Hodgkin's disease

Autologous stem cell transplantation for Hodgkin's disease: busulfan, melphalan and thiotepa compared to a radiation-based regimen

Summary:

We evaluated prognostic factors and treatment outcome of patients with relapsed/refractory Hodgkin's disease (HD) receiving autologous stem cell transplantation (ASCT). In total, 92 patients received total body irradiation, cyclophosphamide and etoposide (TBI/CY/E) (n=42) or busulfan, melphalan and thiotepa (Bu/Mel/T) (n=50) supported with ASCT. A total of 33 (66%) patients receiving the Bu/Mel/T regimen had a prior history of dose-limiting irradiation. Mucositis, hepatic and pulmonary toxicities were the main causes of morbidity and mortality, irrespective of the conditioning regimen. The transplant-related mortality was 15%. With a median follow-up of 6 years (range 2.5–11), the cumulative probabilities of survival, event-free survival (EFS) and relapse at 6 years were 55, 51 and 32%. The 6-year Kaplan–Meier (KM) probabilities of EFS for patients with less advanced disease (patients in first chemotherapy-responsive relapse or second remission (n=42)) and more advanced disease (all other patients (n=50)) were 60 and 44%. No differences in toxicities and efficacy between the conditioning regimens were found. ASCT is an effective treatment for patients with refractory/relapsed HD. Female patients and patients with less advanced disease at transplant had a better outcome. Patients with prior irradiation benefited from the Bu/Mel/T regimen.

Main

Hodgkin's disease (HD) is a highly chemosensitive malignancy with approximately 50–60% of patients being cured with conventional chemotherapy/radiation therapy. Patients with stage III or IV disease who fail to attain a complete remission or relapse after induction chemotherapy, however, are rarely cured from standard salvage therapies.1 High-dose chemotherapy with or without radiation therapy supported with autologous stem cell transplantation (HDC/ASCT) is potentially curative for this subset of patients.2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21 Total body irradiation (TBI) in combination with high-dose cyclophosphamide (CY) (TBI/CY)3,4 and etoposide (TBI/CY/E),5,6, and the combination of CY, carmustine and etoposide (CVB),5,6,9,10,12,13,14,15,16 carmustine, etoposide, cytosine arabinoside with either melphalan (BEAM)18,19 or cyclophosphamide (BEAC)20 constitute the most common high-dose regimens evaluated. The superiority of a specific regimen, however, has not been demonstrated.3,5,6

In 1993, the Fred Hutchinson Cancer Research Center (FHCRC) reported the outcomes of 127 patients with relapsed/refractory HD treated with chemotherapy-only (n=66) or TBI-based (n=61) regimens followed by autologous (n=68), allogeneic (n=53) and syngeneic (n=6) bone marrow (BM) transplantation.3 The high-dose regimens evaluated were TBI/CY (n=47), CVB (n=47), Cy and busulfan (Bu) (n=18) and others (n=15). The actuarial 5-year event-free survival (EFS) was 18% for the entire group and 22 and 14% for allogeneic and autologous recipients, respectively. No differences in EFS between the TBI-based and non-TBI-based regimens were demonstrated. In later reports, 27 patients with HD who received TBI/CY/E (n=10)22 or high-dose busulfan, melphalan and thiotepa (Bu/Mel/T) (n=17) followed by ASCT23 were found to have an actuarial 2-year EFS of 45 and 46%, respectively.

Since randomized trials comparing the efficacy and toxicity of TBI-based and non-TBI-based regimens for patients with refractory/relapsed HD have not been reported and are unlikely to be carried out, this study compares outcomes and toxicities of patients who received the TBI/CY/E and Bu/Mel/T regimens followed by ASCT.

Patients and methods

From 9/90 to 7/98, 92 patients with histologically confirmed HD were included in Phase II trials evaluating the TBI/CY/E and Bu/Mel/T regimens. The institutional review board of the FHCRC or Puget Sound Oncology Consortium (PSOC) approved the protocols and all patients gave written informed consent. Eligibility criteria, pretreatment evaluation and PSOC participants have been described elsewhere.22,23,24,25 Briefly, the main criteria to assign patients to the TBI/CY/E or Bu/Mel/T regimen was a prior history of dose-limiting radiation therapy (DLRT), defined as prior irradiation greater than 20 Gy to the liver or mediastinum or 30 Gy to the central nervous system (CNS). Initially, patients without DLRT were treated with the TBI/CY/E regimen, while patients who received DLRT were offered the CBV regimen, which has been previously reported.16 In 1993, patients with prior DLRT were offered the Bu/Mel/T regimen. By 1995, as experience was gained with this regimen, Bu/Mel/T was offered to both patients with and without DLRT. After 1995, physician preference determined which conditioning regimen was administered to patients without prior DLRT. Patients enrolled in PSOC centers after 1995 were usually given Bu/Mel/T because of greater difficulty delivering TBI in smaller centers.

HD was classified according to the Ann Arbor staging system26 and the Rye histopathologic classification.27 Patients aged 12–65 years (up to 70 years. for Bu/Mel/T) were eligible for both preparative regimens if they had failed primary treatment or were in first sensitive/untreated relapse or beyond second remission or relapse. Patients had to have a bilirubin <2 mg/dl, creatinine <2.0, pulmonary function as measured by a diffusion lung capacity for carbon monoxide (DLCO) >60%, adequate cardiac function as measured by ejection fraction (EF) >40% and a Karnofsky score of >70. Based on the clinical history prior to peripheral blood stem cell (PBSC) mobilization and HDC/ASCT, patients in second remission or with untreated or chemotherapy-sensitive first relapse were classified as having less advanced disease while all other patients were considered to have more advanced disease.22,23,24,25

Patient characteristics

TBI/CY/E and Bu/Mel/T regimens

A total of 42 patients received TBI/CY/E and 50 patients received the Bu/Mel/T regimen. A total of 39 patients (TBI/Cy/E, n=25; Bu/Mel/T, n=14) were treated prior to 1995 and 53 after 1995 (TBI/CY/E, n=17; Bu/Mel/T, n=36). The TBI/CY/E regimen included more patients who had stage III/IV disease and BM as a source of hematopoietic stem cells compared to those treated with the Bu/Mel/T regimen (88 vs 56%, P<0.005 and 26 vs 2%, P<0.01, respectively). However, a higher proportion of patients who were classified as having more advanced disease status received the Bu/Mel/T regimen (66 vs 40%, P<0.01). Of the patients who received the Bu/Mel/T regimen 64% had a prior history of dose-limiting irradiation (Table 1).

Table 1 Patient characteristics

HDC regimens

TBI/CY/E

Patients received 12 Gy TBI, delivered in 1.5 Gy fractions twice a day for 4 days, with fractions separated by at least 6 h from a dual cobalt-60 source, at a dose rate of 6–7 cGy/min (n=32) or via linear accelerator at 8 cGy/min (n=10). Intravenous infusion of E (60 or 30 mg/kg for patients aged >55 years) over 4 h was administered on day −4, followed by a day of rest. CY (100 or 60 mg/kg for patients aged >55 years) was infused over 1–2 h on day −2, followed by a day of rest. Stem cells were infused on day 0.22,24,25

Bu/Mel/T

All patients received phenytoin, 24 h before the first dose of busulfan, continuing until 24 h after the final dose of busulfan. Patients received busulfan 1 mg/kg/dose p.o. every 6 h on days −8, −7 and −6 for a total dose of 12 mg/kg. Melphalan (50 mg/m2 i.v. per day) was given on days −5 and −4 for a total dose of 100 mg/m2. Thiotepa (250 mg/m2 i.v. per day) was administered on days −3 and −2 for a total dose of 500 mg/m2. Stem cells were infused 48 h after the last dose of thiotepa.23,25

Supportive care

Patients were given supportive care in accordance with the following guidelines, although there were minor inter-institutional differences. Prophylactic systemic antibiotics were administered when the absolute neutrophil count (ANC) was <0.5 × 109/l and were discontinued after neutrophil engraftment when counts recovered to ANC >0.5 × 109/l. Patients who were serologically positive for herpes simplex virus were treated with prophylactic acyclovir. Platelet transfusions were administered when the platelet level was <20 × 109/l.

BM and PBSC collection, cryopreservation and infusion

The techniques for marrow aspiration and PBSC harvest following the administration of recombinant human granulocyte colony-stimulating factor (rhG-CSF) alone or with chemotherapy, cryopreservation, thawing and infusion have been described elsewhere.28,29,30 A total of 12 patients received marrow as a source of hematopoietic stem cells.31,32 PBSCs were mobilized mainly with chemotherapy and rhG-CSF and were not purged.29,33 The combination of CY/E was the most common regimen used for PBSC mobilization (n=40). Other chemotherapy regimens were dexamethasone, cytarabine and cisplatin (DHAP) (n=4), CY alone (n=2), CY Taxol (n=1), cyclophosphamide, etoposide and cisplatin (CEP) (n=3), ifosfamide+etoposide+vinblastine (n=2) and dexamethasone (n=1).

Post-transplant treatment

rhG-CSF, recombinant human granulocyte–macrophage colony-stimulating factor (rhGM-CSF), recombinant human interleukin 3 (rhIL-3) or granulocyte-macrophage colony-stimulating factor-interleukin-3 fusion protein (PIXY321) were administered from day 1 after transplant until engraftment to 42 (45%) patients, as per supportive care protocols in effect at the time of transplant. Ten patients who were engrafted, without a major organ toxicity or infection, with a CR, PR or stable disease and not receiving corticosteroids, were treated with interleukin-2 (IL-2) with or without lymphokine-activated killer cells within 24–58 days post transplant as per a protocol designed to explore the toxicity of post transplant immunotherapy.34 A total of 12 patients (13%) received local radiation therapy post transplant to sites of persistent disease. Restaging to assess all sites of prior disease was performed at 60 days post transplant, 1 year and thereafter according to clinical indications.

Regimen-related toxicity

Regimen-related toxicity (RRT) was assessed according to the Bearman score.35 Idiopathic pneumonia syndrome (IPS) was defined as pulmonary infiltrates without infectious etiology.36 The diagnosis of veno-occlusive disease (VOD) was made on the basis of hepatomegaly and/or liver tenderness, weight gain >2% of baseline and an elevated serum bilirubin >2 mg/dl and/or histologically with damage to the endothelial cells at the termini of hepatic venules, dilatation of the sinusoids and necrosis of hepatocytes.37

Statistical analysis

Outcomes examined included survival and EFS and were calculated from day 0 of transplantation. Comparison of proportions was made with the Fisher's test. Probabilities of survival were estimated from day 0 to the day of last contact and from day 0 to the date of death or relapse censored by the date of last contact according to the method of cumulative incidence estimates.38 The log-rank test was used to compare survival curves. Univariate, multivariate and stepwise Cox regression analyses were performed to identify prognostic factors associated with EFS. Age, gender, histology, stage of disease, BM involvement, disease status before transplantation, the number of conventional regimens, prior DLRT, transplant preparative regimen and graft source were evaluated.

Results

Engraftment

Of 92 patients who received HDC/ASCI, Seven (8%) patients died without neutrophil or platelet engraftment before day 30 and were excluded from the engraftment analysis. Neutrophil and platelet recovery occurred at a median of 11 days each for patients who received TBI/CY/E and 11 and 12 days after the Bu/Mel/T regimen, respectively.

Toxicity

Regimen-related toxicity

The main grade 3 toxicities were mucositis, hepatic, pulmonary and renal. Oral grade 3 mucositis occurred in 4% of patients receiving Bu/Mel/T and in 2% after TBI/CY/E. Hepatic grade 3 toxicity was observed in 2% of patients irrespective of the regimen. Renal and pulmonary toxicities occurred in 2% of patients of each regimen. Of 42 patients who received TBI/CY/E, three (7%) died secondary to RRT. The causes of death were IPS (n=2) and VOD (n=1). RRT deaths occurred in six (12%) of 50 patients who received Bu/Mel/T. These deaths were attributed to IPS (n=2), bowel perforation (n=2) and VOD (n=2). Four of these six patients who died secondary to pulmonary and gastrointestinal toxicities after Bu/Mel/T therapy had a prior history of dose-limiting radiation therapy. There were no statistically significant differences in the rate of RRT deaths between the two regimens (7 vs 12%, P=0.3).

Deaths from other causes

Hemorrhage (n=2) and CMV infection (n=1) were the cause of death in three patients conditioned with the TBI-based regimen. Bacterial infections (n=2) were fatal in two patients who received Bu/Mel/T. One patient who received TBI/CY/E died 7 years after transplant from secondary myelodysplasia. Overall, transplant-related mortality (TRM) occurred in seven (17%) patients receiving TBI/CY/E and in eight (16%) patients after Bu/Mel/T therapy. Two (11%) of 18 patients without DLRT and six (19%) of 32 patients who had dose-limiting radiation therapy died from transplant complications (P=0.3). No statistically significant differences were observed in TRM rates between TBI/CY/E and Bu/Mel/T (17 vs 16%, P=0.9), irrespective of the disease status before transplantation and the history of prior radiation therapy.

Outcome according to regimen

HDC regimen

TBI/CY/E. With a median follow-up of 5 years (range 4–10) after transplantation, 22 (52%) patients are alive while 19 (45%) remain in continued remission. A total of 16 (38%) have relapsed and 13 (31%) died from disease progression.

Bu/Mel/T

With a median follow-up of 3.5 years (range 2.5–7) since transplantation, 26 (52%) patients are alive, with 23 (46%) remaining in continued remission. A total of 17 (34%) have relapsed and 14 (28%) died from disease progression. One patient died of unknown cause.

Influence of prior dose-limiting radiation therapy

Among 50 patients receiving Bu/Mel/T, there were 18 patients without prior DLRT and 11 of 18 (61%) remain in continued remission compared to 12 (38%) of 32 patients who had prior DLRT (P=0.1). Overall, RRT deaths and overall TRM within the first 180 days of transplant were 11 and 11% for patients without DLRT and 13 and 19% for those who had prior DLRT, respectively. The probabilities of EFS at 5-years for patients without DLRT (n=18) were 55 and 36% for those who had prior DLRT (n=32) (P=0.07) after Bu/Mel/T therapy. There were no statistically significant differences in outcomes and toxicities between patients without DLRT and those who had prior DLRT.

Survival

The 5-year cumulative estimates of survival, EFS and relapse for TBI/CY/E were 57, 49 and 36% and 52, 42 and 34% for Bu/Mel/T (Figure 1); none of these results between the two regimens were significant. The 5-year probabilities of EFS for patients with less advanced disease or more advanced disease status before transplantation were: TBI/CY/E, 59 and 35% (P=0.06) (Figure 2); Bu/Mel/T, 59 and 33% (0.03) (Figure 3).

Figure 1
figure1

Event-free survival of patients with Hodgkin's disease who received TBI/CY/E (- - - - - - -) or the Bu/Mel/T (———) preparative regimens.

Figure 2
figure2

Event-free survival of patients with Hodgkin's disease who received the TBI/CY/E preparative regimen according to disease status before transplantation (less advanced (———), more advanced (- - - - - - -)).

Figure 3
figure3

Event-free survival of patients with Hodgkin's disease who received the Bu/Mel/T preparative regimen according to disease status before transplantation (less advanced, (———), more advanced (- - - - - - -)).

Prognostic factors

The multivariate analysis found that two factors, gender and disease status at the time of transplant, significantly affected EFS. Male patients had a 2.5. times greater risk of relapse or death (95% confidence interval 1.34–4.83) compared to female patients, P=0.004. Patients with more advanced disease (primary refractory disease, refractory relapse or >2nd remission) at transplant were 2.0 times more likely to die or relapse (95% confidence interval 1.13–3.71) than patients with less advanced disease, P=0.016. There was no statistically significant influence of age, stage of disease at transplant, marrow involvement, high-dose therapy regimen, histology, time from diagnosis to transplant or number of lines conventional chemotherapy regimens used prior to transplant.

Discussion

This retrospective comparison revealed no differences between TBI/CY/E and Bu/Mel/T. It would require a large, prospective randomized trial, however, to prove equivalency with sufficient statistical power. Since it is unlikely that such a study will be performed, this type of retrospective study is necessary. Other studies comparing TBI/CY/E with chemotherapy-only regimens have similarly shown no differences.5,6 TRM in our study was 16%, which is similar to the City of Hope series but higher than the 5% TRM reported by Stanford University. Another Stanford University study, however, reported a 15% treatment-related mortality.39 In the three studies, VOD was the principal cause of toxic death after TBI/CY/E therapy, but pulmonary toxicity also accounted for increased RRT in the City of Hope and FHCRC series. Infection and hemorrhage were additional contributing factors for TRM in the present study. While the Stanford study included 82% of patients who were in a minimal disease state, this subset of patients accounted for only 54 and 58% of the patients included in the City of Hope and the FHCRC series, respectively.

From several studies of patients with refractory/relapsed HD, using a variety of doses and schedules of the CBV regimen, the EFS has ranged between 25 and 48% at 3 years of follow-up.6,12,13,14,17 Similar outcomes have also been reported after therapy with the high-dose BEAM18,19,40 and BEAC20,40 regimens. Recently, the Spanish GEL-TAMO Cooperative Group reported outcomes of 494 patients.41 In that series, 443 (90%) of the patients received chemotherapy-only regimens: CBV (53%), BEAM (18%), BEAC (14%) and others (5%). The actuarial rate of relapse for the entire group was 45%. The Bu/Mel/T regimen evaluated in our study demonstrated a comparable efficacy to the TBI-based and non-TBI-based regimens previously reported.2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,40,41 In the current series, patients with more advanced disease or had received prior DLRT, who had an outcome expected to be poor, had an EFS of 33 and 36% at 5 years, respectively, after the Bu/Mel/T regimen. It was not possible to directly compare the outcome of these patients to the TBI-based regimen since prior DLRT is generally an exclusion for TBI. A history of prior irradiation to the chest and more advanced disease status are factors significantly associated with increased toxicity in our series3,16 and also in a report by Wheeler et al.42 In our study 32 (64%) of the 50 patients who received the Bu/Mel/T regimen had a prior DLRT. Of these 32 patients, 23 (72%) had more advanced disease. Six of eight toxic deaths secondary to the Bu/Mel/T regimen occurred in this subset of patients compared with two in the less advanced group. Although longer follow-up is required, the Bu/Mel/T regimen could be a therapeutic alternative for this subset of poor prognosis patients.

Several adverse prognostic factors have been identified for patients with refractory/relapsed HD after HDC therapy.5,6,8,10,12,13,14,17,18,20,21,38,43,44,45,46,47,48,49 In a study of 65 patients with relapsed or refractory HD, Moskowitz found that B symptoms, extranodal disease and less than 1 year remission duration were all adverse prognostic indicators.50 A French registry study of 280 patients with HD found chemosensitive disease and first relapse to be good prognostic indicators for survival.45 The Spanish GEL-TAMO study reported that active disease at the time of transplant and two or more conventional chemotherapy regimens were adverse prognostic factors for outcome. In our study, male patients and patients with more advanced disease at transplant had a poorer outcome when compared to female patients or patients with less advanced disease. We did not find the number of chemotherapy regimens to be significant but this is probably because 78% of our patients had received more than a single chemotherapy regimen. A seven-factor international prognostic score (IPS) has been shown to be useful for predicting freedom from progression in newly diagnosed patients with HD.49 Its value in predicting outcome after HDC for relapsed/refractory disease is, however, unknown.

Since the outcome after Bu/Mel/T appears similar to other HDC regimens, strategies for diminishing the main toxicities of this tri-alkylator regimen are being evaluated. These include the use of epithelial growth factors which may reduce mucositis, one of the main toxicities of this regimen.

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Acknowledgements

Supported by grants from the National Institutes of Health CA 18029, CA 47748, CA 15704 and the Jose Carreras Foundation against Leukemia. FG-D was supported by a grant from Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico.

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Correspondence to W Bensinger.

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Gutierrez-Delgado, F., Holmberg, L., Hooper, H. et al. Autologous stem cell transplantation for Hodgkin's disease: busulfan, melphalan and thiotepa compared to a radiation-based regimen. Bone Marrow Transplant 32, 279–285 (2003). https://doi.org/10.1038/sj.bmt.1704110

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Keywords

  • Hodgkin's disease
  • autologous
  • stemcell transplant
  • total body irradiation
  • high dose chemotherapy

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