Adult T-cell leukemia/lymphoma

What every physician needs to know:

Adult T-cell leukemia/lymphoma (ATL) is a distinct subtype of mature or peripheral T-cell lymphomas associated with the human T-cell lymphotrophic virus type 1 (HTLV-1).

HTLV-1 is a human retrovirus that is endemic in certain parts of the world, including the northern and southern islands of Japan, the Caribbean, parts of Sub-Saharan Africa, parts of South America, and the Middle East. Sporadic cases of ATL occur in North America, Western Europe, India, and Australia often, but not always, due to immigrant populations from endemic areas. The most common routes of transmission are mother to child through breast feeding, blood transfusions, or sexual transmission.

Only 2 to 5% of affected individuals will ever develop symptomatic ATL, with the vast majority remaining as asymptomatic carriers throughout their life. Human T-cell lymphotrophic virus type 2 (HTLV-2) was thought to carry an increased risk; however currently this paradigm is now questioned as to whether it causes any known human disease.

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ATL usually occurs in adulthood and comprises only 1 to 2% of T-cell lymphomas in the United States and Europe, though accounts for a much higher proportion in endemic areas such as Japan. There are several distinct clinical presentations termed: smoldering, chronic, acute, and lymphoma.

While definitions are now published, the subtypes exist in a spectrum, and at times there is overlap between presentations. All subtypes require serologic evidence of anti-HTLV-1/2 antibodies, as well as subsequent confirmatory tests (enzyme-linked immunosorbent assay [ELISA]/Western blot). The most conclusive diagnostic technique is demonstration of clonal integration of the HTLV-1 virus into tumor tissue; however this test is not widely available, and positive serology with appropriate evidence of T-cell lymphoma consistent with ATL is sufficient in most cases.

The smoldering and chronic subtypes are generally indolent and can be treated with biologic therapies or even observed, while the aggressive forms, acute and lymphoma, can be rapidly progressive and become life threatening in a short period of time. In these aggressive forms, combination chemotherapy is attempted with responses seen but durable remissions are relatively uncommon. As such, consolidation with allogeneic stem cell transplantation is increasingly considered, after induction chemotherapy in appropriate patients.

The smoldering subtype is characterized by circulating abnormal T-cells (often called flower cells) but with a normal absolute lymphocyte count and no more than 5% of the cells being abnormal. Serum lactate dehydrogenase (LDH) should be less than or equal to one and a half times normal, with skin lesions or lung involvement noted at times.

The chronic form can present in a similar fashion to the smoldering form but is defined by an elevated absolute lymphocyte count and an LDH level up to twice normal. Patients with the chronic form may have bone marrow or splenic involvement. The more aggressive subtypes include the acute form, which is defined as an elevated number of circulating cells, LDH greater than twice normal, frequent hypercalcemia, and more extensive extranodal involvement including the central nervous system (CNS), bone, and gastrointestinal tract. The lymphoma presentation is an aggressive subtype similar to the acute form, but with a paucity of circulating cells and more prominent lymphadenopathy.

Are you sure your patient has adult T-cell leukemia/lymphoma? What should you expect to find?

You would expect to find:

  • New diagnosis of a T-cell lymphoma
  • Endemic area or risk factor (recommend HTLV-1/2 antibodies on all newly diagnosed patients)
  • Elevated white blood cell count, characteristic “flower” cells may, or may not be present
  • Lymphadenopathy may be present
  • Hypercalcemia
  • Osteolytic bone lesions
  • Skin lesions, patches and/or nodules may be present

Beware of other conditions that can mimic adult T-cell leukemia/lymphoma:

Other conditions that can mimic adult T-cell leukemia/lymphoma:

  • Peripheral T-cell lymphoma
  • Mycosis fungoides
  • Other forms of T-cell lymphoma
  • Acute lymphoblastic lymphoma/leukemia
  • Large granular leukemia
  • A reactive process could be confused with the indolent forms of this disease

Which individuals are most at risk for developing adult T-cell leukemia/lymphoma:

The overwhelming majority of patients are from endemic areas of Japan, Caribbean islands, and Sub-Subharan Africa. Given increased exposure to people from endemic areas and rare cases of HTLV-1 associated lymphomas in people without any identifiable risks, we at least consider testing for HTLV-1/2 antibodies in all newly diagnosed patients with T-cell lymphoma, as the finding of HTLV 1/2 positivity may change the treatment recommendations in critical ways.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

Human T-cell lymphotrophic virus type 1/2 serology

Essential for diagnosis (rare cases of HTLV-1 negative ATL have been reported, but the diagnosis was made on clinical grounds rendering it difficult to exclude that these were other forms of T-cell lymphoma).

Complete blood count

Elevated white blood cell count with peripheral blood smear review commenting on nuclear folding, also known as “flower cells”.

Comprehensive metabolic panel

As a result of the profound diuretic capabilities of hypercalcemia it is not uncommon for patients to present profoundly volume depleted, with evidence of acute renal failure. The hypercalcemia is thought to arise from osteoclast activation by the malignant ATL cells.

Lactate dehydrogenase

Often elevated, given the aggressive nature of the underlying disease. The absolute level guides the differentiation between smoldering, chronic, and acute/lymphoma subtypes.

What imaging studies (if any) will be helpful in making or excluding the diagnoses of adult T-cell leukemia/lymphoma?

Helpful imaging studies:
  • MRI (magnetic resonance imaging) scan of brain if focal neurologic changes are present and/or noted on physical exam
  • CT scan of chest, abdomen, pelvis to demonstrate lymphadenopathy
  • Bone marrow biopsy
In selected cases:
  • Lumbar puncture
  • Positron emission tomography (PET) scan

If you decide the patient has adult T-cell leukemia/lymphoma, what therapies should you initiate immediately?

Aggressive disease subtypes: Intravenous hydration, allopurinol (renally dosed), plan institution of chemotherapy.

Indolent subtypes: Confirm diagnosis.

More definitive therapies?

For the aggressive subtypes, combination chemotherapy remains the primary therapy. Regimens such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) have activity in terms of responses but little to no durable benefit. As a result, more aggressive regimens are often considered.

In one randomized phase III study, the regimen VCAP-AMP-VECP (VCAP [vincristine, cyclophosphamide, doxorubicin, and prednisone], AMP [doxorubicin, ranimustine, and prednisone], VECP [vindesine, etoposide, carboplatin, and prednisone]) demonstrated improvement over CHOP-14, but its utility in the United States of America (US) is limited as agents (vindesine and ranimustine) in the regimen are not available in the US. As a result, outside of a clinical trial, we recommend an induction regimen like infusional EPOCH (infusional etoposide, doxorubicin, vincristine, with bolus cyclophosphamide and oral prednisone), with the knowledge that this alone is likely insufficient to result in a durable remission.

Small series have shown responses to anti-retrovirals in combination with interferon alfa (p53 status may be important in this situation). However, a meta-analysis suggested that any benefit of this approach may be largely confined to indolent subtypes. A recent series combining this approach with combination chemotherapy suggested some additional benefit. However, this was not a prospective study and therefore patient selection and possible additional toxicity of the approach could not be assessed or recommended as a standard therapy.

Other agents with anecdotal evidence of utility include oral arsenic trioxide, in combination with antivirals and interferon alpha; preclinical data on the efficacy of bortezomib may lead to combination strategies. An anti C-C chemokine receptor type 4 (CCR4) antibody (KW-0761) showed activity in a phase II study, and further trials with this agent are underway. The role of allogeneic stem cell transplantation in first or second complete remission appears to be the only curative option, autologous stem cell transplantation seems of little benefit. Clinical trials are increasingly important in the management of ATL.

What other therapies are helpful for reducing complications?

Other therapies

If a patient has gastrointestinal complaints, consider checking for strongyloides antibodies, given the rare finding of concomitant infestation seen at disease presentation. If positive, immediately consult the department of infectious disease given the difficulty of acquiring an adequate supply of ivermectin.

Patients may be profoundly immunosuppressed with this disorder. Findings concerning for Pneumocystis pneuminia (PCP) likely require consideration of empiric treatment.

CNS relapses are reported, although there is no data showing prophylaxis to reduce this complication.

Consider antimicrobial prophylactic measures during induction therapy including:

  • Antiviral: Acyclovir
  • Antifungal: Fluconazole
  • Anti-PCP: Bactrim

What should you tell the patient and the family about prognosis?

Many times patients present with significant symptoms requiring immediate therapy, due to the rapidly progressive nature of the disease. In aggressive subtypes, while the overall prognosis is poor, there are long term survivors, including those cured of the disease. However, this appears to be primarily achieved in the context of allogeneic transplantation. For those with smoldering or chronic ATL, this often runs an indolent course and prognosis is more akin to an indolent lymphoma; however evolution to aggressive disease may occur, in which case prognosis is poor.

For aggressive subtypes we recommend a planned treatment paradigm that involves discussion of allogeneic transplantation in first remission for patients in whom this is feasible. Given the frequent difficulties in identifying stem cell donors in these populations, early consultation at a transplant center is advised.

It is important to explain the disease in the context of HTLV-1 infection, to help conceptualize the rarity of the development of ATL with only 2 to 5% ever developing lymphoma. With regard to testing other family members to determine carrier status, at this time we defer to our infectious disease colleagues regarding asymptomatic testing, but explain to the patient and his or her family that, at this time, we do not have a strategy to treat or eradicate HTLV-1 in a carrier.

Strategies such avoiding breast feeding in HTLV-1 positive mothers are being undertaken to reduce the incidence in Japan.

What if scenarios.

Poor performance status raises concern for initiation of cytotoxic combination chemotherapy

Frequently, performance status decline is due to burden of disease and may improve dramatically with correction of underlying metabolic derangements.

Pathology comes back another subtype of lymphoma but human T-cell lymphotrophic virus type 1 antibody positive

Another subtype of lymphoma such as, peripheral T-cell lymphoma not otherwise specified [PTCL-NOS], anaplastic large-cell lymphoma [ALCL], or mycosis fungoides. Statistically, patients with T-cell lymphoma who are HTLV-1 positive are much more likely to have ATL than a coincidental T-cell lymphoma in the setting of HTLV-1 infection.

No matched unrelated donors

Newer stem cell sources (cord blood and haploidentical) may make this option available for patients with ATL.

Matched siblings carry human T-cell lymphotrophic virus type 1

Data from Japan suggests that HTLV-1 positivity does not exclude a potential donor.


HTLV-1 appears to be a necessary factor in the development of ATL. However, why a small percentage of carriers develop ATL when the majority never do is poorly understood. Strongyloides infection increasing the risk of development of ATL has been reported.

What other clinical manifestations may help me to diagnose adult T-cell leukemia/lymphoma?

A new diagnosis of T-cell lymphoma, unexplained hypercalcemia, persistent unexplained rash, or lymphocytosis in an individual from an endemic area should prompt evaluation of HTLV-1 status and biopsy of appropriate tissue.

What other additional laboratory studies may be ordered?

  • Uric acid
  • Strongyloides antibody

What’s the evidence?

Tsukasaki, K, Hermine, O, Bazarbachi, A. “Definition, prognostic factors, treatment, and response criteria of adult T-cell leukemia-lymphoma: a proposal from an international consensus meeting”. J Clin Oncol. vol. 27. 2009. pp. 453-9. [An international consensus manuscript describing the key characteristics in the diagnosis and management of ATL.]

Tsukasaki, K, Utsunomiya, A, Fukuda, H. “VCAP-AMP-VECP compared with biweekly CHOP for adult T-cell leukemia-lymphoma: Japan Clinical Oncology Group Study JCO9801”. J Clin Oncol. vol. 25. 2007. pp. 5458-64 . [Describes the outcomes of VCAP-AMP-VECP in Japan in aggressive ATL. Article has limited utility in US given two drugs are unavailable.]

Ratner, L, Harrington, W, Feng, X. ” Human T cell leukemia virus reactivation with progression of adult T-cell leukemia-lymphoma”. PLoS One. vol. 4. 2009. pp. 4420[Describes the outcomes of ATLL (adult T-cell leukemia-lymphoma) with EPOCH, followed by antivirals and interferon alpha maintenance.]

Bazarbachi, A, Plumelle, Y, Ramos, JC. “Meta-analysis on the use of zidovudine and interferon-alfa in adult T-cell leukemia/lymphoma showing improved survival in the leukemic subtypes”. J Clin Oncol. vol. 28. 2010. pp. 4177-83 . [A meta-analysis of antiviral and interferon alpha therapy in the initial management of certain subtypes of ATL.]

Kchour, G, Tarhini, M, Kooshyar, MM. ” Phase 2 study of the efficacy and safety of the combination of arsenic trioxide, interferon alpha, and zidovudine in newly diagnosed chronic adult T-cell leukemia/lymphoma (ATL)”. Blood. vol. 113. 2009. pp. 6528-32 . [A phase II study introducing arsenic trioxide as a potential agent with efficacy in ATL in combination with antivirals and interferon alpha.]

Nasr, R, El-Sabban, ME, Karam, JA. ” Efficacy and mechanism of action of the proteasome inhibitor PS-341 in T-cell lymphomas and HTLV-I associated adult T-cell leukemia/lymphoma”. Oncogene. vol. 24. 2005. pp. 419-30 . [Pre-clinical rationale for the use of bortezomib in ATL.]

Ishida, T, Joh, T, Uike, N. ” Defucosylated Anti-CCR4 Monoclonal Antibody (KW-0761) for Relapsed Adult T-Cell Leukemia-Lymphoma: A Multicenter Phase II Study”. J Clin Oncol. vol. 30. 2012. pp. 837-42 . [Initial efficacy experience of KW-0761 as a single agent in relapsed ATL.]

Hishizawa, M, Kanda, J, Utsunomiya, A. “Transplantation of allogeneic hematopoietic stem cells for adult T-cell leukemia: a nationwide retrospective study”. Blood. vol. 116. 2010. pp. 1369-76. [Large retrospective report of the outcomes of allogeneic stem cell transplantation in ATL.]