Introduction:
T-cell acute lymphoblastic leukemia (T-ALL) originating from early T-cell precursors (ETP-ALL) has distinct immunophenotype (CD1a-CD8-CD5-/weak and positive for myeloid or stem-cell markers [My-HSC+]) and is associated with poor outcome with 5-year (yr) survival <25%. Some T-ALL cases are transcriptionally similar to ETP-ALL but the level of CD5 expression is not low enough to meet the immunophenotypic criteria of ETP-ALL (near-ETP ALL), and their outcome remains unknown (Coustan-Smith et al. Lancet Oncol 2009). The aim of this study is to characterize the patients (pts) with ETP-ALL, near-ETP ALL, and other T-ALL, and compare their outcomes.
Methods:
We reviewed 217 pts with newly diagnosed T-ALL or T-cell lymphoblastic lymphoma (T-LL) who received treatment at our institution between 8/2000 and 2/2020. Of the 217 pts, 196 pts with full immunophenotypic data were classified into: 1) ETP if CD1a-CD8-CD5-/weakMy-HSC+ (N=36), 2) near-ETP if CD1a-CD8-CD5strongMy-HSC+ (N=27), and 3) non-ETP if not classified as ETP or near-ETP (N=133). Minimal residual disease (MRD) was assessed by multicolor flow cytometry with a sensitivity of 10−4 cells. Overall survival (OS) was calculated from the start date of treatment to the date of death, or last follow-up. Event-free survival (EFS) was calculated from the start date of treatment to the date of death or treatment failure, or last follow-up. Cox regression model was used for univariate and multivariate analysis (MVA). Allogeneic stem cell transplantation (allo-SCT) was considered as a time-dependent variable.
Results:
Pts characteristics are summarized in Table 1. ETP-ALL pts tended to be older than near-ETP/non-ETP ALL pts. ETP/near-ETP ALL pts were more likely to present with ALL, and less likely to have diploid karyotype. By definition, near-ETP ALL had significantly higher CD5 expression compared with ETP-ALL (median 94% vs 6%, p < 0.001). CD117 was less likely to be positive in near-ETP ALL than in ETP-ALL (8% vs 67%, p = 0.001), whereas there was no difference in CD13 (p = 1), CD34 (p = 1), and HLA-DR (p = 0.157) positivity rates. Among 55 pts with available mutation data, NOTCH1 was most frequently mutated across all 3 subtypes (31% vs 70% vs 35% in ETP vs near-ETP vs non-ETP), whereas DNMT3A mutations and RAS/RTK mutations were more enriched in ETP-ALL (DNMT3A: 25% vs 0% vs 7%; RAS/RTK: 38% vs 0% vs 14% in ETP vs near-ETP vs non-ETP). Mutations in transcription factor genes were detected in ETP-ALL and near-ETP ALL, but not in non-ETP ALL (31% vs 40% vs 0% in ETP vs near-ETP vs non-ETP, Figure 1). Treatment was mainly based on hyper-CVAD (HCVAD). Complete remission (CR)/CR with incomplete count recovery rate was similar among 3 subtypes (84% vs 85% vs 90% in ETP vs near-ETP vs non-ETP). MRD negativity rate was 74% vs 56% vs 92% in ETP vs near-ETP vs non-ETP. More ETP/near-ETP ALL pts received allo-SCT in CR1 (39% vs 22% vs 5% in ETP vs near-ETP vs non-ETP). With a median follow-up of 71 months (95% CI: 56-100), 59 pts relapsed and 83 died. The estimated 5-yr EFS and 5-yr OS rates for the entire cohort were 53% (95% CI: 46%-61%) and 57% (95% CI: 49%-64%), respectively. The 5-yr EFS/OS rates were 26/34%, 48/57%, 62/63% in ETP, near-ETP, and non-ETP ALL, respectively. ETP-ALL pts had significantly worse survival than did non-ETP ALL pts (p = 0.002 for EFS, p = 0.007 for OS), whereas there was no difference in outcome between near-ETP and non-ETP ALL (p = 0.28 for EFS, p = 0.673 for OS, Figure 2). Allo-SCT in CR1 did not improve the outcome in near-ETP ALL (5-yr OS 63% vs 55%, p = 0.638) and non-ETP ALL pts (67% vs 62%, p = 0.903). In contrast, among ETP-ALL pts, allo-SCT seemed to be beneficial with borderline significance (5-yr OS 36% vs 27%, p = 0.06). Survival advantage of additional nelarabine (nel) to HCVAD therapy was observed only in non-ETP ALL pts (5-yr OS 77% vs 51% in HCVAD+nel vs HCVAD, p = 0.001, Figure 3). MVA revealed that age ≥60 (HR 2.38, p = 0.022), elevated WBC ≥100×109/L (HR 2.99, p = 0.001), and ETP phenotype (HR 2.10, p = 0.018) were significant prognostic factors for OS. Among 90 pts with MRD data, age ≥60 (HR 2.97, p = 0.044), WBC ≥100×109/L (HR 4.25, p <0.001), and positive MRD (HR 2.24, p = 0.04) were found to be prognostic (Table 2).
Conclusions:
ETP-ALL pts had poor outcome that is improved with allo-SCT, whereas near-ETP ALL pts showed similar survival rate to non-ETP ALL pts. Novel therapies targeting myeloid/stem cells are expected to improve the outcome in ETP-ALL and near-ETP ALL pts.
Kantarjian:Ascentage: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; BMS: Research Funding; Immunogen: Research Funding; Jazz: Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Sanofi: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive biotechnologies: Honoraria; Amgen: Honoraria, Research Funding; Aptitute Health: Honoraria; BioAscend: Honoraria; Delta Fly: Honoraria; Janssen: Honoraria; Oxford Biomedical: Honoraria; Abbvie: Honoraria, Research Funding. Ravandi:Xencor: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; AstraZeneca: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding. Jain:Cellectis: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fate Therapeutics: Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; Pfizer: Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Aprea Therapeutics: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Incyte: Research Funding; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Konopleva:Amgen: Consultancy; AstraZeneca: Research Funding; Genentech: Consultancy, Research Funding; Calithera: Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Forty-Seven: Consultancy, Research Funding; Sanofi: Research Funding; Kisoji: Consultancy; Agios: Research Funding; AbbVie: Consultancy, Research Funding; Eli Lilly: Research Funding; Rafael Pharmaceutical: Research Funding; Ascentage: Research Funding; Ablynx: Research Funding; Cellectis: Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding. Short:Takeda Oncology: Consultancy, Honoraria, Research Funding; Astellas: Research Funding; Amgen: Honoraria; AstraZeneca: Consultancy. Sasaki:Daiichi Sankyo: Consultancy; Pfizer Japan: Consultancy; Otsuka: Honoraria; Novartis: Consultancy, Research Funding. DiNardo:MedImmune: Honoraria; Novartis: Consultancy; ImmuneOnc: Honoraria; Calithera: Research Funding; Agios: Consultancy, Honoraria, Research Funding; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Syros: Honoraria. Kadia:Novartis: Honoraria; Pfizer: Honoraria, Research Funding; Ascentage: Research Funding; Cellenkos: Research Funding; Astra Zeneca: Research Funding; Genentech: Honoraria, Research Funding; Cyclacel: Research Funding; Pulmotec: Research Funding; Astellas: Research Funding; Incyte: Research Funding; Celgene: Research Funding; Abbvie: Honoraria, Research Funding; BMS: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Amgen: Research Funding. Garcia-Manero:Bristol-Myers Squibb: Consultancy, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy; Merck: Research Funding; Novartis: Research Funding; Onconova: Research Funding; Amphivena Therapeutics: Research Funding; H3 Biomedicine: Research Funding; AbbVie: Honoraria, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Daver:Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding. Jabbour:Adaptive Biotechnologies: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding.
