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2816 Blinatumomab with De-Escalated Chemotherapy for Infant KMT2A-Rearranged B-Cell Acute Lymphoblastic Leukemia

Program: Oral and Poster Abstracts
Session: 613. Acute Lymphoblastic Leukemias: Therapies Excluding Allogeneic Transplantation: Poster II
Hematology Disease Topics & Pathways:
Research, Lymphoid Leukemias, ALL, Clinical Practice (Health Services and Quality), Bispecific Antibody Therapy, Clinical Research, Diseases, Treatment Considerations, Biological therapies, Lymphoid Malignancies
Sunday, December 8, 2024, 6:00 PM-8:00 PM

Angus Hodder, MBBS1,2*, Avijeet Kumar Mishra, MD, MBBS3*, Philip Connor4*, Michelle Cummins5*, Danny Cheng, MA, MBBS, MRCP1*, Michael Gattens6*, Brenda Gibson, MD7*, Danielle Ingham8*, Katherine Lindsay9*, Andrea Malone, MD10*, Majid Madni11*, John Moppett12*, Jayashree Motwani13*, Pritesh Patel14*, Subramaniam Ramanathan, MD, DM15*, Anindita Roy, MD, PhD16, Beki James, MD17*, Phil Ancliff1*, Ajay Vora1 and Jack Bartram1*

1Great Ormond Street Hospital for Children, London, United Kingdom
2Wellcome Sanger Institute, London, United Kingdom
3Cincinnati Children's Hospital, Cincinnati, OH
4Children's Hospital For Wales, Cardiff, GBR
5Bristol Royal Hospital For Children, Bristol, GBR
6Addenbrookes Hospital, Cambridge, Cambridge, GBR
7Department of Paediatric Haematology, Royal Hospital for Sick Children, Glasgow, United Kingdom
8Leeds Children's Hospital, Leeds, GBR
9Alder Hey Children's Hospital, Liverpool, United Kingdom
10Children’s Health Ireland, Dublin, IRL
11Department of paediatric haematology and oncology, Nottingham University Hospitals, Nottingham, United Kingdom
12Bristol Royal Hospital For Sick Children, Bristol, GBR
13Birmingham Children's Hospital, Birmingham, GBR
14Great Ormond Street Hospital, London, United Kingdom
15Newcastle Upon Tyne NHS Foundation Trust, Newcastle Upon Tyne, ENG, GBR
16Department of Paediatrics, University of Oxford, Oxford, United Kingdom
17Leeds Teaching Hospital NHS Trust, Leeds, United Kingdom

Introduction

Approximately 80% of infants with B-cell acute lymphoblastic leukemia (B-ALL) harbor KMT2A rearrangements, defining a uniquely aggressive subtype of ALL with a poor outcome demonstrated by 5-year event free survival (EFS) < 40% in recent major international trials. Treatment is challenging due to the high rate of relapse, where intensification of chemotherapy has led to unacceptably high treatment-related mortality (TRM). Myeloid blocks in Interfant-06 did not reduce the risk of relapse but caused excess toxicity with a serious adverse event rate of 37% with the trial overall reporting a TRM of 7.1%. Relapse occurs early, often within the first year of treatment before a potential stem cell transplant (SCT) on traditional protocols. Early data from the blinatumomab pilot trial within the Interfant group has shown promise for the CD3/CD19 bi-specific T-cell engager. However, this pilot added blinatumomab to an intensive chemotherapy backbone with no reduction in chemotherapy, leading to caution in further reducing chemotherapy in the successor Interfant-21 trial. Within the United Kingdom (UK) Children’s Cancer and Leukaemia Group (CCLG) we developed a treatment guideline to address the unacceptably high TRM and early relapse. All infants with KMT2A-rearranged B-ALL receive blinatumomab to replace toxic consolidation chemotherapy blocks (removal of myeloid blocks and protocol 1B) as a bridge to risk stratified allocation of further de-intensified chemotherapy or early SCT.

Methods

Patients were eligible if they had KMT2A-rearranged B-ALL, and aged < 365 days at diagnosis. All patients received a standard Interfant induction followed by a 28-day cycle of blinatumomab. High risk (HR) patients, were defined as infants who were <6 months at presentation with a white cell count >300 and/or a prednisolone poor response, or had minimal residual disease (MRD) > 1% at day 33 or MRD >0.01% at end of cycle one of blinatumomab. HR patients proceeded directly to SCT after one cycle of blinatumomab if MRD <0.01%. Medium risk (MR) patients were all other patients and proceeded to a second cycle of blinatumomab, followed by delayed intensification with OCTADAD (dexamethasone, vincristine, daunorubicin, pegylated asparaginase, cyclophosphamide and cytarabine) and oral maintenance with removal of MARMA block (high dose cytarabine, high dose methotrexate, pegylated asparaginase). For MR patients compared to the Interfant blinatumomab pilot this represents a 90% reduction in total cytarabine (from 28050 to 2850 mg/m2), 50% reduction in pegylated asparaginase (from 4000 to 2000 iu/m2), 66% reduction in cyclophosphamide (from 3000 to 1000 mg/m2), 45% reduction in 6-mercaptopurine (from 4575 to 2520 mg/m2) and removes high-dose methotrexate. For HR patients, there is a 96% reduction in cytarabine (from 26520 to 1050 mg/m2), a 66% reduction in pegylated asparaginase (from 3000 to 1000 iu/m2), and completely removes high dose methotrexate, cyclophosphamide and 6-mercaptopurine. Blinatumomab treatment failures and early relapses were brought to a national panel to be considered for chimeric antigen receptor T-cell (CART) therapy.

Results

We collected outcome data on 27 infants with KMT2A-rearranged B-ALL (17 MR, 10 HR) who presented since the 1st of January 2021, with a median follow-up of 15 months (mean 20 months). All infants received blinatumomab with 25/27 (93%) achieving a complete molecular remission (MRD <0.01%). There were 5 relapses (4 MR, 1 HR), with 1 death in the MR group due to disease, resulting in an overall survival at of 93%, and an EFS of 78% at 2 years. Four out of the 5 relapses were subsequently treated with CART therapy and remain in remission. There were no treatment-related deaths.

Conclusions

For infants with KMT2A-rerranged B-ALL, chemotherapy intensification has merely caused severe toxicity without improving outcomes. Overall, our data suggests the chemotherapy backbone can be radically de-escalated. Given most patients relapse within the first 18 months, our initial survival rates are encouraging. We plan to further reduce induction intensity by removing cytarabine and anthracycline for all patients and reducing induction to 15 days in patients who have achieved MRD <5% who are suitable to receive blinatumomab at this level of disease.

Disclosures: Gibson: Vertex: Membership on an entity's Board of Directors or advisory committees; GSK: Current holder of stock options in a privately-held company; Novartis: Current holder of stock options in a privately-held company. Vora: Beigene: Other: Lectures; Medac: Other: Support for attending meetings.

*signifies non-member of ASH