LGL leukemia can be divided into T and NK cell associated diseases, with T-cell disease being significantly more common and less aggressive than NK cell disease [1, 9,10,11]. T-LGL leukemia, as noted above, is a rare lymphoproliferative disorder with variable but generally indolent course [2, 3, 12]. In this condition, CD3+/CD8+ T lymphocytes proliferate and can infiltrate bone marrow, liver, and spleen . Symptoms are often due to anemia and neutropenia, as well as autoimmune features and arthralgias . This may explain our patient’s preliminary diagnosis of lupus. These patients can also have persistent lymphocytosis, hypergammaglobulinemia, and splenomegaly . The majority of patients with T-LGL leukemia will eventually need some treatment, which is often immunosuppressive .
As noted above, what makes this case particularly unique and notable is the aggressiveness of her disease and profound and persistent neutropenia to 0. Furthermore, the GVHD prevention after transplant was a novel approach. This is one of the first such cases of allogeneic stem cell transplant for T-LGL leukemia in the USA. This case is particularly remarkable given the severity of her neutropenia and multiple failed prior lines of treatment, and the effectiveness of stem cell transplant in treating this previously refractory disease. We hope to raise awareness of allogeneic bone marrow transplant as treatment for refractory T-LGL leukemia.
Genome-wide mutational analysis of LGL leukemia cells appeared to be enriched in cellular signaling cascades that have been implicated in the abnormal survivability of the cells . In particular, signal transducer and activator of transcription factor 3 (STAT3) is a mutation that has been described in approximately one-third to half of LGL leukemia cases [3, 13, 14]. Mutations in STAT5b have been associated with a more aggressive clinical course (PMID: 23596048). Blockage of interleukin 6 (IL6) has also been shown to return adequate LGL cell apoptosis, suggesting its involvement in LGL leukemia . Additional pathways have been implicated, including MAPK, RAS-RAF1, MEK/ERK, and NFKB . Shah et al.  also showed that LGL leukemia patients have dysregulation of Fas-mediated apoptosis. Gazitt and Loughran  described how neutropenia, as seen in our patient, is a fairly common sign of LGL leukemia. They also discuss how associated immunocompromise contributes to the morbidity and mortality associated with LGL leukemia. They discuss how LGL leukemia causes neutropenia through a few mechanisms, including hypoplasia, inhibitory cytokines, and elevated Fas ligand, which can cause apoptosis in neutrophils .
T-LGL is often a fairly indolent disease, but our case shows how it can be aggressive, progressive, and debilitating. Alekshun et al.  performed a review of 13 cases of aggressive T-cell LGL leukemias. They noted that most patients with aggressive disease were CD3+, CD8+, CD56+, and CD57–. However, our patient had CD57 positivity. They noted that patients with aggressive T-LGL leukemia had B-symptoms, lymphadenopathy, cytopenias, and splenomegaly.
Standard of care therapies
Treatment for LGL leukemia often begins when patients develop severe neutropenia, symptomatic neutropenia, or constitutional symptoms due to transfusion-dependent anemia . However, many patients do not require therapy . Immunosuppression is the backbone of first-line LGL leukemia treatment, consistent with our understanding above that LGL leukemia represents constitutively activated lymphocytes . This first-line treatment often involves methotrexate, cyclophosphamide, and cyclosporine . Some reports note that cyclosporine or oral weekly methotrexate leads to responses in about 75% of cases . Our patient underwent a fairly similar regimen, but unfortunately did not have a good response. Growth factors such as erythropoietin or granulocyte colony-stimulating factor (GCSF) can help to augment response to therapy. Patients need to undergo at least 4 months of treatment before assessing for response, via clinical and blood count assessment [1, 18]. It has been shown that about 50% of patients respond to these regimens, and all of these treatment options lead to fairly similar responses . Second-line treatment is variable and can include purine analogs, such as pentostatin, which our patient received, and alemtuzumab [17, 3].
Some of the current research on LGL leukemia treatment has focused on novel therapies that are more targeted towards the disease’s pathogenesis. As noted above, STAT3 has been implicated in LGL leukemia. The JAK inhibitor, tofacitinib, which works on the JAK-STAT pathway, was studied in a small population of nine patients with refractory T-LGL leukemia and associated rheumatoid arthritis . In that trial, six of nine patients had hematologic response, and five out of seven had improvement in neutropenia. Moignet and Lamy noted promising results in trials of JAK/ STAT inhibitors and cytokine inhibitors for LGL leukemia.
There are also some data regarding alemtuzumab, a monoclonal antibody against CD52 that is often used in organ transplantation, as a potential treatment for LGL leukemia. Dumitriu and colleagues performed a phase 2 open-label study of alemtuzumab in patients with T-cell LGL leukemia . This was a small but somewhat promising study, as 14 of 19 patients had positive response. However, alemtuzumab causes prolonged depletion of B and T lymphocytes, which can be both helpful and harmful . The benefits of treatment with alemtuzumab may not outweigh the risks of profound and prolonged immunosuppression in more mild cases of T-LGL leukemia . Alemtuzumab treatment is associated with viral reactivation, particularly of cytomegalovirus (CMV) . This can have serious consequences for immunocompromised patients, as well as those anticipating or undergoing stem cell transplant.
Stem cell transplant
Alekshun et al.  published a case report of a patient with aggressive T-cell LGL leukemia who underwent aggressive multimodal treatment and eventually autologous bone marrow transplant. Their patient presented with acute-onset B symptoms, anemia, low platelets, and hepatosplenomegaly. The malignant cells in his blood showed CD3+, CD8+, and CD56+, and T-cell receptors showed clonal rearrangement. He was diagnosed with aggressive T-LGL leukemia. He underwent treatment with cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) alternated with methotrexate and cytarabine. He also received intrathecal methotrexate and cytarabine. GCSF and alemtuzumab were given to help mobilize peripheral blood hematopoietic cells. He then received carmustine, etoposide, cytarabine, and melphalan (BEAM) as a conditioning regimen before autologous stem cell transplant. This study showed that autologous stem cell transplant could be a treatment option for T-cell LGL leukemia. However, their patient’s neutropenia was not as severe as in the patient described heein. The British Society of Hematology’s 2011 guidelines for T-cell neoplasms note that patients with aggressive T- LGL leukemia should undergo more intensive combination chemotherapy, but they noted that there are insufficient data to support one regimen over another .
La Nasa et al.  published another case that demonstrated the role of stem cell transplant in LGL leukemia. They treated a 57-year-old man with LGL leukemia and multiple sclerosis (MS) with allogeneic stem cell transplant from a sibling who was an HLA-identical match. Their patient underwent a conditioning regimen with fludarabine, busulfan, and cyclophosphamide. He underwent GVHD prophylaxis with cyclosporine and methotrexate. He was doing well at 3 years of follow-up and had complete remission of his LGL leukemia. To note, his MS also improved after hematopoietic stem cell transplantation (HSCT). This also highlights the autoimmune manifestations of LGL leukemia.
In 2016, the European Society for Blood and Marrow Transplantation  published a review of stem cell transplant for T-LGL leukemia. They discussed escalating therapy with intensive chemotherapy and possibly stem cell transplant for aggressive cases. They described 15 patients who had either autologous HSCT or allogeneic HSCT for T-cell LGL leukemia. Five patients underwent autologous stem cell transplant, and ten underwent allogeneic stem cell transplant. A variety of conditioning regimens were used, including BEAM, cyclophosphamide with total body irradiation (CY-TBI), fludarabine, melphalan, and alemtuzumab, and others. There were also a variety of previous treatments for each of the patients. These data all indicate that there is no standardized way to treat LGL leukemia, especially more complicated, refractory, or aggressive cases. This also highlights the variety of ways to prepare patients for bone marrow transplant for this condition. Thus, all of this only indicates the need for further research on and awareness of bone marrow transplant, both autologous and allogeneic, to treat LGL leukemia.
Three of the patients in the above-mentioned review who had autologous transplant had complete response, and two had progression of disease. Three were alive at last follow-up. Of the ten patients who had allogeneic stem cell transplant, five had complete response, two had partial response, one had progression, one had relapse, and one did not have data on his disease response. Seven of the patients who underwent allogeneic stem cell transplant had GVHD. Five patients had acute GVHD, and two patients had chronic GVHD. Of the patients who had acute GVHD, two patients had grade 1, one had grade 2, one had grade 3 acute, and one had grade 4 disease. Two additional patients had what was described as extensive chronic GVHD. Five of the ten patients who underwent allogeneic stem cell transplant were alive at last follow-up. One patient died of fungal infection, another died of viral and fungal infection, one died of GVHD and viral infection, and another died of relapse. This shows that bone marrow transplant for LGL leukemia is not without risks.
Donato and colleagues also described their experience with two patients with T-cell LGL leukemia who they treated with reduced-intensity allogeneic stem cell transplant, similar to our case . One of their patients was a 54-year-old woman with profound anemia and splenomegaly due to T-cell LGL leukemia. She underwent treatment with methotrexate, cyclosporine, equine antithymocyte globulin, and alemtuzumab. She then underwent a fludarabine and melphalan conditioning regimen before a related donor stem cell transplant. The other patient was a 34-year-old woman with T-cell LGL leukemia and associated lymphocytosis and infections. She failed treatment with a splenectomy and cyclosporine. She underwent conditioning with rabbit anti-thymocyte globulin, fludarabine, and melphalan, before nonrelated donor stem cell transplant. Both patients underwent GVHD prophylaxis with tacrolimus and methotrexate. The latter had stage 1 skin GVHD. Both patients achieved complete remission, and at the time of that publication both were in complete response greater than 1 year after transplant.