Non-Hodgkin Lymphoma
Summary of Key Points
Incidence
• Non-Hodgkin lymphoma (NHL) is the most common hematologic malignancy; more than 70,000 were estimated to be diagnosed in the United States in 2012. Diffuse large B-cell (DLBCL) and follicular lymphoma (FL) are the most common subtypes, each comprising approximately one third of cases in the Western Hemisphere.
• In the Western hemisphere, approximately 85% of lymphomas are of B-cell origin and 15% are of T-cell/natural killer-cell origin. T-cell lymphomas have a higher incidence in parts of Asia.
Etiology and Biology
• Etiology of most lymphomas is complex and multifactorial. Defects in host immunity that increase the risk and infections associated with NHL include Helicobacter pylori, Epstein-Barr virus (EBV), human immunodeficiency virus (HIV), human T-cell leukemia/lymphoma virus type I (HTLV-I), hepatitis C, and human herpesvirus–8 (HHV-8).
• Specific genetic abnormalities associated with lymphomas include translocations of BCL-2 (t(14;18)) in FL and DLBCL; BCL-6 (t(3;16)) in DLBCL; BCL-10 (t(11;18)) in mucosa-associated lymphoid tissue lymphoma; MYC (t(8;14), t(2;8), t(8;22) in Burkitt lymphoma and subsets of DLBCL; BCL-1 (t(11;14)) in mantle cell lymphoma (MCL); and ALK (t(2;5)) in anaplastic lymphoma kinase (ALK) + anaplastic large T-cell lymphoma (ALCL).
• Gene expression profiling can subdivide the largest group of lymphomas, DLBCL, into three subtypes with distinct pathogenetic mechanisms and decidedly different prognoses.
Differential Diagnosis
• Excisional biopsy is preferred for initial diagnosis and should be reviewed by an experienced hematopathologist. Fresh-frozen tissue should be collected for additional studies.
• World Health Organization (WHO) Classification of Lymphoid Malignancies recognizes lymphomas that may be unclassifiable with morphologic features alone. Clinical and molecular features are essential for subclassification of lymphomas.
Staging Evaluation
• Staging evaluation includes patient history and physical examination; complete blood cell count and chemistry studies including lactate dehydrogenase; computed tomography (CT) of chest, retroperitoneum, and pelvis; and bone marrow biopsy. Positron emission tomography (PET) aids in the detection of extranodal disease and is more sensitive than CT alone.
Primary Therapy
• Rituximab, a chimeric monoclonal antibody against CD20, is an essential component of the front-line and relapsed treatment of B-cell lymphomas.
• Treatment of indolent lymphomas such as follicular lymphoma, marginal zone lymphoma, and lymphoplasmacytic lymphoma is for palliative benefit and is not curative; treatment is frequently curative for DLBCL, ALK+ ALCL, Burkitt lymphoma, and lymphoblastic lymphoma; and proper dose-intensity of therapy is essential.
• MCL demonstrates remarkable clinical heterogeneity; no curative therapy exists, but a subset of patients can have a long indolent course without therapy.
• Peripheral T-cell lymphomas (PTCLs) other than ALK+ ALCL have a poor prognosis and are difficult to cure with standard therapy.
1. A 70-year-old man is diagnosed with mantle cell lymphoma (MCL) after an excisional biopsy of an enlarged cervical lymph node. Staging evaluation demonstrates stage IV disease with involvement of his bone marrow and an enlarged spleen. Complete blood cell count is normal except for an elevated absolute lymphocyte count of 8000/µL. The patient does not have any symptoms related to his lymphoma and enjoys golfing on a regular basis. The best initial management plan for this patient is:
A R-CHOP × six to eight cycles
C R-Bendamustine × six cycles followed by an autologous stem cell transplant
D R-Bendamustine × six cycles followed by a reduced intensity allogeneic stem cell transplant
E An initial period of close observation with initiation of therapy when symptoms ensue or progression of disease
2. Which of the following patients has the best prognosis if treated with R-CHOP × 6 cycles at full doses?
A A 22-year-old woman with a 12-cm mediastinal mass, Ann Arbor stage I, low-risk IPI, and a diagnosis of primary mediastinal B-cell lymphoma (PMBL)
B A 22-year-old woman with a 4-cm cecal mass, Ann Arbor stage I, and a diagnosis of Burkitt lymphoma (BL)
C A 22 year-old woman with a 6-cm retroperitoneal mass and 2-cm cervical mass, Ann Arbor stage III, low-risk IPI, and a diagnosis of diffuse large B-cell lymphoma (DLBCL)
D A 22-year-old woman with a 3-cm bilateral cervical masses, Ann Arbor stage II, low-risk IPI, MYC translocation, and a diagnosis of DLBCL.
E An 82-year-old woman with a 6-cm retroperitoneal mass and 2-cm cervical mass, Ann Arbor stage III, low-risk IPI, and a diagnosis of diffuse large B-cell lymphoma (DLBCL)
3. A 55-year-old man is diagnosed with diffuse large B-cell lymphoma (DLBCL) and achieves a complete remission with six cycles of R-CHOP therapy. Two months after the end of his initial therapy, he is noted to have an enlarged cervical lymph node and biopsy demonstrates recurrent DLBCL with an MYC translocation. He is started on R-ICE with plans for autologous stem cell transplantation and has stable disease after two cycles of therapy. What is the best next step in his management?
A Continue with R-ICE for two more cycles and then reassess
4. A 45-year-old woman has new symptoms of an enlarged left cervical mass after being treated for follicular lymphoma (FL) 5 years earlier. She was treated with six cycles of R-CHOP therapy and achieved a complete remission. Repeat biopsy demonstrates recurrent FL without features of transformation. Staging evaluation demonstrates stage IV disease with retroperitoneal lymph nodes involved and 50% of the bone marrow replaced by FL. What is the best treatment option?
5. A 55-year-old woman is diagnosed with stage III DLBCL and undergoes therapy with R-CHOP × six cycles. Her involved lymph node chains at diagnosis included a cervical neck mass 2 × 2 cm, a mediastinal mass 4 × 4 cm, and a peripancreatic nodal mass of 5 × 3 cm. CT done 4 weeks after therapy demonstrates resolution of the cervical nodes, mediastinal nodes that are 0.8 × 0.8 cm, and a peripancreatic mass that is 2.5 × 2 cm. At this point, the best next step is:
1. Answer: E. Patients with MCL demonstrate remarkable heterogeneity with regard to clinical behavior, and as many as 15% of newly diagnosed patients will benefit from deferred therapy. Because no clinical tools currently exist to select these patients, an initial period of close observation is appropriate for patients who present without symptoms. Almost 100% of MCL patients will have an advanced stage of disease, and this does not mandate immediate therapy. R-CHOP results in complete remission in less than 50% of patients and is inferior to aggressive chemotherapy in MCL such as R-hyperCVAD or immunochemotherapy followed by autologous stem cell transplant. Answers B to D are highly effective for MCL but have unacceptable toxicity in patients older than 70 years. Allogeneic transplantation is promising in the management of relapsed MCL for a subset of patients but is experimental in newly diagnosed patients.
2. Answer: C. Young patients with low-risk IPI have a very good prognosis with R-CHOP chemotherapy with 5-year overall survival rates in the 75% range based on the MInT study. The other patients in this group require special consideration and may need therapy other than R-CHOP alone. PMBL patients should be treated with dose-intensive regimens such as dose-adjusted EPOCH-R or be given mediastinal radiation. BL patients and subsets of DBLCL with MYC translocations do poorly with R-CHOP therapy alone and probably need a more intensive approach. Elderly patients with DLBCL may do well with R-CHOP therapy but often need dose reductions and use of colony-stimulating factors to get through therapy. Overall, their prognosis is worse than their younger counterparts.
3. Answer: D. Autologous stem cell transplantation (ASCT) was established as the standard of care for chemosensitive relapsed DLBCL based largely on a randomized study, the Parma study, in the era before rituximab in which 40% of patients could be cured with this approach. In the recent CORAL study, patients initially treated with rituximab-containing regimens had much poorer outcomes with ASCT, resulting in questioning the use of this approach in all patients who have experienced relapse. This patient has multiple reasons to not proceed with ASCT at this point: early relapse after initial therapy, disease that is insensitive to salvage chemotherapy, and MYC translocation. He should be referred for a novel agent in the context of a clinical trial or be prescribed palliative measures only.
4. Answer: C. Although all of the listed choices are appropriate therapies for patients with relapsed FL, bendamustine-rituximab is the best choice. Recently, it was demonstrated to have superior response rates and survival rates than fludarabine in relapsed FL. Radioimmunotherapy has high response rates in relapsed FL but is contraindicated in patients with extensive bone marrow involvement. Repeat therapy with the initial regimen in FL is an option if the first therapy lasted more than 3 years before progression, but the cumulative anthracycline dosing with repeat R-CHOP therapy is a concern in a young woman. Bortezomib has some activity in relapsed FL but should be given in the context of a clinical trial and is best used in combination.
5. Answer: B. FDG-PET/CT is the best choice because it has the potential to distinguish between residual tumor cells and tissue necrosis at the end of therapy in a noninvasive way. Salvage therapy for DLBCL should never be initiated without tissue confirmation, and biopsy in this area is problematic owing to surrounding vital structures. Functional imaging such as FDG-PET is best done 6 to 8 weeks after the end of therapy. If no residual uptake is seen, then the patient is likely in complete remission and should move on to surveillance. Radiation therapy after therapy for advanced DLBCL is controversial and would have significant toxicities if given to the retroperitoneum.
