NCCN: Continuing Education
Target Audience: This activity is designed to meet the educational needs of oncologists, nurses, pharmacists, and other healthcare professionals who manage patients with cancer.
Accreditation Statements
In support of improving patient care, National Comprehensive Cancer Network (NCCN) is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.
Medicine (ACCME): NCCN designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Nursing (ANCC): NCCN designates this educational activity for a maximum of 1.0 contact hour.
Pharmacy (ACPE): NCCN designates this knowledge-based continuing education activity for 1.0 contact hour (0.1 CEUs) of continuing education credit. UAN: JA4008196-0000-20-012-H01-P
All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: (1) review the educational content; (2) take the posttest with a 66% minimum passing score and complete the evaluation at https://education.nccn.org/node/88590; and (3) view/print certificate.
Pharmacists: You must complete the posttest and evaluation within 30 days of the activity. Continuing pharmacy education credit is reported to the CPE Monitor once you have completed the posttest and evaluation and claimed your credits. Before completing these requirements, be sure your NCCN profile has been updated with your NAPB e-profile ID and date of birth. Your credit cannot be reported without this information. If you have any questions, please e-mail education@nccn.org.
Release date: November 10, 2020; Expiration date: November 10, 2021
Learning Objectives:
Upon completion of this activity, participants will be able to:
Integrate into professional practice the updates to the NCCN Guidelines for T-Cell Lymphomas
Describe the rationale behind the decision-making process for developing the NCCN Guidelines for T-Cell Lymphomas
Disclosure of Relevant Financial Relationships
The NCCN staff listed below discloses no relevant financial relationships:
Kerrin M. Rosenthal, MA; Kimberly Callan, MS; Genevieve Emberger Hartzman, MA; Erin Hesler; Kristina M. Gregory, RN, MSN, OCN; Rashmi Kumar, PhD; Karen Kanefield; and Kathy Smith.
Individuals Who Provided Content Development and/or Authorship Assistance:
Steven M. Horwitz, MD, Panel Chair, has disclosed that he has received consulting fees from Astex Pharmaceuticals, Celgene Corporation, Janssen Pharmaceutica Products, LP, Kura Oncology, Inc., Kyowa Hakko Kirin Co., Ltd., ADCT, C4 Therapeutics, Curio, Myeloid Therapeutics, Verastem, Seattle Genetics, Inc., and Takeda Pharmaceuticals North America, Inc.; and that he has received grant/research support from Celgene Corporation, Daiichi-Sankyo Co., Forty Seven, Inc., ADCT, Aileron, Corvus, Trillium, Verastem, Portola Pharmaceuticals, Inc., and Seattle Genetics, Inc.
Stephen Ansell, MD, PhD, Panel Vice Chair, has disclosed that he has received grant/research support from Bristol-Myers Squibb, Seattle Genetics, Takeda Pharmaceuticals North America, Inc., AI Therapeutics, Inc., Regeneron Pharmaceuticals, Inc., Trillium Therapeutics Inc., Affimed, and ADC Therapeutics.
Stefan K. Barta, MD, MRCP, MS, Panel Member, has disclosed that he has received grant/research support from Bayer Healthcare, Celgene Corporation, Merck & Co., Inc., and Seattle Genetics, Inc.; consulting fees from Janssen Pharmaceutica Products, LP, and Monsanto; and honoraria from Mundipharma.
Ahmet Dogan, MD, PhD, Panel Member, has disclosed that he has served as a scientific advisor for AbbVie, Inc.; received consulting fees from EUSA Pharma, Seattle Genetics, Inc., and Takeda Pharmaceuticals North America, Inc.; received grant/research support from Genentech, Inc. and Takeda Pharmaceuticals North America, Inc.; and received honoraria from Physicians Education Resource.
Aaron M. Goodman, MD, Panel Member, has disclosed that he has received consulting fees from EUSA Pharma and Seattle Genetics, Inc.
Gaurav Goyal, MD, Panel Member, has disclosed that he has no relevant financial relationships.
Ahmad Halwani, MD, Panel Member, has disclosed that he has received grant/research support from AbbVie, Inc., Bayer HealthCare, Genentech, Inc., Immune Design, Pharmacyclics, and Roche Laboratories, Inc.
Bradley M. Haverkos, MD, MPH, MS, Panel Member, has disclosed that he has received consulting fees from Viracta Therapeutics.
Deepa Jagadeesh, MD, MPH, Panel Member, has disclosed that she has served as a scientific advisor for Kyowa Hakko Kirin Co., Ltd., Atara Biotherapeutics, Veratem, and Seattle Genetics, Inc.; and has received grant/research support from MEI Pharma Inc., Debiopharm, Regeneron Pharmaceuticals, Inc., and Seattle Genetics, Inc.
Neha Mehta-Shah, MD, Panel Member, has disclosed that she receives consulting fees from Kyowa Hakko Kirin Co., Ltd., C4 Therapeutics, and Karyopharm Therapeutics Inc.; and that she has received grant/research support from Bristol-Myers Squibb, Celgene Corporation, Genentech/Roche, Innate Pharma S.A., Verastem, Inc., and Corvus Pharmaceuticals, Inc.
Barbara Pro, MD, Panel Member, has disclosed that she has received grant/research support from Verastem, Inc., Seattle Genetics, Inc., and Takeda Pharmaceuticals North America, Inc.; honoraria from Seattle Genetics, Inc., and Takeda Pharmaceuticals North America, Inc.; and consulting fees from Seattle Genetics, Inc.
Aaron Shaver, MD, PhD, Panel Member, has disclosed that he has no relevant financial relationships.
Lubomir Sokol, MD, PhD, Panel Member, has disclosed that he has received consulting fees from Kyowa Hakko Kirin Co., Ltd.
Basem M. William, MD, Panel Member, has disclosed that he has received consulting fees from Celgene Corporation, Kyowa Hakko Kirin Co., Ltd., Guidepoint Global, and Techspert; and grant/research support from Incyte Corporation and Dova.
Jasmine Zain, MD, Panel Member, has disclosed that she has received consulting fees from Verastem, Mundi Pharma, and Curio Biotech SA; and she is a speaker and has received consulting fees and grant/research support from Seattle Genetics, Inc.
Mary A. Dwyer, MS, CGC, Director, Guidelines Operations, NCCN, has disclosed that she has no relevant financial relationships.
Hema Sundar, PhD, Oncology Scientist/Senior Medical Writer, NCCN, has disclosed that she has no relevant financial relationships.
To view all of the conflicts of interest for the NCCN Guidelines panel, go to NCCN.org/disclosures/guidelinepanellisting.aspx.
This activity is supported by educational grants from AstraZeneca; Celgene Corporation; Coherus BioSciences; Genentech, a member of the Roche Group; and TESARO, a GSK Company. This activity is supported in part by an educational grant from Bayer Healthcare Pharmaceuticals. This activity is supported by an independent medical education grant from Bristol-Myers Squibb. This activity is supported by a medical education grant from Exelixis, Inc. This activity is supported by an independent educational grant from Merck & Co., Inc.
Hepatosplenic T-Cell Lymphoma
Hepatosplenic T-cell lymphoma (HSTCL) is a rare lymphoproliferative disorder associated with an aggressive clinical course and a worse prognosis.1,2 HSTCL accounts for ≤2% of all cases of T-cell lymphoma diagnosed worldwide, and in up to 20% of cases develops in the setting of chronic immune suppression or immune dysregulation particularly inflammatory bowel disease (IBD), hematologic malignancies, and previous solid organ transplant.3,4 The concomitant use of tumor necrosis factor-α (TNF-α) inhibitors and thiopurine-based immunomodulators has been identified as a risk factor for developing HSTCL among patients with IBD.5,6
HSTCL is most often characterized by spleen, liver, and bone marrow involvement. Lymphadenopathy is uncommon and patients frequently present with systemic symptoms, hepatosplenomegaly, cytopenias, and sometimes hemophagocytic lymphohistiocytosis (HLH).7,8 Clinical presentation is highly nonspecific and a high index of suspicion is required to make the diagnosis. In most cases, the neoplastic cells typically arise from lymphocytes having the surface expression of T-cell receptor δ (TCRδ) and TCRɣδ.9,10 In rare cases, neoplastic cells may express TCRαβ.11–13 TCRɣδ variant has a male predominance with a median age of 35 years, whereas TCRαβ variant occurs more commonly in women aged >50 years.4 Both are considered immunophenotypic variants of the same disease and are managed the same way. These Guidelines Insights focus on the diagnosis and treatment of HSTCL as outlined in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for T-Cell Lymphomas.
Diagnosis
Diagnosis of HSTCL is most frequently established by a core needle biopsy of bone marrow or liver with adequate immunophenotyping (either by immunohistochemistry or cell surface marker analysis by flow cytometry) as well as through molecular studies (see HSTCL-1, above).4 Splenectomy may be required in equivocal cases, and core needle biopsy of spleen could be considered in some cases at centers of excellence with expertise performing this procedure. It is common for several biopsies to be needed prior to making a definitive diagnosis, because biopsy results may be inconclusive. Examination of peripheral blood smear, bone marrow aspirate, and fine needle aspiration of liver may be helpful but are not solely sufficient for the diagnosis.
Interpretation of cytotoxic cells seen on the bone marrow biopsy specimen may be difficult, and additional liver biopsy may be helpful to confirm the diagnosis. Liver biopsy with adequate immunophenotyping should be reviewed by a hematopathologist.14 HSTCL is typically characterized by the following immunophenotypes: CD2+, CD3+, CD4−, CD5−, CD8±, CD56±, TCRɣδ+, TIA1+, TdT, and granzyme B−.15 An immunohistochemistry panel to evaluate for HSTCL typically includes CD20, CD3, CD10, Ki-67, CD5, CD30, CD2, CD4, CD8, CD7, CD56, EBER-ISH, TCRβ, TCRδ, TIA-1, and granzyme B. Cell surface marker analysis by flow cytometry often includes kappa/lambda, CD45, CD3, CD5, CD19, CD10, CD20, CD30, CD4, CD8, CD7, CD2, TCRδ, TCRαβ, and TCRɣδ.14
Molecular analysis or other assessment of clonality can be used to detect clonal TCR gene rearrangements (see TCLYM-A, page 1466). Identification of TCRɣ gene rearrangement on molecular analysis reflects the clonality of the T cells. However, the molecular clonality studies cannot be used to define the T-cell subtype (αβ vs ɣδ) because TCRβ and TCRɣ gene rearrangements may be seen in both αβ and ɣδ HSTCL.12
Isochromosome 7q and trisomy 8 are the most common chromosomal abnormalities in HSTCL.16–19 Isochromosome 7q and ring chromosome 7 are associated with loss of 7p and amplification of 7q, resulting in altered expressions of several oncogenes located on chromosome 7 (CHN2, ABCB1, and PPP1R9A).20 Gene expression profiling studies have identified distinct molecular signatures that distinguish HSTCL from other T-cell lymphomas.21–23 In a whole-exome sequencing study on 68 primary HSTCL tumors, mutations in chromatin-modifying genes, including SETD2, INO80, and ARID1B (occurring almost exclusively in HSTCL compared with other T-cell lymphoma subtypes), were present in 62% of cases.23 In addition, STAT5B, STAT3, and PIK3CD mutations have also been identified in 31%, 9%, and 9% of cases, respectively.23 STAT3 and STAT5 mutations, however, are not unique to HSTCL and have also been identified in large granular lymphocytic leukemia (LGLL) and other T-cell lymphoma subtypes.24–27
It is essential to consider other natural killer (NK)/T-cell neoplasms with significant overlapping features with HSTCL in the differential diagnosis (eg, ɣδ T-cell LGLL, T-lymphoblastic leukemia, primary cutaneous γδ T-cell lymphoma, intestinal monomorphic epitheliotropic intestinal T-cell lymphoma, aggressive NK-cell leukemia, Epstein-Barr virus [EBV]–positive T-cell and NK-cell lymphoproliferative diseases of childhood, and, rarely, other T-cell lymphomas with expression of TCRɣδ).14,28 Fluorescence in situ hybridization and/or karyotyping to identify isochromosome 7q and trisomy 8 and mutation analysis to identify SETD2, INO80, and TET3 mutations would be useful for the differential diagnosis for HSTCL (see HSTCL-1, page 1462).19,23 Nonneoplastic, transient conditions leading to an increase in ɣδ T-cells with a similar phenotype, including infections such as ehrlichiosis and other tick-borne diseases, should also be considered in the differential diagnosis of HSTCL.29,30
Workup
Initial workup should include a comprehensive medical history and physical examination, including a full skin evaluation and routine laboratory studies (bone marrow biopsy ± aspirate, CBC with differential, comprehensive metabolic panel, and assessment of serum uric acid and lactate dehydrogenase levels) (see HSTCL-2, page 1463). FDG-PET/CT and/or CT of chest/abdomen/pelvis with contrast of diagnostic quality are essential for workup. In the absence of lymphadenopathy, normal FDG uptake in lymph nodes is a pertinent negative finding on PET/CT scan that could differentiate HSTCL from other lymphomas.31 CT scan of the neck and CT or MRI of the head may be useful in some cases. Multigated acquisition (MUGA) scan or echocardiogram is recommended under certain circumstances. Quantitative PCR for EBV and cytomegalovirus reactivation as well as serology testing for HIV and human T-cell lymphotropic virus (HTLV-1) may be useful in selected cases. Human leukocyte antigen (HLA) typing is recommended for all patients eligible for transplant, because HSTCL is associated with a poor outcome in the absence of a consolidative allogeneic hematopoietic cell transplant (HCT). Early referral to transplant is advisable for planning purposes.13
Hemophagocytic lymphohistiocytosis (HLH) is a rare but potentially life-threatening hyperinflammatory syndrome. HLH in adults is most often associated with an underlying hematologic malignancy, especially T-cell lymphomas.7 HSTCL should be considered in the differential diagnosis when evaluating patients presenting with symptoms associated with HLH. Diagnostic workup to confirm the lymphoma subtype and prompt initiation of treatment of underlying T-cell lymphoma is often required (see TCLYM-B, 2 of 3, available with this article at JNCCN.org).
Treatment
HSTCL has been underrepresented in prospective clinical studies, and treatment recommendations are based on the evidence mainly from small case reports or case series and single-center retrospective studies.4 Outcomes are poor with CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone)-based chemotherapy regimens. More intensive non–CHOP-based chemotherapy regimens, such as ICE (ifosfamide/carboplatin/etoposide) or IVAC (ifosfamide/etoposide/cytarabine) have been associated with potentially improved outcomes.32–35 Purine analogs (pentostatin or cladribine) either as monotherapy or in combination with alemtuzumab have also demonstrated modest activity.36–41
Few studies have reported improved survival outcomes with autologous or allogeneic HCT as consolidation therapy for patients with disease in first or second remission.34,42,43 Some studies have also reported that graft-versus-lymphoma effect conferred by allogeneic HCT may result in long-term survival in a significant proportion of patients with HSTCL, and that active disease at the time of transplant was not necessarily associated with poor outcomes.42,43 The efficacy of allogeneic HCT in relapsed or refractory disease has also been demonstrated in several case reports.44–46
A more recent individual-level meta-analysis (which represents the largest aggregation of all published studies and case reports to date: 166 patients with a diagnosis of HSTCL) compared the response rates and overall survival outcomes of 84 patients with HSTCL treated with CHOP or CHOP-like regimens (n=50) or non–CHOP-based regimens, specifically those containing cytarabine, platinum, and etoposide (n=34).35 Non–CHOP-based regimens were associated with an overall response rate of 82% compared with 52% for CHOP or CHOP-like regimens (P=.006), and median survival was 37 and 18 months, respectively (P=.00014). Use of non–CHOP-based regimens was a significant predictor of higher response rate (P=.049) and improved survival (P=.026).
This study also demonstrated a benefit for HCT on survival and the superiority of allogeneic HCT over autologous HCT. The 2-year survival rate was 12% for patients who did not receive HCT compared with 41% and 56%, respectively, for those who received autologous HCT and allogeneic HCT. In the absence of data from prospective and randomized studies, the results of this largest meta-analysis support the use of induction therapy with non–CHOP-based regimens followed by consolidation with allogeneic HCT as an effective treatment approach (associated with improved survival) for all eligible patients with HSTCL. Autologous HCT has also been shown to provide some benefit for patients when an allogeneic HCT is not feasible.34 In a retrospective series of 14 patients with HSTCL, induction therapy with ICE or IVAC followed by consolidation with autologous HCT was associated with improved outcomes compared with use of a CHOP or CHOP-like regimen.34
NCCN Recommendations
The optimal treatment approach for HSTCL remains undefined given the absence of data from prospective randomized clinical studies. Enrollment in a clinical trial, if an appropriate one is available, is the preferred initial treatment option for all patients with HSTCL. The goal of initial therapy is to induce complete or near-complete response to allow successful bridging to HCT, preferably an allogeneic HCT. Because HSTCL is non-nodal, Lugano response criteria do not apply for response assessment, and PET-negative response should be confirmed by bone marrow biopsy and, in selected cases, liver biopsy.
CHOP is not considered adequate therapy.35 The NCCN Guidelines for T-Cell Lymphomas have included ICE as the preferred regimen for induction therapy because it is used in most NCCN Member Institutions (see HSTCL-A, page 1465). Other intensive induction therapy regimens, such as IVAC and hyper-CVAD (cyclophosphamide/vincristine/doxorubicin/dexamethasone) alternating with high-dose methotrexate and cytarabine, may also be appropriate.34,35 Alemtuzumab + pentostatin, CHOEP (cyclophosphamide/doxorubicin/vincristine/etoposide/prednisone), dose-adjusted EPOCH (etoposide/prednisone/vincristine/cyclophosphamide/doxorubicin), and DHAP or DHAX (dexamethasone/cytarabine) + cisplatin or oxaliplatin are included as alternative options.
Consolidation therapy with allogeneic HCT is recommended for eligible patients experiencing complete or partial response after initial induction or second-line therapy (see HSTCL-3, page 1464).35,40,43 Consolidation therapy with autologous HCT can be considered if a suitable donor is not available or in patients who are ineligible for allogeneic HCT.34
Patients with disease not responding to primary treatment or those with progressive disease should be treated with alternate induction therapy regimens before receiving treatment for relapsed/refractory disease.4 Purine analogs or regimens recommended for second-line therapy for primary T-cell lymphoma, not otherwise specified may be appropriate for the management of patients with relapsed/refractory HSTCL. Responses have been observed with alemtuzumab, pralatrexate, and ESHAP (etoposide/methylprednisone/cytarabine/cisplatin).4
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NCCN CATEGORIES OF EVIDENCE AND CONSENSUS
Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise noted.
Clinical trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
PLEASE NOTE
The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. The NCCN Guidelines Insights highlight important changes in the NCCN Guidelines recommendations from previous versions. Colored markings in the algorithm show changes and the discussion aims to further the understanding of these changes by summarizing salient portions of the panel's discussion, including the literature reviewed.
The NCCN Guidelines Insights do not represent the full NCCN Guidelines; further, the National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding their content, use, or application of the NCCN Guidelines and NCCN Guidelines Insights and disclaims any responsibility for their application or use in any way.
The complete and most recent version of these guidelines is available free of charge at NCCN.org.
© National Comprehensive Cancer Network, Inc. 2020. All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN.
