{"id":"lymphoma-roadmap","name":"Lymphoma roadmap: from a jaw tumour in Uganda and the first human cancer virus to gene-expression subtypes, PET-adapted chemotherapy, CAR-T cells, bispecific antibodies and the genetics-directed trials now recruiting","route":"/roadmaps/lymphoma-roadmap/","eras":[{"era":"1958-1981","title":"Two viruses, found because lymphoma is the cancer you can get hold of","description":"Denis Burkitt described a tumour involving the jaws in African children in 1958 and mapped where it occurred; the geography pointed at an infectious cause. In 1964 Epstein, Achong and Barr saw virus particles in lymphoblasts cultured from one of his biopsies, the first virus ever found in a human tumour, and the start of the field that now includes human papillomavirus, hepatitis B and C, Helicobacter pylori and human herpesvirus 8. Neither paper has an abstract indexed on Europe PMC, so no figure from them is quoted here.\n\nThe second virus came from the other side of the lymphoid system. Poiesz, Gallo and colleagues isolated type C retrovirus particles from the lymphocytes of a patient with a T-cell lymphoma in 1980, the first human retrovirus, characterising a reverse transcriptase that preferred magnesium to manganese and six particle proteins unlike those of any known primate retrovirus. The year after, Hinuma's group in Japan found antibodies to a related antigen in all 44 patients with adult T-cell leukaemia they tested, in 26 per cent of healthy adults from endemic areas and in almost none from elsewhere. Human T-lymphotropic virus type 1 is now screened for in blood donations.","status":"historic","refs":[{"id":"paper-burkitt-sarcoma-involving-jaws-african-children-br-j-surg-1958","kind":"paper","name":"A sarcoma involving the jaws in African children","route":"/key-papers/paper-burkitt-sarcoma-involving-jaws-african-children-br-j-surg-1958/","tldr":"A surgeon working in Uganda described a tumour of the jaw in children that nobody had named, and the pattern of where it occurred led, six years later, to the discovery of the first human cancer virus."},{"id":"paper-epstein-virus-particles-burkitt-lymphoblasts-lancet-1964","kind":"paper","name":"Virus particles in cultured lymphoblasts from Burkitt's lymphoma","route":"/key-papers/paper-epstein-virus-particles-burkitt-lymphoblasts-lancet-1964/","tldr":"Looking at cells grown from an African child's jaw tumour under an electron microscope, three researchers in London saw virus particles, the first virus ever linked to a human cancer."},{"id":"paper-poiesz-htlv-retrovirus-cutaneous-t-cell-lymphoma-pnas-1980","kind":"paper","name":"Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma","route":"/key-papers/paper-poiesz-htlv-retrovirus-cutaneous-t-cell-lymphoma-pnas-1980/","tldr":"The first retrovirus found in people was isolated from the blood cells of a patient with a skin lymphoma, and turned out to cause a leukaemia endemic in southern Japan and the Caribbean."},{"id":"paper-hinuma-adult-t-cell-leukaemia-antigen-pnas-1981","kind":"paper","name":"Adult T-cell leukemia: antigen in an ATL cell line and detection of antibodies to the antigen in human sera","route":"/key-papers/paper-hinuma-adult-t-cell-leukaemia-antigen-pnas-1981/","tldr":"Japanese researchers found an antigen in cells from a patient with an unusual leukaemia, then found antibodies to it in every one of 44 patients with that leukaemia and in a quarter of healthy adults where the disease clusters."},{"id":"idea-prev-ebv-vaccine","kind":"idea","name":"An Epstein-Barr virus vaccine to prevent nasopharyngeal cancer and lymphomas","route":"/ideas/idea-prev-ebv-vaccine/","tldr":"EBV infects almost everyone and causes nasopharyngeal cancer, some lymphomas and some stomach cancers. A vaccine given before infection could remove those cancers."}],"trials":[],"papers":[{"id":"paper-burkitt-sarcoma-involving-jaws-african-children-br-j-surg-1958","name":"A sarcoma involving the jaws in African children","route":"/key-papers/paper-burkitt-sarcoma-involving-jaws-african-children-br-j-surg-1958/","journal":"British Journal of Surgery","year":1958,"whatItMeans":"The clinical description that set off the search for a cancer virus. It is also an argument for geographic epidemiology: Burkitt found the cause by asking where the disease was, not by looking down a microscope."},{"id":"paper-epstein-virus-particles-burkitt-lymphoblasts-lancet-1964","name":"Virus particles in cultured lymphoblasts from Burkitt's lymphoma","route":"/key-papers/paper-epstein-virus-particles-burkitt-lymphoblasts-lancet-1964/","journal":"Lancet","year":1964,"whatItMeans":"The start of viral oncology. Everything in cancer prevention that works by preventing or treating an infection, from hepatitis B vaccination to Helicobacter eradication for gastric MALT lymphoma, descends from the idea this paper established."},{"id":"paper-poiesz-htlv-retrovirus-cutaneous-t-cell-lymphoma-pnas-1980","name":"Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma","route":"/key-papers/paper-poiesz-htlv-retrovirus-cutaneous-t-cell-lymphoma-pnas-1980/","journal":"Proceedings of the National Academy of Sciences","year":1980,"whatItMeans":"The first human retrovirus, and the start of the line of work that identified HIV three years later. For lymphoma it means that adult T-cell leukaemia/lymphoma has a known, transmissible, preventable cause, and that screening blood donors and advising on breastfeeding in endemic areas are cancer prevention measures."},{"id":"paper-hinuma-adult-t-cell-leukaemia-antigen-pnas-1981","name":"Adult T-cell leukemia: antigen in an ATL cell line and detection of antibodies to the antigen in human sera","route":"/key-papers/paper-hinuma-adult-t-cell-leukaemia-antigen-pnas-1981/","journal":"Proceedings of the National Academy of Sciences","year":1981,"whatItMeans":"The seroepidemiology that tied a virus to a cancer across a population rather than in one patient. It is the reason blood donations are screened for human T-lymphotropic virus type 1 in Japan and elsewhere, and the reason breastfeeding advice is part of cancer prevention in endemic regions."}]},{"era":"1998-2010","title":"How little is enough: the Hodgkin de-escalation programme begins","description":"Hodgkin lymphoma was curable before anyone knew what it was made of, and by the 1990s the question had become how much treatment could be removed. HD10 answered it for early favourable disease, randomising 1,370 patients in a two by two design and finding no difference between four and two cycles of ABVD (five-year freedom from treatment failure 93.0 against 91.1 per cent, p = 0.39) or between 30 Gy and 20 Gy of involved-field radiotherapy (p = 1.00). Two cycles with 20 Gy became the standard, and the four-cycle, 30 Gy group had the most toxicity.\n\nThe reason the question mattered arrived in full later. The Dutch cohorts measured what cure costs: 48.5 per cent of survivors developed a second cancer within 40 years, with risk still raised at 35 years, and 50 per cent developed cardiovascular disease, with coronary heart disease and heart failure still four to six times the population rate after 35 years. The second-cancer risk did not fall for patients treated between 1989 and 2000 compared with those treated in the 1960s and 1970s, despite the less toxic protocols introduced in between.","status":"historic","refs":[{"id":"paper-ghsg-hd10-reduced-intensity-early-hodgkin-nejm-2010","kind":"paper","name":"GHSG HD10: reduced treatment intensity in early-stage favourable Hodgkin lymphoma","route":"/key-papers/paper-ghsg-hd10-reduced-intensity-early-hodgkin-nejm-2010/","tldr":"Two cycles of ABVD chemotherapy and a lower radiotherapy dose cured early favourable Hodgkin lymphoma as well as four cycles and a higher dose, so patients could be given less treatment and fewer late effects."},{"id":"paper-schaapveld-second-cancer-risk-40-years-hodgkin-nejm-2015","kind":"paper","name":"Second cancer risk up to 40 years after treatment for Hodgkin's lymphoma","route":"/key-papers/paper-schaapveld-second-cancer-risk-40-years-hodgkin-nejm-2015/","tldr":"Of nearly 4,000 Dutch people cured of Hodgkin lymphoma, almost half developed another cancer within forty years, and the gentler treatments introduced in the late 1980s had not reduced that risk."},{"id":"paper-van-nimwegen-cardiovascular-disease-after-hodgkin-jama-intern-med-2015","kind":"paper","name":"Cardiovascular disease after Hodgkin lymphoma treatment: 40-year disease risk","route":"/key-papers/paper-van-nimwegen-cardiovascular-disease-after-hodgkin-jama-intern-med-2015/","tldr":"Half of 2,524 people treated for Hodgkin lymphoma developed heart or valve disease within forty years, and the risk was still four to six times the general population's after thirty-five years."},{"id":"paper-travis-breast-cancer-after-hodgkin-radiotherapy-jama-2003","kind":"paper","name":"Breast cancer following radiotherapy and chemotherapy among young women with Hodgkin disease","route":"/key-papers/paper-travis-breast-cancer-after-hodgkin-radiotherapy-jama-2003/","tldr":"In young women treated for Hodgkin lymphoma, breast cancer risk rose with the radiation dose to the breast, and fell when chemotherapy or radiation had stopped the ovaries working."},{"id":"hd10","kind":"trial","name":"GHSG HD10","route":"/trials/hd10/","status":"positive","tldr":"Halving the chemotherapy and cutting the radiation dose by a third worked just as well for early Hodgkin lymphoma with favourable features, and caused fewer side effects."},{"id":"lymphoma-ev-late-effects-of-the-treatments-given-now","kind":"idea","name":"Measure the late effects of the treatments being given now, not the ones given in 1975","route":"/ideas/lymphoma-ev-late-effects-of-the-treatments-given-now/","tldr":"Everything known about the long-term cost of curing lymphoma comes from people treated decades ago with much larger radiation fields. Nobody knows the forty-year risks of what is given today."}],"trials":[{"id":"hd10","name":"GHSG HD10","route":"/trials/hd10/","outcomes":[{"endpoint":"Freedom from treatment failure at 5 years","primary":true,"unit":"%","arms":[{"name":"Four cycles of ABVD","value":93,"note":"95 per cent confidence interval 90.5 to 94.8"},{"name":"Two cycles of ABVD","value":91.1,"note":"88.3 to 93.2"}],"p":"0.39","source":"https://doi.org/10.1056/NEJMoa1000067"}],"setting":"Early-stage Hodgkin lymphoma with a favourable prognosis: four or two cycles of ABVD, each followed by 30 Gy or 20 Gy of involved-field radiotherapy, in a two by two design","enrolled":1370,"enrolledBasis":"registry"}],"papers":[{"id":"paper-ghsg-hd10-reduced-intensity-early-hodgkin-nejm-2010","name":"GHSG HD10: reduced treatment intensity in early-stage favourable Hodgkin lymphoma","route":"/key-papers/paper-ghsg-hd10-reduced-intensity-early-hodgkin-nejm-2010/","journal":"New England Journal of Medicine","year":2010,"whatItMeans":"Patients with early favourable Hodgkin lymphoma are cured with two cycles of ABVD and 20 Gy of involved-site radiotherapy; later trials tested whether PET can spare radiotherapy altogether."},{"id":"paper-schaapveld-second-cancer-risk-40-years-hodgkin-nejm-2015","name":"Second cancer risk up to 40 years after treatment for Hodgkin's lymphoma","route":"/key-papers/paper-schaapveld-second-cancer-risk-40-years-hodgkin-nejm-2015/","journal":"New England Journal of Medicine","year":2015,"whatItMeans":"The reason every current Hodgkin lymphoma trial is a de-escalation trial, and the reason survivors need lifelong surveillance rather than discharge at five years. It is also a warning about assuming that a gentler protocol is a safer one until a cohort has been followed long enough to say."},{"id":"paper-van-nimwegen-cardiovascular-disease-after-hodgkin-jama-intern-med-2015","name":"Cardiovascular disease after Hodgkin lymphoma treatment: 40-year disease risk","route":"/key-papers/paper-van-nimwegen-cardiovascular-disease-after-hodgkin-jama-intern-med-2015/","journal":"JAMA Internal Medicine","year":2015,"whatItMeans":"The reason cardiac surveillance belongs in Hodgkin lymphoma survivorship care, the reason smoking cessation is a specific intervention for this group rather than general advice, and part of the reason modern protocols try to limit both mediastinal radiation and cumulative anthracycline dose."},{"id":"paper-travis-breast-cancer-after-hodgkin-radiotherapy-jama-2003","name":"Breast cancer following radiotherapy and chemotherapy among young women with Hodgkin disease","route":"/key-papers/paper-travis-breast-cancer-after-hodgkin-radiotherapy-jama-2003/","journal":"JAMA","year":2003,"whatItMeans":"The dose-response curve behind breast surveillance programmes for women irradiated for Hodgkin lymphoma as teenagers or young adults, which in several countries start at 25 or eight years after radiotherapy and use magnetic resonance imaging as well as mammography."}]},{"era":"2000-2020","title":"Reading the genes, and the twenty years it took to make that useful","description":"Alizadeh and Staudt showed in 2000 that diffuse large B-cell lymphoma contains at least two diseases that look identical under the microscope. Rosenwald profiled 240 biopsies in 2002, found germinal-centre, activated and type 3 subgroups, and built a 17-gene survival predictor independent of the International Prognostic Index; the stromal and immune signatures in that paper anticipated the tumour microenvironment era. Hans put the classification within reach of ordinary pathology in 2004, using CD10, BCL6 and MUM1 to split 152 cases into germinal-centre and non-germinal-centre groups with five-year survival of 76 against 34 per cent.\n\nThen the field stalled. The classification predicted outcome but did not direct treatment, and the trials that selected patients by it, PHOENIX among them, failed. The genetic classifications of 2018 were the answer to why: Chapuy's five clusters from 304 tumours and Schmitz's four subtypes from 574 both cut the disease finer than the stain could, and Schmitz's MCD and BN2 subtypes carried a mechanism, chronic active B-cell receptor signalling, with a drug class already in the clinic. Wright's LymphGen tool in 2020 turned cohort clustering into a probability for one patient's tumour, and extended the classification to seven subtypes that share genetics with indolent and extranodal lymphomas.","status":"historic","refs":[{"id":"paper-alizadeh-nature","kind":"paper","name":"Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling","route":"/key-papers/paper-alizadeh-nature/","tldr":"Paper cited by one term page, indexed on Europe PMC as PubMed record 10676951 and published in Nature; the citing page links this DOI, which is how the record was matched."},{"id":"paper-rosenwald-molecular-profiling-dlbcl-nejm-2002","kind":"paper","name":"The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma","route":"/key-papers/paper-rosenwald-molecular-profiling-dlbcl-nejm-2002/","tldr":"Reading which genes were switched on in 240 lymphoma samples sorted one disease into three, and the group whose cells looked like a particular stage of normal B-cell development lived the longest."},{"id":"paper-hans-immunohistochemistry-cell-of-origin-dlbcl-blood-2004","kind":"paper","name":"Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray","route":"/key-papers/paper-hans-immunohistochemistry-cell-of-origin-dlbcl-blood-2004/","tldr":"Three ordinary laboratory stains, available in any hospital, were shown to sort lymphoma into the same two prognostic groups that an expensive gene-expression machine had found."},{"id":"paper-chapuy-molecular-subtypes-dlbcl-nat-med-2018","kind":"paper","name":"Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes","route":"/key-papers/paper-chapuy-molecular-subtypes-dlbcl-nat-med-2018/","tldr":"Reading the whole genetic picture of 304 lymphomas, rather than one gene at a time, sorted them into five groups that arise by different routes and respond differently."},{"id":"paper-schmitz-genetics-pathogenesis-dlbcl-nejm-2018","kind":"paper","name":"Genetics and pathogenesis of diffuse large B-cell lymphoma","route":"/key-papers/paper-schmitz-genetics-pathogenesis-dlbcl-nejm-2018/","tldr":"Sequencing 574 lymphomas found four genetic patterns that recur, two of which depend on a signalling route that an existing tablet can block."},{"id":"paper-wright-lymphgen-genetic-subtypes-dlbcl-cancer-cell-2020","kind":"paper","name":"A probabilistic classification tool for genetic subtypes of diffuse large B cell lymphoma with therapeutic implications","route":"/key-papers/paper-wright-lymphgen-genetic-subtypes-dlbcl-cancer-cell-2020/","tldr":"A tool that takes one patient's tumour genetics and gives the probability that it belongs to each of seven genetic groups, rather than sorting whole cohorts into clusters."},{"id":"paper-phoenix-ibrutinib-r-chop-non-gcb-dlbcl-jco-2019","kind":"paper","name":"Randomized phase III trial of ibrutinib and R-CHOP in non-germinal centre B-cell diffuse large B-cell lymphoma (PHOENIX)","route":"/key-papers/paper-phoenix-ibrutinib-r-chop-non-gcb-dlbcl-jco-2019/","tldr":"Adding a targeted tablet to standard first-line chemotherapy failed overall, helped people under 60 substantially, and harmed people over 60 by making them unable to finish the chemotherapy."},{"id":"cell-of-origin","kind":"term","name":"Cell of origin (GCB vs ABC)","route":"/terms/cell-of-origin/","tldr":"Whether a large B-cell lymphoma resembles a germinal-centre B cell or an activated B cell; the activated type does worse and depends on different pathways."},{"id":"lymphoma-ev-genetic-subtype-directed-first-line","kind":"idea","name":"Assign first-line treatment in diffuse large B-cell lymphoma by genetic subtype, not by a three-antibody stain","route":"/ideas/lymphoma-ev-genetic-subtype-directed-first-line/","tldr":"Three genetic classifications of the commonest aggressive lymphoma exist and none of them yet decides anyone's treatment. The trial that would change that has not been run."}],"trials":[],"papers":[{"id":"paper-alizadeh-nature","name":"Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling","route":"/key-papers/paper-alizadeh-nature/","journal":"Nature","year":2000,"whatItMeans":"One term page on OnCo cites this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing page listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand."},{"id":"paper-rosenwald-molecular-profiling-dlbcl-nejm-2002","name":"The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma","route":"/key-papers/paper-rosenwald-molecular-profiling-dlbcl-nejm-2002/","journal":"New England Journal of Medicine","year":2002,"whatItMeans":"The reason a pathology report on diffuse large B-cell lymphoma says germinal-centre or non-germinal-centre, and the origin of every attempt since to treat the two differently. It also made the case that microarray profiling could do something the clinical index could not, which is what pulled genomics into haematology."},{"id":"paper-hans-immunohistochemistry-cell-of-origin-dlbcl-blood-2004","name":"Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray","route":"/key-papers/paper-hans-immunohistochemistry-cell-of-origin-dlbcl-blood-2004/","journal":"Blood","year":2004,"whatItMeans":"The practical form of cell-of-origin classification, used in pathology laboratories worldwide. When a report says germinal-centre or non-germinal-centre, this is almost always the algorithm behind it."},{"id":"paper-chapuy-molecular-subtypes-dlbcl-nat-med-2018","name":"Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes","route":"/key-papers/paper-chapuy-molecular-subtypes-dlbcl-nat-med-2018/","journal":"Nature Medicine","year":2018,"whatItMeans":"One of the two foundational genetic classifications of diffuse large B-cell lymphoma. Neither has yet changed what a patient receives outside a trial, but together they are the reason precision-medicine trials in this disease now select by genetics rather than by cell of origin."},{"id":"paper-schmitz-genetics-pathogenesis-dlbcl-nejm-2018","name":"Genetics and pathogenesis of diffuse large B-cell lymphoma","route":"/key-papers/paper-schmitz-genetics-pathogenesis-dlbcl-nejm-2018/","journal":"New England Journal of Medicine","year":2018,"whatItMeans":"The genetic nosology that precision-medicine trials in diffuse large B-cell lymphoma now use to pick patients. It gives a mechanism, not just a label: two of the four subtypes point at a drug class that already exists."},{"id":"paper-wright-lymphgen-genetic-subtypes-dlbcl-cancer-cell-2020","name":"A probabilistic classification tool for genetic subtypes of diffuse large B cell lymphoma with therapeutic implications","route":"/key-papers/paper-wright-lymphgen-genetic-subtypes-dlbcl-cancer-cell-2020/","journal":"Cancer Cell","year":2020,"whatItMeans":"The piece that turns a research classification into something a trial can use on one person's biopsy, with a probability attached rather than a flat label. It is the reason genetics-directed lymphoma trials became possible at all."},{"id":"paper-phoenix-ibrutinib-r-chop-non-gcb-dlbcl-jco-2019","name":"Randomized phase III trial of ibrutinib and R-CHOP in non-germinal centre B-cell diffuse large B-cell lymphoma (PHOENIX)","route":"/key-papers/paper-phoenix-ibrutinib-r-chop-non-gcb-dlbcl-jco-2019/","journal":"Journal of Clinical Oncology","year":2019,"whatItMeans":"A failure worth reading: the drug worked where patients could tolerate the regimen it was added to, and harmed where they could not. It is the strongest argument in lymphoma for designing first-line combinations around what an older patient can finish."}]},{"era":"2005-2022","title":"Everything that failed to beat R-CHOP, and the one thing that did","description":"R-CHOP has been the first-line standard for aggressive B-cell lymphoma since rituximab was added to CHOP, and almost nothing has improved on it. CALGB 50303 compared dose-adjusted EPOCH-R, which many centres had adopted on single-arm evidence, and found no difference in progression-free or overall survival with substantially more febrile neutropenia, mucositis and neuropathy. GOYA substituted obinutuzumab in 1,418 patients and got a hazard ratio of 0.92 with more grade 3 to 5 and fatal adverse events, despite the same substitution working in follicular lymphoma and chronic lymphocytic leukaemia. REMARC added two years of lenalidomide maintenance and delayed progression without extending life. PHOENIX added ibrutinib and failed overall, helping patients under 60 and harming those over 60 by stopping them finishing the chemotherapy.\n\nWhat worked was subtraction and substitution rather than addition. FLYER showed that four cycles of R-CHOP with two extra rituximab doses was non-inferior to six in young patients with low-risk limited-stage disease, at three-year progression-free survival of 96 per cent and roughly a quarter fewer adverse events. POLARIX replaced vincristine with polatuzumab vedotin and improved progression-free survival, the only first-line improvement in two decades.","status":"current","refs":[{"id":"paper-calgb-50303-da-epoch-r-vs-r-chop-jco-2019","kind":"paper","name":"Dose-adjusted EPOCH-R compared with R-CHOP as frontline therapy for diffuse large B-cell lymphoma: clinical outcomes of the phase III intergroup trial Alliance/CALGB 50303","route":"/key-papers/paper-calgb-50303-da-epoch-r-vs-r-chop-jco-2019/","tldr":"An intensive infusional chemotherapy regimen that many centres had adopted on single-arm evidence was no better than the standard when finally compared head to head, and was harder to tolerate."},{"id":"paper-goya-obinutuzumab-vs-rituximab-chop-dlbcl-jco-2017","kind":"paper","name":"Obinutuzumab or rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in previously untreated diffuse large B-cell lymphoma","route":"/key-papers/paper-goya-obinutuzumab-vs-rituximab-chop-dlbcl-jco-2017/","tldr":"A newer antibody against the same target did not improve first-line treatment of the commonest aggressive lymphoma, although it had improved treatment of two other B-cell cancers."},{"id":"paper-remarc-lenalidomide-maintenance-dlbcl-jco-2017","kind":"paper","name":"Lenalidomide maintenance compared with placebo in responding elderly patients with diffuse large B-cell lymphoma treated with first-line R-CHOP","route":"/key-papers/paper-remarc-lenalidomide-maintenance-dlbcl-jco-2017/","tldr":"Two years of a tablet after chemotherapy delayed relapse in older people with aggressive lymphoma but did not help them live longer."},{"id":"paper-phoenix-ibrutinib-r-chop-non-gcb-dlbcl-jco-2019","kind":"paper","name":"Randomized phase III trial of ibrutinib and R-CHOP in non-germinal centre B-cell diffuse large B-cell lymphoma (PHOENIX)","route":"/key-papers/paper-phoenix-ibrutinib-r-chop-non-gcb-dlbcl-jco-2019/","tldr":"Adding a targeted tablet to standard first-line chemotherapy failed overall, helped people under 60 substantially, and harmed people over 60 by making them unable to finish the chemotherapy."},{"id":"paper-flyer-four-vs-six-cycles-r-chop-lancet-2019","kind":"paper","name":"Four versus six cycles of CHOP chemotherapy in combination with six applications of rituximab in patients with aggressive B-cell lymphoma with favourable prognosis (FLYER)","route":"/key-papers/paper-flyer-four-vs-six-cycles-r-chop-lancet-2019/","tldr":"Young people with early, low-risk aggressive lymphoma did just as well with four rounds of chemotherapy as with six, and had roughly a quarter fewer side effects."},{"id":"paper-polarix-polatuzumab-rchp-nejm-2022","kind":"paper","name":"POLARIX: swapping vincristine for the antibody-drug conjugate polatuzumab vedotin in first-line treatment of diffuse large B-cell lymphoma","route":"/key-papers/paper-polarix-polatuzumab-rchp-nejm-2022/","tldr":"Replacing one chemotherapy drug in R-CHOP with a CD79b antibody-drug conjugate modestly reduced progression (2-year PFS 76.7% versus 70.2%) without changing survival or side effects."},{"id":"flyer","kind":"trial","name":"FLYER","route":"/trials/flyer/","status":"positive","tldr":"Young people with early, low-risk aggressive lymphoma got two fewer rounds of chemotherapy and did just as well, with about a third fewer side effects recorded."},{"id":"calgb-50303","kind":"trial","name":"Alliance/CALGB 50303","route":"/trials/calgb-50303/","status":"negative","tldr":"An intensive infusion chemotherapy schedule, widely believed to be better for aggressive lymphoma, was compared head to head with the standard and was not better, only harder to tolerate."},{"id":"goya","kind":"trial","name":"GOYA","route":"/trials/goya/","status":"negative","tldr":"A newer antibody against the same target as rituximab was tested in first-line treatment for the commonest aggressive lymphoma and did not work better, while causing more side effects."},{"id":"remarc","kind":"trial","name":"REMARC","route":"/trials/remarc/","status":"mixed","tldr":"Two years of a tablet taken after chemotherapy delayed relapse in older people with aggressive lymphoma but did not help them live longer, and caused low white cell counts in over half."},{"id":"polarix","kind":"trial","name":"POLARIX","route":"/trials/polarix/","status":"positive","tldr":"The trial that improved on R-CHOP for the first time in twenty years, by swapping vincristine for an ADC."}],"trials":[{"id":"flyer","name":"FLYER","route":"/trials/flyer/","outcomes":[{"endpoint":"Progression-free survival at 3 years","primary":true,"unit":"%","arms":[{"name":"Four cycles R-CHOP plus two rituximab","n":293,"value":96},{"name":"Six cycles R-CHOP","n":295,"note":"3 percentage points lower; the one-sided 95 per cent confidence interval for the difference had a lower limit of 0 per cent"}],"source":"https://doi.org/10.1016/S0140-6736(19)33008-9"}],"setting":"Aged 18 to 60 with stage I or II aggressive B-cell lymphoma, normal lactate dehydrogenase, no bulk: four cycles of R-CHOP with six doses of rituximab against six cycles of R-CHOP","enrolled":588,"enrolledNote":"The registry records 592 enrolled; four patients withdrew consent before treatment, so the intention-to-treat analysis covers 588.","enrolledBasis":"analysed"},{"id":"calgb-50303","name":"Alliance/CALGB 50303","route":"/trials/calgb-50303/","outcomes":[{"endpoint":"Progression-free survival","primary":true,"arms":[{"name":"Dose-adjusted EPOCH-R","note":"two-year rate 78.9 per cent"},{"name":"R-CHOP","note":"two-year rate 75.5 per cent"}],"hr":0.93,"ci":[0.68,1.27],"p":"0.65","source":"https://doi.org/10.1200/JCO.18.01994"},{"endpoint":"Overall survival","arms":[{"name":"Dose-adjusted EPOCH-R","note":"two-year rate 86.5 per cent"},{"name":"R-CHOP","note":"two-year rate 85.7 per cent"}],"hr":1.09,"ci":[0.75,1.59],"p":"0.64"},{"endpoint":"Febrile neutropenia","unit":"%","arms":[{"name":"Dose-adjusted EPOCH-R","value":35},{"name":"R-CHOP","value":17.7}]}],"setting":"Untreated diffuse large B-cell lymphoma: six cycles of dose-adjusted EPOCH-R against six cycles of R-CHOP","enrolled":491,"enrolledNote":"524 patients were registered on the study; 491 were eligible and form the final analysis.","enrolledBasis":"analysed"},{"id":"goya","name":"GOYA","route":"/trials/goya/","outcomes":[{"endpoint":"Investigator-assessed progression-free survival","primary":true,"arms":[{"name":"Obinutuzumab with CHOP","n":706,"note":"three-year rate 70 per cent"},{"name":"Rituximab with CHOP","n":712,"note":"three-year rate 67 per cent"}],"hr":0.92,"ci":[0.76,1.11],"p":"0.39","source":"https://doi.org/10.1200/JCO.2017.73.3402"}],"setting":"Untreated advanced diffuse large B-cell lymphoma: obinutuzumab with CHOP against rituximab with CHOP","enrolled":1418,"enrolledBasis":"registry"},{"id":"remarc","name":"REMARC","route":"/trials/remarc/","outcomes":[{"endpoint":"Progression-free survival","primary":true,"unit":"months","arms":[{"name":"Lenalidomide maintenance","note":"median not reached"},{"name":"Placebo","value":58.9}],"hr":0.708,"ci":[0.537,0.933],"p":"0.01","source":"https://doi.org/10.1200/JCO.2017.72.6984"},{"endpoint":"Overall survival","arms":[{"name":"Lenalidomide maintenance"},{"name":"Placebo"}],"hr":1.218,"ci":[0.861,1.721],"p":"0.26"}],"setting":"Aged 60 to 80, in complete or partial response after six or eight cycles of R-CHOP: two years of lenalidomide maintenance against placebo","enrolled":650,"enrolledBasis":"registry"},{"id":"polarix","name":"POLARIX","route":"/trials/polarix/","outcomes":[{"endpoint":"Progression-free survival at 2 years","primary":true,"unit":"%","arms":[{"name":"Pola-R-CHP","n":440,"value":76.7},{"name":"R-CHOP","n":439,"value":70.2}],"hr":0.73,"ci":[0.57,0.95],"p":"0.02","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2115304"},{"endpoint":"Progression-free survival at 5 years","unit":"%","arms":[{"name":"Pola-R-CHP","value":64.9},{"name":"R-CHOP","value":59.1}],"hr":0.77,"ci":[0.62,0.97],"source":"https://ascopubs.org/doi/10.1200/JCO-25-00925"},{"endpoint":"Overall survival at 5 years","unit":"%","arms":[{"name":"Pola-R-CHP","value":82.3},{"name":"R-CHOP","value":79.5}],"hr":0.85,"ci":[0.63,1.15],"source":"https://ascopubs.org/doi/10.1200/JCO-25-00925"}],"setting":"Untreated DLBCL, IPI 2-5, age 18-80: Pola-R-CHP vs R-CHOP","enrolled":879,"enrolledNote":"ClinicalTrials.gov lists 1,000 participants (actual); the NEJM 2022 primary analysis randomised 879 patients (440 Pola-R-CHP, 439 R-CHOP).","enrolledBasis":"randomised"}],"papers":[{"id":"paper-calgb-50303-da-epoch-r-vs-r-chop-jco-2019","name":"Dose-adjusted EPOCH-R compared with R-CHOP as frontline therapy for diffuse large B-cell lymphoma: clinical outcomes of the phase III intergroup trial Alliance/CALGB 50303","route":"/key-papers/paper-calgb-50303-da-epoch-r-vs-r-chop-jco-2019/","journal":"Journal of Clinical Oncology","year":2019,"whatItMeans":"R-CHOP remains the standard first-line regimen for diffuse large B-cell lymphoma. The trial is also the clearest lesson in the disease about adopting a regimen on single-arm data: dose-adjusted EPOCH-R had been used widely for a decade before this comparison existed."},{"id":"paper-goya-obinutuzumab-vs-rituximab-chop-dlbcl-jco-2017","name":"Obinutuzumab or rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in previously untreated diffuse large B-cell lymphoma","route":"/key-papers/paper-goya-obinutuzumab-vs-rituximab-chop-dlbcl-jco-2017/","journal":"Journal of Clinical Oncology","year":2017,"whatItMeans":"Rituximab remains the CD20 antibody used in first-line diffuse large B-cell lymphoma. The result is a warning against assuming an antibody improvement carries from one B-cell malignancy to another: the same substitution improved progression-free survival in chronic lymphocytic leukaemia and in follicular lymphoma."},{"id":"paper-remarc-lenalidomide-maintenance-dlbcl-jco-2017","name":"Lenalidomide maintenance compared with placebo in responding elderly patients with diffuse large B-cell lymphoma treated with first-line R-CHOP","route":"/key-papers/paper-remarc-lenalidomide-maintenance-dlbcl-jco-2017/","journal":"Journal of Clinical Oncology","year":2017,"whatItMeans":"A clean example of a progression-free survival benefit that did not become a survival benefit. Lenalidomide maintenance did not become standard practice after this trial, and the figures are the reason."},{"id":"paper-phoenix-ibrutinib-r-chop-non-gcb-dlbcl-jco-2019","name":"Randomized phase III trial of ibrutinib and R-CHOP in non-germinal centre B-cell diffuse large B-cell lymphoma (PHOENIX)","route":"/key-papers/paper-phoenix-ibrutinib-r-chop-non-gcb-dlbcl-jco-2019/","journal":"Journal of Clinical Oncology","year":2019,"whatItMeans":"A failure worth reading: the drug worked where patients could tolerate the regimen it was added to, and harmed where they could not. It is the strongest argument in lymphoma for designing first-line combinations around what an older patient can finish."},{"id":"paper-flyer-four-vs-six-cycles-r-chop-lancet-2019","name":"Four versus six cycles of CHOP chemotherapy in combination with six applications of rituximab in patients with aggressive B-cell lymphoma with favourable prognosis (FLYER)","route":"/key-papers/paper-flyer-four-vs-six-cycles-r-chop-lancet-2019/","journal":"Lancet","year":2019,"whatItMeans":"Four cycles rather than six for young patients with limited-stage, low-risk aggressive B-cell lymphoma. The saving is two cycles of anthracycline and vincristine in people who will live for decades afterwards."},{"id":"paper-polarix-polatuzumab-rchp-nejm-2022","name":"POLARIX: swapping vincristine for the antibody-drug conjugate polatuzumab vedotin in first-line treatment of diffuse large B-cell lymphoma","route":"/key-papers/paper-polarix-polatuzumab-rchp-nejm-2022/","journal":"New England Journal of Medicine","year":2022,"whatItMeans":"POLARIX gave the first new first-line standard for DLBCL since rituximab was added to CHOP, and pola-R-CHP is now approved and widely used, especially in higher-risk or ABC-type disease. The gain is modest and survival is unchanged, so many clinicians still use R-CHOP in lower-risk or GCB-type patients. Cost and subgroup uncertainty drive ongoing debate."}]},{"era":"2006-2019","title":"The scan after two cycles, and what it is good for","description":"Four large trials asked the same question from different directions: can a positron emission tomography scan after two cycles of chemotherapy decide what happens next. The answer turned out to be asymmetric.\n\nIntensifying on a positive scan works. EORTC H10 switched scan-positive early-stage patients from ABVD to escalated BEACOPP with involved-node radiotherapy and raised five-year progression-free survival from 77.4 to 90.6 per cent. De-escalating on a negative scan works for chemotherapy. HD18 shortened escalated BEACOPP from six or eight cycles to four in scan-negative advanced disease with five-year progression-free survival of 92.2 against 90.8 per cent and half the severe infections; AHL2011 switched scan-negative patients to ABVD after two cycles of escalated BEACOPP with five-year progression-free survival of 85.7 against 86.2 per cent and grade 3 to 4 anaemia falling from 69 to 28 per cent. RATHL had already shown that bleomycin could be dropped after a negative scan in advanced disease.\n\nDe-escalating on a negative scan does not work for radiotherapy. HD16 omitted 20 Gy after a negative scan and lost 7.3 percentage points of five-year progression-free survival; H10 could not demonstrate non-inferiority in either risk group, and in the favourable group five-year progression-free survival was 99.0 per cent with radiotherapy against 87.1 per cent without.","status":"current","refs":[{"id":"paper-eortc-h10-pet-adapted-early-hodgkin-jco-2017","kind":"paper","name":"Early positron emission tomography response-adapted treatment in stage I and II Hodgkin lymphoma: final results of the randomized EORTC/LYSA/FIL H10 trial","route":"/key-papers/paper-eortc-h10-pet-adapted-early-hodgkin-jco-2017/","tldr":"In early Hodgkin lymphoma, switching to more intensive chemotherapy when the scan was still positive raised five-year freedom from progression from 77 to 91 per cent."},{"id":"paper-ghsg-hd18-pet-guided-escalated-beacopp-lancet-2017","kind":"paper","name":"PET-guided treatment in patients with advanced-stage Hodgkin's lymphoma (HD18): final results of an open-label, international, randomised phase 3 trial by the German Hodgkin Study Group","route":"/key-papers/paper-ghsg-hd18-pet-guided-escalated-beacopp-lancet-2017/","tldr":"People whose scan cleared after two rounds of the most intensive Hodgkin regimen could stop after four rounds instead of six or eight, halving severe infections with no loss of control."},{"id":"paper-ahl2011-pet-adapted-treatment-advanced-hodgkin-lancet-oncol-2019","kind":"paper","name":"PET-adapted treatment for newly diagnosed advanced Hodgkin lymphoma (AHL2011): a randomised, multicentre, non-inferiority, phase 3 study","route":"/key-papers/paper-ahl2011-pet-adapted-treatment-advanced-hodgkin-lancet-oncol-2019/","tldr":"Starting with the most intensive Hodgkin chemotherapy and switching to the gentler standard once the scan cleared gave the same disease control with far less anaemia, bleeding risk and infection."},{"id":"paper-ghsg-hd16-pet-guided-early-favourable-hodgkin-jco-2019","kind":"paper","name":"Positron emission tomography-guided treatment in early-stage favorable Hodgkin lymphoma: final results of the international, randomized phase III HD16 trial by the German Hodgkin Study Group","route":"/key-papers/paper-ghsg-hd16-pet-guided-early-favourable-hodgkin-jco-2019/","tldr":"Trying to spare radiotherapy on the strength of a clear scan after two rounds of chemotherapy cost about seven people in a hundred their remission."},{"id":"paper-rathl-interim-pet-adapted-abvd-advanced-hodgkin-nejm-2016","kind":"paper","name":"RATHL: adapted treatment guided by interim PET-CT in advanced Hodgkin lymphoma","route":"/key-papers/paper-rathl-interim-pet-adapted-abvd-advanced-hodgkin-nejm-2016/","tldr":"Using a PET scan after two cycles to decide the rest of treatment let patients with a clear scan drop bleomycin, sparing their lungs without losing cure, while those with a positive scan were escalated to stronger chemotherapy."},{"id":"hd16","kind":"trial","name":"GHSG HD16","route":"/trials/hd16/","status":"negative","tldr":"Trying to spare people radiotherapy by using a clear scan after two rounds of chemotherapy cost them about seven in a hundred in disease control, so the radiotherapy stayed."},{"id":"hd18","kind":"trial","name":"GHSG HD18","route":"/trials/hd18/","status":"positive","tldr":"People whose scan was clear after two rounds of the most intensive Hodgkin chemotherapy could stop after four rounds instead of six or eight, with the same disease control and far fewer severe infections."},{"id":"ahl2011","kind":"trial","name":"AHL2011","route":"/trials/ahl2011/","status":"positive","tldr":"Starting with the most intensive Hodgkin chemotherapy and switching to the gentler standard once the scan cleared gave the same results with markedly less anaemia, low platelets and infection."},{"id":"eortc-h10","kind":"trial","name":"EORTC/LYSA/FIL H10","route":"/trials/eortc-h10/","status":"mixed","tldr":"In early Hodgkin lymphoma, people whose scan was still positive after two rounds did much better on more intensive chemotherapy, and people whose scan was clear still needed their radiotherapy."},{"id":"rathl","kind":"trial","name":"RATHL","route":"/trials/rathl/","status":"positive","tldr":"Showed that patients whose PET scan is clear after two cycles can safely drop bleomycin and its lung toxicity."},{"id":"deauville-score","kind":"term","name":"Deauville five-point scale","route":"/terms/deauville-score/","tldr":"A 1-to-5 score for how bright a lymphoma looks on PET compared with the liver; 1-3 is considered a complete metabolic response."},{"id":"lymphoma-ev-radiotherapy-free-early-hodgkin","kind":"idea","name":"A radiotherapy-free cure for early Hodgkin lymphoma that actually holds","route":"/ideas/lymphoma-ev-radiotherapy-free-early-hodgkin/","tldr":"Every attempt to drop radiotherapy from early Hodgkin lymphoma on the strength of a clear scan has cost people their remission. Changing the chemotherapy as well is the next attempt."}],"trials":[{"id":"hd16","name":"GHSG HD16","route":"/trials/hd16/","outcomes":[{"endpoint":"Progression-free survival at 5 years, scan-negative patients","primary":true,"unit":"%","arms":[{"name":"Chemotherapy with radiotherapy","value":93.4,"note":"95 per cent confidence interval 90.4 to 96.5"},{"name":"Chemotherapy alone","value":86.1,"note":"81.4 to 90.9"}],"hr":1.78,"ci":[1.02,3.12],"source":"https://doi.org/10.1200/JCO.19.00964"},{"endpoint":"Overall survival at 5 years","unit":"%","arms":[{"name":"Chemotherapy with radiotherapy","value":98.1},{"name":"Chemotherapy alone","value":98.4}]}],"setting":"Early-stage favourable Hodgkin lymphoma: two cycles of ABVD with 20 Gy involved-field radiotherapy against the same chemotherapy with radiotherapy omitted if the scan after two cycles is negative","enrolled":1150,"enrolledBasis":"registry"},{"id":"hd18","name":"GHSG HD18","route":"/trials/hd18/","outcomes":[{"endpoint":"Progression-free survival at 5 years, scan-negative cohort","primary":true,"unit":"%","arms":[{"name":"Four cycles of escalated BEACOPP","n":501,"value":92.2,"note":"95 per cent confidence interval 89.4 to 95.0"},{"name":"Six or eight cycles of escalated BEACOPP","n":504,"value":90.8,"note":"87.9 to 93.7"}],"source":"https://doi.org/10.1016/S0140-6736(17)32134-7"},{"endpoint":"Progression-free survival at 5 years, scan-positive cohort","unit":"%","arms":[{"name":"Escalated BEACOPP","n":217,"value":89.7},{"name":"Escalated BEACOPP with rituximab","n":217,"value":88.1}],"p":"0.46"},{"endpoint":"Severe infections, scan-negative cohort","unit":"%","arms":[{"name":"Four cycles of escalated BEACOPP","n":498,"value":8},{"name":"Six or eight cycles of escalated BEACOPP","n":502,"value":15}]}],"setting":"Aged 18 to 60 with newly diagnosed advanced-stage Hodgkin lymphoma: treatment intensity set by the scan after two cycles of escalated BEACOPP","enrolled":1945,"enrolledNote":"The registry target was 1,500; 2,101 patients were recruited, 156 were found ineligible, and 1,945 were randomised across the two scan-defined cohorts in the Lancet report.","enrolledBasis":"randomised"},{"id":"ahl2011","name":"AHL2011","route":"/trials/ahl2011/","outcomes":[{"endpoint":"Progression-free survival at 5 years","primary":true,"unit":"%","arms":[{"name":"Scan-driven switch to ABVD","n":410,"value":85.7,"note":"95 per cent confidence interval 81.4 to 89.1"},{"name":"Six cycles of escalated BEACOPP","n":413,"value":86.2,"note":"81.6 to 89.8"}],"hr":1.084,"ci":[0.737,1.596],"p":"0.65","source":"https://doi.org/10.1016/S1470-2045(18)30784-8"},{"endpoint":"Grade 3 to 4 anaemia","unit":"%","arms":[{"name":"Scan-driven switch to ABVD","n":407,"value":28},{"name":"Six cycles of escalated BEACOPP","n":413,"value":69}]}],"setting":"Aged 16 to 60 with newly diagnosed advanced Hodgkin lymphoma: six cycles of escalated BEACOPP against a switch to ABVD after a negative scan at two cycles","enrolled":823,"enrolledNote":"The ClinicalTrials.gov record carries no enrolment count; 823 patients were randomised in the Lancet Oncology report, 413 to standard treatment and 410 to the scan-driven arm.","enrolledBasis":"randomised"},{"id":"eortc-h10","name":"EORTC/LYSA/FIL H10","route":"/trials/eortc-h10/","outcomes":[{"endpoint":"Progression-free survival at 5 years, scan-positive patients","primary":true,"unit":"%","arms":[{"name":"Escalated BEACOPP with involved-node radiotherapy","value":90.6},{"name":"ABVD with involved-node radiotherapy","value":77.4}],"hr":0.42,"ci":[0.23,0.74],"p":"0.002","source":"https://doi.org/10.1200/JCO.2016.68.6394"},{"endpoint":"Progression-free survival at 5 years, scan-negative favourable group","unit":"%","arms":[{"name":"ABVD with involved-node radiotherapy","value":99},{"name":"ABVD alone","value":87.1}],"hr":15.8,"ci":[3.8,66.1]},{"endpoint":"Progression-free survival at 5 years, scan-negative unfavourable group","unit":"%","arms":[{"name":"ABVD with involved-node radiotherapy","value":92.1},{"name":"ABVD alone","value":89.6}],"hr":1.45,"ci":[0.8,2.5]}],"setting":"Stage I and II Hodgkin lymphoma: standard ABVD with involved-node radiotherapy against treatment adapted to the scan after two cycles, intensifying for a positive scan and dropping radiotherapy for a negative one","enrolled":1925,"enrolledNote":"1,950 patients were randomly assigned and 1,925 had an early scan, of whom 361 (18.8 per cent) were positive.","enrolledBasis":"analysed"},{"id":"rathl","name":"RATHL","route":"/trials/rathl/","outcomes":[{"endpoint":"Progression-free survival at 3 years (PET2-negative)","primary":true,"unit":"%","arms":[{"name":"ABVD","n":470,"value":85.7},{"name":"AVD","n":465,"value":84.4}],"source":"https://www.nejm.org/doi/full/10.1056/NEJMoa1510093"}],"setting":"Advanced Hodgkin lymphoma: interim-PET-guided omission of bleomycin (AVD) vs continued ABVD","enrolled":1214,"enrolledBasis":"registry"}],"papers":[{"id":"paper-eortc-h10-pet-adapted-early-hodgkin-jco-2017","name":"Early positron emission tomography response-adapted treatment in stage I and II Hodgkin lymphoma: final results of the randomized EORTC/LYSA/FIL H10 trial","route":"/key-papers/paper-eortc-h10-pet-adapted-early-hodgkin-jco-2017/","journal":"Journal of Clinical Oncology","year":2017,"whatItMeans":"The interim scan should be used to intensify treatment in early Hodgkin lymphoma, not to withhold radiotherapy. The 99.0 per cent five-year progression-free survival in the scan-negative favourable group with combined-modality treatment is the number any radiotherapy-sparing strategy has to match."},{"id":"paper-ghsg-hd18-pet-guided-escalated-beacopp-lancet-2017","name":"PET-guided treatment in patients with advanced-stage Hodgkin's lymphoma (HD18): final results of an open-label, international, randomised phase 3 trial by the German Hodgkin Study Group","route":"/key-papers/paper-ghsg-hd18-pet-guided-escalated-beacopp-lancet-2017/","journal":"Lancet","year":2017,"whatItMeans":"The basis for four cycles of escalated BEACOPP as the German standard when the interim scan is negative, and the reason rituximab was abandoned as an addition to that regimen. The authors recommend the scan-guided strategy for all patients with advanced-stage disease."},{"id":"paper-ahl2011-pet-adapted-treatment-advanced-hodgkin-lancet-oncol-2019","name":"PET-adapted treatment for newly diagnosed advanced Hodgkin lymphoma (AHL2011): a randomised, multicentre, non-inferiority, phase 3 study","route":"/key-papers/paper-ahl2011-pet-adapted-treatment-advanced-hodgkin-lancet-oncol-2019/","journal":"Lancet Oncology","year":2019,"whatItMeans":"Confirmation, by a different route from HD18, that the interim scan can safely direct de-escalation in advanced Hodgkin lymphoma, and that most of the toxicity of escalated BEACOPP can be avoided in the 84 per cent of patients who respond early."},{"id":"paper-ghsg-hd16-pet-guided-early-favourable-hodgkin-jco-2019","name":"Positron emission tomography-guided treatment in early-stage favorable Hodgkin lymphoma: final results of the international, randomized phase III HD16 trial by the German Hodgkin Study Group","route":"/key-papers/paper-ghsg-hd16-pet-guided-early-favourable-hodgkin-jco-2019/","journal":"Journal of Clinical Oncology","year":2019,"whatItMeans":"Radiotherapy cannot be omitted in early-stage favourable Hodgkin lymphoma on the basis of a negative interim scan without a clinically relevant loss of tumour control. The scan is better at identifying who needs more than at identifying who needs less."},{"id":"paper-rathl-interim-pet-adapted-abvd-advanced-hodgkin-nejm-2016","name":"RATHL: adapted treatment guided by interim PET-CT in advanced Hodgkin lymphoma","route":"/key-papers/paper-rathl-interim-pet-adapted-abvd-advanced-hodgkin-nejm-2016/","journal":"New England Journal of Medicine","year":2016,"whatItMeans":"An interim PET scan after two cycles guides treatment of advanced Hodgkin lymphoma: drop bleomycin if negative, intensify if positive."}]},{"era":"2011-2026","title":"Indolent lymphoma: how long to treat, and the two-year mark that splits the disease","description":"Follicular lymphoma is treated in episodes across decades, so the questions are about duration and sequence rather than intensity. PRIMA randomised 1,018 responders to two years of rituximab maintenance or observation and reported median progression-free survival of 10.5 against 4.1 years at nine years, with ten-year overall survival of about 80 per cent in both arms: the cleanest demonstration in lymphoma that delaying progression and extending life are different things.\n\nCasulo gave the field the marker that matters. Of 588 patients given first-line R-CHOP, 19 per cent progressed within two years, and their five-year overall survival was 50 per cent against 90 per cent, with an index-adjusted hazard ratio of 6.44. That group now triggers a repeat biopsy, because transformation is the commonest cause, and goes to treatment that does not depend on chemotherapy sensitivity.\n\nFor the rest of the disease the options multiplied. GALLIUM and RELEVANCE changed the first line; ELARA and ZUMA-5 brought CAR-T, with complete responses in 69 and 74 per cent; ELM-2 and the other CD20 bispecific antibodies brought off-the-shelf alternatives, with a 73.4 per cent complete response rate for odronextamab; ROSEWOOD paired a Bruton tyrosine kinase inhibitor with a type II antibody; inMIND added a CD19 antibody to lenalidomide and rituximab for a progression-free survival hazard ratio of 0.43. In marginal zone lymphoma, IELSG-19 remains the only randomised first-line systemic trial.","status":"current","refs":[{"id":"paper-prima-final-rituximab-maintenance-follicular-jco-2019","kind":"paper","name":"Sustained progression-free survival benefit of rituximab maintenance in patients with follicular lymphoma: long-term results of the PRIMA study","route":"/key-papers/paper-prima-final-rituximab-maintenance-follicular-jco-2019/","tldr":"After nine years the antibody maintenance group had gone more than six years longer before their lymphoma returned, and exactly as many people in each group were alive."},{"id":"paper-casulo-pod24-follicular-lymphoma-jco-2015","kind":"paper","name":"Early relapse of follicular lymphoma after R-CHOP defines patients at high risk for death: an analysis from the National LymphoCare Study","route":"/key-papers/paper-casulo-pod24-follicular-lymphoma-jco-2015/","tldr":"One in five people whose follicular lymphoma came back within two years of first treatment had half the five-year survival of everyone else, which is why that two-year mark now changes the plan."},{"id":"paper-elara-tisagenlecleucel-follicular-nat-med-2022","kind":"paper","name":"Tisagenlecleucel in adult relapsed or refractory follicular lymphoma: the phase 2 ELARA trial","route":"/key-papers/paper-elara-tisagenlecleucel-follicular-nat-med-2022/","tldr":"A single infusion of reprogrammed immune cells cleared follicular lymphoma completely in about seven of ten heavily pretreated people, with no severe cytokine release syndrome at all."},{"id":"paper-zuma-5-axi-cel-indolent-lymphoma-lancet-oncol-2022","kind":"paper","name":"Axicabtagene ciloleucel in relapsed or refractory indolent non-Hodgkin lymphoma (ZUMA-5): a single-arm, multicentre, phase 2 trial","route":"/key-papers/paper-zuma-5-axi-cel-indolent-lymphoma-lancet-oncol-2022/","tldr":"The first CAR-T trial in slow-growing lymphoma: more than nine in ten responded and three quarters went into complete remission, with severe neurological events in about one in five."},{"id":"paper-elm-2-odronextamab-follicular-ann-oncol-2024","kind":"paper","name":"Safety and efficacy of odronextamab in patients with relapsed or refractory follicular lymphoma","route":"/key-papers/paper-elm-2-odronextamab-follicular-ann-oncol-2024/","tldr":"A two-headed antibody given alone put nearly three quarters of people with repeatedly relapsed follicular lymphoma into complete remission, lasting a median of two years."},{"id":"paper-inmind-tafasitamab-lenalidomide-rituximab-follicular-lancet-2026","kind":"paper","name":"Tafasitamab, lenalidomide, and rituximab in relapsed or refractory follicular lymphoma (inMIND): a global, phase 3, randomised controlled trial","route":"/key-papers/paper-inmind-tafasitamab-lenalidomide-rituximab-follicular-lancet-2026/","tldr":"Adding a third antibody, directed at a different target, to the usual tablet-and-antibody pairing added about eight months before follicular lymphoma progressed again."},{"id":"paper-ielsg-19-chlorambucil-rituximab-malt-jco-2017","kind":"paper","name":"Final results of the IELSG-19 randomized trial of mucosa-associated lymphoid tissue lymphoma: improved event-free and progression-free survival with rituximab plus chlorambucil versus either chlorambucil or rituximab monotherapy","route":"/key-papers/paper-ielsg-19-chlorambucil-rituximab-malt-jco-2017/","tldr":"The first randomised trial of first-line drug treatment for MALT lymphoma: the combination of an old tablet and an antibody beat either alone on relapse, and nobody lived longer."},{"id":"prima-follicular","kind":"trial","name":"PRIMA","route":"/trials/prima-follicular/","status":"mixed","tldr":"Two years of an antibody given every two months after chemotherapy more than doubled the time before follicular lymphoma came back, but after nine years the two groups were equally likely to be alive."},{"id":"elara","kind":"trial","name":"ELARA","route":"/trials/elara/","status":"positive","tldr":"A single infusion of a patient's own reprogrammed immune cells cleared follicular lymphoma completely in about seven out of ten people who had already been through several treatments."},{"id":"zuma-5","kind":"trial","name":"ZUMA-5","route":"/trials/zuma-5/","status":"positive","tldr":"ZUMA-5 showed that a single infusion of CD19 CAR-T cells put most people with heavily pretreated follicular lymphoma into remission, and that many of those remissions have lasted for years."},{"id":"rosewood","kind":"trial","name":"ROSEWOOD","route":"/trials/rosewood/","status":"positive","tldr":"Adding a targeted tablet to an antibody roughly doubled the chance of the lymphoma shrinking and tripled the time before it grew again, in people whose follicular lymphoma had already returned twice."},{"id":"ielsg-19","kind":"trial","name":"IELSG-19","route":"/trials/ielsg-19/","status":"mixed","tldr":"The first randomised trial of first-line drug treatment for MALT lymphoma found that combining an old tablet with an antibody delayed relapse better than either alone, without anyone living longer."},{"id":"lymphoma-tx-pod24","kind":"term","name":"POD24: progression of follicular lymphoma within two years, and why it changes the plan","route":"/terms/lymphoma-tx-pod24/","tldr":"Most follicular lymphoma comes back slowly and is treated again without much loss of life expectancy. For about one in five people it comes back within two years of the first chemotherapy, and that group needs a different plan, usually a biopsy first and then cellular or antibody treatment rather than more of the same."}],"trials":[{"id":"prima-follicular","name":"PRIMA","route":"/trials/prima-follicular/","outcomes":[{"endpoint":"Progression-free survival (median)","primary":true,"unit":"years","arms":[{"name":"Rituximab maintenance","n":505,"value":10.5},{"name":"Observation","n":513,"value":4.1}],"hr":0.61,"ci":[0.52,0.73],"source":"https://doi.org/10.1200/JCO.19.01073"},{"endpoint":"Overall survival at 10 years","unit":"%","arms":[{"name":"Rituximab maintenance","value":80},{"name":"Observation","value":80}],"p":"0.7948"}],"setting":"High tumour burden follicular lymphoma responding to first-line immunochemotherapy: two years of rituximab maintenance against observation","enrolled":1018,"enrolledNote":"1,217 patients received induction; 1,018 completed it and were randomised between maintenance and observation.","enrolledBasis":"randomised"},{"id":"elara","name":"ELARA","route":"/trials/elara/","outcomes":[{"endpoint":"Complete response rate","primary":true,"unit":"%","arms":[{"name":"Tisagenlecleucel","n":94,"value":69.1}],"ci":[58.8,78.3],"source":"https://doi.org/10.1038/s41591-021-01622-0"},{"endpoint":"Objective response rate","unit":"%","arms":[{"name":"Tisagenlecleucel","n":94,"value":86.2}],"ci":[77.5,92.4]}],"setting":"Relapsed or refractory follicular lymphoma after two or more lines, or relapsing after an autologous transplant: a single infusion of tisagenlecleucel","enrolled":97,"enrolledNote":"The registry records 98 enrolled; 97 received tisagenlecleucel and 94 formed the efficacy set.","enrolledBasis":"treated"},{"id":"zuma-5","name":"ZUMA-5","route":"/trials/zuma-5/","outcomes":[{"endpoint":"Overall response rate (independent review, primary analysis)","primary":true,"unit":"%","arms":[{"name":"Axicabtagene ciloleucel","n":104,"value":92,"note":"95% CI 85 to 97; median follow-up 17.5 months; 84 follicular and 20 marginal zone lymphoma"}],"source":"https://doi.org/10.1016/s1470-2045(21)00591-x"},{"endpoint":"Complete response (primary analysis)","unit":"%","arms":[{"name":"Axicabtagene ciloleucel","n":104,"value":74}],"source":"https://doi.org/10.1016/s1470-2045(21)00591-x"},{"endpoint":"Grade 3 or worse cytokine release syndrome","unit":"%","arms":[{"name":"Axicabtagene ciloleucel","n":148,"value":7}],"source":"https://doi.org/10.1016/s1470-2045(21)00591-x"},{"endpoint":"Grade 3-4 neurological events","unit":"%","arms":[{"name":"Axicabtagene ciloleucel","n":148,"value":19}],"source":"https://doi.org/10.1016/s1470-2045(21)00591-x"}],"setting":"Relapsed or refractory follicular or marginal zone lymphoma after two or more lines of therapy: single-arm axicabtagene ciloleucel CAR-T","enrolled":159,"enrolledBasis":"registry"},{"id":"rosewood","name":"ROSEWOOD","route":"/trials/rosewood/","outcomes":[{"endpoint":"Overall response rate by independent central review","primary":true,"unit":"%","arms":[{"name":"Zanubrutinib with obinutuzumab","n":145,"value":69},{"name":"Obinutuzumab alone","n":72,"value":46}],"p":"0.001","source":"https://doi.org/10.1200/JCO.23.00775"},{"endpoint":"Progression-free survival (median)","unit":"months","arms":[{"name":"Zanubrutinib with obinutuzumab","n":145,"value":28},{"name":"Obinutuzumab alone","n":72,"value":10.4}],"hr":0.5,"ci":[0.33,0.75]}],"setting":"Relapsed or refractory follicular lymphoma after two or more lines including an anti-CD20 antibody and an alkylating agent: zanubrutinib with obinutuzumab against obinutuzumab alone","enrolled":217,"enrolledBasis":"registry"},{"id":"ielsg-19","name":"IELSG-19","route":"/trials/ielsg-19/","outcomes":[{"endpoint":"Event-free survival at 5 years","primary":true,"unit":"%","arms":[{"name":"Chlorambucil with rituximab","value":68,"note":"95 per cent confidence interval 60 to 76"},{"name":"Chlorambucil alone","value":51,"note":"42 to 60"},{"name":"Rituximab alone","value":50,"note":"42 to 59"}],"hr":0.54,"ci":[0.38,0.77],"p":"0.0009","source":"https://doi.org/10.1200/JCO.2016.70.6994"}],"setting":"Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue needing systemic treatment: chlorambucil, rituximab, or both","enrolled":454,"enrolledBasis":"registry"}],"papers":[{"id":"paper-prima-final-rituximab-maintenance-follicular-jco-2019","name":"Sustained progression-free survival benefit of rituximab maintenance in patients with follicular lymphoma: long-term results of the PRIMA study","route":"/key-papers/paper-prima-final-rituximab-maintenance-follicular-jco-2019/","journal":"Journal of Clinical Oncology","year":2019,"whatItMeans":"The number to give a patient deciding about maintenance: a median of six and a half extra years before the next treatment, and no difference in how long they live. Both halves belong in the conversation."},{"id":"paper-casulo-pod24-follicular-lymphoma-jco-2015","name":"Early relapse of follicular lymphoma after R-CHOP defines patients at high risk for death: an analysis from the National LymphoCare Study","route":"/key-papers/paper-casulo-pod24-follicular-lymphoma-jco-2015/","journal":"Journal of Clinical Oncology","year":2015,"whatItMeans":"The single most used prognostic marker in follicular lymphoma, and the reason a relapse at 20 months is handled differently from one at 30 months. It is now a standard stratification factor and a standard eligibility criterion in trials of the disease."},{"id":"paper-elara-tisagenlecleucel-follicular-nat-med-2022","name":"Tisagenlecleucel in adult relapsed or refractory follicular lymphoma: the phase 2 ELARA trial","route":"/key-papers/paper-elara-tisagenlecleucel-follicular-nat-med-2022/","journal":"Nature Medicine","year":2022,"whatItMeans":"Chemotherapy-free cellular therapy for follicular lymphoma that has stopped responding, with a toxicity profile mild enough that the treatment is deliverable outside the largest centres."},{"id":"paper-zuma-5-axi-cel-indolent-lymphoma-lancet-oncol-2022","name":"Axicabtagene ciloleucel in relapsed or refractory indolent non-Hodgkin lymphoma (ZUMA-5): a single-arm, multicentre, phase 2 trial","route":"/key-papers/paper-zuma-5-axi-cel-indolent-lymphoma-lancet-oncol-2022/","journal":"Lancet Oncology","year":2022,"whatItMeans":"Axicabtagene ciloleucel as an option in relapsed follicular and marginal zone lymphoma. Compared with tisagenlecleucel in ELARA, the response rates are higher and the neurological toxicity substantially greater, which is the trade-off a patient and centre weigh."},{"id":"paper-elm-2-odronextamab-follicular-ann-oncol-2024","name":"Safety and efficacy of odronextamab in patients with relapsed or refractory follicular lymphoma","route":"/key-papers/paper-elm-2-odronextamab-follicular-ann-oncol-2024/","journal":"Annals of Oncology","year":2024,"whatItMeans":"An off-the-shelf alternative to CAR-T for repeatedly relapsed follicular lymphoma: no apheresis, no manufacturing wait, and a complete response rate in the same range, at the cost of continued treatment rather than a single infusion."},{"id":"paper-inmind-tafasitamab-lenalidomide-rituximab-follicular-lancet-2026","name":"Tafasitamab, lenalidomide, and rituximab in relapsed or refractory follicular lymphoma (inMIND): a global, phase 3, randomised controlled trial","route":"/key-papers/paper-inmind-tafasitamab-lenalidomide-rituximab-follicular-lancet-2026/","journal":"Lancet","year":2026,"whatItMeans":"A new combination for relapsed or refractory follicular lymphoma that adds a CD19-directed antibody to the established lenalidomide and rituximab pairing, with the largest progression-free survival hazard ratio reported in the setting."},{"id":"paper-ielsg-19-chlorambucil-rituximab-malt-jco-2017","name":"Final results of the IELSG-19 randomized trial of mucosa-associated lymphoid tissue lymphoma: improved event-free and progression-free survival with rituximab plus chlorambucil versus either chlorambucil or rituximab monotherapy","route":"/key-papers/paper-ielsg-19-chlorambucil-rituximab-malt-jco-2017/","journal":"Journal of Clinical Oncology","year":2017,"whatItMeans":"The only randomised evidence for first-line systemic treatment of MALT lymphoma. It supports the combination when systemic treatment is needed, and the identical survival across arms supports taking time over that decision."}]},{"era":"2015-2026","title":"Cells and engagers: the immune treatments that work when chemotherapy does not","description":"ZUMA-1, JULIET and TRANSCEND NHL 001 established CD19 CAR-T in large B-cell lymphoma after two or more lines between 2017 and 2020, with objective responses in 73 per cent and complete responses in 53 per cent in the largest of them, and grade 3 or worse cytokine release syndrome in 2 per cent for lisocabtagene maraleucel against much higher rates for the other products.\n\nThen the three products split in the second line. ZUMA-7 and TRANSFORM both beat salvage chemotherapy with an autologous transplant. BELINDA, testing tisagenlecleucel in the same setting, did not: median event-free survival was 3.0 months in both arms. The explanation most often offered is the 52-day median interval from leukapheresis to infusion, during which 25.9 per cent of the CAR-T group progressed against 13.8 per cent of the standard-care group, compounded by a baseline imbalance that favoured the comparator. It is a cross-trial inference, and the fact that it is the best available explanation for a 322-patient randomised failure says something about how the field measures what it is doing.\n\nThe CD20 bispecific antibodies arrived alongside and solved the logistics rather than the biology: no apheresis, no manufacturing wait, available the week the decision is made. STARGLO, EPCORE NHL-1, POLARGO and ECHELON-3 between them now give transplant-ineligible relapsed diffuse large B-cell lymphoma four options with randomised or pivotal evidence where a decade ago it had none.","status":"current","refs":[{"id":"paper-transcend-nhl-001-liso-cel-lancet-2020","kind":"paper","name":"Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study","route":"/key-papers/paper-transcend-nhl-001-liso-cel-lancet-2020/","tldr":"The pivotal study of the third CAR-T product for lymphoma, built from a fixed one-to-one mix of two kinds of T cell, with severe immune side effects in only a small minority."},{"id":"paper-juliet-tisagenlecleucel-dlbcl-nejm-2019","kind":"paper","name":"JULIET: tisagenlecleucel for adults with relapsed or refractory diffuse large B-cell lymphoma","route":"/key-papers/paper-juliet-tisagenlecleucel-dlbcl-nejm-2019/","tldr":"In adults with aggressive lymphoma after at least two prior treatments, tisagenlecleucel produced responses in 52% and complete responses in 40%, most of which lasted."},{"id":"paper-zuma-1-axi-cel-nejm-2017","kind":"paper","name":"ZUMA-1: axicabtagene ciloleucel for refractory large B-cell lymphoma, the first CAR-T approved for lymphoma","route":"/key-papers/paper-zuma-1-axi-cel-nejm-2017/","tldr":"In lymphoma refractory to chemotherapy, where expected survival was around six months, a single CAR-T infusion produced responses in 82% of patients and long-term remission in about 40%."},{"id":"paper-zuma-7-axi-cel-second-line-nejm-2022","kind":"paper","name":"ZUMA-7: axi-cel CAR-T instead of salvage chemotherapy and transplant for large B-cell lymphoma that relapses early","route":"/key-papers/paper-zuma-7-axi-cel-second-line-nejm-2022/","tldr":"For lymphoma that came back within a year, going straight to CAR-T beat the decades-old chemotherapy-then-transplant approach, and later improved survival."},{"id":"paper-transform-liso-cel-lancet-2022","kind":"paper","name":"TRANSFORM: liso-cel CAR-T versus salvage chemotherapy and transplant in early-relapsing large B-cell lymphoma","route":"/key-papers/paper-transform-liso-cel-lancet-2022/","tldr":"In TRANSFORM, a second CD19 CAR-T, lisocabtagene maraleucel, also beat chemotherapy-plus-transplant as second-line treatment, with a low rate of severe side effects."},{"id":"paper-belinda-tisagenlecleucel-second-line-nejm-2022","kind":"paper","name":"Second-line tisagenlecleucel or standard care in aggressive B-cell lymphoma","route":"/key-papers/paper-belinda-tisagenlecleucel-second-line-nejm-2022/","tldr":"The one second-line CAR-T trial that failed. Its result is best explained by how long the cells took to make and what patients received while they waited."},{"id":"paper-polargo-polatuzumab-r-gemox-dlbcl-jco-2026","kind":"paper","name":"Polatuzumab vedotin plus rituximab, gemcitabine, and oxaliplatin in relapsed or refractory diffuse large B-cell lymphoma: results from the phase III, randomized POLARGO trial","route":"/key-papers/paper-polargo-polatuzumab-r-gemox-dlbcl-jco-2026/","tldr":"Adding an antibody-drug conjugate to an outpatient chemotherapy pairing added seven months of median survival for people with relapsed aggressive lymphoma who could not have a transplant."},{"id":"paper-echelon-3-brentuximab-lenalidomide-rituximab-dlbcl-jco-2025","kind":"paper","name":"Brentuximab vedotin combination for relapsed diffuse large B-cell lymphoma","route":"/key-papers/paper-echelon-3-brentuximab-lenalidomide-rituximab-dlbcl-jco-2025/","tldr":"Adding a CD30-directed antibody-drug conjugate to a tablet-and-antibody pairing added about five months of median survival for heavily pretreated people with relapsed aggressive lymphoma."},{"id":"zuma-7","kind":"trial","name":"ZUMA-7","route":"/trials/zuma-7/","status":"positive","tldr":"The trial that moved CAR-T ahead of transplant as second-line treatment for early-relapsing large B-cell lymphoma, with a survival benefit."},{"id":"transform","kind":"trial","name":"TRANSFORM","route":"/trials/transform/","status":"positive","tldr":"The second trial to show a CAR-T beats transplant in early-relapsing large B-cell lymphoma."},{"id":"belinda","kind":"trial","name":"BELINDA","route":"/trials/belinda/","status":"negative","tldr":"The one second-line CAR-T trial that failed, a reminder that manufacturing time and trial design can erase a real effect."},{"id":"transcend-nhl-001","kind":"trial","name":"TRANSCEND NHL 001","route":"/trials/transcend-nhl-001/","status":"positive","tldr":"The study that registered the third CAR-T cell product for lymphoma, built from a fixed one-to-one mix of two kinds of T cell, with fewer severe immune side effects than its predecessors."},{"id":"juliet","kind":"trial","name":"JULIET","route":"/trials/juliet/","status":"positive","tldr":"The pivotal study of the second CAR-T cell product approved for adult lymphoma, which put about a third of people with no remaining options into a lasting remission."},{"id":"polargo","kind":"trial","name":"POLARGO","route":"/trials/polargo/","status":"positive","tldr":"Adding an antibody-drug conjugate to a gentle outpatient chemotherapy pairing added about seven months of life for people with relapsed aggressive lymphoma who could not have a transplant."},{"id":"lymphoma-ev-manufacturing-time-as-a-trial-endpoint","kind":"idea","name":"Report the time from apheresis to infusion as a trial endpoint, not a logistics footnote","route":"/ideas/lymphoma-ev-manufacturing-time-as-a-trial-endpoint/","tldr":"The best explanation for why one second-line CAR-T trial failed when two succeeded is how long the cells took to make. That interval is almost never a reported endpoint."}],"trials":[{"id":"zuma-7","name":"ZUMA-7","route":"/trials/zuma-7/","outcomes":[{"endpoint":"Event-free survival (median)","primary":true,"unit":"months","arms":[{"name":"Axi-cel","n":180,"value":8.3},{"name":"Standard care","n":179,"value":2}],"hr":0.4,"ci":[0.31,0.51],"p":"<0.001","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2116133"},{"endpoint":"Overall survival at 4 years","unit":"%","arms":[{"name":"Axi-cel","value":54.6},{"name":"Standard care","value":46}],"hr":0.73,"ci":[0.54,0.98],"p":"0.03","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2301665"}],"setting":"Large B-cell lymphoma refractory or relapsed within 12 months of frontline therapy: axi-cel vs salvage chemotherapy + autologous transplant","enrolled":359,"enrolledBasis":"registry"},{"id":"transform","name":"TRANSFORM","route":"/trials/transform/","outcomes":[{"endpoint":"Event-free survival (median)","primary":true,"unit":"months","arms":[{"name":"Liso-cel","n":92,"value":29.5},{"name":"Standard care","n":92,"value":2.4}],"hr":0.36,"ci":[0.24,0.52],"source":"https://ashpublications.org/blood/article/141/14/1675/493918"}],"setting":"Primary refractory or early-relapsed LBCL, transplant-eligible: liso-cel vs salvage + autologous transplant","enrolled":184,"enrolledBasis":"registry"},{"id":"belinda","name":"BELINDA","route":"/trials/belinda/","outcomes":[{"endpoint":"Event-free survival (median)","primary":true,"unit":"months","arms":[{"name":"Tisagenlecleucel","n":162,"value":3},{"name":"Standard care","n":160,"value":3}],"hr":1.07,"ci":[0.82,1.4],"source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2116596"}],"setting":"Early-relapsed/refractory aggressive B-cell lymphoma: tisagenlecleucel vs salvage + transplant","enrolled":330,"enrolledBasis":"registry"},{"id":"transcend-nhl-001","name":"TRANSCEND NHL 001","route":"/trials/transcend-nhl-001/","outcomes":[{"endpoint":"Objective response rate","primary":true,"unit":"%","arms":[{"name":"Lisocabtagene maraleucel","n":256,"value":73}],"ci":[66.8,78],"source":"https://doi.org/10.1016/S0140-6736(20)31366-0"},{"endpoint":"Complete response rate","unit":"%","arms":[{"name":"Lisocabtagene maraleucel","n":256,"value":53}],"ci":[46.8,59.4]},{"endpoint":"Grade 3 or worse cytokine release syndrome","unit":"%","arms":[{"name":"Lisocabtagene maraleucel","n":269,"value":2}]}],"setting":"Relapsed or refractory large B-cell lymphoma after at least one prior line, including double-hit and transformed disease: lisocabtagene maraleucel at three dose levels","enrolled":269,"enrolledNote":"The registry records 387 enrolled; 344 underwent leukapheresis and 269 received at least one dose of lisocabtagene maraleucel, of whom 256 were in the efficacy-evaluable set.","enrolledBasis":"treated"},{"id":"polargo","name":"POLARGO","route":"/trials/polargo/","outcomes":[{"endpoint":"Overall survival (median)","primary":true,"unit":"months","arms":[{"name":"Polatuzumab with R-GemOx","n":129,"value":19.5},{"name":"R-GemOx","n":126,"value":12.5}],"hr":0.6,"ci":[0.43,0.83],"p":"0.0017","source":"https://doi.org/10.1200/JCO-25-02849"}],"setting":"Relapsed or refractory diffuse large B-cell lymphoma not eligible for an autologous transplant: polatuzumab vedotin added to rituximab, gemcitabine and oxaliplatin","enrolled":255,"enrolledNote":"The registry records 270, which includes the 15-patient safety run-in; 255 were randomised and analysed.","enrolledBasis":"randomised"}],"papers":[{"id":"paper-transcend-nhl-001-liso-cel-lancet-2020","name":"Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study","route":"/key-papers/paper-transcend-nhl-001-liso-cel-lancet-2020/","journal":"Lancet","year":2020,"whatItMeans":"The evidence that made lisocabtagene maraleucel the CD19 CAR-T product most often chosen for older or frailer patients, because its severe cytokine release syndrome rate is a fraction of the other two products'."},{"id":"paper-juliet-tisagenlecleucel-dlbcl-nejm-2019","name":"JULIET: tisagenlecleucel for adults with relapsed or refractory diffuse large B-cell lymphoma","route":"/key-papers/paper-juliet-tisagenlecleucel-dlbcl-nejm-2019/","journal":"New England Journal of Medicine","year":2019,"whatItMeans":"JULIET, with ZUMA-1, showed that CAR-T could rescue a substantial minority of adults with chemotherapy-refractory lymphoma and that complete responders often stay in remission. The lower toxicity of a 4-1BB construct and the option of bridging therapy made it usable in a broader population. The high drop-out between enrolment and infusion remains a lesson about turnaround time."},{"id":"paper-zuma-1-axi-cel-nejm-2017","name":"ZUMA-1: axicabtagene ciloleucel for refractory large B-cell lymphoma, the first CAR-T approved for lymphoma","route":"/key-papers/paper-zuma-1-axi-cel-nejm-2017/","journal":"New England Journal of Medicine","year":2017,"whatItMeans":"ZUMA-1 showed that CAR-T can cure a meaningful fraction of adults whose aggressive lymphoma no longer responds to chemotherapy, a group with a historical median survival of about six months (SCHOLAR-1). Axi-cel became the first CAR-T approved for lymphoma and later the first to beat standard second-line therapy in ZUMA-7. The comparatively high neurotoxicity of CD28-costimulated products was also first characterised here."},{"id":"paper-zuma-7-axi-cel-second-line-nejm-2022","name":"ZUMA-7: axi-cel CAR-T instead of salvage chemotherapy and transplant for large B-cell lymphoma that relapses early","route":"/key-papers/paper-zuma-7-axi-cel-second-line-nejm-2022/","journal":"New England Journal of Medicine","year":2022,"whatItMeans":"ZUMA-7 rewrote second-line treatment for aggressive lymphoma: patients whose disease returns within a year of R-CHOP should be offered CAR-T rather than salvage chemotherapy and transplant. It is also one of the few cell-therapy trials to show an overall survival benefit despite crossover. Patients relapsing later than 12 months were not studied and transplant remains standard for them if chemosensitive."},{"id":"paper-transform-liso-cel-lancet-2022","name":"TRANSFORM: liso-cel CAR-T versus salvage chemotherapy and transplant in early-relapsing large B-cell lymphoma","route":"/key-papers/paper-transform-liso-cel-lancet-2022/","journal":"The Lancet","year":2022,"whatItMeans":"TRANSFORM confirmed ZUMA-7's conclusion with a different CD19 CAR-T and a more permissive design that allowed bridging chemotherapy, making the results closer to real-world practice. Liso-cel's low toxicity makes it attractive for older or frailer patients and for outpatient delivery. Together the two trials made CAR-T the standard second-line therapy for early-relapsing aggressive lymphoma."},{"id":"paper-belinda-tisagenlecleucel-second-line-nejm-2022","name":"Second-line tisagenlecleucel or standard care in aggressive B-cell lymphoma","route":"/key-papers/paper-belinda-tisagenlecleucel-second-line-nejm-2022/","journal":"New England Journal of Medicine","year":2022,"whatItMeans":"The reason second-line CAR-T is offered with axicabtagene ciloleucel or lisocabtagene maraleucel rather than tisagenlecleucel. The trial is also the strongest evidence in the field that the interval between apheresis and infusion, and what is given during it, is part of the treatment rather than logistics around it."},{"id":"paper-polargo-polatuzumab-r-gemox-dlbcl-jco-2026","name":"Polatuzumab vedotin plus rituximab, gemcitabine, and oxaliplatin in relapsed or refractory diffuse large B-cell lymphoma: results from the phase III, randomized POLARGO trial","route":"/key-papers/paper-polargo-polatuzumab-r-gemox-dlbcl-jco-2026/","journal":"Journal of Clinical Oncology","year":2026,"whatItMeans":"An option with a demonstrated survival benefit for transplant-ineligible relapsed diffuse large B-cell lymphoma, a group for whom very little has ever shown one. The fatal adverse event imbalance belongs in the conversation alongside the survival figure."},{"id":"paper-echelon-3-brentuximab-lenalidomide-rituximab-dlbcl-jco-2025","name":"Brentuximab vedotin combination for relapsed diffuse large B-cell lymphoma","route":"/key-papers/paper-echelon-3-brentuximab-lenalidomide-rituximab-dlbcl-jco-2025/","journal":"Journal of Clinical Oncology","year":2025,"whatItMeans":"The evidence behind the United States approval of brentuximab vedotin with lenalidomide and a rituximab product for relapsed or refractory diffuse large B-cell lymphoma after two or more lines in patients not eligible for an autologous transplant or CAR-T. It is also the first demonstration that a CD30-directed conjugate helps in a disease where CD30 expression is variable."}]},{"era":"2017-2026","title":"Mantle cell lymphoma: three ways to use a Bruton tyrosine kinase inhibitor, and none of them extends life","description":"LyMa established three years of rituximab maintenance after autologous transplantation in patients under 66, with four-year event-free survival of 79 against 61 per cent and an overall survival benefit, which is rare for a maintenance strategy in lymphoma.\n\nFor older patients the question became where to put the Bruton tyrosine kinase inhibitor. SHINE added ibrutinib to bendamustine-rituximab and gained 28 months of progression-free survival (80.6 against 52.9 months, hazard ratio 0.75) with no survival difference. ECHO repeated the design with acalabrutinib and gained 17 months (66.4 against 49.6, hazard ratio 0.73), again with no survival difference and grade 3 or greater adverse events in roughly 89 per cent of both arms. ENRICH took the opposite route and removed the chemotherapy: ibrutinib with rituximab beat immunochemotherapy with an adjusted hazard ratio of 0.69, driven almost entirely by the comparison against R-CHOP (0.37) rather than against bendamustine-rituximab (0.91).\n\nTRIANGLE meanwhile asked whether the autologous transplant is still needed in younger patients when ibrutinib is added to induction and maintenance. Taken together, the four trials mean a person over 60 with mantle cell lymphoma now has a chemotherapy-free first-line option, and that nobody has yet shown any of these strategies makes them live longer.","status":"current","refs":[{"id":"paper-lyma-rituximab-maintenance-after-transplant-mantle-cell-nejm-2017","kind":"paper","name":"Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma","route":"/key-papers/paper-lyma-rituximab-maintenance-after-transplant-mantle-cell-nejm-2017/","tldr":"Three years of an antibody every two months after a stem cell transplant kept younger people with mantle cell lymphoma in remission longer and helped them live longer."},{"id":"paper-shine-ibrutinib-bendamustine-rituximab-mantle-cell-nejm-2022","kind":"paper","name":"Ibrutinib plus bendamustine and rituximab in untreated mantle-cell lymphoma","route":"/key-papers/paper-shine-ibrutinib-bendamustine-rituximab-mantle-cell-nejm-2022/","tldr":"Adding a targeted tablet to first-line chemotherapy gave older people with mantle cell lymphoma about two and a half more years before relapse, without helping them live longer."},{"id":"paper-echo-acalabrutinib-bendamustine-rituximab-mantle-cell-jco-2025","kind":"paper","name":"Acalabrutinib plus bendamustine-rituximab in untreated mantle cell lymphoma","route":"/key-papers/paper-echo-acalabrutinib-bendamustine-rituximab-mantle-cell-jco-2025/","tldr":"Repeating the SHINE design with a more selective targeted tablet gave another seventeen months before relapse, and again did not extend life."},{"id":"paper-enrich-ibrutinib-rituximab-mantle-cell-lancet-2025","kind":"paper","name":"Ibrutinib and rituximab versus immunochemotherapy in patients with previously untreated mantle cell lymphoma (ENRICH): a randomised, open-label, phase 2/3 superiority trial","route":"/key-papers/paper-enrich-ibrutinib-rituximab-mantle-cell-lancet-2025/","tldr":"The first trial to show that a chemotherapy-free first-line combination beats immunochemotherapy in older people with mantle cell lymphoma."},{"id":"paper-triangle-ibrutinib-mantle-cell-lymphoma-dreyling-lancet-2024","kind":"paper","name":"TRIANGLE: ibrutinib with immunochemotherapy with or without autologous transplant versus immunochemotherapy and transplant in untreated mantle cell lymphoma","route":"/key-papers/paper-triangle-ibrutinib-mantle-cell-lymphoma-dreyling-lancet-2024/","tldr":"Adding ibrutinib to first-line treatment for younger people with mantle cell lymphoma kept more of them free of treatment failure at three years, and the stem cell transplant that was standard was not shown to add benefit once ibrutinib was used."},{"id":"lyma","kind":"trial","name":"LyMa","route":"/trials/lyma/","status":"positive","tldr":"Three years of an antibody every two months after a stem cell transplant kept younger people with mantle cell lymphoma in remission longer and helped them live longer."},{"id":"shine","kind":"trial","name":"SHINE","route":"/trials/shine/","status":"mixed","tldr":"Adding a targeted tablet to first-line chemotherapy gave older people with mantle cell lymphoma about two and a half more years before the disease returned, but they did not live longer."},{"id":"enrich","kind":"trial","name":"ENRICH","route":"/trials/enrich/","status":"positive","tldr":"A British and Nordic trial took chemotherapy out of first-line treatment for older people with mantle cell lymphoma and found the two-drug, chemotherapy-free combination worked better."},{"id":"triangle","kind":"trial","name":"TRIANGLE","route":"/trials/triangle/","status":"positive","tldr":"TRIANGLE showed that adding the pill ibrutinib to the chemotherapy given to younger people with mantle cell lymphoma keeps the disease away for longer, and that when ibrutinib is used the stem cell transplant that used to be compulsory no longer adds a clear benefit while adding side effects."},{"id":"lymphoma-ev-fixed-duration-chemotherapy-free-first-line","kind":"idea","name":"Fixed-duration, chemotherapy-free first-line treatment for the indolent lymphomas","route":"/ideas/lymphoma-ev-fixed-duration-chemotherapy-free-first-line/","tldr":"Several treatments now work without chemotherapy, but most are given until the disease comes back. Giving them for a fixed time and stopping is the version patients would choose."}],"trials":[{"id":"lyma","name":"LyMa","route":"/trials/lyma/","outcomes":[{"endpoint":"Event-free survival at 4 years","primary":true,"unit":"%","arms":[{"name":"Rituximab maintenance","n":120,"value":79,"note":"95 per cent confidence interval 70 to 86"},{"name":"Observation","n":120,"value":61,"note":"51 to 70"}],"p":"0.001","source":"https://doi.org/10.1056/NEJMoa1701769"},{"endpoint":"Progression-free survival at 4 years","unit":"%","arms":[{"name":"Rituximab maintenance","n":120,"value":83,"note":"73 to 88"},{"name":"Observation","n":120,"value":64,"note":"55 to 73"}]}],"setting":"Under 66 at diagnosis with mantle cell lymphoma, after R-DHAP induction and autologous stem-cell transplantation: three years of rituximab maintenance against observation","enrolled":240,"enrolledNote":"299 patients entered the trial; 257 were transplanted and 240 were randomised between maintenance and observation after transplantation.","enrolledBasis":"randomised"},{"id":"shine","name":"SHINE","route":"/trials/shine/","outcomes":[{"endpoint":"Progression-free survival (median)","primary":true,"unit":"months","arms":[{"name":"Ibrutinib with bendamustine and rituximab","n":261,"value":80.6},{"name":"Placebo with bendamustine and rituximab","n":262,"value":52.9}],"hr":0.75,"ci":[0.59,0.96],"p":"0.01","source":"https://doi.org/10.1056/NEJMoa2201817"},{"endpoint":"Complete response rate","unit":"%","arms":[{"name":"Ibrutinib with bendamustine and rituximab","n":261,"value":65.5},{"name":"Placebo with bendamustine and rituximab","n":262,"value":57.6}],"p":"0.06"}],"setting":"Aged 65 or over with untreated mantle cell lymphoma: ibrutinib added to six cycles of bendamustine and rituximab, with rituximab maintenance","enrolled":523,"enrolledBasis":"registry"},{"id":"enrich","name":"ENRICH","route":"/trials/enrich/","outcomes":[{"endpoint":"Progression-free survival","primary":true,"arms":[{"name":"Ibrutinib with rituximab","n":199},{"name":"Rituximab with R-CHOP or bendamustine","n":198}],"hr":0.69,"ci":[0.52,0.9],"p":"0.0034","source":"https://doi.org/10.1016/S0140-6736(25)01432-1"},{"endpoint":"Progression-free survival, R-CHOP stratum","arms":[{"name":"Ibrutinib with rituximab"},{"name":"R-CHOP","n":53}],"hr":0.37,"ci":[0.22,0.62]},{"endpoint":"Progression-free survival, bendamustine-rituximab stratum","arms":[{"name":"Ibrutinib with rituximab"},{"name":"Bendamustine with rituximab","n":145}],"hr":0.91,"ci":[0.66,1.25]}],"setting":"Aged 60 or over with untreated stage II to IV mantle cell lymphoma: ibrutinib with rituximab against rituximab with R-CHOP or bendamustine","enrolled":397,"enrolledNote":"ENRICH has no ClinicalTrials.gov record; it was registered with EudraCT as 2015-000832-13, and the figure is the number randomised in the Lancet report.","enrolledBasis":"randomised"},{"id":"triangle","name":"TRIANGLE","route":"/trials/triangle/","outcomes":[{"endpoint":"Failure-free survival at 3 years, arm A+I against arm A","primary":true,"unit":"%","arms":[{"name":"Arm A+I: R-CHOP/R-DHAP + ibrutinib, transplant, ibrutinib maintenance","n":292,"value":88,"note":"95% CI 84 to 92; median follow-up 31 months"},{"name":"Arm A: R-CHOP/R-DHAP and autologous transplant","n":288,"value":72,"note":"95% CI 67 to 79"}],"hr":0.52,"p":"0.0008 (one-sided)","source":"https://doi.org/10.1016/S0140-6736(24)00184-3"},{"endpoint":"Failure-free survival at 3 years, arm A against arm I (superiority of transplant not shown)","primary":true,"unit":"%","arms":[{"name":"Arm A: R-CHOP/R-DHAP and autologous transplant","n":288,"value":72},{"name":"Arm I: R-CHOP/R-DHAP + ibrutinib, ibrutinib maintenance, no transplant","n":290,"value":86,"note":"95% CI 82 to 91"}],"hr":1.77,"p":"0.9979 (one-sided)","source":"https://doi.org/10.1016/S0140-6736(24)00184-3"},{"endpoint":"Grade 3 to 5 haematological adverse events during maintenance or follow-up","unit":"%","arms":[{"name":"Arm A+I","n":231,"value":50},{"name":"Arm I","n":269,"value":28},{"name":"Arm A","n":238,"value":21}],"source":"https://doi.org/10.1016/S0140-6736(24)00184-3"},{"endpoint":"Grade 3 to 5 infections during maintenance or follow-up","unit":"%","arms":[{"name":"Arm A+I","n":231,"value":25},{"name":"Arm I","n":269,"value":19},{"name":"Arm A","n":238,"value":13}],"source":"https://doi.org/10.1016/S0140-6736(24)00184-3"}],"setting":"Previously untreated mantle cell lymphoma in patients up to 65 fit for transplant: alternating R-CHOP and R-DHAP induction followed by autologous transplant (arm A), the same with ibrutinib added to induction and as two-year maintenance (arm A+I), or ibrutinib-containing induction and maintenance without transplant (arm I)","enrolled":870,"enrolledBasis":"registry"}],"papers":[{"id":"paper-lyma-rituximab-maintenance-after-transplant-mantle-cell-nejm-2017","name":"Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma","route":"/key-papers/paper-lyma-rituximab-maintenance-after-transplant-mantle-cell-nejm-2017/","journal":"New England Journal of Medicine","year":2017,"whatItMeans":"One of the few maintenance strategies in lymphoma that improved overall survival rather than only progression-free survival, and the reason three years of rituximab became standard after autologous transplantation in mantle cell lymphoma."},{"id":"paper-shine-ibrutinib-bendamustine-rituximab-mantle-cell-nejm-2022","name":"Ibrutinib plus bendamustine and rituximab in untreated mantle-cell lymphoma","route":"/key-papers/paper-shine-ibrutinib-bendamustine-rituximab-mantle-cell-nejm-2022/","journal":"New England Journal of Medicine","year":2022,"whatItMeans":"Twenty-eight extra months of progression-free survival, with no survival gain and a high rate of severe adverse events in both arms. It set up the two trials that followed: ECHO, which substituted a more selective inhibitor, and ENRICH, which removed the chemotherapy."},{"id":"paper-echo-acalabrutinib-bendamustine-rituximab-mantle-cell-jco-2025","name":"Acalabrutinib plus bendamustine-rituximab in untreated mantle cell lymphoma","route":"/key-papers/paper-echo-acalabrutinib-bendamustine-rituximab-mantle-cell-jco-2025/","journal":"Journal of Clinical Oncology","year":2025,"whatItMeans":"A second randomised confirmation that adding a Bruton tyrosine kinase inhibitor to first-line bendamustine-rituximab delays progression in older patients with mantle cell lymphoma, with a toxicity profile that did not improve as much as the drug's selectivity promised."},{"id":"paper-enrich-ibrutinib-rituximab-mantle-cell-lancet-2025","name":"Ibrutinib and rituximab versus immunochemotherapy in patients with previously untreated mantle cell lymphoma (ENRICH): a randomised, open-label, phase 2/3 superiority trial","route":"/key-papers/paper-enrich-ibrutinib-rituximab-mantle-cell-lancet-2025/","journal":"Lancet","year":2025,"whatItMeans":"The authors' conclusion is that ibrutinib-rituximab should be considered a new standard-of-care option for first-line treatment of older patients with mantle-cell lymphoma. The subgroup split means it is clearly better than R-CHOP and roughly equivalent to bendamustine-rituximab."},{"id":"paper-triangle-ibrutinib-mantle-cell-lymphoma-dreyling-lancet-2024","name":"TRIANGLE: ibrutinib with immunochemotherapy with or without autologous transplant versus immunochemotherapy and transplant in untreated mantle cell lymphoma","route":"/key-papers/paper-triangle-ibrutinib-mantle-cell-lymphoma-dreyling-lancet-2024/","journal":"The Lancet","year":2024,"whatItMeans":"Ibrutinib during induction and as maintenance should be part of first-line treatment for younger patients with mantle cell lymphoma; whether transplant adds anything to an ibrutinib-containing regimen is still being followed."}]},{"era":"2007-2026","title":"The T-cell lymphomas, where almost nothing has been randomised","description":"Two trials carry most of the randomised evidence for the T-cell lymphomas, and one of them is not randomised. JCOG9801 is the only controlled trial ever run exclusively in adult T-cell leukaemia/lymphoma: 118 patients, a complete response rate of 40 against 25 per cent for an intensive Japanese regimen over biweekly CHOP, three-year overall survival of 24 against 13 per cent that did not reach significance on two-sided testing, and grade 4 thrombocytopenia in 74 against 17 per cent. SMILE is a 38-patient single-arm phase 2 that made extranodal NK/T-cell lymphoma treatable, with an overall response rate of 79 per cent and one-year overall survival of 55 per cent, by building the regimen on asparaginase rather than on an anthracycline.\n\nECHELON-2 is the exception that shows what is possible: brentuximab vedotin with CHP improved survival in CD30-positive peripheral T-cell lymphoma in a global double-blind randomised trial. ALCANZA did the same for cutaneous T-cell lymphoma.\n\nEverything else, including the choice of first-line regimen in peripheral T-cell lymphoma not otherwise specified, rests on single-arm studies and registry series. Several randomised trials are recruiting at last, in peripheral T-cell lymphoma with the T follicular helper phenotype and in NK/T-cell disease.","status":"current","refs":[{"id":"paper-jcog9801-vcap-amp-vecp-adult-t-cell-leukaemia-jco-2007","kind":"paper","name":"VCAP-AMP-VECP compared with biweekly CHOP for adult T-cell leukemia-lymphoma: Japan Clinical Oncology Group Study JCOG9801","route":"/key-papers/paper-jcog9801-vcap-amp-vecp-adult-t-cell-leukaemia-jco-2007/","tldr":"The only randomised trial run exclusively in the virus-driven adult T-cell leukaemia found an intensive Japanese regimen produced more complete remissions than standard chemotherapy, at considerable cost in toxicity."},{"id":"paper-smile-chemotherapy-nk-t-cell-lymphoma-jco-2011","kind":"paper","name":"Phase II study of SMILE chemotherapy for newly diagnosed stage IV, relapsed, or refractory extranodal natural killer (NK)/T-cell lymphoma, nasal type: the NK-Cell Tumor Study Group study","route":"/key-papers/paper-smile-chemotherapy-nk-t-cell-lymphoma-jco-2011/","tldr":"An asparaginase-based regimen produced a response in four out of five people with an aggressive nasal lymphoma that resists ordinary chemotherapy, and nearly all of them developed dangerously low white cell counts."},{"id":"paper-horwitz-lancet","kind":"paper","name":"Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial","route":"/key-papers/paper-horwitz-lancet/","tldr":"Paper cited by one cancer page, indexed on Europe PMC as PubMed record 30522922 and published in The Lancet; the citing page links this DOI, which is how the record was matched."},{"id":"paper-alcanza-brentuximab-vedotin-lancet-2017","kind":"paper","name":"ALCANZA: brentuximab vedotin versus physician's choice in CD30-positive cutaneous T-cell lymphoma","route":"/key-papers/paper-alcanza-brentuximab-vedotin-lancet-2017/","tldr":"In CD30-expressing mycosis fungoides and primary cutaneous anaplastic large cell lymphoma, the antibody-drug conjugate brentuximab vedotin produced lasting responses in more than half of patients, far more than methotrexate or bexarotene."},{"id":"jcog9801","kind":"trial","name":"JCOG9801","route":"/trials/jcog9801/","status":"mixed","tldr":"The only randomised trial ever run exclusively in the virus-driven T-cell leukaemia found an intensive Japanese regimen better than standard chemotherapy, at the cost of much more severe low blood counts."},{"id":"smile-enktl","kind":"trial","name":"SMILE","route":"/trials/smile-enktl/","status":"positive","tldr":"An asparaginase-based regimen gave a response in four out of five people with an aggressive nasal lymphoma that had always resisted standard chemotherapy, and nearly all of them had dangerously low white cell counts."},{"id":"echelon-2","kind":"trial","name":"ECHELON-2","route":"/trials/echelon-2/","status":"positive","tldr":"ECHELON-2 was the first trial in decades to improve on CHOP chemotherapy for T-cell lymphoma: swapping vincristine for the antibody-drug conjugate brentuximab vedotin helped patients live longer, especially those with anaplastic large cell lymphoma."},{"id":"alcanza","kind":"trial","name":"ALCANZA","route":"/trials/alcanza/","status":"positive","tldr":"ALCANZA showed that brentuximab vedotin produced lasting improvement in the skin disease of far more people with CD30-positive cutaneous T-cell lymphoma than the standard tablets methotrexate or bexarotene."},{"id":"lymphoma-ev-randomised-evidence-for-the-t-cell-lymphomas","kind":"idea","name":"Randomised evidence for the T-cell lymphomas, including the ones that are not in Europe or North America","route":"/ideas/lymphoma-ev-randomised-evidence-for-the-t-cell-lymphomas/","tldr":"Adult T-cell leukaemia has had one randomised trial, in 1998. Most T-cell lymphoma treatment rests on single-arm studies, and the diseases concentrated outside Europe and North America have the least evidence of all."}],"trials":[{"id":"jcog9801","name":"JCOG9801","route":"/trials/jcog9801/","outcomes":[{"endpoint":"Complete response rate","primary":true,"unit":"%","arms":[{"name":"VCAP-AMP-VECP","value":40},{"name":"Biweekly CHOP","value":25}],"p":"0.020","source":"https://doi.org/10.1200/JCO.2007.11.9958"},{"endpoint":"Overall survival at 3 years","unit":"%","arms":[{"name":"VCAP-AMP-VECP","value":24},{"name":"Biweekly CHOP","value":13}],"p":"0.085 one-sided, 0.169 two-sided"}],"setting":"Untreated aggressive adult T-cell leukaemia/lymphoma: six courses of VCAP-AMP-VECP every four weeks against eight courses of CHOP every two weeks","enrolled":118,"enrolledNote":"The registry lists a target of 130; 118 patients were enrolled and analysed in the Journal of Clinical Oncology report.","enrolledBasis":"analysed"},{"id":"smile-enktl","name":"SMILE","route":"/trials/smile-enktl/","outcomes":[{"endpoint":"Overall response rate after two cycles","primary":true,"unit":"%","arms":[{"name":"SMILE","n":38,"value":79,"note":"90 per cent confidence interval 65 to 89"}],"source":"https://doi.org/10.1200/JCO.2011.35.6287"},{"endpoint":"Overall survival at 1 year","unit":"%","arms":[{"name":"SMILE","n":38,"value":55,"note":"95 per cent confidence interval 38 to 69"}]}],"setting":"Newly diagnosed stage IV, relapsed or refractory extranodal natural killer/T-cell lymphoma, nasal type: two cycles of dexamethasone, methotrexate, ifosfamide, asparaginase and etoposide","enrolled":38,"enrolledNote":"No ClinicalTrials.gov record was found for this study when the registry was searched on 1 October 2026; 38 eligible patients were enrolled and analysed in the Journal of Clinical Oncology report.","enrolledBasis":"analysed"},{"id":"echelon-2","name":"ECHELON-2","route":"/trials/echelon-2/","outcomes":[{"endpoint":"Progression-free survival (blinded independent central review)","primary":true,"unit":"months","arms":[{"name":"A+CHP (brentuximab vedotin, cyclophosphamide, doxorubicin, prednisone)","n":226,"value":48.2},{"name":"CHOP","n":226,"value":20.8}],"hr":0.71,"ci":[0.54,0.93],"p":"0.0110","source":"https://doi.org/10.1016/s0140-6736(18)32984-2"},{"endpoint":"Febrile neutropenia","unit":"%","arms":[{"name":"A+CHP (brentuximab vedotin, cyclophosphamide, doxorubicin, prednisone)","n":226,"value":18},{"name":"CHOP","n":226,"value":15}],"source":"https://doi.org/10.1016/s0140-6736(18)32984-2"},{"endpoint":"Peripheral neuropathy","unit":"%","arms":[{"name":"A+CHP (brentuximab vedotin, cyclophosphamide, doxorubicin, prednisone)","n":226,"value":52},{"name":"CHOP","n":226,"value":55}],"source":"https://doi.org/10.1016/s0140-6736(18)32984-2"}],"setting":"Untreated CD30-positive peripheral T-cell lymphoma: brentuximab vedotin with cyclophosphamide, doxorubicin and prednisone (A+CHP) against CHOP","enrolled":452,"enrolledBasis":"registry"},{"id":"alcanza","name":"ALCANZA","route":"/trials/alcanza/","outcomes":[{"endpoint":"Objective global response lasting at least 4 months (independent review)","primary":true,"unit":"%","arms":[{"name":"Brentuximab vedotin","n":64,"value":56.3,"note":"Median follow-up 22.9 months"},{"name":"Physician's choice (methotrexate or bexarotene)","n":64,"value":12.5}],"p":"<0.0001","source":"https://doi.org/10.1016/S0140-6736(17)31266-7"},{"endpoint":"Grade 3-4 adverse events","unit":"%","arms":[{"name":"Brentuximab vedotin","n":66,"value":41},{"name":"Physician's choice (methotrexate or bexarotene)","n":62,"value":47}],"source":"https://doi.org/10.1016/S0140-6736(17)31266-7"}],"setting":"Previously treated CD30-positive cutaneous T-cell lymphoma (mycosis fungoides or primary cutaneous anaplastic large cell lymphoma): brentuximab vedotin against physician's choice of methotrexate or bexarotene","enrolled":131,"enrolledBasis":"registry"}],"papers":[{"id":"paper-jcog9801-vcap-amp-vecp-adult-t-cell-leukaemia-jco-2007","name":"VCAP-AMP-VECP compared with biweekly CHOP for adult T-cell leukemia-lymphoma: Japan Clinical Oncology Group Study JCOG9801","route":"/key-papers/paper-jcog9801-vcap-amp-vecp-adult-t-cell-leukaemia-jco-2007/","journal":"Journal of Clinical Oncology","year":2007,"whatItMeans":"The Japanese standard regimen for aggressive adult T-cell leukaemia/lymphoma rests on this trial. Three-year overall survival of 24 per cent with the better arm is the plainest statement of how much room remains, and is why allogeneic transplantation, mogamulizumab and antiviral approaches have all been pursued since."},{"id":"paper-smile-chemotherapy-nk-t-cell-lymphoma-jco-2011","name":"Phase II study of SMILE chemotherapy for newly diagnosed stage IV, relapsed, or refractory extranodal natural killer (NK)/T-cell lymphoma, nasal type: the NK-Cell Tumor Study Group study","route":"/key-papers/paper-smile-chemotherapy-nk-t-cell-lymphoma-jco-2011/","journal":"Journal of Clinical Oncology","year":2011,"whatItMeans":"The regimen that made extranodal NK/T-cell lymphoma treatable. The usual explanation is that asparaginase is not a substrate of the P-glycoprotein pump this tumour expresses, which would explain why it works where anthracycline-based regimens do not; that mechanism is widely repeated but has been contradicted by at least one series."},{"id":"paper-horwitz-lancet","name":"Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial","route":"/key-papers/paper-horwitz-lancet/","journal":"The Lancet","year":2019,"whatItMeans":"One cancer page on OnCo cites this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing page listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand."},{"id":"paper-alcanza-brentuximab-vedotin-lancet-2017","name":"ALCANZA: brentuximab vedotin versus physician's choice in CD30-positive cutaneous T-cell lymphoma","route":"/key-papers/paper-alcanza-brentuximab-vedotin-lancet-2017/","journal":"The Lancet","year":2017,"whatItMeans":"Brentuximab vedotin is a standard for CD30-positive cutaneous T-cell lymphoma requiring systemic therapy, including large cell transformation."}]},{"era":"2026-2032","title":"What the registry says is coming","description":"The Hodgkin de-escalation question gets its best-designed attempt yet. RADAR (NCT04685616, 1,042 estimated participants; recruiting) randomises ABVD against A2VD, which replaces the bleomycin with brentuximab vedotin, and omits radiotherapy entirely in anyone with a Deauville score of 1 to 3 after two cycles; primary completion is listed for September 2030.\n\nThe oldest patients with diffuse large B-cell lymphoma finally get their own trials. POLAR BEAR (NCT04332822, 300 estimated participants; recruiting) tests polatuzumab vedotin in place of vincristine in R-miniCHOP in people aged 80 or over, or 75 or over and frail by a geriatric assessment, with a primary completion date of 28 December 2025 that has now passed. ARCHED (NCT05820841, 330 estimated participants; recruiting) adds acalabrutinib to R-miniCHOP, with primary completion listed for February 2029.\n\nThe bispecific antibodies move to the front. A National Cancer Institute trial (NCT06337318, 600 estimated participants; recruiting) compares mosunetuzumab with rituximab as first treatment for low tumour burden follicular lymphoma, with primary completion listed for 31 March 2032, and a European trial (NCT06006117, 260 estimated participants; recruiting) runs mosunetuzumab with lenalidomide against the investigator's choice in relapsed marginal zone lymphoma, primary completion September 2027. In primary central nervous system lymphoma, PRIMA-CNS (NCT06830421, 340 estimated participants; recruiting) compares conventional immunochemotherapy with a short induction and an autologous transplant in elderly patients, primary completion 31 August 2029. FORTplus (NCT05045664, 100 estimated participants; recruiting) tests whether an anti-CD20 antibody makes a 4 Gy radiotherapy dose safe in early follicular lymphoma, primary completion 30 September 2027.","status":"emerging","refs":[{"id":"radar-hodgkin","kind":"trial","name":"RADAR","route":"/trials/radar-hodgkin/","status":"active","tldr":"An international trial asking whether swapping one old chemotherapy drug for a targeted antibody lets most people with early Hodgkin lymphoma avoid radiotherapy altogether."},{"id":"polar-bear","kind":"trial","name":"POLAR BEAR","route":"/trials/polar-bear/","status":"active","tldr":"A Nordic trial asking whether the antibody-drug conjugate that improved first-line treatment for younger patients also helps people in their eighties, who were barely represented in the original trial."},{"id":"arched","kind":"trial","name":"ARCHED","route":"/trials/arched/","status":"active","tldr":"A German trial adding a targeted tablet to the reduced-dose chemotherapy used for older people with aggressive lymphoma, to see whether it delays relapse."},{"id":"mosun-lbt-fl","kind":"trial","name":"Mosunetuzumab against rituximab in low tumour burden follicular lymphoma","route":"/trials/mosun-lbt-fl/","status":"active","tldr":"A large American trial testing whether a two-headed antibody that recruits the immune system should replace the standard antibody as the first treatment for slow-growing follicular lymphoma."},{"id":"mosun-len-mzl","kind":"trial","name":"Mosunetuzumab with lenalidomide in relapsed marginal zone lymphoma","route":"/trials/mosun-len-mzl/","status":"active","tldr":"A European trial for a lymphoma that rarely gets its own study, testing a two-headed antibody with a tablet against the three combinations doctors currently choose between."},{"id":"prima-cns","kind":"trial","name":"PRIMA-CNS","route":"/trials/prima-cns/","status":"active","tldr":"The first randomised trial asking whether older people with lymphoma of the brain do better with a short intensive course and a stem cell transplant than with the gentler long regimen that is standard in Germany."},{"id":"fortplus","kind":"trial","name":"FORTplus","route":"/trials/fortplus/","status":"active","tldr":"A trial testing whether a radiotherapy dose one sixth of the standard works as well for early follicular lymphoma when an antibody is given alongside it."},{"id":"lymphoma-ev-radiotherapy-free-early-hodgkin","kind":"idea","name":"A radiotherapy-free cure for early Hodgkin lymphoma that actually holds","route":"/ideas/lymphoma-ev-radiotherapy-free-early-hodgkin/","tldr":"Every attempt to drop radiotherapy from early Hodgkin lymphoma on the strength of a clear scan has cost people their remission. Changing the chemotherapy as well is the next attempt."},{"id":"lymphoma-ev-fixed-duration-chemotherapy-free-first-line","kind":"idea","name":"Fixed-duration, chemotherapy-free first-line treatment for the indolent lymphomas","route":"/ideas/lymphoma-ev-fixed-duration-chemotherapy-free-first-line/","tldr":"Several treatments now work without chemotherapy, but most are given until the disease comes back. Giving them for a fixed time and stopping is the version patients would choose."}],"trials":[],"papers":[]},{"era":"What sets the pace","title":"Four things no trial on this page has fixed","description":"First, the genetics have not reached the clinic. Three classifications and a probabilistic tool exist, and not one first-line treatment decision anywhere is made by genetic subtype outside a trial. The gap between Schmitz in 2018 and a trial that assigns treatment by LymphGen is the clearest unfinished business in the disease.\n\nSecond, nothing acts on a blood test. Circulating tumour DNA predicts outcome at diagnosis, detects residual disease better than imaging, reads cell of origin from plasma and flags transformation before it declares itself, and no randomised trial has yet shown that changing treatment on the strength of it helps anyone.\n\nThird, the T-cell lymphomas have almost no randomised evidence, and the diseases concentrated in east Asia, the Caribbean, west Africa and Latin America have least of all. Adult T-cell leukaemia/lymphoma has had exactly one controlled trial, in 1998.\n\nFourth, access. Rituximab transformed B-cell lymphoma in 1997 and is still unavailable or unaffordable in much of the world; asparaginase, which makes NK/T-cell lymphoma treatable, is intermittently supplied; CAR-T requires an apheresis service, a cryopreservation chain and a centre able to manage cytokine release syndrome. The treatments on this page cure a higher proportion of people with lymphoma than of any other common cancer, in the places that have them.","status":"current","refs":[{"id":"paper-wright-lymphgen-genetic-subtypes-dlbcl-cancer-cell-2020","kind":"paper","name":"A probabilistic classification tool for genetic subtypes of diffuse large B cell lymphoma with therapeutic implications","route":"/key-papers/paper-wright-lymphgen-genetic-subtypes-dlbcl-cancer-cell-2020/","tldr":"A tool that takes one patient's tumour genetics and gives the probability that it belongs to each of seven genetic groups, rather than sorting whole cohorts into clusters."},{"id":"paper-scherer-ctdna-lymphoma-subtypes-genome-evolution-sci-transl-med-2016","kind":"paper","name":"Distinct biological subtypes and patterns of genome evolution in lymphoma revealed by circulating tumour DNA","route":"/key-papers/paper-scherer-ctdna-lymphoma-subtypes-genome-evolution-sci-transl-med-2016/","tldr":"A blood test read the genetic type of a lymphoma without a biopsy, detected disease left behind better than scans did, and spotted the change from a slow lymphoma into an aggressive one before it showed."},{"id":"paper-jcog9801-vcap-amp-vecp-adult-t-cell-leukaemia-jco-2007","kind":"paper","name":"VCAP-AMP-VECP compared with biweekly CHOP for adult T-cell leukemia-lymphoma: Japan Clinical Oncology Group Study JCOG9801","route":"/key-papers/paper-jcog9801-vcap-amp-vecp-adult-t-cell-leukaemia-jco-2007/","tldr":"The only randomised trial run exclusively in the virus-driven adult T-cell leukaemia found an intensive Japanese regimen produced more complete remissions than standard chemotherapy, at considerable cost in toxicity."},{"id":"b-global-access","kind":"bottleneck","name":"Most of the world has almost no cancer care","route":"/bottlenecks/b-global-access/","tldr":"Seven in ten cancer deaths happen in low- and middle-income countries, where radiotherapy, pathology, surgery and drugs are scarce."},{"id":"b-rare-cancers","kind":"bottleneck","name":"Rare and paediatric cancers without markets","route":"/bottlenecks/b-rare-cancers/","tldr":"Taken together rare cancers are a fifth of all cancers, but each one alone is too small for a company to invest in."},{"id":"b-biomarker-validation","kind":"bottleneck","name":"Biomarkers are not validated or standardised","route":"/bottlenecks/b-biomarker-validation/","tldr":"Tests that decide who gets a drug are often not validated prospectively and are measured differently in every lab."},{"id":"lymphoma-ev-genetic-subtype-directed-first-line","kind":"idea","name":"Assign first-line treatment in diffuse large B-cell lymphoma by genetic subtype, not by a three-antibody stain","route":"/ideas/lymphoma-ev-genetic-subtype-directed-first-line/","tldr":"Three genetic classifications of the commonest aggressive lymphoma exist and none of them yet decides anyone's treatment. The trial that would change that has not been run."},{"id":"lymphoma-ev-ctdna-instead-of-the-interim-scan","kind":"idea","name":"Use circulating tumour DNA instead of the interim scan to decide what happens next","route":"/ideas/lymphoma-ev-ctdna-instead-of-the-interim-scan/","tldr":"A blood test detects lymphoma left behind better than a scan does, and no trial has yet used it to change anyone's treatment."},{"id":"lymphoma-ev-randomised-evidence-for-the-t-cell-lymphomas","kind":"idea","name":"Randomised evidence for the T-cell lymphomas, including the ones that are not in Europe or North America","route":"/ideas/lymphoma-ev-randomised-evidence-for-the-t-cell-lymphomas/","tldr":"Adult T-cell leukaemia has had one randomised trial, in 1998. Most T-cell lymphoma treatment rests on single-arm studies, and the diseases concentrated outside Europe and North America have the least evidence of all."},{"id":"lymphoma-ev-the-drugs-that-cure-and-the-places-without-them","kind":"idea","name":"The drugs that cure lymphoma, and the places that do not have them","route":"/ideas/lymphoma-ev-the-drugs-that-cure-and-the-places-without-them/","tldr":"Lymphoma is among the most curable common cancers where the drugs exist. Rituximab is thirty years old and still out of reach for many of the people who need it."}],"trials":[],"papers":[{"id":"paper-wright-lymphgen-genetic-subtypes-dlbcl-cancer-cell-2020","name":"A probabilistic classification tool for genetic subtypes of diffuse large B cell lymphoma with therapeutic implications","route":"/key-papers/paper-wright-lymphgen-genetic-subtypes-dlbcl-cancer-cell-2020/","journal":"Cancer Cell","year":2020,"whatItMeans":"The piece that turns a research classification into something a trial can use on one person's biopsy, with a probability attached rather than a flat label. It is the reason genetics-directed lymphoma trials became possible at all."},{"id":"paper-scherer-ctdna-lymphoma-subtypes-genome-evolution-sci-transl-med-2016","name":"Distinct biological subtypes and patterns of genome evolution in lymphoma revealed by circulating tumour DNA","route":"/key-papers/paper-scherer-ctdna-lymphoma-subtypes-genome-evolution-sci-transl-med-2016/","journal":"Science Translational Medicine","year":2016,"whatItMeans":"The paper that established lymphoma as the solid-tumour field where circulating tumour DNA works best, because the mutations are many and the tumour sheds. It underpins the response-adapted trial designs now being built on molecular rather than radiographic response."},{"id":"paper-jcog9801-vcap-amp-vecp-adult-t-cell-leukaemia-jco-2007","name":"VCAP-AMP-VECP compared with biweekly CHOP for adult T-cell leukemia-lymphoma: Japan Clinical Oncology Group Study JCOG9801","route":"/key-papers/paper-jcog9801-vcap-amp-vecp-adult-t-cell-leukaemia-jco-2007/","journal":"Journal of Clinical Oncology","year":2007,"whatItMeans":"The Japanese standard regimen for aggressive adult T-cell leukaemia/lymphoma rests on this trial. Three-year overall survival of 24 per cent with the better arm is the plainest statement of how much room remains, and is why allogeneic transplantation, mogamulizumab and antiviral approaches have all been pursued since."}]}],"watch":[{"item":"POLAR BEAR primary completion: polatuzumab vedotin in place of vincristine in R-miniCHOP for patients aged 80 or over, or 75 or over and frail (300 estimated participants; recruiting). The registry date has passed and no report has appeared","expected":"2025-12-28","source":"https://clinicaltrials.gov/study/NCT04332822","refs":[{"id":"polar-bear","kind":"trial","name":"POLAR BEAR","route":"/trials/polar-bear/","status":"active","tldr":"A Nordic trial asking whether the antibody-drug conjugate that improved first-line treatment for younger patients also helps people in their eighties, who were barely represented in the original trial."},{"id":"polatuzumab-vedotin","kind":"drug","name":"Polatuzumab vedotin","route":"/drugs/polatuzumab-vedotin/","status":"approved","tldr":"Polatuzumab vedotin is an ADC against CD79b that, swapped into the classic R-CHOP regimen, became the first improvement on frontline lymphoma therapy in twenty years."}]},{"item":"Mosunetuzumab with lenalidomide against the investigator's choice in relapsed or refractory marginal zone lymphoma, primary completion (260 estimated participants; recruiting)","expected":"2027-09","source":"https://clinicaltrials.gov/study/NCT06006117","refs":[{"id":"mosun-len-mzl","kind":"trial","name":"Mosunetuzumab with lenalidomide in relapsed marginal zone lymphoma","route":"/trials/mosun-len-mzl/","status":"active","tldr":"A European trial for a lymphoma that rarely gets its own study, testing a two-headed antibody with a tablet against the three combinations doctors currently choose between."},{"id":"mosunetuzumab","kind":"drug","name":"Mosunetuzumab","route":"/drugs/mosunetuzumab/","status":"approved","tldr":"Mosunetuzumab is a fixed-duration CD20 bispecific approved for follicular lymphoma and studied with polatuzumab in large B-cell lymphoma."}]},{"item":"FORTplus primary completion: 4 Gy radiotherapy with an anti-CD20 antibody against standard-dose radiotherapy with rituximab in early-stage follicular lymphoma (100 estimated participants; recruiting)","expected":"2027-09-30","source":"https://clinicaltrials.gov/study/NCT05045664","refs":[{"id":"fortplus","kind":"trial","name":"FORTplus","route":"/trials/fortplus/","status":"active","tldr":"A trial testing whether a radiotherapy dose one sixth of the standard works as well for early follicular lymphoma when an antibody is given alongside it."},{"id":"obinutuzumab","kind":"drug","name":"Obinutuzumab","route":"/drugs/obinutuzumab/","status":"approved","tldr":"Obinutuzumab is a glycoengineered CD20 antibody that recruits immune cells and kills B cells more directly than rituximab. Paired with venetoclax for a fixed 12 months in chronic lymphocytic leukaemia, it keeps over half of patients treatment-free six years later, and it is also used in follicular lymphoma; first-dose infusion reactions are common and managed by splitting the dose."}]},{"item":"ARCHED primary completion: acalabrutinib added to R-miniCHOP in older adults with untreated diffuse large B-cell lymphoma (330 estimated participants; recruiting)","expected":"2029-02","source":"https://clinicaltrials.gov/study/NCT05820841","refs":[{"id":"arched","kind":"trial","name":"ARCHED","route":"/trials/arched/","status":"active","tldr":"A German trial adding a targeted tablet to the reduced-dose chemotherapy used for older people with aggressive lymphoma, to see whether it delays relapse."},{"id":"acalabrutinib","kind":"drug","name":"Acalabrutinib","route":"/drugs/acalabrutinib/","status":"approved","tldr":"Acalabrutinib is a cleaner BTK blocker with fewer heart and bleeding problems than ibrutinib. In February 2026 it became half of the first all-oral, fixed-duration CLL regimen."}]},{"item":"PRIMA-CNS primary completion: conventional immunochemotherapy against short induction with autologous transplant in elderly primary central nervous system lymphoma (340 estimated participants; recruiting)","expected":"2029-08-31","source":"https://clinicaltrials.gov/study/NCT06830421","refs":[{"id":"prima-cns","kind":"trial","name":"PRIMA-CNS","route":"/trials/prima-cns/","status":"active","tldr":"The first randomised trial asking whether older people with lymphoma of the brain do better with a short intensive course and a stem cell transplant than with the gentler long regimen that is standard in Germany."}]},{"item":"RADAR primary completion: brentuximab vedotin in place of bleomycin, with radiotherapy omitted entirely after a Deauville score of 1 to 3 in early-stage Hodgkin lymphoma (1,042 estimated participants; recruiting)","expected":"2030-09","source":"https://clinicaltrials.gov/study/NCT04685616","refs":[{"id":"radar-hodgkin","kind":"trial","name":"RADAR","route":"/trials/radar-hodgkin/","status":"active","tldr":"An international trial asking whether swapping one old chemotherapy drug for a targeted antibody lets most people with early Hodgkin lymphoma avoid radiotherapy altogether."},{"id":"brentuximab-vedotin","kind":"drug","name":"Brentuximab vedotin","route":"/drugs/brentuximab-vedotin/","status":"approved","tldr":"The ADC that made the modern field credible (2011), for Hodgkin lymphoma and CD30+ lymphomas."}]},{"item":"Mosunetuzumab against rituximab as first treatment for low tumour burden follicular lymphoma, primary completion (600 estimated participants; recruiting)","expected":"2032-03-31","source":"https://clinicaltrials.gov/study/NCT06337318","refs":[{"id":"mosun-lbt-fl","kind":"trial","name":"Mosunetuzumab against rituximab in low tumour burden follicular lymphoma","route":"/trials/mosun-lbt-fl/","status":"active","tldr":"A large American trial testing whether a two-headed antibody that recruits the immune system should replace the standard antibody as the first treatment for slow-growing follicular lymphoma."},{"id":"mosunetuzumab","kind":"drug","name":"Mosunetuzumab","route":"/drugs/mosunetuzumab/","status":"approved","tldr":"Mosunetuzumab is a fixed-duration CD20 bispecific approved for follicular lymphoma and studied with polatuzumab in large B-cell lymphoma."}]}]}