diagnosis all patients were studied by a comprehensive NGS panel targeting 40 DNA genes and 29 RNA fusion driver genes. MRD status was assessed by qPCR and high-resolution multicolor flow cytometry at established check-points during consolidation and maintenance therapy.


17 patients were enrolled between December 2018 to April 2020 (table1). Overall, the CR rate was 94.2%. At a median follow-up of 9 months (range 3-19 months), we recorded a RI of 12.5%, an OS of 93.7%, and a DFS of 81.2%. 16 patients continue on study and 14 patients are in 1st CR, MRD-negative by flow cytometry and qPCR.

Six patients (35.2 %) experienced 12 Treatment Emergent Adverse Event (TEAE), 10 out of whom were infections, with grade 3-4 neutropenia (Table 2). We only recorded one death from SARS-Cov2 infection (Interstitial Pneumonia) in a patient in MRD-negative complete remission. There were no treatment-related deaths.


In patients with CBFL, the regimen consisting of intensive chemotherapy and consolidation chemotherapy in association with Mido, followed by Mido maintenance, had an acceptable safety profile and excellent response rates with a significant proportion of patients in MRD-negative complete remission. Trial is continuing to accrue (EudraCT Number 2017-002094-18; ClinicalTrials ID: NCT 03686345). This work was supported by a grant from Fondazione Regionale per la Ricerca Biomedica (FRRB 2015).

Disclosures: Krampera: Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Todisco: Jannsen, Abbvie, Jazz: Membership on an entity's Board of Directors or advisory committees. Veronese: Novartis: Other: Travel Expenses; Bayer: Honoraria; AstraZeneca: Other: Travel Expenses; Janssen Cilag: Honoraria.

OffLabel Disclosure: Midostaurin for treatment of Core Binding Factor Leukemia. The drug has been used as KIT inhibitor.

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