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Mature T and NK cell Neoplasms

Lead: Eysa Al Solamy & Kevin Imrie
Date of last revision: August 9, 2020.

Terms of use: These guidelines are a statement of consensus of the OCC Hematology site group regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult the Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient's care or treatment. Use of this site and any information on it is at your own risk.

  1. Diagosis and pathologic classification

    T cell lymphomas are a heterogeneous group of malignancies of the immune system with over 20 subtypes according to the 2016 revision of the WHO classification of lymphoid neoplasms. Overall, T cell lymphoma represents a small proportion (~10-15%) of non-Hodgkin lymphomas. While these entities have variable clinical outcomes, they are generally aggressive with poor long-term prognosis. The diagnosis of the T-cell lymphomas is challenging and requires expert pathology review. This treatment policy will summarize our approach the following subtypes:

    • Peripheral T-cell lymphoma not otherwise specified
    • T-cell prolymphocytic leukemia
    • Adult T-cell leukemia/lymphoma
    • T-cell large granular lymphocytic leukemia
    • Extranodal NK/T cell lymphoma, nasal type
    • Anaplastic large cell lymphoma
      • Systemic ALK positive
      • Systemic ALK negative
      • Breast-implant associated
      • Primary cutaneous
    • Angioimmunoblastic T-cell lymphoma
    • Hepatosplenic T-cell lymphoma
    • Enteropathy-associated T-cell lymphoma

    Our approach to the management of the cutaneous T-cell lymphomas will be addressed in the separate cutaneous T-cell lymphoma policy document.

    Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS)

    PTCL-NOS is a diagnosis of exclusion, requiring the exclusion of reactive processes as well as other specific PTCL subtypes [1]. The baseline investigations, response assessment and follow up of a number of the specific T-cell entities is similar to that of PTCL. Differences are highlighted below in the sections devoted to the specific entities.

  2. Baseline testing

    • Full history and physical including ECOG performance status and frailty index if appropriate.
    • CBC, Albumin, LDH, LFTs (Bilirubin, ALT, ALP), creatinine, uric acid
    • Hepatitis B surface antigen, Hepatitis B core antibody, Hepatitis C antibody and HIV serology
    • CT head, neck, chest abdomen & pelvis
    • FDG-PET/CT (may be omitted in patients being treated with palliative intent)
    • TB skin test for patients born outside of North America and Europe
    • MUGA scan or 2D echo (Age >60 or with cardiovascular risk factors) pre-anthracycline chemotherapy
    • Bone marrow biopsy
    • Lumbar puncture (if CNS IPI 4+, encroachment of dura, ATLL, or otherwise felt to be at high risk)
    • Pathology review if not reported at Sunnybrook or UHN

    Testing specific to specific subtypes:

    AILT: SPEP, Immunoglobulin profile, DAT
    ATLL: HTLV1, HIV serology

  3. Staging and prognostic factors

    Patients should be staged according to the revised staging system for Primary nodal lymphomas. The prognosis of T-cell lymphoma can be stratified using the International Prognostic index (IPI), more commonly used for diffuse large B cell lymphoma. Adverse risk factors include:

    • Age > 60
    • Stage III/IV disease
    • LDH above upper limit of normal
    • Extra-nodal site > 1
    • ECOG > 2

    The 5-year overall survival is worse for T-cell lymphoma but the IPI is predictive (2). Other risk assessment models have been studied but are no better predictive than the IPI (3).

  4. Treatment

    First line therapy:

    Choice of chemotherapy regimen: As outcomes are suboptimal with all standard regimens, patients should be offered participation in clinical trials if available. CHOP has traditionally been the most commonly used regimen in PTCL with an overall response rate (ORR) of ~80% and a complete response is ~40% (4,5). Early relapses are common in responders. CHEOP (CHOP+Etoposide) has been reported to improve event-free but not overall survival in fit patients <60 years but not in older patients (6). Other front-line chemo regimens have been studied but have not proven to be more promising than CHOP or CHOEP (6-8). The ECHELON-2 trial reported improved PFS and OS with CHP+ Brentuximab vedotin (BV) in patients with CD30+ peripheral T cell lymphomas. Funding for this regimen is currently under consideration by CCO NDFP (24).

    We will offer CHEOP to fit patients <60 years and CHOP for others

    Limited stage

    CHEOP or CHOP x 4 followed by PET response assessment 4-6 weeks post last chemotherapy. For patients felt to be at high risk, 6 cycles of chemotherapy should be considered

    • If in complete metabolic response: Observe
    • If PET positive (Deauville 4/5): Radiation ³30 Gy

    Advanced stage

    • CHEOP or CHOP x 6. Selected patients with bulk or with specific anatomic localizations may be considered for consolidative radiotherapy
    • Autologous stem cell transplant will not typically be offered as part of front-line therapy. (4,9)

    CNS Prophylaxis:

    • Patients who are at high risk according to the CNS IPI (>3 risk factors) should be considered for prophylaxis
    • Administration of 2-4 cycles of high-dose MTX (3g/m2) on day 10 after CHOEP cycles is the preferred option for fit patients under age 70
    • 4 doses of IT MTX/AraC/hydrocortisone if not appropriate for HD-MTX

    Supportive/Ancillary treatment:

    Response assessment:

    • CT between cycles 3 and 4 to ensure at least PR (Advanced stage)
    • CT 4 weeks following the last cycle of chemotherapy. If residual abnormalities are identified on CT, a PET should be performed 4-6 weeks following last cycle of chemotherapy. Response will be assessed according to Lugano criteria. Patients failing to achieve a complete metabolic response should have biopsy to confirm refractory disease

    Follow-up:

    • Follow up visits every 3 months x 2 years, every 6 months x 3 years. Follow up will be transferred back to primary care physician between years 3 and 5
    • At each visit: history and physical exam, CBC, LDH every 6 months; include TSH every 6 months if thyroid irradiated
    • Counselling on physical and psychosocial issues, smoking cessation, age-appropriate cancer screening, immunizations
    • Screening mammography and MRI starting at years 8-10 for women who received radiation to breast tissue

    Second-line

    • All patients with relapsed/refractory PTCL potentially eligible for further treatment will be discussed at MCC.
    • If eligible for high-dose therapy: GDP and referral for autologous stem cell transplant.
    • Patients not eligible for stem cell transplant and those who relapse after transplant may be considered for treatment with romidepsin or pralatrexate (8,10,11). Both Romidepsin and Pralatrexate are funded through CCO-NDFP. See cancercareontario.ca/en/drugformulary/drugs for eligibility criteria for these agents.

T-cell prolymphocytic leukemia (T-PLL)

  1. Diagnosis and pathologic classification

    T cell prolymphocytic leukemia (T-PLL) is an extremely rare disease, clinically aggressive T cell neoplasm composed of lymphoid cells, typically with involvement of the blood, bone marrow, lymph nodes, spleen and extranodal structures, especially skin comprising approximately 2 % of mature lymphocytic leukemias in adults. There is a slight male predominance. Patients with ataxia telangiectasia have a greatly increased incidence of T-PLL with a different epidemiologic profile (12).

    The peripheral blood will demonstrate >5000/microL (5 x 109/L) of cells with a T-PLL phenotype. Tumor cells express high levels of CD52 and also express pan-T cell markers (CD2, CD3, and CD7) and TCL1 or MTCP1. Abnormalities of 14q32 or Xq28 are characteristic. Serologic and polymerase chain reaction testing for human T-lymphotropic virus, type I, is negative. Criteria for diagnosis have been proposed by the T-PLL International Study Group (TPLL-ISG) (12).

  2. Baseline investigations

    See PTCL-NOS above.

  3. Staging and prognosis

    Patients will be staged as per PTCL-NOS above. T-PLL is an aggressive leukemia with median survival of less than one year, and typically becomes quickly resistant to standard lymphoma therapies. A minority of cases has a more chronic course.

  4. Treatment

    First-line

    • Alemtuzumab induction therapy for 10 to 12 weeks (to achieve best response)
    • Consideration of consolidation with allogeneic stem cell transplant where feasible.

    Second line

    • After relapse, the prognosis of T-PLL is dismal. Repeat treatment with alemtuzumab may have activity in patients with T-PLL. In the absence of a clinical trial option, palliative care will be offered to most

Adult T-cell leukemia/lymphoma

Introduction

Adult T-cell lymphoma/leukemia (ATL) is a rare lymphoproliferative neoplasm of mature CD4+ CD25+ T cells caused by infection with the retrovirus human T-lymphotropic virus type 1 (HTLV-1). HTLV-1 is a retrovirus endemic in southwestern Japan, Caribbean, Canadian First Nations, and Southwestern United States. Between 1-5% of individuals infected with the virus will develop T-cell leukemia/lymphoma with an average latency period of more than 30 year (13).

  1. Diagnosis and pathologic classification

    The malignant cells carry a flower- like or clover-shaped appearance characterized by condensed nuclear chromatin and inconspicuous nucleoli. At least 5% of circulating abnormal T lymphocytes are required to diagnose ATL in patients without histologically proven tumor lesions. These cells express the surface T-cell lymphocytic markers CD2, CD4, CD5, CD45RO, CD29, and T-cell receptor (TCR) and are usually negative for CD7, CD8, and CD26 and show reduced CD3 expression. The lymphocytic activation markers HLA-DP, DQ, DR, and interleukin-R (CD25) are always present. Clonal rearrangements of the TCR genes are typically present. Patients must also demonstrate antibodies to HTLV-1 as well as the presence of clonally integrated HTLV-1 DNA into the cellular DNA of neoplastic T-cells.

    Clinical Subtypes:

    Adult T-cell lymphoma/leukemia is a heterogeneous disease that has been classified into four main categories (14): Acute, Lymphoma, Smoldering, & Chronic.

    Smoldering Chronic Lymphoma Acute
    Anti-HTVL-1 antibody + + + +
    Lymphocytosis <4 >4 <4 +/-
    Abnormal T lymphocytes >5% + <1% +
    Flower cells Occasionally Occasionally No Yes
    Calcium Normal Normal Normal/raised Normal/raised
    LHD <1.5xN <2xN Normal/raised Normal/raised
    Nodes No +/- Yes +/-
    Liver/spleen No +/- +/- +/-
    Skin +/- +/- +/- +/-
    Bone lesions No No +/- +/-
    Marrow Involvement No No +/- +/-

  2. Baseline testing

    • As per PTCL-NOS above.
    • HTLV-1/HIV antibody testing
    • Strongyloides serology
    • All patients require an LP

  3. Prognosis

    Overall, prognosis in ATL remains poor. For those with the acute or lymphoma subtype, the median survival is less than 1 year. Although smoldering and chronic ATLs are characterized by indolent courses initially, the prognosis remains guarded, with 5-year survival of 40% and 50%, respectively, and approximately half of these patients experience progression to acute ATL (13).

  4. Treatment (15)

    First-line:

    • All patients should be offered entry into clinical trials if available
    • Infectious diseases for consideration of AZT/Interferon or alternate antiretroviral therapy
    • HLA typing and be considered for allogeneic stem cell transplantation if clinically appropriate
    • In the absence of clinical trials, lymphoma/acute patients will be treated with hyper-CVAD x 6 for fit patients vs CHOP for less fit patients
    • Prophylactic CNS therapy should be considered for all patients with aggressive ATL and Up-front
    • Prophylaxis for PJP and viral.

T-cell Large Granular Lymphocytic Leukemia (T-LGL)

T-LGL is a clonal disorder of large lymphocytes (typically >0.5x109/L) characterized by splenomegaly and neutropenia. Approximately 40% of patients have an associated condition such as Rheumatoid arthritis (16).

  1. Diagnosis and pathologic classification

    Diagnosis is typically made on morphology and flow cytometry of peripheral blood but bone marrow biopsy may be required. The majority of cases (85%) have a cytotoxic T-cell phenotype with the remaining of natural killer lineage. There does not appear to be a meaningful difference in clinical outcomes between the two groups. T-LGL of NK lineage needs to be distinguished from Aggressive NK cell leukemia which presents much more fulminantly and from LGL lymphocytosis in which patients are minimally symptomatic.

  2. Baseline testing

    Typical testing for most patients will include:

    • Assessment for underlying autoimmune disease such as Rheumatoid arthritis
    • CBC, differential, blood film
    • Peripheral blood flow cytometry
    • Liver function tests, uric acid, LDH
    • Hepatitis B (including core antibody) & C
    • TB skin test for patients born outside of North America and Europe
    • DAT, RF, ANA
    • CT neck, chest, abdomen, pelvis
    • A bone marrow biopsy may be considered in some patients

  3. Staging and prognostic factors

    Patients with T-LGL will be considered to have stage IV disease according to the Ann Arbor stage. Prognosis generally parallels that of the underlying immune disorder if present. Median survivals are reported to be in excess of 10 years. 15-50% of severely neutropenic patients with LGL are reported to experience recurrent infections.

  4. Treatment

    Many asymptomatic patients with LGL can be safely monitored off therapy even with severe neutropenia (ANC <0.5). Indications for treatment include patients with moderate neutropenia and recurrent infections, symptomatic anemia, as well as associated immune conditions requiring therapy. It should be noted that some patients with profound neutropenia never experience recurrent infections and may be carefully observed if reluctant to consider treatment.

    First-line:

    • For patients with an underlying autoimmune condition requiring treatment, treatment should be planned in conjunction with the patient’s rheumatologist.
    • For other patients, first-line treatment typically consists of Methotrexate (MTX) +/- prednisone. MTX is typically started at a dose of 10 mg/m2/week. Long-term steroids should be avoided if possible.

    Beyond first-line:

    • Treatment beyond first line should be reserved for patients with ongoing complications and not given solely for low blood counts.
    • Low dose cyclophosphamide or cyclosporine may both be considered.
    • Growth factors such as G-CSF and erythropoietin are generally reserved for episodic adjunctive treatment.

Extranodal NK/T cell lymphoma, nasal type

Extranodal NK/T cell lymphoma, nasal type is an aggressive with a strong geographic predilection for Southeast Asian and South American populations which is observed less commonly in North America and Europe (17).

  1. Diagnosis and pathologic classification

    The clinical presentation of these lymphomas is almost exclusively extranodal. The most common site of presentation is the nasal cavity and nasopharynx and less commonly the paranasal sinuses, Waldeyer ring, and the oropharynx. Rarely cases may present in other organs, however, the majority of these cases can be shown to have occult nasal primaries. Extension from the nasal cavity and / or nasopharynx into paranasal sinuses is common. Diagnosis can be hampered by the presence of extensive necrosis, so biopsy specimens should be as large as possible. Specimens should be sent fresh to distinguish between surface- and cytoplasmic CD3 expression. Demonstration of EBV is a diagnostic requirement as is CD56 or the presence of cytotoxic molecules. EBV-negative cases and those that do not demonstrate CD56 or cytotoxic molecules should be considered to be PTCL-NOS (see above).

  2. Baseline testing

    • Baseline testing is in large part similar to PTCL-NOS above, including FDG-PET scan and Bone marrow biopsy.
    • In addition, nasal panendoscopy should be performed regardless of initial site of presentation with consideration given to random biopsies when no lesion is seen.
    • A pre-chemotherapy MRI of the head, neck and brain will typically be required for planning of radiation in patients with nasal presentations.

  3. Staging and prognostic factors

    Patients will be staged according to the Lugano classification and IPI. The IPI is of limited utility as most patients will fall into the low or low intermediate groups despite having a relatively poor prognosis. A prognostic factor index for NK cell lymphomas (PINK-E) which includes age >60, Stage III/IV, non-nasal disease, distant lymph node involvement, decreased platelet count, low serum albumen and Epstein-Barr DNA in blood was able to separate patients into low, intermediate and high-risk groups (18).

  4. Treatment

    Early stage (I/II):

    • SMILE x 2, followed by radiation of at least 50Gy, followed by a further 2-4 cycles of SMILE (sandwiched) (19).
    • Selected patients non-considered fit for intensive chemotherapy may be treated with radiation alone.

    Advanced stage:

    • DDGP x 4-6 cycles.

    Response assessment:

    As per PTCL-NOS above

    Beyond first line:

    • All relapsed/recurrent patients will be discussed at MCC.
    • Patients given anthracycline-based chemotherapy such as CHOP may be treated with SMILE in second line.
    • For patients refractory to or relapsed after SMILE and radiotherapy, salvage chemotherapy and allogenic stem cell transplantation may be considered, however, outcomes are poor.

Anaplastic large cell lymphoma (ALCL)

  1. Diagnosis and pathologic classification

    ALCL is an uncommon malignancy accounting for ~2% of non-Hodgkin lymphoma. It is generally considered to be a relatively good prognosis subtype of aggressive lymphoma, but consists of four quite distinct forms based on clinical features with different behaviors and outcomes (20):

    • Primary systemic ALCL, ALK positive (ALK-positive ALCL).
    • Primary systemic ALCL, ALK negative (ALK-negative ALCL).
    • Breast implant associated ALCL (BI-ALCL).
    • Primary cutaneous ALCL (PC-ALCL).

    The diagnosis is made on tissue biopsy based on the morphologic appearance, expression of CD30 on the tumor cells and absence of B cell surface markers. ALK is expressed in ~50% of the cases of systemic ALCL, but is uncommonly expressed in BI-ALCL and PC-ALCL.

  2. Baseline testing

    Baseline testing for patients with systemic ALCL is similar to those with PTCL-NOS (above). Documentation of CD30 and ALK positivity are critically important.

  3. Staging and prognostic factors

    Patients will be staged according to the Ann Abor stage and IPI. The IPI has been found to be an independent predictor of outcome, though survival is generally better than would be predicted for comparable patients with DLBCL Systemic ALK+ patients have significantly better outcomes that those that are ALK- (21).

  4. Treatment (Systemic ALCL)

    First-line

    We will offer CHEOP to fit patients <60 years and CHOP for others.

    Limited stage non-bulky, ALK+;
    CHEOP x4 followed by PET response assessment 4-6 weeks post last chemotherapy;

    • If in complete metabolic response: Observe
    • If PET positive (Deauville 4/5): Radiation ³30 Gy.

    Limited stage bulky or ALK-;
    CHOP or CHOEP x6 followed by PET response assessment 4-6 weeks post last chemotherapy;

    • If in complete remission: Observe. Selected patients with bulk or with specific anatomic localizations may be considered for consolidative radiotherapy.
    • If PET positive (Deauville 4/5): Radiation ³30 Gy.


    Advanced stage;

    • CHOP or CHOEP x6; Selected patients with bulk or with specific anatomic localizations may be considered for consolidative radiotherapy.

    Note: cyclophosphamide, doxorubicin, prednisone in combination with the anti-CD30 antibody, Brentuximab vedotin (BV) has been reported to be associated with improved progression free survival and overall survival compared to CHOP in patients with previously untreated CD30+ peripheral T cell lymphomas (22). This regimen is not currently funded by CCO, but is under consideration. Funding of BV is currently reserved for relapse after multiagent chemotherapy.

    Response assessment

    As per PTCL-NOS above.

    Follow-up: As per PTCL-NOS above.

    Second-line

    Brentuximab vedotin (BV) is the preferred second line therapy. Phase II data for relapsed/refractory ALCL with ORR 85%, CR 57% and duration of response (DOR) 12.6 months (23). This agent is generally administered every 3 weeks until progression or unacceptable toxicity. BV is funded by CCO for patients who have failed at least one line of multiagent chemotherapy and have a performance status of 0 or 1.

    Beyond second-line

    Patients who fail after second line therapy will be discussed at MCC.

Breast-implant associated (BI-ALCL)

BI-ALCL is a recently described subtype of T cell lymphoma recognized in the 2016 WHO classification of lymphoid neoplasms (24). It is now recognized to be a rare complication of textured breast implantation with an estimated lifetime risk of 1:1000-1:10,000, occurring typically 7-10 years after implantation. The management of patients with such presentations is complex should be planned in a multidisciplinary fashion with close communication, and preferably concurrent multidisciplinary assessment by Hematology, Plastic surgery and surgical oncology as appropriate.

  1. Diagnosis and pathologic classification

    The majority of patients will present with effusions adjacent to the implant, so cytologic examination of a large volume (10-50ml) aspirate is essential. Repeat aspiration may be necessary in patients with a high index of suspicion of BI-ALCL.

  2. Baseline investigations

    Full history and physical examination including ECOG performance status and examination of both breasts

    • CBC, Albumin, LDH, LFTs (Bilirubin, ALT, ALP), creatinine
    • Breast US and MRI
    • PET/CT. This may be performed before or after capsulectomy
    • Bone marrow biopsies are not routinely performed.

    For patients felt to be a at high likelihood of requiring chemotherapy:

    • Hepatitis B surface antigen, Hepatitis B core antibody, Hepatitis C antibody
    • Muga scan or 2D echo.

  3. Staging and prognostic factors

    Virtually all patients with BI-ALCL have early Ann Arbor stage disease. A validated BI-ALCL specific TNM staging system has been developed and validated (25):

    Stage:

    IA: Effusion only or disease penetrating into the capsule.
    IIA: Disease limited to the breast but with evidence of lymphoma invading beyond the capsule into the surrounding tissue.
    IIB: Involvement of a single regional lymph node.
    IV: Any disease outside the ipsilateral breast and regional lymph nodes.

    Prognosis of patients is generally excellent with 10 OS of >95% for patients with stage I disease and >80% for those with stage II disease (26).

  4. Treatment

    First-line

    Limited stage (I-IIA);

    • Complete resection of any mass and the surrounding implant capsule (total capsulectomy).
    • Suspicious lymph nodes require exploration and biopsy.
    • Explantation of the contralateral textured breast implant is recommended.
    • Adjuvant radiation or chemotherapy is not recommended for patients with limited stage disease who undergo complete excision.

    Advanced stage;

    • Advanced stage presentations of BI-ALCL are rare.
    • Patients will typically undergo surgical management as per limited stage above followed by CHOP.
    • All advanced stage BI-ALCL patients will be discussed in MCC.

    Response assessment:

    Patients who have not had a PET/CT prior to capsulectomy will have one performed at 6-8 weeks post operatively.

    Follow-up:

    • Patients will be followed every 3 months x 2 years with history, physical examination, CBC and LDH.
    • Type and timing of breast reconstruction will be decided by the patient in partnership with her surgeon.
    • Patients will be reimaged with CT or PET/CT 12 months post-op.

    Second-line and beyond:

    • Patients with localized recurrences after surgical management have a favorable prognosis and may be considered for localized treatment.
    • Patients with systemic relapse will be treated similar to newly diagnosed systemic ALCL.
    • Patients relapsing after multiagent chemotherapy are potentially eligible for treatment with BV.
    • All patients relapsing after primary therapy will be discussed at MCC.

    Primary cutaneous ALCL (PC-ALCL)

    The management of PC-ALCL is addressed within the cutaneous lymphoma policy document.

Angioimmunoblastic T-cell lymphoma (AITL)

  1. Diagnosis and pathologic classification

    Angioimmunoblastic T-cell lymphoma is a rare subtype accounting for 1-2% of all NHL. It typically occurs in those aged >65 (27). Patients typically present with prominent constitutional symptoms with advanced stage disease. The morphologic appearance is quite characteristic with the malignant cells representing a minority of the cellular component of the biopsy.

  2. Baseline investigation

    As per PTCL-NOS above.
    SPEP, Immunoglobulin profile, DAT.

  3. Staging and prognostic factors

    Patients are staged as per PTCL-NOS above. Overall prognosis is poor with a 5-year survival of ~30-35%. The IPI appears to be predictive, but patients with low risk (0-1 risk factors) fare much worse than comparable patients with DLBCL.

  4. Treatment

    • There is no generally accepted standard regimen to treat patients with AITL.
    • Patients not eligible for clinical trials will be treated as per PTCL-NOS above
    • Autologous stem cell transplantation will generally be reserved for patients failing first line treatment.

Hepatosplenic T-cell lymphoma (HSTL)

Hepatosplenic T-cell lymphoma is a rare entity accounting for <1% of all non-Hodgkin lymphomas. It typically presents dramatically, often in younger adult males with systemic symptoms, hepatosplenomegaly, and abnormal blood counts (28).

  1. Diagnosis and pathologic classification

    The diagnosis is most commonly made on liver biopsy, though lymph node or bone marrow biopsy may also be diagnostic. HSTL characteristically involves the sinusoids with monotonous, medium-sized lymphoid cells with round or slightly irregular nuclei.

  2. Baseline investigations

    As per PTCL-NOS above. Given the very poor prognosis, potentially eligible patients should be considered for HLA-testing early after presentation.

  3. Staging and prognostic factors

    As per PTCL-NOS above. The IPI and PIT are of limited prognostic utility. Median survival is <1 year with conventional chemotherapy (29,30).

  4. Treatment

    Prognosis with conventional chemotherapy is poor. There is suggestion from retrospective studies that patients treated with etoposide, platinum, or cytarabine based regimens have better outcomes than those treated with CHOP/CHOP-like regimens and that survival may be better with stem cell transplantation (29). There is anecdotal evidence suggesting splenectomy be considered in patients with severe thrombocytopenia at presentation (30).

    OCC policy:

    • Enrollment in clinical trials should be considered, if available.
    • If no trial is available, ICE regimen should be considered.
    • Allogenic Stem cell transplantation in first remission should be considered.
    • All patients with HSTL should be discussed at MCC.

Enteropathy- associated T-cell lymphoma (EATL)

Introduction

Approximately 10% of intestinal lymphomas have a T-cell immunophenotyped. EATL is a primary intestinal lymphoma that is often, but not always, associated with celiac sprue. It is a rare disease with an annual incidence rate of 0.5-1 per million. EATL occurs predominantly in middle- aged men and is localized primarily in the small bowel.

  1. Diagnosis and pathologic classification

    Recent studies indicate that EATL consists of 2 diseases that are morphologically and genetically distinct and differ with respect to their frequency of association with celiac sprue (31).

    Enteropathy-associated T-cell lymphoma; EATL (type 1): is characterized genetically by chromosome 9q31.3 gain or 16q12.1 deletion and is strongly associated with celiac sprue and the HLA-DQ2 haplotype. frequently have a large-cell or pleomorphic cytology and may express CD30.

    Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL): previously known as Type II EATL (32). MEITL mainly involves jejunum and ileum. Characterized by chromosome 8q24 gain and, less commonly, by 1q and 5q gains. EATL type 2 is less frequently associated with celiac sprue and the HLA-DQ2 haplotype. Microscopically, the tumor typically consisted of dense monomorphic, small- to medium-sized lymphocytes with frequent expression of CD56.

  2. Baseline investigations

    • As per PTCL-NOS above
    • Celiac sprue work-up including measurement of anti-endomysial and anti-tissue transglutaminase antibodies
    • Endoscopic small bowel biopsy, to determine the true incidence of celiac sprue among EATL patients and to determine more accurately its correlation with survival.

  3. Staging & prognostic factors

    Clinically these lymphomas appear as ulcerated plaques or strictures in the proximal jejunum, however other regions in the stomach, small and large bowel have been described [32]. Surgery is usually required to establish diagnosis and avoid perforation during therapy. Tumor cells range from small, medium mixed to large or anaplastic lymphoid cells. Lymphoid tumor cells demonstrate the following immunophenotype: CD3, CD4-, CD5-, CD8+/-, CD30, CD56, TCR-beta and TIA-1. In situ hybridization for EBV. TCR genes are rearranged. Chromosomal abnormalities are often found.

    • EATL has a poor prognosis due to treatment resistance and sepsis or perforation of the bowel at diagnosis or during the course of treatment (33).

  4. Treatment

    • The best current treatment choice is high-dose chemotherapy.
    • Anthracycline-based chemotherapy regimens cycles of CHOP chemotherapy at 3 weekly intervals preceded by surgical resection and followed by ASCT, although this procedure can only be applied to a highly selected number of patients able to tolerate it.
    • If a short course of chemotherapy is planned then whole abdominal radiation at a dose of 25 Gy in 20 fractions should be added.
    • Further studies are needed to verify whether innovative therapies might be of help in treating or preventing EATL.
    • Strict adherence to a GFD remains the best option to prevent EATL in patients with CD (33).

References:

  1. Weisenburger DD, Savage KJ, Harris NL et al. Peripheral T-cell lymphoma not otherwise specified: a report of 340 cases from the International Peripheral T-cell Lymphoma Project. Blood. 2011;117(12):3402-3408.
  2. Savage KJ, Harris NL, Vose JM et al ALK- anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project. Blood 2008;111(12):5496-5504.
  3. Beaven AW. And Diehl LF. Peripheral T-cell lymphoma, NOS, and anaplastic large cell lymphoma. ASH Education Book 2015: 550-558.
  4. Reimer P, Rudiger T, Geissinger E et al. Autologous Stem-Cell Tranplantation as first-line therapy in peripheral T-cell lymphomas: results of a prospective multicenter study. J Clin Oncol. 2009;27(1):106-113.
  5. Simon A, Peoch M, Casassus P et al. Upfront VIP-reinforced-ABVD (VIP-rABVD) is not superior to CHOP/21 in newly diagnosed peripheral T cell lymphoma. Results of the randomized phase III trial GOELAMS-LTP95. Br J Haematol. 2010;151(2): 159-66
  6. Schmitz N, Trumper L, Ziepert M et al. Treatment and prognosis of mature T-cell and NK-cell lymphoma: an analysis of patients with T-cell lymphoma treated in studies of the German High-Grade Non-Hodgkin Lymphoma Study Group. Blood 2010;116(18):3418-25.
  7. Moskowitz A, Lunning MA, Horwitz SM. How I treat the peripheral T cell lymphomas. Blood 2014;123(17):2636-44.
  8. Altmann A et al. Alemtuzumab Added to CHOP for Treatment of Peripheral T-Cell Lymphoma (PTCL) in Previously Untreated Young and Elderly Patients: Pooled Analysis of the International ACT-1/2 Phase III Trials. Blood 2018, 132; 1622
  9. d’Amore F, Relander, T, Lauritzsen, Jantunen Esa et al. Up-Front Autologous stem-cell transplantation in peripheral t-cell lymphoma: NLG-T-01. J Clin Oncol. 2012;30(25):3093-99.
  10. Coiffier B, Pro B, Prince HM et al. Romidepsin for the treatment of relapsed/refractory peripheral T-cell lymphoma: a pivotal study update demonstrates durable responses. J Hamatol Oncol. 2014;7:11.
  11. O’Connor OA et al. Pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma: results from the pivotal PROPEL study. J Clin Oncol 2011: 29; 1182-9
  12. B. Staber et al., “Special Report Consensus criteria for diagnosis , staging , and treatment response assessment of T-cell prolymphocytic leukemia,” vol. 134, no. 14, pp. 2–4, 2019.
  13. Mehta-shah, L. Ratner, and S. M. Horwitz, “Adult T-Cell Leukemia / Lymphoma,” vol. 13, no. 8, 2020.
  14. J. Moskowitz, M. A. Lunning, and S. M. Horwitz, “How I Treat How I treat the peripheral T-cell lymphomas,” vol. 123, no. 17, pp. 2636–2644, 2014.
  15. Bazarbachi A et al. How I treat adult T-cell leukemia/lymphoma. Blood 2011; 118: 1736-1745
  16. Lamy T et al. How I treat LGL Leukemia. Blood 2011; 117: 2764-2774.
  17. Tse E et al. How I treat NK/T-cell lymphomas. Blood 2013; 121: 4997-5005
  18. Kim SJ et al. A prognostic index for natural killer cell lymphoma after non-anthracycline-based treatment: a multicentre, retrospective analysis. Lancel Oncology 2016; 17: 389-400
  19. Kwong YL et al. SMILE for natural killer/T-cell lymphoma: analysis of safety and efficacy from the Asia Lymphoma Study Group. Blood. 2012;120(15):2973-2980
  20. Vose J et al. International T cell and natural killer/T cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol 2008: 26;4124
  21. Savage KJ et al. ALK- anaplastic large-cell lymphomas clinically and immunophenotypically different from both ALK+ ALCL and peripheral T cell lymphoma, not otherwise specified: report from the international Peripheral T cell lymphoma project. Blood 2008; 111: 5496
  22. Horwitz S et al. Brentuximab vedotin with chemotherapy for CD30-positive peripheral T cell lymphoma (ECHELON-2): a global, double-blind, randomized, phase 3 trial. Lancet 2019; 393: 229
  23. Pro B, Advani R, Brice P et al. Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study. J Clin Oncol. 2012;30(18):2190-96.
  24. Mehta-Shah N et al. How I treat breast implant-associated anaplastic large cell lymphoma. Blood 2018; 132: 1889-1898
  25. Horwitz SM et al. NCCN guidelines insights: Non-Hodgkin’s lymphomas. J Natl Compr Canc Netw 2018; 16: 123-135
  26. Clemens MW. Et al. Complete surgical resection is essential for the management of patients with breast implant-associated anaplastic large cell lymphoma. J Clin Oncol 2016; 34: 160-168
  27. Lunning MA et al. Angioimmunoblastic T-cell lymphoma: the many-faced lymphoma. Blood 2017: 129; 1095-1102
  28. Foss FM et al. Incidence and outcomes of rare T cell lymphomas from the T Cell Project: hepatosplenic, enteropathy associated and peripheral gamma delta T cell lymphomas. Am J Hematology 2020; 95:151-155
  29. Klebaner D et al. Intensive Induction Therapy Compared With CHOP for Hepatosplenic T-cell Lymphoma. Clinical lymphoma, myeloma & leukemia. 2019
  30. Gumbs AA et al. Importance of early splenectomy in patients with hepatosplenic T-cell lymphoma and severe thrombocytopenia. Ann Surg Oncol 2009; 16:2014.
  31. Delabie et al., “Enteropathy-associated T-cell lymphoma: Clinical and histological findings from the international peripheral T-Cell lymphoma project,” Blood, vol. 118, no. 1, pp. 148–155, 2011.
  32. Tian, S. Y. Xiao, Q. Chen, H. Liu, and J. Ping, “Monomorphic epitheliotropic intestinal t-cell lymphoma may mimic intestinal inflammatory disorders,” Int. J. Immunopathol. Pharmacol., vol. 33, 2019.
  33. Di Sabatino, F. Biagi, P. G. Gobbi, and G. R. Corazza, “How I treat How I treat enteropathy-associated T-cell lymphoma,” vol. 119, no. 11, pp. 2458–2468, 2012.
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