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Treatment of Primary Progressive Hodgkin’s and Aggressive Non-Hodgkin’s Lymphoma: Is There a Chance for Cure?

From the First Department of Internal Medicine, University Hospital Cologne, Cologne, Germany.

Address reprint requests to Andreas Josting, MD, First Department of Internal Medicine, University Hospital Cologne, Joseph-Stelzmann-Str. 9, 50924 Cologne, Germany, email dr.andreas_josting{at}uni-koeln.de

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To determine differences in prognosis between primary progressive Hodgkin’s disease (HD) and aggressive non-Hodgkin’s lymphoma (NHL), we retrospectively analyzed patients with progressive lymphoma who were treated with different salvage chemotherapy regimens including high-dose chemotherapy (HDCT) followed by autologous stem-cell support (ASCT).

PATIENTS AND METHODS: One hundred thirty-one patients with primary progressive lymphoma (HD, n = 67; NHL, n = 64) were enrolled. Primary progressive disease was defined as disease progression during first-line chemotherapy or only transient response (complete or partial response lasting 90 days) after induction treatment. Patients 60 years or younger with progressive lymphoma were eligible to receive HDCT with ASCT.

RESULTS: The overall response rate after salvage chemotherapy for patients with primary progressive HD and NHL was 33% and 15%, respectively. Twenty-five HD patients (37%) received HDCT. Most patients with NHL had progressive disease under salvage treatment, with only six patients (10%) receiving HDCT. Of those, only two patients were alive and in continuous complete remission 3 and 12 months after HDCT. No patient with NHL survived longer than 26 months after first diagnosis. Actuarial OS after 5 years was 19% for all HD patients; 53% for HD patients receiving HDCT, and 0% for patients who did not receive HDCT. In HD patients, multivariate regression analysis identified chemosensitive disease on salvage treatment (P = .0001) and HDCT (P = .031) as significant prognostic factors for freedom from treatment failure. Significant prognostic factors for OS are chemosensitive disease (P = .0005), HDCT (P = .039), and B symptoms at the time of progress (P = .046).

CONCLUSION: There are striking differences in the prognosis of patients with progressive HD and aggressive NHL. The prognosis of progressive NHL patients is dismal. Most patients have rapidly progressive disease after salvage treatment and are, therefore, excluded from HDCT programs. In contrast, progressive HD patients can achieve long-term survival after HDCT.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
DEPENDING ON THE histology and risk factor profile, 30% to 75% of patients with advanced Hodgkin’s lymphoma (HD) and aggressive non-Hodgkin’s lymphoma (NHL) can be cured with front-line treatment.^1,2 Patients who relapse after attaining complete response (CR) might still be cured by chemotherapy followed by high-dose chemotherapy (HDCT) with autologous stem-cell transplantation (ASCT).^3,4 However, those patients with primary progressive lymphoma, defined as progression during induction treatment or within 90 days after the end of treatment, have a particularly poor prognosis.

Treatment results with second-line chemotherapy have generally been disappointing in patients with both primary progressive HD⁵ and aggressive NHL.⁶ Given the lack of curative treatment for this group, HDCT with ASCT has been attempted resulting in some responses.^7-9 However, patients receiving HDCT undergo a considerable selection. In addition, there is a substantial variation in patient characteristics, including a broad range of different histologies, relapse status, and variable definitions of primary progressive and primary refractory disease.^7,10,11

The effectiveness of HDCT and ASCT in patients with primary progressive HD seems to be well established in large trials from transplantation centers, suggesting that this procedure represents the treatment of choice for all patients after induction failure.^12,13 However, there is a proportion of patients who are not treated with HDCT because of rapidly progressive disease. In contrast, most of the published studies using HDCT and ASCT in aggressive NHL hardly allow the assessment of whether patients with primary progressive disease are long-term disease-free survivors.

Therefore, we retrospectively analyzed patients with primary progressive HD and aggressive NHL who were treated at our facility with salvage treatment followed by HDCT and ASCT. The purpose of the present analysis is to assess whether and to what extent long-term disease-free survival can be achieved, justifying the use of aggressive treatment modalities for the whole group. We show that the results reported from selected series might be overestimated and that there are striking differences in the prognosis of patients with primary progressive HD and aggressive NHL.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Selection
Patients with primary progressive HD and aggressive NHL (defined by the Revised European-American Lymphoma classification) who were treated at the University Hospital of Cologne between 1990 and 1998 were included in this retrospective analysis. To be eligible, patients between the age of 18 and 68 years had to have biopsy-proven HD (n = 67) or aggressive NHL (n = 64) at diagnosis. Eligibility before study entry included: adequate organ function as defined by a creatinine clearance more than 60 mL/min; serum transaminases less than three times the normal value; bilirubin less than 2 mg/dL; left ventricular ejection fraction greater than 0.45; forced expiratory volume in first-second or diffusion capacity of carbon monoxide more than 60% of predicted capacity; Eastern Cooperative Oncology Group performance status 2; WBCs 3,500/µL; hemoglobin level 8 g/dL; and platelets 100.000/µL. Patients were required to test negative for antibody against human immunodeficiency virus and to be free of active infections. All patients signed consent forms that were based on the Institutional Review Board Guidelines.

Patients with HD had received cyclophosphamide, vincristine, procarbazine, and prednisone alternating with doxorubicin, bleomycin, vinblastine, and dacarbazine (COPP/ABVD); cyclophosphamide, vincristine, procarbazine, and prednisone alternating with doxorubicin, bleomycin, and vinblastine alternating with ifosamide, methotrexate, etoposide, and prednisone (COPP/ABV/IMEP); bleomycin, etoposide, doxorubicin, cyclophophamide, vincristine, procarbazine, and prednisone (BEACOPP), or similar regimens. All NHL patients had been treated with an anthracycline-containing regimen at first diagnosis. Thirty-four patients (51%) with HD and seven patients (11%) with NHL had received both chemotherapy and radiotherapy during first-line treatment. Fifty-three of the patients (53%) were initially treated at the University Hospital of Cologne. Primary progressive disease was defined as either disease progression during first-line chemotherapy or only transient response (CR or partial response [PR] lasting 90 days) after induction treatment. Progressive disease required the following: 1) 25% increase from nadir in the sum of the products of the greatest diameter of any previously identified abnormal node for partial responders or nonresponders; and 2) appearance of any new lesion during or 90 days after the end of therapy. Whenever possible, another biopsy was performed at the time of disease progression. Survival data of all patients were updated in December 1998.

Conventional-Dose Salvage Therapy
For patients with HD, failure to respond to reinduction chemotherapy (< 50% decrease in the sum of the products of the greatest diameter of measurable lesions) was considered a prerequisite for HDCT during the first years of the observation period (1990 to 1994). This criterion was dropped in 1995 because of reports from other trials subsequently allowing chemoresistant HD patients to proceed to HDCT/ASCT. Sensitivity to conventional-dose salvage chemotherapy was a prerequisite for HDCT and ASCT in patients with aggressive NHL. Patients who did not meet these response criteria after up to four cycles of salvage chemotherapy were treated with an alternative regimen or radiotherapy instead.

Staging Procedures
Before salvage chemotherapy, the extent of disease was assessed by chest x-ray, abdominal sonography, computed tomography, and bone marrow biopsy. Restaging was performed after two and four cycles of salvage therapy. After the end of salvage therapy and before HDCT/ASCT, all sites of initial disease manifestations were reassessed by adequate methods, including pathologic restaging for patients who had bone marrow involvement before salvage therapy.

Conditioning Regimen
Patients younger than 60 years of age were excluded from HDCT. The conditioning regimen used for patients with HD was carmustine 300 mg/m² on day -7, etoposide 150 mg/m² every 12 hours on day -7 to -4, cytarabine 200 mg/m² every 12 hours on day -7 to -4, and melphalan 140 mg/m² on day -3 (BEAM) or, alternatively, cyclophosphamide 1.5 g/m² on day -6 to -3, etoposide 100 mg/m² every 12 hours on day -6 to -3, and carmustine 100 mg/m² on day -6 to -4 (CVB). NHL patients were treated with BEAM.

Definition of Response
A CR was defined as the disappearance of all clinical and radiographic evidence of disease for at least 1 month. PR was defined as a greater than 50% reduction in the product of the largest diameter and its perpendicular of measurable disease lasting more than 1 month. Any response less than PR was considered as treatment failure.

Statistics
Freedom from treatment failure (FFTF) was measured from the date of entry into the salvage protocol until progression, relapse, or death from any cause. Overall survival (OS) was measured from the date of entry into the salvage protocol until death from any cause. Demographics and disease characteristics were summarized using descriptive statistics. Follow-up started with the beginning of the salvage regimen. OS and FFTF were estimated according to the method of Kaplan and Meier.¹⁴ Patient characteristics were subjected to univariate analysis for each of the outcome variables (FFTF and OS). The variables tested were sex, age, Karnofsky performance score at progress, B symptoms at progress, stage at progress, chemosensitive disease at progress, and the use of HDCT. All variables found to have a P < .05 in univariate evaluation were considered to be candidates for Cox regression analysis.¹⁵ For proportional hazard analysis, candidate variables were examined by stepwise removal on the basis of likelihood ratios. Removal and entry levels of significance were 0.1 and 0.05, respectively. No adjustments were made for multiple comparison, and all P values were two-sided. All statistical analyses were performed using SPSS 6.1 (SPSS, Inc, Chicago, IL).

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Characteristics
Patient characteristics and treatment regimens used are listed for patients with HD in Table 1 and for patients with NHL in Table 2. One hundred thirty-one patients were eligible between April 1990 and December 1998. There were 87 men (66%) and 44 women (34%). Progression was proven by biopsy in 61 patients with HD (95%) and in 50 patients (78%) with NHL, and/or demonstrated unequivocally on radiographic studies.

Sixty-four patients had primary progressive NHL with the following histologies: diffuse large B-cell lymphoma (56 patients, 87%); large B-cell lymphoma, unclassified (eight patients, 13%). The median age for patients with NHL was 48 years (range, 18 to 68 years). Stage at progress by Ann Arbor criteria was stage I in two patients (3%), stage II in 20 patients (31%), stage III in 30 patients (31%), and stage IV in 12 patients (47%). Nine patients (14%) had extranodal disease at progress, six patients (9%) had bone marrow involvement, five patients (8%) had bulky disease (> 5 cm), three patients (5%) had liver involvement, and three patients (5%) had lung involvement.

Conventional-Dose Salvage Therapy
After documented progress, all patients received second-line chemotherapy. Patients with primary progressive HD were treated with dexamethasone, carmustine, etoposide, cytarabine, and melphalan (Dexa-BEAM) (n = 61) or dexamethasone, cytarabine, cisplatin (DHAP) + sequential cyclophosphamide, methotrexate, vincristine, and etoposide (HDCT) (n = 6). For patients with primary progressive HD, the overall response rate was 40% (22 CR and five PR). Of those patients treated with DHAP + sequential HDCT, four patients achieved CR (66%), and two patients had progressive disease. Eighteen patients treated with Dexa-BEAM achieved a CR (29%), and five patients (8%) achieved a PR.

Patients with aggressive NHL were treated with different salvage regimens, including dexamethasone, idarubicin, ifosfamide, and etoposide (DIZE) (n = 18); ifosfamide, idarubicin, and etoposide (IIVP-16) (n = 12); vincristine, methotrexate, ifosfamide, teniposide, cytarabine, dexamethasone, cyclophosphamide, and doxorubicin (B-ALL protocol) (n = 11); Dexa-BEAM (n = 8); or DHAP followed by sequential HDCT (n = 15). The overall response rate for patients with primary progressive NHL was 15% (four CR and six PR). There was no statistically significant difference between the different salvage regimens used. It should be noted, however, that the response rate of the Dexa-BEAM regimen was 0% (none of eight patients achieved a PR or CR).

HDCT and ASCT
The source of stem cells was bone marrow in 19% and peripheral blood in 81% of the cases. Five patients received radiotherapy to residual lymphoma after HDCT. Twenty-five patients (37%) with primary progressive HD were treated with CVB (10%) or BEAM (27%). Status before HDCT was as follows: 17 patients (68%) had CR, three patients (12%) had PR, and five patients (20%) had nonresponsive disease to conventional salvage therapy. Two patients (3%) with CR after conventional treatment were not treated with HDCT because of insufficient stem-cell collection. Forty patients (63%) with HD had rapidly progressive disease and were, therefore, excluded from HDCT. Six patients (10%) with primary progressive NHL were treated with HDCT (BEAM); 58 patients (90%) were not treated with HDCT because of rapidly progressive disease (76%), age greater than 60 years (8%), insufficient stem-cell collection (3%), or rejection (3%).

Survival Data
The actuarial OS at 5 years for patients with HD was 19% versus 0% for patients with aggressive NHL. Mean OS for patients with HD was 27.1 months (95% confidence interval [CI], 19.5 to 34.8); mean OS for patients with NHL was 6.8 months (95% CI, 5.2 to 8.3) (Fig 1). Currently, 12 patients with HD and two patients with NHL are alive. The actuarial FFTF at 5 years for patients with HD was 17% versus 0% for patients with NHL. Mean FFTF for HD was 18 months (95% CI, 10.0 to 26.1); mean FFTF for NHL was 2.5 months (95% CI, 1.9 to 3.0) (Fig 2). The actuarial OS at 5 years for patients with primary progressive HD who were treated with HDCT and ASCT was 53% versus 0% for HD patients who were not. The mean OS for patients with HD treated with HDCT/ASCT was 56.2 months (95% CI, 41.6 to 70.8). In contrast, HD patients who were not treated with HDCT/ASCT had a mean OS of 11.2 months (95% CI, 7.7 to 14.7) (Fig 3). Ten patients with HD are in continuous CR, with a mean follow-up of 59 months (range, 16 to 96 months). In contrast, only two patients with NHL are in continuous CR 3 and 12 months after HDCT and ASCT.

View larger version (15K): [in this window] [in a new window]   Fig 1. Actuarial OS of 131 primary progressive HD patients (n = 67) and aggressive NHL patients (n = 64).

View larger version (14K): [in this window] [in a new window]   Fig 2. Actuarial FFTF of 131 primary progressive HD patients (n = 67) and aggressive NHL patients (n = 64).

View larger version (16K): [in this window] [in a new window]   Fig 3. Actuarial OS of primary progressive HD patients treated with (n = 25) or without (n = 42) HDCT.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

Although the results with HDCT and ASCT indicate that HD patients can successfully be treated after primary treatment failure, a high proportion will ultimately succumb to progressive disease before HDCT. Prognostic factors for FFTF in patients with primary progressive HD include chemosensitive disease and the use of HDCT. Prognostic factors for OS were chemosensitivity, HDCT, and B symptoms at the time of progress.

Treatment approaches for patients with primary progressive lymphoma include salvage chemotherapy, radiotherapy, or HDCT with ASCT. Conventional salvage regimens have given disappointing results in the vast majority of patients.^5,10 In patients with primary progressive lymphoma, response on salvage treatment is low and the duration of response is often short.^6,16 In addition, extensive disease limits the use of radiotherapy. HDCT might be a possible option for these poor prognosis patients. The rationale for HDCT stems from the steep dose-response curve of alkylating agents that seems to exist between applied dose and response in human tumors.¹⁷

Several investigators have evaluated prognostic factors for relapsed and progressive patients who benefit from HDCT with ASCT.^18-21 The most important factors identified are the remission status (CR > PR > no change) before HDCT and chemosensitivity. In general, patients with resistant NHL do not benefit from HDCT. In contrast, recently published studies in patients with HD have confirmed that some patients with disease resistant to conventional salvage therapy or chemotherapy-untested progression clearly benefit from HDCT and ASCT, with reported long-term survival and/or progression-free survival (PFS) rates of 10% to 30% in such patients.^22,23 Because of their poor prognosis, patients with resistant disease and rapid disease progression are often excluded from myeloablative therapy. Therefore, determining the proportion of patients failing induction therapy who may benefit from HDCT is a difficult task for transplant centers. Referral bias and specific program eligibility criteria are confounding factors.

Patients with primary progressive HD have an extremely poor outcome with conventional salvage treatment. The 8-year OS ranges between 0% and 8%. FFTF in second remission is 0% at 4 to 8 years, as reported in small series.^5,6,16 By contrast, the results of HDCT and ASCT in those patients are more promising. The European Bone Marrow Transplant registry (EBMT) reported an analysis on 290 patients with primary progressive disease who received HDCT and ASCT.¹² The 5-year actuarial PFS and OS were 30% and 34%, respectively. The Autologous Blood and Marrow Transplant Registry (ABMTR) recently reported a PFS of 38% and an OS of 50% at 3 years in 122 patients with primary induction failure.¹³ In a single institution analysis evaluating the efficacy of HDCT exclusively in induction failures, Reece et al²² reported a 42% PFS at a median of 3.6 years. Similarly, an updated report from Stanford showed an event-free survival of 49% at 4 years,⁸ and Gianni et al²³ observed an event-free survival of 31% at 4 years. Studies by Yuen et al²⁴ and Andrè et al²⁵ reported improved outcome after HDCT and ASCT for refractory HD when compared with historical control groups treated with conventional chemotherapy. Thus, HDCT and ASCT should be considered for HD patients with primary induction failure.

Although these results indicate that a proportion of HD patients can be successfully rescued with HDCT after primary treatment failure, the majority will develop recurrent disease. In addition, because of the selection of patients before referral for HDCT, these data overestimate the true salvage rate. In our analysis, the FFTF for the whole group of patients with primary progressive HD was 19% at 5 years. Only one third of all patients (37%) with primary progressive disease having a mean survival of 56 months were treated with HDCT, including long-term survivors up to 8 years. In our analysis, only five patients with chemoresistant primary progressive HD received HDCT. During 1990 to 1994, sensitivity to conventional-dose salvage chemotherapy was a prerequisite for HDCT at our institution. Although the PFS rates in chemoresistant patients are lower compared with chemosensitive patients, the former group should not routinely be excluded from subsequent HDCT and ASCT in future trials.^22,23 Our results also show that a high proportion of chemoresistant patients rapidly succumb to progressive disease. Forty-one percent of the patients not receiving HDCT had rapidly progressive disease and died within 1 to 4 months after disease progression. Insufficient stem-cell collection and poor performance status also contributed to ineligibility for HDCT in this group. In a multivariate analysis, chemosensitive disease and the use of HDCT were independent prognostic factors for OS and FFTF, underscoring the importance of response to second-line chemotherapy. Although in our series the number of chemoresistant patients treated with HDCT was small, the independence of both variables in the multivariate analysis suggests that there might be a small number of refractory HD patients who can be cured with HDCT.

In patients with aggressive NHL and induction failure, an effective assessment of the outcome using conventional salvage chemotherapy or HDCT with ASCT is hampered by the number of variables in most reported studies. The main confounding factors include histology and the definition of refractory disease. Previously published studies of HDCT in patients with NHL involve a mixture of different histologies, including aggressive, intermediate-, and low-grade NHL. Several series examining HDCT after induction failure also included patients who relapsed as late as a year after CR to front-line therapy.^7,10,13 Therefore, it must be emphasized that it is difficult to discern a clear picture from the literature for this group of patients.

In our study, only 10% of patients with aggressive NHL were treated with HDCT and ASCT. The response rate to conventional chemotherapy was 15%. Most of the patients (76%) had rapidly progressive disease and died within 1 year after the start of salvage therapy.

Our results underline the difficulty of retrospective analyses from transplant centers to determine how many patients were excluded from HDCT because of continued disease progression. Patient selection bias is inherent in HDCT studies. In our analysis, HDCT, considered as standard treatment, was only applied in a minority of patients with HD and aggressive NHL. What can be done to improve the outlook for the entire group of patients with induction failure?

The dismal outcome of patients with primary progressive lymphoma, even with dose-intensified therapies, underlines the need to evaluate new treatment strategies. These strategies should lead to earlier identification of currently untreatable patients for whom palliative modalities should be used, including new therapeutic options. Allogeneic bone marrow transplant with marrow cells uninvolved by malignancy may have advantages over autologous transplantation. Donor lymphoid cells can potentially mediate a graft-versus-lymphoma effect. However, reports using allogeneic bone marrow transplants in patients with induction failure show a substantial procedure-related mortality of up to 75%, questioning the feasibility of this approach in larger series.^26-28

New drugs, including monoclonal antibodies, radioimmuno-conjugates, and immunotoxins, or cell-mediated approaches, such as minitransplants, are being investigated in these patients.^29-32 However, the rapidly proliferating disease in most patients with progressive lymphoma might not be controlled with immunotherapeutic approaches, which probably have a more important role in destroying residual disease. Other alternatives include double HDCT at the time of progress. Because it is clear that HDCT is most effective in patients with chemosensitive disease and minimal tumor burden at the time of HDCT, salvage treatment is of major importance. More effective salvage chemotherapy regimens capable of producing high response rates are needed. The identification of patients at high risk for induction failure and modifications of primary treatment to address this risk hold the greatest promise for cure in patients with primary progressive HD and aggressive NHL.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. Canellos GP, Anderson JR, Propert KJ, et al: Chemotherapy of advanced Hodgkin’s disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med 327:1478-1483, 1992[Abstract]

2. Fischer RI, Gaynor ER, Dahlberg S, et al: Comparison of standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma. N Engl J Med 328:1002-1006, 1993[Abstract/Free Full Text]

3. Linch DC, Winfield D, Goldstone AH, et al: Dose intensification with autologous bone marrow transplantation in relapsed and resistant Hodgkin’s disease: Results of a BNLI randomized trial. Lancet 341:1051-1054, 1993[Medline]

4. Philip T, Guglielmi C, Hagenbeek A, et al: Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive NHL. N Engl J Med 333:1540-1545, 1995[Abstract/Free Full Text]

5. Longo DL, Duffey PL, Young RC, et al: Conventional-dose salvage combination chemotherapy in patients relapsing with Hodgkin’s disease after combination chemotherapy: The low probability for cure. J Clin Oncol 10:210-218, 1992[Abstract]

6. Cabanillas F, Velasquez WS, McLauphlin P, et al: Results of recent salvage chemotherapy regimens for lymphoma and Hodgkin’s disease. Semin Hematol 25:47-50, 1988 (suppl 2)[Medline]

7. Stiff JS, Dahlberg S, Forman SJ, et al: Autologous bone marrow transplantation for patients with relapsed or refractory diffuse aggressive non-Hodgkin’s lymphoma: Value of augmented preparative regimens—A Southwest Oncology Group trial. Blood 16:48-55, 1998

8. Nademannee A, O‘Donnell MR, Snyder DS, et al: High-dose therapy with or without total body irradiation followed by autologous bone marrow and/or peripheral blood stem cell transplantation for patients with refractory and relapsed Hodgkin’s disease: Factors predictive of prolonged survival. Blood 85:1381-1390, 1991[Abstract/Free Full Text]

9. Chopra R, McMillan AK, Linch DC, et al: The place of high-dose BEAM therapy and autologous bone marrow transplantation in poor-risk Hodgkin’s disease: A single center eight year study of 155 patients. Blood 81:1137-1145, 1993[Abstract/Free Full Text]

10. Saez R, Dahlberg S, Appelbaum F, et al: Autologous bone marrow transplantation in adults with non-Hodgkin’s lymphoma: A Southwest Oncology Group Study. Oncol 12:75-85, 1994

11. Phillips GL, Fay JW, Herzig RH, et al: The treatment of progressive non-Hodgkin’s lymphoma with intensive chemoradiotherapy and autologous marrow transplantation. Blood 75:831-838, 1990[Abstract/Free Full Text]

12. Sweetenham JW, Taghipou G, Linch DC, et al: Thirty percent of adult patients with primary refractory Hodgkin’s disease are progressive free at 5 years after high-dose therapy and autologous stem cell transplantation: Data from 290 patients reported to the EBMT. Blood 88:486a, 1996 (suppl 1)

13. Lazarus HM, Rowlings PA, Zhang MJ, et al: Autotransplants for Hodgkin’s disease in patients never achieving remission: A report from the Autologous Blood and Marrow Transplant registry. J Clin Oncol 17:534-545, 1999[Abstract/Free Full Text]

14. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958

15. Cox DR: Regression models and life tables. Stat Soc 34:187-202, 1972

16. Bonfante V, Santoro A, Viviani S, et al: Outcome of patients with Hodgkin’s disease failing after primary MOPP-ABVD. Oncol 15:528-534, 1997

17. Frei E, Canellos GP: Dose: A critical factor in cancer chemotherapy. Am J Med 69:585-594, 1980[Medline]

18. Crump M, Smith AM, Brandwein J, et al: High-dose etoposide and melphalan, and autologous bone marrow transplantation for patients with advanced Hodgkin’s disease: Importance of disease status at transplant. J Clin Oncol 11:704-711, 1993[Abstract]

19. Rappoport AP, Rowe JM, Kouides PA, et al: One hundred autotransplants for relapsed or refractory Hodgkin’s disease and lymphoma: Value of pretransplant disease status for predicting outcome. J Clin Oncol 11:2351-2361, 1993[Abstract/Free Full Text]

20. Josting A, Katay I, Rueffer U, et al: Favorable outcome of patients with relapsed or refractory Hodgkin’s disease treated with high-dose chemotherapy and stem cell rescue at the time of maximal response to conventional salvage therapy (Dexa-BEAM). Oncol 9:289-295, 1998

21. Horning SJ, Chao NJ, Negrin RS, et al: High-dose therapy and autologous hematopoietic progenitor cell transplantation for recurrent and refractory Hodgkin‘s disease: Analysis of the Stanford University results and prognostic indices. Blood 89:801-813, 1997[Abstract/Free Full Text]

22. Reece DE, Barnett MJ, Shepherd JD, et al: High-dose cyclophosphamide, carmustine, and etoposide with or without cisplatin and autologous transplantation for patients with Hodgkin’s disease who fail to enter a complete remission after combination chemotherapy. Blood 86:451-456, 1995[Abstract/Free Full Text]

23. Gianni AM, Bregni M, Siena S, et al: High-dose sequential chemo-radiotherapy with peripheral blood progenitor cell support for relapsed or refractory Hodgkin’s disease: A 6-year update. Ann Oncol 4:889-891, 1993[Abstract/Free Full Text]

24. Yuen AR, Rosenberg SA, Hoppe RT, et al: Comparison between conventional salvage chemotherapy and high-dose therapy with autografting for recurrent and refractory Hodgkin’s disease. Blood 89:814-822, 1997[Abstract/Free Full Text]

25. Andrè M, Henry-Amar M, Pico JL, et al: Comparison of high-dose therapy and autologous stem-cell transplantation with conventional therapy for Hodgkin’s disease induction failure: A case-control study. J Clin Oncol 17:222-229, 1999[Abstract/Free Full Text]

26. Chopra R, Goldstone AH, Pearce R, et al: Autologous versus allogeneic bone marrow transplantation for non-Hodgkin’s lymphoma: A case-controlled analysis of the European Bone Marrow Transplant Group registry data. J Clin Oncol 10:1690-1697, 1992[Abstract/Free Full Text]

27. Milpied N, Fielding AK, Pearce RM, et al: Allogeneic bone marrow transplantation is not better than autologous transplant for patients with relapsed Hodgkin’s disease. J Clin Oncol 14:1291-1296, 1996[Abstract/Free Full Text]

28. Anderson JE, Litzow MR, Appelbaum FR, et al: Allogeneic, syngeneic, and autologous marrow transplantation for Hodgkin’s disease: The 21-year Seattle experience. J Clin Oncol 11:2342-2350, 1993[Abstract/Free Full Text]

29. Coiffier B, Haion C, Ketterer N, et al: Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: A multicenter phase II study. Blood 92:1927-1932, 1998[Abstract/Free Full Text]

30. Liu SY, Eary JF, Petersdorf SH, et al: Follow-up of relapsed B-cell lymphoma patients treated with iodine-131-labeled anti-CD20 antibody and autologous stem-cell rescue. J Clin Oncol 16:3270-3278, 1998[Abstract]

31. Engert A, Diehl V, Schnell R, et al: A phase-I study of an anti-CD25 ricin A-chain immunotoxin (RFT5-SMPT-dgA) in patients with refractory Hodgkin’s lymphoma. Blood 89:403-410, 1997[Abstract/Free Full Text]

32. Khouri IF, Keating M, Korbling M, et al: Transplant-lite: Induction of graft-versus-malignancy using fludarabine-based nonablative chemotherapy and allogeneic blood progenitor-cell transplantation as treatment for lymphoid malignancies. J Clin Oncol 16:2817-2824, 1998[Abstract]

Submitted April 12, 1999; accepted August 18, 1999.

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				M. Zhang, Z. Yao, H. Patel, K. Garmestani, Z. Zhang, V. S. Talanov, P. S. Plascjak, C. K. Goldman, J. E. Janik, M. W. Brechbiel, et al. Effective therapy of murine models of human leukemia and lymphoma with radiolabeled anti-CD30 antibody, HeFi-1 PNAS, May 15, 2007; 104(20): 8444 - 8448. [Abstract] [Full Text] [PDF]

				A. Josting, M. Sieniawski, J.-P. Glossmann, O. Staak, L. Nogova, N. Peters, M. Mapara, B. Dorken, Y. Ko, B. Metzner, et al. High-dose sequential chemotherapy followed by autologous stem cell transplantation in relapsed and refractory aggressive non-Hodgkin's lymphoma: results of a multicenter phase II study Ann. Onc., August 1, 2005; 16(8): 1359 - 1365. [Abstract] [Full Text] [PDF]

				R. Schnell, M. Dietlein, J. O. Staak, P. Borchmann, K. Schomaecker, T. Fischer, W. Eschner, H. Hansen, F. Morschhauser, H. Schicha, et al. Treatment of Refractory Hodgkin's Lymphoma Patients With an Iodine-131-Labeled Murine Anti-CD30 Monoclonal Antibody J. Clin. Oncol., July 20, 2005; 23(21): 4669 - 4678. [Abstract] [Full Text] [PDF]

				J. Rodriguez, M. D. Caballero, A. Gutierrez, C. Solano, R. Arranz, J. J. Lahuerta, J. Sierra, M. Gandarillas, J. A. Perez-Simon, J. Zuazu, et al. Autologous stem-cell transplantation in diffuse large B-cell non-Hodgkin's lymphoma not achieving complete response after induction chemotherapy: the GEL/TAMO experience Ann. Onc., October 1, 2004; 15(10): 1504 - 1509. [Abstract] [Full Text] [PDF]

				T. Baetz, A. Belch, S. Couban, K. Imrie, J. Yau, R. Myers, K. Ding, N. Paul, L. Shepherd, J. Iglesias, et al. Gemcitabine, dexamethasone and cisplatin is an active and non-toxic chemotherapy regimen in relapsed or refractory Hodgkin's disease: a phase II study by the National Cancer Institute of Canada Clinical Trials Group Ann. Onc., December 1, 2003; 14(12): 1762 - 1767. [Abstract] [Full Text] [PDF]

				P. Borchmann, J. F. Treml, H. Hansen, C. Gottstein, R. Schnell, O. Staak, H.-f. Zhang, T. Davis, T. Keler, V. Diehl, et al. The human anti-CD30 antibody 5F11 shows in vitro and in vivo activity against malignant lymphoma Blood, November 15, 2003; 102(10): 3737 - 3742. [Abstract] [Full Text] [PDF]

				M. D. Caballero, J. A. Perez-Simon, A. Iriondo, J. J. Lahuerta, J. Sierra, J. Marin, M. Gandarillas, R. Arranz, J. Zuazu, V. Rubio, et al. High-dose therapy in diffuse large cell lymphoma: results and prognostic factors in 452 patients from the GEL-TAMO Spanish Cooperative Group Ann. Onc., January 1, 2003; 14(1): 140 - 151. [Abstract] [Full Text] [PDF]

				V. Diehl, H. Stein, M. Hummel, R. Zollinger, and J. M. Connors Hodgkin's Lymphoma: Biology and Treatment Strategies for Primary, Refractory, and Relapsed Disease Hematology, January 1, 2003; 2003(1): 225 - 247. [Abstract] [Full Text] [PDF]

				E. Weidmann, S.-Z. Kim, A. Rost, H. Schuppert, G. Seipelt, D. Hoelzer, and P. S. Mitrou Bendamustine is effective in relapsed or refractory aggressive non-Hodgkin's lymphoma Ann. Onc., August 1, 2002; 13(8): 1285 - 1289. [Abstract] [Full Text] [PDF]

				S. J. Horning, R. T. Hoppe, S. Breslin, N. L. Bartlett, B. W. Brown, and S. A. Rosenberg Stanford V and Radiotherapy for Locally Extensive and Advanced Hodgkin's Disease: Mature Results of a Prospective Clinical Trial J. Clin. Oncol., February 1, 2002; 20(3): 630 - 637. [Abstract] [Full Text] [PDF]

				C. Ferme, N. Mounier, M. Divine, P. Brice, A. Stamatoullas, O. Reman, L. Voillat, J. Jaubert, P. Lederlin, P. Colin, et al. Intensive Salvage Therapy With High-Dose Chemotherapy for Patients With Advanced Hodgkin's Disease in Relapse or Failure After Initial Chemotherapy: Results of the Groupe d'Etudes des Lymphomes de l'Adulte H89 Trial J. Clin. Oncol., January 15, 2002; 20(2): 467 - 475. [Abstract] [Full Text] [PDF]

				A. Josting, J. Franklin, M. May, P. Koch, M. K. Beykirch, J. Heinz, C. Rudolph, V. Diehl, and A. Engert New Prognostic Score Based on Treatment Outcome of Patients With Relapsed Hodgkin's Lymphoma Registered in the Database of the German Hodgkin's Lymphoma Study Group J. Clin. Oncol., January 1, 2002; 20(1): 221 - 230. [Abstract] [Full Text] [PDF]

				T. Kewalramani, A. D. Zelenetz, E. E. Hedrick, G. B. Donnelly, S. Hunte, A. C. Priovolos, J. Qin, N. C. Lyons, J. Yahalom, S. D. Nimer, et al. High-dose chemoradiotherapy and autologous stem cell transplantation for patients with primary refractory aggressive non-Hodgkin lymphoma: an intention-to-treat analysis Blood, October 1, 2000; 96(7): 2399 - 2404. [Abstract] [Full Text] [PDF]

				A. Josting, U. Rueffer, J. Franklin, M. Sieber, V. Diehl, and A. Engert Prognostic factors and treatment outcome in primary progressive Hodgkin lymphoma: a report from the German Hodgkin Lymphoma Study Group Blood, August 15, 2000; 96(4): 1280 - 1286. [Abstract] [Full Text] [PDF]

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