Anaplastic large T/null cell lymphoma

Anaplastic large T/null cell lymphoma

What every physician needs to know:

Anaplastic large T-cell lymphoma (ALCL) is a rare but potentially curable disease that often presents with systemic symptoms such as fever, night sweats, and weight loss. ALCL commonly affects patients under the age of 40 and can be confused with Hodgkin lymphoma or primary mediastinal diffuse large B cell lymphoma. ALCL occurs as both a systemic and a primary cutaneous variant. The two variants have very different natural histories and treatment paradigms. One of the most important predictors of a better treatment outcome with systemic ALCL, but not cutaneous ALCL, is the presence of the ALK (anaplastic lymphoma kinase) protein.

Are you sure your patient anaplastic large T/null cell lymphoma? What should you expect to find?

There are two variants of anaplastic large T-cell lymphoma (ALCL), a systemic variant and a primary cutaneous variant.

Systemic ALCL generally presents with painless lymphadenopathy. B symptoms such as night sweats and unintentional weight loss are present in the majority of patients. ALCL on average affects younger patients than other non-Hodgkin lymphomas and accounts for approximately 40% of non-Hodgkin lymphomas in pediatric patients. Extranodal involvement occurs in 40 to 60% of patients with skin, bone, soft tissue, and lung being common sites of involvement. Many patients will have shortness of breath as a result of bulky mediastinal adenopathy and/or pleural effusions.

It is very important to distinguish cutaneous involvement with systemic ALCL from primary cutaneous ALCL, since the latter has a much more indolent natural history and is treated very differently from systemic disease. Any patient presenting with cutaneous involvement, however, should be presumed to have systemic disease until proven otherwise.

Beware of other conditions that can mimic anaplastic large T/null cell lymphoma:

Distinguishing ALCL from other lymphomas

Hodgkin lymphoma and ALCL can be morphologically and immunophenotypically similar and both disproportionately affect younger patients. As a result, caution must be exercised in making the correct diagnosis. The mediastinal variant of diffuse large B cell lymphoma also affects a similar patient demographic as ALCL and can share pathologic features such as expression of CD30. Primary cutaneous ALCL must be distinguished from systemic ALCL with cutaneous involvement since the two entities are treated very differently and have different natural histories.

ALCL can also mimic infectious or rheumatologic diseases due to the presence of fevers and rash. Also, clonal T cell populations (as well as clonal B cell populations) are sometimes present in the lymph nodes or peripheral blood of patients with rheumatologic or infectious conditions. Otherwise healthy patients over the age of 60 can also sometimes have benign clonal T cell populations in the peripheral blood. The presence of widespread adenopathy, the lack of empiric evidence of infection such as positive blood cultures, and a negative serologic evaluation for rheumatologic disease can often quickly exclude conditions that mimic lymphoma.

Tissue biopsy is mandatory for establishing the diagnosis of ALCL.

ALCL, Hodgkin lymphoma, and primary mediastinal large B cell lymphoma (PMLBCL) all share clinical, morphologic, and immunophenotypic similarities. All three diseases have a tendency to affect younger patients and to present with bulky mediastinal adenopathy and/or pleural effusions. All three entities can express CD30. There are several ways to distinguish these diseases.

Hodgkin lymphoma frequently expresses CD15 which is almost universally absent in ALCL and mediastinal diffuse large B-cell lymphoma (DLBCL). Hodgkin lymphoma often expresses Pax-5 and BOB-1 which are not expressed in ALCL, though both entities can express Oct-1. Forty to 60% of patients with ALCL will have a t(2;5), and up to another 20% will have variant translocations such as t(1;2), t(2;3), and inv(2). None of these cytogenetic abnormalities are common in Hodgkin lymphoma or primary mediastinal large B-cell lymphoma (PMLBCL). As a result of these translocations, ALCL will often express the ALK protein and will frequently, though not always, have T cell markers such as CD2, CD3, CD4, CD5, or CD 7 which are not expressed on either Hodgkin lymphoma or DLBCL. ALCL should not express the B cell marker CD20 which is expressed in PMLBCL and occasionally in Hodgkin lymphoma. Epithelial membrane antigen-1 (EMA) is commonly expressed on ALCL but not expressed in PMLBCL or Hodgkin lymphoma.

There is a variant of diffuse large B cell lymphoma (DLBCL) that is CD20 negative and expresses EMA as well as the ALK protein. However, morphologically, ALK+ DLBCL usually has plasmacytic differentiation and is CD138+ by immunophenotyping. Neither of these features would be seen in ALCL.

Distinguishing systemic ALCL from primary cutaneous ALCL is based largely on clinical grounds. Primary cutaneous ALCL can be confirmed when physical examination, radiographic studies, and a bone marrow biopsy show no evidence of disseminated disease. Also, primary cutaneous ALCL usually does not express the ALK protein or EMA.

Which individuals are most at risk for developing anaplastic large T/null cell lymphoma:

Systemic ALCL accounts for approximately 2.5% of non-Hodgkin lymphomas diagnosed in North America each year, with roughly 1,500 cases diagnosed annually. The median age of patients with primary systemic ALCL is the mid 30s. There is a bimodal age distribution, with peaks in childhood/adolescence and again in late adulthood. Adults with ALK negative systemic ALCL have a higher median age (58 years), than patients with ALK positive ALCL (34 years).

There appears to be a male predominance, particularly in ALK positive cases, in which the male/female ratio is approximately 3:1. In one series, the male predominance of ALK positive cases was especially striking in patients under the age of 30, with a male/female ratio of 6.5:1.

HIV infection appears to be a risk factor for T cell lymphomas including ALCL, with a 15 fold incidence in HIV infected individuals. Patients who have undergone hematopoietic stem cell transplantation or solid organ transplantation may be at higher risk for ALCL, though the vast majority of post-transplant lymphoproliferative disorders are of B cell origin.

Some reports have suggested that Epstein-Barr virus (EBV) is important in the pathogenesis of ALCL, though other reports have refuted this, and there is no clear link between clinical mononucleosis and the subsequent development of ALCL.

Primary cutaneous ALCL is uncommon with only a few hundred cases diagnosed each year and affects a similar demographic as ALK negative systemic ALCL, with a median age at diagnosis of 55.

There is no known familial inheritance pattern with either variant of ALCL and no clearly identified environmental exposures that trigger the disease.

Recently, the Food and Drug Administration (FDA) determined that there is a link between prosthetic breast implants and a unique variant of ALCL. Patients who develop ALCL in this setting usually present with a late onset, non-resolving seroma. The diagnosis of ALCL is generally made when the seroma fluid is aspirated or drained. Despite being ALK negative, the disease is generally indolent and the initial treatment consists of removing the prosthetic implants. Systemic therapy should be reserved for patients who have evidence of disease outside of the breast or recurrent/persistent disease after removal of the prostheses. Fatalities in this setting are rare. Special screening for lymphoma and empiric removal of breast implants in the absence of symptoms is not necessary.

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

Initial testing

An excisional lymph node biopsy is preferred to make the diagnosis. A core needle biopsy may be acceptable as long as there is enough tissue for histology, flow cytometry, cytogenetics, and gene rearrangement studies. A fine needle aspirate is almost always inadequate to establish the diagnosis. Biopsy of skin lesions and/or a bone marrow biopsy can also help establish the diagnosis.

Useful laboratory tests include a complete blood count to assess for sequelae of bone marrow involvement, such as anemia and thrombocytopenia.

Occasionally circulating lymphoma cells will be visible on peripheral blood smear.

An elevated LDH is suggestive of lymphoma and impacts prognosis. A normal LDH does not rule out lymphoma, nor does an elevated LDH conclusively establish the diagnosis.

HIV testing is important, since HIV is a risk factor for lymphoma and acute HIV infection can present with many of the same symptoms as ALCL, including fever, weight loss, and lymphadenopathy.

A comprehensive metabolic profile is important to assess for renal and liver impairment as a result of mechanical obstruction of the ureters and biliary ducts respectively, or from direct organ involvement with lymphoma. Impaired organ function can also affect chemotherapy selection and dosing. Hyperphosphatemia, hyperuricemia, hyperkalemia, and/or renal impairment can suggest spontaneous tumor lysis syndrome from an aggressive ALCL.

Additional testing if a diagnosis of ALCL is confirmed

Females of reproductive age should undergo a serum or urine pregnancy test if chemotherapy is contemplated, since most chemotherapeutics are teratogenic, particularly if given in the first trimester. Males should be counselled about sperm banking and warned that many men will be transiently infertile as a result of the disease itself, especially if they have “B” symptoms such as night sweats and unintentional weight loss.

If anthracycline based chemotherapy is planned, patients should have an assessment of left ventricular function by either echocardiogram or Multi Gated Acquisition Scan (MUGA).

A lumbar puncture for cell count, differential, cytology, flow cytometry, protein, and glucose is only necessary if there is clinical or radiographic evidence of central nervous system (CNS) involvement. Lumbar puncture is not otherwise warranted, given that ALCL does not commonly affect the central nervous system.

Specific pathology tests useful in ALCL

There are several important tests used by the pathologist to establish the diagnosis of ALCL.

Morphologically, both cutaneous and systemic ALCL consist of large blastic cells with nuclei that are frequently horse-shoe or kidney shaped with prominent nucleoli and abundant cytoplasm. ALCL can contain a large number of Reed-Sternberg like cells and thus can be confused for Hodgkin lymphoma.

ALCL is usually positive for CD30, CD45, and EMA but unlike Hodgkin lymphoma, ALCL is almost always CD15 negative. Hodgkin lymphoma often expresses Pax5 and BOB1 which are not expressed in ALCL, though both entities can express Oct1. About 60% of ALCL will express one or more T cell associated antigens such as CD3, CD4, CD5, or CD7, but the remainder of cases can have the “null” phenotype and express no T cell antigens. B cell antigens like CD20 are not expressed, which can be useful in differentiating ALCL from primary mediastinal diffuse large B cell lymphoma, another morphologic mimic of ALCL that can be CD30 positive.

About 40 to 60% of ALCL with have a t(2;5), with up to another 20% having variant translocations such as t(1;2), t(2;3), and inv (2). All of these can lead to expression of the ALK protein which has prognostic and emerging therapeutic implications in ALCL. Primary cutaneous ALCL is usually ALK negative and does not express EMA, but is otherwise morphologically similar to systemic ALCL. T cell receptor gene rearrangement studies demonstrate a clonal rearrangement in over 80% of cases. However, a clonal T cell receptor gene rearrangement is not necessarily diagnostic of T cell lymphoma, nor does the absence of an identifiable clonal rearrangement definitively exclude the diagnosis of T cell lymphoma.

Providers must consider the entire clinical and pathologic spectrum of the patient’s presentation in establishing or excluding a diagnosis of ALCL.

What imaging studies (if any) will be helpful in making or excluding the diagnosis of anaplastic large T/null cell lymphoma?

Computed tomography (CT) scans of the chest, abdomen, and pelvis are useful, both for establishing the diagnosis and staging the extent of lymphoma. Widespread or bulky adenopathy is more suggestive of lymphoma than carcinoma, infectious, or inflammatory conditions.

Positron emission tomography (PET) scanning is not generally helpful in making the diagnosis, since inflammatory conditions and other cancers that present in a similar fashion to ALCL will often be fluorodeoxyglucose (FDG) positive. PET can be useful as a baseline to assess disease burden during and several weeks after completion of chemotherapy to assess response, though this remains to be validated.

CT scans of the neck are optional but most disease in the neck can be followed adequately by palpation. CT or MRI of the head/brain is only necessary if there are signs or symptoms of CNS involvement, since ALCL in adults rarely affects the CNS.

If you decide the patient has anaplastic large T/null cell lymphoma, what therapies should you initiate immediately?

Once the diagnosis of ALCL is definitively established, patients should initiate chemotherapy, unless they have comorbidities that preclude chemotherapy administration.

If patients are very symptomatic, corticosteroids such as prednisone or dexamethasone can be initiated in the interval between the diagnostic biopsy and the receipt of the results. Before initiating corticosteroids in this setting the clinician must be confident that enough tissue was obtained for the pathologist to perform all necessary tests to establish the diagnosis, since corticosteroids could obscure the results of a future biopsy if the initial biopsy did not yield sufficient material to establish a diagnosis.

If the patient has signs of active tumor lysis syndrome they should be hydrated and initiated on allopurinol. In rare circumstances, rasburicase may be necessary if the uric acid is very high. A general guideline would be to consider rasburicase if the initial uric acid is over 10 or there is evidence of uric acid induced nephropathy, such as an otherwise unexplained elevation in creatinine in the presence of hyperuricemia.

More definitive therapies?

Initial therapy

T cell lymphomas are rare diseases and most treatment paradigms are extrapolated from the more common aggressive B cell lymphomas. Patients should be encouraged to participate in well designed clinical trials if available.

Outside of a clinical trial, most patients are treated with anthracycline based chemotherapy. CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) given every 3 weeks for six cycles is the most commonly used regimen. CHOP can be given every 2 weeks, but there is no definitive evidence that this schedule improves the treatment outcome in ALCL. Studies of more aggressive regimens such as HyperCVAD (course A: cyclophosphamide, vincristine, doxorubicin, dexamethasone; course B: methotrexate, cytarabine), MegaCHOEP (dose-escalated CHOP plus etoposide), and VIP-reinforced-ABVD (etoposide, ifosfamide, cisplatin alternating with doxorubicin, bleomycin, vinblastine, dacarbazine) have not demonstrated superior outcomes to CHOP.

A retrospective analysis of a German trial of aggressive lymphomas, including ALCL, suggested that the addition of etoposide to CHOP (CHOEP) may improve outcome in patients under the age of 60 with a normal LDH. It is reasonable to utilize CHOEP in this patient population, though the results have not been confirmed in a randomized, prospective trial and are contradicted by a second German trial showing no benefit to MegaCHOEP.

Patients with localized stage I or II disease should be considered for involved field radiotherapy after six cycles of anthracycline based (CHOP or CHOEP) chemotherapy. Abbreviated chemotherapy (three cycles) followed by radiotherapy has not been validated in early stage disease the way such an approach has been evaluated in diffuse large B cell lymphoma. Thus, six cycles of chemotherapy prior to radiotherapy is preferred.

Patients with primary cutaneous ALCL can often be treated with local radiotherapy, or in the presence of multifocal cutaneous disease, single agents such as oral methotrexate. Aggressive multiagent chemotherapy is rarely necessary and care must be taken not to over treat these patients.

Post-remission therapy

If a patient achieves an initial remission, the decision regarding subsequent treatment is dependent on ALK status and the International Prognostic Index (IPI). Patients with ALK positive ALCL who enter a complete remission are generally observed. Patients with ALK negative ALCL who enter a complete remission (CR) with initial therapy should be stratified by IPI. Those with an IPI of 0 or 1 generally are not offered transplantation in first remission, while patients with an IPI of 2 or higher should be considered for autologous transplantation in first remission. Patients who achieve a partial remission (PR) with initial therapy should be considered for salvage treatment.

Relapsed/refractory disease

Regardless of ALK status, patients who fail to achieve an initial CR, or who relapse after an initial CR, require salvage therapy if their medical condition otherwise permits. As with upfront treatment, patients should be offered participation in well designed clinical trials, since the optimal therapy in this setting remains undefined.

The only drug specifically approved by the FDA to treat relapsed/refractory peripheral T cell lymphoma (PTCL) is the antifolate pralatrexate, which has a response rate of 27%, with a median duration of response of just over 9 months. However, in patients with an adequate performance status and hematologic reserve, combination therapy should be considered prior to single agent therapy.

Gemcitabine is a particularly active drug in T cell lymphomas in general, and is often combined with platinum drugs (increasingly oxaliplatin though historically cisplatin) with or without corticosteroids. Other traditional lymphoma salvage regimens such as ICE (ifosfamide, carboplatin, etoposide) and DHAP (dexamethasone, cytarabine, cisplatin) are also utilized.

Patients who have failed a prior autologous transplantation who subsequently remit should be offered allogeneic transplantation if they are suitable candidates and a donor is available. Patients who did not undergo autologous transplant in first remission, and who subsequently enter a complete remission should be offered autologous transplantation, although the data is conflicting as to whether or not autologous transplantation is beneficial in this setting.

Allogeneic transplantation may be preferable for patients who fail to achieve a CR with salvage therapy, even if they have not undergone a prior autologous transplant. Transplantation of any kind is less effective in the setting of refractory disease and generally should not be offered if a patient is not responding to salvage chemotherapy.

A number of agents are currently being studied or have been studied in relapsed/refractory PTCL. These include the histone deacetylase inhibitors romidepsin and belinostat, the fusion protein denileukin diftitox, the anti-CD52 antibody alemtuzumab, and the anti-CD4 antibody zanolimumab. None however are yet approved by the FDA for this indication. A promising therapy for relapsed/refractory ALCL is the humanized anti-CD30 antibody-tubulin inhibitor conjugate brentuximab vedotin. Brentuximab vedotin has a very high response rate in relapsed/refractory ALCL and is being considered for FDA approval. Specific inhibitors of the ALK protein are also in development and one, crizotinib, has shown promise in a very small number of patients with ALK positive ALCL.

What other therapies are helpful for reducing complications?

Pegfilgrastim or filgrastim are useful in most patients receiving combination chemotherapy to decrease the chance of febrile neutropenia.

Patients with a high disease burden or elevated uric acid should be initiated on allopurinol for the first 10 to 14 days of the first cycle of chemotherapy, and should be monitored for tumor lysis syndrome.

Rarely, rasburicase may be necessary if the patient has severe spontaneous or treatment induced tumor lysis syndrome.

Patients receiving pralatrexate require folic acid and vitamin B12 supplementation.

Patients receiving trimethoprim/sulfamethoxazole or probenecid concomitantly with pralatrexate may be at increased risk of pralatrexate-induced toxicity, and should be monitored accordingly.

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

ALCL is potentially a curable disease. The prognosis is dependent on ALK status and the IPI score. Overall survival (OS) for all patients with ALK positive ALCL is 70 to 90% at 5 years, with a failure free survival (FFS) of approximately 60%.

The 5 year OS and FFS with ALK positive ALCL and an IPI score of 0 or 1 are 90% and 80% respectively, but only 33% and 25% respectively with an IPI score of 4 or 5. Five year OS and FFS are 49% and 36% for all patients with ALK negative ALCL. Substratifying within ALK negative ALCL, patients with an IPI score of 0 or 1 have a 5 year OS and FFS of 74% and 62% respectively, while both values are only 13% with an IPI score of 4 or 5. (See Table I)