Autologous stem cell transplantation for primary refractory Hodgkin’s disease: results and clinical variables affecting outcome

M. Constans1, A. Sureda1,+,§, M. J. Terol2, R. Arranz3, M. D. Caballero4, A. Iriondo5, I. Jarque6, E. Carreras7, J. M. Moraleda8, D. Carrera9, A. León10, A. López11, C. Albó12, J. Díaz-Mediavilla13, P. Fernández-Abellán14, J. C. García-Ruiz15, F. Hernández-Navarro16, R. Mataix17, J. Petit18, M. J. Pascual19, J. Rifón20, J. García-Conde2, J. M. Fernández-Rañada3, M. V. Mateos4, J. Sierra1 and E. Conde5

1 Hospital de la Santa Creu i Sant Pau, Barcelona; 2 Hospital Clínico, Valencia; 3 Hospital La Princesa, Madrid; 4 Hospital Clínco Universitario, Salamanca; 5 Hospital Marqués de Valdecilla, Santander; 6 Hospital La Fe, Valencia; 7 Hospital Clínic i Provincial, Barcelona; 8 Hospital Morales Messeguer, Murcia; 9 Hospital Central de Asturias, Oviedo; 10 Hospital de Jerez, Jerez de la Frontera; 11 Hospital Vall d’Herbrón, Barcelona; 12 Hospital Xeral-Cíes, Vigo; 13 Hospital Clínico San Carlos, Madrid; 14 Hospital Genal de Alicante, Alicante; 15 Hospital de Cruces, Baracaldo; 16 Hospital La Paz, Madrid; 17 Hospital de Gran Canaria Dr. Negrín, Las Palmas de Gran Canaria; 18 Institut Català d’Oncologia, L’Hospitalet de Llobregat; 19 Hospital Carlos Haya, Málaga; 20 Clínica Universitaria de Navarra, Pamplona

Received 23 October 2002; revised 8 January 2003; accepted 23 January 2003

Abstract

Background:

Patients with primary refractory Hodgkin’s disease (PR-HD) have a dismal prognosis when treated with conventional salvage chemotherapy. We analyzed time to treatment failure (TTF), overall survival (OS) and clinical variables influencing the outcome in patients undergoing autologous stem cell transplantation (ASCT) for PR-HD and reported to the Grupo Español de Linfomas/Trasplante Autólogo de Médula Ósea (GEL/TAMO).

Patients and methods:

Sixty-two patients, 41 males and 21 females with a median age of 27 years (range 13–55) were analyzed. Forty-two patients (68%) had advanced stage at diagnosis, 47 (76%) presented with B symptoms and 29 (47%) with a bulky mediastinal mass. Seventy-five percent of the patients had received more than one line of therapy before ASCT. Thirty-three patients received bone marrow as a source of hematopoietic progenitors, and 29 peripheral blood. Six patients were conditioned with high-dose chemotherapy plus total-body irradiation and 56 received chemotherapy-based protocols.

Results:

One-year transplantation-related mortality was 14% [95% confidence interval (CI) 6% to 23%]. Response rate at 3 months after ASCT was 52% [complete remission in 21 patients (34%), partial remission in 11 patients (18%)]. Actuarial 5-year TTF and OS were 15% (95% CI 5% to 24%) and 26% (95% CI 13% to 39%), respectively. The presence of B symptoms at ASCT was the only adverse prognostic factor significantly influencing TTF [relative risk (RR) 1.75, 95% CI 0.92–3.35, P = 0.08]. The presence of B symptoms at diagnosis (RR 2.08, 95% CI 0.90–4.79, P = 0.08), MOPP-like regimens as first-line therapy (RR 3.84, 95% CI 1.69–9.09, P = 0.001), bulky disease at ASCT (RR 2.79, 95% CI 0.29–6.03, P = 0.009) and two or more lines of therapy before ASCT (RR 2.24, 95% CI 0.95–5.27, P = 0.06) adversely influenced OS.

Conclusions:

In our experience, although overall results of ASCT in PR-HD patients are poor, one-quarter of the patients remain alive at 5 years. Despite this, other therapeutic strategies should be investigated in this group of patients to improve the outcome.

Key words: autologous stem cell transplantation, Hodgkin’s disease, induction failure

Introduction

Most patients suffering from Hodgkin’s disease (HD) can be successfully treated with radiotherapy (RT) or conventional- dose chemotherapy (CT), with 70% of them being alive 10 years after diagnosis [1, 2]. However, the outcome for patients for whom initial induction CT fails is poor. The use of conventional- dose, second-line CT produces low remission rates, with long-term disease-free survival in no more than 10% of patients [3, 4].

High-dose therapy with autologous stem cell transplantation (ASCT) has been extensively tested in patients with relapsed and refractory HD during recent years. Reported series from single institutions [514] demonstrated that 20–30% of patients with primary refractory HD (PR-HD) may achieve long-term disease-free survival after high-dose therapy. More recently, two large retrospective registry-based studies [16, 17] and the prospective French protocol [18] analyzed the outcome of 175, 122 and 62 patients, respectively, diagnosed with PR-HD. The authors conclude that ASCT can offer long-term disease-free survival in a subset of patients with PR-HD and that a high-dose CT approach is better than second- or third-line salvage therapy for these patients.

In this study we analyze time to treatment failure (TTF), overall survival (OS) and clinical variables affecting outcome in a group of 62 PR-HD patients autografted and reported to the Grupo Español de Linfomas/Trasplante Autólogo de Médula Ósea (GEL/TAMO) database.

Patients and methods

From January 1984 to June 2001, 62 patients who had received ASCT for PR-HD were selected from 755 patients communicated to the GEL/TAMO Spanish Cooperative Group. Eight of these patients (13%) have already been reported in the European Group for Blood and Marrow Transplantation (EBMT) retrospective analysis [16]. Reported data were centrally reviewed to detect inconsistencies. All reporting physicians were contacted to provide additional information on patients’ characteristics at presentation when required. Follow-up was updated in June 2002, when all living patients had been followed at least 1 year after ASCT.

Eligibility criteria
Common eligibility criteria for ASCT in all institutions were age <=65 years, left ventricular ejection fraction >50%, forced expiratory volume in 1 s >50%, diffusion capacity of the lung for carbon monoxide >50% predicted and absence of major organ dysfunction with a cause different from that of HD. All patients gave written informed consent before undergoing ASCT according to the Ethics Committees guidelines.

Study definitions
PR-HD patients were those who did not achieve a complete remission (CR) or a partial remission (PR) with first-line CT. The definition therefore included patients with progressive or stable disease. Patients in early relapse (first CR <3 months) were not included.

Patients were staged according to the Ann Arbor system [19] and evaluated at the time of ASCT, on day 90 after ASCT, every 6 months for the first 2 years, then yearly or as clinically indicated. Patients who survived >90 days after ASCT without evidence of tumor, by clinical and radiological evaluation, were classified as CR. Patients with small residual radiographic abnormalities that did not progress for 6 months after transplantation were also classified as being in CR. Partial remission was defined as a >=50% reduction of pre-transplantation measurable disease, for at least 1 month. Patients achieving <50% tumor reduction after ASCT were considered as non-responders.

Statistical analysis
Survival analyses were performed according to the Kaplan–Meier method [20]. OS was calculated in months from the date of autologous stem cell reinfusion to the date of death from any cause. TTF was measured in months from the date of transplantation to the time of failure or death from any cause following previously described criteria for non-Hodgkin’s lymphomas [21]. Overall transplantation-related mortality (TRM) was defined as death from any cause other than HD. For the purpose of this analysis TRM was divided into early TRM (death from any cause other than lymphoma occurring within the first 100 days after ASCT) and late TRM (death from any cause other than lymphoma occurring beyond the first 100 days after ASCT).

Comparison of the survival curves in univariate analysis was performed using the log-rank test [22]. Analysis of prognostic factors influencing both CR and TRM rates was performed by Fisher’s exact test and logistic regression analysis. Comparison of continuous variables was performed by Mann–Whitney U-test and linear regression analysis.

Multivariate analysis was performed using a forward stepwise Cox proportional-hazards model. The prognostic factors analyzed for both TTF and OS were: age at transplantation, year of transplantation (up to December 1993 versus from January 1994), complementary RT, first-line therapy (MOPP-like regimens versus other protocols), number of treatment lines (one versus two or more), time interval between diagnosis and ASCT (<12 months versus >=12 months), conditioning regimen [total-body irradiation (TBI) versus CT alone], source of stem cells [bone marrow (BM) versus peripheral blood (PB)], Ann Arbor stage (limited versus advanced), B symptoms, extranodal involvement, BM involvement, bulky disease and Eastern Cooperative Oncology Group performance status (0–1 versus >=2). The last six characteristics were evaluated at diagnosis and before ASCT.

All P values reported are two-sided and statistical significance is defined as P <0.05. The statistical analyses were computed with SPSS statistical software.

Results

Patients
The main characteristics of the 62 patients at diagnosis and at ASCT are shown in Tables 1 and 2, respectively. Forty-one patients (66%) were male and 21 female (34%). The median age at the time of ASCT was 27 years (range 13–55). At initial presentation, most patients (68%) had stage III/IV disease. Other adverse features were B symptoms (76%) and bulky disease (47%).


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Table 1. Characteristics of the patients at diagnosis.
 

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Table 2. Characteristics of the patients at autologous stem cell transplantation
 
Initial treatment had varied according to the initial HD stage, the date of diagnosis, and the protocol used in each hospital: most patients received either MOPP or derivatives (n = 11, 18%), ABVD (n = 19, 31%) or MOPP alternating with ABVD (n = 32, 52%). Adjuvant RT was used in 22 of the 62 patients, according to active protocols in participating institutions. Sixteen patients only received one line of therapy before ASCT; clinical characteristics both at diagnosis and at transplantation of these 16 patients did not significantly differ from those of the 46 patients who were autografted after receiving a salvage protocol. The time interval between diagnosis and the date of ASCT ranged from 4 to 27 months, with a median of 12 months.

Source of autologous stem cells
Thirty-three patients (53%) were autografted using BM as the source of hematopoietic stem cells. BM was harvested under general anesthesia and cryopreserved following standard guidelines. ASCT from PB progenitor cells (PBPCs) was performed in 29 patients (47%).

High-dose therapy and transplantation procedures
Details of high-dose therapy are given in Table 2. TBI regimens were used in 10% of the patients (n = 6). The remaining 90% received CT-only high-dose regimens, the most frequent being CBV (n = 25, 40%), which consisted of cyclophosphamide [1.2–1.8 g/m2 intravenously (i.v.) x 4 days], etoposide (125–400 mg/m2 twice daily i.v. x 3 days) and carmustine (300–600 mg/m2 i.v. x 1 day). BEAM CT (n = 19, 31%) included carmustinem (300–400 mg/m2 i.v. x 1 day), etoposide (150–200 mg/m2 i.v. x 4 days), cytarabine (100–200 mg/m2 twice daily i.v. x 4 days) and melphalan (140 mg/m2 i.v. x 1 day). BEAC was administered to seven patients (11%), and this regimen consisted of carmustine (300–400 mg/m2 i.v. x 1 day), etoposide (150–200 mg/m2 i.v. x 4 days), cytarabine (200 mg/m2 twice daily i.v. x 4 days) and cyclophosphamide (1.5–2.5 g/m2 i.v. x 3 days). Five patients (9% of the series) received other combination CT protocols. Twelve patients (12%) received complementary RT on residual masses immediately after hematological recovery.

A total of 25 patients (40%) received granulocyte colony-stimulating factor or granulocyte–macrophage colony-stimulating factor until the absolute neutrophil count exceeded 0.5 x 109/l for 3 consecutive days.

Hematological recovery and complications
Hematological recovery. One patient died on day 13 with no evidence of engraftment. For the remaining 61, the median time to recover a neutrophil count >0.5 x 109/l was 14.5 days (range 8–73) and to achieve a self-sustained platelet count >20 x 109/l was 16 days (range 8–73). Hematological recovery was significantly faster in patients autografted with PBPCs compared with BM for both granulocytes and platelets [12 (8–54) days versus 17 (11–73) days, P <0.0001, and 12 (8–73) days versus 21 (13–72) days, P = 0.006, respectively]. Growth factor administration after ASCT resulted in a significantly faster granulocyte recovery in BM autografts [14.5 (11–50) days versus 20 (13–73) days, P <0.0001] but not in PB grafts. Platelet recovery was not significantly influenced by growth factor administration after ASCT.

Transplantation-related mortality. Nine patients (14.5%) died after ASCT due to procedure-related complications. Overall TRM was 14% [95% confidence interval (CI) 6% to 23%] at 1 year. Both the use of MOPP-like protocols as first-line therapy [relative risk (RR) 25.1, 95% CI 2.6–250.0, P = 0.0002] and the use of BM as the source of hematopoietic progenitors for transplantation (RR 5.96, 95% CI 0.6–56.3, P = 0.06) were significant adverse prognostic factors for TRM in the multivariate analysis. All patients who experienced TRM died within the first 100 days after transplantation (early TRM), with no patients dying from late infectious complications or secondary malignancies. The causes of death were infectious episodes in four patients (bacterial in three and fungal in one patient), idiopathic pneumonitis/adult respiratory distress syndrome in two patients, multiorgan failure in two patients and cardiac toxicity in one patient.

Response to ASCT and survival
Nine patients (14%) died within the first 3 months after ASCT due to TRM and were not evaluable for response. At the same time-point, 21 patients (34%) were considered as complete responders. Eleven patients (18%) were in PR and 21 (34%) did not respond or progressed after ASCT. In the multivariate analysis, there was a trend to lower probability of reaching CR after ASCT in patients with advanced Ann Arbor stages (RR 2.88, 95% CI 0.86–9.63, P = 0.08) and in patients with B symptoms at transplantation (RR 7.23, 95% CI 0.84–62.11, P = 0.07).

The actuarial TTF at 5 years was 15% (95% CI 5% to 24%) for the entire group with an OS of 26% (95% CI 13% to 39%) at the same time-point (Figure 1). Median follow-up of the surviving patients was 34 months (range 12–179). The presence of B symptoms both at diagnosis and before ASCT were significant adverse prognostic factors for TTF (P = 0.031 and P = 0.005, respectively) (Figure 2). The use of MOPP-like regimens as first-line CT was of border-line significance. In the multivariate analysis (Table 3), the presence of B symptoms at ASCT was the only adverse prognostic factor significantly influencing TTF.



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Figure 1. Overall survival (OS) at 5 years of the total series.

 


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Figure 2. Time to treatment failure (TTF) according to the presence of B symptoms at autologous stem cell transplantation.

 

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Table 3. Adverse prognostic factors influencing time to treatment failure and overall survival in multivariate analysis
 
In the univariate analysis, the presence of B symptoms at diagnosis, BM involvement and bulky disease at ASCT and the use of MOPP as first-line therapy significantly reduced OS in the entire population of patients. In the multivariate analysis (Table 3), absence of B symptoms at diagnosis, first-line therapy other than MOPP-like regimens, only one line of CT before ASCT and absence of bulky disease at ASCT significantly improved survival after transplantation. With the combination of these four adverse-prognosis factors we were able to differentiate two subgroups of patients with significantly different probabilities of survival after transplantation (OS 50 ± 14% versus 15 ± 6% for patients with none or one, or two to four, adverse prognostic factors, respectively) (Figure 3). Of note, patients with four prognostic factors presented an OS of 0% at 2 years.



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Figure 3. Overall survival (OS) according to the number of adverse prognostic factors from the multivariate analysis.

 
Relapse after ASCT
Of the 21 patients who were in CR 3 months after transplantation, eight (38%) relapsed at a median time of 16 months (range 4–125) after ASCT. Four patients (50%) relapsed within the first year after ASCT; nevertheless, 50% of the series relapsed >1 year after transplantation, >10 years after transplantation in one case. Seven out of the eight relapsed patients died from progressive disease at a median time of 11 months (range 5–32) after relapse.

Discussion

The outcome of PR-HD patients with conventional CT is extremely poor. In the series of Longo et al. [3], 51 patients failing MOPP therapy underwent salvage therapy with the MOPP/CABS combination, RT or other conventional treatments; median survival was 16 months and no patient was alive at 8 years. In another study of 415 patients initially treated with MOPP-ABVD, 39 were considered as induction failures and underwent salvage therapy with CEP (lomustine, etoposide and prednimustine). The CR rate was 41% but the 8-year rate of freedom from second progression was 0% and the 8-year survival rate was 8% [4]. A recent study from Stanford University reported a more favorable outcome, with a 4-year actuarial OS of 38% for patients with PR-HD, although with longer follow-up, further relapses were observed [10].

The results of several single-institution studies as well as two large retrospective registry-based analysis suggest a superior outcome for patients who receive high-dose therapy and ASCT in this setting but with noticeable differences from one study to another. While a study of City of Hope National Medical Center recorded a 2-year disease-free survival rate of 67% in a small group of six patients with a median follow-up of only 25 months [5], other centers have reported lower disease-free survival rates, although always higher than those reported for conventional-dose salvage therapy. Chopra et al. [7] showed a 5-year actuarial progression-free survival (PFS) of 33% in a group of 46 patients with PR-HD; the same figure was reported in 19 patients receiving high-dose CT and hyperfractionated TBI at Memorial Sloan-Kettering Cancer Center [6] and in the report from Stanford, the use of high-dose therapy for patients in induction failures produced a 4-year actuarial OS and freedom from progression of 44% and 52%, respectively [10, 11].

Our results with respect to 5-year actuarial TTF (15%, 95% CI 5% to 24%) and OS (26%, 95% CI 13% to 39%) are somewhat inferior to those presented by Sweetenham et al. [16] and Lazarus et al. [17] in the two retrospective registry-based studies already published but not significantly different from a single-institution analysis [8] and from the French prospective results of 67 PR-HD patients included in the H89 trial [18]. In the EBMT analysis [16], 175 PR-HD patients were presented; actuarial 5-year PFS and OS were 32% and 36%, respectively. In the Autologous Blood and Marrow Transplant Registry (ABMTR) analysis on 122 patients undergoing ASCT after an induction failure [17], actuarial probabilities at 3 years were 38% and 50% for PFS and OS, respectively. The reasons for these discrepancies are not clear but one must be aware of the fact that under the definition of induction failure different subsets of patients with different long-term outcome can be included. In the ABMTR analysis almost 50% of the patients whose response to salvage CT before ASCT was known had a chemosensitive disease before transplantation. This might explain the fact that CR rate after transplantation was higher in the ABMTR analysis (50% of the patients) than in the EBMT and the GEL/TAMO retrospective studies (30% and 34%, respectively). In our series, advanced stages and the presence of B symptoms at ASCT were both associated with lower probabilities of attaining a CR after transplantation. Almost 50% of the patients presented stages III/IV at ASCT, 25% of them had B symptoms and nine patients (15% of the series) presented with both adverse prognostic factors.

Another indirect indication of the diversity of diseases included under the name of induction failures or PR-HD patients is the wide time interval between diagnosis and ASCT. Median time from diagnosis to transplantation is similar in the three registry-based retrospective analysis, about 1 year. Nevertheless, ranges are different; in the EBMT studies there was at least one patient autografted >10 years after diagnosis. This patient and others probably do not represent ‘true’ primary refractory patients. As indicated by other authors [7], there is a subset of chronically evolving patients who have to be taken into account when analyzing and comparing data from different centers.

Results of ASCT in PR-HD patients are also worse than in other subgroups of patients because of a higher TRM. Overall TRM in our series was 14% (95% CI 6% to 23%) at 1 year, which is comparable to other reports. Interestingly, in our study all TRMs were observed in the first 100 days after ASCT and were mainly due to infectious episodes. There were no late infectious deaths or deaths due to secondary malignancies. Adverse prognostic factors for TRM were the use of BM as the source of hematopoietic progenitors and the use of MOPP-like protocols as first-line therapy. It is conceivable that TRM has already decreased in this subgroup of patients because BM is no longer used as hematopoietic support in the autologous transplantation setting and nitrogen mustard is not a first-line drug for HD patients; doxorubicin-containing regimens have become the gold standard in the treatment of HD.

Of the many variables that we examined, the presence of B symptoms at diagnosis, the use of MOPP-like protocols as first-line therapy, the administration of two or more lines of treatment before transplantation and the presence of bulky disease at ASCT were correlated with survival. Actuarial 5-year OS was 50% in patients with none or one prognostic factor and decreased to 15% at 5 years in patients with two or three adverse prognostic factors (Figure 3). In patients with three adverse prognostic factors at transplantation, median survival after ASCT was 6 months. Several of these prognostic factors have also been indicated by other authors: Lazarus et al. [17] found that the presence of B symptoms at diagnosis as well as Karnofsky performance status at ASCT correlated with survival and that the absence of these two factors was associated with an excellent 2-year survival of 87%. In the EBMT analysis, Sweetenham et al. [16] found that patients receiving more than one line of CT before transplantation did worse, in terms of both OS and PFS. Nevertheless, this factor did not come out in the multivariate analysis. The question of whether or not to administer a salvage therapy in patients with PR-HD is of clinical interest. Our results, as well as those of others [16], suggest that patients should undergo ASCT without receiving a second-line therapy. Nevertheless, and considering that this is a retrospective analysis, results have to be taken with caution.

No randomized analysis between conventional salvage CT and high-dose therapy with autologous hematopoietic support has been performed up to now. Nevertheless, there are two case-control studies which address this issue. A single-center study by Yuen et al. [10] has reported improved outcome after transplantation compared with a historical control group given conventional salvage CT for refractory HD. Thirteen of 60 patients in this matched comparison underwent autotransplantation for primary induction failure; the 4-year event-free survival was 52% in those treated with an autograft, compared with 19% in the conventional treatment group. More recently, André et al. [23] also indicated a better outcome after transplantation in a group of 86 patients who underwent an ASCT because of failure of conventional first-line CT when compared with a previously matched group of 258 conventionally treated patients.

In conclusion, our results indicate that long-term outcome of PR-HD is poor in patients treated with ASCT due to a low CR after transplantation and a high TRM. Nevertheless, specific subgroups of patients with no adverse prognostic factors at transplantation might benefit from this approach. Investigational therapies such as allogeneic transplantation after a reduced-intensity conditioning protocol should be pursued in PR-HD patients in order to improve overall results.

Acknowledgements

This work was partially supported by grants number FIS 94/0063-01 and FIS 97/0626 awarded by the Fondo de Investigaciones Sanitarias del Ministerio de Sanidad y Consumo, Spain.

Footnotes

+ Correspondence to: Dr A. Sureda, Clinical Hematology Division, Hospital de la Santa Creu i Sant Pau, Antoni Maria i Claret, 167, 08025 Barcelona, Spain. Tel: +34-93-2919396; Fax: +34-93-2919466; E-mail: asureda{at}hsp.santpau.es Back

§ Both authors contributed equally to the development of this work. Back

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