This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Josting, A. Articles by Engert, A. Search for Related Content PubMed PubMed Citation Articles by Josting, A. Articles by Engert, A. Social Bookmarking                            What's this?

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

From the First Department of Internal Medicine, University Hospital Cologne, and German Hodgkin’s Lymphoma Study Group, Cologne; Medizinische Universitätsklinik Münster, Medizinische Klinik A, Münster; Ludwig-Maximilians-Universität München, Klinikum Großhadern, Medizinische Klinik III, Munich; Klinikum der Albert-Ludwig-Universität Freiburg, Innere Medizin I, Freiburg; and Carl-Thiem-Klinikum Cottbus, II Medizinische Klinik, Cottbus, Germany.

Address reprint requests to Andreas Josting, MD, First Department of Internal Medicine, University Hospital Cologne, Joseph-Stelmann-Str 9, 50924 Cologne, Germany; email: andreas.josting{at}uni-koeln.de

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To evaluate salvage treatment outcome of patients with relapsed Hodgkin’s disease (HD) and to distinguish different risk groups using identified prognostic factors.

PATIENTS AND METHODS: From 4,754 patients registered in the German Hodgkin’s Lymphoma Study Group (GHSG) database between 1988 and 1999, 422 patients with early (n = 170) or late (n = 252) relapsed HD were identified. One hundred seven patients (25%) relapsed after radiotherapy (RT) for early stages, 133 patients (32%) after combined-modality therapy for intermediate stages, and 182 patients (43%) after chemotherapy (CT) and RT to initial bulky disease or residual lymphoma for advanced stages. At relapse, characteristics of these 422 patients (median age, 38 years; range, 17 to 77) were stage III/IV, 45%; B symptoms, 24%; elevated erythrocyte sedimentation rate, 29%; anemia, 13%; and Karnofsky performance score, less than 90 in 13%. At first relapse, salvage treatment was RT in 13%, CT in 54%, and high-dose chemotherapy (HDCT) with autologous stem-cell transplantation (ASCT) in 33%.

RESULTS: Median follow-up time after relapse was 45 months. Freedom from second failure (FF2F) and overall survival (OS) were 81% and 89% for relapse after RT, 33% and 46% for early relapse after CT, and 43% and 71% for late relapse after CT, respectively. In multivariate analysis, independent risk factors were time to relapse, clinical stage at relapse, and anemia at relapse. Four subgroups with significantly different FF2F and OS were identified. The prognostic score was predictive for patients who relapsed after RT, CT with conventional CT salvage, and CT with HDCT/ASCT.

CONCLUSION: In the GHSG database, time to relapse and clinical stage and anemia at relapse are relevant factors and can be used to form a prognostic score for HD patients at relapse.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
DEPENDING ON stage and risk factor profile, up to 95% of patients with Hodgkin disease (HD) at first presentation reach complete remission (CR) after initial standard treatment.^1-3 Depending on their initial treatment, patients who relapse after achieving CR have different treatment options, including radiotherapy for localized disease in previously nonirradiated areas, conventional salvage chemotherapy, and high-dose chemotherapy (HDCT) followed by stem-cell transplantation.⁴ Conventional chemotherapy is the treatment of choice for patients who relapse after radiotherapy for early-stage HD. The survival of these patients is at least equal when compared with advanced-stage patients initially treated with chemotherapy.^5-7 In contrast, patients with relapsed HD after primary chemotherapy generally have a poorer prognosis. The therapeutic options include salvage radiotherapy, salvage chemotherapy, and HDCT with stem-cell transplantation.

More recently, new approaches, such as sequential HDCT, tandem HDCT, allogeneic stem-cell transplantation, or nonmyeloablative conditioning with allogeneic blood progenitor cell transplantation ("mini-transplants"), have been investigated in relapsed HD.^8-10 Since more aggressive approaches are associated with increased toxicity, an accurate pretreatment prognostic assessment of patients is required to help in the selection of the most appropriate therapeutic regimen.

In the present study, we retrospectively analyzed patients with relapsed HD registered in the database of the German Hodgkin’s Lymphoma Study Group (GHSG). Patient characteristics, salvage treatment, and prognostic factors were evaluated at the time of relapse. The purpose of the present analysis was to determine independent factors correlated with treatment outcome. We demonstrate that time to relapse, stage at relapse, and anemia at relapse can be used to construct a prognostic factor model that distinguishes patients with different degrees of prognosis at relapse ranging from good (score 0), moderate (score 1), poor (score 2), to very poor (score 3).

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Selection
Patients with relapsed HD were retrospectively analyzed using the database of the GHSG. Relapse was distinguished from primary progressive disease by a period of at least 3 months in remission after completion of first-line treatment. Recruitment into the GHSG trials for early stages (HD4 and HD7), intermediate stages (HD5 and HD8), and advanced stages (HD6 and HD9) began in 1988 and continued until 1998 (Table 1).^11-15

Early relapse was defined as CR after first-line therapy lasting 3 to 12 months. Late relapse was defined as CR lasting more than 12 months after completion of induction treatment. A second biopsy at the time of relapse was recommended. This analysis is based on data extracted from the database and patient files from September 1999 to January 2000.

Salvage Therapy
Data on salvage chemotherapy included the type of regimen and the number of cycles. Sensitivity to conventional-dose salvage chemotherapy, defined as a more than 50% decrease in the sum of the products of the greatest diameter of measurable lesions, was assessed after two to three chemotherapy courses. Data relating to salvage radiotherapy included field and size, ie, total nodal irradiation, mantle field, extended-field, and involved-field radiation, and dose delivered. Data on HDCT included type of hematopoietic graft, preparative regimen, and chemosensitivity before transplantation.

Staging Procedures
Before salvage therapy, the extent of disease was assessed by chest x-ray, abdominal ultrasound, computed tomography, and bone marrow biopsy. Restaging was performed after salvage chemotherapy and/or radiotherapy. After the end of the salvage therapy and before autologous stem-cell transplantation (ASCT), all sites of initial disease were reassessed by adequate methods, including bone marrow biopsy for patients who had bone marrow involvement before salvage therapy.

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

Statistics
All patients who received salvage therapy with curative intent were included. Freedom from second treatment failure (FF2F) was measured from the date of entry onto the salvage protocol until progression, relapse, or death from any cause. Overall survival (OS) was measured from the date of entry onto the salvage protocol until death from any cause. Demographics and disease characteristics were summarized using descriptive statistics. OS and FF2F rates were estimated according to the method of Kaplan and Meier.¹⁶ The prognostic significance of various factors was tested by multivariate Cox regression analysis for each of the outcome variables (FF2F and OS).¹⁷

The following factors documented at relapse were analyzed for their prognostic influence: age, sex, histologic subtype at first diagnosis, stage, B symptoms, relapse sites, duration of response, Karnofsky performance score, primary treatment protocol, extranodal involvement, hemoglobin, serum alkaline phosphatase, serum lactate dehydrogenase, serum albumin, WBC count, absolute and relative lymphocyte counts, and erythrocyte sedimentation rate (ESR). Candidate factors were examined by stepwise procedures. Removal and entry levels of significance were .1 and .05, respectively. No adjustment was made for multiple comparisons, and all P values were two-sided. All statistical analyses were performed using SPSS 6.1 software (SPSS, Inc, Chicago, IL).

After analyzing the prognostic factors, we investigated prognostic score models combining relevant prognostic factors. OS was the primary end point for assessment of the score, and FF2F was used as a secondary end point. The objective was to identify groups of relapsed patients with particularly aggressive or responsive disease, based on characteristics available at the time of relapse.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Characteristics
A total of 471 patients with relapsed HD were identified. Forty-nine patients were excluded from the final analysis for the following reasons: non-Hodgkin’s lymphoma histology at relapse (n = 24), lack of data on salvage therapy (n = 14), refusal of salvage therapy (n = 6), and palliative radiotherapy, defined as radiotherapy not delivered to all involved sites (n = 5). Thus, 422 patients with early (n = 170) or late (n = 252) relapse were available for the final analysis. Patient characteristics are listed in Table 2.

One hundred seven patients (25%) had been treated with radiotherapy alone at initial diagnosis, 168 patients (40%) were treated with COPP/ABVD, 107 patients (25%) with COPP/ABV/IMEP, and 39 patients (10%) with BEACOPP (7% BEACOPP baseline; 3% BEACOPP escalated).^13,15 Two hundred sixty-three patients (62%) had received both chemotherapy and radiotherapy during first-line treatment.

The median age of all patients at relapse was 38 years (range, 17 to 77 years). Relapse was proven by biopsy in 301 patients (71%) and/or demonstrated unequivocally on radiographic studies. Stage at relapse by Ann Arbor criteria was I in 125 patients (30%), II in 107 (25%), III in 48 (11%), and IV in 142 (34%). At relapse, 59 patients (14%) had lung involvement, 51 (12%) had liver involvement, 38 (9%) had bone involvement, 38 (9%) had bone marrow involvement, and 21 (5%) had extranodal disease. Thirty-one patients (13%) had more than one organ involved. Seventy-one (17%) had Karnofsky performance scores less than 90, and 101 patients (24%) had B symptoms at the time of progression.

Time Until Relapse and Localization of Disease at Relapse
A total of 315 patients treated either with chemotherapy plus radiotherapy (82%) or chemotherapy alone (18%) for intermediate- or advanced-stage HD relapsed after a median period of 14 months (range, 3 to 93 months) after first diagnosis. Of these, 141 patients (45%) had early and 174 patients (55%) had late relapse, with 16 patients (5%) relapsing after more than 5 years. Stage at relapse after first-line chemotherapy by Ann Arbor criteria was stage I in 84 patients (27%), II in 83 patients (27%), III in 36 patients (11%), and IV in 112 patients (35%). One hundred forty-six patients (46%) presented with infield relapse.

From a total of 107 patients receiving first-line radiotherapy, relapse occurred after a median period of 19 months (range, 3 to 98 months) after first diagnosis. Twenty-nine patients (27%) had early and 78 patients (73%) had late relapse, respectively, with 12 patients (11%) relapsing after more than 5 years. Stage at relapse after radiotherapy for early-stage disease by Ann Arbor criteria was stage I in 41 patients (39%), II in 25 (23%), III in 11 (10%), and IV in 30 patients (28%). Twenty-five patients (23%) presented with infield relapse, 50 patients (47%) with outfield relapse, and 32 patients (30%) with both in- and outfield relapse.

Salvage Therapy
The majority of patients who relapsed after radiotherapy for early-stage HD (n = 107) were treated with conventional salvage chemotherapy (n = 100, 93%). Sixty-four patients (60%) were treated with COPP/ABVD, 24 (21%) with BEACOPP, four (4%) with COPP/ABV/IMEP, three with ABVD, two with COPP, and three (3%) with various other regimens. Seven patients (7%) were treated with radiotherapy alone.

Of the 315 patients who relapsed after first-line chemotherapy who were treated with salvage therapy, 128 patients (40%) received conventional salvage chemotherapy, 47 patients (15%) received salvage radiotherapy, and 140 (45%) received salvage chemotherapy followed by HDCT and ACST (Table 3).

At relapse after first-line chemotherapy, 47 patients (15%) were treated with salvage radiotherapy alone. Salvage radiotherapy as second-line treatment included extended-field radiotherapy in 27 patients, involved-field radiotherapy in 17 patients, and total nodal irradiation in three patients. The median dose of radiotherapy delivered was 40 Gy (range, 30.6 to 50 Gy). At the time of relapse, 29 patients (65%) treated with salvage radiotherapy had stage I disease, 16 patients (30%) had stage II, and two patients (5%) had stage III. The overall response rate after salvage radiotherapy was 96% (92% CR and 4% PR).

One hundred forty patients received HDCT and ASCT. The initial salvage chemotherapy regimen was Dexa-BEAM in 90 patients (64%), ifosfamide-containing regimens in 18 patients (13%), DHAP in 14 patients (10%), a COPP/ABVD-like regimen in six patients (4%), BEACOPP in five patients (4%), CEVD in five patients (4%), and other regimens in two (1%). The conditioning regimens used were cyclophosphamide, etoposide, and carmustine in 78 patients (56%), carmustine, etoposide, cytarabine, and melphalan in 44 patients (31%), and others in 17 patients (13%). The stem-cell source was peripheral-blood stem cells in 111 patients (79%), autologous bone marrow in 25 patients (18%), and both in four patients (3%).

Survival and Prognostic Factors
The median follow-up after relapse was 45 months. FF2F and OS were 81% and 89% for patients who relapsed after radiotherapy, 33% and 46% for early relapse after chemotherapy, and 43% and 71% for late relapse after chemotherapy, respectively (Figs 1 through 3).

View larger version (12K): [in this window] [in a new window]   Fig 1. Actuarial OS and FF2F for patients with relapse after irradiation for early-stage HD (n = 107).

View larger version (13K): [in this window] [in a new window]   Fig 2. Actuarial OS and FF2F for patients with early relapsed HD after first-line chemotherapy (n = 138).

View larger version (12K): [in this window] [in a new window]   Fig 3. Actuarial OS and FF2F for patients with late relapsed HD after first-line chemotherapy (n = 168).

To further assess the impact of time to relapse, we performed a multivariate Kaplan-Meier analysis in which patients were grouped according to time of relapse. This analysis demonstrated poor OS in those patients with very early relapse (3 to 6 months) and early relapse (6 to 12 months). In contrast, those patients with later relapse had a more favorable outcome (13 to 18 months, 19 to 36 months, and > 36 months). Importantly, there was no significant difference in terms of OS in patients within the group of patients with early (< 12 months) or late (> 12 months) relapse.

Our analysis of prognostic factors suggests that the prognosis of a patient at relapse can be estimated according to several influential factors. Groups of patients with different prognoses can be defined, possibly requiring salvage treatments of different intensities. We therefore attempted to combine the relevant factors into a single prognostic index or score to allow us to characterize relapsed patients with respect to tumor aggressiveness. Because patients treated with first-line chemotherapy have different salvage options compared with those treated only with first-line radiotherapy, these two groups were considered separately. In addition, as a factor, primary protocol was not explicitly included in the prognostic score. Because age and Karnofsky status are not necessarily related to aggressive disease, these factors were excluded from the prognostic score.

This left time to recurrence, stage, B symptoms, hemoglobin, ESR, and alkaline phosphatase as score candidates. The last four factors were highly correlated. Multivariate selection identified ESR as the most significant of these four factors. However, we decided to work with the hemoglobin rather than ESR because ESR is very sensitive to other conditions, such as infection, and it can fluctuate widely from day to day, whereas hemoglobin is relatively stable. This reasoning parallels that of Hasenclever and Diehl¹⁷ in the derivation of the international prognostic score for newly diagnosed, advanced-stage HD patients. When ESR was removed from the list of candidate factors, stepwise procedures selected the clinical factors of primary protocol, time to relapse, stage, Karnofsky index, and hemoglobin. Thus, the prognostic score was finally calculated on the basis of time to recurrence, stage, and hemoglobin. Scores were early relapse occurrence (within 12 months of the end of primary treatment), stage III or IV at relapse, and anemia. These risk factors can be combined in a prognostic index to form a score with possible values of 0, 1, 2, and 3 in order of worsening prognosis. Figures 4 and 5 show OS and FF2F for the resulting prognostic groups for all patients. The prognostic score was predictive for patients who relapsed after radiotherapy or after conventional chemotherapy or HDCT followed by ASCT (Figs 6 through 8). We calculated the prognostic score hazard ratios (with SEs) for the various patient groups (initial radiotherapy, initial chemotherapy with conventional salvage treatment, and initial chemotherapy with HDCT salvage). These hazard ratios all lay between 1.95 and 2.22, with no significant differences between groups. In addition, this prognostic index also significantly divided different risk groups when only patients under 60 years of age with a Karnofsky score of at least 90 were included (Fig 9). This underscores the clinical relevance in the group of patients who are major candidates for an intensified salvage treatment.

View larger version (17K): [in this window] [in a new window]   Fig 4. Actuarial OS in patients with relapse after chemotherapy: prognostic score (early relapse, stage, hemoglobin).

View larger version (10K): [in this window] [in a new window]   Fig 6. Actuarial OS for patients with relapse after radiotherapy: prognostic score (early relapse, stage, hemoglobin).

View larger version (17K): [in this window] [in a new window]   Fig 9. Actuarial OS for patients with relapsed HD, age < 60 years, and Karnofsky performance score of 90-100: prognostic score (early relapse, stage, hemoglobin).

View larger version (17K): [in this window] [in a new window]   Fig 5. Actuarial FF2F for patients with relapse after chemotherapy: prognostic score (early relapse, stage, hemoglobin).

View larger version (16K): [in this window] [in a new window]   Fig 7. Actuarial OS for patients with relapse after chemotherapy treated with conventional salvage therapy at the time of relapse: prognostic score (early relapse, stage, hemoglobin).

View larger version (15K): [in this window] [in a new window]   Fig 8. Actuarial OS for patients with relapse after chemotherapy treated with HDCT at the time of relapse: prognostic score (early relapse, stage, hemoglobin).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

Patients with localized HD who relapse after radiotherapy alone have satisfactory results when treated with conventional-dose polychemotherapy. The 10-year OS is 57% to 71%, as reported in large series.^5-7 However, stage at relapse is an important prognostic variable in radiotherapy failures. A study from Stanford including more than 100 patients with relapsed HD after subtotal or total nodal irradiation showed that conventional salvage chemotherapy is sufficient in patients with limited stages who have no B symptoms on recurrence (stages IA and IIA). After 10 years, 90% of these patients remained disease-free.¹⁸ In contrast, the 10-year disease-free survival for those with advanced stages at the time of relapse (III or IV) or with B symptoms was 58% and 34%, respectively. An analysis using the International Database on Hodgkin’s Disease showed a worse prognosis for patients whose relapse included an extranodal site and stage IV at relapse and for those patients older than 40 years.¹⁹

The overall prognosis is worse for patients who relapse after first-line chemotherapy when treated with conventional chemotherapy. At present, HDCT followed by ASCT is the treatment of choice for patients with relapsed HD after first-line polychemotherapy. In phase II studies, HDCT followed by ASCT has been shown to produce 30% to 65% long-term disease-free survival in selected patients with refractory and relapsed HD.^20-23 Two randomized studies performed by the British National Lymphoma Investigation and the GHSG/European Bone Marrow Transplantation Group (HDR-1) have shown improved outcome in patients with relapsed HD treated with HDCT.^24,25 Although the results reported with HDCT in patients with late relapse have been superior to those reported in most series of conventional chemotherapy, the use of HDCT in late relapses had been an area of controversy. Patients with late relapse have satisfactory second CR rates when treated with conventional chemotherapy, with OS ranging from 40% to 55%. However, the HDR-1 trial showed improved FF2F after HDCT compared with conventional chemotherapy in patients with late relapse. Therefore, HDCT should be considered as standard treatment for all patients with previous chemotherapy, including those with late relapse.²⁵ Although these results indicate the superiority of HDCT compared with conventional chemotherapy in patients with relapsed HD, a proportion of patients with early relapse will develop recurrent disease after HDCT. On the other hand, a considerable number of good-risk patients might be overtreated with HDCT. Thus, an effective assessment of prognostic factors, assessable at the time of relapse, is required to guide the physician in selecting the most appropriate therapeutic regimen and to evaluate new experimental approaches in very poor-risk relapses.

The results and usefulness of a prognostic factor analysis are naturally limited by the selection of candidate factors for consideration in the analysis. In the present investigation, we investigated those factors that were documented at relapse and that we believed to be potentially relevant, either because they were widely recognized as prognostic at initial diagnosis of HD or prognostic relevance had been demonstrated in previous investigations.

One of the most important prognostic factors for these patients is the duration of the initial remission.^26,27 In 1992, the National Cancer Institute updated their experience with the long-term follow-up of patients who had relapsed after polychemotherapy. On this basis, patients for whom chemotherapy had been unsuccessful were divided into two subgroups: early relapses occurring within 12 months of CR and late relapses after CR lasting more than 12 months. Using conventional chemotherapy for patients with early relapse or late relapse, the projected 11-year survival rates were 11% and 22%, respectively. Derived primarily from treatment failure after mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) and MOPP variants, the conclusions are relevant to other chemotherapy programs that include HDCT and ASCT.²⁸

Many other prognostic factors have been described for patients who relapse after first-line chemotherapy. These include age, sex, histology, relapse sites, stage at relapse, B symptoms, performance status, and extranodal relapse. The impact of these factors is difficult to assess due to confounding factors, such as small number of patients and inclusion of primary progressive HD. In addition, multivariate analyses were not performed systematically.

Lohri et al²⁹ observed favorable outcome for patients with favorable risk factors, such as no stage IV at diagnosis, absence of B symptoms at relapse, and initial remission duration of more than 12 months. The 5-year failure-free survival rate was 82% for those lacking all three (n = 22) and 17% for those who had one or more factors (n = 49).

Fermé et al³⁰ analyzed 100 patients with relapsed or refractory HD who were treated with salvage therapy before high-dose therapy. By univariate analysis, patients with a long initial (< 12 months) remission, untreated relapse, and good performance status showed improved OS.

Reece et al²¹ reported an analysis on 58 patients treated with HDCT and ASCT at the same institution. Four prognostic subgroups were identified according to the presence of the following parameters at relapse: B symptoms, extranodal disease, and initial remission duration less than 12 months. Patients with no risk factor had a 3-year progression-free survival rate of 100%, compared with 81% in patients with one factor, 40% in those with two factors, and 0% in patients with all three factors.

Brice et al³¹ performed one of the largest studies evaluating prognostic factors in relapsed HD. One hundred eighty-seven patients who relapsed after a first CR were included. At first relapse, treatment was conventional (chemo- and/or radiotherapy) in 44% and HDCT followed by ASCT in 56%. Two prognostic factors were identified by multivariate analysis as correlating with both FF2F and OS: initial duration of first remission (ie, < 12 months or > 12 months; P < .0001) and stage at relapse (I to II v III to IV; P = .0013). The FF2F rates for the two factors were 62% and 32% and the OS rates were 44% and 87% according to the presence of zero or two parameters, respectively. Laboratory data were not available in this retrospective analysis.³¹

The present analysis included a much larger number of relapsed patients than previously reported. Our analysis of prognostic factors suggests that the prognosis of a patient with relapsed HD can be estimated according to several factors. We combined the most relevant factors into a prognostic score. This score was calculated on the basis of time to recurrence, stage, and anemia. Early recurrence within 3 to 12 months after the end of primary treatment, stage III or IV relapse, and hemoglobin at relapse (< 10.5 g/dL for females and < 12 g/dL for males) were counted in a score with possible values of 0, 1, 2, and 3 in order of worsening prognosis.

Although the separation of the survival curves for patients with different scores varies between groups of patients, this variation seems to be no more than would be expected due to chance. For patients who had radiotherapy initially, in particular, the curves look different, but (1) the prognosis for these patients is much better overall and (2) the number of events is small, leading to relatively large change variations in the survival curves. We calculated the prognostic score hazard ratios (with SEs) for the various patient groups (initial radiotherapy, initial chemotherapy with conventional salvage, and initial chemotherapy with HDCT salvage). These hazard ratios all lay between 1.95 and 2.22, with no significant differences among groups.

In summary, the prognostic score makes it possible to distinguish patients with different FF2F and OS. The actuarial 4-year FF2F and OS rates for patients who relapsed after chemotherapy with three unfavorable factors were 17% and 27%, respectively. In contrast, patients with none of the unfavorable factors had FF2F and OS rates at 4 years of 48% and 83%, respectively. In addition, the prognostic score was also predictive for patients who relapsed after radiotherapy, for patients who relapsed after conventional chemotherapy or HDCT followed by ASCT, and for patients under 60 years old with a Karnofsky performance score 90; these groups were the major candidate groups for dose intensification. We have not tested the value of the prognostic factor score on an independent sample of relapsed patients. We encourage other investigators to validate the score externally.

In conclusion, our prognostic factor score uses clinical characteristics that can be easily collected at the time of relapse. It separates groups of patients with substantially different outcomes. The prognostic factors identified may be useful to tailor the therapy for subgroups of patients, to define homogeneous cohorts for prospective randomized trials, and to identify more precisely patients with poor-risk relapse who should be treated with innovative approaches.

	ACKNOWLEDGMENTS

 
Supported by grants from the Bundesministerium für Forschung und Technologie and the Deutsche Krebshilfe.

	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. Carde P, Noordijk E, Hagenbeek A, et al: Superiority of EBVP chemotherapy in combination with involved field irradiation (EBVP/IF) over subtotal nodal irradiation (STNI) in favorable clinical stage (CS) I-II Hodgkin’s disease: The EORTC-GPMC H7F randomized trial. Proc Am Soc Clin Oncol 16: 13a, 1997 (abstr 44)

3. Connors JM, Klimo P, Adams G, et al: Treatment of advanced Hodgkin’s disease with chemotherapy: Comparison of MOPP/ABV hybrid regimen with alternating courses of MOPP and ABVD—A report from the National Cancer Institute of Canada clinical trials group. J Clin Oncol 15: 1638-1645, 1997[Abstract]

4. Canellos GP: Treatment of relapsed Hodgkin’s disease: Strategies and prognostic factors. Ann Oncol 9: 91-98, 1998 (suppl 5)

5. Specht L, Horwich A, Ashley S, et al: Salvage of relapse of patients with Hodgkin’s disease in clinical stages I or II who were staged with laparotomy and initially treated with radiotherapy alone: A report from the International Database on Hodgkin’s Disease. Int J Radiat Oncol Biol Phys 30: 805-811, 1994[Medline]

6. Horwich A, Specht L, Ashley S, et al: Survival analysis of patients with clinical stages I or II Hodgkin’s disease who have relapsed after initial treatment with radiotherapy alone. Eur J Cancer 33: 848-853, 1997

7. Healey EA, Tarbell NJ, Kalish LA, et al: Prognostic factors for patients with Hodgkin’s disease in first relapse. Cancer 71: 2613-2620, 1993[CrossRef][Medline]

8. Josting A, Mapara M, Reiser M, et al: A dose-intensified therapy (DIT) prior to HDCT/ASCT in patients with relapsed and refractory lymphoma. Blood 94: 737a, 1999 (suppl 1)

9. Brice P, Divine M, Simon D, et al: Feasibility of tandem autologous stem-cell transplantation (ASCT) in induction failure or very unfavorable (UF) relapse from Hodgkin’s disease (HD): SFGM/GELA Study Group. Ann Oncol 10: 1485-1488, 1999[Abstract/Free Full Text]

10. 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]

11. Rueffer U, Sieber M, Tesch H: Final results of a randomized trial (HD4): 30 Gy extended field plus 10 Gy involved field radiation is equally effective to 40 Gy extended field radiation in patients with Hodgkin’s disease PS I/II. Blood 90:1431a, 997 (suppl 1)

12. Tesch H, Sieber M, Rueffer U, et al: Second interim analysis of the HD7 trial of the GHSG: 2 cycles ABVD plus extended field radio-therapy is more effective than radiotherapy alone in early stage HD. Blood 94: 2113a, 1999

13. Sieber M, Rueffer U, Tesch H, et al: Rapidly alternating COPP + ABV + IMEP (CAI) is equally effective as alternating COPP + ABVD (CA) for Hodgkin’s disease: Final results of two randomized trials for intermediate (HD5 protocol) and advanced (HD6 protocol) stages. Blood 90: 586a, 1997

14. Rueffer U, Sieber M, Pfistner B, et al: Reduction of radiotherapy volume in intermediate Hodgkin‘s disease: Interim analysis of a randomized trial in patients CS I/II of the GHSG. Blood 92: 2580a, 1998

15. Diehl V, Franklin J, Hasenclever D, et al: BEACOPP, a new dose-escalated and accelerated regimen, is at least as effective as COPP/ABVD in patients with advanced-stage Hodgkin‘s lymphoma: Interim report from a trial of the German Hodgkin’s Lymphoma Study Group. J Clin Oncol 16: 3810-3821, 1998[Abstract/Free Full Text]

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

17. Hasenclever D, Diehl V: A prognostic score for advanced Hodgkin’s disease: International Prognostic Factors Project on Advanced Hodgkin’s Disease. N Engl J Med 339: 1506-1514, 1998[Abstract/Free Full Text]

18. Roach MD, Brophy N, Cox R, et al: Prognostic factors for patients relapsing after radiotherapy for early-stage Hodgkin’s disease. J Clin Oncol 8: 623-629, 1990[Abstract]

19. Mauch P, Henry-Amar M: International Database on Hodgkin’s Disease: A cooperative effort to determine treatment outcome. Ann Oncol 3: 59-61, 1992 (suppl 4)[Abstract/Free Full Text]

20. Bierman P, Bagin R, Jagannath et al: High dose chemotherapy followed by autologous hematopoietic rescue in Hodgkin’s disease: Long-term follow-up in 128 patients. Ann Oncol 4: 767-771, 1993[Abstract/Free Full Text]

21. Reece D, Barnett M, Shepherd J, et al: High-dose cyclophosphamide, carmustine (BCNU), and etoposide (VP16-213) with or without cisplatin (CBV +/- P) and autologous transplantation for patients with Hodgkin’s disease who fail to enter a complete remission after combination chemotherapy. Blood 86: 451-458, 1995[Abstract/Free Full Text]

22. 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). Ann Oncol 9: 289-295, 1998[Abstract/Free Full Text]

23. Horning SJ, Chao NJ, Negrin RS, et al: High-dose therapy and autologous hematopoietic progenitor cell transplantation for recurrent or refractory Hodgkin‘s disease: Analysis of the Stanford University results and prognostic indices. Blood 89: 801-813, 1991[Abstract/Free Full Text]

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

25. Schmitz N, Sextro M, Pfistner B, et al: High-dose therapy (HDT) followed by hematopoietic stem cell transplantation (HSCT) for relapsed chemosensitive Hodgkin‘s disease (HD): Final results of a randomized GHSG and EBMT trial (HD-R1). Proc Am Soc Clin Oncol 18: 2a, 1999 (abstr 5)

26. Josting A, Rueffer U, Franklin J, et al: Prognostic factors and treatment outcome in primary progressive Hodgkin lymphoma: A report from the German Hodgkin Lymphoma Study Group (GHSG). Blood 96: 1280-1286, 2000[Abstract/Free Full Text]

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

28. Longo D, Duffey P, Young R, 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]

29. Lohri A, Barnett M, Fairey RN, et al: Outcome of treatment of first relapse of Hodgkin’s disease after primary chemotherapy: Identification of risk factors from the British Columbia experience 1970 to 1988. Blood 77: 2292-2298, 1991[Abstract/Free Full Text]

30. Fermè C, Bastion Y, Lepage E, et al: The MINE regimen as intensive salvage chemotherapy for relapsed and refractory Hodgkin’s disease. Ann Oncol 6: 543-549, 1995[Abstract/Free Full Text]

31. Brice P, Bastion Y, Divine M, et al: Analysis of prognostic factors after the first relapse of Hodgkin’s disease in 187 patients. Cancer 78: 1293-1299, 1996[CrossRef][Medline]

Submitted January 5, 2001; accepted August 14, 2001.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				E. Brusamolino, A. Bacigalupo, G. Barosi, G. Biti, P. G. Gobbi, A. Levis, M. Marchetti, A. Santoro, P. L. Zinzani, and S. Tura Classical Hodgkin's lymphoma in adults: guidelines of the Italian Society of Hematology, the Italian Society of Experimental Hematology, and the Italian Group for Bone Marrow Transplantation on initial work-up, management, and follow-up Haematologica, April 1, 2009; 94(4): 550 - 565. [Abstract] [Full Text] [PDF]

				F. Morschhauser, P. Brice, C. Ferme, M. Divine, G. Salles, R. Bouabdallah, C. Sebban, L. Voillat, O. Casasnovas, A. Stamatoullas, et al. Risk-Adapted Salvage Treatment With Single or Tandem Autologous Stem-Cell Transplantation for First Relapse/Refractory Hodgkin's Lymphoma: Results of the Prospective Multicenter H96 Trial by the GELA/SFGM Study Group J. Clin. Oncol., December 20, 2008; 26(36): 5980 - 5987. [Abstract] [Full Text] [PDF]

				N. L. Bartlett, A. Younes, M. H. Carabasi, A. Forero, J. D. Rosenblatt, J. P. Leonard, S. H. Bernstein, R. G. Bociek, J. M. Lorenz, B. W. Hart, et al. A phase 1 multidose study of SGN-30 immunotherapy in patients with refractory or recurrent CD30+ hematologic malignancies Blood, February 15, 2008; 111(4): 1848 - 1854. [Abstract] [Full Text] [PDF]

				A. Engert, J. Franklin, H. T. Eich, C. Brillant, S. Sehlen, C. Cartoni, R. Herrmann, M. Pfreundschuh, M. Sieber, H. Tesch, et al. Two Cycles of Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine Plus Extended-Field Radiotherapy Is Superior to Radiotherapy Alone in Early Favorable Hodgkin's Lymphoma: Final Results of the GHSG HD7 Trial J. Clin. Oncol., August 10, 2007; 25(23): 3495 - 3502. [Abstract] [Full Text] [PDF]

				N. Bartlett, D Niedzwiecki, J. Johnson, J. Friedberg, K. Johnson, K van Besien, A. Zelenetz, B. Cheson, G. Canellos, and For the Cancer Leukemia Group B Gemcitabine, vinorelbine, and pegylated liposomal doxorubicin (GVD), a salvage regimen in relapsed Hodgkin's lymphoma: CALGB 59804 Ann. Onc., June 1, 2007; 18(6): 1071 - 1079. [Abstract] [Full Text] [PDF]

				M. Sieniawski, J. Franklin, L. Nogova, J.-P. Glossmann, T. Schober, H. Nisters-Backes, V. Diehl, and A. Josting Outcome of Patients Experiencing Progression or Relapse After Primary Treatment With Two Cycles of Chemotherapy and Radiotherapy for Early-Stage Favorable Hodgkin's Lymphoma J. Clin. Oncol., May 20, 2007; 25(15): 2000 - 2005. [Abstract] [Full Text] [PDF]

				A. Evens, J. Altman, B. Mittal, N Hou, A Rademaker, D Patton, L Kaminer, S Williams, S Duffey, D Variakojis, et al. Phase I/II trial of total lymphoid irradiation and high-dose chemotherapy with autologous stem-cell transplantation for relapsed and refractory Hodgkin's lymphoma Ann. Onc., April 1, 2007; 18(4): 679 - 688. [Abstract] [Full Text] [PDF]

				B. W. Schot, J. M. Zijlstra, W. J. Sluiter, G. W. van Imhoff, J. Pruim, W. Vaalburg, and E. Vellenga Early FDG-PET assessment in combination with clinical risk scores determines prognosis in recurring lymphoma Blood, January 15, 2007; 109(2): 486 - 491. [Abstract] [Full Text] [PDF]

				E. Brusamolino and A. M. Carella Treatment of refractory and relapsed Hodgkin's lymphoma: facts and perspectives Haematologica, January 1, 2007; 92(1): 6 - 10. [Full Text] [PDF]

				G. Schellong, W. Dorffel, A. Claviez, D. Korholz, G. Mann, H.-G. Scheel-Walter, J. P.M. Bokkerink, M. Riepenhausen, H. Luders, R. Potter, et al. Salvage Therapy of Progressive and Recurrent Hodgkin's Disease: Results From a Multicenter Study of the Pediatric DAL/GPOH-HD Study Group J. Clin. Oncol., September 1, 2005; 23(25): 6181 - 6189. [Abstract] [Full Text] [PDF]

				A. Sureda, M. Constans, A. Iriondo, R. Arranz, M. D. Caballero, M. J. Vidal, J. Petit, A. Lopez, J. J. Lahuerta, E. Carreras, et al. Prognostic factors affecting long-term outcome after stem cell transplantation in Hodgkin's lymphoma autografted after a first relapse Ann. Onc., April 1, 2005; 16(4): 625 - 633. [Abstract] [Full Text] [PDF]

				A. Josting, L. Nogova, J. Franklin, J.-P. Glossmann, H. T. Eich, M. Sieber, T. Schober, H.-D. Boettcher, U. Schulz, R.-P. Muller, et al. Salvage Radiotherapy in Patients With Relapsed and Refractory Hodgkin's Lymphoma: A Retrospective Analysis From the German Hodgkin Lymphoma Study Group J. Clin. Oncol., March 1, 2005; 23(7): 1522 - 1529. [Abstract] [Full Text] [PDF]

				A. Josting, C. Rudolph, M. Mapara, J.-P. Glossmann, M. Sienawski, M. Sieber, H. H. Kirchner, B. Dorken, D. K. Hossfeld, J. Kisro, et al. Cologne high-dose sequential chemotherapy in relapsed and refractory Hodgkin lymphoma: results of a large multicenter study of the German Hodgkin Lymphoma Study Group (GHSG) Ann. Onc., January 1, 2005; 16(1): 116 - 123. [Abstract] [Full Text] [PDF]

				N. L. Bartlett Therapies for Relapsed Hodgkin Lymphoma: Transplant and Non-Transplant Approaches Including Immunotherapy Hematology, January 1, 2005; 2005(1): 245 - 251. [Abstract] [Full Text] [PDF]

				M. Bendandi, S. A. Pileri, and P. L. Zinzani Challenging paradigms in lymphoma treatment Ann. Onc., May 1, 2004; 15(5): 703 - 711. [Full Text] [PDF]

				C. Montalban, J. F. Garcia, V. Abraira, L. Gonzalez-Camacho, M. M. Morente, J. L. Bello, E. Conde, M. A. Cruz, R. Garcia-Sanz, J. Garcia-Larana, et al. Influence of Biologic Markers on the Outcome of Hodgkin's Lymphoma: A Study by the Spanish Hodgkin's Lymphoma Study Group J. Clin. Oncol., May 1, 2004; 22(9): 1664 - 1673. [Abstract] [Full Text] [PDF]

				S. Laskar, T. Gupta, S. Vimal, M.A. Muckaden, T.K. Saikia, S.K. Pai, K.N. Naresh, and K.A. Dinshaw Consolidation Radiation After Complete Remission in Hodgkin's Disease Following Six Cycles of Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine Chemotherapy: Is There a Need? J. Clin. Oncol., January 1, 2004; 22(1): 62 - 68. [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]

				V. Diehl, J. Franklin, M. Pfreundschuh, B. Lathan, U. Paulus, D. Hasenclever, H. Tesch, R. Herrmann, B. Dorken, H.-K. Muller-Hermelink, et al. Standard and Increased-Dose BEACOPP Chemotherapy Compared with COPP-ABVD for Advanced Hodgkin's Disease N. Engl. J. Med., June 12, 2003; 348(24): 2386 - 2395. [Abstract] [Full Text] [PDF]

				A. Josting, C. Rudolph, M. Reiser, M. Mapara, M. Sieber, H. H. Kirchner, B. Dorken, D. K. Hossfeld, V. Diehl, and A. Engert Time-intensified dexamethasone/cisplatin/cytarabine: an effective salvage therapy with low toxicity in patients with relapsed and refractory Hodgkin's disease Ann. Onc., October 1, 2002; 13(10): 1628 - 1635. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Josting, A. Articles by Engert, A. Search for Related Content PubMed PubMed Citation Articles by Josting, A. Articles by Engert, A. Social Bookmarking                            What's this?