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

A. Josting1,*, M. Sieniawski1, J.-P. Glossmann1, O. Staak1, L. Nogova1, N. Peters2, M. Mapara3, B. Dörken3, Y. Ko4, B. Metzner5, J. Kisro6, V. Diehl1 and A. Engert1

1 University Hospital Cologne, First Department of Internal Medicine, Germany 2 Carl-Thiem-Hospital Cottbus, Second Medical Hospital, Germany 3 University Hospital Charitè Berlin, Section for Hematology/Oncology, Germany4 University Hospital Bonn, Department of Internal Medicine, Germany 5 Klinikum Oldenburg, Department II of Internal Medicine, Germany 6 University Hospital Lübeck, Section for Hematology/Oncology, Germany

* Correspondence to: Dr A. Josting, First Department of Internal Medicine, University Hospital Cologne, Joseph-Stelzmann-Str 9, 50924 Cologne, Germany. Email: andreas.josting{at}uni-koeln.de


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background: Combination chemotherapy can cure patients with non-Hodgkin's lymphoma (NHL), but those who suffer treatment failure or relapse still have a poor prognosis. High-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) can improve the outcome of these patients. We evaluated an intensified high-dose sequential chemotherapy program with a final myeloablative course.

Patients and methods: Inclusion criteria were age 18–65 years, histologically proven primary progressive or relapsed aggressive NHL and eligibility for HDCT. The therapy consists of two cycles DHAP: dexamethasone 40 mg (day 1–4), high-dose cytarabine 2 g/m2 12q (day 2), cisplatin 100 mg/m2 (day 51); patients with partial (PR) or complete remission (CR) received cyclophosphamide 4 g/m2 (day 37), followed by peripheral blood stem cell (PBSC) harvest; methotrexate 8 g/m2 (day 1) plus vincristine 1.4 mg/m2 (day 51); and etoposide 500 mg/m2 (day 58–62). The final myeloblative course was BEAM: cytarabine 200 mg/m2 12q (day 81–84), etoposide 150 mg/m2 12q (day 81–84), melphalan 140 mg/m2 (day 80), carmustin 300 mg/m2 (day 80) followed by PBSCT.

Results: Fifty-seven patients (median age 43 years, range 24–65) were enrolled: 23 (40%) patients were refractory to primary therapy and 34 (60%) patients had relapsed NHL. The response rate (RR) after 2 cycles of DHAP was 72% (9% CR, 63% PR) and at the final evaluation (100 days post transplantation) 43% (32% CR, 11% PR). Toxicity was tolerable. Median follow-up was 25 months (range 1–76 months). Freedom from second failure (FF2F) and overall survival (OS) at 2 years were 25% and 47% for all patients, respectively. FF2F at 2 years for patients with relapse and for patients refractory to primary therapy were 35% and 9% (P=0.0006), respectively. OS at 2 years for patients with relapse and for patients refractory to primary therapy were 58% and 24% (P=0.0044), respectively.

Conclusions: We conclude that this regimen is feasible, tolerable and effective in patients with relapsed NHL. In contrast, the results in patients with progressive disease are unsatisfactory. This program is currently being modified by addition of rituximab for patients with relapsed aggressive NHL.

Key words: high-dose chemotherapy, non-Hodgkin's lymphoma, relapse


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients with aggressive non-Hodgkin's lymphoma (NHL) treated at first diagnosis with polychemotherapy alone or combined chemoradiotherapy can achieve high response rates [1Go–7Go]. However, patients with relapsed or progressive disease still have a poor prognosis. High-dose chemotherapy (HDCT) followed by autologous stem cell transplantation (ASCT) is the treatment of choice for these patients [8Go–16Go]. The most compelling evidence for the superiority of HDCT compared with conventional-dose salvage therapy in relapsed and progressive NHL is based on the randomized ‘Parma trial’ [15Go]. In this study, all patients received two cycles of conventional chemotherapy. The responders were randomized to receive either four cycles of conventional chemotherapy or HDCT (BEAM) followed by autologous stem cell transplantation (ASCT). The response rate was 44% in the group with conventional chemotherapy and 84% in the HDCT group. The analysis at 5 years revealed that patients treated with HDCT had superior outcome as measured by freedom from second failure (FF2F) (12% versus 46%) and by overall survival (OS, 32% and 53%). Therefore, two cycles of conventional salvage chemotherapy followed by HDCT and PBSCT is considered standard treatment for these patients. However, in the ‘Parma trial’ more than 50% of patients treated in the HDCT-arm relapsed and most of them died.

The explanation of high relapse rates after HDCT might be that one cycle of HDCT is not sufficient to control non-proliferate lymphoma cells. Since NHL is a chemosensitive disease, we hypothesized that a more stringent chemotherapy program might improve the treatment results of patients with relapsed/refractory NHL. Sequential high-dose chemotherapy (HDSCT) in accordance with the Norton–Simon hypothesis [17Go] is one possibility of treatment intensification. Following initial cytoreduction, non-cross-resistant agents are given in high doses at short intervals. In general, the transplantation of peripheral blood stem cells and the use of growth factors allow the application of the putatively most effective drugs at the highest possible dose at intervals of 1–3 weeks. HDSCT thereby enables the highest possible dosing over a minimum period of time (dose intensification). In recent years, HDSCT has been investigated in the treatment of solid tumors, hematological and lymphoproliferative disorders. Initial results from phase I/II studies indicated that this treatment modality is safe and effective [18Go–23Go]. We therefore designed a dose and time-intensified HDSCT regimen after initial cytoreduction with two cycles of DHAP in patients with relapsed and refractory NHL. Here we report that this regimen is feasible, tolerable and effective in patients with relapsed NHL.


    Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient selection
Patients with relapsed or refractory NHL were treated in this multicenter phase II study involving 13 centers in Germany (see Appendix). Eligibility criteria included: age between 18 and 65 years, histopathologic proven diagnosis of relapsed or refractory NHL, adequate organ function as defined by a creatinine clearance >60 ml/min, serum transaminases less than three times the normal value, bilirubin <2 mg/dl, left ventricular ejection fraction >0.45, forced expiratory volume in first-second (FEV1) or diffusion capacity of carbon monoxide (DLCO) >60%, Eastern Cooperative Oncology Group (ECOG) performance status ≤2, and white blood cells (WBCs) ≥3500/µl, hemoglobin level ≥8 g/dl, and platelets ≥100000/µl. Patients were required to have negative human immunodeficiency virus tests and to be free of active infections. All patients signed consent forms that were based on the Institutional Review Board Guidelines. The study was approved by the independent ethics committee at each institution.

Primary progressive/refractory disease was defined as disease progression during first-line chemotherapy, or only transient response [complete (CR) or partial response (PR) lasting ≤3 months] 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 non-responders; and (2) the appearance of any new lesion during ≤3 months after the end of therapy. Relapsed disease was defined as disease progression after CR lasting ≥3 months.

Study design and treatment procedures
All patients received two cycles of DHAP as initial salvage treatment in order to reduce tumor volume prior to HDSCT. DHAP consisted of dexamethasone 40 mg i.v. (day 1–4), cisplatin 100 mg/m2 i.v. given as 24-h continuous infusion (day 1), and cytarabine 2000 mg/m2 i.v. over 3 h 12q (day 2). Hydration (250 ml/h) was started 6–12 h before cisplatin infusion. Corticosteroid eye drops were given topically starting 12 h before and continued for 2 days after administration of cytarabine to prevent conjunctivitis. To minimize nausea and vomiting, patients received ondansetrone 8 mg i.v. on days 1 and 2. Twenty-four hours after the last dose of cytarabine, G-CSF was given at a dose of 5 µg/kg/day subcutaneously until leukocytes increased ≥2500/µl for 3 days. The second cycle of DHAP was administered after 14 days providing WBC were >3000/µl and platelets >75 000/µl.

Those patients who achieved PR or CR after DHAP proceeded to the sequential high-dose regimen including high-dose cyclophosphamide (HD-CTX) 4000 mg/m2 +G-CSF (day 37) followed by PBSC harvest, high-dose methotrexate plus vincristine (HD-MTX/VCR) 8000 mg/m2 plus vincristine 1.4 mg/m2 (day 51), high-dose etoposide (HD-VP16) 500 mg/m2 +G-CSF (day 58–62). Finally, a myeloablative treatment (BEAM) with carmustine 300 mg/m2 (day 80), melphalan 140 mg/m2 (day 80), etoposide 150 mg/m2 12q (day 81–84) and cytarabine 200 mg/m2 12q (day 81–84) was given. PBSCs were reinfused and G-CSF administered until hematological recovery (Figure 1 and Table 1). Patients with residual tumor (≥2 cm) at the final evaluation received involved field radiation.



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Figure 1. Overall survival and freedom from second failure for all patients.

 

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Table 1. Chemotherapy dosage

 
Staging procedures
Before salvage chemotherapy, the extent of disease was assessed by chest X-ray, abdominal ultrasound, computed tomography of involved sites, and bone marrow biopsy. Restaging was performed after two cycles of DHAP. All sites of initial disease were reassessed by adequate methods, including bone marrow biopsy for patients who had bone marrow involvement before salvage therapy. Evaluation of the final response was performed 100 days after PBSCT. Further follow-up was carried out at 3-month intervals during the first year, then at 6-month intervals, and every 12 months after 5 years.

Definition of response
CR was defined as the disappearance of all clinical and radiographic evidence of disease for at least 3 months. PR was defined as a greater than 50% reduction in the product of the largest diameter and its perpendicular of measurable disease lasting >1 month. Any response less than PR was considered as treatment failure.

Statistics
The primary end point of this study was freedom from second failure (FF2F); secondary end points were toxicity, remission rate and OS.

Demographics and disease characteristics were summarized using descriptive statistics. Treatment failure was defined as death from any cause, non-CR or non-PR at the end of therapy (≤3 months) and further relapse, no matter which event occurred first.

FF2F was estimated from the date of beginning the protocol to first occurrence of one of the events mentioned above or, if none of these occurred, to the date of last information on complete remission. OS was estimated from the date of beginning the protocol to the date of death or, if no death occurred, to the last documented information on the patient. OS and FF2F rates were estimated according to the method of Kaplan and Meier [24Go]. All statistical analyses were performed using SPSS 10.0. (SPSS Inc, Chicago, IL).


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient characteristics
Fifty-seven patients were included in this study. The median age at study entry was 43 years (range 24–65 years). Twenty-three patients (40%) had primary progressive/refractory disease and 34 (60%) patients relapsed. Thirty-one patients (53%) were in clinical stage III/IV at relapse and 27 (47%) in clinical stage I/II. B symptoms at relapse were present in 19 patients (34%). Hemoglobin level before therapy less than 12 g/dl in male patients or less than 10.5 g/dl in female patients was found in 16 patients (28%). Front-line chemotherapy consisted in 76% of CHOP or, cyclophosphamide, doxorubicin, etoposide, vincristine and prednisone (CHOEP) regimens. Fourteen of the patients (25%) had been treated with combined chemoradiotherapy during first-line therapy. Relapse or progression was proven by biopsy in all patients. Patient characteristics are listed in Table 2.


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Table 2. Patient characteristics

 
Response rates
Response rates are listed in Tables 35. The overall response rate for all patients after two cycles of DHAP was 72% (9% CR and 63% PR). The overall response in patients with relapse was 88% (12% CR, 76% PR). In contrast, the response rate in patients with progressive NHL was 52% (4% CR, 48% PR).


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Table 3. Response after two cycles DHAP

 

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Table 5. Response at the final evaluation (responders to two cycles DHAP)

 
The final evaluation included patients who failed after two cycles of DHAP as well as patients who completed the whole treatment protocol (restaging 100 days after PBSCT). Three patients (5%) received radiotherapy after completing the whole chemotherapy protocol. The response rate at the final evaluation was 43% for all patients (32% CR and 11% PR). Fifty-six per cent of patients with relapsed NHL responded (50% CR and 6% PR), in contrast only 21% of patients with primary progressive NHL (4% CR and 17% PR) responded.

The overall response rate (OR) for patients who responded to two cycles DHAP was 59% (44% CR and 15% PR). For those with relapsed NHL the OR was 64% (57% CR and 7% PR) and 45% (9% CR and 36% PR) in primary progressive NHL, respectively. The OR rate in patients with diffuse large B-cell lymphoma (DLBCL) was lower than in the patients with non-DLBCL, 39% (29% CR and 10% PR) versus 53% (40% CR and 13% PR), respectively (Table 6).


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Table 6. Response after two cycles DHAP and at the final evaluation (patients with DLBCL versus non-DLBCL)

 
Toxicity of DHAP
A total of 105 courses were administered in 57 patients. The main toxicity of DHAP was myelosuppression with leukocytes of less than 1000/µl in 40% of all courses (median duration 0 days; range 0–7 days) and thrombocytopenia of less than 25 000/µl in 51% of all courses (median duration 0 days; range 0–9 days). The mean number of platelet transfusions was 0.6 (range 0–7). The mean number of red blood cells (RBC) units transfused was 0.4 (range 0–6). In 10 courses, patients developed fever (mean 0.2 days; range 0–7 days). WHO grade III and grade IV nausea/vomiting occurred in 12% of all courses. In 4% of all courses patients suffered from mucositis WHO grade III and IV. In two cases we observed elevation of creatinine serum level WHO grade I. One patient developed acute pancreatitis and was excluded from further treatment. No patient died due to treatment-related toxicity.

Toxicity of the sequential high-dose chemotherapy
The sequential high-dose chemotherapy was well tolerated by most of the patients. Most frequently observed hematological toxicities were myelosuppression and thrombocytopenia. Leukocytopenia with leukocytes ≤1000/µl were observed for a median duration of 5 days (range 0–13) after cyclophosphamide, for a median duration of 0 day (0–7) after methotrexate, for 7 days (0–13) after etoposide and for 9 days (6–19) after BEAM. The median duration of thrombocytopenia of less than 25 000/µl was 3.5 days (range 0–20) after cyclophosphamide, 0 day (0–7) after methotrexate and 7 days (0–15) after etoposide.

The mean number of RBC-transfusions was 3.3 after cyclophosphamide (range 0–8), 0.8 after methotrexate (0–4), 3.6 after etoposide (0–10) and 3.6 after BEAM (0–14). The mean number of platelet transfusions was 2.1 after cyclophosphamide (range 0–9), 0.3 after methotrexate (0–5), 2.3 after etoposide (0–7) and 5.8 after BEAM (0–22). Results are summarized in Table 7.


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Table 7. Hematologic toxicity

 
The most often observed non-hematologic toxicities during a total of 135 cycles of HDSCT were mucositis (WHO grade III or IV) in 16%, fever ≥38°C in 40%, nausea/vomiting (WHO grade III or IV) in 16% and elevated creatinine plasma level (WHO grade III or IV) in 7%, the results for each cycle are summarized in Table 8. Pneumonitis was diagnosed in two patients, one after HD-CTX and one after HD-VP-16. One patient died during HDSCT in septic shock during neutropenia after prolonged methotrexate elimination.


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Table 8. Non-hematologic toxicity

 
Survival and causes of death
The median observation time was 25 months (range 1–76 months). The FF2F and OS at 2 years for all patients after initiation of salvage therapy were 25% and 47% for all patients, respectively (Figure 2). FF2F at 2 years for patients with relapse and for patients refractory to primary therapy were 35% and 9% (P=0.0006), respectively. OS at 2 years for patients with relapse and for patients refractory to primary therapy were 58% and 24% (P=0.0044), respectively (Figures 2 and 3).



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Figure 2. Freedom from second failure according to the remission status.

 


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Figure 3. Overall survival according to the remission status.

 
Currently, 13/57 patients are alive (23%). Forty-two patients (74%) died as a result of disease progression and one patient died in septic shock during neutropenia after prolonged methotrexate elimination. One patient was lost to follow-up.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The following findings emerge from this study. (1) DHAP given in short intervals is an effective salvage chemotherapy regimen with low toxicity prior to HDSCT in patients with relapsed NHL. (2) The complete program is feasible with an acceptable acute toxicity rate. (3) The OR rate for all patients was 43%, FF2F and OS at 2 years were 47% and 25%, respectively. (4) The regimen was more effective in patients with relapsed NHL (OR 56%, FF2F and OS at 2 years: 35% and 58%) compared with patients with progressive disease (OR 21%, FF2F and OS at 2 years: 9% and 24%).

Several phase II studies evaluated HDCT and ASCT in patients with relapsed or refractory NHL [8Go–16Go]. Based on the results of a randomized trial, HDCT followed by ASCT is being considered standard treatment for patients with aggressive non-Hodgkin lymphoma failing first-line chemotherapy [15Go]. This strategy produces long-term disease-free survival rate in selected patients, mainly those with chemosensitive relapse [14Go].

The high relapse rates observed in most trials using a single HDCT, however, suggest that this strategy might not be sufficiently effective against non-proliferative cells. Therefore, according to the Norton–Simon hypothesis [17Go], sequential high-dose chemotherapy regimens have been introduced in the treatment of solid tumors and lymphoproliferative disorders [18Go–23Go]. After initial cytoreduction, single-agent non-cross-resistant drugs are given at short intervals. In general, the transplantation of PBSC and the use of growth factors allow the application of the putatively most effective drugs at the highest possible doses with intervals of 1–3 weeks. Sequential high-dose chemotherapy thereby enables the highest possible dosing over a minimum period of time (dose intensification). In a retrospective study, Cortelazzo et al. [25Go] reported the use of a HDSCT regimen in 103 patients with relapsed or refractory NHL. Seventy-nine patients achieved a complete response after autotransplantation. Three-year estimates of overall survival, event-free survival and disease-free survival after a median follow up of 24 months were 67%, 44% and 47%, respectively. The toxicity was low with treatment-related mortality of 4% and the regimen was associated with remarkable response rates allowing further therapy with ASCT.

In our study the patients were treated with two cycles of salvage chemotherapy to reduce tumor burden and to evaluate the chemosensitivity of disease as a predictive factor for HDCT [25Go–27Go]. In addition, all patients were treated with DHAP plus G-CSF to shorten the intervals between cycles. The median time between the first and second cycle of DHAP was 18 days. This represents a dose-escalation by a factor of 1.6 compared with DHAP given at 28-day intervals. The OR after two cycles of DHAP was 72% (9% CR, 64% PR) and thus at least comparable to results observed with other salvage regimens [28Go–32Go]. The toxicity profile was excellent with WHO grade III and IV leucocytopenia and thrombocytopenia occurring in 40% and 51% of all cycles with a mean duration of 0 days, respectively. One patient developed acute pancreatitis and was excluded from further treatment. Neither severe infections nor treatment-related deaths occurred.

The second part of the sequential treatment program consisted of high-dose cyclophosphamide at a dose of 4000 mg/m2. This drug does not have a strong proliferation-dependent cytotoxicity and, therefore, will also kill tumor cells that are out of the cell cycle [33Go]. Methotrexate 8000 mg/m2 and vincristine 1.4 µg/m2 are class II specific anticancer agents with an expected optimal activity when given after cyclophosphamide. Importantly, methotrexate and vincristine are marrow non-toxic drugs and obviate the risk of a second myelosuppressive treatment during early recovery of the marrow after cyclophosphamide [33Go]. Etoposide at 2000 mg/m2 as the final course prior to myelosuppressive therapy with BEAM is a highly active cytotoxic drug in lymphoma patients with moderate toxicity when given as a single agent at high doses. The conditioning regimen used was BEAM (BCNU, etoposide, cytarabine and melphalan) at standard doses.

Despite possible concerns of additive toxicity, the four-step high-dose sequential program as reported in this study proved to be well tolerated. The observed CR rate was 32% and the OR rate was 43% for all patients. In patients with relapsed NHL, the CR rate was 50% and the OR rate was 56%; in contrast, in patients with progressive disease the CR rate was only 4% and the OR rate 22%. These results demonstrate that this regimen is highly effective in patients with relapsed NHL but ineffective in patients with progression during first-line therapy. By the analysis of patients who responded to the first two cycles of DHAP, CR was observed in 44% and OR in 59% patients. The OR in patients with relapsed NHL versus progressive NHL was 64% versus 45%, but the CR was 57% versus 9%, respectively. In addition, patients with relapse had a better outcome than patients with primary progressive disease. FF2F at 2 years for patients with relapse and for patients refractory to primary therapy were 35% and 9% (P=0.0006), respectively. OS at 2 years for patients with relapse and for patients refractory to primary therapy were 58% and 24% (P=0.0044), respectively.

In conclusion, this new three-phase treatment regimen is well tolerated, feasible and effective in patients with relapsed NHL. In contrast, the results in patients with progressive disease are unsatisfactory. This program is currently being modified by the addition of rituximab for patients with relapsed aggressive NHL.


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Table 4. Response at the final evaluation

 
Received for publication October 8, 2004. Revision received March 17, 2005. Accepted for publication March 18, 2005.


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
1. Fisher RI, Gaynor ER, Dahlberg S. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin's Lymphoma. N Engl J Med 1993; 318: 1002–1006.[CrossRef]

2. Schmitz N. EBMT Workshop: High dose therapy in aggressive NHL. Ann Hematol 2001; 80: B24–B25.[ISI][Medline]

3. Kaiser U, Uebelacker I, Abel U. Randomised study to evaluate the use of high-dose therapy as part of primary treatment for ‘aggressive’ lymphoma. J Clin Oncol 2002; 2: 4413–4419.[CrossRef]

4. Koeppler H, Pflüger KH, Eschenbach I et al. Randomised comparison of CHOEP versus CHOEP/IVEP for high-grade non-Hodgkin's lymphoma: Treatment results and prognostic factor analysis in a multi-center trial. Ann Oncol 1994; 5: 49–55.[Abstract]

5. Haioun C, Lepage E, Gisselbrecht C. Survival benefit of high-dose therapy in poor-risk aggressive non-Hodgkin's lymphoma: final analysis of the prospective LNH87-2 protocol-a group d'Etude des lymphomes de l'Adulte study. J Clin Oncol 2000; 18: 3025–3030.[Abstract/Free Full Text]

6. Coiffier B, Lepage E, Brier J et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 2002; 346: 235–242.[Abstract/Free Full Text]

7. Habermann TM, Weller EA, Morrison VA. Phase III trial of rituximab-CHOP vs. CHOP with a second randomization to maintenance rituximab (MR) or observation in patients 60 years of age and older with diffuse large B-cell lymphoma (DLBCL). Blood 2003; 102: 6a (Abstr).

8. Verdonck LF, Dekker AW, de Gast GC. Salvage therapy with ProMACE-MOPP followed by intensive chemoradiotherapy and autologous bone marrow transplantation for patients with non-Hodgkin's lymphoma who failed to respond to first-line CHOP. J Clin Oncol 1992; 10: 1949–1954.[Abstract/Free Full Text]

9. Vose JM, Zhang Mei-Jie, Rowlings PA. Autologous transplantation for diffuse aggressive non-Hodgkin's lymphoma in patients never achieving remission: a report from the autologousblood and marrow transplant registry. J Clin Oncol 2001; 19: 406–413.[Abstract/Free Full Text]

10. Prince HM, Imrie K, Crump M et al. The role of intensive therapy and autologous blood and marrow transplantation for chemotherapy-sensitive relapsed and primary refractory non-Hodgkin's lymphoma: identification of major prognostic groups. Br J Haem 1996; 92: 880–889.[CrossRef][ISI][Medline]

11. Saez R, Dahlberg S, Appelbaum FR et al. Autologous bone marrow transplantation in adults with non-Hodgkin's lymphoma: southwest oncology group study. Hema Oncol 1994; 12: 75–85.[ISI]

12. Nademanee A, Molin A, Dagis A. Autologous stem-cell transplantation for poor-risk and relapsed intermediate- and high-grade non-Hodgkin's lymphoma. Clin Lymphoma 2000; 1: 45–54.

13. Salzman DE, Briggs AD, Vaughan WP. Bone marrow transplantation for non-Hodgkin's lymphoma: a review. Am J Med Sci 1997; 313: 228–235.[ISI][Medline]

14. Kewalramani T, Zelenetz AD, Hedrick EE 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 2000; 96: 2399–2404.[Abstract/Free Full Text]

15. Philip T, Gugliemi C, Hagenbeek A et al. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma. N Engl J Med 1995; 333: 1540–1545.[Abstract/Free Full Text]

16. Josting A, Reiser M, Rueffler U et al. Treatment of primary progressive Hodgkin's and aggressive non-Hodgkin's lymphoma: is there a chance for cure? J Clin Oncol 2000; 18: 332–339.[Abstract/Free Full Text]

17. Norton L, Simon R. The Norton-Simon hypothesis revisited. Canc Treat Rep 1986; 70: 163–169.[ISI]

18. Gianni AM, Siena S, Bregni M 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 1993; 4: 889–891.[Abstract]

19. Gianni AM, Bregni M, Siena S et al. High-dose chemotherapy and autologous bone marrow transplantation compared with MACOP-B in aggressive B-cell lymphoma. N Engl J Med 1997; 336: 1290–1297.[Abstract/Free Full Text]

20. Patrone F, Ballestrero A, Ferrando F et al. Four-step high-dose sequential chemotherapy with double hematopoetic progenitor-cell rescue for metastatic breast cancer. J Clin Oncol 1995; 13: 840–846.[Abstract/Free Full Text]

21. Shea T, Mason JR, Storniolo AM et al. Sequential cycles of high-dose carboplatin administered with recombinant human granulocyte-macrophage colony-stimulating factor and repeated infusions of autologous peripheral-blood progenitor cells: A novel and effective method for delivering multiple courses of dose-intensive therapy. J Clin Oncol 1992; 10: 464–473.[Abstract/Free Full Text]

22. Gianni AM, Taella C, Bregni M et al. High-dose sequential chemo-radiotherapy, a widely applicable regimen, confers survival benefit to patients with high-risk multiple myeloma. J Clin Oncol 1994; 12: 503–509.[Abstract/Free Full Text]

23. Caracciolo D, Gavarotti P, Aglietta M et al. High-dose sequential chemotherapy with blood and marrow cell autograft as salvage treatment in very poor prognosis, relapsed non-Hodgkin's lymphoma. Bone Marrow Transplant 1993; 12: 621–625.[ISI][Medline]

24. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457–481.[ISI]

25. Cortelazzo S, Rambaldi A, Rossi A et al. Intensification of salvage treatment with high-dose sequential chemotherapy improves the outcome of patients with refractory or relapsed aggressive non-Hodgkin's lymphoma. Br J Haem 2001; 114: 333–341.[CrossRef][ISI][Medline]

26. Goldstone AH. High-dose therapy for the treatment of non-Hodgkin's lymphoma. In Armitage JO, Antman KH (eds): High-dose Cancer Theraphy: Pharmacology, Hematopoesis, Stem cells. Baltimore, MD, Williams and Wilkins 1995; 757–779.

27. Engert A, Josting A, Reiser M, Söhngen D, Diehl V. Aktueller Stellenwert der Hochdosistherapie in der Hämatologie und internistischen Onkologie. Med Klin 1999; 8: 431–442.

28. Josting A, Rudolph C, Reiser M et al. Time-intensified dexamethasone/cisplatin/cytarabine: an effective salvage therapy with low toxicity in patients with relapsed and refractory Hodgkin's disease. Ann Oncol 2002; 13: 1628–1635.[Abstract/Free Full Text]

29. Zinzani PL, Tani M, Molinari AL et al. Ifosfamide, epirubicin and etoposide regimen as salvage and mobilizing therapy for relapsed/refractory lymphoma patients. Haematologica 2002; 87: 816–821.[ISI][Medline]

30. Engert A, Schnell R, Kupper F et al. A phase-II study with idarubicin, ifosfamide and VP-16 (IIVP-16) in patients with refractory or relapsed aggressive and high-grade non-Hodgkin's lymphoma. Leuk Lymph 1997; 24: 513–522.[ISI][Medline]

31. Reiser M, Schnell R, Straub G et al. DIZE (dexamethasone, idarubicin, and continuous infusion of ifosfamide and etoposide): an effective and well-tolerated new regimen for patients with relapsed lymphoma. Leuk Lymph 1998; 31: 359–366.[ISI][Medline]

32. Rodriguez MA, Cabanillas FC, Velasquez W et al. Results of a salvage treatment program for relapsing lymphoma: MINE consolidated with ESHAP. J Clin Oncol 1995; 13: 1734–1741.[ISI][Medline]

33. Gianni AM, Bonadonna G. High-dose chemoradiotherapy for sensitive tumors: is sequential better than concurrent drug delivery. Eur J Cancer Clin Oncol 1989; 25: 1027–1030.[CrossRef][ISI][Medline]





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Articles by Engert, A.
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Articles by Josting, A.
Articles by Engert, A.