Introduction:

HR-CTG in B-ALL is considered an adverse prognostic factor along with age and measurable residual disease (MRD) status. The use of potent B-cell targeted drugs like InO and Blina as part of frontline therapy has improved outcomes in adult pts with B-ALL ( Jabbour et al, Lancet Haematology 2022 and 2023) but the impact of baseline HR-CTG needs to be further elucidated .

Methods:

From Oct 2014-Feb 2023 we identified 71 consecutive patients (pts) with Philadelphia (Ph)-negative B-ALL and adequate CTG data who were treated on frontline therapy that included InO and/or Blina along with HCVAD chemotherapy. The intensive phase of treatment protocol consisted of HCVAD 4 courses followed by 4 courses of blina which could be initiated post HCVAD course 2 for high-risk or MRD positive pts and has been published before (Jabbour et al, Lancet Haematology 2022). The protocol was later amended to include fractionated InO from course 2 of HCVAD at a cumulative dose of 2.4 mg/m 2(Short et al, ASCO 2023).

Pts with confirmed Ph-like ALL were excluded. CTG was evaluated and graded as HR based on a combination of conventional karyotyping and fluorescent in situ hybridization data and included low-hypoploidy or near triploidy (Ho-Tr), complex karyotype (CK; ≥5 abnormalities), 14q32 rearrangement ( IGH) and KMT2A re-arrangement as described before (Issa et al, Cancer 2017).

Results:

31 of 71 pts (44%) with Ph- B-ALL had HR-CTG; 14 pts (45%) with Ho-Tr, 8 (26%) pts with KMT2A rearrangement, 6 pts (19%) with CK and 3 pts (10%) with IGH rearrangement (Table 1). The median age of the whole cohort was 33 years (range, 18-60 years); median age was 29 yrs in HR-CTG group compared to 34 yrs in non-HR-CTG group. 12 pts (39%) in the HR group compared to 5 pts (12%) in the non-HR group had a TP53 mutation ( p=0.01). 5/12 (42%) pts in the HR group with TP53 mutation had low-hypoploidy. 7 pts (23%) and 13 (32%) pts in the HR-CTG and non-HR-CTG group respectively had RAS mutations, with 1 pt in each group having both TP53 and RAS mutation. 17 pts (55%) received Blina and 14 pts (45%) received both InO and Blina in the HR group compared to 20 pts (50%) each who received Blina and Blina+ InO in the non-HR group.

A best response of complete remission (CR)/CR with incomplete count recovery (CRi) was obtained in 100% pts (CR=30, CRi=1) in the HR-CTG group, 17 (55%) of whom had concurrent MRD negativity ; in the non-HR-CTG group 39 pts (98%) attained CR and one pt a partial remission, with concurrent MRD negativity attained in 21/39 (54%) pts with CR. At a median follow-up of 31 months (mos) for the full cohort (43 mos for HR pts and 28 mos for the non-HR group) the median overall survival (OS) was not reached (NR) and 3-yr OS was 85% (95% CI, 78-92%); median OS and 3-yr OS were NR and 89% in the HR-CTG group and 74.7 mos and 82% in the non-HR-CTG group ( p=0.64). The median relapse free survival (RFS) was NR in the HR-CTG group and 74 mos in the non-HR group ( p=0.73) while the 3-yr RFS were 74% and 80% respectively. There was no intergroup difference in RFS and OS based on the MRD status at response assessment. 11 HR-CTG pts (35%) underwent allogeneic stem cell transplantation (SCT) (5 Ho-Tr, 4 KMT2Ar, 1 CK, 1 IGHr) in continued remission at a median of 4.8 mos from therapy initiation (IQR 4.5-8.2 mos), 9 of whom went directly to SCT without introduction of a new therapy between the frontline therapy and SCT. Two pts received additional lines of therapy for MRD relapse/progression without morphological relapse before SCT. The 3-year OS in the HR-CTG pts who underwent SCT was 87% and similar to HR pts who did not undergo SCT (89%, p=0.78). 5 pts (12%) underwent SCT in the non-HR-CTG group, 4 for persistent or recurrent MRD positivity and one with Down's syndrome. No pts in either groups developed hepatic sinusoidal obstruction syndrome or a secondary myeloid neoplasm.

Conclusion:

In our analysis, in a prospectively maintained dataset where >90% pts were treated on clinical trial, HR-CTG did not have any significant impact on B-ALL survival outcomes when treated with frontline therapy containing B-cell targeted agents. Further analysis is underway.

Senapati:Kite Pharma: Other: Advisory Board. Jabbour:Takeda: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Ascentage Pharma Group: Consultancy, Honoraria, Research Funding; Adaptive Biotech: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Hikma Pharmaceuticals: Consultancy, Honoraria, Research Funding. Short:Stemline therapeutics: Research Funding; Astellas: Research Funding; Takeda: Consultancy, Research Funding; Amgen: Honoraria; Novartis: Consultancy; AstraZeneca: Consultancy; Pfizer: Consultancy. Jain:Precision Biosciences: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Kite/Gilead: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Ipsen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Genentech: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Beigene: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; AbbVie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Takeda: Research Funding; Medisix: Research Funding; Loxo Oncology: Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Servier: Research Funding; Novalgen: Research Funding; BMS: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Cellectis: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Mingsight: Research Funding; Incyte: Research Funding; ADC Therapeutics: Research Funding; Aprea Therapeutics: Research Funding; Fate Therapeutics: Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; MEI Pharma: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; TransThera Sciences: Research Funding; Newave: Research Funding; Dialectic Therapeutics: Research Funding; CareDX: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Pfizer: Research Funding. Issa:Celgene: Research Funding; Kura Oncology: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; NuProbe: Consultancy; Syndax: Research Funding; Merck: Research Funding. Kadia:Liberum: Consultancy; SELLAS Life Sciences Group: Research Funding; AbbVie, Amgen, Inc, Ascentage Pharma Group, Astellas Pharma Global Development, Astex, AstraZeneca, BMS, Celgene, Cellenkos Inc, Cyclacel, Delta-Fly Pharma, Inc, Genentech, Inc., Genfleet, Glycomimetics, Iterion, Janssen Research and Development: Research Funding; Iterion: Research Funding; Sanofi-Aventis: Consultancy; Daiichi Sankyo, Genentech, Inc., Genzyme, Jazz Pharmaceuticals, Liberum, Novartis, Pfizer, PinotBio, Inc, Pulmotect, Inc, Sanofi-Aventis, Servier: Consultancy; Pfizer: Consultancy, Research Funding; Pulmotect, Inc.: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Hikma Pharmaceuticals: Speakers Bureau; Biologix, Cure, Hikma Pharmaceuticals: Speakers Bureau; Celgene: Research Funding; Astellas Pharma Global Development: Research Funding; AstraZeneca: Research Funding; Glycomimetics: Research Funding; Janssen Research and Development: Research Funding; Ascentage Pharma Group: Research Funding; Jazz Pharmaceuticals, Pfizer, Pulmotect, Inc, Regeneron Pharmaceuticals, SELLAS Life Sciences Group: Research Funding; Amgen, Inc.: Research Funding; Regeneron Pharmaceuticals: Research Funding; Genzyme: Honoraria; GenFleet Therapeutics: Research Funding; Cellenkos Inc.: Research Funding; Novartis: Consultancy; Cure: Speakers Bureau; Delta-Fly Pharma, Inc.: Research Funding; Cyclacel: Research Funding; Agios: Consultancy; Servier: Consultancy; Pinotb-Bio: Consultancy; BMS: Consultancy, Research Funding; Astex: Honoraria. Daver:Novimmune: Research Funding; Novartis: Consultancy; Syndax: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Celgene: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; AROG: Consultancy; Hanmi: Research Funding; Trovagene: Research Funding; Kite, a Gilead company: Consultancy, Research Funding; Jazz: Consultancy; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; FATE: Research Funding; Glycomimetics: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Servier: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Kronos Bio: Research Funding. Ferrajoli:GenMab: Research Funding; Beigene: Research Funding; AstraZeneca: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Genetech: Honoraria; Janssen: Honoraria. Montalban-Bravo:Takeda: Research Funding; Rigel: Research Funding. Pemmaraju:Pacylex: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CancerNet: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; OncLive: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dava Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Aplastic Anemia & MDS International Foundation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CareDx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Patient Power: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Curio Science: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Protagonist Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Stemline: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Magdalen Medical Publishing: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Medscape: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Imedex: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Intellisphere: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Harborside Press: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Menarini Group: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; United States Department of Defense (DOD): Research Funding; Karger Publishers: Other: Licenses; ASCO Cancer.Net Editorial Board: Other: Leadership; ASH Committee on Communications: Other: Leadership; Physician Education Resource (PER): Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PeerView Institute for Medical Education: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Neopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ImmunoGen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CTI BioPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ClearView Healthcare Partners: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Cimeio Therapeutics AG: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Blueprint: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Aptitude Health: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; National Institute of Health/National Cancer Institute (NIH/NCI): Research Funding; HemOnc Times/Oncology Times: Other: Uncompensated; Bristol Myers Squibb Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Ravandi:Amgen: Honoraria, Research Funding; Biomea fusion: Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding; Xencor: Research Funding; Prelude: Research Funding; Syros: Consultancy, Honoraria, Research Funding; Astex/taiho: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kantarjian:AstraZeneca/MedImmune: Honoraria; Astellas Pharma: Honoraria; Ascentage Pharma Group: Honoraria; Abbvie: Consultancy, Honoraria; Jazz Pharmaceuticals (Inst): Honoraria, Research Funding; Novartis: Honoraria; KAHR Medical: Honoraria; Pfizer: Honoraria; Precision Biosciences: Honoraria; Shenzhen Target Rx: Honoraria; Taiho Pharmaceutical: Honoraria; Abbvie (Inst): Research Funding; Amgen (Inst): Research Funding; Amgen: Honoraria; Ipsen: Honoraria; Immunogen (Inst): Honoraria, Research Funding; Daiichih-Sankyo (Inst): Honoraria, Research Funding; Ascentage Pharma (Inst): Research Funding; Bristol-Myers Squibb (Inst): Research Funding; Novartis (Inst): Research Funding.

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2023
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