Treatment and prognosis of adult T cell leukemia-lymphoma

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 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".)

CATEGORIES OF ATL — There are four clinical variants of adult T cell leukemia-lymphoma (ATL) that differ in clinical presentation, prognosis, and need for treatment [1,2]:

●Acute – Patients typically 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 is approximately 5 to 10 percent and median survival is 8 to 10 months when treated with regimens devised for advanced, aggressive non-Hodgkin lymphoma.

●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 [3]. 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 [3].

Therapy is usually offered to patients with acute, lymphoma-type, or unfavorable chronic-type ATL. By contrast, patients with typical chronic or smoldering ATL are initially observed because conventional chemotherapy does not appear to improve their survival [4,5].

Stratification of patients with chronic and smoldering type ATL into prognostic categories may be useful for identifying those who might benefit from treatment using a risk-adapted therapeutic approach. (See 'Prognosis' below.)

The clinical variants of ATL are described below and are discussed in greater detail separately. (See "Clinical manifestations, pathologic features, and diagnosis of adult T cell leukemia-lymphoma".)

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 adult T cell leukemia-lymphoma (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 CD3, CD4, CD8, and CD25. Patients with risk factors should undergo testing for human immunodeficiency virus (HIV).

●Unilateral bone marrow biopsy or aspiration is recommended for all patients. A few reports have described the frequency of bone marrow involvement in various subtypes of ATL [7,8]. As an example, in one study from Japan, bone marrow involvement was detected in 60 of 65 patients (92 percent) with the acute type, but only 7 of 40 patients (18 percent) with the lymphoma type of ATL [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 "Pretreatment evaluation and staging of non-Hodgkin lymphomas", section on 'Imaging'.)

●Endoscopy of the upper gastrointestinal (GI) 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 "Clinical manifestations, diagnosis, and treatment of anthracycline-induced cardiotoxicity" and "Risk and prevention of anthracycline cardiotoxicity".)

●Patients of childbearing 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 females are limited, but males can often participate in sperm banking. (See "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery".)

General approaches to the diagnostic work-up and staging of non-Hodgkin lymphoma are presented separately (table 1). (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma" and "Pretreatment evaluation and staging of non-Hodgkin lymphomas".)

INITIAL TREATMENT

Overview — Patients with acute, lymphomatous, or unfavorable chronic type adult T cell leukemia-lymphoma (ATL) progress quickly without treatment and have a median overall survival (OS) 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 and may increase the risk of transplant complications. Autologous hematopoietic cell transplantation (HCT) does not appear to be effective. Allogeneic HCT may be appropriate for patients with a related or unrelated donor and may result in long-term disease control.

Our treatment suggestions are consistent with the recommendations of an international consensus report [12].

Multiagent regimens — The optimal chemotherapy combination for patients with ATL is unclear and many intensive regimens have been investigated [4,13-18]. Patients may initially respond to treatment with combination chemotherapy regimens devised for advanced, aggressive non-Hodgkin lymphoma, but relapses are common [19]. 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 phase 2 and phase 3 studies [17,18]:

●A phase 3 trial of 118 patients with poor prognosis ATL compared six courses of VCAP-AMP-VECP with eight courses of CHOP-14 (cyclophosphamide, doxorubicin, vincristine, and prednisone every 14 days) [18]. 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 11 months, the following results were reported:

•Patients treated with VCAP-AMP-VECP had a significantly higher rate of complete response (CR) plus CR 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 OS 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 2 study evaluated the clinical efficacy of adding the defucosylated humanized anti-CCR4 antibody mogamulizumab in 53 patients with newly diagnosed aggressive ATL [20]. 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 CR (52 versus 33 percent) and overall response (86 versus 75 percent) rates.

•Higher CR rates among those with blood involvement (100 versus 43 percent) or nodal/extranodal disease (92 versus 73 percent) than among those with skin lesions (50 versus 60 percent).

•Longer median progression-free survival (PFS; 8.5 versus 6.3 months). Median OS had not been reached in either arm after a median follow-up of 13 and 16 months, respectively.

•Higher rates of rash, infusion reactions, thrombocytopenia, lymphopenia, cytomegalovirus infection, and electrolyte disturbances.

●Retrospective review of 39 transplant-ineligible patients with untreated aggressive ATL at a single institution reported that inclusion of mogamulizumab in the initial chemotherapy regimen (eg, including VCAP-AMP-VECP and CHOP-like regimens) was associated with 46 percent four-year OS, compared with 21 percent with chemotherapy alone (hazard ratio [HR] 0.42 [95% CI 0.19-0.96)]; median OS was 36 and 8 months, respectively [21]. The survival advantage with mogamulizumab was seen regardless of age, disease classification, and prognostic index; of note, the probability of four-year OS in patients with cutaneous adverse reactions was 100 percent, compared with 10 percent in patients without such reactions.

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 [22,23]. The evidence supporting this recommendation is discussed separately. (See "Secondary central nervous system lymphoma: Clinical features and diagnosis".)

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, one of the acceptable alternative regimens 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 [24].

For patients ≥70 years, we generally treat with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or a CHOP-like regimen, based on subgroup analysis of the phase 3 trial described above [18]. If available, we suggest that mogamulizumab be given in conjunction with these regimens.

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 [25,26].

Although the randomized phase II study described above suggested that the addition of mogamulizumab to multiagent chemotherapy improves its anti-tumor efficacy [20], several observations after mogamulizumab was approved in Japan suggest an increased risk of acute graft-versus-host disease and transplant-related mortality in allogeneic HCT recipients previously treated with mogamulizumab. As an example, in a retrospective review of 996 patients who underwent allogeneic HCT for ATL, the use of pretransplant mogamulizumab was associated with an increased risk of severe (grade 3/4) graft-versus-host disease (relative risk 1.8), increased non-relapse mortality at one year (44 versus 25 percent), and inferior OS at one year (32 versus 49 percent), especially when it was used within 50 days prior to HCT [27]. The possibility of these complications must be weighed against the potential benefit when considering the use of mogamulizumab in patients who plan to proceed with allogeneic HCT. This increased risk of graft-versus-host disease may be caused by suppressed effector-type regulatory T cells that express CCR4 [28].  

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

●Opportunistic infections – Patients with ATL are immunocompromised and are therefore at risk for potentially lethal opportunistic infections with organisms such as Pneumocystis jirovecii (previously P. carinii), Candida, cytomegalovirus, disseminated cryptococcus, and Strongyloides stercoralis [4]. We routinely administer oral trimethoprim-sulfamethoxazole (TMP-SMX) for P. jirovecii 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 patients without HIV", 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".)

●Tumor lysis syndrome is best prevented with aggressive intravenous fluid hydration to insure a high urine output, rasburicase or allopurinol, and correction of electrolyte disturbances and elements of reversible renal failure (table 2). This is most appropriately performed in a continuously monitored inpatient setting. (See "Uric acid kidney diseases" and "Tumor lysis syndrome: Prevention and treatment", section on 'Treatment of established tumor lysis syndrome'.)

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 [29]. Small, prospective trials and retrospective analyses performed outside of Japan have evaluated the use of the antiviral agent zidovudine (AZT) plus interferon alfa in the treatment of newly diagnosed or relapsed ATL [30-36]. 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 alfa incorporated data from 245 patients with acute (47 percent), chronic (7 percent), smoldering (4 percent), or lymphoma-type (42 percent) ATL [37]. For the 207 patients whose first-line therapy was recorded, the following five-year OS rates were reported:

●AZT plus interferon alfa (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 [38]. While encouraging, we believe that this approach needs further prospective evaluation before it can be widely applied.

Hematopoietic cell transplantation — Both autologous and allogeneic hematopoietic cell transplantations (HCT) have been evaluated in patients with ATL. Allogeneic HCT offers a potential graft-versus-leukemia effect and may be considered for patients with an available donor [39-42]. There is limited experience with autologous HCT for ATL, but it does not appear reduce early relapses [43].

A number of small studies have evaluated the role of myeloablative and nonmyeloablative allogeneic HCT in this disorder [39,42,44-49]. Treatment-related mortality was high, although long-term survival was achieved in some patients, with potential evidence of a graft-versus-HTLV-1 and a graft-versus-tumor effect [46,50]. After allogeneic HCT, HTLV-1 provirus load was significantly decreased in some patients [46,51], suggesting that anti-HTLV-1 immune response is enhanced in these patients.  

Retrospective data are available from Japan regarding 586 patients with ATL who underwent allogeneic HCT between 1992 and 2009 [52]. For the 280 patients who underwent myeloablative conditioning, median 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 toward less treatment-related mortality (hazard ratio [HR] 0.786; 95% CI 0.538-1.148), but greater leukemia-related mortality (HR 1.579; 95% CI 1.080-2.308).

The disease status at the time of HCT impacts outcome. In a retrospective analysis of 214 Japanese patients with acute or lymphomatous subtypes of ATL who underwent allogeneic HCT, the median survival time was 5.9 months and 26 percent were alive at four years post-HCT [41]. The median survival time was significantly longer for those transplanted in first remission (22 months) when compared with those with primary refractory (4 months) or relapsed disease (3 months).

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 [39]. All but one of the patients was treated with a myeloablative conditioning regimen. At the time of transplant, 15 were in CR, 13 in partial remission (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 OS 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.

A multicenter study of HLA-haploidentical HCT with post-transplantation cyclophosphamide (PTCy) in 18 patients was associated with 83 percent one-year overall survival (OS) and 73 percent two-year OS [53]. Rates of overall survival (OS) were 83 percent at one year and 73 percent at two years. One-year non-relapse mortality (NRM) and disease progression were 11 percent and 28 percent, respectively.

PATIENT FOLLOW-UP — Patients with adult T cell leukemia-lymphoma (ATL) 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 P. jirovecii (previously P. carinii), Candida, cytomegalovirus, and Strongyloides stercoralis [4]. 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 patients without HIV" and "Strongyloidiasis" and "Overview of diagnostic tests for cytomegalovirus infection" and "Overview of Candida infections".)

Evaluation during therapy — The VCAP-AMP-VECP regimen is administered in 28-day cycles over six to eight months. During this time, we follow patients serially with clinical examination and computed tomography (CT) scans to determine whether the disease is responding as expected. The prospective studies of VCAP-AMP-VECP have not specifically analyzed time to response parameters; however, in our experience, most responders show objective responses during the initial two cycles. This section describes our usual practice when applying this regimen to patients with previously untreated aggressive ATL.

We perform routine CT scans to evaluate response every two cycles (ie, after two, four, and six cycles). We occasionally perform additional CT scans to confirm progression in patients who show findings suspicious of progressive disease (PD) at other times. PD can be identified clinically in patients with rapidly growing lymph nodes, hypercalcemia, and an apparent increase in peripheral blood tumor cells. Patients with PD after receiving two cycles of induction chemotherapy should be considered for alternative therapies, including allogeneic hematopoietic cell transplantation (HCT), if a donor is available.  

If the disease appears to be responding after two cycles, we continue the VCAP-AMP-VECP regimen. This includes patients without PD who do not meet the criteria for partial response (ie, categorized as having stable disease). For such patients, we usually continue the VCAP-AMP-VECP regimen until apparent PD, partly because there are very few promising regimens other than the VCAP-AMP-VECP regimen. Those with residual lymphadenopathy and circulating ATL cells after four to six cycles of therapy are unlikely to attain a complete response with therapy and may be considered for alternative therapies, including allogeneic HCT, if a donor is available.

The protocols used to evaluate VCAP-AMP-VECP in prospective trials did not provide clinical decision support regarding whether to continue VCAP-AMP-VECP or change the chemotherapy regimen in patients showing stable disease (without evidence of response or progression). As such, clinical decision regarding refractoriness in this setting likely differs among treating physicians. However, this clinical scenario is uncommon since most patients refractory to the VCAP-AMP-VECP regimen manifest with PD rather than long-lasting stable disease.

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, biochemical profile, soluble IL-2 receptor [sIL-2R]). The post-treatment imaging study of choice in patients remains CT. Although 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 (CR) is defined as the disappearance of all clinical and radiographic evidence of disease and the normalization of lactate dehydrogenase (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 (PR) 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 (PD) is ≥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 CR 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 CR, 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".)

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 CR. At these visits, we perform a history and physical examination; complete blood count with differential; evaluation of the peripheral smear; chemistries; LDH; flow cytometry for CD3, CD4, CD8, and CD25; and sIL-2R [54].

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 adult T cell leukemia-lymphoma (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). Small studies of these and other approaches are described here. The use of antiviral therapy is discussed above. (See 'Antiviral therapy' above and 'Hematopoietic cell transplantation' above and "Immunotherapy for the prevention and treatment of relapse following allogeneic hematopoietic cell transplantation".)

Mogamulizumab is a defucosylated humanized anti-CCR4 antibody that is approved for use in Japan [55,56]. A multicenter phase II trial evaluated mogamulizumab monotherapy in 28 patients with relapsed acute (52 percent), lymphomatous (22 percent), or chronic (26 percent) ATL [56].The overall response rate was 50 percent (29 percent complete) and median progression-free and overall survival were 5.2 and 13.7 months, respectively. Toxicity was mostly mild to moderate with the most common toxicities being infusion reactions (89 percent) and rash (63 percent). Interestingly, skin-related adverse effects by mogamulizumab are associated with robust CD8 T cell proliferation [57] and better responses [58]. Regulatory T cells also express CCR4. Mogamulizumab eliminates normal regulatory T cells, resulting in immune activation, including virus-specific cytotoxic T cells [59,60].

Lenalidomide (25 mg/day) was evaluated in a multicenter phase 2 study from Japan, which reported objective responses in 11 of 26 cases (overall response rate, 42 percent; 95% CI 23-63 percent), including at least four complete responses; the rate of tumor control was 73 percent [61]. The median progression-free and overall survival were 3.8 and 20.3 months, respectively. The most frequent grade ≥3 adverse events were neutropenia (65 percent), leukopenia (38 percent), lymphopenia (38 percent), and thrombocytopenia (23 percent).

Limited experience with the anti-CD52 antibody alemtuzumab has also been reported [62,63]. There has also been interest in the use of arsenic trioxide with or without interferon alfa and in the use of all-trans retinoic acid (tretinoin) [35,64-66]. Other new agents for the potential application to the treatment of ATL include pralatrexate (anti-folate), bortezomib (proteasome inhibitor), forodesine (purine nucleoside phosphorylase inhibitor), and histone deacetylase inhibitors [67]. Treatment with anti-PD-1 antibody (immune checkpoint inhibitor) has been reported to accelerate transformation of ATL [68-70].

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 [71]. 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 [40]. The median survival time following relapse was 6.2 months and 19 percent of patients were alive at three years. A complete remission was attained in 2 of 29 patients following withdrawal of immunosuppression, and in four of nine 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 complete remission with cytoreductive therapy, while the three with systemic recurrence progressed despite cytoreductive therapy. A worsening of graft-versus-host disease was seen in six of nine patients receiving DLI.

PROGNOSIS — There are four clinical variants of adult T cell leukemia-lymphoma (ATL): acute, lymphoma-type, chronic, and smoldering. These categories 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 'Categories of ATL' 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 [72]. As such, efforts have been made to develop and validate a prognostic index specific for patients with acute or lymphoma-type ATL.

In a retrospective analysis of 1594 patients with ATL diagnosed and treated in Japan between 2000 and 2009, median survival and four-year survival rate (OS4) differed by clinical variant as follows [41]:

●Acute – 8 month median survival; 11 percent OS4

●Lymphoma-type – 11 month median survival; 16 percent OS4

●Chronic – 32 month median survival; 36 percent OS4

●Smoldering – 55 month median survival; 52 percent OS4

A retrospective nationwide survey of Japanese patients diagnosed with chronic or smoldering type ATL identified soluble interleukin-2 receptor (sIL2-R) as the only independent prognostic factor for survival in multivariate analysis [73]. Patients were stratified into high (sIL-2R >6000 units/mL), intermediate (sIL-2R 1000 to 6000 units/mL), and low (sIL-2R ≤1000 units/mL) risk categories. After a median observation period of 24 months, the following data regarding median survival and OS4 were reported:

●High risk – 1.6 year median survival, 17 percent OS4

●Intermediate risk – 5.5 year median survival, 54 percent OS4

●Low risk – Median survival not reached, 77 percent OS4

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) [72]. 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:

●Stage III or IV – 2 points

●ECOG performance status ≥2 – 1 point

●Age >70 years – 1 point

●Serum albumin <3.5 g/dL – 1 point

●sIL-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.

Genetic profiling of 463 patients reported that specific genetic abnormalities may provide additional prognostic information [74]. STAT3 mutations were more characteristic of indolent ATL (chronic and smoldering subtypes), while aggressive subtypes (acute and lymphoma) were associated with an increased burden of genetic and epigenetic alterations; more TP53 and IRF4 mutations; and numerous copy number alterations, including PD-L1 amplifications and CDKN2A deletions. Multivariate analysis indicated that high-risk ATL-PI, age ≥70 years, PRKCB mutations, and PD-L1 amplifications were independent poor prognostic factors in aggressive ATL. For indolent ATL, IRF4 mutations, PD-L1 amplifications, and CDKN2A deletions were associated with shorter survival.

SUMMARY AND RECOMMENDATIONS

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

●Categories – There are four clinical variants of ATL that differ regarding clinical presentation, prognosis, and need for treatment (see 'Categories of ATL' above):

•Acute ATL

•Lymphoma-type ATL

•Chronic ATL

•Smoldering ATL

●Pretreatment evaluation – Pretreatment evaluation should include history and physical examination, screening laboratory studies, bone marrow examination, lumbar puncture, cardiac function evaluation, and imaging. (See 'Pretreatment evaluation' above.)

●Management – We encourage participation in clinical trial, when possible.

•Indication for treatment – For patients with acute, lymphomatous, or unfavorable chronic type ATL, we recommend initial treatment that includes prophylactic intrathecal chemotherapy (Grade 1B).

Patients with typical (ie, not unfavorable) chronic ATL and smoldering ATL do not require immediate treatment.

•Initial therapy – For initial treatment of ATL, we suggest VCAP-AMP-VECP rather than other combination chemotherapy regimens (Grade 2B). This regimen includes vincristine, cyclophosphamide, doxorubicin, prednisone, ranimustine, vindesine, etoposide, and carboplatin.

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). However, the decision to add mogamulizumab consider a potentially increased risk of acute graft-versus-host disease and transplant-related mortality in patients who will later proceed to allogeneic hematopoietic cell transplantation (HCT).

When these agents are not available, an acceptable alternative 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 CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or a CHOP-like regimen (Grade 2C). (See 'Multiagent regimens' above.)

•Post-remission therapy – Allogeneic HCT offers a potential graft-versus-leukemia effect and may be considered for patients with an available donor. Administration of mogamulizumab should be avoided before HCT. (See 'Hematopoietic cell transplantation' above.)

•Complications – Patients with ATL are at risk for hypercalcemia, tumor lysis syndrome, and opportunistic infections. (See 'Complications of therapy' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Kensei Tobinai, MD, PhD, who contributed to earlier versions of this topic review.