B-Cell Non-Hodgkin Lymphoma (NHL)

Introduction:

NHL is categorized into two groups of B-cell lymphomas and T/NK-Cell lymphomas:

• B-cell lymphomas (85–90%):

  • Aggressive:

    • Diffuse large B-cell lymphoma (DLBCL)

    • High-grade B-cell lymphoma (HGBL)

      • Includes selected lymphomas with MYC and BCL2 rearrangements

      • Historically referred to as “double-hit” lymphoma when MYC and BCL2 rearrangements are present

    • Burkitt lymphoma (BL):

      • Highly aggressive

      • Derived from germinal center B cells

    • Mantle cell lymphoma (MCL):

      • Generally clinically aggressive, although behavior can be heterogeneous

      • Derived from mantle-zone B cells

  • Indolent:

    • Follicular lymphoma (FL):

      • Derived from germinal center B cells

    • Marginal zone lymphoma (MZL):

      • Subtypes: Extranodal, Nodal, Splenic

    • Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL)

    • Lymphoplasmacytic lymphoma (LPL)

• T/NK-cell lymphomas (10-15%): (discussed in a separate post T/NK-Cell Non-Hodgkin lymphoma)

  • Peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS):

    • One of the most common subtype of mature T-cell lymphomas

    • An aggressive mature T-cell lymphoma that does not meet criteria for another defined T-cell lymphoma entity.

  • Cutaneous T-cell lymphoma (CTCL):

    • Mycosis Fungoides

    • Sézary Syndrome

  • Anaplastic large cell lymphoma (ALCL):

    • Can be ALK-positive or ALK-negative

  • Enteropathy-associated T-cell lymphoma (EATL):

    • Rare, aggressive peripheral T-cell lymphoma of the small intestine

    • Strongly associated with celiac disease

  • Hepatosplenic T-cell lymphoma (HSTCL)

  • Adult T-cell leukemia/lymphoma (ATLL)

  • Extranodal NK/T-cell lymphoma (ENKTL)

  • T-cell large granular lymphocytic leukemia (T-LGLL):

    • indolent chronic lymphoproliferative disorder

    • Often with extranodal involvement (peripheral blood, bone marrow, spleen)

Diffuse Large B-Cell Lymphoma (DLBCL)

Background:

• Most common aggressive lymphoma (30% of NHL cases)

• Immunophenotype:

  • Expression of pan–B-cell markers (CD19, CD20, CD22, CD79a, PAX5)

• Classified by cell of origin:

  • Germinal center B-cell (GCB)

    • Historically associated with better outcomes

  • Activated B-cell (ABC)

Work up:

• Lab tests: CBC, CMP, LDH, HBV, HCV and HIV screening

• FISH for MYC rearrangement (assessment for BCL2 and BCL6 rearrangements)

• PET/CT for initial staging and response assessment

• CNS International Prognostic Index (CNS-IPI) score: estimates the risk of CNS relapse in DLBCL treated with R-CHOP-based therapy

  • R-CHOP: Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Vincristine (Oncovin), Prednisone

  • Clinical factors, each get 1 point:

    • Age >60

    • Elevated LDH

    • ECOG >1

    • Ann Arbor stage III-IV

    • >1 extranodal site of involvement

    • Kidney and/or adrenal involvement

  • Risk stratification:

    • Low risk: 0-1 risk factors

      • 2 year CNS relapse rate is ~0.6%

    • Intermediate risk: 2-3 risk factors

      • 2 year CNS relapse rate is ~3%

    • High risk: 4-6 risk factors OR kidney/adrenal/testis involvement

      • 2 year CNS relapse rate is 10%

      • Testicular involvement is not part of the formal CNS-IPI score, but it is still recognized as an independent high-risk factor for CNS relapse.

      • Consider CNS prophylaxis

  • Suggested CNS prophylactic therapy:

    • High-dose systemic MTX 3-3.5 g/m2 for 2-4 cycles

    • Intrathecal methotrexate ± cytarabine may be considered in selected situations (particularly when concern for leptomeningeal disease)

Treatment:

~60–70% of patients are cured with first-line therapy

~10–15% have refractory disease

~20–30% relapse after an initial response

• Stage I-II (30%):

  • Non-bulky:

    • R-CHOP x3 cycles → (PET restaging) + ISRT (Involved-site Radiation Therapy)

    • R-CHOP ×4-6 cycles → (PET restaging) ± ISRT

      • Use of ISRT is based on clinical risk and PET response

  • Bulky (≥7.5 cm):

    • R-CHOP x6 cycles → (PET restaging) ± ISRT

• Stage III/IV (70%):

  • R-CHOP x6 cycles

    • Interim PET/CT after 2-4 cycles for response assessment

    • Screen patients for HBV

  • Pola-R-CHP

    • Polatuzumab vedotin, Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Prednisone

    • Polatuzumab requires PJP and HSV/VZV prophylaxis

  • R-miniCHOP

    • lower dose R-CHOP

    • Consider for very elderly patients (particularly ≥80 years) or patients unable to tolerate full-dose therapy

• Relapsed/refractory disease:

  • If transplant-eligible AND relapse occurred >12 months after initial R-CHOP:

    • Platinum-based therapy → auto-HCT

      • R-DHAP:

        • Rituximab, Dexamethasone, High-dose cytarabine (Ara-C), Cisplatin

      • R-GDP:

        • Rituximab, Gemcitabine, Dexamethasone, Cisplatin

      • RICE:

        • Rituximab, Ifosfamide, Carboplatin, Etoposide

  • If transplant-ineligible OR relapse occurred <12 months after initial R-CHOP:

    • CAR-T cell therapy

      • Axi-cel or Liso-cel

      • Bridging therapy may be used while awaiting CAR-T

    • Pola-BR

      • Polatuzumab vedotin, Bendamustine, Rituximab

    • R-GemOx

      • Rituximab, Gemcitabine, Oxaliplatin

    • CD20 x CD3 Bispecific antibodies:

      • Epcoritamab

      • Glofitamab

    • Glofitamab + GemOX

    • Mosunetuzumab + Polatuzumab vedotin

    • Tafasitamab (Anti-CD19 mAb) + Lenalidomide

• Special consideration:

  • DLBCL of paranasal sinus:

    • R-CHOP x3 cycles → ISRT

  • Testicular DLBCL:

    • R-CHOP + RT to contralateral testes ± CNS intrathecal (IT) treatment

Surveillance: 

• H&P q3-6 months for 5 years, then annually

• CT CAP with contrast q6 months for 2 years, then as indicated

HGBL with MYC, BCL2/BCL6 rearrangements

Background:

• Aggressive with a significantly poorer prognosis

• High risk of CNS involvement

• Confirm MYC and BCL2 ± BCL6 rearrangements by FISH or cytogenetics

Treatment:

• CNS prophylaxis:

  • Preferably with systemic high-dose MTX

• Regimens:

  • R-EPOCH (R-CHOP + Etoposide)

  • DA-EPOCH-R (Dose Adjusted R-EPOCH)

    • Preferred regimen

  • R-CHOP

    • Inferior outcomes

    • Consider for frail, elderly or low-risk patients

  • Pola-R-CHP

  • Clinical trial

Burkitt Lymphoma (BL)

Background:

• Aggressive Lymphoma, originates from mature germinal center B cell

• Immunophenotype:

  • CD5-, CD10+, CD19+, CD20+, CD22+, CD23-

  • TdT-, BCL2-, BCL6+, CD79a, PAX5, surface Ig+ (with light-chain restriction)

  • Extremely high Ki-67 index (~100%) is a hallmark feature

• High risk for TLS

• Associated with MYC rearrangement: t(8;14), t(2;8), t(8;22)

Subtypes:

• Endemic:

  • Typically in patients from equatorial Africa

  • More associated with EBV

  • Involves extranodal sites (breast, ileum, jaw bone, ovaries, kidneys)

• Sporadic:

  • Often in the ileocecal area

  • Not as commonly associated with EBV

• Immunodeficiency:

  • Patients with HIV, post-transplant, or congenital immunodeficiency

Treatment:

• Intense chemotherapy regimens:

  • R-HyperCVAD with alternating high dose MTX and Cytarabine

  • DA-EPOCH-R

  • R-CODOX-M/IVAC + IT CNS prophylaxis

    • 2-4 cycles alternating R-CODOX-M and R-IVAC

      • R-CODOX-M: Rituximab, Cyclophosphamide, Vincristine (Oncovin), Doxorubicin, High-dose Methotrexate

      • R-IVAC: Rituximab, Ifosfamide, Etoposide (VP-16), high-dose Ara-C (Cytarabine)

• No need for maintenance therapy

Follicular Lymphoma (FL)

Background:

• Low grade lymphoma, originates from mature germinal center B cell

• Immunophenotype:

  • CD5-, variable CD10, CD19+, CD20+, CD22+, variable CD23

• Characteristic Chromosome Abnormality:

  • t(14;18) translocation → translocates the BCL2 gene on chromosome 18 to the Ig heavy chain (IgH) locus on chromosome 14 → places BCL2 under the regulatory control of the highly active IgH enhancer elements → over-expression of the BCL2 protein in B cells → blocks the normal apoptotic program

  • Positive BCL2 helps to distinguish FL from BL and other germinal center lymphomas

• Typically presents with multistation LAP, BM involvement, and splenomegaly

  • "Bulky" mass: typically ≥7.5 cm, some studies use 10 cm

Staging:

• Limited stage:

  • Stage I:

    • Single LN region

    • Single group of adjacent nodes

    • Single extranodal lesion without nodal involvement

  • Stage II contiguous:

    • ≥2 adjacent nodal groups on the same side of the diaphragm

• Advanced stage:

  • Stage II non-contiguous:

    • ≥2 non-adjacent nodal groups on the same side of the diaphragm

  • Stage III:

    • Involvement of LN regions on both sides of the diaphragm

      • May include spleen involvement.

  • Stage IV:

    • Additional non-contiguous extralymphatic involvement.

Treatment:

• Most patients can be observed

  • Monitor for Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria:

    • Used to assess tumor burden in FL and guide the decision to initiate therapy vs observation.

    • Treatment should be initiated when the patient meets ≥1 GELF criteria:

      • Any nodal/extranodal tumor mass ≥7 cm

      • ≥3 nodes involvement, each ≥3 cm

      • B symptoms

      • Splenomegaly

      • Pleural effusion, peritoneal ascites

      • Leukemic phase (>5000 malignant cells)

      • Cytopenias (WBC <1000, platelets <100k)

  • Guidelines recommend starting treatment when there is threatened end-organ function, including compression syndromes, regardless of GELF status.

• First Line Treatment:

  • R-CHOP or Obinutuzumab (Obi)-CHOP

  • R-CVP or Obi-CVP

  • BR: Bendamustine, Rituximab

  • Bendamustine + Obi

  • R-Squared (R²): Rituximab + Lenalidomide (Revlimid)

  • Rituximab

    • If low tumor burden or frail patient

  • Radiation therapy

    • If localized, small tumor burden, Stage I or contiguous Stage II

  • Consider rituximab maintenance q2-3 months for 2 years

    • If high tumor burden

• Second Line Treatment:

  • Bendamustine/Rituximab (or Obi): Not recommended if bendamustine already used

  • R-CHOP or Obi + CHOP

  • R-CVP or Obi-CVP

  • R-Squared

• Third Line Treatment:

  • CD20 x CD3 bispecific Ab:

    • Epcoritimab

    • Mosunetuzumab

  • CAR-T cell therapy:

    • Axi-cel

    • Tisa-cel

    • Liso-cel

  • Tazemetostat (EZH2 inhibitor)

  • Zanubrutinib + Obi

Clinical Pearls:

• If B symptoms, sudden change in size of LN, rise in LDH, etc:

  • Consider transformation, may need imaging and biopsy

• Treat grade IIIB follicular lymphoma like DLBCL

Marginal Zone Lymphoma (MZL)

Background:

• Indolent (median survival often >10 years) but risk of transformation to aggressive lymphoma exists

• MZL often arises in the context of chronic immune stimulation from infections or autoimmune diseases:

  • Gastric MALT- H. Pylori Infection

  • Splenic MZL- Hepatitis C infection

  • Small Bowel- Campylobacter jejuni

  • Thyroid- Hashimoto’s disease

  • Parotid- Sjogren’s syndrome

  • Ocular adnexa- Chlamydia psittaci

Diagnosis:

• Tissue biopsy

• Immunophenotyping:

  • CD5–, CD10–, CD19+, CD20+, CD22+, CD23–

• Molecular studies:

  • MYD88 mutation

  • Ig Heavy Chain Variable region (IGHV) sequencing

• Cytogenetic studies:

  • Trisomy 3 and trisomy 18

  • Deletion of 7q:

    • Highly specific for SMZL (30% of cases)

  • t(11;18):

    • Most common in gastric and pulmonary MALT lymphoma

    • Confers resistance to H. pylori eradication.

Subtypes:

• Extranodal (EMZL) or Mucosa-Associated Lymphoid Tissue (MALT):

  • Most common MZL

  • Involves stomach (~60% of cases), lung, ocular adnexa, skin, salivary glands

  • Treatment:

    • For gastric MALT, H. pylori eradication is first-line if infection is present.

    • For localized non-gastric EMZL, ISRT is preferred.

    • Systemic therapy (rituximab ± chemo) if advanced, multifocal, or symptomatic disease.

• Nodal (NMZL):

  • Most patients present with advanced-stage but non-bulky disease

  • Treatment:

    • Similar to follicular lymphoma:

      • Observation for low burden disease

      • Rituximab-based regimens for symptomatic or high burden disease.

• Splenic (SMZL):

  • Prominent splenomegaly and BM involvement, but peripheral LAP is uncommon

  • Treatment:

    • Observation is appropriate for asymptomatic patients.

    • Rituximab monotherapy is preferred for symptomatic disease

    • Antiviral therapy is considered if hepatitis C is present.

      
      
      
      

Mantle Cell Lymphoma (MCL)

Background:

• Subtypes:

  • Classical/conventional MCL

  • Leukemic/non-nodal MCL

• Typically presents with LAP, splenomegaly, BM and GI involvement.

• t(11;14) translocation → Cyclin D1 over-expression (essential for diagnosis)

• TP53 status is an important prognostic and predictive marker

• Disease course ranges from indolent (especially in leukemic/non-nodal MCL) to aggressive.

• Most patients require therapy soon after diagnosis.

Diagnosis:

• Tissue biopsy

• Immunophenotyping:

  • CD5+, CD10–, CD19+, CD20+, CD22+, CD23–, cyclin D1+

• Confirmation of t(11;14) translocation by FISH or IHC

• SOX11 and Ki-67

  • For subtyping and prognostication

• TP53 mutation testing

  • Predicts poor response to standard therapy

Treatment:

• Indolent/ asymptomatic:

  • Observation

• Fit, younger patients (typically ≤65 years):

  • Intensive regimens (alternating R-CHOP, R-DHAP, cytarabine-containing regimens) → auto-HCT + Rituximab maintenance (NORDIC regimen)

• Older or transplant-ineligible patients:

  • Less intensive regimens (BR, R-CHOP, VR-CAP) + Rituximab maintenance

    • VR-CAP: Bortezomib (Velcade), Rituximab, Cyclophosphamide, Doxorubicin (Adriamycin), Prednisone

• Relapsed/refractory disease:

  • Covalent BTK inhibitors (zanubrutinib, acalabrutinib)

  • R-squared

  • Bortezomib (Velcade)

  • CAR T-cell therapy

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL)

Discussed in a separate post "Chronic Lymphocytic Leukemia (CLL)/ SLL"

Lymphoplasmocytic Lymphoma (LPL)/ Waldenstrom Macroglobulinemia (WM)

Background:

• Rare, indolent B-cell NHL characterized by BM infiltration with monoclonal Ig secreting lymphoplasmacytic cells.

• Waldenström Macroglobulinemia (WM) is a variant and most common presentation of LPL.

  • Associated with monoclonal IgM paraprotein

• The diagnosis requires exclusion of other small B-cell lymphomas with plasmacytic differentiation (particularly MZL)

• Associated with MYD88 mutation

  • Present in ~90% LPL/WM cases

  • Also is a predictor of response to treatment

• Associated with hyperviscosity syndrome

Treatment:

• Indications for treatment:

  • Symptoms attributable to lymphoma (not limited to B symptoms)

  • Hyperviscosity syndrome

  • Threatened end-organ function

  • Significant or progressive cytopenia (BM involvement >10%)

  • Significant bulky disease

  • Cryoglobulinemia

  • Steady or rapid progression of disease

• First line regimens:

  • BR

  • Bendamustine + Obinutuzumab

  • R-CHOP or Obi-CHOP

  • R-CVP or Obi-CVP

  • R-squared