Non-Hodgkin lymphoma (NHL):
Adult T-cell leukemia (ATL) was first reported as a distinct clinical entity in Japan in 1977. The clustering of patients in the southwestern part of Japan propelled Japanese investigators to the interest that the disease could be virally induced. Subsequently, human T-cell leukemia virus type I (HTLV-1) was discovered as the causative virus for ATL in 1982. The discoveries of ATL and HTLV-1 ushered in the development of virology, oncology, molecular biology, epidemiology, and other fields of medicine.
Human T-cell leukaemia virus type I (HTLV-1):Adult T cell leukemia is primarily caused by HTLV-1 infection that usually remains asymptomatic. Transactivator protein (tax) and HTLV-1 basic leucine zipper factor (HBZ), the two viral oncoproteins, play an essential role in the development of disease and progression. Tax protein expression takes part in the onset of neoplastic transformation. HBZ protein is expressed on all infected malignant cell lines, which is responsible for the proliferation of leukemic cells.
- Endemicity: North and south parts of Japan, the Caribbean region, Africa, some parts in the Middle East, South, and Central America
- Transmission: Breastfeeding, sexual interaction, and blood transfusion.
Initial presentation may vary, including generalized lymph node swelling, hepatosplenomegaly, skin involvement, and opportunistic infections.
Clinical classification:ATL is classified into four clinical subtypes according to the Shimoyama criteria
- Acute ATL (>50% cases): Presents with leukemic pictures, systemic symptoms, lymphadenopathy, organ infiltration, hypercalcemia, and high serum lactate dehydrogenase (LDH) level
- Chronic ATL: Characterized by presence of skin, lung and liver involvement, lymphocytosis (≥4 × 103 cells/μL) with normal LDH, and calcium
- Further two subgroups: favorable (better prognosis) and unfavorable (poorer prognosis with at least one poor prognostic factor such as elevated LDH, elevated BUN, and decreased albumin)
- Lymphomatous ATL: Characterized by extensive lymphadenopathy, organomegaly, markedly increased LDH, hypercalcemia, and < 1% presence of circulating leukemic cells in the peripheral blood.
- Smoldering ATL: Presents with lung or skin involvement, normal lymphocyte count, normal or mildly increased LDH
Cutaneous involvement:All forms of ATL may demonstrate variable skin findings.
Tumor lysis syndrome, as well as central nervous system involvement, may be seen in aggressive ATL. Due to severe immunosuppression, all ATL patients are at increased risk for infections, including fungal, viral, and parasitic infections, specifically strongyloidiasis.
Diagnosis of adult T cell leukemia requires a comprehensive history review in conjunction with laboratory and pathologic survey.
Peripheral blood smear:In the acute and chronic leukemic phase, the WBC count may increase with circulating atypical cells.
- Flower cell or cloverleaf (PATHOGNOMIC): Condensed chromatin with a convoluted or polylobated nucleus
Molecular diagnosis:The sensitivity for the diagnosis of HTLV-1 is higher with ELISA than with Western Blot and negative test rules out ATL
- Western Blot and/or PCR (if Western Blot is indeterminate)
Tissue biopsy:Excisional lymph node biopsy, skin biopsy, and GI tract biopsy in conjunction with flow cytometry and immunohistochemistry (IHC) are helpful for the diagnosis. Bone marrow aspiration and biopsy may also be needed for diagnosis and staging.
- Flow cytometry & immunohistochemistry (IHC):
- Express: CD2, CD4, CD5, CD45RO, CD29, and T-cell receptor αβ
- Do not express: CD7, CD8, or CD26
- Reduced expression: CD3
Differential diagnosis:The differential diagnosis of ATLL includes other mature T‐cell neoplasms
- T‐cell prolymphocytic leukaemia (T‐PLL)
- Sézary syndrome (SS)
- Peripheral T‐cell lymphomas
- Hodgkin disease
Treatment is tailored according to clinical subtype and patients characteristics. Chemotherapy or antiviral regimen is generally the first-line treatment for aggressive type (acute, lymphoma, and chronic with unfavorable features). Antiviral regimen or watchful waiting is a reasonable first-line for smoldering and favorable chronic subtypes. For skin lesions, ultraviolet B (NB-UVB) and psoralen and ultraviolet A (PUVA) can be used.
Antiviral therapy:Patients with leukemic forms of ATL showed improved results with first-line antiviral therapy (zidovudine and interferon), whereas patients with lymphoma type showed a better outcome with chemotherapy.
- Zidovudine (AZT) + interferon (IFN)
- Standard chemotherapeutic regimen:
- VCAP-AMP-VECP (LSG-15) regimen: Vincristine, cyclophosphamide, doxorubicin, prednisone-doxorubicin, ranimustine, and prednisone-vindesine, etoposide, carboplatin, prednisone
- Alternative regimens:
- Modified EPOCH regimen: Etoposide, prednisolone, vincristine, carboplatin, and doxorubicin; carboplatin is substituted for cyclophosphamide)
- Hyper-CVAD regimen: Hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone
- CHOP regimen: Cyclophosphamide, doxorubicin, vincristine, and prednisone
- CHOEP regimen: Cyclophosphamide, doxorubicin, etoposide, vincristine, and prednisone
Allogeneic Stem Cell Transplantation
Monoclonal Antibody Therapy Brentuximab Vedotin
- Brentuximab vedotin (BV): CD30-directed monoclonal antibody
- Mogamulizumab: Humanized anti-CCR4 monoclonal antibody (approved for relapsed/resistant ATL in Japan)
- Alemtuzumab: Humanized monoclonal antibody against CD52
- Daclizumab: Humanized monoclonal antibody that binds to CD25 (interleukin-2 receptor alpha chain) that is over-expressed on ATL cells
Prognosis:Patients who have rapidly progressive disease carry a poor prognosis due to the chemo-resistance of malignant cells and severe immunosuppression.
- Aggressive ATL (acute, lymphoma, and chronic (unfavorable) type): Have a poor prognosis with an overall survival rate of less than a year
- Favorable chronic and smoldering subtypes: Carry a relatively good prognosis, and watchful waiting is generally preferred until disease progression occurs