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Annals of Oncology Advance Access published online on February 16, 2007
Annals of Oncology, doi:10.1093/annonc/mdl496
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© 2007 European Society for Medical Oncology

Phase I/II trial of total lymphoid irradiation and high-dose chemotherapy with autologous stem-cell transplantation for relapsed and refractory Hodgkin's lymphoma

AM Evens1, JK Altman1, BB Mittal2, N Hou3, A Rademaker3, D Patton1, L Kaminer1, S Williams1, S Duffey1, D Variakojis4, S Singhal1, MS Tallman1, J Mehta1, JN Winter1 and LI Gordon1,*

1 Division of Hematology/Oncology, Hematopoietic Stem Cell Transplant Program and Lymphoma Program, Feinberg School of Medicine, Northwestern University and the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
2 Department of Radiation Oncology
3 Department of Preventive Medicine
4 Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

* Correspondence to: Dr L. I. Gordon, Division of Hematology/Oncology, Feinberg School of Medicine, Northwestern University, 676 North St Clair, Suite 850, Chicago, IL 60611, USA. Tel: +1-312-695-4517, Fax: +1-312-695-6189, E-mail: l-gordon{at}northwestern.edu.


   Abstract
Top
 Abstract
introduction
 patients and methods
 results
 discussion
 appendix 1
 Acknowledgements
 References
 
Background: The standard approach to treatment of relapsed/refractory Hodgkin's lymphoma (HL) is high-dose chemotherapy conditioning followed by autologous hematopoietic stem-cell transplantation (aHSCT). We report the results of a prospective phase I/II clinical trial of accelerated hyperfractionated total lymphoid irradiation (TLI) immediately followed by high-dose chemotherapy for relapsed/refractory HL.

Patients and methods: Forty-eight patients underwent aHSCT with either sequential TLI/chemotherapy (n = 32) or chemotherapy-alone conditioning (n = 16), based on prior radiation exposure. The first 22 patients enrolled on trial received escalating doses of etoposide (1600–2100 mg/m2) with high-dose carboplatin and cyclophosphamide.

Results: No dose-limiting toxicity was seen and TLI/chemotherapy was well tolerated. The 5-year event-free survival (EFS) estimate for all patients was 44% with overall survival (OS) of 48%. Five-year EFS and OS for the TLI/chemotherapy group was 63% and 61%, respectively, compared with 6% and 27%, respectively, for the chemotherapy-alone group (P < 0.0001 and P = 0.04, respectively). Patients with primary induction failure HL who received TLI/chemotherapy had 5-year EFS and OS rate of 83%. The 100-day treatment-related mortality was 4.2% and two secondary cancers were seen. Significant factors predicting survival by multivariate analysis included TLI/chemotherapy conditioning and B symptoms at relapse.

Conclusions: Sequential TLI/chemotherapy conditioning for relapsed/refractory HL is safe and associated with excellent long-term survival rates.

autologous transplantation, Hodgkin's lymphoma, outcomes, prognosis, therapy, total lymphoid irradiation


   introduction
Top
 Abstract
 introduction
patients and methods
 results
 discussion
 appendix 1
 Acknowledgements
 References
 
The treatment of patients with primary refractory/relapsed Hodgkin's lymphoma (HL) includes salvage chemotherapy followed by autologous hematopoietic stem-cell transplantation (aHSCT), with or without radiation. A number of aHSCT conditioning regimens have been studied including carmustine, etoposide, cytarabine, and melphalan and cyclophosphamide, carmustine, and etoposide (CBV). Long-term survival rates of 45%–51% have been reported [1–10].

Yaholom et al. [11] reported that total lymphoid irradiation (TLI) followed by high-dose chemotherapy is feasible, but was associated with treatment-related mortality (TRM) of 17% including 11% grade 5 pulmonary toxicity. In an updated report, [12] accelerated fractionation TLI was administered twice daily over 5 days followed by CBV chemotherapy for previously unirradiated patients, while previously irradiated patients received accelerated fractionation involved-field radiotherapy (IFRT) followed by CBV chemotherapy. Overall 5-year event-free survival (EFS) was 68%, with TRM of 3.6%.

We report the results of a prospective phase I/II clinical trial for patients with relapsed/refractory HL conditioned with accelerated hyperfractionated TLI that was immediately followed by high-dose cyclophosphamide, carboplatin, and etoposide. Carboplatin is an active agent in HL [12–15] and was added in high doses in lieu of carmustine in an attempt to minimize pulmonary toxicity. Etoposide was dose escalated in the phase I portion of this clinical trial. Toxicity data were collected for all patients; response, survival, and prognostic data were analyzed, and we report the results of the phase I and phase II portions of the study.


   patients and methods
Top
 Abstract
 introduction
 patients and methods
results
 discussion
 appendix 1
 Acknowledgements
 References
 
patients
This prospective clinical trial was initiated first as a phase I trial in 1993 and amended in 1999 to a phase II trial. The protocol was approved by the Institutional Review Board of Northwestern University. Forty-eight patients were enrolled and transplanted from November 1993 through November 2005. All patients entered had biopsy-confirmed relapsed or primary refractory HL and signed informed consent. All cases were reviewed by a single hematopathologist (DV). Patients were staged according to the Cotswold modification of the Ann Arbor system, and bulky disease was defined by a mass of at least 10 cm (largest diameter) or a bulky mediastinum (a ratio greater than one-third between the largest transverse diameter of the thorax at the diaphragm on a standing posteroanterior chest radiograph) [16].

conditioning regimen
Salvage chemotherapy before aHSCT was administered at the discretion of the treating physician, but most commonly was etoposide, solumedrol, cytarabine, and cisplatin. All patients were assigned to receive combination of TLI with high-dose chemotherapy, unless they had received prior radiation over 2000 cGy, in which case they received chemotherapy-alone conditioning. Accelerated hyperfractionated TLI was administered as an outpatient, starting 4–5 weeks before transplantation. All patients were treated by a single radiation oncologist (BBM). Patients receiving TLI were treated twice daily at 150 cGy (at least 6 h apart) 5 days per week. Patients received morning radiation at 150 cGy to all nodal sites: cervical, axillary, mediastinal, spleen, paraaortic, and pelvic nodes; while the afternoon treatment was delivered to sites of previous and current disease as noted clinically and/or radiographically with 150 cGy. The aim was to deliver a cumulative dose of 1500 cGy to previously uninvolved nodal sites and spleen (if not involved with disease) with a cumulative dose of 3000 cGy to sites of current or previous disease.

Conditioning chemotherapy consisted of high-dose carboplatin, cyclophosphamide, and etoposide. Chemotherapy doses were calculated on the basis of adjusted ideal body weight for all patients (40% of the difference of actual to ideal body weight added to ideal body weight for body surface area calculation). All 48 patients received carboplatin 450 mg/m2/day by continuous intravenous infusion (CIV) on days –6 to –4 (total dose = 1350 mg/m2) and cyclophosphamide 60 mg/kg/day over 1 h on days –3 and –2 (total dose = 120 mg/kg). The first 22 patients enrolled on the phase I component of the protocol received escalating doses of etoposide by CIV (days –6 to –4) with cohorts of four patients treated at each dose level, unless dose-limiting toxicity (DLT) occurred. Dosing levels of etoposide were 400 mg/m2/day (six patients), 450 mg/m2/day (four patients), 500 mg/m2/day (four patients), 600 mg/m2/day (four patients), and 700 mg/m2/day (four patients), with the total dose of 2100 mg/m2 (700 mg/m2) being the preplanned maximum dose. One DLT occurred at dose level 1 of etoposide (sepsis), with no further DLT or maximum tolerated dose experienced. The remaining 26 patients were treated on the phase II component of the trial. One patient had bone marrow stem cells harvested, while the remaining 47 patients had peripheral blood stem cells collected.

posttransplant evaluation
Patients were evaluated at days +60 and +120 following aHSCT with chest radiograph, computed tomography (CT) imaging and positron emission tomography (PET) or gallium scanning. Thereafter, chest radiograph was repeated every 3 months and tumor staging (CT and PET or gallium) were completed every 6 months through at least 2 years.

statistical analysis
EFS was calculated from day 0 of aHSCT to treatment failure (defined as relapse, secondary malignancy, or death from any cause). Overall survival (OS) was calculated from day 0 of aHSCT to the date of death from any cause or until the date of last known follow-up. Among conditioning regimens, patient characteristics, engraftment times, and sites of relapse following aHSCT were compared using Fisher's exact tests. Survival analyses were carried out using Kaplan–Meier curves, [17] which were compared using log-rank testing [18]. Nonrelapse mortality was calculated by death from any cause other than HL. Neutrophil engraftment was defined by absolute neutrophil count ≥0.5 x 109/l sustained for three consecutive days with no subsequent decline, and platelet engraftment defined as platelets ≥20 x 109/l for three consecutive days with no transfusions in the previous 7 days. Primary induction failure (PIF) was defined as patients who did not achieve a complete remission (CR) or partial remission (PR) with first-line chemotherapy; patients in early relapse (first CR <3 months) were not included in this definition. Prognostic factors were evaluated in both univariate and multivariate analyses using Cox proportional hazards regression [19] for indicators of EFS and OS. Twenty-three factors were chosen for prognostic significance in univariate analysis as factors that have shown significance in prior HL aHSCT reports [1–6, 8–10, 12, 20–28] (Appendix 1). Only variables with a P-value of ≤0.05 in univariate analyses were entered into the multivariate model in a stepwise routine fashion. For prognostic factor analyses, hazard ratios (HRs) and their 95% confidence intervals (CIs) are reported. HRs more than one indicate a factor with poor prognosis, while HRs less than one indicate a factor with good prognosis.


   results
Top
 Abstract
 introduction
 patients and methods
 results
discussion
 appendix 1
 Acknowledgements
 References
 
patient characteristics at original diagnosis
Patient characteristics at time of original HL diagnosis are listed in Table 1. Most patients had nodular sclerosis histology and the majority of patients received adriamycin, bleomycin, vinblastine, dacarbazine (ABVD). Approximately one-third of the patients received adjuvant radiation. Response to initial chemotherapy therapy is known for 47 patients with 66% achieving remission (28 CR, three PR), while 34% experienced PIF HL.


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  		Table 1. Patient characteristics at initial diagnosis (n = 48)

 
patient characteristics at relapse and transplant
Patient characteristics at time of relapse before aHSCT are listed in Table 2. Relapse site was nodal in 46/48 patients, with a patient each with relapse in the lungs and stomach only. Both of these patients had not received prior radiation and thus received TLI/chemotherapy conditioning. Twenty-six percent of patients received more than one line of salvage chemotherapy (nine patients received two regimens, one patient three regimens, and one patient five salvage regimens). At the time of transplant, 30 patients were chemotherapy sensitive (eight CR, 22 PR), while 16 patients were chemotherapy resistant [11 stable disease (SD) and five progressive disease (PD)]. SD is defined as: less than a 50% reduction and less than a 25% increase in the sum of the two perpendicular diameters of all measured lesions and the appearance of no new lesions. PD is defined as: more than 25% increase in the sum of products of two perpendicular lesions and/or the appearance of any new lesions. Thirty-two patients received sequential TLI/chemotherapy conditioning; three of 32 had received prior radiation, each <2000 cGy. Sixteen patients received chemotherapy-alone conditioning, of whom, 14 had received prior radiation over 2000 cGy. Two patients had not received prior radiation, and were treated with chemotherapy-alone conditioning (without TLI) at the discretion of the treating physician due to the presence of very bulky mediastinal disease and compromised pulmonary function. These constituted two of the three initial patients treated on protocol in 1993; all subsequent patients without prior radiation, including nine patients with mediastinal disease >5 cm (six patients with mass >10 cm and/or bulky mediastinum), received TLI-based conditioning therapy.


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  		Table 2. Patient characteristics at transplantation (n = 48)

 
Of note, both the TLI/chemotherapy and chemotherapy-alone conditioning groups included a considerable number of patients with high-risk pretransplant features (Table 3). Among the chemotherapy-alone group, 19% of patients had PIF, while 50% were resistant to salvage chemotherapy (including 31% of patients with PD at the time of aHSCT). Furthermore, two of three PIF patients were resistant to salvage chemotherapy (one SD and one PD). Among the TLI/chemotherapy group, 41% of patients had PIF HL, and of the patients who attained initial remission, only 22% (four of 18) maintained remission for >12 months (Table 3). In addition, 25% of patients in the TLI/chemotherapy group were resistant to salvage therapy (all SD), while 16% had both PIF and chemotherapy-resistant disease.


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  		Table 3. Patient characteristics on the basis of conditioning regimen

 
engraftment
Median time to neutrophil engraftment was 10 days (range 8–21 days) and median time to platelet engraftment was 20 days (range 10–61 days).

adverse events
The most common grade 3/4 adverse events were infection and mucositis (Table 4). There were no toxicity differences between the phase I and phase II patients. TLI/chemotherapy was well tolerated. The only additional side-effect seen in patients who received TLI/chemotherapy conditioning compared with chemotherapy alone was radiation recall in the former in six patients (four grade 2, two grade 3). There were no other appreciable differences.


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  		Table 4. Incidence of grade 3 and 4 non-hematologic toxic effects (n = 48)

 
non-hematologic toxicity and secondary malignancy
The overall nonrelapse mortality was 8.3% (four of 48 patients). This included two cases of myelodysplastic syndrome (MDS) at 33 and 81 months following aHSCT. Both patients had received prior mechlorethamine, vincristine, procarbazine, and prednisone and ABVD chemotherapy. The former MDS case was associated with deletion 20q, while the latter had associated trisomy 21 that evolved into acute myeloid leukemia 16 months later. There were no other cases of secondary malignancy. The 100-day TRM for all patients was two of 48 (4.2%). Both deaths were attributed to sepsis, at 1 and 3 months following aHSCT.

outcome
Median follow-up in all 48 patients is 26 months (range 1–132 months). Median follow-up in the 32 patients who received combined TLI/chemotherapy conditioning is 27 months (range 1–132 months). The 5-year EFS and OS estimates for all patients are 44% and 48%, respectively (Figure 1A and B). The 5-year EFS estimates for patients who received combined TLI/chemotherapy conditioning (n = 32) versus chemotherapy-alone conditioning (n = 16) is 63% and 6% (P = <0.0001), respectively, while the 5-year OS estimates are 61% and 27%, respectively, P = 0.04 (Figure 1C and D). The 5-year EFS estimate according to sensitivity to salvage chemotherapy is 54% for patients (n = 30) with chemotherapy-sensitive disease and 21% for patients (n = 16) with chemotherapy-resistant disease, P = 0.09 (Figure 2A and B). The 5-year OS for patients with chemotherapy-sensitive disease is 56% and is 35% for chemotherapy-resistant disease (P = 0.34). When only patients who received combined TLI/chemotherapy conditioning are analyzed, the 5-year EFS survival estimates for chemotherapy-sensitive (n = 22) and resistant (n = 8) disease are 70% and 45%, respectively (P = 0.44), while the 5-year OS are 60% and 60%, respectively (P = 0.86; Figure 2C and D). Interestingly, the 5-year EFS and OS estimate for HL patients with PIF who received TLI/chemotherapy conditioning is 83% (Figure 2E). The survival for patients enrolled on the phase II component compared with the phase I portion of the clinical study are similar (data not shown).


Figure 1
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  		Figure 1. Event-free (EFS) and overall survival (OS) for all relapsed and refractory HL patients and according to conditioning regimen. (A) Kaplan–Meier estimate of EFS for all patients (n = 48). (B) Kaplan–Meier estimate of OS for all patients (n = 48). (C) Kaplan–Meier estimate of EFS and OS for patients who received combined accelerated hyperfractionated total lymphoid irradiation (TLI)/chemotherapy conditioning (n = 32). (D) Kaplan–Meier estimate of EFS and OS for chemotherapy-alone conditioning (n = 16).

 

Figure 2
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  		Figure 2. Survival according to chemotherapy response to salvage therapy before autologous hematopoietic stem-cell transplantation (aHSCT). (A) Kaplan–Meier estimate of event-free survival (EFS) on the basis of disease sensitivity to salvage therapy prior aHSCT for all patients (P = 0.09). There are two unknown responses to salvage therapy. (B) Kaplan–Meier estimate of overall survival (OS) on the basis of disease sensitivity to salvage therapy for all patients (P = 0.34). (C) Kaplan–Meier estimate of EFS on the basis of disease sensitivity to salvage therapy for patients (n = 30) who received accelerated hyperfractionated total lymphoid irradiation (TLI)/chemotherapy conditioning (P = 0.44). (D) Kaplan–Meier estimate of OS on the basis of disease sensitivity to salvage therapy for patients who received TLI and chemotherapy conditioning (P = 0.86). (E) Kaplan–Meier EFS and OS for patients with primary induction failure who received sequential TLI/chemotherapy conditioning (n = 12).

 
relapse
Relapse sites following aHSCT for patients who received chemotherapy alone were nodal in 12 of 14 patients (86%, primarily pulmonary hilum and/or mediastinum); two patients experienced extranodal relapse (liver n = 1 and pleura n = 1). Of the 12 patients with nodal relapse in the chemotherapy-alone group, seven of 12 (58%) relapses occurred in sites that were not previously irradiated. Nodal relapse for patients who received TLI/chemotherapy conditioning was seen in three of seven patients (43%, P = 0.12, compared with chemotherapy alone). The sites of extranodal relapse were pulmonary (n = 2) or bony (iliac n = 1 and ribs n = 1).

prognostic factors for survival
By univariate analysis, radiation before aHSCT and B symptoms at time of relapse were associated with statistically significant inferior EFS and OS, while initial chemotherapy with ABVD-alone and TLI conditioning therapy were associated with statistically significant superior EFS and OS (Table 5). CR to salvage chemotherapy was associated with superior EFS. When analyzing within the group of patients who received TLI/chemotherapy conditioning, only lack of B symptoms at time of relapse (EFS P < 0.0001 and OS P = 0.0007) and CR to salvage chemotherapy (EFS P = 0.04) were significantly associated with improved outcome in univariate analysis. Interestingly, there was a trend for improved survival for PIF patients who received TLI/chemotherapy (EFS P = 0.14 and OS P = 0.06). For patients who received chemotherapy-alone conditioning, no prior radiation (P = 0.01), first CR >12 months (P = 0.02), and CR to salvage chemotherapy (P = 0.04) predicted improved EFS, while only first CR >12 months (P = 0.03) predicted OS. On multivariate analysis of all patients (Table 5), the only significant prognostic survival associations are TLI/chemotherapy conditioning associated with reduced risk of an event (HR 0.16, CI 0.07–0.39, P < 0.0001), while B symptoms at relapse are associated with increased risk of death (HR 3.81, CI 1.34–10.83, P = 0.012).


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  		Table 5. Risk factors for survival (n = 48)

 

   discussion
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
appendix 1
 Acknowledgements
 References
 
We report here the toxic effects and outcomes of 48 relapsed/refractory HL patients treated on a prospective phase I/II clinical trial. We found that we could escalate doses of etoposide to the planned maximum dose of 2100 mg/m2 in combination with high-dose carboplatin and cyclophosphamide and TLI. There have been no secondary solid tumors seen to date and the rate of secondary hematologic malignancies (MDS) is 4.2%. This compares favorably with recently published observations [1, 8, 12, 25], although longer follow-up is needed especially for surveillance of solid tumors. The 5-year EFS and OS for relapsed/refractory HL patients treated with TLI/chemotherapy conditioning on this trial was 63% and 61%, respectively. These excellent survival rates are apparent despite many patients in the TLI/chemotherapy group having negative pretransplant prognostic factors. Notably, 84% of patients (27/32) from the TLI/chemotherapy group had either PIF HL (13/32) or short initial remission of <12 months (14/32).

Few HL aHSCT studies have uniformly included radiation as a planned component of conditioning therapy [6, 7, 11, 12, 29]. The rationale for incorporating radiation into conditioning therapy before transplant for relapsed/refractory HL is the observation that relapses often occur in nodal sites, and indeed, the rate of nodal recurrence in our series was 86% in patients who did not receive TLI and only 42% in patients who did, despite the fact that most of the chemotherapy-alone conditioned patients had received prior radiation. Moreover, of patients who received chemotherapy-alone conditioning, ~60% relapsed in nodal sites that were not previously irradiated.

Our phase I/II clinical trial was based in part on the promising findings of the TLI-based aHSCT conditioning regimen described by Yaholom et al. [11]. At 6.5 years, the actuarial disease-free survivals rate was 50% with an updated report by Moskowitz with EFS of 68% for patients undergoing aHSCT, [12] with no differences in survival between IFRT chemotherapy and TLI chemotherapy patient groups (all patients received radiation in their series). Several differences between the Moskowitz series and our data are apparent. We administered accelerated hyperfractionated TLI over a longer interval at slightly lower doses, and added high-dose carboplatin (in lieu of carmustine) to the conditioning regimen, both in an attempt to reduce pulmonary toxicity. Only patients with chemotherapy-sensitive disease (CR, PR, or minimal response—defined as at least 25% response with normalization of gallium scan) in the Moskowitz series were transplanted, whereas all patients in our series, regardless of response to salvage chemotherapy, proceeded to aHSCT. In addition, Moskowitz et al. [12] incorporated radiation into the conditioning therapy for all patients, irrespective of prior radiation history. In their series, patients who had received prior radiation received IFRT in combination with high-dose chemotherapy conditioning, while patients with no prior radiation received combination TLI/chemotherapy conditioning. In our series, all patients received the same chemotherapy conditioning; patients additionally received TLI if they had no prior radiation or received <2000 cGy.

The number of patients in this series is not large enough to allow a valid comparison between patients receiving TLI/chemotherapy and chemotherapy-alone conditioning. The observation in this series that patients who did not receive radiation with their initial HL treatment had better EFS and OS than patients who had initial radiation is likely an artifact and represents selection bias, since for the most part, only patients with no prior radiation received TLI at the time of transplant, and those patients might have been a more favorable group. We cannot completely reconcile why our results were so poor in patients who received chemotherapy-alone conditioning. One explanation may be that this patient group had a large number of pretransplant high-risk features; 73% had either PIF or initial remission <12 months, 31% had B symptoms at relapse, and 50% had chemotherapy-resistant disease (including 31% with PD) at the time of aHSCT.

It is possible that the outcome of patients receiving chemotherapy-alone conditioning in our series may have been improved by including IFRT as a component of conditioning therapy, especially given the high rate of nodal relapse in this group compared with patients who received TLI/chemotherapy. Moskowitz et al. [12] showed similar outcomes whether patients received TLI/chemotherapy (EFS and OS 68% and 81%, respectively) or IFRT/chemotherapy conditioning (EFS and OS 68% and 84%, respectively). It is also possible that the chemotherapy conditioning regimen used here is an inferior regimen. Moskowitz et al. used total doses of cyclophosphamide 4.5 grams/m2 and etoposide 1 gram/m2 for patients who received TLI and total doses of cyclophosphamide 6 gram/m2, etoposide 1600 mg/m2, and carmustine 300 mg/m2 for patients who received IFRT-based conditioning. This compares to our chemotherapy regimen with total doses of cyclophosphamide 120 mg/kg, etoposide 2100 mg/m2 (after completed dose escalation), and carboplatin 1350 mg/m2.

Many HL aHSCT reports, mostly retrospective, have shown prognostic factors that predict survival including gender, [6] performance status (ECOG), [23] bulky disease, [9] advanced stage of disease [1, 2, 6], anemia [1, 23, 30], and B symptoms at time of relapse [7, 12, 22]; the most commonly reported prognostic factors are length of initial remission (<1 year) [1, 3, 9, 12, 30], extranodal disease at time of relapse [7, 9, 12, 27, 29], number of regimens before aHSCT [2, 4, 5, 23, 27, 29], and degree of sensitivity to salvage chemotherapy [2, 4–7, 9–11, 20, 22, 30]. When all patients in our series are analyzed (n = 48) for responsiveness to salvage chemotherapy, there is a trend towards poorer EFS among chemotherapy-resistant versus sensitive patients (P = 0.09), but this discrepancy is much less apparent in the combined TLI/chemotherapy conditioning group (P = 0.44, Figure 2C and D).

We show by multivariate analysis that TLI/chemotherapy conditioning is associated with reduced risk of an event, while only B symptoms at relapse are associated with increased risk of death (Table 4). Historically, poor outcome has been reported for patients with PIF HL with survival rates ranging from 15% to 45% [5, 20, 21, 24–26, 28], with data using TLI-based therapy showing the highest survival [25]. The 5-year EFS and OS estimates for HL patients with PIF in our series who received TLI/chemotherapy conditioning was 83% (Figure 2E). Thus, it appears that the TLI/chemotherapy regimen was able to overcome PIF as a negative prognostic factor. Alternatively, this might suggest that in the TLI/chemotherapy group, radiation alone might have been enough to salvage some of these patients, but since the majority of patients had early relapse, PIF or other high-risk features, this is unlikely. It is more likely that in relapsed/refractory HL, the combined modality approach of radiation to nodal sites and high-dose chemotherapy is synergistic and radiation is needed to control nodal disease in this setting.

In summary, we report here a prospective phase I/II trial incorporating accelerated hyperfractionated TLI as a component of the conditioning regimen with high-dose chemotherapy for patients with relapsed/refractory HL who had not received prior radiation >2000 cGy. Sequential TLI/chemotherapy was well tolerated and there was a low incidence of TRM and secondary cancers. The survival rates in this and other series integrating TLI into the transplant conditioning regimen are among the highest reported for patients with relapsed/refractory HL. Multicenter studies including radiation with high-dose chemotherapy and aHSCT for patients with relapsed/refractory HL are warranted.


   appendix 1
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
 appendix 1
Acknowledgements
 References
 
prognostic risk factors for survival

HL histology (nodular sclerosis versus mixed cellularity versus lymphocyte predominant)
Initial stage (I/II versus III/IV) and stage at relapse (I/II versus III/IV)
Gender (female versus male)
B symptoms at initial HL diagnosis (yes versus no) and at relapse (yes versus no)
Extranodal disease at relapse
Induction chemotherapy with adriamycin, bleomycin, vinblastine, dacarbazine (ABVD) alone versus all other regimens [including ABVD combination regimens such as mechlorethamine, procarbazine, vincristine, and prednisone (MOPP)-ABVD and non-ABVD regimens]
Response to induction chemotherapy [complete remission (CR)/partial remission (PR) versus stable disease (SD)/progressive disease (PD)]
Primary induction failure
Bulky disease at initial HL diagnosis and at relapse (before aHSCT)
Initial remission <12 months
Anemia at relapse (<12.0 gm/dl for males and <10.5 gm/dl for female versus no anemia)
LDH at relapse (elevated versus normal)
Salvage regimen used (ESHAP-based versus all others)
Response to salvage chemotherapy (CR/PR versus SD/PD; and CR versus PR/SD/PD)
Number of lines of salvage therapy before aHSCT (one versus more than one)
Performance status at relapse (0/1 versus 2 or more)
History of prior radiation
TLI with aHSCT conditioning
Phase of clinical trial (phase I versus phase II)


   Acknowledgements
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
 appendix 1
 Acknowledgements
References
 
The authors wish to acknowledge the hematopoietic stem cell transplant program inpatient and outpatient nurses and nurse practitioners for their dedication and excellent patient care. This work was supported in part through funding from the National Cancer Institute K23 grant (CA109613-A1) to Andrew Evens, and Clinical Oncology Training Program (T32-CA079447) to Jessica Altman. Presented in part at 47th annual American Society of Hematology meeting, Atlanta, GA, December 2005.

Received for publication September 26, 2006. Revision received November 21, 2006. Accepted for publication December 12, 2006.


   References
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
 appendix 1
 Acknowledgements
 References
 
1. Josting A, Rudolph C, Mapara M, et al. (2005) 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 Oncol 16:116–123.[Abstract/Free Full Text]

2. Popat U, Hosing C, Saliba RM, et al. (2004) Prognostic factors for disease progression after high-dose chemotherapy and autologous hematopoietic stem cell transplantation for recurrent or refractory Hodgkin's lymphoma. Bone Marrow Transplant 33:1015–1023.[CrossRef][Web of Science][Medline]

3. Schmitz N, Pfistner B, Sextro M, et al. (2002) Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin's disease: a randomised trial. Lancet 359:2065–2071.[CrossRef][Web of Science][Medline]

4. Sureda A, Arranz R, Iriondo A, et al. (2001) Autologous stem-cell transplantation for Hodgkin's disease: results and prognostic factors in 494 patients from the Grupo Espanol de Linfomas/Transplante Autologo de Medula Osea Spanish Cooperative Group. J Clin Oncol 19:1395–1404.[Abstract/Free Full Text]

5. Czyz J, Dziadziuszko R, Knopinska-Postuszuy W, et al. (2004) Outcome and prognostic factors in advanced Hodgkin's disease treated with high-dose chemotherapy and autologous stem cell transplantation: a study of 341 patients. Ann Oncol 15:1222–1230.[Abstract/Free Full Text]

6. Gutierrez-Delgado F, Holmberg L, Hooper H, et al. (2003) Autologous stem cell transplantation for Hodgkin's disease: busulfan, melphalan and thiotepa compared to a radiation-based regimen. Bone Marrow Transplant 32:279–285.[CrossRef][Web of Science][Medline]

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