Double-Hit Lymphoma

Double hit lymphoma (high grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements) is an aggressive large B-cell lymphoma with rearrangement of the MYC oncogene and of BCL2 (or, less often, BCL6) detected by fluorescence in situ hybridisation. It has a high rate of relapse and central nervous system (CNS) involvement, and conventional immunochemotherapy gives inferior results, so treatment uses intensified regimens.

It accounts for 5% to 10% of diffuse large B-cell lymphoma, with an incidence of about 0.3 to 0.6 cases in 100,000 people each year. Median age at diagnosis is 60 to 65, with a slight male predominance. Triple hit lymphoma (MYC, BCL2 and BCL6) is rarer and carries a worse prognosis.

Cases may arise from transformation of follicular lymphoma (t(14;18)). Patients usually present with advanced stage, bulky extranodal disease, a raised LDH, and a high proliferation index.

Pathophysiology. MYC rearrangement (often to an immunoglobulin locus) drives proliferation, while BCL2 or BCL6 overexpression blocks apoptosis, producing rapidly growing, chemotherapy resistant disease. MYC rearrangement with an immunoglobulin partner has a worse prognosis than with a non-immunoglobulin partner.

Prognosis. With rituximab-CHOP, 2-year survival is about 50% to 60%. Dose adjusted EPOCH with rituximab improves outcomes for some patients, with 5-year survival of about 50% to 60% in selected series. CNS relapse occurs in 10% to 25%, and relapsed disease has a median survival of under 6 months.

• Rapidly enlarging nodal or extranodal mass, B symptoms (fever, night sweats, weight loss).
• Extranodal involvement: bone marrow, CNS, gastrointestinal tract, liver, kidneys, bone.
• Abdominal pain or distension, organ obstruction, spinal cord compression, superior vena cava syndrome.
• Tumour lysis syndrome (renal failure, hyperkalaemia, hyperphosphataemia, hypocalcaemia, hyperuricaemia), especially at the start of treatment.

Red flags.

• Neurological symptoms (CNS involvement) or cord compression.
• Airway or superior vena cava compression, tumour lysis, or markedly high LDH and urate.

• Excisional or core needle biopsy of the largest accessible lesion (fine needle aspiration is insufficient). Morphology: large cells, or intermediate sized cells with a starry sky pattern.
• Immunohistochemistry: CD20, CD10, BCL6, MUM1, MYC and BCL2 (double expression), Ki-67 (often over 80%), and CD5.
• FISH for MYC, BCL2 and BCL6 rearrangements in all patients with a large B-cell lymphoma, and cell of origin (germinal centre) classification.
• Staging with FDG-PET-CT, bone marrow biopsy, LDH, FBC, creatinine, urate, liver tests, hepatitis B and C, HIV serology, and echocardiography.
• CNS risk assessment: lumbar puncture with CSF cytology and flow cytometry, and MRI of the brain in high risk patients (raised LDH, multiple extranodal sites, kidney or adrenal involvement, testicular or breast disease).

Differential diagnosis.

• Diffuse large B-cell lymphoma not otherwise specified and Burkitt lymphoma
• B-lymphoblastic lymphoma and plasmablastic lymphoma
• Transformed follicular lymphoma and mantle cell lymphoma (blastoid)
• Poorly differentiated carcinoma and germ cell tumour

Treatment is intensified, planned by a lymphoma specialist, and starts with prevention of tumour lysis.

Before treatment. Hepatitis B screening with antiviral prophylaxis when positive, fertility counselling, and tumour lysis prophylaxis with hydration:

• Tumour lysis prophylaxis: rasburicase 0.2 mg/kg IV over 30 minutes once daily for 1 to 5 days, for high risk tumour lysis (high tumour burden, raised LDH or urate); maximum 7 days of treatment; monitoring: G6PD status before the first dose, urate (samples on ice), potassium, phosphate, calcium, creatinine, haemolysis, methaemoglobinaemia; adjustment: contraindicated in G6PD deficiency (use allopurinol 300 mg orally daily with hydration), hydrate with 3 L/m2 each day, no renal adjustment, stop when urate is controlled and risk has fallen

First line chemoimmunotherapy.

• Dose adjusted etoposide, doxorubicin, vincristine, cyclophosphamide and prednisolone with rituximab:
  • Chemotherapy: etoposide 50 mg/m2, doxorubicin 10 mg/m2 and vincristine 0.4 mg/m2 (no dose cap) each given daily as a continuous infusion over 96 hours on days 1 to 4, cyclophosphamide 750 mg/m2 IV on day 5 and prednisolone 60 mg/m2 orally daily on days 1 to 5, every 21 days for 6 cycles, with pegfilgrastim 6 mg subcutaneously 24 hours after the end of the infusion; maximum cyclophosphamide 1200 mg/m2 after escalation and cumulative doxorubicin 450 mg/m2; monitoring: FBC twice weekly (the nadir neutrophil and platelet counts decide the next dose), echocardiography at baseline, creatinine, liver tests, urate, neuropathy; adjustment: escalate etoposide, doxorubicin and cyclophosphamide by 20% when the nadir neutrophil count stays over 0.5 x 10^9/L, reduce by 20% when it falls under 0.5 x 10^9/L on 1 or more measurements or platelets fall under 25 x 10^9/L, reduce for bilirubin over 26 micromol/L, use central venous access
  • Rituximab: rituximab 375 mg/m2 IV on day 1 of each cycle, for 6 cycles alongside the chemotherapy; maximum 375 mg/m2 in each dose; monitoring: hepatitis B serology before the first dose, FBC, infusion reactions, tumour lysis, infection; adjustment: start the first infusion at 50 mg/h and increase by 50 mg/h every 30 minutes to a maximum of 400 mg/h, give antiviral prophylaxis for hepatitis B core antibody positivity, premedicate with paracetamol, an antihistamine and hydrocortisone 100 mg IV, omit when the tumour is CD20 negative
• Infection prophylaxis: co-trimoxazole 480 mg orally once daily (or 960 mg orally three times weekly), continued while prednisolone 20 mg daily or more is used for over 4 weeks, during immunosuppressive chemotherapy and until the lymphocyte count has recovered; maximum 960 mg daily; monitoring: FBC, potassium, creatinine, rash; adjustment: halve the dose when creatinine clearance is 15 to 30 mL/min and avoid under 15 mL/min, stop for rash or severe cytopenia and use atovaquone 1500 mg orally once daily with food or inhaled pentamidine 300 mg every 4 weeks, avoid with methotrexate

CNS prophylaxis (high risk patients).

• Intrathecal methotrexate: methotrexate 12 mg (preservative free) intrathecally on day 1 or 2 of each cycle for 4 to 6 doses, with leucovorin 10 mg orally every 6 hours for 8 doses starting 24 hours after each dose, for patients at high risk of CNS relapse; maximum 15 mg in one dose; monitoring: CSF cytology at baseline, FBC, creatinine, chemical arachnoiditis, headache, leukoencephalopathy; adjustment: reduce or stop for neurotoxicity, delay when platelets are under 50 x 10^9/L (bleeding risk at lumbar puncture), avoid when creatinine clearance is under 30 mL/min
• High dose systemic methotrexate is added in selected patients at a specialist centre.

Relapsed or refractory disease. Salvage platinum based chemotherapy followed by high dose therapy and autologous stem cell transplant in fit responding patients, and CAR T-cell therapy for relapsed disease:

• CAR T-cell therapy: axicabtagene ciloleucel 2 x 10^6 CAR T cells/kg IV once (maximum 2 x 10^8 cells), after lymphodepletion with fludarabine 30 mg/m2 IV and cyclophosphamide 500 mg/m2 IV daily on days -5, -4 and -3, for relapsed or refractory disease after 1 or more lines of therapy; maximum 2 x 10^8 cells in a single infusion; monitoring: cytokine release syndrome and neurotoxicity scoring at least daily for 7 days and close observation for 4 weeks, FBC, ferritin and CRP, immunoglobulins, infection; adjustment: treat cytokine release syndrome with tocilizumab 8 mg/kg IV (maximum 800 mg) and neurotoxicity with dexamethasone 10 mg IV, reduce fludarabine when creatinine clearance is under 70 mL/min, advise no driving for 8 weeks

Radiotherapy. Consolidation to bulky or residual disease, and palliative radiotherapy for symptomatic sites.

Monitoring. FBC, creatinine, LDH, urate and electrolytes twice weekly during chemotherapy, interim PET-CT after 2 to 4 cycles and end-of-treatment PET-CT, and clinical review every 3 months for 2 years, then every 6 months to year 5.

Referral and escalation.

• Urgent haematology referral (within days) for suspected aggressive lymphoma.
• Emergency admission for tumour lysis, airway compromise or neurological symptoms.

Special groups.

• Older adults and frail patients: reduced intensity chemoimmunotherapy and geriatric assessment.
• HIV infection: concurrent antiretroviral therapy and infection prophylaxis.
• Pregnancy: individualised treatment with the obstetric team.