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Adult T-Cell Leukemia
Introduction
Adult T-cell leukemia (ATL) is a highly aggressive mature T-cell neoplasm associated with human T-cell lymphotropic virus type 1 (HTLV-1) infection, which affects around 10 million people in the world. Of them, approximately 1-5% eventually develop symptomatic ATL.[1] HTLV-1 is the first human retrovirus and is endemic in the north and south parts of Japan, the Caribbean region, Africa, some parts in the Middle East, South, and Central America.[2] HTLV-1 transmission occurs from mother to child through breastfeeding, sexual interaction, and blood transfusion. Initial presentation may vary, including generalized lymph node swelling, hepatosplenomegaly, skin involvement, and opportunistic infections.
ATL is classified into four clinical subtypes: acute, lymphoma, chronic, and smoldering type. Aggressive ATL (acute, lymphoma, and chronic type with unfavorable prognostic factors) have a poor prognosis with an overall survival rate of less than a year. The favorable chronic and smoldering subtypes carry a relatively good prognosis, and watchful waiting is generally preferred until disease progression occurs. Patients who have rapidly progressive disease carry a poor prognosis due to the chemo-resistance of malignant cells and severe immunosuppression.[3]
Etiology
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Etiology
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.[4]
Epidemiology
Prevalence is high in southwestern Japan, the Caribbean region, West Africa, and northeast Iran, south and Central America, and there is a slight male predominance across the studies. HTLV-1 and ATL are rarely reported in North America. A recent report of ATL cases from 2001 to 2015 in North America showed an incidence rate of 0.06 per 100.000 population.[5] In Japan, the annual incidence was reported to be around 60 per 100.000 carriers with 1000 death each year.[6]
Pathophysiology
ATL is uniformly associated with HTLV-I infection of CD4-positive T cells that play a significant role in the pathogenesis of ATL.[7] The tumor-initiating cell appears to be an HTLV-I infected CD4-positive memory T cell with stem cell-like properties. However, HTLV-1 infection is not enough for malignant transformation. HTLV-1 infects CD4 T-cells and causes cell proliferation and transformation through viral gene products that interact with host proteins and alter gene function. HTLV-1 genome contains Gag, Pol, Env, and regulatory genes Tax and HBZ. Inducing the death of infected cells is achieved by Tax-specific cytotoxic T-cell responses and antibody response against viral proteins (Env, Gag).[8]
Tax and HTLV-1 B-zip protein (HBZ) are the viral regulatory proteins associated with neoplastic transformation and proliferation. HTLV-1 can escape from the host immune response by reducing Tax and activating HBZ expression. HBZ inhibits Tax-dependent viral transcription and induces its own expression. Therefore, it maintains chronic infection. HBZ viral protein is the only one continuously expressed in ATL. It has been reported that clones of ATL cells with the same proviral integration site can have different T cell receptor rearrangements, raising the possibility that ATL may arise from immature HTLV-1 infected hematopoietic progenitors.[9]
ATL is frequently associated with hypercalcemia, which can be severe. The hypercalcemia seen in ATL is thought to arise from cytokines released from the malignant cells. There are several proposed mechanisms, including the production of parathyroid hormone-related protein (PTH-RP), tumor necrosis factor-beta, or interleukin-1, increased RANKL expression (receptor activator of nuclear factor-kB ligand). These factors may also contribute to the genesis of the lytic bone lesions, increased bone turnover, increased serum alkaline phosphatase.[10]
History and Physical
Adult T cell leukemia is clinically classified into four subgroups defined by the Shimoyama criteria: acute, chronic, lymphoma, and smoldering[11].
- Acute subtype accounts for >50% of cases and presents with leukemic pictures, systemic symptoms, lymphadenopathy, organ infiltration, hypercalcemia, and high serum lactate dehydrogenase (LDH) level.
- Chronic ATL is characterized by the presence of skin, lung and liver involvement, lymphocytosis (≥4 × 103 cells/μL) with normal LDH, and calcium. The chronic ATL has two subgroups: favorable and unfavorable. The unfavorable subgroup presents with at least one poor prognostic factor such as elevated LDH, elevated BUN, and decreased albumin[12].
- The lymphomatous form is characterized by extensive lymphadenopathy, organomegaly, markedly increased LDH, hypercalcemia, and less than 1% presence of circulating leukemic cells in the peripheral blood.
- The smoldering form presents with lung or skin involvement, normal lymphocyte count, normal or mildly increased LDH.
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.
Evaluation
Diagnosis of adult T cell leukemia requires a comprehensive history review in conjunction with laboratory and pathologic survey. ATL is diagnosed mainly in patients from HTLV-1-endemic areas, e.g., Southwestern Japan, the Caribbean area, and South America, sub-Saharan Africa, and some regions of the Middle East and Australo-Melanesia.[13] HTLV-1 is transmitted by sexual intercourse, prolonged breast-feeding (at least six months), and exposure to contaminated blood products that contain HTLV-1 infected lymphocytes. Hypercalcemia is noted in approximately 70% of ATL patients. It is multifactorial in etiology, with the most prominent mechanism being humoral hypercalcemia of malignancy.[14] PTHrP is overexpressed in ATL cells, and it is associated with lytic bone lesions. However, PTHrP mRNA is highly expressed in aggressive type ATL when compared to indolent subtypes. Refractory hypercalcemia is also rarely seen in HTLV-1 induced ATL, and it can cause renal dysfunction, neuropsychiatric disturbances, and paralytic ileus on presentation.[15][16] Severe eosinophilia may be present. Dysregulation of the Th2 response against opportunistic pathogens has been blamed for causing eosinophilia.[17] In patients with disseminated strongyloidiasis may also present with eosinopenia.
In the acute and chronic leukemic phase, the white blood cell count may increase with circulating atypical cells. The peripheral blood smear may show condensed chromatin with a convoluted or polylobated nucleus, often called a “flower cell” or “cloverleaf” that is pathognomonic for ATL.[18] HTLV-1 infection should be confirmed by ELISA and Western Blot and/or PCR (if Western Blot is indeterminate). The sensitivity for the diagnosis of HTLV-1 is higher with ELISA than with Western Blot and negative test rules out ATL.[19]
Many other cytologic variants can be observed, such as large cells, anaplastic cells, and Sézary-like cells. Overall, the recommended panel should include CD3, CD4, CD5, CD7, CD8, CD25, and CD30 for the diagnosis.[20] The expression of CD30 is more common in the lymphoma subtype rather than the acute subtype. There are no specific chromosomal abnormalities associated with ATL. Multiple nonspecific chromosomal abnormalities were reported in the literature, including trisomy 3, trisomy 7, monosomy X, and defects in chromosomes 6 and 14.[21] These abnormalities occur more commonly in the aggressive types compared with the chronic type.
An 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. Anaplastic lymphoma kinase (ALK), paired box 5 (PAX5), and terminal deoxynucleotidyl transferase (TdT) are negative in the lymphoma subtype of ATL. A high level of Ki-67 proliferation index is associated with aggressive ATL.[20]
In a clinical setting, evaluation should always include a complete cell blood count with differential, peripheral blood smear, LDH, a TLS panel, including uric acid, phosphate, calcium, potassium, and creatinine levels, and a serum concentration of soluble interleukin 2 (IL-2) receptor. The screening for Glucose-6-phosphate dehydrogenase (G6PD) deficiency should also be considered before proceeding to TLS treatment with rasburicase. HIV and hepatitis panel should also be sent. All patients with newly diagnosed aggressive ATL should have a human leukocyte antigen (HLA) typing as a part of the initial workup.[12]
All patients with aggressive ATL should receive imaging tests to evaluate the extent of lymphadenopathy, splenomegaly, organ infiltration, and skeletal involvement. Either computed tomography (CT) with contrast or positron-emission tomography-computed tomography (PET-CT) should be included as part of the workup; however, treatment should not be delayed solely to obtain PET-CT. CT scan or MRI of the brain and lumbar puncture should also be considered to evaluate the central nervous system involvement by ATL cells or opportunistic infection, especially for aggressive ATL.
Treatment / Management
Patients with acute, lymphomatous, or unfavorable chronic type adult T cell leukemia carry a poor prognosis and have a median overall survival (OS) measured in months. 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.
1. 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. The clinical use of AZT-IFN was first reported by Gill et al. in 1995 for 19 patients with acute-lymphomatous forms of ATL.[22] Most of the patients were in the acute form of the disease, and seven patients had either relapse or treatment failure. This study reported a good overall response rate (ORR) of 58% with complete remission (CR) rate of 26%. The median OS was relatively poor (4.8 months) in previously untreated ATL patients as compared to the survival in the chemotherapy trials by Japan Clinical Oncology Group (JCOG), and several factors were thought to be attributable to this result including disease characteristics. A prospective phase II study by Hermine et al. demonstrated the objective response rate (ORR) of 92% and CR of 58% for the 13 patients treated with AZT-IFN combination as first-line therapy.[23] The median OS was reported at 11 months. However, most of the patients eventually relapsed despite encouraging response rates. A meta-analysis of 254 ATL patients (116 acute, 18 chronic, 11 smoldering, 100 lymphoma patients) reported a five-year OS rate of 46% versus 20% in patients who received first-line antiviral therapy versus first-line chemotherapy, respectively. In the same study, patients with acute ATL who achieved CR with AZT-IFN demonstrated 82% of OS at five years, and those with chronic and smoldering showed 100% of OS at five years.[24] A randomized phase III clinical trial was conducted by the JCOG-LSG to evaluate the efficacy of the combination of AZT and IFN versus watchful waiting for indolent-type ATL patients. Arsenic trioxide, in combination with IFN and AZT, was evaluated in 10 newly diagnosed chronic ATL patients, and ORR was 100%.[25](A1)
2. Chemotherapy
Different chemotherapy regimens have been studied for ATL patients. Most frequently used chemotherapies are VCAP-AMP-VECP (vincristine, cyclophosphamide, doxorubicin, prednisone-doxorubicin, ranimustine, and prednisone-vindesine, etoposide, carboplatin, prednisone), modified EPOCH (etoposide, prednisolone, vincristine, carboplatin, and doxorubicin; carboplatin is substituted for cyclophosphamide), hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone), CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), CHOEP (cyclophosphamide, doxorubicin, etoposide, vincristine, and prednisone).
The Japanese Clinical Oncology Group (JCOG) has initiated a number of clinical trials to evaluate different chemotherapies in Japan. A phase III study from JCOG compared the VCAP-AMP-VECP regimen (known as LSG-15) to biweekly CHOP in untreated acute, lymphoma, or unfavorable chronic ATL patients. The 3-year OS was 24% versus 13% in the VCAP-AMP-VECP arm and CHOP arm, respectively. CR rate (40% versus 25%) and the median OS (13 months versus 11 months) were also superior in VCAP-AMP-VECP arm as compared to CHOP arm. In this study, patients were also administered G-CSF and CNS prophylaxis with cytarabine and intrathecal methotrexate and prednisone.[26] Based on the results, The VCAP-AMP-VECP combination is currently a standard chemotherapeutic regimen for aggressive ATL in Japan. Other recommended alternative regimens in the US include dose-adjusted EPOCH, CHOP, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD).[27][28] For the elderly patients who are not able to tolerate aggressive chemotherapy, CHOP or CHOP-like regimens can be suggested.(A1)
3. Allogeneic Stem Cell Transplantation
The role of stem cell transplantation (SCT) has been investigated in aggressive ATL, given the poor outcomes with standard treatment modalities. Few studies have been reported autologous SCT, and it has been shown to be associated with poor clinical outcomes, including high transplantation-related mortality.[29] In 1996, the first successful allogeneic bone marrow transplantation was reported.[30] PCR on peripheral blood became negative for HTLV-I after transplantation, and the patient remained in complete remission in 23 months. Allo-SCT was suggested as a new strategy to eradicate HTLV1-positive cells. However, treatment-related toxicity and mortality were reported by 40% for immunocompromised patients. In a large nationwide Japanese retrospective study of 386 patients who underwent allogeneic SCT, overall survival at three years was 33% in a median follow-up of 41 months. Donor HTLV-1 seropositivity was found to be adversely associated with disease-related mortality in patients who received related grafts.[31](B2)
Retrospective studies showed no significant difference in overall survival between myeloablative conditioning (MAC) and reduced-intensity conditioning (RIC), although a mild trend for overall survival was observed in favor of RIC-received older patients.[32] In a recent meta-analysis, the pooled rates of CR, OS, and PFS were reported at 73%, 40%, and 37%, respectively. The incidence of relapse and non-relapse mortality (NRM) was found to be high at 36% and 29%, respectively.[33] In an updated retrospective study of 1594 patients with acute and lymphoma ATL, significantly prolonged median survival time was observed in patients who received the transplant in the first remission when compared to those transplanted in the setting of primary refractory or relapsed disease (22 months vs. 3 months).[34](A1)
4. Monoclonal Antibody Therapy
- Brentuximab Vedotin
Brentuximab vedotin (BV) is a CD30-directed monoclonal antibody. The efficacy and safety were studied in clinical trials for ATL patients. A phase I study evaluated the combination of frontline BV and cyclophosphamide, doxorubicin, and prednisone (CHP) in CD30 positive peripheral T-cell lymphoma with all patients, including ATL, achieving CR.[35] After a median follow up of 59.6 months, 50% of the patients showed durable responses and median PFS and OS were not reached.[36] The ECHELON-2 trial compared BV-CHP combination with CHOP in 452 newly diagnosed CD30-positive peripheral T-cell lymphoma patients. BV-CHP combination showed significantly better progression-free survival and overall survival as compared to CHOP. However, the number of ATL patients was quite limited in this study.[37] A phase II study is currently active to assess the efficacy and safety of BV and combination chemotherapy.(A1)
2. Mogamulizumab
Mogamulizumab is a humanized anti-CCR4 monoclonal antibody that is approved for relapsed or resistant ATL in Japan. The single-agent activity was demonstrated in a phase II study with the ORR of 50%, OS of 14 months, and progression-free survival of 5.3 months, months in relapsed ATL patients.[38] A phase II randomized study compared Mogamulizumab plus LSG-15 regimen with LSG-15 alone for untreated aggressive ATL. A CR rate and median PFS were 52% versus 33% and 8.5 months versus 6.3 months for the mogamulizumab plus LSG-15 arm versus the single LSG-15 arm, respectively.[39] Studies reported frequent immune-related side effects, including skin rash, infusion reactions.(A1)
A phase II trial that was done outside Japan comparing Mogamulizumab with chemotherapy in 71 relapsed/refractory ATL patients showed the single-agent activity with ORR of 11% versus 0%. Several retrospective studies also reported severe acute graft-versus-host disease (GvHD) with the use of Mogamulizumab, especially prior to allo-HSCT.[40] A study showed significant survival outcomes with increased nonrelapse mortality in patients who received pre-transplant Mogamulizumab as compared to those who did not.[41] More prospective studies are needed to evaluate the safety and efficacy of Mogamulizumab given before or after allo-HSCT.
3. Alemtuzumab
Alemtuzumab is a humanized monoclonal antibody against CD52 that has demonstrated clinical activity against chronic lymphocytic leukemia (CLL), cutaneous T-cell lymphoma (CTCL), and peripheral T-cell lymphoma (PTCL). ATL cells express CD52 more frequently than other peripheral T cell lymphoma. Alemtuzumab, in combination with cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP) regimen, was evaluated in 24 patients with peripheral T-cell lymphoma (PTCL) between 2003 and 2005. A total of 17 patients (71%) achieved complete remission, and the overall median duration of response was 11 months.[42] However, survival rates were unsatisfactory, and the risk of CMV infection limited its effectiveness. In a phase II study of 29 patients receiving single-agent alemtuzumab, the overall objective response rate was 52%. However, the median duration of response was only 14.5 months among the 15 responders, and the median OS was reported at 5.9 months.[43](A1)
4. Daclizumab
Daclizumab is a humanized monoclonal antibody that binds to CD25 (interleukin-2 receptor alpha chain) that is over-expressed on ATL cells. Its manufacturing was stopped in 2009 due to its side effects, including hepatic toxicity. In 2016, a new form (daclizumab high-yield process) was approved by the FDA for relapsing multiple sclerosis. In phase I/II trial of daclizumab monotherapy (8 mg/kg) for 34 patients with ATL, no response was found in 18 patients with aggressive ATL.[44] Lower dose daclizumab (1 mg/kg) was evaluated in combination with standard CHOP chemotherapy in a phase II trial of 15 patients with ATL. The median overall survival was ten months, and CR was 33%.[45] At present, daclizumab is not widely used as a treatment strategy.
5. Other novel approaches
Several new treatment strategies are being studied to increase survival. A phase II study assessing the efficacy of immunomodulatory agent Lenalidomide for aggressive ATL reported encouraging results. The ORR, OS, and median PFS were 42%, 20.3 months, 3.8 months, respectively.[46] Studies reported high programmed cell death ligand 1 (PD-L1) expression on ATL cells. A study demonstrated poor survival rates with PD-L1 positive ATL compared to PD-L1 negative ATL. However, administering PD-1 inhibitor nivolumab to ATL patients showed rapid progression in a phase II study.[47] More studies are needed to assess the role of checkpoint inhibitors. Histone deacetylase (HDAC) inhibitors, anti-Tax vaccine, denileukin diftitox (IL-2 diphtheria toxin protein) are among the other therapy options currently being investigated.
Differential Diagnosis
The differential diagnoses are other mature T-cell malignancies, including peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), anaplastic large cell lymphoma (ALCL), angioimmunoblastic T-cell lymphoma (AITL), mycosis fungoides and Sézary syndrome. In some cases, the presence of Reed Sternberg-like cells (RS) in peripheral T-cell lymphomas (PTCLs) may lead to a misdiagnosis of lymphocyte-rich classical Hodgkin lymphoma.
Prognosis
Adult T cell leukemia is chemoresistant and carries a poor prognosis despite the recent progress in treatment modalities. In general, the prognosis of acute and lymphoma subtypes is poor compared with that of chronic and smoldering types. Lymphoma Study Group from 1984 to 1987 reported that median survival time was 6 months for acute type, 10 months for the lymphoma type, and 24 months for the chronic type.[11] In a retrospective study of 1594 ATL patients treated with intensive combination chemotherapy and allogeneic hematopoietic stem cell transplantation between 2000 and 2009, the median survival times were 8.3, 10.6, 31.5, and 55 months in patients with acute, lymphoma, chronic, and smoldering types, respectively. The median survival time was reported at 5.9 months in patients who underwent allogeneic hematopoietic stem cell transplantation (7%).[34]
The OS at 4 years for acute, lymphomatous, chronic, and smoldering subtypes were 11%, 16%, 36%, and 52%, respectively. Although outcomes appear to be slightly better when comparing two studies, the long-term prognosis of ATL is still unsatisfactory. Based on 854 patients with newly diagnosed ATL between 1983 and 1987, the Japan Clinical Oncology Group-Lymphoma Study Group (JCOG-LSG) identified five prognostic factors, including advanced performance status (PS), high lactic dehydrogenase (LDH), age ≥40 years, ≥3 involved lesions, and hypercalcemia.[48] Several researchers attempted to establish a prognostic index to determine prognosis in patients with acute and lymphoma subtypes ATL. Most recently, Katsuya et al. identified five independent poor prognostic factors for acute and lymphoma subtypes in newly diagnosed patients, including Ann Arbor stage (stage III/IV, 2 points), performance status (ECOG score 2-4, 1 point), age≥70 (1 point), serum albumin ≤3.5 g/dL (1 point), and sIL-2R level≥20,000 U/mL (1 point).[7] Median survival times were 3.6, 7.3, and 16.2 months for patients with high (5-6 points), intermediate (3-4 points), and low risk (0-2 points).
Other poor prognostic factors were identified in several studies for acute and lymphoma subtypes, including bone marrow involvement, skin involvement, and monocytosis.[49] Eosinophilia, high LDH, high BUN, and low albumin were found to be associated with poor prognosis in the chronic subtype of ATL.[50] Additional factors associated with poor prognosis include elevated serum level of interleukin-5, expression of C-C chemokine receptor 4 (CCR4), lung resistance-related protein, p53 mutation, and p16 deletion.[51][52] Lastly, the expression of nuclear c-Rel and interferon regulatory factor-4 (IRF-4) was found to be associated with antiviral resistance and represents a poor prognosis.[52]
Complications
Opportunistic infections due to severe immunosuppression are frequently reported in patients with ATL. Prophylactic trimethoprim/sulfamethoxazole should be given for pneumocystis jirovecii pneumonia. If needed, screening can be considered. Prophylaxis against herpes-zoster virus, gram-negative bacterial and fungal infection; strongyloidiasis stercoralis infection screening should also be considered in ATL patients. Tumor lysis syndrome is an oncologic emergency with high mortality risk. Vigorous intravenous hydration, rasburicase should be initiated immediately. Allopurinol administration is generally recommended 24 hours prior to starting the anti-cancer therapy.
Deterrence and Patient Education
Adult T cell leukemia is primarily caused by HTLV-1 infection that is transmitted through breastfeeding, sexual contact, and blood transfusion. Although most of the individuals who carry HTLV-1 infection remain asymptomatic, they are at an increased lifetime risk for developing ATL. There is no uniform screening. However, patients should avoid prolonged breastfeeding (more than six months); condom use should be encouraged by physicians. Patients should be educated for the risks of intravenous drug-related infections, including HTLV-1.
Enhancing Healthcare Team Outcomes
Adult T cell leukemia is uncommon and aggressive neoplasm caused by HTLV-1 infection that infects 10 million people in the world. Of them, 5% of infected people eventually develop symptomatic ATL. HTLV-1 is the first human retrovirus discovered and is endemic in Japan, the Caribbean region, Africa, and some parts in the Middle East, South, and Central America. HTLV-1 transmission is through breastfeeding, sexual interaction, and blood transfusion. The overall prognosis is poor. Hence, preventive measures are of utmost importance. ATL is clinically classified into four subgroups defined by the Shimoyama criteria: acute, chronic, lymphoma, and smoldering. The treatment is chosen based on clinical and patient characteristics. Currently, chemotherapy or the antiviral regimen is the first-line treatment for aggressive type (acute, lymphoma, and chronic with unfavorable features).
An antiviral regimen or watchful waiting is a reasonable first-line for smoldering and favorable chronic subtypes. Different chemotherapy regimens are used in clinical practice including VCAP-AMP-VECP (vincristine, cyclophosphamide, doxorubicin, prednisone-doxorubicin, ranimustine, and prednisone-vindesine, etoposide, carboplatin, prednisone), modified EPOCH (etoposide, prednisolone, vincristine, carboplatin, and doxorubicin; carboplatin is substituted for cyclophosphamide), CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), CHOEP (cyclophosphamide, doxorubicin, etoposide, vincristine, and prednisone), hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone). ATL patients are increased risk of opportunistic infections due to severe immunosuppression, therefore, appropriate screening, prevention, and prompt recognition are essential. These patients are likely encountered by primary care physicians. Early recognition and referral to a specialist are important to avoid delay in treatment. Researchers are working on novel approaches and focusing on clinical trial participation. Collaborative work is important to find effective therapeutic strategies to improve survival in ATL.
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