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. 2025 May 7;9(5):e70128.
doi: 10.1002/hem3.70128. eCollection 2025 May.

Peripheral T- and natural killer-cell lymphomas: ESMO-EHA Clinical Practice Guideline for diagnosis, treatment, and follow-up

Francesco d'Amore  1   2 , Massimo Federico  3 , Laurence de Leval  4 , Fredrik Ellin  5   6 , Olivier Hermine  7   8 , Won Seog Kim  9 , François Lemonnier  10   11 , Joost S P Vermaat  12 , Gerald Wulf  13 , Christian Buske  14 , Martin Dreyling  15 , Mats Jerkeman  16 ; ESMO and EHA Guidelines Committees
Affiliations

Peripheral T- and natural killer-cell lymphomas: ESMO-EHA Clinical Practice Guideline for diagnosis, treatment, and follow-up

Francesco d'Amore et al. Hemasphere. .
No abstract available

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Conflict of interest statement

F. d. A. reports institutional fees for an advisory role from Frost; institutional fees as local principal investigator (PI) from Genmab; institutional fees for the implementation of a clinical trial as coordinating PI from Servier; non‐remunerated membership of the Scientific Committee for the European School of Haematology and the Clinical Advisory Committee for the WHO (T‐cell lymphoma working group); and non‐remunerated roles as project lead for the European Union's HARMONY Alliance (contact person of associated member institution Aarhus University Hospital), lead author of ESMO−EHA CPG for T‐cell lymphomas, Chairman of the Nordic Lymphoma Group (NLG) T‐cell lymphoma working group and PI for the RESILIENCE trial at Aarhus University Hospital. M. F. reports no potential conflicts of interest. L. D. L. reports institutional fees for advisory board membership from AbbVie, Blueprint Medicines, and Novartis; and institutional fees for expert testimony and travel support from Roche. F. E. reports institutional fees for writing educational material from Roche Sweden; and a non‐remunerated role as local PI for Celgene (observational study). O. H. reports personal fees from AB Science (as consultant, co‐founder, and for scientific support); personal stocks and shares from AB Science (co‐founder); personal ownership interest in Inatherys (co‐founder); institutional fees for advisory board membership from Bristol Myers Squibb (BMS), Celgene and Novartis; and institutional funding from AbbVie, AB Science, Alexion, Blueprint, BMS, Celgene, Novartis, Roche, and Takeda. W. S. K. reports personal and institutional fees as a coordinating PI from BeiGene, Boryong, Kyowa‐Kirin, Roche, and Sanofi; and a non‐remunerated advisory role for Celltrion (regular consulting). F. L. reports personal fees for advisory board membership from BMS, Kiowa, and Miltenyi; personal fees as an invited speaker from AstraZeneca and Takeda; and personal travel grants from Gilead, Janssen, and Roche. J. S. P. V. reports no potential conflicts of interest. G. W. reports personal fees for advisory board membership from Clinigen, Novartis, and Takeda; personal fees as an invited speaker from Gilead and Takeda; an institutional role as local PI from Gilead, Janssen, Miltenyi, Novartis, Roche, and Verastem; non‐remunerated speaker for the German Society of Hematology and Medical Oncology (DGHO); non‐remunerated membership of the DGHO, Experimental Cancer Research (AEK), German Cancer Aid (DKH), and German Lymphoma Alliance (GLA); and has received product samples from Gilead and Roche. C. B. reports personal fees for advisory board membership from AbbVie, BeiGene, Celltrion, Gilead Sciences, Incyte, Janssen, Lilly Deutschland GmbH, MorphoSys, Novartis, Pfizer, Regeneron, Roche, and Sobi; personal fees as an invited speaker from AbbVie, BeiGene, Celltrion, Gilead Sciences, Incyte, Janssen, Lilly Deutschland GmbH, MorphoSys, Novartis, Pfizer, Regeneron, Roche, and Sobi; and institutional funding from AbbVie, Amgen, Bayer, Celltrion, Janssen, MSD, Pfizer, and Roche (all for investigator‐sponsored clinical trials and registries). M. D. reports personal fees as an advisory board member from AbbVie, AstraZeneca, BeiGene, BMS/Celgene, Gilead, Janssen, Lilly/Loxo, Novartis, and Roche; personal fees as an invited speaker for AstraZeneca, BeiGene, Gilead/Kite, Janssen, Lilly, Novartis, and Roche; institutional research grants from AbbVie, Bayer, Celgene, Gilead/Kite, Janssen, Lilly, and Roche; and non‐renumerated membership of the American Society of Clinical Oncology (ASCO), American Society of Hematology (ASH; subcommittee), DGHO (prior Board member), European Hematology Association (EHA; Executive Board), ESMO (Faculty), and the Lymphoma Research Foundation (Mantle Cell Lymphoma Consortium). M. J. reports personal fees for advisory board membership from Genmab, Gilead, and Roche; personal fees as an invited speaker from AbbVie; institutional funding from AbbVie, AstraZeneca, Celgene, and Roche; an institutional role as coordinating PI from BioInvent; and non‐remunerated membership of ASCO, ASH, and the EHA.

Figures

Figure 1
Figure 1
Overview of first‐line treatment in nodal PTCL. a Purple: algorithm title; dark green: RT; blue: systemic anticancer therapy or their combination; turquoise: non‐systemic anticancer therapies or combination of treatment modalities; white: other aspects of management and non‐treatment aspects. ALCL, anaplastic large cell lymphoma; ALK, anaplastic lymphoma kinase; auto‐HSCT, autologous hematopoietic stem‐cell transplantation; BV‐CHP, brentuximab vedotin–cyclophosphamide–doxorubicin–prednisolone; CHOEP, cyclophosphamide–doxorubicin–vincristine–etoposide–prednisolone; CHO(E)P, cyclophosphamide–doxorubicin–vincristine(–etoposide)–prednisolone; ChT, chemotherapy; CR, complete remission; IPI, International Prognostic Index; ISRT, involved‐site radiotherapy; NOS, not otherwise specified; PTCL, peripheral T‐cell or natural killer‐cell lymphoma; RT, radiotherapy; TFHL, follicular helper T‐cell‐derived lymphoma. aFor subtype‐specific treatment algorithms, see Supporting Information: Figures S2 and S3. bCan be considered for patients with high‐risk ALK‐positive ALCL with no CR after three cycles of ChT (III, B).
Figure 2
Figure 2
Overview of first‐line treatment in extranodal PTCL. a Purple: algorithm title; orange: surgery; dark green: RT; blue: systemic anticancer therapy or their combination; turquoise: non‐systemic anticancer therapies or combination of treatment modalities; white: other aspects of management and non‐treatment aspects; dashed lines: optional therapy. ALCL, anaplastic large cell lymphoma; allo‐HSCT, allogeneic hematopoietic stem‐cell transplantation; auto‐HSCT, autologous hematopoietic stem‐cell transplantation; BIA, breast implant associated; BV‐CHP, brentuximab vedotin–cyclophosphamide–doxorubicin–prednisolone; CHO(E)P, cyclophosphamide–doxorubicin–vincristine(–etoposide)–prednisolone; CHOP, cyclophosphamide–doxorubicin–vincristine–prednisolone; ChT, chemotherapy; CR, complete remission; CRT, chemoradiotherapy; EATL, enteropathy‐associated T‐cell lymphoma; EMA, European Medicines Agency; ENKTCL, extranodal natural killer‐ or T‐cell lymphoma; FDA, Food and Drug Administration; HDT, high‐dose chemotherapy; HSTCL, hepatosplenic T‐cell lymphoma; iNKLPD‐GI, indolent natural killer‐cell lymphoproliferative disorders of the gastrointestinal tract; ISRT, involved‐site radiotherapy; iTLPD‐GI, indolent T‐cell lymphoproliferative disorders of the gastrointestinal tract; IVE, ifosfamide–etoposide–epirubicin; MEITL, monomorphic epitheliotropic intestinal T‐cell lymphoma; MTX, methotrexate; NOS, not otherwise specified; P‐GEMOX, pegylated L‐asparaginase–gemicitabine–oxaliplatin; PR, partial remission; PTCL, peripheral T‐cell or natural killer‐cell lymphoma; RT, radiotherapy; TCL, T‐cell lymphoma. aFor subtype‐specific treatment algorithms, see Supporting Information: Figures S4–S10. bNew entity with insufficient data for clinical recommendation. Small case series suggest poor efficacy of anthracycline‐based regimens and biological studies indicate similarities with HSTCL. Consider a strategy similar to HSTCL. cNot EMA or FDA approved. dFDA approved, not EMA approved. eIf chemosensitive (CR or PR), consider early allo‐HSCT due to the high risk of early progression.
Figure 3
Figure 3
Overview of first‐line treatment in leukemic PTCL. a Purple: algorithm title; blue: systemic anticancer therapy or their combination; turquoise: non‐systemic anticancer therapies or combination of treatment modalities; white: other aspects of management and non‐treatment aspects. Allo‐HSCT, allogeneic hematopoietic stem‐cell transplantation; ANKL, aggressive natural killer‐cell leukemia; ATLL, adult T‐cell leukemia or lymphoma; CHO(E)P, cyclophosphamide–doxorubicin–vincristine(–etoposide)–prednisolone; ChT, chemotherapy; CR, complete remission; EMA, European Medicines Agency; FDA, Food and Drug Administration; hyper‐CVAD, hyperfractionated cyclophosphamide–vincristine–doxorubicin–dexamethasone–methotrexate–cytarabine; IFN‐α, interferon‐α; mSMILE, modified dexamethasone–methotrexate–ifosfamide–pegylated L‐asparaginase–etoposide; MTX, methotrexate; NK‐LGL, natural killer‐cell large granular lymphocytic leukemia; PR, partial remission; PTCL, peripheral T‐cell or natural killer‐cell lymphoma; T‐LGL, T‐cell large granular lymphocytic leukemia; T‐PLL, T‐cell prolymphocytic leukemia. aFor subtype‐specific treatment algorithms, see Supporting Information: Figures S11–S14. bNot EMA or FDA approved but available via named‐patient access. cNot EMA or FDA approved. dNo limitation in treatment duration for MTX and cyclosporin A; treatment with cyclophosphamide should be limited to 12 months due to the risk of second malignancy.
Figure 4
Figure 4
Treatment of r/r nodal PTCL. Purple: algorithm title; blue: systemic anticancer therapy or their combination; turquoise: non‐systemic anticancer therapies or combination of treatment modalities; white: other aspects of management and non‐treatment aspects. 5‐aza, 5‐azacitidine; ALCL, anaplastic large cell lymphoma; ALK, anaplastic lymphoma kinase; allo‐HSCT, allogeneic hematopoietic stem‐cell transplantation; auto‐HSCT, autologous hematopoietic stem‐cell transplantation; BV, brentuximab vedotin; ChT, chemotherapy; CR, complete remission; DHAP, dexamethasone–high‐dose cytarabine–cisplatin; EMA, European Medicines Agency; FDA, Food and Drug Administration; GDP, gemcitabine–dexamethasone–cisplatin; ICE, ifosfamide–carboplatin–etoposide; IVAC, ifosfamide–etoposide–cytarabine; MTX, methotrexate; NOS, not otherwise specified; PR, partial remission; PTCL, peripheral T‐cell or natural killer‐cell lymphoma; r/r, relapsed or refractory; TFHL, follicular helper T‐cell derived lymphoma. aNot EMA or FDA approved. bPatients who did not receive first‐line BV or those with late relapse after an initial response. cPatients refractory to BV.
Figure 5
Figure 5
Treatment of r/r extranodal PTCL. Purple: algorithm title; orange: surgery; dark green: RT; blue: systemic anticancer therapy or their combination; turquoise: non‐systemic anticancer therapies or combination of treatment modalities; white: other aspects of management and non‐treatment aspects; dashed lines: optional therapy. ALCL, anaplastic large cell lymphoma; ALK, anaplastic lymphoma kinase; allo‐HSCT, allogeneic hematopoietic stem‐cell transplantation; BIA, breast implant associated; BM, bone marrow; BV, brentuximab vedotin; CD, cluster of differentiation; ChT, chemotherapy; CR, complete remission; DHAP, dexamethasone–high‐dose cytarabine–cisplatin; EATL, enteropathy‐associated T‐cell lymphoma; EMA, European Medicines Agency; ENKTCL, extranodal natural killer‐ or T‐cell lymphoma; FDA, Food and Drug Administration; GDP, gemcitabine–dexamethasone–cisplatin; HSCT, hematopoietic stem‐cell transplantation; HSTCL, hepatosplenic T‐cell lymphoma; ICE, ifosfamide–carboplatin–etoposide; ICI, immune checkpoint inhibitor; iNKLPD‐GI, indolent natural killer‐cell lymphoproliferative disorders of the gastrointestinal tract; ISRT, involved‐site radiotherapy; iTLPD‐GI, indolent T‐cell lymphoproliferative disorders of the gastrointestinal tract; IVAC, ifosfamide–etoposide–cytarabine; MEITL, monomorphic epitheliotropic intestinal T‐cell lymphoma; MTX, methotrexate; NOS, not otherwise specified; PR, partial remission; PTCL, peripheral T‐cell or natural killer‐cell lymphoma; r/r, relapsed or refractory; RT, radiotherapy; TCL, T‐cell lymphoma. aNo specific recommendations available. Due to shared biological features, consider treating as r/r HSTCL. bNot EMA or FDA approved. cConsider alemtuzumab if CD52‐positive tumor cells demonstrated by flow cytometry (e.g., BM or peripheral blood sample).
Figure 6
Figure 6
Treatment of r/r leukemic PTCL. Purple: algorithm title; orange: surgery; blue: systemic anticancer therapy or their combination; turquoise: non‐systemic anticancer therapies or combination of treatment modalities; white: other aspects of management and non‐treatment aspects. Allo‐HSCT, allogeneic hematopoietic stem‐cell transplantation; ANKL, aggressive natural killer‐cell leukemia; ATLL, adult T‐cell leukemia or lymphoma; BV, brentuximab vedotin; CCR4, C‐C chemokine receptor type 4; CD, cluster of differentiation; ChT, chemotherapy; CR, complete remission; DDGP, dexamethasone–cisplatin–gemcitabine–pegylated L‐asparaginase; EMA, European Medicines Agency; FDA, Food and Drug Administration; GDP, gemcitabine–dexamethasone–cisplatin; HSCT, hematopoietic stem‐cell transplantation; JAK3, Janus kinase 3; MTX, methotrexate; NK‐LGL; natural killer‐cell large granular lymphocytic leukemia; P‐GEMOX, pegylated L‐asparaginase–gemicitabine–oxaliplatin; PR, partial remission; PTCL, peripheral T‐cell or natural killer‐cell lymphoma; r/r, relapsed or refractory; T‐LGL, T‐cell large granular lymphocytic leukemia; T‐PLL, T‐cell prolymphocytic leukemia. aAfter a treatment‐free period of ≥6 months in patients who still have CD52‐positive tumor cells. bNot EMA or FDA approved. cIn patients who do not respond to MTX, cyclophosphamide, or cyclosporin A.
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