Aggressive non-Hodgkin lymphoma

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Aggressive NHL comprises clinically and biologically distinct mature B- and T-cell cancers. DLBCL may present with a rapidly enlarging node, extranodal mass, B symptoms or organ failure. Burkitt lymphoma can double in roughly a day and commonly involves abdomen, marrow or CNS. Peripheral T-cell lymphomas often cause systemic inflammation, skin, marrow or extranodal disease. Record tempo, immune suppression, HIV, travel and infection, and examine all nodes, spleen, skin, Waldeyer ring, testes and neurological system. Stabilise compression and lysis without sacrificing diagnostic tissue.

Excision biopsy is preferred. A large core is acceptable when surgery is unsafe or a deep mass is accessible radiologically, but repeat with excision if classification remains uncertain. Communicate the differential so fresh tissue reaches flow and microbiology and fixed tissue supports architecture, immunohistochemistry and FISH. DLBCL requires cell lineage, CD20, proliferation, EBV and protein expression assessment. MYC rearrangement testing is recommended in newly presenting high-grade B-cell disease, with BCL2 and BCL6 testing if MYC is rearranged. Double expression by immunohistochemistry is not the same as double-hit genetics.

Stage FDG-avid lymphoma with PET-CT and obtain FBC, film, renal, liver, bone, LDH, urate, phosphate, calcium, immunoglobulins, HIV, hepatitis B and C and pregnancy testing. Echocardiography precedes anthracycline. Bone marrow biopsy is selective when PET or cytopenia leaves a discordant question. Calculate IPI from age, stage, LDH, performance and extranodal sites. Assess CNS symptoms and risk sites; use MRI, CSF flow or cytology only when safe and clinically indicated. Testicular ultrasound or organ-specific imaging follows examination.

R-CHOP-21 combines rituximab 375 mg/m² IV, cyclophosphamide 750 mg/m² IV, doxorubicin 50 mg/m² IV and vincristine 1.4 mg/m² IV capped at 2 mg on day 1, with prednisolone 100 mg orally days 1–5, repeated every 21 days. Cycle number and radiotherapy depend on stage, bulk and response. For untreated DLBCL with IPI 2–5, NICE recommends polatuzumab vedotin 1.8 mg/kg with R-CHP; vincristine is omitted because both drugs cause neuropathy. Use exact protocol and antimicrobial, lysis and G-CSF support.

Selected entities depart from these backbones. Burkitt needs immediate dose-intensive systemic and intrathecal therapy with rituximab in a specialist centre. Primary mediastinal large B-cell lymphoma uses a specific chemoimmunotherapy and radiotherapy strategy. High-grade B-cell lymphoma with MYC and BCL2 rearrangements requires expert risk-led regimen selection; evidence does not support automatically calling every MYC-positive tumour double hit. Peripheral T-cell lymphoma often uses CHOP-like therapy, with brentuximab-containing treatment in eligible CD30-positive systemic anaplastic large-cell lymphoma. Histology must precede regimen.

CNS prophylaxis is controversial because systemic relapse risk, CNS risk and high-dose methotrexate toxicity interact. Assess CNS-IPI plus kidney or adrenal, testicular, breast, intravascular and other high-risk biology. Intrathecal therapy protects mainly the leptomeninges; systemic high-dose methotrexate penetrates brain but can delay curative systemic cycles and cause renal injury. Agree route, dose and timing through the lymphoma MDT and do not compromise on-time systemic immunochemotherapy without a clear benefit rationale.

Assess response clinically and with end-of-treatment PET at the appropriate interval. Routine interim PET should not drive unscheduled escalation outside a validated protocol. Deauville 1–3 usually represents complete metabolic response. Persistent focal score 4–5 needs review and often biopsy. For chemosensitive relapse after a longer remission, salvage immunochemotherapy followed by high-dose therapy and autologous transplant remains important. Primary refractory or early relapsed large B-cell disease can be eligible for commissioned CAR-T; later-line polatuzumab, bispecific antibodies or antibody–drug conjugates follow NICE and antigen context.

Supportive care includes lysis prevention, Pneumocystis and antiviral prophylaxis when regimen indicated, hepatitis B reactivation prevention with anti-CD20 treatment, G-CSF according to febrile-neutropenia risk and fertility preservation. Rituximab can cause infusion reactions and late hypogammaglobulinaemia. Anthracycline cumulative dose, vincristine neuropathy and cyclophosphamide bladder and gonadal toxicity require monitoring. Fever after treatment receives immediate neutropenic-sepsis care rather than waiting for clinic.

Key points

Aggressive NHL is an umbrella: diffuse large B-cell lymphoma is common, but Burkitt, high-grade B-cell, primary mediastinal and peripheral T-cell lymphomas need different protocols.
First-line diagnostic procedure is excision biopsy; if unsafe, obtain multiple large cores and preserve tissue for morphology, flow, immunohistochemistry, FISH and molecular tests.
In newly presenting high-grade B-cell lymphoma, test MYC rearrangement; if present, add BCL2 and BCL6 FISH and identify the MYC partner as recommended by NICE.
Baseline FDG PET-CT is the preferred staging study for FDG-avid aggressive lymphoma; record largest mass, extranodal sites, IPI and potential CNS risk.
Start tumour-lysis prophylaxis before systemic therapy when burden or LDH is high; rasburicase is contraindicated in G6PD deficiency.
R-CHOP-21 remains a curative standard for many DLBCL groups; NICE recommends polatuzumab vedotin with R-CHP for untreated adult DLBCL with IPI 2–5.
Burkitt lymphoma requires an immediate dose-intensive, CNS-active specialist regimen and cannot be treated as ordinary DLBCL.
Do not give routine CNS prophylaxis from one risk factor: assess CNS-IPI, kidney or adrenal, testis, breast and other high-risk sites and discuss evidence and toxicity in MDT.
Use end-of-treatment PET with Deauville scoring; biopsy residual avidity when feasible because inflammation and necrosis can mimic refractory lymphoma.
Primary refractory or relapse within 12 months increasingly follows a CAR-T pathway; later chemosensitive relapse may proceed through salvage and autologous transplant.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Acquired lymphoid genetics

Somatic rearrangements and mutations in mature B or T cells dysregulate proliferation, apoptosis, antigen signalling and epigenetic control, creating distinct aggressive entities.

Immune and viral drivers

HIV, post-transplant immunosuppression, EBV, HTLV-1 and chronic immune stimulation contribute to selected subtypes and alter infection and treatment planning.

Transformation

Indolent follicular, marginal-zone or other lymphoma can acquire additional lesions and transform into aggressive large-cell disease with rapid focal growth.

Therapy-related context

Previous cytotoxic therapy and immune treatment can precede secondary lymphoid neoplasms, but most DLBCL arises de novo without a preventable exposure.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Rapid clonal expansion
High proliferative fractions produce fast-growing nodal or extranodal masses, constitutional inflammation and a strong response to correctly selected cytotoxic treatment.
2
Oncogenic rearrangements
MYC with BCL2 and sometimes BCL6 rearrangements defines high-risk biology requiring FISH-based classification beyond morphology and immunohistochemical protein expression.
3
Extranodal tropism
Aggressive clones may involve gut, skin, testis, kidney, adrenal, marrow or CNS, producing organ-specific emergencies and relapse patterns.
4
Lysis and inflammatory toxicity
Large chemosensitive burden can break down spontaneously or after treatment, while antibodies and cellular therapies can trigger cytokine and neurological syndromes.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Rapid nodal growth

A firm enlarging node or mass over days to weeks, often with LDH rise and B symptoms, suggests aggressive rather than indolent biology.

Extranodal disease

Gastrointestinal pain, skin lesion, testicular swelling, renal or adrenal mass, neurological deficit or marrow failure may be the dominant presentation.

Lysis patternRed flag

Rising urate, phosphate, potassium, LDH and creatinine with falling calcium can precede treatment in a bulky highly proliferative lymphoma.

Compressive anatomyRed flag

Stridor, facial swelling, cord symptoms, obstruction or perforation requires simultaneous stabilisation and expedited tissue diagnosis.

Transformation pattern

One rapidly growing or unusually PET-avid site within known indolent lymphoma should be selected for biopsy rather than assuming uniform progression.

Red flags requiring action

A mass doubling over days, LDH rise, spontaneous lysis, cytopenias or extranodal organ failure suggests highly aggressive biology and needs same-day haemato-oncology review.
Orthopnoea, stridor, facial swelling, neurological deficit, bowel obstruction or renal obstruction requires emergency anatomical management before an ordinary outpatient biopsy pathway.
Fever, hypotension, hypoxia or confusion during or after immunochemotherapy is neutropenic sepsis until treated, even if the last neutrophil count was normal.
New confusion, cranial neuropathy, testicular disease, renal or adrenal involvement or high CNS-IPI raises CNS lymphoma risk and needs specialist staging rather than automatic prophylaxis.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
Reference standard: excision or adequate core biopsyFirst stepReference standard
Why
Establish architecture, lineage and exact aggressive lymphoma entity.
Interpretation and limitations
Integrate morphology, flow, immunohistochemistry, EBV and genetics; preserve tissue and repeat biopsy if necrosis or small cores cannot support classification.
02
MYC, BCL2 and BCL6 FISH
Why
Identify rearranged high-grade B-cell biology that changes prognosis and may alter regimen.
Interpretation and limitations
Test MYC in newly presenting high-grade B-cell lymphoma; if rearranged, add BCL2, BCL6 and MYC partner. Protein double expression is a separate finding.
03
First-line staging: FDG PET-CTFirst line
Why
Map nodal and extranodal burden and establish response baseline.
Interpretation and limitations
Record stage, largest mass and high-risk sites. Biopsy a discordantly intense lesion when transformation or a second process is possible.
04
Lysis and treatment baseline
Why
Prevent metabolic death and select safe immunochemotherapy.
Interpretation and limitations
Check FBC, renal, liver, calcium, phosphate, potassium, urate, LDH, coagulation, immunoglobulins, viral serology, pregnancy, ECG and echocardiogram.
05
Selective CNS assessment
Why
Diagnose symptomatic CNS disease and refine prophylaxis for high-risk patients.
Interpretation and limitations
Use MRI brain or spine and CSF flow plus cytology when safe; do not lumbar-puncture through raised pressure, coagulopathy or an unstable mass.
06
End-of-treatment PET
Why
Distinguish complete metabolic response from residual active disease.
Interpretation and limitations
Use Deauville scoring at the protocol interval; biopsy score 4–5 when feasible before high-dose salvage because infection and inflammation are avid.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Infection

Tuberculosis, EBV, HIV, fungal and bacterial disease can produce necrotic nodes, fever, splenomegaly and PET avidity; send tissue for microbiology as well as histology.

Metastatic carcinoma or melanoma

Rapid nodes and extranodal masses can be non-haematological cancer; broad immunohistochemistry and clinical imaging prevent an empiric lymphoma regimen.

Classical Hodgkin lymphoma

Large CD30-positive cells and mediastinal disease overlap, but architecture, PAX5, B-cell markers, EBV and background identify a different curative pathway.

Indolent lymphoma

Small-cell morphology and long tempo suggest indolent disease, but a discordantly fast or intensely avid site must be biopsied for transformation.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01Suspected aggressive lymphomaStabilise and secure adequate tissueFirst stepA rapidly progressive nodal or extranodal mass, lysis or organ compromise is present.

1Assess airway, vascular, cord, bowel, renal and CNS threat and begin lysis and sepsis management.
2Obtain excision or multiple large cores before steroids when possible, allocating tissue for flow, histology, genetics and microbiology.
3Stage with PET-CT, obtain organ and viral baseline and classify subtype, IPI and CNS risk in the lymphoma MDT.

02New DLBCLDeliver curative first-line immunochemotherapyFirst lineAlternativeIntegrated pathology confirms DLBCL without a subtype-specific alternative pathway.

1Review stage, IPI, cardiac reserve, neuropathy, lysis, hepatitis B and fertility before the first cycle.
2Use R-CHOP or NICE-supported polatuzumab-R-CHP for IPI 2–5 with exact cycle, G-CSF and antimicrobial protocol.
3EscalationComplete on-time systemic treatment, add selected radiotherapy and assess end PET rather than escalating from an unvalidated interim scan.

03Burkitt or special entityMove immediately to subtype protocolMorphology, phenotype or genetics identifies Burkitt, high-grade double-hit, mediastinal or T-cell lymphoma.

1EscalationEscalate lysis monitoring and protect CNS diagnostic material and fertility without delaying urgent therapy.
2Use the specialist entity-specific systemic and CNS-active regimen rather than default R-CHOP.
3Monitor response and organ toxicity through the named protocol and plan transplant or cellular therapy when biology indicates.

04Refractory or relapsed LBCLRe-biopsy and choose transplant or CAR-TPET and tissue confirm persistent disease or lymphoma returns after remission.

1Re-biopsy accessible disease, restage PET and CNS risk and review CD19, prior drugs, performance and organ function.
2Use early-relapse CAR-T or salvage immunochemotherapy according to timing, eligibility and current NICE commissioning.
3Consolidate chemosensitive later relapse with autologous transplant or select approved later-line antibody and bispecific treatment.

Key medicines and prescribing safety4 treatments · regimens, roles and cautions

Curative standard immunochemotherapy for many adults with DLBCL, with cycle number and radiotherapy determined by stage and protocol.

R-CHOP-21

Give rituximab 375 mg/m² IV, cyclophosphamide 750 mg/m² IV, doxorubicin 50 mg/m² IV and vincristine 1.4 mg/m² IV capped at 2 mg on day 1, plus prednisolone 100 mg orally daily on days 1–5, every 21 days.

Screen hepatitis B and provide antiviral prophylaxis when indicated; prevent rituximab reactions and lysis. Monitor neutropenic sepsis, cardiac function, neuropathy, ileus, gonadal toxicity and vesicant injury. Vincristine is fatal if given intrathecally and pregnancy must be prevented.

NICE-recommended first-line option for untreated adult DLBCL with IPI score 2–5.

Polatuzumab vedotin with R-CHP

Give polatuzumab vedotin 1.8 mg/kg IV every 21 days with protocol rituximab, cyclophosphamide, doxorubicin and prednisolone for six cycles; omit vincristine and follow the commissioned additional rituximab schedule.

Verify the complete protocol and G-CSF plan. Monitor peripheral neuropathy, cytopenias, infection, liver injury, infusion reaction and progressive multifocal leukoencephalopathy; review strong CYP3A interactions with the MMAE payload and prevent pregnancy.

Rapidly removes existing uric acid before and during treatment of a highly proliferative bulky lymphoma.

Rasburicase

Give 0.2 mg/kg IV once daily for up to 7 days for high-risk or established tumour lysis, individualising duration to burden, urate and response under the current BSH protocol.

Contraindicated in G6PD deficiency because of haemolysis and methaemoglobinaemia; test at-risk ancestry if urgency permits. Send post-dose urate samples on ice for immediate analysis.

Curative-intent strategy for selected relapsed aggressive B-cell lymphoma, particularly after a longer first remission.

Salvage with autologous transplant

Use the exact centre platinum-containing or other salvage immunochemotherapy for the protocol number of cycles, assess PET response, then give high-dose conditioning with autologous stem-cell rescue in eligible chemosensitive later relapse.

Consider early-relapse CAR-T instead. Adjust for renal, cardiac, marrow and hearing reserve, provide lysis, infection, transfusion and fertility support and avoid delaying referral until multiple ineffective regimens have been given.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Tumour lysis syndrome

Potassium, phosphate and urate release can cause arrhythmia, seizure and renal failure before or soon after immunochemotherapy.

Compression and perforation

Bulky nodal or gastrointestinal disease can obstruct airway, vessels, bowel, ureter or cord and can perforate during rapid treatment response.

CNS relapse

Selected anatomical sites and high clinical risk increase CNS recurrence, which has poor prognosis and requires deliberate staging and prophylaxis decisions.

Refractory or relapsed disease

Primary resistant or early relapsed lymphoma may need platinum-based salvage, autologous transplant, CAR-T or bispecific antibody treatment.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

During initial therapy monitor examination, FBC, renal, liver, lysis chemistry, infection, neuropathy and cardiac symptoms at every cycle and more frequently during high-risk lysis.
For anti-CD20 therapy track hepatitis B prophylaxis, infusion reactions, immunoglobulins and recurrent infection; avoid live vaccines during substantial B-cell depletion.
Preserve dose intensity in curative treatment where safely possible, using protocol G-CSF and toxicity modifications rather than unexamined repeated delays.
Use end-of-treatment PET at the correct interval, biopsy uncertain residual avidity and avoid routine surveillance PET after complete remission.
After transplant, CAR-T or bispecific therapy monitor infection, cytopenia, immunoglobulin failure, cytokine and neurological toxicity and revaccination through the cellular programme.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Umbrella is not regimen

Aggressive behaviour does not make every lymphoma DLBCL. Burkitt and T-cell entities can be curable only when the first protocol matches their biology.

Double expressor differs

MYC and BCL2 protein overexpression is not equivalent to rearrangement. FISH identifies the genetic category and prevents misleading shorthand.

Tissue before steroid

Steroids can rapidly destroy lymphoma architecture. Protect diagnostic material unless airway, cord or another organ emergency makes immediate cytoreduction unavoidable.

Systemic treatment comes first

CNS prophylaxis that delays curative immunochemotherapy can trade one theoretical risk for a proven systemic hazard; timing must be explicit and evidence led.

Relapse timing directs platform

Primary refractory or early relapsed LBCL behaves differently from a chemosensitive late relapse and increasingly moves directly toward CAR-T rather than automatic transplant salvage.

11Common pitfallsFrequent interpretation and management errors.

01
Do not begin R-CHOP from a fine-needle aspirate or an unreviewed label of high-grade lymphoma.
02
Do not call immunohistochemical MYC and BCL2 double expression a double-hit lymphoma without FISH.
03
Do not omit HIV and hepatitis B testing before rituximab-containing curative therapy.
04
Do not use ordinary R-CHOP for confirmed Burkitt lymphoma or assume every peripheral T-cell lymphoma follows a B-cell regimen.
05
Do not escalate from an inflammatory interim PET focus outside a validated protocol, and biopsy end-treatment residual avidity when feasible.
06
Do not give high-dose methotrexate prophylaxis without renal, interaction and systemic-cycle timing review.