|Year : 2017 | Volume
| Issue : 1 | Page : 8-13
Primary mediastinal large B cell lymphoma: Frontline treatment with an alternating chemotherapy regimen based on high dose methotrexate - A single institution experience
Natalie Wehde1, Gudrun Borte2, Andre Liebmann3, Haifa Kathrin Al-Ali1, Dietger Walter Niederwieser1, Wolfram Poenisch1
1 Department of Hematology, University Hospital Leipzig, Johannisallee 32A 04103, Germany
2 Department of Radiology, University Hospital Leipzig, Liebigstr 20 04103, Germany
3 Department of Radiotherapy, St. Georg Hospital, Delitzscher Str. 141 04129, Leipzig, Germany
|Date of Web Publication||17-Jan-2017|
Department of Hematology, University Hospital Leipzig, Johannisallee 32A 04103, Leipzig
Source of Support: None, Conflict of Interest: None
Background and Aims: In this retrospective analysis, we report our experience with the high-dose methotrexate-based chemotherapy B-ALL protocol of the German ALL study group followed by consolidative mediastinal radiotherapy in patients with adult primary mediastinal large B-cell lymphoma (PMLBCL) as a single-center trial. Setting and Design: Nineteen patients with newly diagnosed/untreated PMLBCL who were treated between June 1999 and May 2013 were included. Patients received a high-dose methotrexate protocol consisting of six cycles. Materials and Methods: Patients received thrice block A [day 1: methotrexate 1,500 mg/m2 for 24 h; days 1-5: ifosfamide 800 mg/m2; days 4-5: VM-26 100 mg/m2 and ara-C 2x150 mg/m2 (bid); days 1-5: dexamethasone 10 mg/m2 p.o.] and thrice block B [day 1: vincristine 2 mg i.v., MTX as in block A; days 1-5: cyclophosphamide 200 mg/m2; days 4-5: adriamycin 25 mg/m2; days 1-5: dexamethasone 10 mg/m2 p.o.] applied alternatively every 3 weeks. Results: After chemotherapy five patients achieved CR, nine patients CRu and four patients PR. The restaging procedures after consolidation radiotherapy showed an overall response rate of 95% (9 CR and 9 CRu). With a median follow-up of 56 months, progression free survival and overall survival at 60 months were 88%. The most common grade 3/4 hematological toxicities were leukocytopenia and neutropenia (100%), thrombocytopenia (95%), and anemia (63%). Conclusion: Our data suggest that the current high-dose methotrexate-based chemotherapy protocol followed by consolidation mediastinal radiotherapy in patients with adult PMLBCL is feasible, effective, and moderately tolerated.
Keywords: Frontline treatment, high-dose methotrexate, primary mediastinal large B-cell lymphoma
|How to cite this article:|
Wehde N, Borte G, Liebmann A, Al-Ali HK, Niederwieser DW, Poenisch W. Primary mediastinal large B cell lymphoma: Frontline treatment with an alternating chemotherapy regimen based on high dose methotrexate - A single institution experience. J Med Soc 2017;31:8-13
|How to cite this URL:|
Wehde N, Borte G, Liebmann A, Al-Ali HK, Niederwieser DW, Poenisch W. Primary mediastinal large B cell lymphoma: Frontline treatment with an alternating chemotherapy regimen based on high dose methotrexate - A single institution experience. J Med Soc [serial online] 2017 [cited 2020 Apr 1];31:8-13. Available from: http://www.jmedsoc.org/text.asp?2017/31/1/8/198427
| Introduction|| |
Primary mediastinal large B-cell lymphoma (PMLBCL) is recognized as the distinct subtype of diffuse large B-cell lymphoma (DLBCL) in the World Health Organization classification of neoplasms of the hematopoietic lymphoid tissue.  PMLBCL constitutes approximately 2% to 4% of non-Hodgkin's lymphomas. In contrast to the more elderly population affected by DLBCL, PMLBCL occurs mainly in young patients (median age, 30-35 years), with a female predominance, and is very rare in patients aged >60 years.  Furthermore, systemic involvement at diagnosis is less common, and most patients are Stage I-II. These patients have bulky mediastinal masses with the frequent invasion of adjacent structures, often with pleural and pericardial effusions. Up to 50% of the patients have symptoms of a superior vena cava syndrome.  Mediastinal lymphomas display a diffuse growth pattern with variable degrees of sclerosis, which can explain the frequent persistence of residual tumors even after successful treatment.  Involvement of the central nervous system (CNS) is an important, albeit relatively infrequent complication of PMLBCL. 
The precise role for 18 F-fluorodeoxyglucose-positron-emission-tomography-computed tomography (FDG-PET-CT) in monitoring disease status in patients with residual mediastinal masses at the end of therapy is under evaluation. ,,, In a phase 2 study with a dose-adjusted etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and rituximab treatment in 51 patients with PMLBCL the FDG-PET-CT had a positive predictive value of 17% and a negative value of 100%.  The preliminary results of an international phase 2 trial (International Extranodal Lymphoma Study Group-26 study) showed that the achievement of a complete response (CR) after rituximab/anthracycline-containing chemotherapy predicted a significantly longer progression-free survival (PFS) with high sensitivity but poor specificity (negative predictive value of 0.98 but positive predictive value of only 0.15) and showed a borderline impact (P = 0.052) on overall survival (OS).  These data indicate that further evaluation is required before risk-adapted planned therapy based on FDG-PET evaluation alone of PMLBCL could be applied.
Gene expression profiling strongly supports a relationship between PMLBCL and the nodular sclerosis subtype of classical Hodgkin's lymphoma; the supposed cell of origin for both diseases being a thymic B-cell. ,
There is no standard treatment for PMLBCL. Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) with or without consolidation radiotherapy is not sufficient since cure rates do not exceed 50-60%. ,,,, One approach to improving response rates of PMLBCL involves the addition of CD20 monoclonal antibody rituximab in nonmethotrexate-containing regimens. ,, Several retrospective studies have investigated the efficacy of intensive chemotherapy regimens such as methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B) or other third-generation chemotherapies, followed in almost all cases by radiotherapy, with evidence of the superiority of intensive regimens over CHOP-type chemotherapy. ,,,,, These intensive chemotherapy regimens produce high overall response rates (ORR) in the range of 70-90%. While a therapy with rituximab in CHOP-like regimen shows a significant benefit in patients with PMLBCL, it is still unclear whether third-generation chemotherapy with additional rituximab can improve outcome. 
Fietz et al.  investigated the use of a high-dose methotrexate-based alternating chemotherapy regimen (B-acute lymphoblastic leukemia [ALL] protocol of the German ALL study group [GMALL])  followed by consolidative mediastinal radiotherapy first as a single-center trial, then later as a prospective multicenter phase 2 study in 44 patients between 1988 and 2004. Response rates exceeded 90% with an OS rate of 80% in the single-center group (8.6 years median follow-up) and 82% in the multicenter group (2.5 years follow-up). Short-term toxicity was manageable. In a prospective study of adult PMLBCL, the combination of rituximab and six short intensive methotrexate-containing chemotherapy cycles (GMALL B-ALL/NHL 2002 protocol) showed a 3-year OS of 90% in 37 patients younger than 55 years and of 67% in five elderly patients.  These results were comparable with the second study using the same combination protocol of rituximab and methotrexate-containing chemotherapy with a 3-year OS of 100% in 15 patients.  In this retrospective analysis, we report our experience with the high-dose methotrexate-based chemotherapy B-ALL protocol of the GMALL study group followed by consolidation mediastinal radiotherapy in patients with adult PMLBCL as a single-center trial.
| Methods|| |
Patients with newly diagnosed PMLBCL who were treated in our institution between June 1999 and May 2013 were included in this retrospective analysis. The diagnostic material was obtained by transbronchialbiopsy, transthoracic CT-guided biopsy or mediastinoscopy of the mediastinal mass. Inclusion criteria were a histologically proven PMLBCL, age 18-75 years, and no prior chemotherapy or radiotherapy. Before therapy, all patients received routine staging procedures, including complete physical examination, laboratory tests, including serum lactate dehydrogenase (LDH), chest X-ray, CT scan of the brain, chest, abdomen, and pelvis, bone marrow aspirate, and biopsy. The disease stage was evaluated according to the Ann Arbor staging system. Bulky disease was defined as a mediastinal mass exceeding one-third of the thoracic diameter or a mediastinal mass with a diameter at the widest point of >10 cm. The age-adjusted International Prognostic Index (aaIPI) was determined for the cohort based on performance status (0, 1 vs. ≥2), LDH (normal or elevated) and stage (I/II vs. III/IV) (0 factors, low risk; 1 factor, low-intermediate risk; 2 factors, high-intermediate risk; 3 factors, high risk).  Exclusion criteria for treatment in this protocol were CNS involvement or positive HIV screening serotest. All patients gave written informed consent for the applied treatment and the use of anonymized personal data for clinical research. The clinical trial and the informed consent form were approved by the ethical committees and local authorities in accordance with federal regulations and the declaration of Helsinki.
Patients were treated according to the B-ALL protocol of the GMALL based on high-dose methotrexate consisting of six chemotherapy cycles: Thrice block A (day 1, methotrexate 1500 mg/m2 for 24 h; days 1-5, ifosfamide 800 mg/m2; days 4-5, VM-26 100 mg/m2 and ara-C 2 × 150 mg/m2 (bid); days 1-5, dexamethasone 10 mg/m2 p.o.) and thrice block B (day 1, vincristine 2 mg i.v., MTX as in block A; days 1-5, cyclophosphamide 200 mg/m2; days 4-5, adriamycin 25 mg/m2; days 1-5, dexamethasone 10 mg/m2 p.o.) applied alternatively every 3 weeks (block A1, B1, A2, B2, A3, B3). ,, Ten percent of the methotrexate dose was given as a 30-min bolus, 90% as a 23.5-h continuous infusion. After 42 h, a rescue with folinic acid was initiated and intensified if methotrexate levels remained elevated. Since January 2005, 13 patients received additional treatment with rituximab 375 mg/m2 on day 0 of each cycle.  Supportive care was according to standard procedures and included G-CSF 5 ΅g/kg/day s.c. from day 7. All patients were scheduled for consolidation involved-field radiation of the initial mediastinal mass after completion of chemotherapy with 40 Gy in daily fractions of 2.0 Gy over 20 days. Radiotherapy was delivered using a CT-planned 3D-conformal 10 MV-photon-beam technique.
Patients were assigned a response category based on standard criteria. CR was defined as a complete resolution of all symptoms and clinical signs of disease and disappearance of radiographic evidence of measurable disease.  CR unconfirmed (CRu) was defined as the persistence of residual fibrotic mediastinal remnants (reduction >75%) in radiologic images without other signs or symptoms of the disease. Partial response (PR) was defined as a >50% reduction of the tumor mass as assessed by the sum of the products of the largest perpendicular diameters of any measurable lesions. Nonresponse was defined as anything less than PR. Progressive disease was defined as either growth during therapy or regrowth following response.
Treatment response was determined during the first 4 weeks after the end of chemotherapy and 6 weeks after radiotherapy completion. This evaluation included complete physical examination, complete blood count, chest X-ray, and CT scan of the chest, abdomen, and pelvis. Further examinations including PET scan were performed depending on follow-up results.
Side effects were evaluated daily in terms of laboratory and clinical investigations, medical history, and a full physical examination. Toxicity was monitored daily throughout the treatment using the National Cancer Institute Common Toxicity version 2.0. Patients were followed up at 4-weekly intervals during the first 3 months after the end of treatment and thereafter at 12-weekly intervals over 5 years.
Descriptive statistical analyses were obtained for demographic and baseline variables. Patients were followed to a closeout date of at least March 31, 2015. Analysis of OS and PFS included all patients who commenced treatment. OS was measured from the time of inclusion into the protocol till death, and PFS from the time of inclusion till relapse, progression, or death. OS and PFS were estimated using the Kaplan-Meier survival analysis.
| Results|| |
Nineteen patients with previously untreated PMLBCL were enrolled in this retrospective analysis. All patients completed at least one cycle of a chemotherapy regimen based on high-dose methotrexate and were therefore available for analysis. Baseline demographics and disease characteristics are shown in [Table 1]. Median age was 39 (range 19-63) years, only one patient was older than 60 years. None of the patients had bone marrow involvement. Bulky disease was present in most patients (n = 14). The majority of patients presented with early-stage disease, good or moderate reduced performance status (Eastern Cooperative Oncology Group ≤ 2), and elevated LDH. According to the aaIPI, most patients (n = 15) had either low intermediate or high intermediate risk disease. Seventeen patients (89%) received consolidation radiotherapy to the mediastinal mass.
|Table 1: Baselines characteristics and measurements in 19 patients with primary mediastinal large B-cell lymphoma|
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A total of 15 of the 19 patients completed the six cycles chemotherapy based on high-dose methotrexate and consolidation with radiotherapy of the mediastinal mass. During the second cycle of chemotherapy one patient with preexisting pneumonia died following respiratory tract infection and septicemia during the chemotherapy-induced leukocyte nadir. Three patients with CRu discontinued chemotherapy prematurely at their own request after 3 (n = 1) or 5 (n = 2) cycles. These patients also received additional radiotherapy. [Figure 1] shows the response of patients after two, four, and six cycles of chemotherapy and after radiotherapy. The remission achieved after four cycles chemotherapy was rarely complete; further two cycles, however, increased the rate of CR and CRu from 21% to 74%. After chemotherapy, 5 patients (26%) achieved CR, 9 patients (47%) CRu and 4 patients (21%) obtained PR [Table 2]. The restaging procedures after consolidation radiotherapy showed an ORR of 95% (9 CR and 9 CRu). In the absence of intrathecal CNS-prophylaxis, no patient experienced CNS involvement. With a median follow-up for surviving patients of 56 months, PFS and OS at 60 months were 88% [Figure 2]. One elderly female patient with CR died of a myocardial infarction 32 months after treatment. No patient developed a relapse during the observation time.
|Figure 1: Cumulative percentage of response after each chemotherapy cycle in 19 patients with primary mediastinal large B-cell lymphoma and frontline treatment with an alternating chemotherapy regimen based on high-dose methotrexate and consolidation radiotherapy to the mediastinal mass|
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|Figure 2: Progression free survival and overall survival in 19 patients with primary mediastinal large B-cell lymphoma and frontline treatment with an alternating chemotherapy regimen based on high-dose methotrexate and consolidation radiotherapy to the mediastinal mass|
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|Table 2: Best confi rmed response in 19 patients with primary mediastinal large B-cell lymphoma after frontline treatment with an alternating chemotherapy regimen based on high-dose methotrexate and consolidation radiotherapy to the mediastinal mass|
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Toxicity was assessed daily during the administration of all 105 cycles (block A: n = 54; block B: n = 51) of chemotherapy and radiation therapy. From the total of 19 patients, all patients experienced grade 3/4 hematological toxicities [Table 3]. Most of these were leukocytopenia and neutropenia (n = 19, 100%), thrombocytopenia (n = 18, 95%), and anemia (n = 12, 63%). No patient had bleeding related to thrombocytopenia. Moderate bacterial and/or mycotic infections (grade 2) were seen in one neutropenic patient and severe infections (grade 3) in 14 neutropenic patients. One neutropenic patient with preexisting pneumonia died following respiratory tract infection and septicemia during the second cycle of chemotherapy. 12 patients with grade 3/4 mucositis need a pain treatment step 3 after the WHO pain ladder with oral morphine, or in the case of insufficient oral resorption, with intravenous morphine.
|Table 3: Incidence of hematological and nonhematological toxicities in 105 cumulative cycles of an alternating chemotherapy regimen based on high-dose methotrexate|
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Hematotoxicity was substantially more pronounced in chemotherapy block A with grade 3/4 toxicity for leukocytes in 91% of cycles compared with 69% in block B (P < 0.005), for granulocytes in 91% versus 71% (P < 0.01), and for platelets in 80% versus 33% (P < 0.001). Other toxicities included elevated transaminases grade 2 in 7 (37%) and grade 3 in 6 (32%) patients only in the first block A chemotherapy cycle and grade 1 nausea in all patients despite antiemetic prophylaxis.
The leading toxicity during radiotherapeutic series was dysphagia with CTC 0° in 2 patients (11%), CTC I° in 12 patients (66%), CTC II° in 3 patients (17%) and CTC III° in 1 patient (6%). Only mild dermatitis (all Patients ≤ CTC I°) and no further toxicities were assessed. Radiotherapeutic acute reactions disappeared within 2-3 weeks after the end of series completely.
| Discussion|| |
There is no established standard treatment for PMLBCL in adult patients. Early experience suggested poor results with CHOP chemotherapy alone. ,, Based on these disappointing results with CHOP-like therapy, the study group of Knauf started exploring dose intensification with a methotrexate-based alternating chemotherapy regimen in the late 1980s.  In this prospective trial, the ORR in 43 evaluable patients was 93% (CR and CR with residual fibrotic mediastinal remnants: 63%, PR: 30%) including two patients with early death following infectious complications. Our observation confirms the efficacy of this alternating chemotherapy regimen in the treatment of PMLBCL in adults. In our analysis, the ORR after six cycles of chemotherapy was 95% (CR/CRu: 74%, PR: 21%).
Following consolidation radiotherapy, the CR/CRu rate of 74% increased to 95% (CR: n = 9, CRu: n = 9). Owing to the prominent fibrotic component of PMLBCL, a residual fibrotic mediastinal remnant is often present on completion of therapy. It remains uncertain whether this is residual disease or simple fibrotic tissue. Residual tumor tissues of this type were detected after completion of chemo/radiotherapy in nine of our patients. In all cases, these appear have been comprise of residual fibrotic scar tissue, since no relapses occurred during the follow-up. In consideration of the long-term toxicity of thoracic radiotherapy, the optimal integration of PET scanning to minimize radiotherapy use in further studies should be investigated.
Our ORR compares very favorably with these reported by Fietz  and Pohlen et al.  for a similar methotrexate-based alternating chemotherapy regimen or for other third-generation chemotherapy regimen and radiotherapy. For example, for the MACOP-B or MACOP-B/VACOP-B regimen response rates ranged from 80% to 100% and CR/CRu rates from 80% to 90%. ,,,,,
CNS involvement is found in patients with PMLBCL more often than in other lymphomas after CHOP-like therapy.  The high dose methotrexate therapy used by us can penetrate the blood-brain barrier and thus, prevent CNS relapse. In accordance with Fietz,  we observed no CNS relapses despite the absence of intrathecal prophylaxis.
None of our patients showed the progression of disease during treatment or relapsed later. In general, relapse rarely affects PMLBCL patients, most relapses occur within the first 12 months after the completion of first-line treatment. ,,,, This results in a high PFS rate between 75% and 90% at 5 years that is comparable to the PFS rate of 88% after 5 years reported here.
Alongside efficacy, toxicity rates are another key factor that must be taken into consideration, and these were similar to those that have been reported in other methotrexate-based alternating chemotherapy regimens. ,, High-dose methotrexate is responsible for a considerable part of the toxicity, in particular mucositis. The reported incidence of mucositis grade 3/4 after high-dose methotrexate therapy ranges from 20% to 60% ,, consistent with our observed rate of approximately 30%. We also observed severe hematological side effects in 100% of our patients. Neutropenia grade 3 or 4 was transient under prophylactic G-CSF therapy and neither prolongation of therapy nor dose reduction was necessary. The toxicity profile required hospitalization in most patients.
The early death rate in our study was 5%, which is similar to other high dose methotrexate regimens, varying from 4% to 10%. ,,
Our data suggest that the current high-dose methotrexate-based chemotherapy protocol followed by consolidative mediastinal radiotherapy in patients with adult PMLBCL is feasible, effective, and moderately tolerated.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]