High Incidence of Induction Failure and Poor Outcome in Patients with Gamma Delta T Cell Acute Lymphoblastic Leukemia
Authors: Dallas Mari H , Thomas Paul , Choi John , Evans William E. , Inaba Hiroto , Jeha Sima , Pui Ching-Hon 
Published: October 2019

Abstract
The two lineages of T cells, αβ and γδ, diverge early in development and recognize ligands differently. γδ T cells are not restricted by the major histocompatibility complex (MHC)and can recognize peptides, non-peptides as well as small molecules. The effector functions of αβ and γδ T cells are also biologically distinct. Mature T cell lymphomas derived from the γδ lineage are often aggressive with poor prognosis. For T cell acute lymphoblastic leukemia (T-ALL), it is customary to view the TCR expression on lymphoblasts as an indicator for the maturational state, although identification of the heterodimer can distinguish two distinct T cells. The αβ and γδ T cells are derived from different lineages with distinct developmental stages and biological characteristics. Here we evaluated the clinical presentation and outcomes of patients with γδ T-ALL who were treated on protocol to determine the impact of lineage specification on T-ALL prognosis.
From January 2004 to July 2014, 100 consecutive patients with newly diagnosed T- ALL were enrolled onto the Total Therapy XV or XVI study at St. Jude Children's Research Hospital (SJCRH). Of the 100 patients, 93 had diagnostic samples screened and confirmed for γδ TCR and were evaluable for follow up. Patients received risk-adaptive treatment consisted of remission induction, consolidation and continuation as previously described.
Of the 93 patients, 12 (13%) had γδ T-ALL. With the exception of higher percentage of γδT-ALL patients classified to have high risk disease based on high MRD levels (≥1%) at the end of remission induction (25% vs. 11%; P =0.04), there was no significant differences between the two groups in regards to age, gender, race, presenting leukocyte count, presence of a mediastinal mass and CNS involvement at diagnosis. Patients with γδ T-ALL had a significantly higher risk for induction failure with MRD ≥ 1% at day 15 (67% vs. 33%; P =0.006) and day 42 (25% vs. 11%; P =0.04). High portion of patients with γδ T-ALL (40%) were referred for an allogeneic hematopoietic stem cell transplantation. The overall survival was significantly lower for patients with γδ T-ALL compared to non-γδT-ALL at 5 years (63 ± 20% vs. 91 ± 4%) and 10 years (63 ± 38% vs. 88 ± 31%) (P =0.01). The event free survival was lower and relapse rate was higher for the γδ T-ALL patients compared to the non- γδ T-ALL patients, although not significant.
Majority of patients with γδ T-ALL had complex cytogenetic abnormalities (91%) and one patient had normal karyotype. Interestingly, hyperdiploidy (47-53) was common, but only one patient had high hyperdiploidy with a DNA index of 1.17. Immunophenotype showed variable expression of CD34, CD1a, CD2 and CD7. The pairing of the Vγ and Vδ chains expressed by the lymphoblast was identified using high throughput single cell PCR on the expressed cDNA. Out of 12 patients, 9 patients had appropriate consents, samples and successful amplification The TCR was predominately Vδ1 (67%) and the CDRγ region was highly conserved (~88%) between patients. Despite the broad diversity of the rearranged TRG region, the CDR3γ region was highly conserved. The CDR3γ region contained an average of 14.2±2.2 amino acids and each patient had an average of 3.3 ± 2.6 unique amino acids. An average of 11 ± 0.5 amino acids (88%) were conserved amongst the T-ALL patients. All the patients used the terminal TRGC2, suggesting a bias towards a non-disulfide linked TCR. Majority (>75%) of γδ T cell in normal peripheral blood is Vγ9Vδ2, and none of the patients expressed Vδ2. The dominant Vδ1 has been shown to be resistant to activation induced cellular death (AICD) and can persist for many years. This may correlate to the recent association of SET-NUP214, a fusion gene involving 9q34 that is specific for the γδ lineage and confers chemotherapy resistance. Further studies evaluating the genetic alternations will shed insight into to potential mechanisms. In summary, expression of the γδ TCR on T-ALL lymphoblasts identified a subset of patients with high risk for induction failure and poor outcome.

Disclosures
Evans: Prometheus Labs: Patents & Royalties: Royalties from licensing TPMT genotyping.