We performed a retrospective analysis of 35 patients with primary diffuse large B-cell lymphoma of the mediastinum treated with high-dose cyclophosphamide, carmustine, and etoposide (CBV) plus autologous hematopoietic cell transplantation to determine outcome and prognostic features for progression-free survival (PFS). Thirty-five patients with primary diffuse large B-cell lymphoma of the mediastinum in first response (complete remission [CR] or partial remission [PR]) with poor prognostic features, with primarily refractory disease, or with relapsed disease following conventional chemotherapy, were treated with CBV and autologous hematopoietic cell transplantation. PFS and overall survival were assessed by the Kaplan-Meier method. Patient characteristics before transplantation were examined by univariate analysis using the log-rank test and by Cox's proportional hazards regression analysis to determine predictors of PFS. Estimated 5-year PFS varied significantly with patient disease status at transplantation. Patients transplanted in first response had an estimated 5-year PFS rate of 83%, compared with 58% and 27% for primarily refractory and relapsed patients, respectively (P = .02). The strongest predictor of PFS was chemotherapy responsiveness immediately before transplantation. Patients with chemotherapy-responsive disease had a significantly greater PFS rate than patients with chemotherapy-nonresponsive disease (risk ratio, 3.60; 95% confidence interval [CI], 1.14 to 11.4). No other factors were found to be significant on univariate or multivariate analysis. Patients with primary diffuse large B-cell lymphoma of the mediastinum can achieve prolonged PFS following high-dose chemotherapy and autologous hematopoietic cell transplantation. Outcomes are strongly correlated with disease status (first response v refractoryv relapsed) at transplantation and chemotherapy responsiveness immediately before transplantation.

PRIMARY DIFFUSE LARGE B-cell lymphoma of the mediastinum (mediastinal large-cell lymphoma) is a distinct clinicopathologic entity recognized in the revised European-American classification of lymphoid neoplasms (REAL classification).1-13 Patients present with an aggressive, locally invasive anterior mediastinal mass, believed to originate from thymic B cells,14 and frequently develop symptoms of airway compromise or superior vena cava (SVC) syndrome. The tumors are usually bulky (>10 cm in diameter), and confined to the thorax at presentation.13 Bone marrow involvement is rare.7,9,11-13 Histology shows large cells with variable nuclear features, B-cell immunophenotype, and frequent compartmentalizing sclerosis.15,16 There is a female predominance and a median age of diagnosis in the fourth decade.7,9,13 Mediastinal large-cell lymphoma may represent 3% to 7% of all diffuse large-cell lymphomas.7,9,11 

Response to treatment and clinical outcome have varied from one series to another, and may be explained by the small number of patients in most series, variable patient characteristics, inconsistent histologic inclusion criteria, and the heterogeneity of therapy. Early studies suggesting that mediastinal large-cell lymphomas were unusually aggressive, with a poorer prognosis than other large-cell lymphomas,2-4 have been contradicted by more recent reports. Complete remission (CR) rates of 53% to 80% have been reported following initial therapy,7,12 with a 50% to 65% overall survival rate at 5 years.7,12,13 Management can be complicated by the presence of residual masses of uncertain significance. Radiation therapy has been administered following chemotherapy, with unclear benefit. Relapses are frequently extranodal, including involvement of the lung, liver, gastrointestinal tract, kidneys, adrenals, ovaries, and CNS.7,9,11 Outcome following additional chemotherapy (salvage therapy) has not been systematically studied. Patients whose disease has relapsed, or who have primarily refractory disease, are often resistant to salvage therapy, with a poor survival rate.7,11,13 

High-dose chemotherapy with autologous bone marrow transplantation (ABMT) has been successfully used in aggressive non-Hodgkin's lymphoma (NHL) as treatment intensification for patients with poor prognostic features and as salvage treatment for patients with refractory or relapsed disease following conventional chemotherapy.17-19The role of ABMT in patients with mediastinal large-cell lymphoma is not well defined. The outcome following ABMT and an analysis of prognostic features in this subset of patients is the focus of this report.

MATERIALS AND METHODS

Thirty-five patients who underwent ABMT between January 1987 and June 1995 at two Harvard tertiary care hospitals (Brigham and Women's Hospital and Beth Israel Hospital) for treatment of mediastinal large-cell lymphoma were included in this study. Patients were treated in accordance with protocols approved by the human research protection committees at each hospital. This group represents all known patients who underwent ABMT with this diagnosis at these institutions. All patients had histologically confirmed diffuse large-cell NHL, with B-cell antigen expression and varying degrees of sclerosis, and a predominant mediastinal mass at the time of initial presentation.

Prior therapy and response.

Patients received various chemotherapeutic regimens as initial treatment, as determined by their primary physicians. One patient received mantle irradiation alone as initial therapy. All other patients received a doxorubicin-containing regimen; 13 patients received regimens that contained six or more drugs. One patient received intrathecal methotrexate for CNS prophylaxis. Eight patients received consolidating radiation therapy, including five patients who achieved an initial CR to chemotherapy (two of whom were transplanted in first response and three of whom were transplanted following relapse) and three patients with refractory disease. It should be noted that the provision of radiation therapy, following either initial chemotherapy, salvage chemotherapy, or ABMT, was determined at the discretion of physicians involved and was not based on uniform criteria.

Patients who had complete resolution of their disease by all available imaging techniques (plain radiographic imaging, with or without computed tomographic [CT] scans, and with or without gallium scans) for at least 3 months' duration were considered to be in CR. Patients who had a greater than 50% reduction in measurable disease for at least 3 months were considered to be in partial remission (PR). Based on physician preferences, a subset of patients assumed to be at high risk of relapse was selected a priori to proceed to ABMT in first response (CR or PR). Response to initial chemotherapy in these patients was based on restaging evaluation performed before ABMT. Patients who did not achieve a CR or PR, or who developed progressive disease within 3 months of completion of initial therapy, were considered to have primarily refractory disease. Patients who developed disease progression off chemotherapy, following an initial CR or PR, were considered to have relapsed disease. For the purpose of analysis, patients were classified into three disease status groups based on their response to initial chemotherapy and timing of ABMT: first response (CR or PR), primarily refractory, and relapsed.

Gallium scans were not performed routinely on all patients, and therefore gallium avidity was not included in the definition of response. However, if a gallium scan was performed, it must be negative for a patient to be considered in CR. The predictive value of gallium scanning, before and after ABMT, was examined for the cohort of patients who underwent studies. Gallium scan results were obtained from official radiologists' interpretation. All false-positive scans (scans interpreted as positive in patients who remain progression-free) were reviewed with a radiologist to exclude the possibility of physiologic perihilar uptake. The majority of scans (86%) were performed with single-photon emission computed tomography (SPECT) imaging.

Ten patients with poor prognostic features went straight to ABMT following initial therapy, all of whom had achieved a CR or substantial PR. The remaining 25 patients, including two patients with a PR and all refractory and relapsed patients, received further chemotherapy before ABMT. Nine patients received more than two salvage regimens. Twenty-three patients were treated with 36 courses of conventional-dose cytoreductive salvage chemotherapy, such as ifosfamide, carboplatin, and etoposide (ICE),20 n = 12; etoposide, methylprednisolone, cytarabine, and cisplatin (ESHAP),21 n = 6; prednisone, doxorubicin, cyclophosphamide, etoposide, cytarabine, bleomycin, vincristine, methotrexate, and leucovorin (ProMACE-CytaBOM),22 n = 3; dexamethasone, cytarabine, and cisplatin (DHAP),23 n = 3; etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone (EPOCH),24 n = 2; or a modified regimen, n = 10. Two patients were treated on a salvage protocol with high-dose ICE chemotherapy and peripheral blood hematopoietic cell support.25 Four patients (including one patient transplanted in first PR, two relapsed patients, and one refractory patient) received consolidating radiation therapy following salvage therapy and before ABMT.

Patient characteristics.

Patient characteristics are listed in Table1. The median age at ABMT was 29 years (range, 17 to 50). Twenty-one of 35 patients (60%) were female.

Table 1.

Patient Characteristics

Total no.  35  
Age (yr)  
 Median  29  
 Range 17-50  
Follow-up (mo)  
 Median  47  
 Range 19-84  
Sex  
 Male  14  
 Female  21 
Status at ABMT  
 First CR  4  
 First PR  
 Primarily refractory  12  
 Relapsed  11  
Response to salvage chemotherapy  
 CR  2  
 PR  7  
 Stable or progressive disease  16  
No. of chemotherapy regimens pre-ABMT 
 1  10  
 2  16  
 ≥3  9  
Chemotherapy responsiveness at ABMT  
 Responsive  20  
 Nonresponsive 15  
Prior marrow involvement  2  
Source of progenitor cells  
 Peripheral blood hematopoietic cells  2  
 Marrow alone  22  
 Both  11  
Radiation therapy  
 Initial therapy  8  
 Salvage therapy  4  
 ABMT consolidation 14 
Total no.  35  
Age (yr)  
 Median  29  
 Range 17-50  
Follow-up (mo)  
 Median  47  
 Range 19-84  
Sex  
 Male  14  
 Female  21 
Status at ABMT  
 First CR  4  
 First PR  
 Primarily refractory  12  
 Relapsed  11  
Response to salvage chemotherapy  
 CR  2  
 PR  7  
 Stable or progressive disease  16  
No. of chemotherapy regimens pre-ABMT 
 1  10  
 2  16  
 ≥3  9  
Chemotherapy responsiveness at ABMT  
 Responsive  20  
 Nonresponsive 15  
Prior marrow involvement  2  
Source of progenitor cells  
 Peripheral blood hematopoietic cells  2  
 Marrow alone  22  
 Both  11  
Radiation therapy  
 Initial therapy  8  
 Salvage therapy  4  
 ABMT consolidation 14 

Twelve patients were transplanted in first response. Four patients were transplanted in first CR. These included two patients with stage IV disease at presentation, both of whom had large mediastinal masses, one with bone marrow involvement and the other with multiple pulmonary nodules. The remaining two patients transplanted in first CR had locally extensive stage IIE disease and bilateral pleural effusions: one with pericardial involvement and the other with extension into the chest wall.

Eight patients were transplanted in first PR. These included five patients with stage IV disease at presentation, four of whom had diffuse pulmonary involvement and one with characteristic liver and renal involvement. The remaining three patients transplanted in first PR had stage II disease, one of whom had a large mass at presentation (>20 cm), and another who remained persistently gallium-positive before ABMT. Two patients in PR received additional cytoreductive therapy before ABMT, which resulted in a slight reduction in mass size in one and a second PR with conversion to gallium negativity in the other. Both of these patients were considered to have chemotherapy-responsive disease at ABMT. One of seven PR patients evaluated was gallium-positive immediately before ABMT. Following ABMT, six of eight patients in first PR had a further reduction in measurable disease, including two further PRs, two CRs, and one with resolution of the previously positive gallium scan. The two remaining PR patients had stable gallium-negative disease, and may have been in first CR with residual nonmalignant radiographic abnormalities at ABMT.

Twelve patients had primarily refractory disease and 11 patients had relapsed disease, and received salvage chemotherapy before ABMT. Of 12 patients with primarily refractory disease, eight remained refractory after salvage treatment, while two achieved a CR and two achieved a PR. Of 11 patients with relapsed disease, seven were refractory to salvage therapy, while four achieved a PR.

Patients who achieved a CR or PR to chemotherapy immediately before ABMT were considered to have chemotherapy-responsive disease. All others were considered to have chemotherapy-nonresponsive disease. At ABMT, 15 patients (43%) had chemotherapy-nonresponsive disease.

Two patients had prior bone marrow involvement and received peripheral blood hematopoietic cells alone at ABMT, 22 patients received marrow alone, and 11 received both marrow and peripheral blood hematopoietic cells. Fourteen patients received consolidating radiation therapy following ABMT, including five patients transplanted in first PR, four relapsed patients, and five refractory patients.

Therapy.

Details of the transplant procedure have been previously described,26,27 and consisted of cyclophosphamide twice daily concomitant with twice-daily etoposide and daily carmustine (BCNU) on days −7 to −3. Total doses of cyclophosphamide ranged from 6,000 to 7,200 mg/m2 (the majority received 6,000 mg/m2), etoposide 1,200 to 2,000 mg/m2 (the majority received 1,600 mg/m2), and BCNU 450 mg/m2. Marrow and peripheral blood hematopoietic cells were collected, frozen, and thawed using standard techniques. Peripheral blood hematopoietic cells were mobilized with granulocyte colony-stimulating factor, usually during the recovery phase from chemotherapy. All patients received unpurged, unmanipulated stem cells, with the exception of one patient who received B1-purged marrow and one patient who received marrow primed with interleukin-3.

ABMT response criteria and follow-up.

Patients were restaged within 3 months of engraftment with plain radiographs and CT scans, with or without gallium scans. Patients with no measurable disease at ABMT were considered nonassessable for response. CR and PR were considered as previously defined. New sites of disease following ABMT or a greater than 25% increase in previously noted disease constituted progressive disease. All other patients were considered to have stable disease. Patients were monitored for potential relapse using a variety of tests, including routine blood tests, serial radiographs, CT scans, and gallium scans, at variable time intervals (∼ every 3 months in the first year, followed by every 6 to 12 months thereafter).

Statistical analysis.

Data were analyzed using the SAS statistical package (SAS Institute, Cary, NC). Progression-free survival (PFS) and overall survival estimates were obtained by the Kaplan-Meier method.28 Time to disease progression was calculated as the time from stem-cell reinfusion to the time of documented disease progression, relapse, or date last known alive. Overall survival times were calculated as the time from stem-cell reinfusion until death or date last known alive. Univariate comparisons of groups defined by patient characteristics determined before reinfusion for predicting PFS, and the value of pre- and post-ABMT gallium scan results for predicting relapse rates were evaluated using the log-rank test.29 Prognostic variables were considered simultaneously in a proportional hazards regression analysis30 and through the use of a backward selection model.

RESULTS

Toxicity.

Among 35 autotransplants, there were no early treatment-related deaths. One patient died of myelodysplastic syndrome without evidence of disease progression at 67 months following ABMT, which likely represents a late complication. Another patient has undergone successful resection of an early-stage lung cancer.

Response.

The median follow-up time is 47 months (range, 19 to 84). Six patients were transplanted with unmeasurable disease and were not assessable for response. Following ABMT, four additional patients had CRs, eight had PRs, seven had stable disease, and nine had disease progression. One additional patient was not assessable secondary to bronchial collapse and lung consolidation, making accurate radiographic restaging impossible. Ten of 15 patients with PR or stable disease underwent gallium scanning after ABMT, and four were persistently positive. Three of these four patients with positive gallium scans received consolidating radiation therapy post-ABMT, and all four had gradual resolution of gallium positivity and remain without disease progression at last follow-up evaluation.

PFS and overall survival.

PFS and overall survival are shown in Fig1. Fifteen patients have developed progressive disease following ABMT, while 20 patients (57%) remain free of disease progression. All relapses occurred within 7 months of ABMT. The median PFS has not yet been reached. The median overall survival time is 67 months. The estimated 5-year PFS and overall survival rate by Kaplan Meier analysis is 57% (95% confidence interval [CI], 40% to 73%).

Fig. 1.

(A) PFS and (B) overall survival in patients with mediastinal large-cell lymphoma following ABMT.

Fig. 1.

(A) PFS and (B) overall survival in patients with mediastinal large-cell lymphoma following ABMT.

The following factors were evaluated by univariate analysis as prognostic variables for PFS: age, sex, age-adjusted International Index31 at diagnosis (low/low-intermediate vhigh-intermediate/high), mediastinal mass size at diagnosis (<10 cmv ≥10 cm), presence of pleural effusion at diagnosis, B-symptoms at diagnosis, SVC syndrome at diagnosis, disease stage at ABMT (localized v advanced), presence of extranodal disease at ABMT, radiation therapy (at any time during treatment), chemotherapy responsiveness immediately before ABMT, and disease status at ABMT (first response v primarily refractory vrelapsed). Of these factors, only chemotherapy responsiveness and disease status at ABMT were found to be statistically significant (Table 2 and Figs 2 and3).Although multiple testing was performed, the only two variables found to be significant were both highly significant, and were anticipated a priori.

Table 2.

Univariate Analysis (N = 35)

Factor  No. of Patients  P Value  
Age (yr)  35 .097  
Sex  
 Male  14  .408  
 Female  21 
Age-adjusted international index  
 High  21  .403 
 Low  14  
Mediastinal mass size (cm)  
 <10  12 .668  
 ≥10  14  
Pleural effusion at presentation 
 Yes  12  .930  
 No  17  
B-symptoms  
 Yes 16  .480  
 No  18  
SVC syndrome  
 Yes  13 .264  
 No  22  
Stage at ABMT  
 Localized  26 .079  
 Advanced  9  
Radiation therapy  
 Yes  24 .646  
 No  11  
Extranodal sites at ABMT  
 Yes  .205  
 No  27  
Chemotherapy responsiveness at ABMT 
 Responsive  20  .007  
 Nonresponsive  15  
Disease status at ABMT  
 First response (CR or PR)  12  
 Primarily refractory  12  .023  
 Relapsed  11   
Factor  No. of Patients  P Value  
Age (yr)  35 .097  
Sex  
 Male  14  .408  
 Female  21 
Age-adjusted international index  
 High  21  .403 
 Low  14  
Mediastinal mass size (cm)  
 <10  12 .668  
 ≥10  14  
Pleural effusion at presentation 
 Yes  12  .930  
 No  17  
B-symptoms  
 Yes 16  .480  
 No  18  
SVC syndrome  
 Yes  13 .264  
 No  22  
Stage at ABMT  
 Localized  26 .079  
 Advanced  9  
Radiation therapy  
 Yes  24 .646  
 No  11  
Extranodal sites at ABMT  
 Yes  .205  
 No  27  
Chemotherapy responsiveness at ABMT 
 Responsive  20  .007  
 Nonresponsive  15  
Disease status at ABMT  
 First response (CR or PR)  12  
 Primarily refractory  12  .023  
 Relapsed  11   

Patients with missing data for a given factor were excluded.

Fig. 2.

PFS in patients with mediastinal large-cell lymphoma following ABMT by disease status at transplantation (first response, primarily refractory, or relapsed).

Fig. 2.

PFS in patients with mediastinal large-cell lymphoma following ABMT by disease status at transplantation (first response, primarily refractory, or relapsed).

Fig. 3.

PFS in patients with mediastinal large-cell lymphoma following ABMT by chemotherapy responsiveness immediately before transplantation.

Fig. 3.

PFS in patients with mediastinal large-cell lymphoma following ABMT by chemotherapy responsiveness immediately before transplantation.

Ten of 12 patients in first response, seven of 12 patients with primarily refractory disease, and three of 11 patients with relapsed disease remain free of disease progression. The 5-year estimated PFS for patients transplanted in first response is 83% (95% CI, 62% to 100%), compared with 58% (95% CI, 30% to 86%) and 27% (95% CI, 1% to 53%) for primarily refractory and relapsed patients, respectively (P = .02). Fifteen of 20 patients with chemotherapy-responsive disease at ABMT remain free of disease progression, compared with five of 15 patients with chemotherapy-nonresponsive disease. The estimated 5-year PFS for chemotherapy-responsive patients is 75% (95% CI, 56% to 94%), compared with 33% (95% CI, 9% to 57%) for chemotherapy-nonresponsive patients (P = .007).

A multivariate analysis was performed using a Cox proportional hazards regression model assessing PFS. The two variables found to be significant on univariate analysis were included in the model (chemotherapy responsiveness and disease status at ABMT), as well as variables that almost reached significance or were believed to be potential confounders (age, International Index at diagnosis, and disease stage at ABMT). Due to a strong correlation between chemotherapy responsiveness and disease status at ABMT, these two factors canceled each other out on multivariate analysis. A backward selection process resulted in disease status being dropped from the model, suggesting that chemotherapy responsiveness was the strongest of the two significant predictors. Controlling for age, International Index at presentation, and disease stage at ABMT, patients with chemotherapy-responsive disease have a significantly greater PFS than patients with chemotherapy-nonresponsive disease (risk ratio, 3.60; 95% CI, 1.14 to 11.4). No other predictors were found to be significant on multivariate analysis.

Gallium scans and residual disease.

Twenty patients with previously positive gallium scans had gallium scans performed immediately before ABMT (including six PR, 10 primarily refractory, and four relapsed patients). Four of nine gallium-positive patients have developed progressive disease, compared with one of 11 gallium-negative patients. The 5-year estimated relapse rate for patients with positive scans before ABMT is 44%, compared with 9% for patients with negative scans (P = .06). Although this does not meet statistical significance, these results suggest that gallium scans performed immediately before ABMT may offer some predictive value. Twenty-three patients underwent gallium scanning on initial restaging following ABMT (including six PR, 12 primarily refractory, and five relapsed patients). Three of seven patients with positive gallium scans have developed progressive disease, compared with five of 16 with negative gallium scans. The 5-year estimated relapse rate is 43% and 31% for patients with positive and negative scans, respectively (P = .55). The predictive value of gallium scans performed for initial restaging following ABMT is questionable.

Thirteen of 19 responding or stable-disease patients (68%) had residual mediastinal abnormalities following ABMT. Only four of these 13 patients (31%) with residual abnormalities have developed progressive disease, suggesting that a large proportion of residual abnormalities following ABMT are nonmalignant.

DISCUSSION

Clinical characteristics and response following conventional chemotherapy for mediastinal large-cell lymphoma have been well documented.2-13 There have been no systematic studies assessing outcome following salvage chemotherapy. Patients who have progressive disease or relapse following conventional chemotherapy appear to be highly refractory to salvage chemotherapy, with poor survival.7,11,13 Patients with mediastinal large-cell lymphoma have been observed to have low rates of bone marrow involvement, which may make them amenable for treatment strategies that include ABMT.7,9,11-13 

We performed a retrospective analysis of 35 patients with mediastinal large-cell lymphoma following ABMT. Overall, the patient characteristics appear representative of previous cohorts described undergoing conventional therapy, including female predominance, young age, frequent bulky tumors, and low incidence of marrow involvement. The treatment was well tolerated and there were no early treatment-related deaths. Of note, one patient died of myelodysplastic syndrome and another has undergone successful resection of an early-stage lung cancer.

Twelve patients with poor prognostic features underwent ABMT in first response, with an estimated 5-year PFS rate of 83%. Haioun et al18 found a 5-year PFS rate of 59% in high-risk NHL patients treated with ABMT in first CR, while Martelli et al19 found a PFS rate at 55 months of 73% for patients treated with ABMT in first PR for aggressive NHL. Our results also compare favorably to the 71% 3-year PFS reported for initial responders following conventional chemotherapy for mediastinal large-cell lymphoma, which included both low- and high-risk patients.13 Thus, patients with mediastinal large-cell lymphoma appear to do remarkably well following ABMT in first response. It is important to recognize that some patients in clinical PR may actually represent patients in CR with residual fibrotic changes, which can continue to resolve over time. In our study, six of eight patients in PR had evidence of further response following ABMT.

Eleven patients with relapsed disease underwent ABMT with an estimated 5-year PFS of 27%. Four of 11 patients had chemotherapy-responsive disease (responsive relapse), while seven of 11 had chemotherapy-nonresponsive disease (resistant relapse), but outcomes were similar between the two groups. This result is similar to the 3-year PFS rate of 30% reported by Philip et al17following ABMT in relapsed patients with aggressive NHL.

Twelve patients were transplanted with primarily refractory disease with an estimated 5-year PFS of 58%. This result is strikingly better than the 3-year PFS of 0% reported by Philip et al17following ABMT in refractory patients with aggressive NHL. It is also remarkably better than the 0% 3-year PFS reported by Lazzarino et al13 for patients with refractory mediastinal large-cell lymphoma treated with a variety of salvage regimens, only three of whom underwent ABMT. This high survival rate may in part be explained by several factors. While all refractory patients in the studies by Philip et al17 and Lazzarino et al13 remained nonresponsive to further chemotherapy, four of 12 patients in our study were chemotherapy-responsive to a subsequent regimen. Three of these four patients received CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) as first-line therapy, which has been suggested to be an inferior regimen in mediastinal large-cell lymphoma.9 It is also possible that some patients with bulky disease and large residual nonmalignant masses were incorrectly classified as refractory. However, eight of 11 refractory patients had positive gallium scans following initial chemotherapy, while the remainder had enlarging masses on CT scan or biopsy-proven active disease. Overall, it would appear that treatment intensification with ABMT for patients with primarily refractory mediastinal large-cell lymphoma results in a high response rate, and may reflect a more favorable biology in this subset.

The strongest predictor of PFS in our study was the presence of chemotherapy-responsive disease immediately before ABMT. Patients with chemotherapy-responsive disease had a significantly greater estimated 5-year PFS compared with patients who were chemotherapy-nonresponsive (75% v 33%, P = .007). The prognostic importance of chemotherapy responsiveness at ABMT has previously been reported for aggressive NHL.17 No other variables analyzed were found to be significant on multivariate analysis. Bulky mediastinal masses (>10 cm)7,13 and the presence of a pleural effusion at presentation12 have been associated with poorer outcome following initial chemotherapy in mediastinal large-cell lymphoma. This association was not found following ABMT. However, due to the small sample size, there is limited power to detect significant prognostic factors.

In this study, there was no significant difference in outcome between patients who received radiation therapy before or after ABMT, and those who did not. However, the patients who received radiation therapy were heterogeneous in character and were treated at varying time points. The role of radiation therapy in the treatment of mediastinal large-cell lymphoma cannot be directly assessed from this study and is yet to be defined.

Due to the difficulty in interpreting residual radiographic abnormalities, we examined retrospectively the correlation between pre- and post-ABMT gallium scan results to long-term outcome following ABMT. Gallium scan imaging has been reported to be a strong predictor of residual tumor viability following therapy for diffuse large-cell lymphoma.32 In our study, patients who were gallium-negative pre-ABMT had a lower likelihood of relapse than patients who were gallium-positive (5-year estimated relapse rate of 9% v 44%, P = .06). Gallium scans performed for restaging following ABMT were a less reliable indicator of outcome. The 5-year estimated relapse rate for patients with positive gallium scans post-ABMT is 43%, compared with 31% for patients with negative scans (P = .55). This is in contrast to results reported by Vose et al,33 who found that SPECT gallium scans performed on day +100 following ABMT for NHL had a high predictive value, especially for patients with residual mediastinal masses. False-positive results may reflect residual inflammation following high-dose chemotherapy. The majority of restaging scans were performed between 2 and 3 months following engraftment. Thus, the earlier timing may in part be responsible for these discrepant results. Nonetheless, our study suggests that early posttransplant gallium scans should be interpreted with caution.

Despite the small patient number and retrospective format of this study, we believe that our results help to clarify clinical response and outcome following ABMT in patients with mediastinal large-cell lymphoma. A preliminary analysis of 29 patients by Popat et al34 provides the only available data on ABMT in this subgroup. With a median follow-up duration of 958 days, they reported a 51% PFS rate in induction-failure patients, and a 75% and 33% PFS rate for patients with sensitive and refractory relapse, respectively.

We conclude that outcome following ABMT in patients with mediastinal large-cell lymphoma appears to be as good, and perhaps better than in patients with other aggressive NHLs. Early intensification of poor-prognosis patients in first response results in a high incidence of durable remissions. In addition, primarily refractory patients can achieve long-term survival following ABMT, and should strongly be considered for early intensification. The role of ABMT as part of primary therapy for patients with mediastinal large-cell lymphoma should be studied further in a prospective fashion.

ACKNOWLEDGMENT

We gratefully acknowledge E. John Orav for providing biostatistical assistance.

Supported by National Institutes of Health Grants no. CA38493 and CA39542.

Address reprint requests to Catherine Wheeler, MD, Hematology-Oncology Division, Beth Israel Hospital, 330 Brookline Ave, Boston, MA, 02214.

The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. section 1734 solely to indicate this fact.

REFERENCES

REFERENCES
1
Harris
NL
Jaffe
ES
Stein
H
Banks
PM
Chan
JKC
Cleary
ML
Delsol
G
De Wolf-Peeters
C
Falini
B
Gatter
KC
Grogan
TM
Isaacson
PG
Knowles
DM
Mason
DY
Muller-Hermelink
HK
Pileri
SA
Piris
MA
Ralfkiaer
E
Warnke
RA
A revised European-American classification of lymphoid neoplasms: A proposal from the International Lymphoma Study Group.
Blood
84
1994
1361
2
Lichtenstein
AK
Levine
A
Taylor
CR
Boswell
W
Rossman
S
Feinstein
DI
Lukes
RJ
Primary mediastinal lymphoma in adults.
Am J Med
68
1980
509
3
Miller
JB
Variakojis
D
Bitran
JD
Sweet
DL
Kinzie
JJ
Golomb
HM
Ultmann
JE
Diffuse histiocytic lymphoma with sclerosis: A clinicopathologic entity frequently causing superior venacaval obstruction.
Cancer
47
1981
748
4
Trump
DL
Mann
RB
Diffuse large cell and undifferentiated lymphomas with prominent mediastinal involvement. A poor prognostic subset of patients with non-Hodgkin's lymphoma.
Cancer
50
1982
277
5
Levitt
LJ
Aisenberg
AC
Harris
NL
Linggood
RM
Poppema
S
Primary non-Hodgkin's lymphoma of the mediastinum.
Cancer
50
1982
2486
6
Yousem
SA
Weiss
LM
Warnke
RA
Primary mediastinal non-Hodgkin's lymphomas: A morphologic and immunologic study of 19 cases.
Am J Clin Pathol
83
1985
676
7
Jacobson
JO
Aisenberg
AC
Lamarre
L
Willet
CG
Linggood
RM
Miketic
LM
Harris
N
Mediastinal large cell lymphoma. An uncommon subset of adult lymphoma curable with combined modality therapy.
Cancer
62
1988
1893
8
Haioun
C
Gaulard
P
Roudot-Thoraval
F
Divine
M
Jouault
H
Lebourgeois
JP
Kuentz
M
Farcet
JP
Reyes
F
Mediastinal diffuse large-cell lymphoma with sclerosis: A condition with a poor prognosis.
Am J Clin Oncol
12
1989
425
9
Todeschini
G
Ambrosetti
A
Meneghini
V
Pizzolo
G
Menestrina
F
Chilosi
M
Benedetti
F
Veneri
D
Cetto
GL
Perona
G
Mediastinal large-B-cell lymphoma with sclerosis: A clinical study of 21 patients.
J Clin Oncol
8
1990
804
10
Al-Sharabati
M
Chittal
S
Duga-Neulat
I
Laurent
G
Mazerolles
C
al-Saati
T
Brousset
P
Delsol
G
Primary anterior mediastinal B-cell lymphoma: A clinicopathologic and immunohistochemical study of 16 cases.
Cancer
67
1991
2579
11
Lazzarino
M
Orlandi
E
Paulli
M
Boveri
E
Morra
E
Brusamolino
E
Kindl
S
Rosso
R
Astori
C
Buonanno
MC
Magrini
U
Bernasconi
C
Primary mediastinal B-cell lymphoma with sclerosis: An aggressive tumor with distinct clinical and pathologic features.
J Clin Oncol
11
1993
2306
12
Kirn
D
Mauch
P
Shaffer
K
Pinkus
G
Shipp
MA
Kaplan
WD
Tung
N
Wheeler
C
Beard
CJ
Canellos
GP
Shulman
LN
Large-cell and immunoblastic lymphoma of the mediastinum: Prognostic features and treatment outcome in 57 patients.
J Clin Oncol
11
1993
1336
13
Lazzarino
M
Orlandi
E
Paulli
M
Strater
J
Klersy
C
Gianelli
U
Gargantini
L
Rousset
MT
Gambacorta
M
Morra
E
Lavabre-Bertrand
T
Magrini
U
Manegold
C
Bernasconi
C
Moller
P
Treatment outcome and prognostic factors for primary mediastinal (thymic) B-cell lymphoma: A multicenter study of 106 patients.
J Clin Oncol
15
1997
1646
14
Addis
BJ
Isaacson
PG
Large cell lymphoma of the mediastinum: A B-cell tumor of probable thymic origin.
Histopathology
10
1986
379
15
Lamarre
L
Jacobson
JO
Aisenberg
AC
Harris
NL
Primary large cell lymphoma of the mediastinum: A histologic and immunophenotypic study of 29 cases.
Am J Surg Pathol
13
1989
730
16
Scarpa A, Bonetti F, Menestrina F, Menegazzi M, Chilosi M, Lestani M, Bovolenta C, Zamboni G, Fiore-Donati L: Mediastinal large-cell lymphoma with sclerosis: Genotypic analysis establishes its B nature. Virchows Arch (A) 412:17, 1987
17
Philip
T
Armitage
JO
Spitzer
G
Chauvin
F
Jagannath
S
Cahn
J
Colombat
P
Goldstone
A
Gorin
N
Flesh
M
Laporte
J
Maraninchi
D
Pico
J
Bosly
A
Anderson
C
Schots
R
Biron
P
Cabinillas
F
Dicke
K
High-dose therapy and autologous bone marrow transplantation after failure of conventional chemotherapy in adults with intermediate-grade or high-grade non-Hodgkin's lymphoma.
N Engl J Med
316
1987
1493
18
Haioun
C
Lepage
E
Gisselbrecht
C
Bastion
Y
Coiffier
B
Brice
P
Bosly
A
Dupriez
B
Nouvel
C
Tilly
H
Lederlin
P
Biron
P
Briere
J
Gaulard
P
Reyes
F
Benefit of autologous bone marrow transplantation over sequential chemotherapy in poor-risk aggressive non-Hodgkin's lymphoma: Updated results of the prospective study LNH87-2.
J Clin Oncol
15
1997
1131
19
Martelli
M
Vignetti
M
Zinzani
P
Gherlinzoni
F
Meloni
G
Fiacchini
M
De Sanctis
V
Papa
G
Martelli
MF
Calabresi
F
Tura
S
Mandelli
F
High dose chemotherapy followed by autologous bone marrow transplantation versus dexamethasone, cisplatin, and cytarabine in aggressive non-Hodgkin's lymphoma with partial response to front-line chemotherapy: A prospective randomized Italian multicenter study.
J Clin Oncol
14
1996
534
20
Fields
KK
Zorsky
PE
Hiemenz
JW
Kronish
LE
Elfenbein
GJ
Ifosfamide, carboplatin, and etoposide: A new regimen with a broad spectrum of activity.
J Clin Oncol
12
1994
544
21
Velasquez
WS
McLaughlin
P
Tucker
S
Hagemeister
FB
Swan
F
Rodriguez
MA
Romaguera
J
Rubenstein
E
Cabanillas
F
ESHAP—An effective chemotherapy regimen in refractory and relapsing lymphoma: A 4-year follow-up study.
J Clin Oncol
12
1994
1169
22
Longo
DL
DeVita
VT
Duffey
PL
Wesley
MN
Ihde
DC
Hubbard
SM
Gilliom
M
Jaffe
ES
Cossman
J
Fisher
RI
Young
RC
Superiority of ProMACE-CytaBOM over ProMACE-MOPP in the treatment of advanced diffuse aggressive lymphoma: Results of a prospective randomized trial.
J Clin Oncol
9
1991
25
23
Velasquez
WS
Cabanillas
F
Salvador
P
McLaughlin
P
Fridik
M
Tucker
S
Jagannath
S
Hagemeister
FB
Redman
JR
Swan
F
Barlogie
B
Effective salvage therapy for lymphoma with cisplatin in combination with high-dose ara-c and dexamethasone (DHAP).
Blood
71
1988
117
24
Wilson
WH
Bryant
G
Bates
S
Fojo
A
Wittes
RE
Steinberg
SM
Kohler
DR
Jaffe
ES
Herdt
J
Cheson
BD
Chabner
B
EPOCH chemotherapy: Toxicity and efficacy in relapsed and refractory non-Hodgkin's lymphoma.
J Clin Oncol
11
1993
1573
25
(abstr)
Wheeler
C
Shulman
LN
Elias
E
Sieff
C
Churchill
WH
Ayash
L
Uhl
L
Benjamin
R
Gaynes
L
McCauley
M
Thompson
L
Mazanet
R
Antman
K
Richardson
P
Schnipper
L
Wegner
S
Tepler
I
Schwartz
G
Antin
J
Sequential ifosfamide, carboplatin and etoposide with steroids and cyclophosphamide/G-CSF mobilized peripheral blood progenitor cell support (SPICE) in relapsed lymphoma.
Proc Am Soc Clin Oncol
14
1995
312
26
Wheeler
C
Antin
JH
Churchill
WH
Come
SE
Smith
BR
Bubley
GJ
Rosenthal
DS
Rappeport
JM
Ault
KA
Schnipper
LE
Eder
JP
Cyclophosphamide, carmustine and etoposide with autologous bone marrow transplantation in refractory Hodgkin's disease and non-Hodgkin's lymphoma: A dose-finding study.
J Clin Oncol
8
1990
648
27
Wheeler
C
Strawderman
M
Ayash
L
Churchill
WH
Bierer
BE
Elias
A
Gilliland
DG
Antman
K
Guinan
EC
Eder
JP
Weinstein
H
Schwartz
G
Ferrara
J
Mazanet
R
Rimm
IJ
Tepler
I
McCarthy
P
Mauch
P
Ault
K
Gaynes
L
McCauley
M
Schnipper
LE
Antin
JH
Prognostic factors for treatment outcome in autotransplantation of intermediate-grade and high-grade non-Hodgkin's lymphoma with cyclophosphamide, carmustine, and etoposide.
J Clin Oncol
11
1993
1085
28
Kaplan
EL
Meier
P
Nonparametric estimation from incomplete observations.
J Am Stat Assoc
58
1958
457
29
Peto R, Peto J: Asymptomatically efficient rank invariant test procedures. J R Stat Soc (A) 15:185, 1972
30
Cox DR: Regression models and life tables (with discussion). J R Stat Soc (B) 34:187, 1972
31
The International Non-Hodgkin's Lymphoma Prognostic Factors Project
A predictive model for aggressive non-Hodgkin's lymphoma.
N Engl J Med
329
1993
987
32
Kaplan
WD
Jochelson
MS
Herman
TS
Lee
LM
Stomper
PC
Takvorian
T
Andersen
JW
Canellos
GP
Gallium-67 imaging: A predictor of residual tumor viability and clinical outcome in patients with diffuse large-cell lymphoma.
J Clin Oncol
8
1990
1966
33
Vose
JM
Bierman
PH
Anderson
JR
Harrison
KA
Dalrymple
GV
Byar
K
Kessinger
A
Armitage
JO
Single-photon emission computed tomography gallium imaging versus computed tomography: predictive value in patients undergoing high-dose chemotherapy and autologous stem-cell transplantation for non-Hodgkin's lymphoma.
J Clin Oncol
14
1996
2473
34
(suppl 1, abstr)
Popat
U
van Besien
K
Amin
K
Giralt
S
Mehra
R
Khouri
I
Williams
P
Andersson
B
Przepiorka
D
Gajewski
J
Champlin
R
Autologous transplantation is curative treatment for patients with recurrent and refractory primary mediastinal lymphoma.
Blood
88
1996
124a