Outcome of Patients with T-Cell Acute Lymphoblastic Leukemia/Lymphoma with Early T-Cell Precursor-like Immunophenotype with Strong CD5 Expression

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^-CD5^strongMy-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.