Early T-Precursor ALL/Lbl Profiling in Adult Population. A10-Years Single Centre Experience

Introduction:

Early T-precursor ALL/LBL (ETP-ALL) is a subtype of T-ALL/T-LBL that have a unique immunophenotype. It was initially recognized as a very high-risk T-ALL that retains a multilineage differentiation potential, expression of lymphoid, myeloid as well as stem cell markers. ETP-ALL is defined by expression of cCD3, absent CD1a & CD8 expression, dim to negative CD5 & >25% of blasts with ≥1 or more myeloid &/ or stem cell markers and absent MPO. ETP-ALL was listed as a provisional entity in the 4^th edition of the WHO classification as a high-risk T-ALL/LBL and introduced as a separate entity in the 5^th edition of WHO and ICC classification (2022).

Patients and Method:

This is a single center retrospective study performed in National Center for Cancer Care and Research, Hamad Medical Corporation over 10 years duration between 2013 and 2022, aimed to assess the clinicopathologic, cytogenomic profiling and survival data of cases with ETP-ALL compared to non-ETP ALL/LBL cases. All patients were subtyped using flow cytometry immunophenotyping as: ETP-ALL, cortical or medullary.

Results:

A total of 89 T-ALL adult patients were diagnosed as T-ALL, among which 28 cases (31.4%) have met the diagnostic criteria of ETP-ALL immunophenotype. The median age of ETP-ALL in our cohort was 31.8(±10.6 ) years with significant male predominance (25/28, 89%). No difference between ETP-ALL and non-ETP-ALL regarding age, gender, hemoglobin level, platelets, or blasts percentage at presentation. Patients with ETP-ALL tend to have lower total leukocytic count at presentation, with statistically significant difference compared to non-ETP-ALL (p.0.003). In our cohort 68% or ETP-ALL was stratified as high risk compared to 38% among non ETP-ALL. Regarding immunophenotyping, ETP-ALL has significantly higher expression of CD117, CD34, CD13, CD33, HLA-DR, cytoplasmic CD79a & CD11b (p.<0.05) and significantly lower expression of CD5, CD2 & surface CD3 compared to non-ETP ALL (p=<0.05). CD7 is consistently positive in all T-ALL cases in our cohort. GATA3 immunostain is positive in ~90% of ETP-ALL. One case in our cohort was negative for cytoplasmic CD3 and T-cell immunophenotype was evidenced by TCR clonality and GATA3 positivity.

Karyotype (KT) was performed in 23/28 cases (82%). The cytogenetic findings in ETP-ALL cohort include normal KT in 34.8%, deletions in 17.4%, complex KT in 26.1% of cases and other abnormalities detected in 21.7%. The latter group includes one case with BCL11B rearrangement. Complex KT & near tetraploidy were only detected in ETP-ALL (p<0.05). Deletions were equally represented between both groups.

ETP/ALL are specially enriched in rearrangement of ABL-1 on chromosome 9 compared to non-ETP ALL (P. 0.035). Chromosome 9 rearrangements involves: +9, del(9)(p11), i(9)(q10) & ch9 translocations; including BCR::ABL-1 rearrangement. CDKN2A rearrangements are prevalent among non-ETP-ALL 11/26 (42.3%) compared to ETP-ALL 5/18 (27.7%). However, with no statistically significant difference and no difference in TRAD/14q or MLLq23 rearrangement. NGS performed on 8 cases revealed recurrent mutations involving PHF6 (2 cases), DNMT3, ETV6, IKZF1, SH2B3, WT1, PHF6, FLT3-itd, PRPF8, TP53 and EZH2

ETP-ALL showed higher rate of induction failure compared to other T-ALL subtypes (P. 0.005). The 6-yearsOS rate is ~50.3% in ETP-ALL compared to 81% in non ETP-ALL. P. >0.005. It is clearly demonstrated that the predicted OS of ETP-ALL showed progressive shortening over years compared to almost stable predicted survival rate in non ETP-ALL.

Conclusion:

ETP-ALL is an interesting & unique entity of Precursor T-ALL with multilineage differential potential. Our results showed that patients with ETP-ALL have significantly higher expression of myelomonicytic, stem cell and B-lineage associated markers (p.<0.05) and significantly lower expression of CD5, CD2 & surface CD3 compared to non-ETP ALL (p=<0.05). GATA 3 immunostain is positive in ~90% of ETP-ALL in ETP/ALL and is a useful marker for lineage establishment in cases with very primitive phenotype. ETP/ALL are specially enriched in rearrangement of ABL-1 on chromosome 9 (P. 0.035). ETP-ALL showed higher rate of induction failure compared to other T-ALL subtypes (P. 0.005). The predicted OS of ETP-ALL is shorter than non-ETP-ALL with progressive shortening of predicted OS over years compared to almost stable OS in non ETP-ALL.

No relevant conflicts of interest to declare.