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An aggressive B-cell lymphoma defined not by how it looks but by two genetic faults in the same cell: a rearrangement of MYC, which drives growth, and one of BCL2, which blocks the cell from dying. It behaves worse than ordinary diffuse large B-cell lymphoma, so finding the rearrangements changes the treatment.
What it is. Two genes have to be broken for this diagnosis. MYC is a master switch for cell growth; BCL2 is the brake on programmed cell death. A cell that is told to grow and is also prevented from dying becomes a lymphoma that behaves worse than either fault alone would predict. The rearrangements are found by fluorescence in situ hybridisation, a test done on the biopsy, and they are the diagnosis. Nothing about the way the cells look under a microscope reliably identifies them, which is why every aggressive B-cell lymphoma is now tested.
How it differs from its family. It is a separate entity from diffuse large B-cell lymphoma, although it was carved out of it. WHO-HAEM5 named it diffuse large B-cell lymphoma / high-grade B-cell lymphoma with MYC and BCL2 rearrangements, so that a tumour made of large cells and one made of smaller blastoid cells can carry the same name once the genetics are known; the two books describe it as a homogeneous group with a germinal-centre gene expression profile and a close relationship to follicular lymphoma. Its gene expression overlaps that of Burkitt lymphoma, which is the other aggressive germinal-centre disease driven by MYC.
Where the two classifications disagree, and why it matters to a reader. Until 2022, cases with MYC and BCL6 rearrangements were counted in the same category. Both books removed them, because their gene expression and mutations are varied and differ from the MYC and BCL2 group. WHO-HAEM5 sends them back to diffuse large B-cell lymphoma or to high-grade B-cell lymphoma not otherwise specified, chosen on how the cells look. The International Consensus Classification created a new provisional entity for them instead, called high-grade B-cell lymphoma with MYC and BCL6 rearrangements. So a person with MYC and BCL6 rearrangements may be told they have a double-hit lymphoma by one pathologist and diffuse large B-cell lymphoma by another, and both are following a 2022 classification.
What the signature adds. The gene expression signature that characterises this entity can be present without the rearrangements. In the study that defined it, the signature was found in 27 per cent of germinal-centre diffuse large B-cell lymphomas, only half of which had the double rearrangement, and the people who carried the signature had worse outcomes after standard immunochemotherapy whether or not the rearrangements were there: a five-year time to progression of 57 per cent against 81 per cent. A commercial assay (the DLBCL90 NanoString panel) reproduced that result. The clinical implication is uncomfortable and honest: the test in daily use identifies some but not all of the biologically distinct group.
How it is treated. More intensively than diffuse large B-cell lymphoma, with prophylaxis against spread to the brain and spinal cord, which is more likely here. The regimens and the evidence for them, which is observational rather than randomised, are written on the diffuse large B-cell lymphoma page and in the treatment layer of this family.
No United Kingdom population figure exists under the name the 2022 classifications gave this entity, and the corpus does not invent one. What can be said is how often the genetics are found when they are looked for: in the gene-expression study that defined the double-hit signature, 25 of 157 germinal-centre diffuse large B-cell lymphomas carried rearrangements of both MYC and BCL2, and 27 per cent of the whole series carried the signature even though only half of those had the rearrangements. That cohort was assembled to contain the cases, so it is not a population frequency.
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: 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, Adult T-cell leukaemia/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
Every aggressive B-cell lymphoma biopsy is tested by fluorescence in situ hybridisation for MYC, and if MYC is rearranged, for BCL2 and BCL6. A lymphoma cannot be identified as double-hit by appearance, by immunohistochemistry for MYC and BCL2 protein, or by the cell-of-origin assay; dual protein expression is a separate and much commoner finding with its own, lesser, prognostic weight. Follicular lymphoma is excluded from the entity by both classifications even when it carries both rearrangements.
Treated more intensively than diffuse large B-cell lymphoma, and with prophylaxis against disease in the brain and spinal cord, which is more frequent here. There has never been a randomised trial confined to this entity: the intensified regimens in use were adopted from retrospective comparisons after the group was shown to do less well with standard immunochemotherapy. The regimens, the doses and the evidence behind each are on the diffuse large B-cell lymphoma page and in the treatment layer of this family.
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Query for this cancer: (TITLE:"High-grade B-cell lymphoma with MYC and BCL2 rearrangements" OR ABSTRACT:"High-grade B-cell lymphoma with MYC and BCL2 rearrangements" OR TITLE:"double-hit lymphoma" OR ABSTRACT:"double-hit lymphoma" OR TITLE:"Double-hit lymphoma" OR ABSTRACT:"Double-hit lymphoma" OR TITLE:"DHL" OR ABSTRACT:"DHL" OR TITLE:"HGBL-MYC/BCL2" OR ABSTRACT:"HGBL-MYC/BCL2" OR TITLE:"HGBCL-DH-BCL2" OR ABSTRACT:"HGBCL-DH-BCL2") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about High-grade B-cell lymphoma with MYC and BCL2 rearrangements (double-hit lymphoma), not a curated reading list.
The revised fourth edition of the WHO classification created high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements as a category of its own, which made testing for the rearrangements routine.
An analysis of 157 germinal-centre diffuse large B-cell lymphomas defined a 104-gene double-hit signature present in 27 per cent of them, only half of which carried the rearrangements; those with the signature had a five-year time to progression of 57 per cent against 81 per cent.
Both removed cases with MYC and BCL6 rearrangements from the double-hit entity. WHO-HAEM5 reassigns them by appearance; the International Consensus Classification made them a provisional entity of their own.
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Anyone who has ever had hepatitis B can have the virus wake up when rituximab strips out their B cells, sometimes months later and sometimes fatally. A blood test before the first dose, and a tablet for those who need it, prevents almost all of it.
A shortage of antibodies because treatment has wiped out the B cells or plasma cells that make them, as CD19 CAR-T, CD20 antibodies and BCMA therapies deliberately do. It leaves patients prone to infections, sometimes for years, and is managed with immunoglobulin infusions.
Treatments that remove B cells also remove the antibodies B cells make, and some people never make them again. When repeated chest and sinus infections follow, donated antibody given monthly by drip or weekly under the skin prevents them.
Reactions around the moment a drug is given: chills, fever or breathlessness from antibodies (infusion reactions), true allergy (hypersensitivity, rarely anaphylaxis), and leakage of a damaging drug into tissue around the vein (extravasation).
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