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4202 Project Evolve, Evaluation of Lineage Switch (LS), an International Initiative: Preliminary Results Reveal Dismal Outcomes in Patients with LS

Program: Oral and Poster Abstracts
Session: 612. Acute Lymphoblastic Leukemias: Clinical and Epidemiological: Poster III
Hematology Disease Topics & Pathways:
Lymphoid Leukemias, ALL, Acute Myeloid Malignancies, AML, Diseases, Lymphoid Malignancies, Myeloid Malignancies, Human
Monday, December 11, 2023, 6:00 PM-8:00 PM

Sara K. Silbert, MD1, Cynthia Harrison2*, D. Nathan Biery2*, Alexandra Semchenkova3*, Elena Zerkalenkova, PhD3*, Anna Alonso-Saladrigues4*, Kaylyn Utley, MD5*, Ibrahim Aldoss, MD6,7, Liping Zhao8*, Sneha Fernandes, MBBS9*, Jeremy D. Rubinstein, MD, PhD10, Naomi Torres Carapia11*, Bill H. Chang, MD, PhD12, Anant Vatsayan, MBBS13,14, Barbara De Moerloose15*, Holly L. Pacenta, MD16*, Dennis John Kuo, MD, MS17*, Gabriele Escherich, MD18*, Benjamin J. Lee, PharmD19*, Michele S. Redell, MD20, Mandi R. Fitzjohn21*, Daniel P. Larson, MD22*, Nicolas Duployez, PharmD, PhD23*, Raymund S. Cuevo24*, Rui Rochelle He, PhD25*, David S. Dickens26*, Firas El Chaer, MD27, Kelly Reed28*, Matthias Wolfl29*, Sunil S. Raikar, MD30, Süreyya Savaşan, MD31*, Latika Puri, MBBS32*, Zhubin J. Gahvari, MD, MS33, Aimee C. Talleur, MD34, Hisham Abdel-Azim, MD35, Aghiad Chamdin, MD36*, Marlie R.M. Provost37*, Vanessa A. Fabrizio, MD38, Kerstin Mezger, MD39*, Alexandra McLean Stevens40*, Emily M. Hsieh, MD11, Hao-Wei Wang, MD, PhD41*, Constance M. Yuan, MD, PhD41*, Ulrich A. Duffner, MD42, Jing Pan43*, Sara Ghorashian, FRCPath, PhD44*, Susana Rives4*, Chloe Hoang45*, Kara L. Davis, DO46, Elad Jacoby, MD47, Alexander Popov, MD3*, Adam Lamble, MD48* and Nirali N. Shah, M.D.49

1National Cancer Institute, NIH, Pediatric Oncology Branch, Bethesda, MD
2Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD
3Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation
4Leukemia and Lymphoma Department. Pediatric Cancer Center Barcelona, Hospital Sant Joan de Déu de Barcelona, Barcelona, Spain. Institut de Recerca Sant Joan de Déu, Barcelona Spain, Barcelona, Spain
5Children's Hospital Colorado, Aurora, CO
6City of Hope, Duarte, CA
7Hematology/HCT, City of Hope National Medical Center, Duarte, CA
8State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
9Great Ormond Street Hospital for Children London, London, United Kingdom
10Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
11Children's Hospital Los Angeles, Los Angeles, CA
12Doernbecher Children's Hospital, Oregon Health & Science University, Portland, OR
13Children's National Hospital/ George Washington University School of Medicine and Health Sciences, Washington, DC
14Children's National Medical Center, Washington, DC
15Ghent University Hospital, Ghent, Belgium
16Cook Children's Hospital, Fort Worth, TX
17Rady Children's Hospital, University of California San Diego, San Diego, CA
18Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
19Department of Pharmacy, University of California Irvine, Orange, CA
20Texas Children's Cancer Center/Baylor College of Medicine, Houston, TX
21Children's Hospital Colorado, Denver, CO
22Mayo Clinic, Rochester, MN
23Laboratory of Hematology, Centre Hospitalier Universitaire (CHU) Lille, Lille, France
24Inova Schar Cancer Institute, Fairfax, VA
25Inova Fairfax Hospital, Falls Church, VA
26Department of Pediatrics, University of Iowa, Iowa City, IA
27Department of Medicine, Division of Hematology and Oncology, University of Virginia Comprehensive Cancer Center, Charlottesville, VA
28University of Virginia, Charlottesville, VA
29University Children’s Hospital Würzburg, Würzburg, Germany
30Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University and Children's Healthcare of Atlanta, Atlanta, GA
31Children's Hospital of Michigan, Detroit, MI
32Loma Linda Children's Hospital, San Bernardino, CA
33University of Wisconsin School of Medicine and Public Health, Madison, WI
34Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN
35School of Medicine Cancer Center, Children Hospital and Medical Center, Loma Linda University, Loma Linda, CA
36Children's Hospital of Michigan, Central Michigan University, Detroit, MI
37Rocky Mountain Hospital for Children, Denver, CO
38University of Colorado Anschutz, Denver, CO
39Clinic of Paediatric Haematology and Oncology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
40Texas Children's Hospital Baylor College of Medicine, Houston, TX
41Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD
42Helen Devos Children's Hospital, Grand Rapids, MI
43State Key Laboratory of Experimental Hematology, Boren Clinical Translational Center, Department of Hematology, Beijing Gobroad Boren Hospital, Bejing, China
44UCL Great Ormond Street Institute of Child Health, London, ENG, GBR
45Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD
46Department of Pediatrics, Hematology, Oncology, and Stem Cell Transplant and Regenerative Medicine, Stanford University, Stanford, CA
47Department of Pediatric Hematology-Oncology, Safra Children's Hospital, Sheba Medical Center, Tel Aviv, Israel
48Seattle Children's - Hematology-Oncology, Seattle, WA
49Pediatric Oncology Branch, National Institutes of Health, Bethesda, MD

Introduction: Lineage switch (LS) refers to the transformation of acute leukemia from one cell lineage to another (e.g., lymphoid (ALL) to myeloid (AML)). This rare phenomenon, distinct from treatment induced malignancy (i.e., t-AML) and mixed phenotype acute leukemia (MPAL), is increasingly being observed following cell surface antigen targeting. Given challenges in the diagnosis and treatment of LS, Project EVOLVE was developed to globally identify cases of LS following immunotherapy.

Methods: A protocol and data collection form for this IRB exempt study was widely disseminated to capture deidentified LS case information across multiple centers and cancer consortia. This included collection of data from published reports of LS, with authors contacted to obtain additional information.

For this analysis, LS was defined by the emergence of cell-surface markers warranting reclassification of the original leukemia as a different lineage derivation based on the immunophenotype, including cases of AML emerging alongside the original ALL. “Confirmed” LS cases included those where retention of original cytogenetic or molecular aberrations and/or the clonal immunoglobulin rearrangement patterns were verified to confirm the clonal relationship. “Suspected” LS cases included those where samples to confirm clonality marker retention could not be obtained, but the clinical presentation was consistent with LS. The term “transition” was applied when immunophenotypic shifts were transient. Cases with new cytogenetic abnormalities unrelated to the original diagnosis and compatible with t-AML were excluded. Statistical analysis was primarily descriptive. Data cut-off was July 26, 2023.

Results: A total of 58 cases were identified, including 19 cases referenced in prior publications. Of the 58, 11 cases were excluded from this initial analysis, including: 4 cases of t-AML, 2 cases of T-ALL to AML, and 5 “transition” cases. Collectively, 47 cases of LS (43 “confirmed”; 4 “suspected”), spanning across 3 continents and 8 countries, were analyzed. (Fig. 1A)

Cases included transition from B-ALL to AML in 36 (76.6%) and to MPAL/biphenotypic/ambiguous lineage in 11 (23.4%). Two likely had MPAL at diagnosis and a third with chronic myeloid leukemia. The median age at initial diagnosis was 8.4 years (range, 1 day-76.5 years); median age at LS presentation was 11.0 years (range 0.4-77.3 years). Twenty-three (48.9%) were male and 19 (40.4%) had prior stem cell transplant (SCT). Baseline cytogenetics showed KMT2A rearrangement in 27 (57.4%). Baseline myeloid antigen co-expression was seen in 22 of 23 patients with submitted data, but variation in degree of expression across patients and antigens was substantial.

The most proximal immunotherapy prior to development of LS was CAR T-cells in 23 (48.9%) and blinatumomab in 24 (51.1%). The median time from the most proximal immunotherapy to development of LS was 1.6 months (range, 7 days-36.5 months). In 7 (29.2%) patients receiving blinatumomab, LS developed during the infusion. LS presented as isolated marrow relapse in 27 (57.4%), isolated CNS in 2 (4.3%), isolated non-CNS extramedullary disease in 3 (6.4%), combined relapse in 14 (29.8%) and unreported in 1.

First line treatment for LS was chemotherapy induction in 31 (66.0%), palliative care/no therapy in 8 (17.0%), and alternative therapies in the remaining 8 (17.0%). In 35 (74.5%) patients, remission induction was the goal of first line therapy. Fifteen (31.9%) achieved a complete remission (CR) of whom 2 were treated with palliative intent.

Across all patients, 8 (17.0%) are alive in remission, the longest being 4.7 years from LS diagnosis; 2 (4.3%) are alive with active LS and 37 (78.7%) died from LS, their original disease, or complications of treatment of LS (Fig 1B). For those alive in CR (n=8), 7 (87.5%) proceeded to a consolidative SCT for treatment of LS and 1 patient, an octogenarian remains in remission after AML directed therapy.

Conclusions: LS is emerging as an important mechanism of immune escape following immunotherapy. Project EVOLVE provides the largest dataset of patients with LS to date. This systematic, international effort reveals substantial complexity and variability in diagnosing and managing LS. Unfortunately, outcomes following LS are grim, underscoring the critical need to identify risk factors of and optimal therapies for this leukemia transformation.

Disclosures: Aldoss: KiTE: Consultancy; Sobi: Consultancy; Jazz: Consultancy; Pfizer: Consultancy; Amgen: Consultancy, Honoraria; Takeda: Consultancy. Vatsayan: Pfizer: Current equity holder in publicly-traded company; Illumina: Current equity holder in publicly-traded company. Dickens: Tempus Inc.: Honoraria; Syndax: Research Funding; American Academy of Pediatrics: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Iowa Cancer Consortium: Membership on an entity's Board of Directors or advisory committees; American Society of Pediatric Hematology Oncology: Membership on an entity's Board of Directors or advisory committees. El Chaer: CTI Biopharma: Consultancy; DAVA Oncology: Other: Travel grant; Association of Community Cancer Centers: Consultancy; Arog Pharmaceuticals: Research Funding; Novartis: Research Funding; MEI Pharma: Research Funding; BioSight: Research Funding; PharmaEssentia: Research Funding; Sanofi: Research Funding; Sumitomo Pharma Oncology: Consultancy, Research Funding; Fibrogen: Research Funding; AbbVie: Consultancy; Amgen: Consultancy, Research Funding; Bristol Myers Squib: Research Funding; Celgene: Research Funding; MorphoSys: Consultancy. Reed: Sumitomo Pharma America: Other: reimbursement of time presenting or training related to the BBI-TP-3654-102 study. Abdel-Azim: Adaptive: Research Funding. Fabrizio: Adaptimmune: Consultancy. Ghorashian: Novartis: Honoraria; UCLB: Patents & Royalties. Shah: Immunoadoptive Cell Therapy Private Limited: Consultancy, Other: Scientific Advisory Board; VOR: Consultancy, Research Funding; CARGO: Consultancy; Lentigen: Research Funding.

*signifies non-member of ASH