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Treatment and prognosis of adult T cell leukemia-lymphoma
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: May 2013. | This topic last updated: Jun 12, 2013.

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

INDICATIONS FOR TREATMENT — As mentioned above, there are four clinical variants of ATL: 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 ATL while patients with typical chronic or smoldering ATL are observed initially. This is principally because conventional chemotherapy does not appear to improve the survival of patients with chronic or smoldering ATL [3,4]. The five-year survival rate of patients with chronic and smoldering ATL was 47 percent in one study [5].

As an example, a retrospective evaluation of 26 patients with smoldering ATL 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, most patients with acute or lymphoma-type ATL have a survival without treatment measured in days to weeks. A brief description of the clinical variants of ATL is given below. This is described in more detail separately. (See "Clinical manifestations, pathologic features, and diagnosis of adult T cell leukemia-lymphoma".)

  • 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 [5]. Median survival is two to five years, however, there is a subgroup of patients with unfavorable chronic-type ATL 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 approximately three years [5].

PRETREATMENT EVALUATION — The pretreatment evaluation both determines the bulk of disease and provides information about the individual's comorbidities that are likely to have an 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 ATL [6]:

  • Laboratory studies include a complete blood count with differential, chemistries with liver and renal function and electrolytes including calcium, LDH, albumin, uric acid, soluble interleukin-2 receptor, 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 was detected in approximately 28 percent in one study mainly consisting of lymphoma-type ATL [7,8].
  • 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 [9]. Although the FDG-avidity of ATL is not well established, positron emission tomography (PET) scanning is recommended if it is possible prior to therapy. (See "Initial evaluation and staging of non-Hodgkin lymphoma", section on 'Routine imaging studies'.)
  • Endoscopy of the upper gastrointestinal tract with biopsy should be considered for all patients [10]. 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 ATL, options for women are limited, but men can often participate in sperm banking. (See "Fertility preservation in patients undergoing gonadotoxic treatment or gonadal resection".)

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 "Initial evaluation and staging of non-Hodgkin lymphoma".)

INITIAL TREATMENT

Overview — Patients with acute, lymphomatous, or unfavorable chronic type ATL 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 chemotherapeutic agents and because the patients have an underlying immunocompromised state associated with their HTLV-1 infection. Cell-mediated immunity is impaired in ATL patients while humoral immunity remains intact.

The greatest experience with ATL 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 [6,11]. When added to conventional therapy, the defucosylated humanized anti-CCR4 antibody mogamulizumab appears to improve response rates and progression-free survival, but is not widely available outside of Japan. Autologous hematopoietic cell transplantation (HCT) does not appear to be effective. Allogeneic HCT may be appropriate for patients with a related or unrelated donor.

Multiagent regimens — The optimal chemotherapy combination for patients with ATL is unclear and many intensive regimens have been investigated [3,12-17]. Patients may initially respond to treatment with combination chemotherapy regimens devised for advanced, aggressive NHL, but relapses are common [18]. 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 [11]. The use of VCAP-AMP-VECP is supported by prospective phase II and III trials [16,17]:

  • Patients treated with VCAP-AMP-VECP had a significantly higher rate of complete response plus complete response unconfirmed compared with those treated with CHOP-14 (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-14 arm.

  • A randomized phase II trial, presented in abstract form only, evaluated the addition of the defucosylated humanized anti-CCR4 antibody mogamulizumab in 53 patients with newly diagnosed aggressive ATL [19]. Patients received four courses of VCAP-AMP-VECP with or without mogamulizumab (1 mg/kg), administered once every two weeks for a total of eight doses. The addition of mogamulizumab resulted in:

  • Higher complete response (52 versus 33 percent) and overall response (86 versus 75 percent) rates.
  • Higher response rates among those with acute (55 versus 29 percent), lymphoma-type (50 versus 43 percent) and unfavorable chronic (33 versus 0 percent) subtypes.
  • Longer median progression-free survival (8.6 versus 6.4 months).
  • Similar toxicity overall, with an increased rate of non-serious skin disorders.

All patients with acute, lymphoma-type, or unfavorable chronic type ATL 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 [20,21]. 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. When available, we suggest the addition of mogamulizumab to VCAP-AMP-VECP. 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. The ranimustine and vindesine used in this regimen are not available in some countries, including the United States. For patients treated by clinicians who do not have access to these agents, an acceptable alternative regimen is hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD). While hyper-CVAD is frequently used to treat other forms of T cell lymphoma, there are limited data regarding the use of hyper-CVAD for the treatment of ATL [22].

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 ATL cannot be controlled with oral etoposide for a clinically meaningful duration [23,24].

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, based on the subgroup analysis of the phase III study described above [17].

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

  • Patients with ATL are immunocompromised and are therefore at risk for potentially lethal opportunistic infections with organisms such as Pneumocystis jirovecii (previously carinii), Candida, cytomegalovirus, disseminated cryptococcus, 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 ATL. 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 pneumonia in non-HIV-infected patients", section on 'Prophylaxis'.)
  • Hypercalcemia, which can be severe, is one of the most significant complications in ATL 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 [25]. 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 (table 2). This is most appropriately performed in a continuously monitored inpatient setting. (See "Uric acid renal diseases" and "Tumor lysis syndrome: Prevention and treatment", section on 'Treatment of established TLS'.)
  • 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'.)

Antiviral therapy — The benefit of antiviral agents in ATL is controversial. The HTLV-1 virus is thought to be in a latent state in patients with ATL and so antiviral agents, if active, would be expected to act through a mechanism other than antiviral activity [26]. Small, prospective trials and retrospective analyses performed outside of Japan have evaluated the use of the antiviral agent zidovudine (AZT) plus interferon alpha in the treatment of newly diagnosed or relapsed ATL [27-33]. Median survival times with this regimen have ranged from 6 to 18 months. Some of these trials included patients with less aggressive variants of ATL who would be expected to have a good prognosis without any treatment.

A 2010 meta-analysis of AZT plus interferon-alpha incorporated data from 245 patients with acute (47 percent), chronic (7 percent), smoldering (4 percent), or lymphoma-type (42 percent) ATL [34]. For the 207 patients whose first-line therapy was recorded, the following five-year overall survival rates were reported:

  • AZT plus interferon alpha (75 patients) — 46 percent
  • Chemotherapy (77 patients) — 20 percent
  • Chemotherapy followed by antiviral therapy (55 patients) — 12 percent

Patients with acute, chronic, and smoldering ATL appeared to benefit from first-line antiviral therapy, whereas patients with lymphoma-type ATL did not. For patients with chronic or smoldering ATL, this combination was reported to result in 100 percent five-year survival. Based on the results of this retrospective analysis, the investigators suggested this combination regimen as the first-line therapy in leukemic subtypes of ATL [35]. While encouraging, we believe that this approach needs further prospective study before it can be widely applied.

Hematopoietic cell transplantation — Both autologous and allogeneic hematopoietic cell transplantations (HCTs) have been attempted to improve outcomes in patients with ATL. Although experience is somewhat limited, autologous HCT does not appear to be of benefit due to frequent early relapses [36]. Allogeneic HCT offers a potential graft-versus-leukemia effect and may be considered for patients with an available donor [37,38].

A number of small non-randomized studies have evaluated the role of myeloablative and nonmyeloablative allogeneic HCT in this disorder [37,39-43]. 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 [41,44]. After allogeneic HCT, provirus load was significantly decreased in some patients [41,45], suggesting that anti-HTLV-1 immune response is enhanced in these patients. Phase II studies of nonmyeloablative and myeloablative allogeneic HCT are underway in Japan [3,46,47].

Retrospective data are available from Japan regarding 386 patients with ATL who underwent allogeneic HCT from an HLA-matched related donor (154 patients), HLA-mismatched related donor (43 patients), unrelated marrow donor (99 patients), or unrelated cord blood donor (90 patients) [48]. After a median follow-up of 41 months, the estimated three-year survival rate was 33 percent. Four factors were significantly associated with worse outcomes: age >50 years, male sex, disease not in complete remission at the time of HCT, and unrelated donor source.

In another analysis of this patient cohort, patients who developed either mild to moderate (grade 1/2) or severe (grade 3/4) acute graft-versus-host disease (GVHD) had a significantly lower disease-related mortality when compared with those patients who did not develop GVHD [49]. Patients with grade 1/2 GVHD had superior overall survival than those without GVHD (hazard ratio [HR] 0.65; 95% CI 0.45-0.93). In contrast, survival was inferior in patients with grade 3/4 GVHD (HR 1.64; 95% CI 1.10-2.42), likely due to an increase in treatment-related mortality (HR 3.50; 95% CI 2.01-6.11).

In another analysis, this cohort was expanded to include 586 patients with ATL who underwent allogeneic HCT between 1992 and 2009 [50]. For the 280 patients who underwent myeloablative conditioning, median overall survival (OS) and estimated three-year survival were 9.5 months (95% CI 6.7-18.0 months) and 39 percent (33 to 45 percent), respectively. Corresponding values for the 306 patients who underwent reduced intensity conditioning were 10 months (7.2 to 14.0 months) and 34 percent (29 to 40 percent), respectively. When compared with myeloablative conditioning, reduced intensity conditioning was associated with a trend towards less treatment-related mortality (HR 0.786; 95% CI 0.538-1.148), but greater leukemia-related mortality (HR 1.579; 95% CI 1.080-2.308).

Another retrospective analysis included 40 patients with acute or lymphoma-type ATL who had undergone allogeneic HCT either as part of their initial therapy or at relapse [37]. 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-ATL effect.

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

Patients with ATL 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 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). The post-treatment imaging study of choice in patients remains computed tomography (CT). Although positron emission tomography (PET) scans have not been prospectively validated in patients with ATL, we perform a combined PET/CT, if available.

Using information gathered from the history, physical, and CT scan, disease response is determined using the Japan Clinical Oncology Group (JCOG) response criteria [6]:

  • Complete response is defined as the disappearance of all clinical and radiographic evidence of disease and the normalization of LDH 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 5 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. (See "Radiation-related risks of imaging studies".)

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 [51].

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 ATL 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 ATL 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 ATL and patients should be referred for enrollment in clinical trials. Although not widely available outside of Japan, mogamulizumab is well tolerated and active in this setting. Other areas of investigation include the use of antiviral agents or antibody therapy. Patients who have undergone allogeneic hematopoietic cell transplantation (HCT) may respond to withdrawal of immunosuppression or immunotherapy with donor lymphocyte infusion (DLI). (See 'Antiviral therapy' above and 'Hematopoietic cell transplantation' above and "Immunotherapy for the prevention and treatment of relapse following hematopoietic cell transplantation".)

ATL cells express CCR4 on the surface [52]. A defucosylated humanized anti-CCR4 antibody (mogamulizumab) has been reported to be effective to ATL cases and has been approved for use in Japan [53,54]. A multicenter phase II trial evaluated the use of mogamulizumab monotherapy in 28 patients with relapsed acute (52 percent), lymphomatous (22 percent), or chronic (26 percent) ATL [54]. Toxicity was mostly mild to moderate with the most common toxicities being infusion reactions (89 percent) and rash (63 percent). The overall response rate was 50 percent (29 percent complete) and median progression-free and overall survival of 5.2 and 13.7 months, respectively.

Limited experience with the anti-CD52 antibody alemtuzumab has also been reported [55,56]. 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) [32,57-59]. Other new agents for the potential application to the treatment of ATL include pralatrexate (anti-folate), bortezomib (proteasome inhibitor), forodesine (purine nucleoside phosphorylase inhibitor), histone deacetylase inhibitor, and lenalidomide [47].

There is a paucity of data regarding the efficacy of radiation therapy in patients with ATL. A retrospective analysis of 10 consecutive patients with relapsed or refractory ATL treated with radiation therapy (mean 35.4 Gy; range 12 to 60 Gy) reported that all patients had an at least partial response with 40 percent attaining a complete response within the treatment field [60]. Toxicity was generally mild to moderate and included cutaneous reactions, mucositis, and ocular toxicity. Radiation therapy may provide palliation of patients who have symptoms related to a single disease site.

In a retrospective analysis of 35 patients with relapsed or refractory ATL following allogeneic HCT, the median time to relapse was less than four months [38]. The median survival time following relapse was 6.2 months and 19 percent of patients were alive at three years. A complete remission (CR) was attained in 2 of 29 patients following withdrawal of immunosuppression, and in 4 of 9 patients following DLI with or without prior cytoreductive therapy. Six patients had discontinued immunosuppressive therapy prior to relapse. Of these, the three with local recurrence attained a CR with cytoreductive therapy, while the three with systemic recurrence progressed despite cytoreductive therapy. A worsening of graft-versus-host disease (GVHD) was seen in 6 of 9 patients receiving DLI.    

PROGNOSIS — As described separately, there are four clinical variants of ATL: acute, lymphoma-type, chronic, and smoldering. These differ greatly in their presentation and prognosis. The clinical course of acute and lymphoma-type ATL is aggressive with survival without treatment measured in months. In contrast, most cases of chronic or smoldering ATL are more indolent with survival without treatment measured in years. (See 'Indications for treatment' above.)

Prognostic indices used for other non-Hodgkin lymphomas, such as the International Prognostic Index, are not very useful in this patient population, largely because the vast majority of patients would be classified as having intermediate- or high-risk [61]. As such, efforts have been made to develop and validate a prognostic index specific for patients with acute or lymphoma-type ATL.

A retrospective Japanese study of 807 patients with newly diagnosed acute or lymphoma-type ATL diagnosed between 2000 and 2009 randomly divided subjects into two groups that were used to create and validate a prognostic index for acute and lymphoma-type ATL (the ATL-PI) [61]. The median survival was 7.7 months overall. A point-based system was developed using the presence or absence of the following markers of poor outcome in the training group:

  • Ann Arbor stage III or IV — 2 points
  • Eastern Cooperative Oncology Group (ECOG) Performance status ≥2 — 1 point
  • Age >70 years — 1 point
  • Serum albumin <3.5 g/dL — 1 point
  • Soluble interleukin-2 receptor (IL-2R) >20,000 U/mL — 1 point

Total scores ranged from zero to six. This prognostic model separated the validation group into three populations with different outcomes: high (5 or 6 points), intermediate (3 or 4 points), and low (0, 1, or 2 points) risk groups that had median survival times of 4.6, 7.0, and 16.2 months, respectively. Corresponding rates of overall survival at two years were 6, 17, and 37 percent, respectively.

SUMMARY AND RECOMMENDATIONS

  • Adult T cell leukemia-lymphoma (ATL) 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 ATL: 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 ATL while patients with typical chronic or smoldering ATL 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 have an impact on 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 ATL require treatment. 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). When available, we also suggest the addition of the defucosylated humanized anti-CCR4 antibody mogamulizumab to VCAP-AMP-VECP rather than the administration of VCAP-AMP-VECP alone (Grade 2B). Data regarding the use of antiviral therapy for acute and chronic variants are insufficient. Some agents contained in VCAP-AMP-VECP and mogamulizumab are not available in some countries, including the United States. For patients treated by clinicians that do not have access to these agents, an acceptable alternative regimen is hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD), although its evidence is limited. 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.)
  • Allogeneic HCT offers a potential graft-versus-leukemia effect and may be considered for patients with an available donor. (See 'Hematopoietic cell transplantation' above.)

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