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2874 The MEK Inhibitor Selumetinib in Combination with Dexamethasone Leads to Responses in Adult and Pediatric Patients with Relapsed RAS-Pathway Mutated Acute Lymphoblastic Leukemia: Results of a Phase 1/2 Study

Program: Oral and Poster Abstracts
Session: 614. Acute Lymphoblastic Leukemias: Therapies, Excluding Transplantation and Cellular Immunotherapies: Poster II
Hematology Disease Topics & Pathways:
Lymphoid Leukemias, ALL, Combination therapy, Diseases, Therapies, Lymphoid Malignancies
Sunday, December 10, 2023, 6:00 PM-8:00 PM

Britta Julia Vormoor, MD1*, Tobias Menne, PhD2*, Joshua Savage, PhD3*, Amit Patel, PhD4*, Anna Castleton5*, Adele Kay Fielding, MBBS, PhD6, Donna Lancaster7*, Anne Louise Latif8*, Nick Morley9*, Geoff Shenton10*, Gareth Veal, PhD11*, Julie Irving12*, Pam Kearns, MBChB, PhD, FRCPC3*, Lucinda Billingham3* and Josef Vormoor, MD PhD13

1Princess Maxima Center for Pediatric Oncology, Utrecht, Utrecht, Netherlands
2Newcastle Upon Tyne NHS Hospitals Foundation Trust, Newcastle, United Kingdom
3Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, United Kingdom
4University of Birmingham, Birmingham, United Kingdom
5The Christie Hospital NHS Trust, Manchester, United Kingdom
6UCL Cancer Institute, London, United Kingdom
7Royal Marsden NHS Foundation Trust, Sutton, United Kingdom
8Beatson West of Scotland Cancer Centre, GLASGOW, United Kingdom
9Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom
10Great North Children’s Hospital, Newcastle, United Kingdom
11Newcastle University, Newcastle, United Kingdom
12Newcastle University, Newcastle Upon Tyne, ENG, GBR
13Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands


Relapsed acute lymphoblastic leukemia (ALL) is a major therapeutic challenge and novel treatment strategies are urgently sought. RAS-pathway activating mutations are found in 38% of relapsed pediatric B-cell precursor (BCP) ALL patients (J Irving, Blood, 2014). Additional mutations that activate the RAS-signalling cascade (NF1, BRAF, IKZF2, IKZF3, JAK1) have also been found with varying frequencies in relapsed ALL. Selumetinib, a potent MEK1/2 inhibitor, works synergistically with dexamethasone in mouse models of RAS-pathway mutated ALL by enhanced upregulation of the proapoptotic protein, BIM (EC Matheson, Haematologica, 2019).


We conducted an international, parallel cohort, dose-finding and expansion trial to evaluate the combination of selumetinib with dexamethasone in adult and pediatric patients with relapsed/refractory T- or BCP-ALL harbouring RAS-pathway activating mutations. Selumetinib was supplied free of charge by AstraZeneca. Details of in-/exclusion criteria, treatment and dosages are described by T. Menne, BMJ open, 2022. The trial was conducted according to the Declaration of Helsinki and after medical ethics committees of participating countries had approved the protocol. The trial was registered under NCT03705507 and ISRCTN92323261 and sponsored by the University of Birmingham.


The trial opened to recruitment on 17-Apr-2018, the first patient was recruited on 18-May-2018. Twelve patients were included, 8 adults and 4 children. Six of the 8 adult patients had relapsed/refractory T-ALL, the remaining patients had BCP-ALL. Further patient characteristics are summarized in table 1.

Pharmacokinetic measurements demonstrated lower maximum concentrations for pediatric patients on dose level -1, and no significant effect of CYP3A4 induction was observed.

A total of 561 Adverse Events (AEs) were reported for 11/12 patients. For 1 patient who died on day 3 of treatment due to leukemia related events, no AEs were reported. 3/11 patients (27%) had AEs of a maximum grade 1-3, 5 patients (45%) had a maximum AE grade 4, and 3 patients (27%) suffered a grade 5 AE (2x sepsis, pneumonia). Further details of AEs are depicted in table 2.

Sixteen serious adverse events (SAEs) were observed in 9 patients. Of those, 11 were due to infection, and all 9 patients had an SAE involving infection, most frequently neutropenic fever or sepsis. Three SAEs were fatal: one concerned a child with sepsis who had stopped trial treatment 14 days previously. Two patients were adults: one became septic 2 days after being admitted for myopathy/weakness and collapsed shortly after starting antibiotics. The 2nd patient was admitted with fever, diagnosed with pneumonia and died 5 days later of cardiac arrest. All fatal events occurred before the last of 3 urgent safety measures were implemented in September 2019, changing the continuous dexamethasone dosing to pulsed doses and mandating antimicrobial prophylaxis. The 5 non-infection SAEs were anaemia, constipation, myopathy/weakness, fatigue and heart failure.

Response data are available for 9/12 patients. Two patients died before reaching the 1st bone marrow assessment after 28 days, and 1 patient stopped trial treatment after 11 days. Of the remaining 9 patients, 5 were non-responders (56%) and 4 (44%) had a complete remission (CR), or a CR with incomplete platelet recovery (3 adults, 1 child; response rate 44%). Of the 4 patients in CR, 2 adults had relapsed T-ALL and stayed on treatment for 3 to almost 5 months. Of the responding BCP-ALL patients, 1 patient died of pneumonia in cycle 2, and 1 pediatric patient progressed after cycle 2 then discontinued.


Recruitment to the trial was unexpectedly slow, due to competing new treatment options (commercial CAR-T cells, blinatumomab, inotuzumab), delays in opening international centres and recruitment stops due to COVID. Initially, the trial suffered from frequent SAEs concerning infections, which lead to a total of 3 urgent safety measures in 2018 and 2019, including lowering the dose of dexamethasone in the 2nd half of cycle 1, mandating fluoroquinolone and co-trimoxazole prophylaxis and finally changing continuous dexamethasone to pulses. The response data with 44% of patients achieving a CR is promising and will need to be further evaluated in the context of targeted treatment approaches for RAS-altered leukemias, especially for relapsed T-ALL.

Disclosures: Menne: Kite/Gilead, Amgen, Novartis, Pfizer, Celgene/BMS, Daiichi Sankyo, Atara, F. Hoffmann-La Roche Ltd, Janssen, BMS, CTI BioPharma, Blueprint Medicines, Sanofi-Aventis, Spark Therapeutics: Divested equity in a private or publicly-traded company in the past 24 months, Honoraria; Janssen, AstraZeneca, Novartis: Research Funding; Kite/Gilead, Takeda, Janssen, F. Hoffmann-La Roche Ltd, Servier, Novartis, Celgene/BMS, Pfizer, Incyte: Speakers Bureau; Amgen, Jazz, Pfizer, Bayer, Kyowa Kirin, Celgene/BMS, Kite/Gilead, Janssen, Takeda: Other: Travel grants; Kite/Gilead, Amgen, Novartis, Pfizer, Celgene/BMS, Daiichi Sankyo, Atara, Roche, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Fielding: Amgen, Incyte, Pfizer, Novartis: Consultancy. Morley: Abbvie: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Takeda: Honoraria. Kearns: AstraZeneca: Consultancy.

*signifies non-member of ASH