Sections

Treatment

Approach Considerations

Treatment of B-cell lymphoma varies according to the disease type. See Guidelines for first- and second-line treatment recommendations.

Chimeric antigen receptor (CAR) T-Cell therapy

In CAR T-cell therapy, the patient's own T-cells are genetically engineered to express a specific CAR; in the case of B-cell lymphoma, this is typically CD19. After a blood sample has been obtained from the patient, the CAR molecule is introduced into the patient’s T cells through viral or nonviral approaches. The cells undergo a brief round of expansion in the laboratory and are then infused back into the patient.

The infused T cells become activated when they recognize the target antigen on the surface of the tumor. Once activated, the T cells undergo massive expansion in the body, proliferating and producing multiple different cytokines. These cytokines improve the T cells’ function, helping them traffic to the tumor site and start killing the tumor cells by expressing cytotoxic molecules (eg, granzymes and perforins).

Cytokine release syndrome is a potentially life-threatening adverse effect of CAR T-cell therapy. Tocilizumab is approved for the treatment of severe or life-threatening cytokine release syndrome induced by CAR T-cell therapy.^[17]

For full discussion of CAR T-cell therapy, see Cancer Immunotherapy with Chimeric Antigen Receptor (CAR) T-Cells

Axicabtagene ciloleucel

In 2017, the US Food and Drug Administration (FDA) approved axicabtagene ciloleucel (Yescarta), a CD19-directed CAR T-cell therapy, for relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) after at least two other lines of systemic treatment have failed. It is not indicated for the treatment of patients with primary central nervous system lymphoma.

FDA approval was based on results from the ZUMA-1 study, an open-label, multicenter trial that enrolled 111 patients from 22 institutions. Study patients received the target dose of axicabtagene ciloleucel (2 × 10⁶ cells/kg) after low-dose conditioning with cyclophosphamide and fludarabine for 3 days. The modified intention-to-treat population involved 101 patients who received axicabtagene ciloleucel. In adults with R/R DLBCL, the response rates were approximately 60-80%, with complete responses seen in 40-70% of patients. After receiving axicabtagene ciloleucel, 40% of patients maintained their complete response at 6-month follow-up.^{[18, 19]}

The trial had a median survival follow-up of 8.7 months. Common adverse reactions included cytokine release syndrome, hypotension, encephalopathy and febrile neutropenia. In addition, prolonged cytopenias, hypogammaglobulinemia, and serious infections can occur.^[18]

Tisagenlecleucel

Tisagenlecleucel (Kymriah) is approved for treatment of R/R DLBCL in adult patients who have received 2 or more lines of systemic therapy. Indications include DLBCL not otherwise specified, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma. Approval was based on the single-arm, open-label, multicenter, phase 2 JULIET trial in adults with R/R DLBCL and DLBCL after transformation from follicular lymphoma. Eligible patients must have been treated with at least 2 prior lines of therapy, including an anthracycline and rituximab, or relapsed following stem cell transplantation.^[20]

Study patients received a single infusion of tisagenlecleucel following completion of lymphodepleting chemotherapy. The overall response rate for the 68 evaluable patients was 50% (95% CI: 37.6, 62.4) with a complete response (CR) rate of 32% (95% CI: 21.5, 44.8). With a median follow-up time of 9.4 months, the duration of response (DOR) was longer in patients with a best overall response of CR, as compared with a best overall response of partial response (PR). In patients who achieved CR, the estimated median DOR was not reached (95% CI: 10.0 months, not estimable [NE]). The estimated median response duration in patients in PR was 3.4 months (95% CI: 1.0, NE). Common adverse reactions included cytokine release syndrome, hypogammaglobulinemia, infections, and encephalopathy.^[21]

Lisocabtagene maraleucel

Lisocabtagene maraleucel (Breyanzi) is a CD19-directed CAR T-cell therapy for adults with R/R large B-cell lymphoma (LBCL) after two or more lines of systemic therapy, including DLBCL not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B. It is not indicated for primary CNS lymphoma.

Safety and efficacy were evaluated in TRANSCEND, an open-label, multicenter, single-arm trial. Patients (n=268) with R/R large B-cell non-Hodgkin lymphoma after at least 2 lines of therapy. Study patients received a single infusion of lisocabtagene maraleucel following completion of lymphodepleting chemotherapy. Of those patients, 54% achieved CR (95% CI: 47%-61%) and 19% achieved PR (95% CI:14%-26%). Median duration of response for all responders was 16.7 months (CR was not reached; PR: 1.4 months [95% CI: 1.1-2.2 months). Among all responders, 65% had remission for at least six months and 62% had remission lasting at least nine months. Most common adverse reactions were fatigue, cytokine release syndrome, musculoskeletal pain, nausea, headache, encephalopathy, infections (pathogen unspecified), decreased appetite, diarrhea, hypotension, tachycardia, dizziness, cough, constipation, abdominal pain, vomiting, and edema.^[22]

Natural killer cell therapy

Unlike anti-CD19 CAR T-cell therapy, treatment with natural killer (NK) cells that have been modified to express an anti-CD19 has been shown to promote no increase in the levels of inflammatory cytokines, including interleukin-6, over baseline. A phase 1/2 trial of HLA-mismatched anti-CD19 CAR-NK cells derived from cord blood, in 11 patients with relapsed or refractory CD19-positive cancer, reported response to treatment in the majority of cases, without the development of cytokine release syndrome, neurotoxicity, or graft-versus-host disease.^[23]

Monoclonal antibodies

Polatuzumab vedotin-piiq (Polivy) is an FDA-approved anti-CD79b antibody drug indicated for multiply relapsed or refractory DLBCL. A clinical trial has shown longer duration of remission when polatuzumab is added to bendamustine and rituximab. Common reported adverse effects include progressive multifocal leukoencephalopathy (PML), peripheral neuropathy, tumor lysis syndrome and fetal toxicity.^{[24, 25]}

Other monoclonal antibodies undergoing phase 2 clinical trials include the following:

Brentuximab vedotin
Blinatumomab
Tafasitamab

Mosunetuzumab is the newest monoclonal antibody; it binds to CD3 and CD20. A phase 1/2 clinical trial showed long-lasting responses with a very tolerable safety profile in patients with B-cell non-Hodgkin lymphoma (NHL) who had received at least 1 prior therapy, who had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and for whom there was no available therapy that would be expected to improve survival. Compared with patients who had already progressed despite CAR T-cell therapy, patients treated with mosunetuzumab showed better response (objective response rate 37%,complete remission 22%). Common adverse reaction included cytokine release syndrome, headache, and insomnia.^[26]

Hematopoietic cell transplantation

Patients with relapsed or refractory DLBC should be considered for autologous hematopoietic cell transplantation (HCT) when CAR T-cell therapy is not available. For transplant-ineligible patients, the goal of care should be limiting the symptoms. CAR T-cell therapy can be administered. Such patients can participate in newer clinical trials.^[16]

Complications

Complications arising from therapy include the following:

Neutropenic fever after chemotherapy is not uncommon and can be life-threatening if associated with sepsis.
Tumor lysis syndrome after chemotherapy is possible in patients with bulky disease.
Severe hemorrhagic cystitis is sometimes observed after high-dose cyclophosphamide therapy.
Cytokine release syndrome (CRS) is sometimes associated with CAR-T therapy.

Consultations

Radiation oncologists are often consulted because radiation plays a role in management of B-cell lymphoma; it is considered the treatment of choice in early-stage indolent lymphoma and has a role in consolidation of treatment in localized aggressive lymphoma.

A surgical consultation is indicated when central venous access devices are employed, especially when stem cell or bone marrow transplantation is considered.

Transfer

Patients with lymphoma who are being managed at peripheral health care facilities may require their care to be transferred to a tertiary care or research institute for access to clinical trials and investigational agents.

Patients who are profoundly ill or are experiencing significant complications from either the disease or its therapy also warrant transfer to a facility that is better equipped to handle such emergencies.

Diet

Typically, no dietary restrictions exist for patients with non-Hodgkin lymphoma (NHL). Patients with prolonged neutropenia following chemotherapy, especially those undergoing high-dose chemotherapy with hematopoietic precursor cell rescue, are provided with a reduced-bacteria diet. Patients with high tumor burden undergoing chemotherapy may be at risk for tumor lysis syndrome and sometimes require a diet low in uric acid and potassium.

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Media Gallery

Neoplastic follicles comprising cleaved cells (centrocytes) and larger cells with vesicular nuclei and prominent 2-3 nucleoli (centroblasts).
Mantle cell lymphoma. Small lymphoid cells with oval to slightly irregular nuclei and clumped chromatin and rare admixed pink histiocytes.
Diffuse large B-cell non-Hodgkin lymphoma. Large cells with abundant cytoplasm and large round-ovoid nuclei with thick nuclear membrane and multiple prominent nucleoli.
Burkitt lymphoma. Normal architecture is entirely replaced by lymphoma cells and evenly dispersed macrophages, starry sky (250×).
Burkitt lymphoma cells with round noncleaved nuclei and strongly basophilic cytoplasm (1000×).
Compartmentalizing fibrosis and infiltrate of medium-sized to large lymphoid cells.
Lymphoma cells show strong membranous positivity with CD20 indicative of B-cell origin.

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Table 1. Chromosomal Abnormalities in B-Cell Non-Hodgkin Lymphoma

Cytogenetic Abnormality	Histology	Antigen Rearrangement	Oncogene Expression
t(14;18)(q32;q21)	Follicular, diffuse large cell	IgH*	bcl- 2
t(11;14)(q13;q32)	Mantle cell	IgH	cyclin-D1/bcl-1
t(1;14)(p22;q32)	MALT lymphoma	IgH	bcl- 10
t(11;18)(q21;q21)	MALT lymphoma	IgH	Unknown
t(9;14)(p13;q32)	Lymphoplasmacytic lymphoma	IgH	PAX-5
8q24 translocations t(8;14)(q24;q32) t(2;8)(p11-12;q24) t(8;22)(q24;q11)	Burkitt lymphoma	IgH Ig-8 Ig-6	c-myc
Trisomy 12, deletion 11q22-23, 17p13, and 6q21	CLL	…	…
*Immunoglobulin H (IgH) MALT = Mucosa-associated lymphoid tissue.

Table 2. Characteristic Immunophenotypes of Major Subtypes of Lymphoma

Lymphoma	Immunophenotype
Follicular	CD20⁺, CD3^-, CD10⁺, CD5^-, BCL2⁺, CD23^-/+, CD43^-, cyclinD-1^-, BCL6⁺
Small lymphocytic	CD 20⁺, CD3^-, CD10^-, CD5⁺, CD23⁺,
MALT	CD20⁺, CD3^-, CD 10^-, CD5^-, CD23^-/+, BCL2⁺
Marginal zone	CD20⁺, CD3^-, CD 10^-, CD5^-, CD23^-/+, CD43^-/+, cyclinD-1^-, BCL2
Mantle cell	CD20⁺, CD23^-/+, CD10^-/+, CD5⁺, CD43^-/+, cyclinD-1+
Mediastinal large B-cell	CD20⁺, CD30+, MUM-1⁺
Burkitt	slg⁺,CD20⁺, Tdt^-, CD10⁺, BCL2-^-, BCL6⁺, Ki-67⁺ (≥95%)
B-lymphoblastic	slg-, CD19+, CD10^-/+, CD20^-/+, TdT⁺
MALT = mucosa-associated lymphoid tissue.

Table 3. Lugano Modification of the Ann Arbor Staging System.

Stage		Area of Involvement	Extranodal (E) Status
I	Single node or adjacent group of nodes		Single extranodal lesions without nodal involvement
II	Multiple lymph node groups on same side of diaphragm		Stage I or II by nodal extent with limited contiguous extranodal involvement
II bulky*	Multiple lymph node groups on same side of diaphragm with “bulky disease”.		N/A
III	Multiple lymph node groups on both sides of diaphragm; nodes above the diaphragm with spleen involvement		N/A
IV	Multiple noncontiguous extranodal sites		N/A
*Stage II bulky disease considered limited or advanced as determined by histology and a number of prognostic factors. Suffixes A and B are not required X for bulky disease replaced with documenting of largest tumor diameter Definition of “Bulky” disease varies depending on lymphoma histology.

Table 4. Non-Hodgkin lymphoma staging.

Stage		Area of Involvement	Extranodal (E) Status
I	Single node or adjacent group of nodes		Single extranodal lesions without nodal involvement
II	Multiple lymph node groups on same side of diaphragm		Stage I or II by nodal extent with limited contiguous extranodal involvement
II bulky*	Multiple lymph node groups on same side of diaphragm with “bulky disease”		N/A
III	Multiple lymph node groups on both sides of diaphragm; nodes above the diaphragm with spleen involvement		N/A
IV	Multiple noncontiguous extranodal sites		N/A

Table 3. International Society for Cutaneous Lymphoma/European Organization for Research and Treatment of Cancer tumor-node-metastasis classification for cutaneous B-cell lymphoma

Tumor	Involvement	Node	Involvement	Metastatic Spread	Involvement
T1	Solitary skin involvement T1a: ≤5 cm diameter T1b: >5 cm diameter	N0	No lymph node involvement	M0	No evidence of extracutaneous non-lymph node disease
T2	Multiple lesions limited to one body region or two contiguous body regions T2a: all-disease in a < 15-cm diameter T2b: all-disease in a >15- and < 30-cm diameter T2c: all-disease in a >30-cm diameter	N1	Involvement of one peripheral lymph node region	M1	Evidence of extracutaneous non-lymph node disease
T3	Generalized skin involvement T3a: multiple lesions involving two noncontiguous body regions T3b: multiple lesions involving three body regions	N2	Involvement of two or more peripheral lymph node regions or involvement of any lymph node region that does not drain an area of current or prior skin involvement
		N3	Central lymph nodes involvement

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Author

Mohammad Muhsin Chisti, MD, FACP Associate Professor of Medicine (Hematology and Oncology), Oakland University William Beaumont School of Medicine; Medical Director of Research, Karmanos Cancer Institute

Mohammad Muhsin Chisti, MD, FACP is a member of the following medical societies: American College of Physicians, American Medical Association, American Society of Clinical Oncology, American Society of Hematology, Medical Society of the State of New York

Disclosure: Nothing to disclose.

Coauthor(s)

Haresh Kumar, MBBS Resident Physician, Department of Internal Medicine, St Joseph Mercy Oakland Hospital

Disclosure: Nothing to disclose.

Sumeet K Yadav, MD, MBBS Resident Physician, Department of Internal Medicine, St Joseph Mercy Oakland Hospital

Sumeet K Yadav, MD, MBBS is a member of the following medical societies: American College of Physicians, Asian Medical Students' Association International, Bangladesh Medical and Dental Council, European Society for Medical Oncology, Nepal Medical Association, We Care, Jahurul Islam Medical College and Hospital

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences

Disclosure: Nothing to disclose.

Additional Contributors

Ajeet Gajra, MD Associate Professor of Medicine, Director of Hematology/Oncology Fellowship Program, State University of New York Upstate Medical University; Consulting Staff, Department of Internal Medicine, Division of Hematology and Oncology, Veterans Affairs Medical Center

Ajeet Gajra, MD is a member of the following medical societies: American Association for Cancer Research, American Medical Association, American Society of Hematology

Disclosure: Nothing to disclose.

Neerja Vajpayee, MD Associate Professor, Department of Pathology, State University of New York Upstate Medical University

Neerja Vajpayee, MD is a member of the following medical societies: American Society of Hematology, College of American Pathologists, United States and Canadian Academy of Pathology

Disclosure: Nothing to disclose.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous authors Sara J Grethlein, MD, and Uzma Athar, MD, to the development and writing of the source article.