INTRODUCTION — Adult T-cell lymphoma-leukemia (ATLL) is a peripheral T-cell neoplasm associated with infection by the human T-lymphotropic virus, type I (HTLV-1). Although it is considered one of the highly aggressive T-cell non-Hodgkin lymphoma (NHL) variants, the disease course is variable and sometimes quite indolent.

Four clinical variants of ATLL have been described: acute, lymphoma-type (lymphomatous), chronic and smoldering; these appear to have differing genomic alterations and varying clinical courses, and may require different treatment.

The treatment of ATLL is discussed here. The epidemiology, pathogenesis, clinical features, pathology, and diagnosis of ATLL are discussed separately. (See "Clinical manifestations, pathologic features, and diagnosis of adult T cell lymphoma-leukemia".)

INDICATIONS FOR TREATMENT — As mentioned above, there are four clinical variants of ATLL: acute, lymphoma-type, chronic, and smoldering [1,2]. These differ greatly in their presentation and prognosis. Therapy is usually offered to patients with acute, lymphoma-type, or unfavorable chronic type ATLL while patients with typical chronic or smoldering ATLL are observed initially. This is principally because conventional chemotherapy does not appear to improve the survival of patients with chronic or smoldering ATLL and a significant percentage will survive without treatment for more than five years [3,4].

As an example, a retrospective evaluation of 26 patients with smoldering ATLL reported that 14 (54 percent) were alive without tumor progression at median follow-up of 6.5 years [4]. For those who died, the median time to transformation to a more aggressive variant was 38 months.

In contrast, patients with acute or lymphoma-type ATLL have a survival without treatment measured in days to weeks. A brief description of the clinical variants of ATLL is given below. This is described in more detail separately. (See "Clinical manifestations, pathologic features, and diagnosis of adult T cell lymphoma-leukemia".)

• Acute — These patients present with systemic symptoms, organomegaly, lymphadenopathy, an elevated lactate dehydrogenase (LDH) level, and circulating malignant cells. Survival with treatment is measured in months to a year. Four-year survival rates are approximately 5 to 10 percent and median survival is 8 to 10 months when treated with regimens devised for advanced, aggressive NHL.
• Lymphoma-type — This variant is characterized by prominent lymphadenopathy without blood involvement. Prognosis is poor with a survival similar to that of patients with the acute variant.
• Chronic — These patients present with skin lesions, mild lymphadenopathy, and leukocytosis with an absolute lymphocytosis that may be stable for months to years. Median survival is approximately two years, however, there is a subgroup of patients with unfavorable chronic-type ATLL which is defined by a low serum albumin, high LDH, or high blood urea nitrogen concentration. These patients have a poor prognosis similar to that of the acute and lymphoma variants.
• Smoldering — These patients are often asymptomatic except for frequent skin and/or pulmonary lesions. They have normal blood lymphocyte counts with less than 5 percent circulating neoplastic cells and normal calcium levels. Median survival without treatment is more than five years.

PRETREATMENT EVALUATION — The pretreatment evaluation both determines the bulk of disease and provides information about the individual's comorbidities that are likely to have impact on treatment options. In addition to a history and physical examination, it is our practice to perform the following pretreatment studies in patients with ATLL [5]:

• Laboratory studies include a complete blood count with differential, chemistries with liver and renal function and electrolytes including calcium, LDH, albumin, uric acid, and flow cytometry for CD4, CD8, and CD25. Patients with risk factors should undergo testing for HIV.
• Unilateral bone marrow biopsy or aspiration is recommended for all patients. Bone marrow involvement occurs in approximately 28 percent [6].
• Lumbar puncture is recommended for all patients with acute or lymphoma-type variants but may be performed at the start of therapy if intrathecal chemotherapy is a component of the treatment regimen. Cerebrospinal fluid should be sent for cytology and/or flow cytometry.

A contrast-enhanced computed tomography (CT) scan of the neck, chest, abdomen and pelvis should be performed. This study provides critical information on the measurement of disease prior to treatment and aids in staging [7]. The FDG-avidity of ATLL is not well established and may be variable. As such, positron emission tomography (PET) scanning is reserved for use in clinical trials [8]. (See "Evaluation, staging, and prognosis of non-Hodgkin lymphoma", section on Imaging studies.)

• Endoscopy of the upper gastrointestinal tract with biopsy should be considered for all patients [9]. Although GI tract involvement is more frequent in aggressive variants than indolent variants, a fraction of the latter still have GI tract involvement.
• A study of cardiac ejection fraction (eg, echocardiogram or MUGA) should be performed if anthracyclines are used. (See "Cardiotoxicity of anthracycline-like chemotherapy agents".)
• Men and women of child-bearing potential should receive counseling about the potential effect of treatment on their fertility and options for fertility-preserving measures. Given the urgent need for treatment with ATLL, options for women are limited, but men can often participate in sperm banking. (See "Preservation of fertility in patients undergoing cytotoxic therapy".)

General approaches to the diagnostic work-up and staging of non-Hodgkin lymphoma are presented separately (table 1). (See "Clinical presentation and diagnosis of non-Hodgkin lymphoma" and "Evaluation, staging, and prognosis of non-Hodgkin lymphoma".)

INITIAL TREATMENT — Patients with acute, lymphomatous, or unfavorable chronic type ATLL progress quickly without treatment and have a median overall survival measured in months. Treatment of these variants has been challenging since the tumor cells have an intrinsic resistance to most chemotherapy agents and because the patients have an underlying immunocompromised state from their HTLV-1 infection.

The greatest experience with ATLL comes from the Japan Clinical Oncology Group (JCOG). The best treatment for these patients is unclear and patients should be enrolled in clinical trials whenever possible. However, for patients who are not eligible for a clinical trial or for those who do not wish to participate in a trial, we offer the following guidelines. Combination chemotherapy, as described in the next section, is the main treatment option. Autologous hematopoietic cell transplantation (HCT) does not appear to be effective. Allogeneic HCT, although demonstrating a potential benefit in initial reports, is reserved for use in clinical trials.

Multiagent regimens — The optimal chemotherapy combination for patients with ATL is unclear and many intensive regimens have been investigated [3,10-15]. Patients may initially respond to treatment with combination chemotherapy regimens devised for advanced, aggressive NHL, but relapses are common [16]. The median survival time for patients with acute, lymphoma-type, or unfavorable chronic type ATL treated in prospective trials that employed multiagent chemotherapy has ranged from 5 to 13 months.

Of those evaluated in prospective trials, the regimen that appears to result in the longest median survival is VCAP-AMP-VECP (also known as LSG15), which includes treatment with vincristine, cyclophosphamide, doxorubicin, prednisone, ranimustine, vindesine, etoposide, and carboplatin. The use of VCAP-AMP-VECP is supported by a prospective phase II and III trials [14,15]:

• A phase III randomized trial of 118 patients with poor prognosis ATLL compared six courses of VCAP-AMP-VECP with eight courses of biweekly CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) [15]. Both groups of patients were given granulocyte colony stimulating factor (G-CSF) support and intrathecal prophylaxis with cytarabine, methotrexate, and prednisone. At a median follow-up of 10.9 months, the following results were reported:

• - Patients treated with VCAP-AMP-VECP had a significantly higher rate of complete response plus complete response unconfirmed compared with those treated with CHOP (40 versus 25 percent, respectively). Overall response did not differ between the two arms (72 and 66 percent, respectively).
• - The three-year overall survival rate (without censoring patients who went on to transplantation) showed a trend that favored the VCAP-AMP-VECP arm (24 versus 13 percent).
• - Only 32 percent of the patients on the VCAP-AMP-VECP arm and 49 percent of the patients on the CHOP arm were able to complete therapy as planned. Toxicities were more common in the VCAP-AMP-VECP arm including grade 4 neutropenia (98 versus 83 percent), grade 4 thrombocytopenia (74 versus 17 percent), grade 3/4 infection (32 versus 15 percent), and electrolyte disturbances.
• - There were three treatment related deaths in the VCAP-AMP-VECP arm (two from sepsis, one from interstitial pneumonitis) and none in the CHOP arm.

All patients with acute, lymphoma-type, or unfavorable chronic type ATLL should be treated with combination chemotherapy. Given a 10 to 25 percent risk for involvement of the central nervous system (CNS) at diagnosis or relapse, we recommend that all patients receive intrathecal chemotherapy for CNS prophylaxis [17,18]. The evidence supporting this recommendation is discussed elsewhere. (See "Secondary involvement of the central nervous system by non-Hodgkin lymphoma".)

We suggest the use of VCAP-AMP-VECP plus intrathecal chemotherapy rather than other regimens of combination chemotherapy. This regimen requires six to eight months of weekly chemotherapy with G-CSF support. The trials supporting the use of this regimen enrolled patients up to the age of 69 years.

Although some investigators have reported anecdotal experiences suggesting the efficacy of oral etoposide, the evidence supporting its efficacy is inadequate, and most patients with aggressive subtypes of ATLL cannot be controlled with oral etoposide for a clinically meaningful duration [19,20].

Elderly patients — As previously noted, VCAP-AMP-VECP plus intrathecal chemotherapy is associated with significant toxicity. Elderly patients (principally those older than 70 years of age) are less able to tolerate this aggressive regimen. Thus, for patients over 70 years old, we suggest the use of CHOP or CHOP-like regimens.

Supportive factors — The treatment of patients with ATLL requires close attention to the following issues that often surround chemotherapy administration:

• Patients with ATLL are immunocompromised and are therefore at risk for potentially lethal opportunistic infections with organisms such as Pneumocystis jirovecii (previously carinii), candida, cytomegalovirus, and Strongyloides stercoralis [3]. We routinely administer oral trimethoprim-sulfamethoxazole (TMP-SMX) for Pneumocystis jiroveci pneumonia (PCP) prophylaxis. TMP/SMX can be myelosuppressive and may synergize with chemotherapy to result in a more profound and longer nadir. As such, blood counts must be monitored during therapy. In addition, we administer antifungals to all patients receiving chemotherapy for ATLL. Anti-strongyloides agents are given to patients with a past and/or present exposure to the parasite in the tropics. (See "Treatment and prevention of Pneumocystis carinii (P. jirovecii) pneumonia in non-HIV-infected patients", section on 'Prophylaxis'.)

• Hypercalcemia, which can be severe, is one of the most significant complications in ATLL patients. There is no routine prophylaxis given, but patients must be followed closely so that treatment can be initiated emergently. (See "Treatment of hypercalcemia".)

• Physicians preparing to treat patients with one of the highly aggressive NHLs need to be aware that there is a significant risk of tumor lysis syndrome [21]. This syndrome is best prevented via appropriate treatment with aggressive intravenous fluid hydration, rasburicase or allopurinol, correction of any prior electrolyte disturbances and elements of reversible renal failure, as well as the provision of sufficient fluids to insure a high urine output. This is most appropriately performed in a continuously monitored inpatient setting. (See "Tumor lysis syndrome", section on 'Treatment of established TLS' and "Uric acid renal diseases".)

• Oncologic emergencies and treatment-related hematologic toxicities are common in the highly aggressive NHLs. The patient's physicians must always be alert to their potential presence, and be prepared to deal with them urgently and effectively. (See "Clinical presentation and diagnosis of non-Hodgkin lymphoma", section on 'Oncologic emergencies'.)

Hematopoietic cell transplantation — Both autologous and allogeneic hematopoietic cell transplantations (HCTs) have been attempted to improve outcomes in patients with ATLL. Although experience is somewhat limited, autologous HCT does not appear to be of benefit due to frequent early relapses [22]. Allogeneic HCT offers a potential graft-versus-leukemia effect and has shown promise in initial studies, but should be reserved for use in clinical trials.

A number of small non-randomized studies have evaluated the role of myeloablative and nonmyeloablative allogeneic HCT in this disorder [23-28]. Treatment-related mortality was high, although long-term survival was achieved in some patients, with evidence of a graft-versus-HTLV-1 and a graft-versus-tumor effect [25,29]. Phase II studies of nonmyeloablative allogeneic HCT are underway in Japan [3,30].

The largest retrospective analysis included 40 patients with acute or lymphoma-type ATLL who had undergone allogeneic HCT either as part of their initial therapy or at relapse [28]. All but one of the patients was treated with a myeloablative conditioning regimen. At the time of transplant, 15 were in CR, 13 in PR, 3 had stable disease, and 9 had progressive disease. Of the patients evaluable after HCT, all but one achieved a CR. The median survival time of all cases after HCT was 9.6 months. There were 16 deaths related to transplant. The three-year rates of overall survival and relapse-free survival were 45 and 34 percent, respectively. Acute and chronic graft-versus-host disease developed in 26 and 15 patients, respectively. Among the 10 patients who relapsed after HCT, five were able to achieve a second CR. Three of these CRs were obtained by reduction or cessation of immunosuppressive therapy alone suggesting a graft-versus-ATLL effect.

PATIENT FOLLOW-UP — After completion of the initially planned treatment of ATLL, patients should be evaluated to determine the disease response to treatment and should be followed longitudinally for relapse.

Patients with ATLL are immunocompromised and are therefore at risk for potentially lethal opportunistic infections with organisms such as Pneumocystis jirovecii (previously carinii), candida, cytomegalovirus, and Strongyloides stercoralis [3]. While prophylaxis for such infections is generally given, clinicians need to consider these organisms when patients decompensate. (See "Epidemiology, clinical manifestations, and diagnosis of Pneumocystis carinii (P. jirovecii) pneumonia in non-HIV-infected patients" and "Strongyloidiasis" and "Diagnosis of cytomegalovirus" and "Overview of Candida infections".)

Response evaluation — One month following the completion of planned therapy (or sooner if the outcome is unfavorable), the response to treatment should be documented by history, physical examination, and laboratory studies (complete blood count, lactate dehydrogenase, and biochemical profile). Since PET-scans have not been prospectively validated in patients with ATLL, the post-treatment imaging study of choice in patients remains computed tomography (CT).

Using information gathered from the history, physical, and CT scan, disease response is determined using the Japan Clinical Oncology Group (JCOG) response criteria [5]:

• Complete response is defined as the disappearance of all clinical and radiographic evidence of disease and the normalization of lactate dehydrogenase level for at least four weeks. As carriers of HTLV-1 frequently have abnormal circulating lymphocytes, some abnormal lymphocytes can be present as long as they account for less than five percent of the total circulating lymphocytes. Some institutions do not require LDH normalization for the determination of complete response since there are other factors that could lead to its elevation, however, eliminating LDH from the response evaluation may overestimate the response rate.
• Partial response is a reduction in measurable disease by at least 50 percent with a more than 75 percent reduction in the absolute abnormal lymphocyte count for at least four weeks without the development of new lesions or disease progression. LDH must have decreased to less than 1.5 of the normal upper limit.
• Progressive disease is an at least 50 percent increase in the size of measurable disease or the appearance of new lesions during treatment.
• Stable disease includes those patients not achieving a CR, PR, or PD.

Patients who fail to obtain a complete response are treated as refractory disease. This is discussed below. (See 'Treatment of recurrent or refractory disease' below.)

Surveillance for relapse — Following the completion of therapy, restaging, and documentation of complete remission, patients are seen at periodic intervals to monitor for treatment complications and assess for possible relapse. The frequency and extent of these visits depends upon the comfort of both the patient and physician. There have been no prospective, randomized trials comparing various schedules of follow-up. Our approach is based upon the following general understandings:

• The majority of relapses occur during the first year after completion of treatment.
• Relapses are usually symptomatic and are rarely identified solely on the basis of routine imaging.
• If a relapse is picked up a few weeks earlier because of more intense monitoring, it is unlikely to improve outcome.
• When planning the post-treatment surveillance strategy, care should be taken to limit the number of CT scans, particularly in younger individuals, given concerns about radiation exposure and the risk for second malignancies.

Our approach to patient surveillance is to schedule patient visits monthly during the first year, every two months during the second year, and every three months starting two years after complete response. At these visits, we perform a history and physical examination, complete blood count with differential, evaluation of the peripheral smear, chemistries, LDH, and flow cytometry for CD4, CD8, and CD25 [31].

It is recommended that relapsed disease suggested by changes on imaging be confirmed by biopsy. As such, a biopsy is recommended to document relapsed disease before proceeding to salvage therapy.

In some patients with ATLL relapse occurs as the appearance of leukemic cells in the peripheral blood alone. In addition, it is sometimes difficult to recognize leukemic cells by morphology alone. In such situations, flow cytometry of the peripheral blood mononuclear cells, especially evaluating the T4:T8 ratio, is easily performed and effective for estimating the leukemic cell kinetics in the peripheral blood. In particular, since ATLL cells show a characteristic phenotype that is both CD4 and CD25 positive, flow cytometry can be performed in most cases to identify leukemic cells in the peripheral blood.

TREATMENT OF RECURRENT OR REFRACTORY DISEASE — There is little information on the treatment of recurrent or refractory ATLL and patients should be referred for enrollment in clinical trials. Areas of investigation include the use of antiviral agents or antibody therapy.

The benefit of antiviral agents in ATLL is unclear. The HTLV-1 virus is thought to be in a latent state in patients with ATLL and so antiviral agents, if active, would be expected to act through a mechanism other than antiviral activity [32]. Small, prospective trials performed outside of Japan have evaluated the use of the antiviral agent zidovidine (AZT) plus interferon alpha in the treatment of newly diagnosed or relapsed ATLL [33-38]. Median survival times with this regimen have ranged from 6 to 18 months. Some of these trials included patients with less aggressive variants of ATLL who would be expected to have a good prognosis without any treatment. In addition, antiviral therapy has not been directly compared with either chemotherapy or placebo. While encouraging, this approach needs further study before it can be widely applied.

Limited experience with the anti-CD52 antibody alemtuzumab has been reported [39,40]. There has also been interest in the use of arsenic trioxide with or without interferon alpha and in the use of all-trans retinoic acid (tretinoin) [38,41-43].

SUMMARY AND RECOMMENDATIONS

• Adult T-cell lymphoma-leukemia (ATLL) is a peripheral T-cell neoplasm associated with infection by the human T-lymphotropic virus, type I (HTLV-1). (See 'Introduction' above.)

• There are four clinical variants of ATLL: acute, lymphoma-type, chronic, and smoldering which differ greatly in their presentation and prognosis. Therapy is usually offered to patients with acute, lymphomatous, or unfavorable chronic type ATLL while patients with typical chronic or smoldering ATLL are observed initially. (See 'Indications for treatment' above.)

• The pretreatment evaluation both determines the bulk of disease and provides information about the individual's comorbidities that are likely to impact upon treatment options. In addition to a history and physical examination, it is our practice to perform laboratory studies, unilateral bone marrow biopsy and/or aspiration, lumbar puncture, cardiac function evaluation, and imaging in all patients. Fertility counseling should be offered to patients in child-bearing years. (See 'Pretreatment evaluation' above.)

• The best treatment for these patients is unclear and patients should be enrolled in clinical trials whenever possible. However, for patients who are not eligible for a clinical trial or for those who do not wish to participate in a trial, we offer the following guidelines:

• - All patients with acute, lymphoma-type, or unfavorable chronic type ATLL require treatment with combination chemotherapy. We recommend that these patients also receive intrathecal chemotherapy for CNS prophylaxis (Grade 1B). (See 'Initial treatment' above and "Secondary involvement of the central nervous system by non-Hodgkin lymphoma".)
• - We suggest the use of VCAP-AMP-VECP rather than other regimens of combination chemotherapy (Grade 2B). For older patients or those with comorbidities that exclude VCAP-AMP-VECP as an option, we suggest the use of CHOP or CHOP-like regimens (Grade 2C). (See 'Multiagent regimens' above.)
• - Physicians preparing to treat patients with ATLL need to be aware that hypercalcemia is a frequent complication and that there is a significant risk of tumor lysis syndrome. (See "Tumor lysis syndrome", section on 'Treatment of established TLS' and "Uric acid renal diseases".)

       - Allogeneic HCT offers a potential graft-versus-leukemia effect and has shown promise in initial studies, but should be reserved for use in clinical trials. (See 'Hematopoietic cell transplantation' above.)

• After completion of the initially planned treatment of ATLL, patients should be evaluated to determine the disease response to treatment and should be followed longitudinally for relapse. (See 'Patient follow-up' above.)

• Patients with ATLL are immunocompromised and are therefore at risk for potentially lethal opportunistic infections with organisms such as Pneumocystis jirovecii (previously carinii), candida, cytomegalovirus, and Strongyloides stercoralis. (See "Epidemiology, clinical manifestations, and diagnosis of Pneumocystis carinii (P. jirovecii) pneumonia in non-HIV-infected patients" and "Strongyloidiasis" and "Diagnosis of cytomegalovirus" and "Overview of Candida infections".)

• There is little information on the treatment of recurrent or refractory ATLL and patients should be referred for enrollment in clinical trials whenever possible. (See 'Treatment of recurrent or refractory disease' above.)