|Photomicrograph of HE-stained diffuse large cell B-cell lymphoma. Click to enlarge.
According to the WHO classification, DLBCL includes multiple subtypes and constitutes about 35% of all non-Hodgkin lymphomas. Morphologically, blast-like cells are present with often prominent nucleoli and more or less diffuse growth. The group is heterogeneous in terms of karyotypical deviation. Most frequently, t(3;14)(q27;q32) (BCL6 gene involved), t(8;14)(q24;q32) (MYC gene involved) and t(14;18)(q21;q32) (BCL2 gene involved) are present. The last indicates follicle-center cell origination and better prognosis.
Median age of disease debut is high (over 70 years), and as many men as women develop the disease. Patients are often seriously ill with rapid disease progression, large tumor spreading, and general symptoms. Untreated, patients have a survival time of a few months maximum. The disease history is usually short. Sixty percent have primary lymph node involvement, 40% have primary extra nodal involvement. Around 50-60% can be cured with combination chemotherapy, possibly with radiation therapy. The prognosis for those with localized disease is significantly better.
|Photomicrograph of HE-stained mediastinal large cell B-cell lymphoma. Click to enlarge.
||Photomicrograph of CD30-stained mediastinal large cell B-cell lymphoma. Click to enlarge.
Mediastinal (thymic) large cell B-cell lymphoma is a subentity of DLBCL occuring in the mediastinum having distinct clinical, immunophenotypical, and genotypical characteristics. The clinical profile may be aggressive with tendency for vena cava superior syndrome and thrombosis of larger veins in the mediastinum, neck, and upper extremities. Treatment is the same as for DLBCL otherwise.
In the new WHO classification, there are a series of more rare variants of DLBCL.
Based on gene expression analyses (micro array), DLBCL is separated into three subgroups:
- Germinal center cell-derived DLBCL
- Activated B-cell-compatible DLBCL
- Group which does not fit into the other two. Most mediastinal are included in this group.
The prognoses are different for all three with the poorest for activated B-DLBCL.
This disease group requires prompt treatment at a hospital with special expertise within the field. If primary treatment is not successful, few patients live more than 1-2 years despite standard chemotherapy. Patients begin as soon as possible with combination chemotherapy without dose reduction after an adequate evaluation. The CHOP regimen has in controlled clinical studies shown to be as effect and causes less side effects than regimens including an increased number of chemotherapy drugs. A large German study published as two articles shows, however, that patients under 60 years with normal LDH have higher response rates and better disease-free survival if etoposide is added to CHOP chemotherapy (CHOEP21). Patients with elevated LDH were not included in this study. This study also shows that for patients over 60 years, there are significantly better response rates and survival by giving CHOP courses every 14 days (CHOP14) with growth factor support (G-CSF given days 4–12 between cycles). The differences were most noticeable for patients with elevated LDH, but applicable also for the entire patient group. A study from the French GELA-group shows better response rates and survival with addition of rituximab to all 8 CHOP cycles given every 21 days than CHOP given alone. The differences were greatest for patients with good prognosis (low IPI score). There has until recently been an open question of whether CHOP 14 will give even better results by adding rituximab. Results from the HOVON study which randomized patients over 65 years between CHOP14 with or without rituximab show a significant benefit for CHOP14 + rituximab.
There is currently no convincing evidence that high-dose treatment with autologous stem cell support in the first remission has a place in treatment.
The MINT study was recently concluded and preliminary data show a benefit in combining CHOP-based chemotherapy and rituximab for patients < 60 years with relatively good prognosis (age-adjusted IPI 0-1). This shows that rituximab also plays a role in younger patients and that a low IPI score does not prevent further improvement of results.
Based on results from a series of randomized studies, the Norwegian Lymphoma Group has concluded that all patients with aggressive B-cell lymphomas should now be given rituximab as part of primary treatment.
Standard treatment for patients 18–65 years
For confined disease in stage I and II1, with two neighboring lymph node stations, 3-6 courses of CHOP21 (alternatively CHOP14, see below) + rituximab is given followed by local radiation therapy, 2 Gy x 15-20. Six cycles are given for stage I bulky disease and/or raised LDH and stage II1, otherwise 3 cycles. With raised LDH, which is a sign of high proliferation rate in the tumor, CHOP14 can be used with rituximab. In cases of complete remission after 3 and 6 cycles, radiation therapy can be excluded. Discussion is open, however, for replacing radiation therapy by giving more cycles (4-6) in situations where radiation will cause high morbidity (such as to the oral cavity) or unwanted doses to organs at risk (lungs, kidneys, heart, CNS, etc.)
For radiation therapy, ITV is defined as the original tumor volume (GTV) with 2–3 cm margin, thus the distance from GTV to the field border is 3-4 cm in the craniocaudal direction. In the transversal plane, the margin is defined from GTV to ITV as 1-2 cm and the distance to the field limit should then be 2-3 cm. A CT dose plan is recommended. Otherwise, the same principles apply for organs at risk as described previously for Hodgkins lymphoma.
For advanced disease (stage II2-IV), the age-adjusted IPI 0-1 recommends now CHOP21 + rituximab for 6-8 cycles. Certain patients with expected poor prognosis (IPI 2-3) may receive more intensive treatment in the form of CHOEP21 + rituximab, CHOP14 with rituximab or CHOEP14 with rituximab. Courses every 14 days are recommended especially with raised LDH, a sign of high proliferation rate in the tumor. If the patient is in CR after 3 cycles, or has minimal residual disease not assumed to represent vital tumor tissue, then 6 cycles are given, otherwise 8 cycles. Recently, attention has been given to the point that high-dose intensity (both of chemotherapy and steroids) increases the risk for infection of pneumocystic jirovecii, and it is recommended to give trimethoprim sulfamethoxazole for prophylaxis to all who are given cycles every 14 days. CNS prophylaxis is given to certain patients with high risk. If PR is not reached after 3 cycles, it is indicated to change to the second line regimen (MIME) and consider whether the patient is a candidate for high dose treatment with autologous stem cell support. We recommend primarily that patients with age-adjusted IPI score II-III are included in the the ongoing Nordic phase II study (CRY-04), involving 6 cycles of CHOEP14 + rituximab as well as one cycle of high-dose MTX and one cycle of high-dose Ara-C. The study is being conducted by Oslo University Hospital.
With localized confined disease, local radiation therapy should be considered (2 Gy x 18-20). ITV is defined as residual tumor with margins described above. Residual changes should be biopsied prior. If vital tumor tissue is confirmed, the alternative to radiation therapy is second line chemotherapy and consolidation with HDT with SCS.
Standard treatment for patients older than 65 years
For localized disease in stages I and II1, 3 to 6 CHOP21 + rituximab courses are given followed by local radiation therapy (2 Gy x 20). Six courses are given for stage I bulky disease and/or elevated LDH and for stage II1. For elevated LDH, as sign of high proliferation rate of tumor, it is recommended to treat with CHOP14 with rituximab. With complete remission after 3 and 6 courses, radiation therapy can be avoided. A new study seems to indicate that there is no gain in use of radiation therapy after 4 CHOP cycles for this age group. Where radiation therapy is expected to cause bothersome side effects, it is recommended to avoid radiation therapy after 4 cycles especially in patients over 70 years. The principles for radiation therapy are as given previously.
For advanced disease in stages II2 - IV, CHOP-21 with rituximab is given for patients with normal LDH and CHOP14 + rituximab to patients with elevated LDH. As a rule, 6 courses are given, for patients with IPI score 3-5 additionally 2 rituximab cources.
Many patients in higher age groups are debilitated when treatment begins, which often leads to a lower tolerance for treatment, especially the first course. Because of this, it is recommended to reverse the first course of CHOP, that is, start with prednisolon 100 mg daily for 4 days together with fluid therapy, then administer chemotherapy/rituximab on day 5.
For patients older than 65 years with serious comorbidies, it is important to consider whether these patients will gain from chemotherapy with curative intent. This assessment may be difficult, and should in most cases be handled by an oncology or hematology unit. If the lymphoma is the cause of the reduced medical condition, it may be correct to start intensive treatment, but to reconsider the treatment intensity early during treatment. A French study shows better survival with CHOP chemotherapy than COP for patients over 69 years, but the difference is not particularly large. Elderly patients may have poor tolerance for prednisone and vincristine. Dosage reductions must be carefully considered based on anamnesis and the clinical examination. For patients older than 80 years we suggest 50% dose reduction of i.v drugs in the CHOP regimen and full-dose rituximab. Routine use of G-CSF is recommended in international guidelines. Rituximab should be added to enhance the treatment effect, which is not expected to cause more toxicity.
For patients with poor prognosis and increased risk for CNS recurrence (stage II-IV < 65 years with age-adjusted IPI 2-3), there is an ongoing Nordic phase II study (CHIC). Treatment involves 2 high-dose methotrexate courses with CHOP14-rituximab followed by 4 CHOEP14 + rituximab cycles in addition to one course of high-dose cytarabine.
With the 1st, 3rd, and 5th cycles, liposomal cytarabine is given intraspinally.
Standard treatment for patients younger than 18 years
Adolescents tolerate chemotherapy relatively well. German data show that adolescents 15-18 years have an equivalently good prognosis as children less than 15 years when treated according to the more intensive German lymphoma protocols for children and adolescents. We therefore recommend treatment from the GM-ALL B ALL/NHL 2002 with rituximab protocol. The treatment schedule is analogous to the regimen used for Burkitt's lymphoma/leukemia.
Treatment after failure of first line treatment and treatment for recurrence
High-dose treatment with autologous stem cell support as consolidative treatment in the second remission improves survival in selected patients with recurrence. Patients under 65 years with recurrence and satisfactory organ function are candidates for HDT with SCS as standard treatment. The same applies for patients with failure of the first line regimen. The condition is that they must reach at least partial remission with three IME cycles, possibly with addition of rituximab. The IME regimen is used to avoid additional cardiotoxicity of anthracyclines before the high-dose regimen. Another option is the DHAP regiment. This patient group should be evaluated by a university hospital if there is recurrence. In young patients with an aggressive disease (for example recurrence within 6 months) more intensive treatment such as the IKE regimen should be considered. Around half of patients achieve satisfactory remission, and of those who complete HDT with SCS, five-year recurrence-free survival is about 40%. The Norwegian Lymphoma Group now recommends that rituximab is added as part of recurrence treatment before HDT with SCS in patients who have not received this before and where more than one year has passed since completing first-line treatment that has included rituximab. However, it is recommended that two doses of rituximab are used as in vivo purging with stem cell harvesting with the purpose of reducing the threat for tumor cell contamination of the transplant. Patients who do not reach satisfactory stem cell harvesting or have recurrence after HDT with SCS can be considered for inclusion in protocols for allogenous stem cell transplantation with reduced conditioning at Oslo University Hospital. This applies especially to younger patients with biologically favorable recurrence.
For patients over 65 years and patients not expected to tolerate high-dose treatment, the goal is palliative prolongation of survival. Only around 5% of these patients are alive after three years. Regimens which can be used are ENAP, trofosfamide, COP, and, IME. Addition of rituximab may be considered for those who have not previously received it or where at least six months have passed since they responded to a regimen containing rituximab. Rituximab monotherapy is unlikely to be of significant benefit.
Radiation therapy should be considered for threatened organ function and pain in localized lymphoma manifestations. Radiation therapy may provide good response and improved quality of life in lymphoma patients with advanced, chemo-resistant disease. With short expected survival time, consider reducing the radiation dose and use fewer fractions than normal.
Experimental treatment for recurrence
The multicenter phase III study ORCHAARD is for patients under 65 years and is testing the new monoclonal antibody ofatumomab in combination with chemotherapy (DHAP) before HDT with SCS for responders.