Recently, Lisa Giulino-Roth, MD, from Weill Cornell Medical College in New York, discussed the management of primary mediastinal B-cell lymphoma, a rare subtype of non-Hodgkin lymphoma that occurs most often in adolescents and young adults. Below, we summarize her approach.
This material was repurposed from “How I treat primary mediastinal B-cell lymphoma” published in the August 23, 2018, edition of Blood.
- PMBCL is a rare subtype of NHL that predominantly occurs in adolescents and young adults.
- There is no standard of care for PMBCL, but initial treatment consists of rituximab and an anthracycline-containing chemotherapy regimen.
- FDG-PET at the completion of therapy is often used to determine response to treatment and whether re-induction chemotherapy or consolidative RT is necessary.
- In the primary refractory or relapsed setting, outcomes are poor. The standard approach is high-dose therapy followed by AHCT.
Primary mediastinal B-cell lymphoma (PMBCL) is a rare subtype of non-Hodgkin lymphoma (NHL) that predominantly occurs in adolescents and young adults (AYAs). Although previously considered a subtype of diffuse large B-cell lymphoma (DLBCL), PMBCL is now recognized by the World Health Organization as a unique entity with distinct clinical and biologic features.
This review presents two case vignettes that highlight the major unanswered clinical questions in PMBCL, including choosing the optimal upfront chemoimmunotherapy regimen, the use of radiation therapy (RT), and defining the role of newly approved and investigational agents.
Diagnosis of PMBCL
The diagnosis of PMBCL can be challenging because the histologic features overlap with nodular sclerosing Hodgkin lymphoma (HL). However, PMBCL has several distinct features. From a biologic standpoint, PMBCL shares many similarities with classical HL, including activation of the JAK-STAT and NF-κB pathways and immune evasion, likely as a result of downregulation of MHC class I and II and upregulation of programmed death ligands.
The malignant cells express B-cell markers (CD19, CD20, CD22, and CD79a) but not surface immunoglobulin. CD30 expression is weak and CD15 is negative. B-cell transcription factors are often positive, including PAX5, OCT2, BCL6, and BOB1.
Clinically, PMBCL typically presents as a bulky mediastinal mass. Local infiltration to the lung, chest wall, pleura, or pericardium is common. Also, unlike other NHL subtypes, PMBCL has a female predominance.
Upfront Therapy for PMBCL
Because PMBCL is uncommon, its clinical management varies across centers, with no single standard of care and few prospective trials to establish a standard therapeutic approach. While a variety of upfront chemotherapy approaches have been studied, there is no consensus on the optimal regimen. The use of RT also varies across centers, with efforts to reduce the exposure to RT in this young, predominantly female population, given the risk for long-term toxicity.
Although there is no single approach to initial therapy, a rituximab-and-anthracycline–containing regimen is used at most centers. In the U.S., the CHOP regimen (cyclophosphamide, doxorubicin, vincristine, prednisone) and subsequent R-CHOP (rituximab-CHOP), which are well established in DLBCL, have historically been the standard treatment of PMBCL. Some European centers have used the more dose-dense V/MACOP-B (etoposide or methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, bleomycin) regimens. R-CHOP and V/MACOP-B are typically administered in conjunction with consolidative radiation for most patients. Both regimens are usually given in combination with RT.
More recently, dose-intensive regimens without RT have been investigated. Based on encouraging results with dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) alone, many centers in the U.S. are moving toward this treatment approach; however, prospective, multicenter studies are needed to confirm that DA-EPOCH-R is superior to R-CHOP.
Pediatric patients with Burkitt lymphoma, DLBCL, or PMBCL have historically been treated on the same protocols. These regimens consist of alternating cycles of dose-intensive multi-agent chemotherapy, including doxorubicin, high-dose methotrexate, and intrathecal chemotherapy for central nervous system prophylaxis. These patients do not typically receive consolidative RT.
Trials are now evaluating the DA-EPOCH-R regimen in pediatric patients, with event-free survival rates ranging from 69% at two years to 81% at three years. Many centers in the U.S. use DA-EPOCH-R, whereas many centers in Europe follow the French-American-British/Mature B-Cell Lymphoma, or FAB/LMB, regimen, with or without rituximab.
Case 1: Diagnosing and Treating PMBCL
An 18-year-old woman presents with a one-month history of back pain and a two-week history of fever and progressive dyspnea. Bloodwork reveals a lactate dehydrogenase level (LDH) of 716 IU/L, and a chest CT scan reveals a 12.1 cm × 7.4 cm anterior mediastinal mass with mass effect on the aortic arch and main pulmonary artery and compression of the superior vena cava. There are several small pulmonary nodules up to 1 cm in size. There is a small pericardial effusion and moderate pleural effusions. Biopsy of the mediastinal mass reveals an abnormal B-cell population that is positive for CD19 and CD20 and negative for CD5, CD10, and surface immunoglobulin.
Microscopic examination reveals a diffuse proliferation of atypical medium- to large-sized lymphoid cells that are positive for CD20, BCL6, BCL2, MUM1, and CD23 and weakly positive for CD30. They are negative for CD3, CD10, and CD15.
Because these findings are consistent with PMBCL, a PET scan is performed. The mediastinal mass is FDG-avid, with a maximum standardized uptake value (SUV) of 20.4. The pulmonary nodules are also FDG-avid, with SUV ranging from 3.0 to 5.4. There are no abnormalities below the diaphragm. Bone marrow and cerebrospinal fluid are negative for lymphoma.
Commentary on Case 1: This patient has a typical presentation of PMBCL with a large mediastinal mass, pleural and pericardial effusions, and metastatic disease to the lungs. She has several risk factors that may be associated with inferior outcome, including LDH above the upper limit of normal, mediastinal mass >10 cm, and advanced-stage disease. She does not have disease in the bone marrow or central nervous system, which is also typical for PMBCL. Given the compression of major vessels from the mediastinal mass, as well as the pleural and pericardial effusions, she requires prompt initiation of therapy.
This patient, considered an AYA, could reasonably be treated on an adult or pediatric regimen. I use the DA-EPOCH-R regimen for the initial treatment of PMBCL. Data suggest that most patients can attain good disease control without the use of RT, although there remains concern for long-term toxicity with this regimen due to high cumulative exposure to anthracycline. Other toxicities to consider are the risk for secondary malignancy due to etoposide and gonadal toxicity from cyclophosphamide, with consequent infertility.
Consolidative Radiation Therapy for PMBCL
Consolidative RT may convert patients from a partial response to a complete response (CR) after chemotherapy. However, the role for RT in all patients, and particularly in patients with a good response to chemotherapy, is unknown.
FDG-PET–Guided Treatment Decisions
FDG-PET is routinely performed at the completion of chemo-immunotherapy in PMBCL to assess remission status. Patients with an end-of-therapy negative PET scan, typically defined as Deauville score of 1 to 3, have improved outcomes compared with those with a positive PET scan, with five-year progression-free survival rates of 99% and 68%, respectively (p<0.001).
More recently, FDG-PET has been used to identify patients for whom RT can be safely omitted, and research has shown that patients with a negative end-of-therapy PET scan who received consolidative RT had similar outcomes to those with a positive scan who received no further therapy.
Future studies evaluating the predictive role of FDG-PET in PMCBL may also include parameters beyond the Deauville score, such as total lesion glycolysis, metabolic tumor volume, and metabolic heterogeneity.
Case 1 Follow-Up: Consolidative Radiation in PMBCL
Once the diagnosis of PMBCL is confirmed, the patient starts treatment with DA-EPOCH-R. Her treatment course is remarkable for an upper-extremity deep vein thrombosis during cycle 1, for which she is placed on enoxaparin, and uncomplicated febrile neutropenia after cycle 2. She continues with DA-EPOCH-R for a total of six cycles. Approximately six weeks later, she undergoes a repeat PET/CT scan that shows that the mediastinal mass now measures 6.3 cm × 1.7 cm and has an SUV of 4.0. The pulmonary modules have resolved. She is assigned a Deauville score of 4. Should she receive further therapy?
Commentary on Case 1: The optimal approach to patients with a positive end-of-therapy PET scan is unclear and presents a particular challenge to clinicians, who must balance maximizing cure with minimizing long-term toxicity. My approach would be to follow closely with a repeat FDG-PET in six to eight weeks without further treatment. If the lesion is increasing in size or in FDG uptake on repeat imaging, I would consider a biopsy to determine whether the patient has primary refractory disease. If the lesion is improved or unchanged on repeat imaging, I would continue to follow without intervention.
Treatment of Relapsed/Refractory PMBCL
PMBCL can relapse or prove refractory to therapy early, with a median time to progression of eight months from diagnosis; most cases occur while on therapy or within 12 months of completion. At the time of relapse, the disease can metastasize beyond the mediastinum, including to extranodal sites, such as the liver, pancreas, kidney, and central nervous system.
For patients who have not previously received RT and have disease that is restricted to the mediastinum, RT alone may be curative. For all others, the treatment of relapsed/refractory disease is typically high-dose chemotherapy, with or without RT, followed by autologous hematopoietic cell transplantation (AHCT). Secondline treatment regimens are similar to those used in DLBCL and include R-ICE (rituximab, ifosfamide, carboplatin, etoposide phosphate) and R-DHAP (rituximab, dexamethasone, high-dose cytarabine, cisplatin).
Relapsed disease can be refractory to chemotherapy, and outcomes in such cases are poor. For patients with chemotherapy-sensitive disease who undergo AHCT, outcomes are more favorable and comparable to relapsed DLBCL.
Immunotherapy in PMBCL
PMBCL tumors harbor numerous molecular alterations that may be amenable to targeting with novel therapies.
In June 2018, the U.S. Food and Drug Administration approved pembrolizumab, a humanized monoclonal antibody that binds PD-1 to prevent the interaction between PD-1 and PD-1 ligands, for adult and pediatric patients with refractory PMBCL or whose disease relapsed after receiving two or more prior lines of therapy. The decision was based on results from the single-arm KEYNOTE-170 trial, in which intravenous pembrolizumab 200 mg every three weeks led to an overall response rate of 45%, including a CR rate of 11%. Other checkpoint inhibitors are being studied in B-cell lymphoma, including PMBCL.
Anti-CD19 chimeric antigen receptor (CAR) T cells have demonstrated activity in CD19-positive B-cell lymphomas and may be an emerging therapy for PMBCL.
Case 2: Treating Relapsed/Refractory PMBCL
A 20-year-old woman presents to the emergency department with a three-week history of cough and a one-week history of a “lump” protruding from her left chest wall. PET/CT scan reveals an anterior mediastinal mass and left infraclavicular and left subpectoral lymph nodes. A biopsy of the mass is consistent with PMBCL. She is treated with six cycles of DA-EPOCH-R and her end-of-therapy PET/CT scan shows a decrease in the size and FDG uptake of the mediastinal mass (Deauville score = 3). The infraclavicular and subpectoral lymph nodes have resolved. She does not receive RT.
Four months later she develops fever and cough. A PET/CT scan reveals an increase in the size and FDG uptake of the mediastinal mass, multiple new bilateral pulmonary nodules, and a PET-avid lesion at the head of the pancreas. A biopsy of the mediastinal mass confirms relapsed PMBCL.
Commentary on Case 2: This patient developed relapsed PMBCL soon after the completion of therapy and presented with disseminated disease. This pattern is common among cases of relapsed/refractory PMBCL and requires aggressive therapy given the poor prognosis. My approach to this patient would be high-dose therapy to try to induce remission if she demonstrates chemotherapy-sensitive disease, followed by AHCT.
In this case, because the patient did not receive RT with initial therapy, RT before or after AHCT could be considered. I use R-ICE as a secondline induction therapy. For patients who don’t respond to secondline therapy, I would consider offering a clinical trial of a novel agent, prioritizing checkpoint inhibitors or CD19 CAR T cell therapy, given the encouraging preliminary results.
The unique clinical and biologic features of PMBCL warrant a treatment approach that is distinct from other B-cell NHL subtypes. There is no standard of care for upfront treatment, although most groups use a chemoimmunotherapy regimen consisting of rituximab and an anthracycline. The role of end-of-therapy FDG-PET scans to guide consolidative therapy decisions is still under investigation. Novel agents such as pembrolizumab may benefit those with refractory disease and ultimately may be used in upfront therapy to improve initial response rates. Because PMBCL predominantly occurs in the AYA population, collaborations between pediatric and adult groups may help to advance outcomes in this rare NHL subtype.