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A T-cell lymphoma caused by a virus, HTLV-1, which is usually caught in infancy through breast milk and causes the lymphoma decades later in a small minority of the people it infects. It occurs in people from south-western Japan, the Caribbean, west and central Africa, parts of South America, Iran and Romania, and it comes in four forms that are treated very differently.
What it is. A cancer of mature CD4-positive T cells caused by human T-lymphotropic virus type 1, the first human retrovirus shown to cause a cancer. The virus is acquired mainly through breastfeeding in infancy, and also through sexual contact and transfusion of cellular blood products. It then sits in the T cells for decades. Only a small minority of the people it infects ever develop the lymphoma, and the latency is usually measured in decades, which is why this is a disease of middle and later life in people who were infected as babies.
The four forms, which are really four diseases. The subclassification proposed by Shimoyama and adopted by the international consensus meetings divides it into acute, lymphoma, chronic and smouldering types. The chronic and smouldering types without unfavourable features are indolent and are watched, in the same way an early chronic lymphocytic leukaemia is watched. The acute and lymphoma types are aggressive and are treated at once. Getting the type right is the first decision and it changes everything that follows.
How it differs from the rest of the T-cell family. Four things recur and none of them belongs to ordinary peripheral T-cell lymphoma. High calcium, often very high, caused by the tumour making parathyroid hormone-related protein; it was found in the blood cells of all 13 patients tested in the study that established the mechanism, and it can present as confusion, thirst and kidney failure before the lymphoma is recognised. Profound suppression of cell-mediated immunity, so that opportunistic infection, and particularly hyperinfection with the worm Strongyloides stercoralis, is a common cause of harm and is looked for before treatment. Involvement of the skin, which may be the only sign for a long time and which the 2019 consensus meeting singled out for a classification of its own. And involvement of the central nervous system, which is common in the aggressive types.
Who should be tested. HTLV-1 serology belongs in the work-up of any T-cell lymphoma or leukaemia in a person who comes from, or whose parents come from, an endemic region. Without the test, the disease is reported as peripheral T-cell lymphoma not otherwise specified and treated on a pathway that does not fit it.
What is known about treating it, honestly. The 2019 international consensus report states the position of the evidence in its own words: as a result of lower-quality clinical evidence, a best practice approach was adopted and the statements were agreed by more than 90 per cent of the authors. That is a consensus, not a trial result, and it applies to the choice of chemotherapy, to the use of antiviral therapy with zidovudine and interferon in the leukaemic types, and to the place of allogeneic stem cell transplant. The treatment rows on this page were moved here from the peripheral T-cell lymphoma page once this record existed.
Concentrated where the virus is. In the registry study that compared endemic and non-endemic areas, 2,055 patients were diagnosed in three prefectures of Kyushu in south-western Japan between 1993 and 2006 against 1,380 in twelve prefectures of Honshu, and 140 patients were recorded in the United States SEER registries between 1993 and 2008. Incidence rose significantly in the non-endemic areas over that period (an average annual change of plus 4.6 per cent in Honshu and plus 6.2 per cent in the United States) while remaining unchanged in endemic Kyushu, which the authors read as the virus travelling with its carriers. A systematic review of HTLV-1 among immigrants and refugees worldwide found a pooled prevalence of 1.28 per cent, rising to 7.27 per cent among people from the Western Pacific region.
Leukaemias, myeloma and MDS live in the marrow and blood; lymphomas grow in lymph nodes and spleen. The node stations are the disease map, not a route of spread, and staging counts them.
In lymphoma the node stations are the disease itself; staging (Ann Arbor / Lugano) counts how many regions and sides of the diaphragm are involved.
Same organ: High-grade B-cell lymphoma with MYC and BCL2 rearrangements (double-hit lymphoma), Mediastinal grey zone lymphoma, Primary effusion lymphoma, Plasmablastic lymphoma, T-cell/histiocyte-rich large B-cell lymphoma, EBV-positive diffuse large B-cell lymphoma, Primary large B-cell lymphoma of the testis, Gastric MALT lymphoma, Ocular adnexal MALT lymphoma, Extranodal NK/T-cell lymphoma, ALK-positive anaplastic large cell lymphoma, ALK-negative anaplastic large cell lymphoma, Breast implant-associated anaplastic large cell lymphoma, Primary cutaneous anaplastic large cell lymphoma, Lymphomatoid papulosis, Mycosis fungoides, Enteropathy-associated T-cell lymphoma, Monomorphic epitheliotropic intestinal T-cell lymphoma, Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), Splenic marginal zone lymphoma, Nodal marginal zone lymphoma, Primary cutaneous marginal zone lymphoma, Primary cutaneous follicle centre lymphoma, Sezary syndrome, Nodal T-follicular helper cell lymphoma, angioimmunoblastic type (angioimmunoblastic T-cell lymphoma), Hepatosplenic T-cell lymphoma, Intravascular large B-cell lymphoma, Lymphomatoid granulomatosis, T-cell prolymphocytic leukaemia, Splenic B-cell lymphoma/leukaemia with prominent nucleoli (formerly B-cell prolymphocytic leukaemia and hairy cell leukaemia variant), T-cell large granular lymphocytic leukaemia, Mixed-phenotype acute leukaemia, Myeloid leukaemia of Down syndrome, Burkitt leukaemia, Marginal zone lymphoma, Cutaneous T-cell lymphoma (mycosis fungoides and Sezary syndrome), Primary mediastinal (thymic) large B-cell lymphoma, Leukaemia (all types), Acute myeloid leukaemia, Acute lymphoblastic leukaemia, Chronic lymphocytic leukaemia, Chronic myeloid leukaemia (CML), Diffuse large B-cell lymphoma, Follicular lymphoma, Hodgkin lymphoma, Mantle cell lymphoma, Multiple myeloma, Non-Hodgkin lymphoma (all types), Myelodysplastic syndromes / neoplasms (MDS), Myeloproliferative neoplasms (PV, ET, myelofibrosis), Polycythaemia vera (PV), Essential thrombocythaemia (ET), Waldenström macroglobulinaemia, Hairy cell leukaemia, Peripheral T-cell lymphomas (including cutaneous T-cell lymphoma), Blastic plasmacytoid dendritic cell neoplasm (BPDCN), Burkitt lymphoma, HIV-associated (AIDS-related) lymphomas, Chronic myelomonocytic leukaemia and MDS/MPN overlap neoplasms, Systemic mastocytosis, Erdheim-Chester disease, Rosai-Dorfman disease and other histiocytic neoplasms, Langerhans cell histiocytosis (LCH), Post-transplant lymphoproliferative disorder (PTLD), FLT3-mutated acute myeloid leukaemia, IDH1- and IDH2-mutated acute myeloid leukaemia, NPM1-mutated and KMT2A-rearranged acute myeloid leukaemia, Secondary and therapy-related acute myeloid leukaemia, Acute promyelocytic leukaemia, Acute myeloid leukaemia in older or unfit patients, Smouldering multiple myeloma, Newly diagnosed multiple myeloma, transplant-eligible, Newly diagnosed multiple myeloma, transplant-ineligible, Relapsed or refractory multiple myeloma, Plasma cell leukaemia, Lower-risk myelodysplastic syndromes, Higher-risk myelodysplastic syndromes, Chronic lymphocytic leukaemia, first treatment, Relapsed or refractory chronic lymphocytic leukaemia, Richter transformation of chronic lymphocytic leukaemia, Chronic myeloid leukaemia, chronic phase, Chronic myeloid leukaemia, accelerated and blast phase, Primary myelofibrosis, Standard-risk B-cell acute lymphoblastic leukaemia in children, High-risk acute lymphoblastic leukaemia in children (high-risk B-ALL and T-ALL), Philadelphia chromosome-positive acute lymphoblastic leukaemia in children (Ph-positive ALL), Philadelphia chromosome-like acute lymphoblastic leukaemia (Ph-like or BCR::ABL1-like ALL), Infant acute lymphoblastic leukaemia (KMT2A-rearranged, under one year), Relapsed and refractory acute lymphoblastic leukaemia in children, Acute myeloid leukaemia in children, Erdheim-Chester disease, Rosai-Dorfman-Destombes disease, Single-system Langerhans cell histiocytosis (bone, skin or one other organ), Multisystem Langerhans cell histiocytosis (with or without risk-organ involvement), Indolent and smouldering systemic mastocytosis, Advanced systemic mastocytosis (aggressive SM, SM with an associated haematological neoplasm, mast cell leukaemia), Early-stage classical Hodgkin lymphoma (stage I to II), Advanced-stage classical Hodgkin lymphoma (stage III to IV), Nodular lymphocyte-predominant Hodgkin lymphoma (nodular lymphocyte-predominant B-cell lymphoma), Relapsed and refractory classical Hodgkin lymphoma
HTLV-1 serology belongs in the work-up of any T-cell lymphoma or leukaemia in a person who comes from, or whose parents come from, south-western Japan, the Caribbean, west or central Africa, parts of South America, Iran or Romania. Without the test the disease is reported as peripheral T-cell lymphoma not otherwise specified and treated on a pathway that does not fit it. A positive test is followed by confirmation that the virus is clonally integrated in the tumour cells, because asymptomatic infection is common in those populations and does not by itself mean lymphoma.
The subclassification proposed by Shimoyama and adopted by the international consensus meetings divides the disease into acute, lymphoma, chronic and smouldering types, using the count of circulating tumour cells, the lactate dehydrogenase, the calcium and the sites involved. It is the first decision and it changes everything: the chronic and smouldering types without unfavourable features are watched, while the acute and lymphoma types are treated at once. The consensus report sets out prognostic factors and a set of response criteria specific to this disease, which is why trials in it are not reported like trials in other lymphomas.
Three things that belong to this disease and not to the rest of the family. Calcium, which can be very high because the tumour makes parathyroid hormone-related protein, and which may present as confusion, thirst or kidney failure before the lymphoma is recognised. Strongyloides stercoralis, because the immune suppression caused by the virus allows hyperinfection, which is fatal and is prevented by screening and treating before immunosuppressive therapy. And the central nervous system, which is commonly involved in the aggressive types and is examined by lumbar puncture.
Caused by human T-lymphotropic virus type 1, acquired in infancy through breastfeeding and causing lymphoma after a latency of decades in a small percentage of those infected. It occurs in people from south-western Japan, the Caribbean, west and central Africa, parts of South America, Romania and Iran, and it is the reason HTLV-1 serology belongs in the work-up of any T-cell lymphoma in a person from those populations. Four clinical types, and they are treated differently. Smouldering and chronic types without unfavourable features are watched, or treated with zidovudine and interferon alfa, which produces long remissions in the leukaemic types; antiviral therapy does not work in the lymphoma type. Acute and lymphoma types are treated with intensive chemotherapy. JCOG9801 randomised 118 patients with aggressive disease to six courses of VCAP-AMP-VECP or eight courses of biweekly CHOP, both with G-CSF and intrathecal prophylaxis: the complete response rate was 40 against 25 per cent and three-year overall survival 24 against 13 per cent, with more toxicity in the intensive arm (grade 4 neutropenia 98 against 83 per cent, grade 3 or 4 infection 32 against 15 per cent). VCAP-AMP-VECP is standard in Japan; outside Japan, CHOP or CHOEP with early referral for allogeneic transplant is more usual. Allogeneic stem cell transplant is the only treatment that cures a minority, and it is offered early because remissions are short. Mogamulizumab, an anti-CCR4 antibody first approved in Japan in 2012, produces responses in relapsed aggressive disease: in the updated phase 2 analysis of 26 relapsed patients, median progression-free survival was 5.2 months and median overall survival 14.4 months, and outcomes were better in patients who developed a rash of grade 2 or more, a signal that is being read as an immune effect rather than a side effect alone. Central nervous system involvement is common and intrathecal prophylaxis is given.
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Query for this cancer: (TITLE:"Adult T-cell leukaemia/lymphoma" OR ABSTRACT:"Adult T-cell leukaemia/lymphoma" OR TITLE:"ATLL" OR ABSTRACT:"ATLL" OR TITLE:"ATL" OR ABSTRACT:"ATL" OR TITLE:"Adult T-cell leukemia/lymphoma" OR ABSTRACT:"Adult T-cell leukemia/lymphoma" OR TITLE:"Adult T-cell leukaemia" OR ABSTRACT:"Adult T-cell leukaemia" OR TITLE:"HTLV-1-associated lymphoma" OR ABSTRACT:"HTLV-1-associated lymphoma") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about Adult T-cell leukaemia/lymphoma, not a curated reading list.
A cluster of T-cell leukaemias in Kyushu was recognised as a single disease, which led to the search for its cause.
Parathyroid hormone-related protein was found to be abundantly expressed in the blood cells of all 13 patients tested, and in HTLV-1 carriers without symptoms, and the viral Tax protein was shown to switch its gene on.
The consensus meeting set out the acute, lymphoma, chronic and smouldering types, the prognostic factors and a set of response criteria specific to the disease, which became the standard reference for trials.
The revised report added the classification of cutaneous disease, disease in the central nervous system, the management of older and transplant-ineligible patients, upfront allogeneic transplant and newer agents, and stated that a best practice approach was adopted because the clinical evidence was of lower quality.
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Bleeding that does not stop by itself, bleeding from more than one site, or new bruising in several places or one large area.
Cumulative dose: risk rises steeply above 400-550 mg/m² (see the anthracycline calculator).
Fatal if given intrathecally: label all syringes.
Dose by Calvert formula using GFR (see the calculators).
Reduce to 75% for CrCl 15-50.
Reduce by 50% for bilirubin 20-50 µmol/L and 75% for 50-85 µmol/L.
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