Extranodal natural killer (NK)/T-cell lymphoma is an aggressive malignancy of putative NK-cell origin, with a minority deriving from the T-cell lineage. Pathologically, the malignancy occurs in two ...forms, extranodal NK/T-cell lymphoma, nasal type; and aggressive NK-cell leukaemia. Lymphoma occur most commonly (80%) in the nose and upper aerodigestive tract, less commonly (20%) in non-nasal areas (skin, gastrointestinal tract, testis, salivary gland), and rarely as disseminated disease with a leukemic phase. Genetic analysis showed mutations of genes involved in the JAK/STAT pathway, RNA assembly, epigenetic regulation, and tumor suppression. In initial clinical evaluation, positron emission tomography computed tomography, and quantification of plasma EBV DNA are mandatory as they are useful for response monitoring and prognostication. In stage I/II diseases, combined chemotherapy and radiotherapy (sequentially or concurrently) is the best approach. Conventional anthracycline-containing regimens are ineffective and should be replaced by non-anthracycline-containing regimens, preferably including L-asparaginase. Radiotherapy alone is associated with high systemic relapse rates and should be avoided. In stage III/IV diseases, non-anthracycline-regimens-containing L-asparaginase are the standard. In relapsed/refractory cases, blockade of the programmed death protein 1 has recently shown promising results with high response rates. In the era of effective non-anthracycline-containing regimens, autologous haematopoietic stem cell transplantation (HSCT) has not been shown to be beneficial. However, allogeneic HSCT may be considered for high-risk or advanced-stage patients in remission or relapsed/refractory patients responding to salvage therapy. Prognostic models taking into account presentation, interim, and end-of-treatment parameters are useful in triaging patients to different treatment strategies.
Natural killer (NK)/T-cell lymphomas and NK-cell leukemias are aggressive malignancies. Occurring worldwide, they show a predilection for Asian and South American populations. Neoplastic cells are ...surface CD3−, cytoplasmic CD3ε+, CD56+, cytotoxic-molecule positive, Epstein-Barr virus (EBV) positive, with germline T-cell receptor gene. Lymphomas occur commonly in the nasal and upper aerodigestive region. Occasional cases present in the skin, salivary gland, testis, and gastrointestinal tract. Rare cases are disseminated with lymphadenopathy, hepatosplenomegaly, and a leukemic phase. Positron emission tomography computed tomography is useful in staging, as lymphomas are 18-fluorodeoxyglucose avid. Quantification of circulating EBV DNA is an accurate biomarker of tumor load. Nasal NK/T-cell lymphomas present mostly with stage I/II disease. Concomitant/sequential chemotherapy and radiotherapy is standard treatment. Radiotherapy alone is inadequate because of high systemic failure rate. For stage III/IV nasal, nonnasal, and disseminated lymphomas, systemic chemotherapy is indicated. Regimens containing l-asparaginase and drugs unaffected by P-glycoprotein are most effective. Hematopoietic stem cell transplantation (HSCT) is not indicated for early-stage nasal lymphomas. HSCT for lymphomas not in remission has poor results. In advanced-stage nasal, nonnasal, disseminated, or relapsed lymphomas, HSCT may be considered when remission is achieved. Prognostic modeling and EBV DNA monitoring may be useful in risk stratification for HSCT.
The quantification of circulating Epstein Barr virus (EBV) DNA loads has played an important role in the diagnosis and management of EBV-associated lymphoid malignancies. Viral load measurement is ...particularly useful for monitoring EBV-DNA in hematopoietic stem cell transplant patients, and for assessing the prognosis or response to therapy of EBV-associated intractable lymphomas like extranodal NK/T-cell lymphoma, nasal type. Cell-free EBV-DNA in plasma can be used as a biomarker for estimating the severity or prognosis of these lymphomas. In addition to plasma, whole blood has been used for the management of transplant patients. Although measuring EBV-DNA has been useful, there is a lack of standardization and the optimal specimens for measuring viral loads are unknown. This can be attributed to the different forms of EBV-DNA that exist in peripheral blood and the different pathologies that result from diverse EBV disease states. As a result, guidelines for EBV diagnosis or the initiation of treatment are unclear. However, the newly established World Health Organization standard for EBV quantification will encourage collaborative studies across institutions and countries to establish proper guidelines for EBV diagnosis and the initiation of treatment.
Background
The role of arsenic trioxide (As2O3) in the maintenance of first complete remission (CR1) in acute promyelocytic leukemia (APL) is unclear.
Methods
A total of 129 consecutive adult ...patients with APL of all risk categories who achieved CR1 with conventional induction (all‐trans retinoic acid ATRA/daunorubicin) and consolidation (daunorubicin/cytarabine induction daunorubicin and consolidation omitted for age ≥70 years) underwent maintenance comprising ATRA (45 mg/m2/day), oral As2O3 (10 mg/day), and ascorbic acid (1 g/day) (AAA) for 2 weeks every 2 months for 2 years.
Results
Over a 17‐year period from August 1, 2002, to July 31, 2019, 63 men and 66 women (median age, 46 years range, 18‐82 years) received AAA maintenance, which was already completed in 117 patients. At a median follow‐up of 100 months (range, 8‐215 months), 17 patients (13%) developed first relapse (R1) (hematologic, n = 14; molecular, n = 3) after a median of 19 months (range, 7‐96 months) from CR1. Two R1 patients had concomitant central nervous system (CNS) involvement. All patients achieved CR2 with oral As2O3‐based salvage. Five patients had a subsequent relapse and died. Eight patients died of unrelated causes while still in CR1. The 5‐year and 10‐year rates of relapse‐free survival (RFS) were 89% and 85%, respectively. The 5‐year and 10‐year rates of overall survival (OS) were 94% and 87%, respectively. Multivariate analysis showed that inferior RFS was associated with FLT3‐ITD (P = .005) and CNS involvement on presentation (P = .004), and inferior OS was associated with therapy‐related APL (P = .03), FLT3‐ITD (P = .03), and relapse (P = .03). The safety profile was favorable, with no grade 3/4 organ toxicities.
Conclusion
CR1 maintenance with AAA is safe and results in favorable long‐term survival in patients with APL.
In a 17‐year period, 129 patients with acute promyelocytic leukemia of all risk categories in first complete remission underwent maintenance with all‐trans retinoic acid, oral arsenic trioxide, and ascorbic acid (AAA) for 2 weeks every 2 months for 2 years. AAA maintenance was safe and resulted in excellent survival rates (5‐year and 10‐year relapse‐free survival of 89% and 85%, respectively; 5‐year and 10‐year overall survival of 94% and 87%, respectively).
Extranodal natural killer (NK)/T‐cell lymphoma, nasal type, and aggressive NK‐cell leukemia are rare, and their standard therapy has not been established. They are Epstein–Barr virus‐associated ...lymphoid malignancies, and tumor cells express P‐glycoprotein leading to multidrug resistance of the disease. Patients with stage IV, relapsed or refractory diseases have a dismal prognosis, with survival measured in months only. To develop an efficacious chemotherapeutic regimen, we conducted a dose‐escalation feasibility study of a new chemotherapeutic regimen, SMILE, comprising the steroid dexamethasone, methotrexate, ifosfamide, l‐asparaginase, and etoposide. The components of SMILE are multidrug resistance‐unrelated agents and etoposide. Etoposide shows both in vitro and in vivo efficacy for Epstein–Barr virus‐associated lymphoproliferative disorders. Eligible patients had newly diagnosed stage IV, relapsed or refractory diseases after first‐line chemotherapy, were 15–69 years of age, and had satisfactory performance scores (0–2). Four dose levels of methotrexate and etoposide were originally planned to be evaluated. At level 1, six patients with extranodal NK/T‐cell lymphoma, nasal type, were enrolled. Their disease status was newly diagnosed stage IV (n = 3), first relapse (n = 2), and primary refractory (n = 1). All of the first three patients developed dose‐limiting toxicities, and one of them died of sepsis with grade 4 neutropenia. A protocol revision stipulating early granulocyte colony‐stimulating factor administration was made. Two out of three additional patients developed dose‐limiting toxicities that were all manageable and transient. For the six enrolled patients, the overall response rate was 67% and the complete response rate was 50%. Although its safety and efficacy require further evaluation, we recommend a SMILE chemotherapy dose level of 1 for further clinical studies. (Cancer Sci 2008; 99: 1016–1020)
NK/T-cell lymphomas Tse, Eric; Kwong, Yok-Lam
Best practice & research. Clinical haematology,
September 2019, 2019-09-00, 20190901, Volume:
32, Issue:
3
Journal Article
Peer reviewed
NK/T-cell lymphomas are extranodal EBV-related malignancies, mostly of NK-cell and occasionally of T-cell lineage. They are divided into nasal, non-nasal, and disseminated subtypes. Nasal NK/T-cell ...lymphomas involve the nose, nasopharynx and the upper aerodigestive tract. Non-nasal NK/T-cell lymphomas involve the skin, gastrointestinal tract, testis and other sites. Disseminated NK/T-cell lymphoma involves multiple organs, and may present with a leukemic phase. Initial evaluation requires positron emission tomography computed tomography (PET/CT) and quantification of circulating EBV DNA. Radiotherapy alone is inadequate with frequent relapses. Anthracycline-containing regimens are ineffective. Regimens incorporating asparaginase are currently the standard. For stage I/II disease, combined chemotherapy and radiotherapy is recommended. For stage III/IV disease, asparaginase-containing regimens are needed. Autologous hematopoietic stem cell transplantation (HSCT) is of limited efficacy, whereas allogeneic HSCT may be useful in patients with stage III/IV and relapsed diseases. Immunotherapy with antibodies against CD30, programmed cell death protein 1 and CD38 is promising.
To explore a more effective treatment for newly diagnosed stage IV, relapsed, or refractory extranodal natural killer/T-cell lymphoma, nasal type (ENKL), we conducted a phase II study of the steroid ...(dexamethasone), methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) regimen.
Patients with newly diagnosed stage IV, relapsed, or refractory disease and a performance status of 0 to 2 were eligible. Two cycles of SMILE chemotherapy were administered as the protocol treatment. The primary end point was the overall response rate (ORR) after the protocol treatment.
A total of 38 eligible patients were enrolled. The median age was 47 years (range, 16 to 67 years), and the male:female ratio was 21:17. The disease status was newly diagnosed stage IV in 20 patients, first relapse in 14 patients, and primary refractory in four patients. The eligibility was revised to include lymphocyte counts of 500/μL or more because the first two patients died from infections. No treatment-related deaths were observed after the revision. The ORR and complete response rate after two cycles of SMILE chemotherapy were 79% (90% CI, 65% to 89%) and 45%, respectively. In the 28 patients who completed the protocol treatment, 19 underwent hematopoietic stem-cell transplantation. The 1-year overall survival rate was 55% (95% CI, 38% to 69%). Grade 4 neutropenia was observed in 92% of the patients. The most common grade 3 or 4 nonhematologic complication was infection (61%).
SMILE chemotherapy is an effective treatment for newly diagnosed stage IV, relapsed or refractory ENKL. Myelosuppression and infection during the treatment should be carefully managed.
Large granular lymphocyte leukemia (LGL L) has been morphologically characterized as a group of lymphoproliferative diseases that include T‐cell large granular lymphocytic leukemia (T‐LGL L) and ...chronic lymphoproliferative disorders of natural killer cells (CLPD‐NK). We investigated mutations in the Src homology 2 (SH2) domain of the signal transducer and activator of transcription 3 (STAT3) gene in Asian cohorts of T‐LGL L and CLPD‐NK (n = 42 and 11, respectively). Two mutations, Y640F and D661Y, were identified using direct sequencing or allele‐specific (AS) PCR. Y640F and D661Y mutations were found in seven and 18 patients, respectively. Two patients were positive for both mutations. Frequencies of STAT3 mutations in T‐LGL L and CLPD‐NK were 47.6% and 27.2%, respectively. Pure red cell aplasia (PRCA) was associated with the mutations (P = 0.005). The mutations were persistently found at stable levels in some patients after more than 5 years using AS‐quantitative PCR. The results of the present study indicate that the SH2 domain of the STAT3 gene is frequently mutated in Asian T‐LGL L and CLPD‐NK, and that PRCA is closely correlated with the mutations.
SH2 domain of the STAT3 gene is frequently mutated in Asian T cell large granular lymphocyte leukemia and chronic lymphoproliferative disorders of NK cells. Pure red cell aplasia is closely associated with the mutations.
How we treat NK/T-cell lymphomas Tse, Eric; Zhao, Wei-Li; Xiong, Jie ...
Journal of hematology and oncology,
06/2022, Volume:
15, Issue:
1
Journal Article
Peer reviewed
Open access
Natural killer (NK)/T-cell lymphomas are aggressive malignancies with a predilection for Asian and South American populations. Epstein-Barr virus (EBV) infection in lymphoma cells is universal. ...Predominantly extranodal, NK/T-cell lymphomas are divided clinically into nasal (involving the nose and upper aerodigestive tract), non-nasal (involving the skin, gastrointestinal tract, testes, and other organs), and aggressive leukaemia/lymphoma (involving the marrow and multiple organs) subtypes. Initial assessment should include imaging with positron emission tomography computed tomography (PET/CT), quantification of plasma EBV DNA as a surrogate marker of lymphoma load, and bone marrow examination with in situ hybridization for EBV-encoded small RNA. Prognostication can be based on presentation parameters (age, stage, lymph node involvement, clinical subtypes, and EBV DNA), which represent patient factors and lymphoma load; and dynamic parameters during treatment (serial plasma EBV DNA and interim/end-of-treatment PET/CT), which reflect response to therapy. Therapeutic goals are to achieve undetectable plasma EBV DNA and normal PET/CT (Deauville score ≤ 3). NK/T-cell lymphomas express the multidrug resistance phenotype, rendering anthracycline-containing regimens ineffective. Stage I/II nasal cases are treated with non-anthracycline asparaginase-based regimens plus sequential/concurrent radiotherapy. Stage III/IV nasal, and non-nasal and aggressive leukaemia/lymphoma cases are treated with asparaginase-containing regimens and consolidated by allogeneic haematopoietic stem cell transplantation (HSCT) in suitable patients. Autologous HSCT does not improve outcome. In relapsed/refractory cases, novel approaches comprise immune checkpoint blockade of PD1/PD-L1, EBV-specific cytotoxic T-cells, monoclonal antibodies, and histone deacetylase inhibitors. Future strategies may include inhibition of signalling pathways and driver mutations, and immunotherapy targeting the lymphoma and its microenvironment.
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