B-Cell Lymphoma Guidelines

Updated: Oct 23, 2017
  • Author: Mohammad Muhsin Chisti, MD, FACP; Chief Editor: Emmanuel C Besa, MD  more...
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Guidelines

Staging

In 2014, the International Conference on Malignant Lymphomas (a multidisciplinary team of researchers representing major lymphoma clinical trial groups and cancer centers from North America, Europe, Japan, and Australasia) published guidelines for the evaluation, staging, and response assessment of patients with malignant lymphomas. This staging system is known as the Lugano Modification of the Ann Arbor staging system. [14]  In 2015, the National Comprehensive Cancer Network (NCCN) adopted this system. [15]

The revised recommendations for staging include the following [14] :

  • Positron emission tomography–computed tomography (PET-CT) is preferred for fluorodeoxyglucose (FDG)-avid lymphomas; CT is indicated for non-avid lymphomas
  • PET-CT is preferred for pretreatment assessment and routine staging
  • Contrast-enhanced CT is more accurate for measurement of nodal size and is also preferred for radiation planning
  • PET-CT is preferred for determining splenic involvement, with cutoff for splenomegaly of more than 13 cm
  • Bone marrow biopsy is usually not required if the PET-CT scan indicates bone or marrow involvement but if the scan is negative, a bone marrow biopsy is indicated to identify involvement by discordant histology, if clinically relevant
  • Liver size is not a reliable measure; liver involvement is suggested by diffusely increased or focal uptake, with or without focal or disseminated nodules
  • Prior Ann Arbor staging divided patients according to absence (A) or presence (B) of disease-related symptoms (B symptoms include weight loss >10%, fever, drenching night sweats); these are not required in NHL staging since they are not prognostic

In addition, these guidelines offered consensus on further modifications to the Ann Arbor staging classification, as shown in Table 1, below [15, 14] :

  Table 4. Non-Hodgkin lymphoma staging. (Open Table in a new window)

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 is considered limited or advanced; this distinction is made on the basis of 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.

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Risk Stratification

The International Prognostic Index (IPI), which was originally designed as a prognostic factor model for aggressive non-Hodgkin lymphoma (NHL), also appears to be useful for predicting the outcome of patients with low-grade lymphoma. This index is also used to identify patients at high risk of relapse, based on specific sites of involvement, including bone marrow, central nervous system, liver, testis, lung, and spleen. [8]  Separate indices have been developed for follicular and mantle cell lymphoma. [9, 10, 11]

The IPI includes the following risk factors [8] :

  • Age ≥ 60 y
  • Elevated lactate dehydrogenase (LDH) level
  • Stage III or IV disease
  • Eastern Cooperative Oncology Group (ECOG) performance status ≥2
  • Two or more extranodal sites

Each factor is worth 1 point. Based on the IPI score, patients can be categorized as follows [8] :

  • Low risk (0-1 point)
  • Low-intermediate risk (2 points)
  • High-intermediate risk (3 points)
  • High risk (4-5 points)

With this model, relapse-free and overall survival rates at 5 years are as follows:

  • 0-1 risk factors - 75%
  • 2-3 risk factors - 50%
  • 4-5 risk factors - 25%
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Follicular Lymphoma

World Health Organization Classification

In 2001, the WHO classification called for grading of follicular lymphoma (FL) from grades 1-3 based on the number of centroblasts per high-power field (hpf). However, the 2008 update consolidated cases with few centroblasts as FL grade 1-2 (low grade) and divided FL grade 3 into 3A (presence) and 3B (absence) of centrocytes. [3, 17]

National Comprehensive Cancer Network (NCCN) guidelines note that that grade 3B is commonly treated as diffuse large B-cell lymphoma (DLBCL), whereas opinion is divided on whether to treat grade 3A as FL or DLBCL. FL of any grade that is found to contain an area of DLBCL should be managed as a DLBCL. [18]

Prior to 2008, primary cutaneous follicle center lymphoma (PCFCL) was classified as a variant of FL. In the 2008 update, its classification was changed to that of a distinct entity. PCFCL may contain a high proportion of large B cells, including large centrocytes and centroblasts. Dissemination beyond the skin is rare. [3]

Diagnosis

In addition to its general guidance on diagnosis of lymphoma, the NCCN recommends the following studies to establish a diagnosis of FL [15] :

  • Immunohistochemistry panel: CD20, CD3, CD5, CD10, BCL2, BCL6, cyclin D1, CD21, or CD23
  • Cell surface marker analysis by flow cytometry: kappa/lambda, CD19, CD20, CD5, CD23, CD10
  • Molecular analysis to detect: antigen receptor gene rearrangements; BCL2 rearrangements
  • Karyotype or FISH: t(14;18); BCL6, 1p36, IRF4/MUM1 rearrangements
  • Immunohistochemistry panel: Ki-67; IRF4/MUM1 for FL grade 3, cyclin D1

Risk stratification

The Groupe d’Etude des Lymphomes Folliculaires (GELF) recommends the following criteria for identifying patients in whom immediate therapy is necessary [19] :

  • Involvement of ≥3 nodal sites, each with a diameter of ≥3 cm
  • Any nodal or extranodal tumor mass with a diameter of ≥7 cm
  • B symptoms
  • Splenomegaly
  • Pleural effusions or peritoneal ascites
  • Cytopenias (leukocytes <1.0 x 10 9/L and/or platelets <100 x 10 9/L)
  • Leukemia (>5.0 x 10 9/L malignant cells)

The NCCN recommends both the GELF criteria and the 2004 Follicular Lymphoma International Prognostic Index (FLIPI) for risk stratification. The FLIPI includes the following risk factors [10] :

  • Age >60 y
  • Ann Arbor Stage III-IV
  • Lactate dehydrogenase (LDH) level above the upper limit of normal
  • Hemoglobin level <12 g/dL
  • Five or more nodal sites of disease

For each factor, the patient receives 1 point. Based on the FLIPI score, patients can be categorized as follows [10] :

  • Low risk (0 or 1 point)
  • Intermediate risk (2 points)
  • High risk (≥3 points)

In 2009, the International Follicular Lymphoma Prognostic Factor Project published an updated score, FLIPI2. The FLIPI2 includes the following risk factors (as with FLIPI1, each factor is worth 1 point) [9] :

  • Age >60y
  • β2-microglobulin (B2M) above the upper limit of normal
  • Bone marrow involvement
  • Hemoglobin level <12 g/dL
  • Longest diameter of the largest involved node >6 cm

Based on the FLIPI2 score, patients can be categorized as low, intermediate, or high risk. [9]

Treatment

The NCCN guidelines suggest the following regimens as first-line therapy (in preference order) [18] :

  • Bendamustine + rituximab (category 1)
  • Bendamustine + obinutuzumab
  • R-CHOP (rituximab, cyclophosphamide, doxorubicin [hydroxydaunorubicin], vincristine [Oncovin], prednisone) (category 1)
  • CHOP + obinutuzumab
  • RCVP (rituximab, cyclophosphamide, vincristine, prednisone) (category 1)
  • CVP + obinutuzumab
  • Rituximab (375 mg/m 2 weekly for 4 doses) – Consider for low tumor burden
  • Lenalidomide + rituximab (category 2B)

For elderly or infirm patients who, in the opinion of treating physician, are unlikely to tolerate most of the above regimens, suggested first-line therapy options include the following:

  • Rituximab (preferred) (375 mg/m 2 weekly for 4 doses)
  • Single-agent alkylators (eg, chlorambucil or cyclophosphamide) ± rituximab
  • Radioimmunotherapy (category 2B)

First-line regimens for consolidation or extended dosing (optional) include the following:

  • Rituximab maintenance – 375 mg/m 2, one dose every 8 wk for 12 doses, for patients initially presenting with high tumor burden (category 1)
  • Obinutuzumab maintenance – 1000 mg every 8 wk for 12 doses
  • Rituximab consolidation –375 mg/m 2 one dose every 8 weeks for 4 doses If initially treated with single-agent rituximab, consolidation with
  • Radioimmunotherapy (after induction with chemotherapy or chemoimmunotherapy) (category 2B)

Options for second-line and subsequent therapy include the following:

  • Chemoimmunotherapy (as listed under first-line therapy)
  • Rituximab
  • Lenalidomide ± rituximab
  • Bendamustine + obinutuzumab
  • Radioimmunotherapy (category 1)
  • Idelalisib – For cases refractory to both an alkylator and rituximab
  • Fludarabine + rituximab
  • RFND (rituximab, fludarabine, mitoxantrone [Novantrone], dexamethasone)
  • See second-line therapy for DLBCL (BCEL-C 2 of 4) without regard to transplantability

Options for second-line consolidation or extended dosing (optional) include the following:

  • Rituximab maintenance – 375 mg/m 2 , one dose every 12 wk for 2 years (category 1)
  • Obinutuzumab maintenance for rituximab-refractory disease (1 g every 8 wk for total of 12 doses)
  • High-dose therapy with autologous stem cell rescue
  • Allogeneic stem cell transplant for highly selected patients
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Marginal Zone Lymphomas of MALT Type

Mucosa-associated lymphoid tissue (MALT) lymphomas are usually localized and are most often observed in the stomach, lung, salivary gland, thyroid, orbit, conjunctiva, and lacrimal gland. An association of MALT lymphomas with autoimmune disease is well known.

The development of gastric MALT lymphomas has been attributed to antigenic stimulation associated with chronic Helicobacter pylori gastritis. Indeed, both the NCCN and ESMO guidelines recommend antibiotic eradication of H pylori as first-line treatment for H pylori–positive patients, including t(11;18)-positive patients. After eradication of H pylori, t(11;18) patients have a <5% response rate to the tumor. They will require involved-site radiation therapy (ISRT) or rituximab. In H pylori –negative patients, involved-site radiation therapy (ISRT), 30 Gy, is the preferred treatment option. Rituximab is an option if radiation therapy is contraindicated. [18]

For non-gastric MALT lymphomas, radiotherapy is preferred but surgery is also an appropriate treatment (and in most cases is required to make the diagnosis). Further treatment may not be needed. When the tumor is incompletely excised, radiotherapy should be considered. In the minority of patients presenting with a more widespread disease, systemic chemotherapy is effective. The majority of stage III-IV MALT lymphomas respond to treatment similar to that for follicular lymphoma. [18]

Therapy for gastric MALToma

European Society for Medical Oncology (ESMO) guidelines for treatment of gastric marginal zone lymphoma of the MALT type include the following recommendations [20] :

  • Helicobacter pylori eradication therapy must be given to all gastric MALT lymphomas, independently of stage, and may be considered for H pylori–negative cases
  • If no signs of lymphoma regression are seen at a repeat endoscopy assessment 2 to 3 months after antibiotic treatment, radiation and systemic oncological therapies should be used, depending on the stage of disease
  • Radiotherapy might be the preferred option for localized disease (eg, 24–30 Gy to the stomach and perigastric nodes given in 3 to 4 weeks)
  • Chemoimmunotherapy is preferred in cases of histological transformation or contraindications to radiotherapy; patients with t(11;18) will most probably be unresponsive to alkylating agents as a sole treatment
  • No accepted standard chemotherapy has been established, but oral alkylating agents (either cyclophosphamide or chlorambucil) or purine nucleoside analogues (fludarabine, cladribine) and the combination of rituximab and bendamustine have shown benefit
  • No data support a rituximab maintenance strategy.
  • Aggressive anthracycline-containing regimens are not usually necessary and should be reserved for the few patients with a very aggressive clinical course or histological transformation
  • Surgery has no role in initial treatment

 

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Mantle Cell Lymphoma

Diagnosis

Mantle cell lymphoma (MCL) is diagnosed in accordance with the World Health Organization criteria for hematological neoplasms and detection of Cyclin D1 expression or the t(11;14) translocation along with mature B-cell proliferation. [20] The National Comprehensive Cancer Network (NCCN) recommends the following studies to establish a diagnosis of MCL [18] :

  • Immunohistochemistry panel: CD20, CD3, CD5, CD10, BCL2, BCL6, cyclin D1, CD21, CD23, Ki-67
  • Cell surface marker analysis by flow cytometry: kappa/lambda, CD19, CD20, CD5, CD23, CD10
  • Fluorescence in situ hybridization (FISH) or cytogenetics for detection of  t(11;14),  t(14;18).
  • Immunohistochemistry for SOX 11, which is expressed in approximately 90% of MCLs but is negative in all other B-cell lymphoid neoplasms except Burkitt lymphomas and lymphoblastic lymphomas

Risk stratification

The European Society for Medical Oncology (ESMO) recommends the 2008 MCL International Prognostic Index (MIPI) for risk stratification. [21]  The MIPI includes the following risk factors [11] :

  • Age: 50-59 (1 point); 60-69 (2 points); ≥70 (3 points)
  • Eastern Cooperative Oncology Group (ECOG) performance status ≥2 (2 points)
  • Lactate dehydrogenase level (ratio to upper limit of normal): 0.67-0.99 (1 point); 1.00-1.49 (2 points); ≥1.50 (3 points)
  • White blood cell count (× 10 9/L): 6700-9999 (1 point); 10,000-14,999 (2 points); ≥15,000 (3 points)

Based on the MIPI score, patients can be categorized as follows [11] :

  • Low risk (0-3 points)
  • Intermediate risk (4-5 points)
  • High risk (≥6 points)

In addition, both the NCCN and ESMO recommend assaying Ki-67 proliferative antigen to evaluate cell proliferation. Low Ki-67 (<30%) is associated with a more favorable prognosis; however, it is not used to guide treatment decisions. [15, 21]

Treatment

The NCCN and ESMO offer similar treatment recommendations, as follows [15, 21]

  • Chemotherapy followed by involved-site radiation therapy (ISRT), 30-36 Gy, is the preferred treatment option for limited stage I or II (non-bulky) disease, although this presentation is rare
  • For advanced-stage disease in younger patients and selected elderly fit patients, the recommended approach is aggressive induction therapy, followed by consolidation therapy consisting of high-dose therapy with autologous stem cell rescue
  • Prophylaxis and monitoring for tumor lysis syndrome should be strongly considered during the induction therapy.
  • In elderly fit patients, less-aggressive induction regimens followed by rituximab maintenance is recommended by both NCCN and ESMO
  • For elderly patients who are not candidates for any of the above chemotherapy regimens, palliative chemotherapy should be considered, using milder chemo-immunotherapy regimens (eg, chlorambucil plus rituximab, bendamustine plus rituximab)
  • For relapsed or refractory disease, recommendations include high-dose therapy with autologous stem cell rescue and second-line agents; allogeneic stem cell transplantation can be considered in selected patients as part of a second-line consolidation

Induction therapy

For induction therapy, aggressive regimens include the following:

  • CALGB regimen (see below)
  • HyperCVAD (cyclophosphamide, vincristine, doxorubicin [Adriamycin], dexamethasone, alternating with high-dose methotrexate and cytarabine) + rituximab
  • Nordic regimen (dose-intensified induction immunochemotherapy with rituximab + cyclophosphamide, vincristine, doxorubicin, prednisone [maxi-CHOP]) alternating with rituximab + high-dose cytarabine)
  • Alternating R-CHOP/RDHAP (rituximab, cyclophosphamide, doxorubicin [hydroxydaunorubicin], vincristine [Oncovin], prednisone)/(rituximab, dexamethasone, high-dose cytarabine [Ara-C], cisplatin [Platinol])
  • RDHAP
  • Sequential R-CHOP/RICE (rituximab, ifosfamide, carboplatin, etoposide)

The CALGB regimen comprises  5 treatments; all but Treatment 5 are accompanied by granulocyte colony-stimulating factor {G-CSF) therapy and infection prophylaxis. The 5 treatments are as follows:

  • Treatments 1 and 2 – R-M-CHOP (rituximab, methotrexate, cyclophosphamide, doxorubicin [hydroxydaunorubicin], vincristine [Oncovin], prednisone)
  • Treatment 2.5 (given if the pre–Treatment 3 bone marrow biopsy contains >15% MCL) – R-M-CHOP
  • Treatment 3 – EAR (etoposide, cytarabdine [Ara-C], rituximab)
  • Treatment 4 – CBV (cyclophosphamide, carmustine [BCNU], etoposide [VP16-213])
  • Treatment 5 - Rituximab

Less aggressive regimens include the following:

  • Bendamustine + rituximab
  • VR-CAP (bortezomib [Velcade], rituximab, cyclophosphamide, doxorubicin [Adriamycin], and prednisone)
  • Cladribine + rituximab (category 2B)
  • R-CHOP
  • Lenalidomide + rituximab
  • Modified rituximab-HyperCVAD in patients older than 65 y

Consolidation therapy

In patients who are candidates for it, high-dose therapy with autologous stem cell rescue plus rituximab maintenance (category 1 for rituximab maintenance) is first-line therapy. In patients who are not candidates, first-line therapy is rituximab maintenance (category 1 following R-CHOP). Second-line consolidation therapy is with allogeneic stem cell transplantation (nonmyeloablative or myeloablative).

Second-line therapy

Second-line therapy regimens include the following:

  • Bendamustine ± rituximab
  • Bendamustine, bortezomib, and rituximab (category 2B)
  • Bortezomib ± rituximab
  • Cladribine + rituximab
  • FC (fludarabine, cyclophosphamide) ± rituximab (category 3)
  • Ibrutinib
  • Ibrutinib, lenalidomide, rituximab (category 2B)
  • Lenalidomide ± rituximab
  • PCR (pentostatin, cyclophosphamide, rituximab) (category 3)
  • PEPC (prednisone, etoposide, procarbazine, cyclophosphamide) ± rituximab (category 3)
  • Venetoclax
  • See second-line therapy for DLBCL (BCEL-C 2 of 4) without regard to transplantability
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Diffuse Large B-Cell Lymphoma

Diagnosis

In addition to its general guidance on diagnosis of lymphoma, the National Comprehensive Cancer Network (NCCN) recommends the following studies to establish a diagnosis of diffuse large B-cell lymphoma (DLBCL) [15] :

  • Immunohistochemistry (IHC) panel: CD20, CD3, CD5, CD10, CD45, BCL2, BCL6, Ki-67, IRF4/MUM1, MYC
  • Cell surface marker analysis by flow cytometry: kappa/lambda, CD45, CD3, CD5, CD19, CD10, CD20
  • Additional IHC panel for subtyping: Cyclin D1, kappa/lambda, CD30, CD138, EBER-ISH, ALK, HHV8
  • Fluorescence in situ hybridization (FISH) or cytogenetics for detection of  t(14;18),  t(3;v),  t(8;14),  t(8;v)

IHC should include adequate markers to differentiate the two subtypes of DLBCL: activated B-cell type (ABC) and germinal center B-cell type (GCB). The subtypes are genetically different diseases, and survival in patients with the ABC subtype is worse than in those with GCB. [22]

Risk stratification

The NCCN and the European Society for Medical Oncology (ESMO) recommend use of the International prognostic index (IPI) for all patients. Age-adjusted International Prognostic Index (aa-IPI) should be used for risk stratification of patients aged 60 years and younger. [15, 23]

The IPI includes the following risk factors:

  • Age >60 years
  • Elevated serum lactate dehydrogenase (LDH) level
  • Eastern Cooperative Oncology Group (ECOG) performance status ≥2
  • Stage III or IV disease
  • Extranodal involvement >1 site

Each risk factor is worth 1 point. On the basis of the IPI score, patients can be categorized as follows:

  • Low risk (0-1 point)
  • Low-intermediate risk (2 points)
  • High-intermediate risk (3 points)
  • High risk (4-5 points)

The aa-IPI includes the following risk factors (1 point is allotted for each factor) [8] :

  • Elevated LDH level
  • Stage III or IV disease
  • ECOG performance status ≥2

Based on the aa-IPI score, patients can be categorized as follows [8] :

  • Low risk (0 points)
  • Low-intermediate risk (1 point)
  • High-intermediate risk (2 points)
  • High risk (3 points)

Treatment

National Comprehensive Cancer Network recommendations [18]

First-line therapy (in alphabetical order) options are as follows:

  • R-CHOP (rituximab, cyclophosphamide, doxorubicin [hydroxydaunorubicin], vincristine, prednisone) (category1)
  • Dose-dense R-CHOP (category 3)
  • Dose-adjusted EPOCH (etoposide, prednisone, vincristine [Oncovin], cyclophosphamide, doxorubicin) + rituximab (category 2B)

First-line therapy options for patients who have poor left ventricular function or are very frail are as follows:

  • RCEPP (rituximab, cyclophosphamide, etoposide, prednisone, procarbazine)
  • RCDOP (rituximab, cyclophosphamide, liposomal doxorubicin, vincristine, prednisone)
  • DA-EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) + rituximab
  • RCEOP (rituximab, cyclophosphamide, etoposide, vincristine, prednisone)
  • RGCVP (rituximab, gemcitabine, cyclophosphamide, vincristine, prednisolone)

Regimens for patients >80 years of age with comorbidities are as follows:

  • R-mini-CHOP
  • RGCVP (rituximab, gemcitabine, cyclophosphamide, vincristine, prednisolone)

First-line consolidation (optional) regimens are as follows:

  • For patients 60–80 y of age: Lenalidomide maintenance (category 2B)
  • For age-adjusted IPI high-risk disease: High-dose therapy with autologous stem cell rescue (category 2B) 

Regimens for concurrent presentation with CNS disease are as follows:

  • Parenchymal: 3 g/m 2 or more of systemic methotrexate given on day 15 of a 21-day R-CHOP cycle with growth factor support
  • Leptomeningeal: Intrathecal methotrexate/cytarabine; consider Ommaya reservoir placement and/or systemic methotrexate (3–3.5 g/m 2)

Second-line and subsequent therapy (intention to proceed to high-dose therapy) regimens are as follows:

  • DHAP (dexamethasone, high-dose cytarabine [Ara-C], cisplatin [Platinol]) ± rituximab
  • ESHAP (etoposide, methylprednisolone [Solu-Medrol], high-dose cytarabine, cisplatin) ± rituximab
  • GDP (gemcitabine, dexamethasone, cisplatin or carboplatin) ± rituximab
  • GemOx (gemcitabine, oxaliplatin) ± rituximab
  • ICE (ifosfamide, carboplatin, etoposide) ± rituximab
  • MINE (mesna, ifosfamide, mitoxantrone, etoposide) ± rituximab

Second-line and subsequent therapy regimens, for patients who are not candidates for high-dose therapy, include the following:

  • Bendamustine ± rituximab
  • Brentuximab vedotin for CD30+ disease (category 2B)
  • CEPP (cyclophosphamide, etoposide, prednisone, procarbazine) ± rituximab - PO and IV
  • CEOP (cyclophosphamide, etoposide, vincristine, prednisone) ± rituximab
  • DA-EPOCH ± rituximab
  • GDP ± rituximab or (gemcitabine, dexamethasone, carboplatin) ± rituximab
  • GemOx ± rituximab
  • Gemcitabine, vinorelbine ± rituximab (category 3)
  • Lenalidomide ± rituximab (non-GCB DLBCL)
  • Rituximab

Follow-up

A PET-CT scan should be performed to confirm complete remission (CR). Patients in CR should receive clinical follow-up with a history and physical examination and laboratory studies (eg, complete blood cell count, comprehensive metabolic panel, lactate dehydrogenase level) every 3-6 months for 5 years and then yearly or as clinically indicated. Imaging studies (CT scan) should be performed no more often than every 6 mo for 2 years after the completion of treatment, and then only as clinically indicated. [18]

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Burkitt Lymphoma

Classification

The 2008 World Health Organization classification identifies the following three clinical variants of Burkitt lymphoma (BL)3:

  • Endemic (eBL) – The most common form of childhood malignancy in equatorial Africa, associated with Epstein-Barr virus (EBV) infection
  •  Sporadic (sBL) – The majority of cases are in the United States and Europe; up to 30% are associated with EBV
  •  Immunodeficiency associated – Occurs in patients with HIV infection, post-transplantation immunosuppression, and congenital immunodeficiency         

Diagnosis

In addition to its general guidance on diagnosis of lymphoma, the National Comprehensive Cancer Network (NCCN) recommends the following studies to establish a diagnosis of Burkitt lymphoma12:

·         Immunohistochemistry panel: CD45(LCA), CD20, CD3, BCL2, BCL6, Ki-67, TdT or

·         Cell surface marker analysis by flow cytometry: kappa/lambda, CD45, CD20, CD3, CD5, CD19, CD10, TdT

·         Fluorescence in situ hybridization (FISH) or cytogenetics for detection of t(8;14), MYC.

·         Epstein-Barr encoding region in situ hybridization (EBER-ISH) can be used to identify EBV

Risk stratification

A prognostic scoring system was developed in 2013 using the Surveillance, Epidemiology, and End Results (SEER) database. Risk factors and points assigned are as follows32:

·         Age 40-59 years or black race/ethnicity: 1 point

·         Age 60-79 years or stage III/IV disease: 2 points

·         Age 80 years and older: 4 points

The four risk groups based on the scoring system are as follows:

·         Low risk (0-1 point)

·         Low-intermediate risk (2 points)

·         High-intermediate risk (3 points)

·         High risk (≥4 points)

With this model, relative survival rates at 5 years are as follows:

·         Low risk - 71%

·         Low-intermediate - 55%

·         High-intermediate - 41%

·         High-risk - 29%

Treatment

Induction Therapy reactivation (NHODG-B)

Low Risk- Combination Regimens

• CALGB 10002 regimen (cyclophosphamide and prednisone followed by cycles containing either ifosfamide or cyclophosphamide; highdose methotrexate, leucovorin, vincristine, dexamethasone, and either doxorubicin or etoposide or cytarabine; or intrathecal triple therapy [methotrexate, cytarabine, and hydrocortisone]) + rituximab.

• CODOX-M (original or modified) (cyclophosphamide, doxorubicin, vincristine with intrathecal methotrexate and cytarabine followed by high-dose systemic methotrexate) ± rituximab (3 cycles)

• Dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) + rituximab (minimum 3 cycles with one additional cycle beyond CR) (regimen includes intrathecal methotrexate) (Data are for patients without CNS disease.)

• HyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) alternating with high-dose methotrexate and cytarabine + rituximab (regimen includes intrathecal therapy)

High Risk- Combination Regimens

• CALGB 10002 regimen (cyclophosphamide and prednisone followed by cycles containing either ifosfamide or cyclophosphamide; highdose methotrexate, leucovorin, vincristine, dexamethasone, and either doxorubicin or etoposide or cytarabine; or intrathecal triple therapy [methotrexate, cytarabine, and hydrocortisone] with prophylactic CNS irradiation in select patients) + rituximab

• CODOX-M (original or modified) (cyclophosphamide, doxorubicin, vincristine with intrathecal methotrexate and cytarabine followed by high-dose systemic methotrexate) alternating with IVAC (ifosfamide, cytarabine, etoposide, and intrathecal methotrexate) ± rituximab

• Dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) + rituximab (for high-risk patients not able to tolerate aggressive treatments) (regimen includes intrathecal methotrexate) (Data are for patients without CNS disease.)

• HyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) alternating with high-dose methotrexate and cytarabine + rituximab (regimen includes intrathecal therapy)

Second-line Therapy (select patients with reasonable remission)

While no definitive second-line therapies exist, there are limited data for the following regimens:

• Dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) + rituximab (minimum 3 cycles with one

additional cycle beyond CR) (regimen includes intrathecal methotrexate) (Data are for patients without CNS disease.)

• RICE (rituximab, ifosfamide, carboplatin, etoposide); intrathecal methotrexate if have not received previously

• RIVAC (rituximab, ifosfamide, cytarabine, etoposide); intrathecal methotrexate if have not received previously

• RGDP (rituximab, gemcitabine, dexamethasone, cisplatin)

• High-dose cytarabine + rituximab

Content.

Follow-up

The NCCN recommends follow up every 2-3 months for the first year after complete response, then every 3 months for the next year, and every 6 months thereafter. Relapse is rare after 2 years.12

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Primary Cutaneous B-Cell Lymphomas

In addition to the National Comprehensive Cancer Network (NCCN), the European Organization for Research and Treatment of Cancer (EORTC) and the International Society for Cutaneous Lymphoma (ISCL) published guidelines for the management of primary cutaneous B-cell lymphomas (CBCL). [24]

Classification

The NCCN and EORTC/ISCL guidelines recommend use of the WHO-EORTC classification for cutaneous B-cell lymphomas (CBCL), which distinguishes the following three main types [25] :

  • Primary cutaneous marginal zone lymphoma (PC-MZL)
  • Primary cutaneous follicle center cell lymphoma (PC-FCL)
  • Primary cutaneous diffuse large B-cell, leg type (PC-DLBCL, LT)

Of note, a germinal (or follicle) center phenotype and large cells in a skin lesion is not equivalent to diffuse large B-cell lymphoma (DLBCL) but is consistent with primary cutaneous germinal/follicle center lymphoma.

Diagnosis

In addition to its general guidance on diagnosis of lymphoma, the NCCN recommends the following studies to establish a diagnosis of CBCL [15] :

  • Immunohistochemistry (IHC) panel: CD20, CD3, CD5, CD10, BCL2, BCL6, IRF4/MUM1
  • Additional IHC panel for subtyping: Ki-67, CD43, CD21, CD23, Cyclin D1, kappa/lambda
  • Assessment of IgM and IgD expression to distinguish between PC-FCL and PC-DLBCL, leg type
  • Fluorescence in situ hybridization (FISH) or cytogenetics for detection of  t(14;18)
  • Bone marrow biopsy in PC-FCL, optional for PC-MZL

Staging

The 2007 TNM classification system of the ISCL/EORTC is used for staging, as shown in Table 3, below. [26]

Table 3. International Society for Cutaneous Lymphoma/European Organization for Research and Treatment of Cancer tumor-node-metastasis classification for cutaneous B-cell lymphoma (Open Table in a new window)

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    

Treatment

PC-FCL and PC-MZL

Both the NCCN and EORTC/ISCL guidelines recommend local radiation therapy or excision for T1-2 PC-FCL and PC-MZL. [15, 24]  The NCCN recommends intralesional steroids or topical therapy including steroids, imiquimod, nitrogen mustard, and bexarotene as alternative treatment options. [15]

For T3 disease, the NCCN recommends radiation therapy; chlorambucil; or cyclophosphamide, vincristine, and prednisone (CVP) with or without rituximab. Extracutaneous disease should be managed using the treatment guidelines for follicular lymphoma. [15]

EORTC/ISCL guidelines recommend systemic rituximab as the first choice of treatment for patients with extensive skin lesions. Combination chemotherapy (eg, R-COP, R-CHOP) should be considered only in exceptional cases, such as in patients with progressive disease not responding to rituximab or patients developing extracutaneous disease. [24]

PC-DBCL, LT

Both guidelines caution that radiation therapy is less effective in PC-DBCL, LT. R-CHOP with local radiation therapy is recommended as first line of treatment for all stages of DBCL, LT. [15, 24] . Because of the lack of studies on relapsed disease, EORTC/ISCL recommend that treatment protocols for relapsed DBCL be followed. [24] .

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