PTCL is a type of non-Hodgkin lymphoma that primarily affects T-cells. It characterizes by recurrent gains on chromosome 7q and high expression of transcription factors and their downstream targets. Treatment options are largely based on a combination of cytotoxic agents.
PTCL is a non-Hodgkin lymphoma
PTCL is a type of non-Hodgkin lymphomoma (NHL). The condition affects T-cells of the peripheral lymphatic system, which carries lymph fluid throughout the body. It usually affects the lymph nodes, although it can also affect the skin, liver, or bone marrow. PTCL is rare and largely incurable, but research is underway to develop new therapies.
Patients with PTCL should consult a hematopathologist for a diagnosis. Because the disease is rare, it is important for patients to undergo a complete evaluation. During the pathology evaluation, the pathologist should review the cases to rule out other possible diagnoses. Occasionally, the diagnosis of PTCL may not be definitive, but the pathologist’s expertise and the clinical picture may point to the correct diagnosis.
Patients with PTCL will undergo a multidrug chemotherapy regimen. The standard regimen for treating this disease has traditionally consisted of cyclophosphamide, doxorubicin, and prednisone. Recent studies suggest that a combination of these drugs can produce better results and longer remissions. Another option for patients with PTCL is a stem cell transplant. This method may help patients with PTCL that has spread to their organs or triggers by a virus.
PTCL is difficult to diagnose, but accurate immunophenotypic analysis can lead to a reliable diagnosis. With proper immunophenotypic analysis, PTCL can categorize into subtypes based on their histological characteristics. Using a REAL classification system makes it easy to identify the correct diagnosis of patients with PTCL.
PTCL is rare and occurs in approximately 10% of non-Hodgkin lymphomoma cases. It affects mature T cells in the lymphoid tissue outside the thymus and accounts for six to ten percent of all NHL cases. It can affect individuals of any age or gender, although males over 60 are more likely to develop it. Patients with PTCL will usually present with symptoms of late stage disease.
It is a mature T-cell neoplasm
T-cell lymphoma is a form of cancer that develops in the immune system. It starts in the thymus, a small organ behind the breastbone and in front of the heart, where T cells produces. If left untreated, this cancer can spread to the bone marrow and form a large tumor. In most cases, chemotherapy is the recommended treatment.
There are several types of T-cell lymphomas, including non-Hodgkin lymphoma. While T-cell lymphomas are rare, they are not unusual and can cause significant problems for patients. This type of cancer affects around seven percent of the population and can be aggressive or indolent.
ATLL is a rare type of T-cell lymphoma. It may develop in the blood, lymph nodes, skin, or multiple organs. It causes by an infection with the Human T-Cell Lymphotropic virus (HTLV-1) and most commonly acquired through breastfeeding. About five percent of people infected with HTLV-1 will develop lymphoma.
It has recurrent gains of chromosome 7q
Recurrent gains of chromosome 7q are a hallmark of PTCL, and a genetic analysis has provided an improved understanding of the disease’s molecular landscape. Despite these gains, PTCL is a heterogeneous group of tumors. However, microarray analysis has uncovered a distinctive biological entity, with an associated proliferation signature. Furthermore, large-scale gene-expression profiling has identified two distinct molecular subtypes: those with high expression of GATA3 and TBX21. Nevertheless, the genetic landscape of PTCL is still incomplete, and more work needs to identify the driver events.
One of the drivers of PTCL is a mutation in the IRF4 gene. This gene is responsible for a large number of immune-related traits, including inflammation, and implicates in the pathogenesis of PTCL. Several studies suggest that a gene, associated with IRF4 involves in the disease. Moreover, a subset of patients with PTCL has a translocation of the IRF4 gene. In this case, CD30 inhibitors may be effective.
Several subgroups of PTCL have chromosome 7q gains. The most frequent gains were seen in AITL and PTCL-US subgroups. These subgroups also showed an increased frequency of simultaneous gains of 5q and 21q.
Recurrent gains of chromosome 7q are known to target the cyclin-dependent kinase (CDK6) gene and the MYC locus. This fusion transcript mimics the human disease and may be a potential therapeutic target.
Patients with PTCL-NOS often show an intermediate genetic feature: TP53/CDKN2A deficiency is more frequent in patients with PTCL-NOS than in patients with non-TFH. TP53 and CDKN2A deficiency may be responsible for the distinct behavior of these patients.
It has high expression of transcription factors and downstream target genes
Mutations in b-catenin (BCL6), CDKN2A/B and TP53 are frequently found in PTCL. The Ctnnb1 mutation in a PTCL clone in the mouse linkes to cellular transformation. Exome sequencing has been performed on mPTCL and showed that 44 genes harbored deleterious somatic mutations. Of note, a high expression of Dis3 and GATA3 was observed in four mPTCL samples.
The mutations in PTCL have distinct oncogenic mechanisms, supporting a targeted treatment approach. Mutations in PTCL-GATA3 involve epigenetic regulators. Hence, hypomethylating agents and histone deacetylase inhibitors are advocated as potential treatment options for PTCL-GATA3-like lymphoma. Moreover, PTCL-GATA3 is frequently associates with PI3K/mTOR activity.
The high expression of these transcription factors associates with increased replication stress in mPTCL. In addition, the expression of RPA2 and CHEK1 was found to be elevated in human T-cell lymphoma cells. Furthermore, both mPTCL and human T-cell lymphomas upregulate genes involved in the ATR pathway. This suggests that replication stress is ongoing in mPTCL and may be related to loss of the TP53/CDKN2A/B pathway.
Genetically engineered mice develop to study mPTCL. These mice contain mutations, introduced in mPTCL through genomic or T-cell-targeted transgenic approaches. These mice develop lymphomas with disease-relevant cellular phenotypes and persistent T-cell activation, which is consistent with a PTCL-GATA3 subtype.
These results suggest that mPTCL is a good model to test new therapeutics in a human patient population. The mPTCL model represents a novel model of PTCL biology and provides rationale for future clinical exploration of ATR inhibitors.
It has a good response to azacitidine plus CHOP
There are currently several trials that test azacitidine plus CHOP in patients with advanced PTCL. Two phase I and two phase II studies have shown promising results, but both limites by a high rate of hematological toxicity.
CC486, an oral azacitidine-based chemotherapy, is an effective initial therapy for PTCL. It produces a long-lasting remission in patients with PTCL-TFH subtype. Azacitidine believes to induce epigenetic priming, which inhibits the proliferation of TFH lymphoma cells. This mechanism may help explain the synergistic effect of azacitidine and CHOP. This combination is currently under evaluation in randomized trial A051902 and will be compared with duvelisib-CHOP.
Despite the success of the first phase I/I study, a larger multicenter phase II study of patients with PTCL found no superiority for azacitidine plus CHOP over CHOP alone. However, a better understanding of PTCL biology and its biomarkers will help to guide future up-front trials. These findings are likely to improve the standard of care and lead to better treatments for this disease type.
While azacitidine plus CHOP is an effective treatment option for patients with peripheral T-cell lymphoma, it has been disappointing to see limited response rates. Currently, the field is interested in testing novel combinations in both untreated and R/R PTCL patients. The article lists several promising combinations where data are currently available and lists ongoing trials that are studying these combinations.
In one study, azacitidine plus CHOP significantly improved patient survival. Patients with PTCL had a median age of 66 years, and their disease stage was stage III or IV. A median PFS and OS were 9.4 months in these patients. In addition, these patients had elevated LDH levels and bone marrow involvement.
