Non-Hodgkin Lymphoma

Epidemiology and Etiology

Non-Hodgkin lymphoma (NHL) is the fifth most common malignancy in the US, with an estimated 77,240 new cases in 2020.¹ Risk factors include immunodeficiency, autoimmune disorders, bacterial infections (H.

Pathology

NHL represents a diverse group of hematologic malignancies derived from B cells, T cells, and rarely NK cells which exist at various stages of differentiation. NHL may be broadly divided into indolent (e.g., follicular, marginal zone, small lymphocytic), aggressive (e.g., diffuse large B cell, mantle cell, peripheral T cell, anaplastic large cell lymphoma), and very aggressive (e.g., Burkitt, precursor B and T lymphoblastic leukemias/lymphomas, adult T cell leukemia-lymphoma) subtypes.³⁹ Several recurrent chromosomal abnormalities have been described in patients with NHL (Table 22-10).

TABLE 22-10

DLBCL, diffuse large B-cell lymphoma; MALT, mucosa-associated lymphoid tissue.

Clinical Presentation

Clinical manifestations depend on the histologic subtype and can be characteristic in some rare subtypes of NHL. For instance, pruritic plaques can be seen in mycosis fungoides (a primary cutaneous T cell NHL) and isolated splenomegaly may occur in splenic marginal zone lymphomas. Occasionally, patients with aggressive lymphomas can present with a spontaneous tumor lysis syndrome (TLS).

Diagnostic Testing

Essential workup often includes history, physical examination, complete blood cell count, chemistry, PET/CT, lymph node biopsy, and in certain cases, bone marrow biopsy. The CSF evaluation is indicated in patients with high-grade lymphomas, HIV-related lymphomas, and involvement of the epidural space, testes, nasopharynx, or paranasal sinuses. Patients suspected to have primary CNS lymphomas require an ophthalmologic examination.

Staging

Patients are staged by the Lugano classification (Table 22-9). Patients with aggressive lymphoma are usually stratified according to the International Prognostic Index, which uses five adverse prognostic factors: age gt;60 years, stage III or IV, serum LDH gt;ULN, #8805;2 extranodal sites involved, and ECOG PS #8805;2. Each is assigned 1-point and higher scores predict a worse overall prognosis.

TREATMENT

Indolent Lymphomas

• Stage I-II: Observation, IFRT, single-agent rituximab, rituximab with chemotherapy, and combined- modality therapy using rituximab, chemotherapy, and IFRT are all options. Gastric mucosa-associated lymphoid tissue (MALT) lymphomas are related to H. pylori infection and respond well to H. pylori-directed therapy. Gastric MALT lymphomas that do not respond to or relapse after H. pylori therapy, and other isolated extranodal lymphomas (salivary gland, breast, conjunctiva) may be treated with IFRT, rituximab, surgery, chemotherapy, or a combination of these modalities.³⁹

• Stage III-IV: There is no convincing evidence to support early intervention compared to “watchful waiting” in asymptomatic patients. A combination of an anti-CD20 antibody (rituximab or obinutuzumab) and chemotherapy or single-agent rituximab can be used for treatment.

• Relapsed disease: First-line therapy can be repeated in patients who were in first remission for gt;2 years. Lenalidomide, PI3 kinase inhibitors (e.g., idelalisib, duvelisib, copanlisib), CD19 CAR-T therapy, and stem cell transplant are all effective options. Tazemetostat is approved for use in patients with relapsed follicular lymphoma that is EZH2 mutated.

Aggressive Lymphomas

• Diffuse Large B-Cell Lymphoma:

î Stage I-II: Limited-stage disease is managed with chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP]) with or without IFRT.

î Stage III-IV: Patients beginning therapy for aggressive lymphomas should be monitored closely for signs of TLS and should receive adequate IV hydration and appropriate prophylaxis with allopurinol and/or rasburicase. Chemotherapy with R-CHOP is standard. Patients with MYC translocations, especially those with “double-hit” lymphomas (combined translocations of MYC and either BCL2 or BCL6), have significantly worse outcomes and are often treated with regimen dose-adjusted R- EPOCH.³⁹ CNS prophylaxis with intrathecal chemotherapy or high-dose methotrexate should be considered for patients with testicular, orbital, epidural, paranasal sinus or extensive bone marrow involvement, or a combination of elevated LDH, serum albumin lt;3.5 g/L, gt;60 years of age, retroperitoneal lymph node involvement, and involvement of gt;1 extranodal site resulting in a high CNS International Prognostic Index (IPI) score. Primary CNS lymphoma is treated with complex regimens that usually incorporate high-dose methotrexate, cytarabine, and rituximab, often with consolidation stem cell transplantation. Whole-brain radiation is an effective therapy but should be avoided if possible, because of the high rate of late neurotoxicity.

• Burkitt lymphoma: Burkitt lymphomas are a highly aggressive form of B-cell lymphoma usually treated with complex multidrug protocols and CNS prophylaxis.

• Aggressive peripheral T-cell lymphomas are generally treated with CHOP or CHOEP-regimens.

• Mantle cell lymphoma (MCL): Chemoimmunotherapy regimens incorporating rituximab, cytarabine, bendamustine, or anthracyclines are often used. Consolidation with autologous stem cell transplantation can be considered in first remission. Maintenance rituximab is considered in select patients. Relapses may be treated with BTK inhibitors or a number of other agents. Brexucabtagene autoleucel is a US FDA-approved CD19 CAR-T therapy for patients with relapsed or refractory mantle cell lymphoma.

• Relapsed/refractory non-Hodgkin lymphoma: Several effective salvage regimens such as ICE (ifosfamide, carboplatin, etoposide), DHAP (dexamethasone, cisplatin, cytarabine), and ESHAP (etoposide, methylprednisone, cytarabine, cisplatin) are available. Rituximab is added to the salvage regimens for B cell lymphomas. Younger, medically fit patients with chemotherapy sensitive disease are candidates for autologous stem cell transplantation at relapse. Allogeneic transpl antation can be considered in patients with relapsed Burkitt or lymphobl astic lymphoma, chemotherapy refractory disease at relapse or a duration of remission of lt;1 year after initial therapy. Additionally, CD19 targeting CAR-T therapies, such as axicabtagene ciloleucel, tisagenlecleucel, brexucabtagene autoleucel, and lisocabtagene maraleucel, are highly effective and are US FDA-approved for use in patients with certain categories of refractory B-cell lymphoma, including DLBCL, primary mediastinal LBCL, DLBCL arising from follicular lymphoma, follicular lymphoma, and MCL.