T-Cell Acute Lymphoblastic Leukemia

T-ALL patients may not always experience the all signs and symptoms below. Patients with other medical conditions that are not leukemia may also experience similar symptoms.

• Recurrent infections due to lack of normal white blood cells (neutrophils)[11]
• Unusual and/or common bleeding and bruising
• Extreme tiredness and swellings in the neck (lymph nodes) or the middle of the chest, causing possible facial swelling
• Unexplained fevers, chills, and/or night sweats
• Unexplained weight loss and/or loss of appetite
• Swollen lymph nodes
• Unexplained skin itch

T-ALL is not a contagious nor inherited condition. Its two main risk factors are age and gender.[8] Most cases of leukemia increase with age, with ALL being the main exception, which peaks in children aged 2 to 5 years. T-ALL is seen to be most prevalent in the adult population, but amongst cases in the pediatric population, it is seen to have a median onset of age 9 and is most prominent to adolescents.[6][10] The disease also is marked male predominance with a three-fold increased risk of developing T-ALL in comparison to females. It is currently unclear as to why T-ALL is preferential towards older children and males.[1]

Basic karyotyping showed structural chromosomal rearrangements in 50-75% of T-ALL patients, primarily inversion and translocations.[1] Diagnostic yield can be substantially increased through further diagnosis through Fluorescent In Situ Hybridization (FISH) and other various molecular technologies, for example Single Nucleotide Polymorphism (SNP) array. The most common structural abnormality is rearrangement of the TCR gene. 95% of T-Cell TCR consist of an alpha and beta chain (encoded by TRA and TRB, respectively), where only 5% of T-Cell TCR consists of gamma and delta chains (encoded by TRG and TRD, respectively).[4]

Karyotyping showed that TRD and TRB undergo recombination most commonly, whereas TRA is seldom involved and TRG is rarely rearranged. These rearrangements affect the normal process of TCR and could lead to cellular machinery failing to correctly repair recombination-activating RAG protein induced double-strand breaks (DSBs).[1] All 30 genes known to illegitimately recombine with TCR genes function primarily to regulate epigenetics through roles such as signal transducers, transcription factors (tumor suppressors or oncogenes), cell cycle regulators, or ribosomal proteins.

T-Cell TCR encoded by TRA, TRD, and TRG at chromosome bands 14q11 and 7q34 become malignant in T-ALL patients.[1] The build-up of malignant T-cells in T-ALL are clones with identical T-cell receptor gene arrangements having taken rise from a single cell. The gene rearrangements, as a result of the malignant cell, juxtapose both TCR genes and other critical genes that code for transcription factors. This results in dysregulation of partner gene transcription, which serves as the main cause of leukemogenesis - a multi-step process of induction, development, and progression of leukemic diseases.[1] 20% of all leukemias demonstrate simultaneous rearrangement of these genes.

Like most cancers, mutations in the DNA begin T-ALL development and lead to loss of function of white blood cells. Different subtypes of leukemia have similarities in their causes, which are a combination of genetics, epigenetic changes, and environmental factors. However, because there are few T-ALL cases in comparison to other subtypes of leukemia, there is currently no clear cause of T-ALL. T-ALL is not contagious nor inherited but specific genetic mutations, commonly including NOTCH1 and CDKN2A, may be passed along which increases susceptibility of T-ALL.[10]

When doctors are suspicious of a patient potentially suffering from T-ALL after careful examination of background (including medical history, signs, and symptoms), doctors would then conduct tests, procedures, and scans to proceed with diagnosis of T-ALL. Some symptoms and medical history may not be specific enough to diagnose T-ALL, so further testing may be required. Doctors may consider some factors mentioned but would not necessarily conduct all tests possible.[11]

Lumbar puncture

To prevent ineffective treatments towards T-Cells that have invaded the CNS, lumbar puncture allows doctors to determine whether the treatments will be effective. This also reveals the spread of T-ALL.[2]

Lumbar Puncture Positions

Currently, standard treatment of T-ALL takes the form of long-term chemotherapy and drug intake to prevent or treat side effects associated with low white blood cell count as a result of intensive chemotherapy regimes. The treatment typically takes place over three stages: induction, consolidation, and maintenance.[3] Treatment is expected to span over approximately two years with the maintenance phase lasting the longest. T-ALL can spread to areas of the brain and spinal cord,[2] which can be diagnosed through lumbar puncture assessment in patients suspected to suffer from T-ALL. Lumbar puncture helps to identify leukemic cells surrounding the cerebrospinal fluid (CSF).[3] Even if leukemic cells are not found in the CSF at the time of diagnosis, it is highly likely that they will spread there with time and progression of the disease. Henceforth, Prophylactic Intrathecal Chemotherapy in CNS lymphoma, a treatment to lower risk of leukemia spreading to the spinal cord and brain by directly administering chemotherapy to the CSF, is crucial.[3]

In comparison to B-ALL, T-ALL patients present more high-risk features including tendency for earlier relapse, CNS involvement, and resistance to chemotherapy. In response, Prophylactic Intrathecal Chemotherapy is further enhanced with CNS radiation therapy.[1] In treating high-risk T-ALL patients, allogeneic hematopoietic stem cell transplantation has been deemed to produce highly successful and promising results. However, its consequence includes increased relapse, which reduces its curative potential. Patients undergoing transplantation must be continuously monitored for Minimal Residual Disease (MRD), usually via qPCR analysis of T-Cell Receptor (TCR) genes to evaluate for fusion transcripts such as SIL-TAL1.[15] Mutation of TAL1 is frequently present in T-ALL patients, where SIL/TAL1 fusion gives rise to inappropriate TAL1 expression, in turn promoting T-Cell leukemogenesis.[4] The analysis is critical to ensure that immediate intervention is taken during early stages of relapse.

Young T-ALL patients showed significant improvement through multimodal therapy, involving initial induction therapy – including a glucocorticoid, vincristine, L-asparaginase, and an anthracycline - for 4 to 6 weeks, intensive combination therapy for 6–8 months, lastly 18–30 months of low-intensity anti-metabolite-based therapy.[8] It is crucial to note the importance of differential treatment amongst youth and adults. Studies have shown that through administering a random variation of either traditional pediatric scheme or intensive block-based chemotherapy, the two groups showed significantly different responses.[4] Although both treatments included administering high-dose methotrexate and asparaginase and allogeneic hematopoietic stem cell transplantation, high survival and low death rates were present for all patients for the first treatment whereas the latter led to a high toxic death rate amongst adults.[16]

In childhood, T-ALL patients can expect a 5-year event free survival and overall survival of, respectively, 70% and 80%.[1] Amongst approximately 25% of children who relapse, survival rate sits at 30-50% and the patients show much poorer prognosis.[1] Monitoring for MRD is critical as previously mentioned, through qPCR analysis, in order to evaluate the efficacy of treatment.

Recent genomic studies have found that a selection of genetic variants in relation to clonal evolution that drive resistance have been found as the basis for T-ALL relapse. Over 20% of patients with relapsed T-ALL showed mutation in the variant cytosolic 5’-nucleotidase II (NT5C2) gene, while the TFDP3 gene has also been found to confer chemoresistance in children.[1]

Although over 100 genes mutations have been identified in T-ALL patients, only NOTCH1 and CDKN2A mutations are considered to be common.[13]

In over 50% of pediatric T-ALL cases, mutations in epigenetic regulators have been identified.[5] This activates mutations of NOTCH1 and gene FBXW7 causes the tumor-suppressing gene to lose its functions, leading to T-ALL.[17]

Near-telomeric location may sometimes generate subtle exchanges in DNA material at the loci involved in oncogenic rearrangements of T-ALL. This causes cryptic translocation and therefore deletes the putative tumor suppressor gene CDKN2A (INK4A). At the same time, TLX1 and NOTCH1 may also be activated at higher frequency than usual. The multistep prognosis of T-ALL has hence been said to intensify and rapidly progress due to accumulation of effects resulting from dysregulation of multiple signaling pathways.[5]