Gamma-Delta T Cell Acute Lymphoblastic Leukemia: A Single-Center Experience

Gamma-delta (γδ) T cell neoplasms are a rare disease entity characterized by an aggressive clinical course [1,2]. The management of these neoplasms associated with high incidence of induction failures and poor clinical outcomes [3]. Here we present two cases of gamma-delta T cell acute lymphoblastic leukemia (γδ T-ALL) successfully treated with chemotherapy and allogeneic stem cell transplant at our institution. We also review the literature and summarize what is known about this disease. In our experience, induction chemotherapy followed by allogeneic stem cell transplantation has been an effective strategy in producing durable remissions. Case Report Gamma-Delta T Cell Acute Lymphoblastic Leukemia: A SingleCenter Experience Donnellan W1, Mineishi S2, Wicker J3 and Paluri R1* 1Division of Hematology Oncology, University of Alabama at Birmingham 2Dept of Bonemarrow Transplantation, University of Alabama at Birmingham 3Dept of Hematopathology, University of Alabama at Birmingham Dates: Received: 09 December, 2016; Accepted: 26 December, 2016; Published: 29 December, 2016 *Corresponding author: Ravi Kumar Paluri, MD., MPH, University of Alabama at Birmingham, Hematology Oncology, NP 254


Introduction
Two different antigen receptors have been described for T lymphocytes. Both have two polypeptide chains that recognize antigen and participate in T cell effector function [4,5]. The more common alpha beta T cell receptor (TCR) is present on the majority of peripheral blood T lymphocytes. In 1986 a second TCR, the gamma-delta receptor, was fi rst described [6,7]. This receptor has subsequently been identifi ed on approximately 1-5% of circulating blood T lymphocytes [8,9].
Immunophenotypically, the vast majority of gamma-delta T lymphocytes are negative for both CD4 and CD8 [10]. This is in contrast to alpha-beta T lymphocytes which are typically CD4+CD8-or CD4-CD8+ [11].
Gamma delta T cell malignancies are rare and comprise a minority of precursor T-cell lymphoblastic leukemias ( T-ALL), T-cell granular lymphocytic leukemias (T-LGL) and peripheral T cell lymphomas (PTCL) [12]. Specifi cally in regards to ALL, 2 -14 % expresses the gamma delta TCR [13,14]. The  T-ALL/LBL, T-LGL, and PTCL subtypes vary in their clinical presentation, treatment response and outcome. Historically,  T-ALL/LBL has been treated similar to lymphoblastic lymphoma/leukemia of other cell origin (i.e. B-ALL). However, the best induction regimen and consolidation strategy for this unique entity remains unknown. In the past the long term survival for patients diagnosed with this disease has been poor despite aggressive therapy [12]. Here we present two cases of  T-ALL/LBL in young adult female patients and describe their management and outcome.

Case 1
Case 1 is a 26 year old pregnant female who initially presented in January 2012 at 25 weeks gestation with left shoulder pain. A routine work up performed by her obstetrician revealed a WBC count of 200,000 with 92% circulating blasts ( Figure 1). She was referred to the high risk obstetrics service at this hospital and hematology was consulted for management.
Peripheral blood fl ow cytometry was performed which was consistent with  T-ALL. She underwent induced vaginal delivery which was uncomplicated and was then transferred to the hematology inpatient service for treatment. Following transfer, a bone marrow aspiration and biopsy was performed that confi rmed acute lymphoblastic leukemia, T-cell lineage, gamma delta subtype ( Figure 2). The blasts expressed CD3,

Discussion
Few series have described the clinical course and outcome of  T-ALL [3]. A small series published in 1991 describes 5 cases of gamma-delta T ALL in children [15]. In this review the mean age at onset of the disease was 1.8 years compared to 5.9 years seen in other pediatric T-ALLs. All patients had marked hepatosplenomegaly which has also been described in adults with this disease. Immunophenotypically these leukemias were CD3+, CD5+, CD7+, CD4-, and CD8-. The majority were negative for TdT and CD1. The management of the patients in this series was not discussed. However, only 1 patient remained alive and in remission at the time of publication.
 T-ALL in the adult population has aggressive clinical course and the management was poorly described [2,3]. One series published in 2005 compared 19 cases of gamma delta T-ALL (9 children, 10 adults) with 22 cases of alpha beta T-ALL (11 children, 11 adults) [14]. In adults the majority of patients with  T-ALL/LBL were men (8 of 10) and only 2 presented with a mediastinal mass. This is in stark contrast to our two patients who were both female and presented with symptoms attributable to a mediastinal mass. OS survival at 5 years in this series was comparable between the gamma delta and alpha beta group (50% vs. 55%, p = 1.000). Treatment strategies however were not discussed.
A third review published in 2002 does describe the treatment and outcome of fi ve adult patients with  T-ALL/LBL [12]. All patients received multiagent induction chemotherapy that  Those who received a transplant relapsed at 16 (allo), 38 (auto) and 10 (auto) months after transplant and died 29, 60 and 14 months after initial diagnosis, respectively. The two that did not receive a transplant both lived for only 9 months.
Here we have presented two cases of  T-ALL in young adult female patients. Complicating the fact that this is a rare disease with a lack of consensus on treatment is that one of these patients presented in the third trimester of pregnancy.
Both patients received induction chemotherapy with standard ALL regimens that included vinca alkaloids, anthracyclines, asparaginase and steroids. Consistent with previous reports, the response to induction chemotherapy was good with both patients entering a complete remission. Despite an initial response, the patient that did not undergo upfront allogeneic stem cell transplant experienced relapse within 8 months of initial treatment. In this patient a second remission was attained with salvage treatment and both patients now remain in complete remission following allogeneic unrelated stem cell transplant.
In conclusion, the rarity of  T-ALL makes prospective studies evaluating the effi cacy of various treatment strategies diffi cult. Treatment recommendations must therefore be garnered through anecdotal reports and small retrospective series. Recent data suggested that it may be prudent to have genetic characterization of the disease along with assessment of minimal residual disease (MRD) in bone marrow to identify the patients with possible good outcomes when treated with pediatric protocols [14]. Another study from Germany demonstrated that patients with poor MRD response has relatively more benefi t from allogeneic transplant in fi rst complete remission (CR) when compared to those with good MRD response [15]. However, there is paucity of this data applicable to the small subset of  T-ALL patients. Therefore it is likely that newer treatment regimens used along with the analysis of MRD may improve outcome of T-ALL in general including this subset, and will better clarify which patients could benefi t from an allogeneic SCT frontline. Based on a review of the literature as well as our own experience administering standard ALL regimen to induce the remission, followed by upfront allogeneic transplantation to eradicate potential residual disease by graft versus tumor effect can be considered in eligible patient to improve the likelihood that long term disease control.