Outcomes of Patients with Primary Mediastinal B-Cell Lymphoma Treated with Dose Adjusted R-EPOCH Regimen: A Single Centre Experience

Abstract

Introduction

Primary Mediastinal B cell lymphoma (PMBCL) is a biologically and clinically distinct subset of diffuse large B cell lymphoma. We analysed the outcomes of our cohort of PMBCL patients treated with Dose adjusted (DA)-R-EPOCH regimen.

Patients and Methods

This is a retrospective analysis of consecutive PMBCL patients who received chemotherapy consisting of DA-R-EPOCH with filgrastim support. Survival analysis was done using Kaplan–Meier method. All calculations were performed using SPSS version 20 for windows.

Results

A total of 43 consecutive suspected PMBCL patients were reviewed for this study, 6 patients were excluded as diagnosis of PMBCL could not be established. All patients except one (97.3%) received 6 cycles of R-DA-EPOCH regimen. Median age of the patients was 27 years (range 15–58). Bulky disease (> 7 cm) was present in 97% patients and 54% patients had extranodal disease. With a median follow up of 40 months, 3-year overall survival was 80.6% (95% CI: 74.0–87.2). The 3-year event free survival was 78.4% (95% CI: 71.6–85.2). There were 6 (16.2%) relapses, 1 (2.7%) primary progression and 7 (23%) deaths. Mediastinal radiotherapy was administered to 17 (45.9%) patients. All the deaths were due to disease progression. Grade III/IV toxicities were seen in 28 (75.7%) patients, febrile neutropenia being the most common one.

Conclusions

DA-R-EPOCH regimen is an effective and tolerable regimen in PMBCL patients even with adverse features.

Background

Primary Mediastinal B cell lymphoma (PMBCL) is a biologically and clinically distinct subset of diffuse large B cell lymphoma (DLBCL) [1]. The Cancer and Leukemia Group B/Alliance group conducted a randomized phase III trial of R‐CHOP versus dose adjusted (DA) R-EPOCH in adults (n = 524) with diffuse large B-cell lymphoma (DLBCL) and reported no difference in survival outcomes [2]. However, the number of patients with PMBCL in this study was small (n = 28) and thus, no definitive conclusions could be drawn by the authors for PMBCL subset. Chemoimmunotherapy, rituximab with CHOP or third-generation regimens like MACOP-B, followed by consolidative radiation has resulted in cure rates in the range of 80%. [3–5] Dunleavy et al. reported a 5-year overall survival of 97% with the DA-R-EPOCH regimen and could omit consolidative mediastinal radiation in 96% of the cases [6]. We analysed the outcomes of our cohort of PMBCL patients treated with DA-R-EPOCH regimen.

Patients and Methods

This is a retrospective analysis of consecutive PMBCL patients treated from January 2012 till January 2019 at Tata Memorial Centre, Mumbai. Treatment-naive PMBCL patients aged ≥ 15 years who received at least 1 cycle were included. The data was retrieved from case files and electronic medical records. The histology was reviewed by three expert hematopathologists according to the World Health Organization (WHO) Classification of Tumors of Haematopoietic and Lymphoid Tissues, 4th edition.

PMBCL was diagnosed based on clinico-pathological features. In histology, patients with intermediate to large cell morphology, with expression of CD30, CD20 and CD 23 were included. In doubtful cases, Rel (counterpart of c-Rel, a protoncogene) and PU.1 (a transcription factor, usually positive in PMBCL) were tested. The patients were defined to have bulky disease when the maximum diameter of the mass was > 7 cm as per the institutional protocol for all lymphomas, however, as most of the literature of PMBCL has taken a cut off > 10 cm for the same, this was also noted. The patients with poor performance score or bulky disease were given prephase chemotherapy as per the institutional protocol. Staging details, lactate dehydrogenase, treatment details, toxicities, response assessment and outcomes were recorded. Patients received chemo-immunotherapy consisting of DA-R-EPOCH with filgrastim support for 6 cycles given on day-care basis using Baxter elastomeric pump. CNS prophylaxis with intrathecal methotrexate was considered in patients with extranodal disease with raised LDH at the discretion of treating oncologist. 18F-fluorodeoxyglucose (FDG) PET/CT was performed after 4 cycles (interim PET) as an institutional policy, however, treatment decision was not changed based on a positive interim PET scan, unless there was disease progression, which is confirmed by a biopsy before initiating salvage therapy. Those patients who had residual disease after 4 cycles underwent repeat PET/CT at completion of 6 cycles. The patients having FDG-avid single site residual disease at the end of 6 cycles underwent localised radiotherapy and further imaging was repeated at three months after completion of radiotherapy. All PET/CT studies were retrospectively reviewed and scored by the same nuclear-medicine physician according to the Deauville 5-point scale (D5PS) without the knowledge of patients’ clinical outcomes. Patients who had a maximum standardized uptake value greater than that of the mediastinal blood pool (MBP) in the residual mediastinal mass underwent repeat scans until normalization or stabilization. MBP activity was defined as the maximum standardized uptake value over the great vessels. Complete metabolic response (CMR) was defined as a completely negative scan or with residual 18-FDG activity below MBP uptake (score 1–2). Score 3 was given when activity was higher than MBP but below the liver uptake while score 4–5 was given for uptake slightly and markedly higher than the liver uptake. Cardiac function was assessed by echocardiography at baseline and after 4 cycles of chemotherapy. Cerebrospinal fluid analysis with cytology and/or flow cytometry was performed if clinically indicated.

Last follow up date and survival status were recorded. Baseline clinical, epidemiological data, treatment, toxicities and response were summarized using descriptive statistics. Survival analysis was done using Kaplan–Meier method. All calculations were performed using SPSS version 20 for windows. Overall survival (OS) was calculated from registration till death or last follow up. Patients who were on palliative care and lost to follow up were censored as an event. Event free survival (EFS) was calculated from the registration date till progression, relapse or death due to any cause or last follow up. Multiple linear regression was used to predict the effects of various parameters on the OS.

Results

A total of 43 consecutive suspected PMBCL patients were reviewed for this study. Four patients were excluded as their final diagnosis turned out to be grey zone lymphoma. Two patients were excluded as the diagnosis was doubtful and sufficient tissue was not available for further review. The baseline features are summarized in Table 1. Median age of the patients was 27 years (range 15–58). Bulky disease (> 7 cm) was present in 97% patients, > 10 cm disease in 23 (62.2%), and 54% patients had extranodal disease, while pleuropericardial effusion was present in 5 (13.5%) patients at baseline. Out of 37 patients, 35 (94.6%) received prephase therapy at baseline in view of symptomatic disease. Thirty-two (86.5%) patients received prephase with injection dexamethasone 16 mg day 1 to 3 and injection cyclophosphamide 275 mg/m² (CP). Two (5.4%) patients received CVP as prephase (vincristine 1.5 mg/m² in addition to CP) while 2 (5.4%) patients received steroid alone as prephase. Thrombotic complications were present in 3 (8.1%) patients with two having SVC while one patient had axillary and sub clavian vein thrombosis. All patients had adequate organ function at baseline. The standard method for administration of DA-R-EPOCH was used [6].

Table 1.

Baseline characteristics

Baseline characteristics	n = 37 (%)
Age in years, median (range)	27 (15–58)
Male, n (%)	20 (54)
Duration of symptoms, in months Median(range)	2 (1–12)
B symptoms, n (%)	13 (35)
PS (ECOG scale) n (%)
0  1  2  3–4	2 (5.4) 28 (75.7) 4 (10.8) 3 (8.1)
Bulky disease, n (%)
> 7 cm   > 10 cm	36 (97.3) 23 (62.2)
Ann Arbor Stage, n (%)
I  II  III  IV	5 (13.5) 12 (32.4) 5 (13.5) 15 (40.5)
Extranodal sites, n (%).
0  1   ≥ 2	17 (45.9) 8 (21.6) 12(32.4)
Pleural effusion, n (%)  Pericardial effusion, n (%)	8 (21.6) 4 (10.8)
IPI score
1  2  3  4	7 (18.9) 14 (37.8) 13 (35.1) 3 (8.1)
Serum albumin at baseline
Median (range) in g/dL   < 4 g/dL, n (%)	4.1 (2.0–4.5) 15 (40.5)
Hemoglobin at baseline
Median (range) in g/dL   < 11 g/dL, n (%)	12.3 (8.2–16.3) 9 (24.3)
LDH at baseline*
Median (range) in U/L
> 2 times of upper limit of normal, n (%)	413 (210–1851) 15 (40.5)

^*LDH Reference Range: 100–190 U/L

All patients except two (94.6%) received 6 cycles of DA-R-EPOCH regimen. CNS prophylaxis in the form of intrathecal methotrexate was administered in 9 (24.3%) patients. Dose escalation was possible in 25 (67.6%) patients, 22 (59.4%) patients could reach at least till level 3 dosing. The dose level details were available for 184 cycles, six (16.2%) patients’ dose levels were not accessible. Out of 184 cycles, 61 (33.1%) cycles were given at dose level 1, 60 (32.6%) at dose level 2, 43 (23.4%) at dose level 3, 18 (9.8%) at dose level 4, and 2 (1.1%) cycles at dose level 5. Grade III/IV toxicities were seen in 28 (75.7%) patients, febrile neutropenia was the most common occurring in 20 (54%) patients [34 episodes in total 221 cycles administered (15.4%)], peripheral neuropathy in 7 (18.9%) patients, left ventricular dysfunction in 1 (2.7%) patient, grade III/IV mucositis in 4 (10.8%) patients, ileus in 1 (2.7%) patients, grade III/IV anemia in 9 (24.3%) patients. Fourteen (37.8%) patients required hospitalisation, median duration was 8 days (3–21 days) and 6 (16.2%) patients had interruptions in therapy. Mediastinal radiotherapy was administered to 17 (45.9%) patients. The median radiation dose was 45 Gy (range 36–46). Four (23.5%) patients received mediastinal RT despite being in CMR as per the prevailing institutional policy. For the remaining 13 (76.5%) patients who received mediastinal RT, the median Deauville Score (DS) was 4 (range 2–5) at the end of chemotherapy. One patient developed Tuberculosis after 5 cycles of chemotherapy, cycle 6 was omitted and patient received mediastinal RT. Another patient had drop in ejection fraction to 46% post 4 cycles DA-R-EPOCH, chemotherapy was changed to R-CEOP for further two cycles and patient was given mediastinal RT. In the overall cohort, there was a complete response in 27 (72.9%) and partial response in 6 (16.2%). Age, ECOG PS, mediastinal mass size, pleuropericardial effusion, stage, IPI, albumin and LDH could not predict the OS, F(8, 27) = 0.653, p = 0.727.

There were 6 (16.2%) relapses and 1 (2.7%) primary progression leading to a total of 7 (18.9%) deaths. All the deaths were due to disease progression. Out of 7 patients who progressed, 4 (57%) had more than one extranodal site while all had mediastinal mass of 10 cm or more. Only supportive care was offered to two patients, one who was primary progressive and another one having disease free interval of less than 3 months. Salvage chemotherapy with DHAP (± Rituximab) was planned for 3 patients, 2 of them progressed after two cycles and were further planned for supportive care alone. Response details were not available for one patient as salvage chemotherapy was taken outside our institution. On patient received GDP chemotherapy, hd CMR after 3 cycles but progressed before ASCT in 4 weeks. Lenalidomide was used in one patient but patient was lost to follow up, thus, response details were not available. Palliative radiotherapy was administered to two patients (one whole brain radiotherapy and another patient received mediastinal RT). With a median follow up of 40 (standard error: 6.8) months, 3-years OS was 80.6% (95% CI: 74.0–87.2). The 3-years EFS was 78.4% (95% CI: 71.6–85.2). Figures 1 and 2 depicts the OS and EFS curves.

Fig. 1.

Kaplan–Meier survival curve showing event free survival (EFS)of the PMBCL patients treated with DA-R-EPOCH regimen (x-axis showing the EFS in months, while y-axis showing the probability of survival)

Fig. 2.

Kaplan–Meier survival curve showing overall survival (OS) of the PMBCL patients treated with DA-R-EPOCH regimen. (x- axis showing the EFS in months, while y-axis showing the probability of survival)

Discussion

The improved outcomes associated with the use of DA-R-EPOCH in PMBCL is thought to be related to dose intensity and the continuous infusion schedule [7, 8]. National Cancer Institute (NCI) phase II study on 51 patients concluded that this regimen is associated with high cure rates [6] In another retrospective cohort of 16 patients from Stanford reported in the same paper, event free survival at 3 y was 100% and no patient received RT [6]. In spite of the small numbers, these results have influenced clinical practice. In another retrospective multicentre study by Giulino-Roth et al., 156 patients (38 children and 118 adults) with PMBCL treated with DA‐R-EPOCH, the estimated 3-years EFS was 85.9%, 3-years OS was 95.4% while radiotherapy was administered in 14.9% patients [7]. In our study, extranodal disease was present in 54% patients in our study while it was found in 53% and 19% patients in NCI study and Stanford cohort, respectively. Similarly, baseline LDH was elevated in nearly all (97.3%) the patients in this study while it was elevated in 78% and 69% patients in NCI study and Stanford cohort, respectively. These comparisons point towards advanced nature of disease in our patients which coupled with poor nutritional status might have resulted in comparatively poorer outcomes in the present study. The poor nutritional status is reflected by lower median hemoglobin and serum albumin levels. However, it clearly establishes the feasibility of DA-R-EPOCH with no grade 5 toxicities, interruption of therapy in 16% of the patients and 94.6% patients completing planned 6 cycles. Non-hematopoietic toxic effects were similar to those reported in previous studies [9, 10].

The role of consolidative mediastinal RT in PMBCL remains a topic of debate. It has been a conventional belief that adding radiation may improve response rate and long-term outcome in PMBCL. However, there have been concerns of increased risk of second malignancies, especially breast cancer and accelerated coronary artery disease. In a single institutional study by Mazzaretto et al., following intensive induction chemotherapy with MACOP-B/ VACOP-B, 42% of patients were in CR and this figure rose to 95% following mediastinal involved-field radiation therapy (IFRT) [11]. However, in another retrospective British-Columbia study of 153 patients, an intention-to-treat analysis failed to reveal any survival advantage or reduced local relapse rate with the routine addition of radiotherapy [12]. Another retrospective study of 45 patients showed that RT was able to convert the effect of immunochemotherapy of CR additionally for approximately 20% (MACOP-B/VACOP-B + R achieved 62% of CR, and with the addition of RT it was 80%) [5]. With the use of DA-R-EPOCH, only 4% required consolidative RT in the NCI study [6].

A multicentre retrospective study by Chan et al. compared patients treated with R-CHOP alone, R-CHOP plus RT, and DA-R-EPOCH found that patients treated with the latter two regimens had significantly better PFS than those receiving R‐CHOP alone (5‐years PFS being around 90% vs 56%, P = 0.02) [13]. Also, the subgroup analysis clearly identified that the patients with bulky fared poorly with R-CHOP alone. Another retrospective study by Malenda et al. compared R-CHOP (n = 25) and DA-R-EPOCH (n = 28) and reported similar PFS and OS [14]. However, there was clear bias as 100% patients receiving DA-R-EPOCH had bulky disease as against 68% patients receiving R-CHOP. The same study also found similar grade 3/4 hematological toxicities but higher grade 1/2 cardiologic complications with DA-R-EPOCH. In our study, left ventricular dysfunction occurred in 1 (2.7%) patient only which can be explained by prolonged infusion of doxorubicin leading to reduced cardiologic complications. In a recent Indian experience (n = 12), the overall response rate was 91.6%, with 75% patients attaining CR, while.

17% attained CR after RT while 8.5% progressed on chemoimmunotherapy. [15] The important point highlighted by the authors is that all 3 patients who relapsed later had baseline bulky disease defined by > 10 cm mediastinal mass, raised LDH, pleuropericardial effusion,with 2 patients having SVC syndrome upfront. This is similar to our study where all patients (n = 7) who progressed had baseline > 10 cm mediastinal mass. Table 2 shows the comparison of results of published studies on PMBCL with details of the outcomes and protocol used and Table 3 compares the toxicities of DA-R-EPOCH in our study with that of the prospective NCI study [6].

Table 2.

Outcomes following chemo (± immuno) therapy in patients with primary mediastinal large B-cell lymphoma in the recent literature

Study (Reference)	Number of adult patients (n)	Type of study	Therapy given	PD on chemo (± immuno) therapy	Mediastinal RT given to %	Median follow up duration	EFS	OS
Xu et al. (4)	40 39	Retrospective	CHOP R-CHOP	16.5%	70% 82.1%	61.0 m	44.2% 76.7% (5-yrs PFS)	48.3% 83.7% (5-yrs)
Dunleavy et al. (6)	51	Prospective	DA-R-EPOCH	1.9%	4%	63.0 m	93%	97%
Giulino-Roth et al. (7)	118	Retrospective	DA-R-EPOCH	1.7%	14.9%	22.6 m	85.9% (3-yrs)	95.4% (3-yrs)
Chan et al. (13)	41 37 46	Retrospective	R-CHOP R-CHOP + RT DA-R-EPOCH	Not available	0% 100% 6%	45.0 m (overall)	56.0% 90% 88.5% (5-yrs PFS)	76.1% 93.9% 96.9% (5-yrs)
Malenda et al. (14)	25 28	Retrospective	CHOP DA-R-EPOCH	4%3.7%	76.0% 59.3%	45.0 m 23.5 m	87% 73.9% (1-yr PFS)	100% 92% (1-yr)
Gogia et al. (15)	12	Retrospective	DA-R-EPOCH	8.3%	16.7%	29.0 m	75% (2-yrs)	83% (2-yrs)
Present study	37	Retrospective	DA-R-EPOCH	2.7%	45.9%	40.0 m	78.4% (3-yrs)	80.6% (3-yrs)

PFS, progression-free survival; OS, overall survival; EFS, event-free survival; m, months; RT, radiotherapy

Table 3.

Toxicities to DA-R-EPOCH regimen in this study as compared to the prospective study by Duleavy et al. (6)

Toxicities (Grade 3/4)	Dunleavy et al6 (n = 51)	Present Study (n = 37)
Hospitalization for FN	13% of cycles	23% of cycles (23/219) 14 (37.8%) patients
Anemia	Not reported	9 (24.3%)
Peripheral Neuropathy	8 (15.7%)	7 (18.9%)
Mucositis	4 (7.8%)	4 (10.8%)
Ileus	0	1 (2.7%)
Left ventricular dysfunction	0	1 (2.7%)
AML	1 (1.9%)	0

There are some important limitations of this study; being retrospective, limited capture of toxicity data was possible and the number of patients were rather small precluding meaningful multivariate analysis of the prognostic factors. Also, some patients in this study received mediastinal RT despite the patient being in CMR as per the prevailing institutional protocol which was later changed as per the availability of data. Despite these limitations, this study provides largest real-world data from India on the outcomes of PMBCL patients treated with DA-R-EPOCH protocol.

Conclusions

DA-R-EPOCH regimen is an effective and tolerable regimen in PMBCL patients even with adverse features.

Authors Contribution

All the authors made substantial contributions in the design, conduct, and analysis part of the research. The article was drafted and approved by all the authors for publication.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Complaince with Ethical Standards

Conflict of interest

The authors declare no competing interests related to the study.