Volume 14, Issue 7 , Pages 775-782, July 2008
Favorable Overall Survival with Fully Myeloablative Allogeneic Stem Cell Transplantation for Follicular Lymphoma
Article Outline
Abstract
Allogeneic stem cell transplantation (Allo-SCT) remains an option for patients with follicular lymphoma (FL). We performed a retrospective analysis to examine long-term disease control and treatment-related mortality (TRM) in a group of patients that underwent transplant for clinically high-risk disease. Thirty-seven patients with indolent FL (follicular small cleaved [FSC], follicular mixed [FM] or FL grades 1 or 2 by WHO criteria) underwent allo-SCT. Patients were in a chemosensitive remission at the time of SCT. The conditioning regimen was typically busulfan-cyclophosphamide (BuCy). Cyclophosphamide-total body irradiation (TBI) was used for unrelated donor SCT. The median age at the time of transplant was 45 years (range: 24-58). The median number of prior chemotherapy regimens was 3 (range: 1-6). Thirty-seven patients received BuCy conditioning and 2 patients underwent reduced intensity conditioning SCT. Seventy-two percent of patients had a matched sibling donor. With a median follow-up of 63.5 months in survivors, the 5-year overall survival is 79.1% (95% confidence interval 66.3%-94.4%). TRM was 15.4%, with an additional case of mortality from breast cancer. These results demonstrate that in selected younger patients, a fully myeloablative allo-SCT utilizing BuCy conditioning provides excellent OS and disease control with low TRM.
Key Words: Allogeneic stem cell transplantation, Follicular lymphoma, Myeloablative
Introduction
Although patients with follicular lymphoma (FL) may achieve long remission durations with current therapies, it remains unlikely that these are curative strategies 1, 2. Recent innovations including combination immunochemotherapy and maintenance with the anti-CD20 monoclonal antibody (mAb) rituximab have demonstrated an improved progression-free (PFS) and overall survival (OS) in patients with FL 3, 4, 5, 6. Despite the advent of immunochemotherapy-based strategies, stem cell transplantation (SCT) approaches remains an attractive option in the management of FL for several reasons.
Dose-intensive chemotherapy has been demonstrated to improve PFS and OS in the relapsed lymphoma setting with the use of autografts to ameliorate the hematologic toxicity of high-dose chemotherapy 7, 8. Tumor graft contamination as part of an SCT procedure can be reduced through the use of purging strategies in the autologous setting (although the benefit of this remains a debatable point given the inconsistent published results) or eliminated through the use of syngeneic or allogeneic stem cells from a healthy donor 8, 9, 10, 11, 12. Donor-derived SCT offers the additional benefit of a potential immunologically mediated graft-versus-lymphoma (GVL) effect that could provide sustained immune surveillance and reduced rate of lymphoma recurrence in the recipient. The evidence of a GVL effect has been indirectly suggested based on a reduction in the rate of relapse in patients undergoing allogeneic SCT (allo-SCT) when compared to autologous SCT (ASCT), but the significance of this effect remains in question, as this has never been tested in a randomized trial 13, 14, 15, 16. Further direct evidence of a GVL effect has been demonstrated through the use of donor lymphocyte infusion (DLI), which may induce remission in patients following allo-SCT 17, 18, 19.
ASCT for FL has been evaluated in the front-line and relapsed setting, and has resulted in an improved PFS when compared to anthracycline-based chemotherapy 8, 20, 21, 22. The randomized European CUP trial was the only study to demonstrate an OS advantage for ASCT in a small group of patients with relapsed FL [8]. Although ASCT has greater applicability in FL (compared to myeloablative allo-SCT) as it can be considered in patients up to age 65 or 70 years and may be performed with a relatively low treatment-related mortality (TRM), data failed to demonstrate a plateau in survival curves, and there are concerns with secondary myelodysplasia and acute leukemia 8, 20, 21, 22.
Allo-SCT remains a potential curative strategy because of the ability to provide dose intensity, a tumor-free stem cell graft and GVL effect from the donor immune system. Registry and single-center reports have failed to clearly demonstrate these advantages, and these data remain difficult to interpret because of sample size, patient selection, and study heterogeneity 9, 10, 15, 23, 24, 25, 26, 27. Applicability also remains a concern, as myeloablative SCT is generally restricted to younger patients and TRM may be high (particularly when considering unrelated donor SCT). Newer reduced-intensity conditioning SCT (RICSCT) techniques are appealing because they increase the availability of allogeneic SCT procedures by increasing the upper age limit, expanding the limit of organ function and comorbidity, and appear to reduce early TRM 19, 23, 25, 27, 28. However, RICSCT needs to be evaluated carefully because the benefits must be weighed against the reduction in dose intensity (and thus tumor control) that the procedure affords. Early registry data from the Center for International Bone Marrow Transplant Research (CIBMTR) demonstrates relapse rates in FL may be increased in patients undergoing RICSCT [27].
We reviewed our experience of allo-SCT for indolent FL. Previously, we have demonstrated favorable results in a cohort of non-Hodgkin lymphoma (NHL) patients with varying histology treated with a busulfan-based preparative regimen [24]. The current analysis was confined to confirmed indolent FL, and reports results of longer follow-up of over 5 years in a cohort of patients treated with myeloablative allo-SCT.
Patients and Methods
Study Design, Patient Evaluation, and Eligibility
We evaluated 37 consecutive patients with FL who underwent myeloablative allo-SCT at Princess Margaret Hospital between January 1, 1989, and December 31, 2005. All patients had a biopsy proved histologic diagnosis of FL (follicular small cleaved or follicular mixed by the REAL classification or follicular grade 1 or follicular grade 2 by the WHO classification). If serial biopsies were available, there were no biopsies that showed evolution to FL grade 3 (follicular large cell lymphoma) or of transformation to diffuse large B cell lymphoma. Data were obtained from a prospectively collected database, and additional information was collected from computerized records or patient charts as required. The Princess Margaret Hospital Research Ethics Board and Cancer Registry Data Access Committee (CRDAC) approved this study.
Patients were eligible to receive allo-SCT if they had a histologic diagnosis of FL as above and had received at least 1 prior chemotherapy regimen (typically cyclophosphamide, doxorubicin, vincristine and prednisone [CHOP]), and were high risk (multiple lines of chemotherapy, short remission duration with prior therapy, prior ASCT, ineligible for ASCT because of lack of adequate stem cell collection, persistent bone marrow involvement), along with appropriate donor availability (matched sibling, syngeneic, or unrelated) and patient and physician preference. Tumor biopsy was not required at the time of disease relapse or progression unless there was concern of transformation to aggressive histology NHL. Each chemotherapy regimen was given as is typical for advanced stage FL (6-8 cycles of CHOP, ≥4 cycles of fludarabine (Flu)-based regimens, 4 courses of single agent rituximab unless there was obvious evidence of disease progression). Transplantation was not offered if the patient had evidence of chemotherapy-refractory lymphoma.
Patients were eligible for allo-SCT if they had at least a stable disease response to chemotherapy prior to transplant (and had no bulky sites of disease), were ≥18 years of age, and had an Eastern Cooperative Oncology Group performance status of 0-2 at the time of allo-SCT [29]. Patients were restaged at the time of relapse or progression with computed tomography (CT) of chest, abdomen, and pelvis and magnetic resonance imaging (MRI), when appropriate. Gallium scans were recommended but were not required. Positron emission tomography scans were not performed. Baseline blood tests included a complete blood count, lactate dehydrogenase, liver enzyme tests, albumin, and serum creatinine. Bone marrow aspirate and biopsy was required prior to allo-SCT and could demonstrate up to 20% residual involvement by lymphoma as long as some chemosensitivity had been demonstrated. Patients were ineligible if they had uncontrolled infection or significant organ dysfunction that would preclude SCT. Disease response to chemotherapy was retrospectively categorized according to the International Working Group Criteria [30].
Conditioning Regimen and BMT Procedure
The preparative regimen consisted of either oral Bu in (1989-2000: 4 mg/kg orally in 4 daily divided doses for 4 days for a total of 16 mg/kg) or intravenous Bu in (2001-2005: 3.2 mg/kg i.v. daily for 4 days) followed by intravenous cyclophosphamide (Cy) 60 mg/kg administered daily for 2 days (total dose of 120 mg/kg). Phenytoin was administered as prophylaxis for Bu-induced seizures. One patient received Cy 60 mg/kg intravenously administered daily for 2 days (total dose 120 mg/kg) with total body irradiation (TBI) 12 Gy in 6 fractions and underwent SCT from an unrelated donor.
GVHD Prophylaxis and Supportive Care
Standard cyclosporine (CSA) and methotrexate (MTX) were used for GVHD prophylaxis. Patients undergoing syngeneic transplantation received an abbreviated course of cyclosporine A at a dose of 1 mg/kg for 28 days in an attempt to induce a GVL effect.
Patients were transplanted in isolation rooms. Antiviral prophylaxis included acyclovir 200 mg orally twice a day or 80 mg i.v. twice a day every 12 hours from days 1-28. Trimethoprim/sulfamethoxazole 2 tablets orally twice a day or an equivalent i.v. dose was employed starting from the day of hospital admission until neutrophil recovery. Trimethoprim/sulfamethoxazole was used for Pneumocystis jiroveci prophylaxis for 1 year post-allo-SCT or longer if patients remained on immunosuppression. Patients with sulfa allergies or significant bone marrow suppression received aerosolized pentamidine at a dose of 300 mg every 2-4 weeks.
Red cell depletion of the donor bone marrow was performed in the case of ABO-incompatible donor-recipient pairs. None of the grafts were ex vivo T cell depleted. Target cell doses were 3.0 × 108 total nucleated cells/kg for marrow transplants and 5 × 106 CD34+ cells/kg for peripheral blood stem cell transplants.
Preemptive screening for cytomegalovirus (CMV) was performed since 1992 using day +35 bronchoscopy or serial CMV antigenemia testing if either donor or recipient was CMV positive. Patients with positive CMV testing were treated with i.v. ganciclovir and intravenous immunoglobulin (IVIG) was used for patients with lung involvement.
Disease status was reassessed at between 3 and 6 months and 1 year posttransplant by repeat imaging and bone marrow aspirate and biopsy, or sooner according to clinical signs or symptoms.
Statistical Methods and Definitions
Thirty-seven patients were diagnosed with FL/FM between 1981 and 2003 and underwent BMT at Princess Margaret Hospital. Patient demographics were summarized using descriptive statistics such as the mean, standard deviation (SD), proportion, and frequency. The Kaplan-Meier method was used for estimating OS and PFS statistics [31]. Univariate Cox proportional hazards regression was used to investigate potential predictors of OS and PFS. Multivariate methods were not performed because of the small sample size. To account for the competing risk of nontreatment-related death in the analysis of TRM, a competing risk model was constructed which is adjusted for non-treatment related deaths. All tests were 2-sided and a P-value of .05 or less was considered statistically significant.
Veno-occlusive disease (VOD) of the liver and both acute and chronic graft-versus-host-disease (aGVHD, cGVHD) were defined as per previously published criteria 32, 33, 34. For survival calculations, patients alive at last follow-up were censored on the date they were last confirmed alive, or alive and progression-free for the PFS outcomes. Time to relapse was evaluated from the date of BMT to the date of confirmed relapse. Patients were censored if they were alive and relapse-free at the date of last follow-up, or on the date of death if they died with no prior relapse.
Results
Patient Characteristics
Table 1 describes the patient demographics. Twenty (51%) were male and the mean age at the time of transplant was 44 with a range of 27 to 60 years. The median time from diagnosis to allo-SCT was 25.5 months (range: 6.2-157.8 months) and the median number of prior chemotherapy regimens was 3 (1-6). All patients received chemotherapy and had at least a stable disease response prior to allo-SCT. Twenty-one percent received prior radiotherapy and 11% had received prior rituximab. There were 4 patients who underwent syngeneic transplant, 2 patients who underwent allo-SCT from a matched unrelated donor (MUD), and 5 patients were transplanted from a 1-antigen mismatched-related donor.
Table 1. Patient Demographics
| Characteristic | N (%) |
|---|---|
| Age at Diagnosis | |
 Median (Range) | 43.1 (21.8-57.5) |
| Sex | |
| Male | 20 (54.1%) |
| Female | 17 (45.9%) |
| Diagnosis | |
| FL1/FSC | 16 (43.2%) |
| FL2/FM | 19 (51.4%) |
| FL | 2 (5.4%) |
| Number of Prior Regimens | |
| 1:2:3:4:5:6 | 4:10:13:4:5:1 |
| Prior therapies | |
| Prior Purine Analog | 9 (24.3%) |
| Prior Alkyaltor | 21 (56.8%) |
| Prior Anthracycline | 34 (91.9%) |
| Prior Platinum | 18 (48.7%) |
| Prior Rituximab | 9 (24.3%) |
| Prior ASCT | 1 (2.7%) |
| Prior Radiotherapy | 7 (18.9%) |
| Time from Diagnosis to BMT (months) − Median (range) | 24.0 (6.2-148.6) |
| Age at BMT | |
| Median (Range) | 45.4 (27.2-59.7) |
| Conditioning | |
| Bu-CY | 36 (97.3%) |
| CY-TBI | 1 (2.7%) |
| Disease status at BMT | |
| CR / CRu | 11 (30%) |
| PR | 22 (59%) |
| SD | 3 (8%) |
| Resistant / Untested relapse | 0 |
| Unknown | 1 (3%) |
| Donor Match | |
| HLA-identical Sibling | 27 (73.0%) |
| Mismatch Donor | 5 (13.5%) |
| Matched Unrelated Donor | 1 (2.7%) |
| Syngeneic Donor | 4 (10.8%) |
| Graft Source | |
| Bone Marrow | 33 (89.2%) |
| Peripheral Blood | 4 (10.8%) |
| Acute GVHD Grade | |
| 0 | 7 (18.9%) |
| I | 6 (16.2%) |
| II | 19 (51.4%) |
| III | 5 (13.5%) |
| Chronic GVHD Grade | |
| None | 15 (40.5%) |
| Limited | 8 (21.6%) |
| Extensive | 12 (32.4%) |
| Not applicable | 2 (5.4%) |
Survival, Relapse, and TRM
The median follow-up for the entire cohort was 48.8 months, with the maximum follow-up of 192 months. Clinical outcomes are described in Table 2. As of the last known follow-up, 1 patient was alive after disease recurrence, 7 patients had died, and 31 were alive with no evidence of disease. Of those who died, 6 were treatment-related (2 patients with bronchiolitis obliterans, 1 patient with Pneumocystis jiroveci pneumonia, 1 patient with multiorgan failure, 1 patient with VOD and candida tropicalis infection, and 1 patient with VOD and aGVHD) and the final death was because of breast cancer. The sole patient who relapsed has required therapy for indolent NHL and and was not on therapy at the time of data analysis. Five-year OS was estimated to be 79% (95% confidence interval [CI]: 66%-94%, see Figure 1), 5-year PFS was estimated to be 76% (95% CI: 63%-92%, Figure 2), and 5-year TRM was 18% (95% CI: 5%-31%, Figure 3).
Table 2. Clinical Outcomes
| Outcome | Value |
|---|---|
| Follow-up (all) | |
| Median (range) months | 59.8 (0.4-192.7) |
| Follow-up (X survivors at last follow-up) | |
| Median (range) months | 64.8 (0.4-192.7) |
| Status at last follow-up | |
| Alive in remission | 29 (78.4%) |
| Alive after relapse | 1 (2.7%) |
| Dead | 7 (18.9%) |
| Overall Survival | |
| Median (95% CI) | Not Reached |
| 1-year (95% CI) | 91.5% (82.8%-100.0%) |
| 5-year (95% CI) | 78.7% (65.7%-94.2%) |
| Progression-Free Survival | |
| Median (95% CI) | Not Reached |
| 1-year | 91.5% (82.8%-100.0%) |
| 5-year | 75.5% (61.9%-92.0%) |
| Treatment-Related Mortality | |
| Median (95% CI) | Not Reached |
| 1-year (95% CI) | 8.5% (0.0%-17.8%) |
| 5-year (95% CI) | 18.2% (4.7%-31.7%) |
Figure 1.
OS from date of allogeneic SCT.
Figure 2.
PFS from date of allogeneic SCT.
Figure 3.
Treatment-related mortality.
aGVHD developed in 80% of cases (grade 3 in 5 cases and none with grade 4) whereas cGVHD developed in 54%. This was limited in 23% and extensive in 31%.
Prognostic Factor Analysis
Univariate regression statistics for predictors of survival, PFS, and TRM are in Table 3. Only age was statistically significant (P < .01) as a predictor for each outcome.
Table 3. Predictors of Progression Free Survival (PFS), Overall Survival (OS), and Treatment related Mortality (TRM)
| PFS | OS | TRM | ||||
|---|---|---|---|---|---|---|
| Predictor | Hazards Ratio (95% CI) | P-Value | Hazards Ratio (95% CI) | P-Value | Hazards Ratio (95%CI) | P-Value |
| Age at BMT | 1.15 (1.04-1.27) | .008 | 1.17 (1.04-1.31) | .008 | 1.20 (1.11-1.31) | <.001 |
| Diagnosis = FL/FM | 1.50 (0.36-6.29) | .58 | 1.20 (0.27-5.36) | .82 | 0.90 (0.18-4.42) | .90 |
| HLA-matched sibling donor | 1.19 (0.24-5.88) | .84 | 0.96 (0.19-4.96) | .96 | 0.75 (0.15-3.88) | .73 |
| Acute GVHD | 1.74 (0.21-14.13) | .61 | 1.48 (0.18-12.33) | .72 | 1.24 (0.15-10.35) | .84 |
| Chronic GVHD | 1.39 (0.33-5.85) | .65 | 1.09 (0.24-4.90) | .91 | 0.81 (0.16-4.00) | .80 |
| ≥3 Prior therapies | 6.02 (0.73-49.36) | .095 | 4.93 (0.59-41.24) | .14 | 3.94 (0.43-36.23) | .23 |
| Prior alkylator | 1.33 (0.32-5.60) | .70 | 1.04 (0.23-4.66) | .96 | 0.76 (0.15-3.83) | .74 |
| Prior purine analog | 1.19 (0.24-5.99) | .83 | 0.56 (0.07-4.69) | .59 | 0.70 (0.09-5.29) | .73 |
| Prior platinum | 1.81 (0.43-7.58) | .42 | 1.41 (0.32-6.31) | .65 | 1.04 (0.22-5.03) | .96 |
| Prior rituximab | 0.75 (0.09-6.14) | .79 | 0.87 (0.10-7.34) | .90 | 1.04 (0.13-8.64) | .97 |
| Prior XRT | 4.05 (0.94-17.44) | .060 | 2.34 (0.45-12.21) | .31 | 2.96 (0.56-15.77) | .20 |
| Graft source = BM | 0.56 (0.07-4.58) | .59 | 0.48 (0.06-3.98) | .48 | 0.39 (0.07-2.25) | .30 |
Discussion
Results of allo-SCT must always be considered in the context of the disease being treated; FL remains a disease with a typically indolent course that is chemosensitive, and patients may enjoy long remissions after therapies that may be intermittently applied over a number of years. Although clinical factors such as those in the FL International Prognostic Index (FLIPI) may identify a high-risk group of patients with a poor expected survival from diagnosis or at relapse, these prognostic factor analyses have not included therapy or remission duration as a factor [35]. Remission duration generally tends to shorten with the application of second-line or subsequent therapies, and thus multiple lines of therapy tends to be a significant factor in determining outcome as this is a marker of presumed chemoresistance.
We chose to exclude follicular grade 3 lymphoma (follicular large cell in the REAL classification), as this entity has been traditionally included with “intermediate grade” (aggressive histology) NHL, and controversy regarding treatment approaches remains, although there is an emphasis on anthracycline-based chemotherapy [36]. The patients have a median age of 44 (young for patients with FL), but patients were fairly heavily pretreated (but chemosensitive at the time of SCT) having received a median of 3 prior chemotherapy regimens in a time frame from diagnosis to allo-SCT of approximately 2 years. Rituximab had been used in a prior regimen in 11% of patients.
Despite this extensive pretreatment, the observed TRM was low at 15%; with a sample size of 39 cases, the 95% CIs range from 5% to 31%, and suggest that good results can be achieved in previously pretreated patients under the age of 60 with the application of a myeloablative allo-SCT regimen. Our data compares favorably with both single-institution and registry series that estimate TRM in this setting to range from 30% to 40% with mature follow-up 9, 10, 14, 26, 37, 38, 39.
The favorable OS in the cohort may be explained in large part because of a low rate of relapse and death from lymphoma. A clear relationship between the absence of cGVHD and relapse could not be demonstrated, likely related to the sample size and the fact that we had few relapse events in the cohort. Even in larger series with more events to analyze, a specific relationship between the presence of cGVHD and reduced relapse has not been clearly demonstrated [9]. Thus, it is difficult to ascertain if the favorable outcome seen in our series reflects efficacy of this busulfan-based preparative regimen or the impact of a GVL effect that could not be demonstrated because of limitations in sample size and number of events.
Our results demonstrate that myeloablative SCT can be performed safely in patients under the age of 60 years, and suggest that a TRM comparable to RICSCT can be possible in a single center experience. Recent data from the CIBMTR from a comparative registry review of FL has shown that TRM (24% in RICSCT versus 25% for myeloablative SCT) appears similar, and an inferior relapse rate was present in the RIC cohort (55% versus 65% at 3 years post-SCT) [27].
Allogeneic transplantation must be considered in the context of other therapies employed for recurrent disease. Randomized trials have evaluated different chemotherapy strategies or chemotherapy compared to ASCT in the setting of relapsed (typically second- or third-line treatment) lymphoma. The EORTC and GLSG randomized trials of immunochemotherapy and maintenance rituximab of R-CHOP report 3-year OSs of 77% to 85% in the rituximab maintenance arm 6, 40, whereas the randomized CUP study reported 4-year OSs of 71% and 77% for the unpurged and purged bone marrow groups that underwent ASCT [8]. The sample sizes in these studies range between 32 and 76 patients per arm, and are thus of similar size to our series. These studies report similar results to our myeloablative allo-SCT series and include less-pretreated patients with shorter follow-up.
The strength of this study is the long follow-up with of a median of over 5 years in survivors and a low relapse rate that demonstrates no recurrences after 4 years with ongoing follow-up now over 16 years post-SCT. Clearly, athough this is a retrospective single center cohort, these results demonstrate the feasibility and efficacy of a transplantation strategy that emphasizes myeloablative allo-SCT in patients without refractory disease. Although RICSCT improves the availability of allo-SCT procedures in this field, myeloablative SCT should still be considered in patients under the age of 60 years with a matched donor (differences in survival outcomes with a small number of alternate donor transplants in this series could not be demonstrated) and acceptable comorbidities.
Randomized trials are the cornerstone of the therapy of FL and remain 1 the key factors in improving OS in the disease 41, 42. Although the majority of novel drugs (radioimmunotherapy, proteasome inhibitors, immunomodulatory agents, or histone deacetylase inhibitors) have yet to clearly define a role, rituximab has become part of the standard of care at the time of diagnosis, at relapse, and as a maintenance agent. The integration of rituximab into allo-SCT strategies remains an important area of research. It has been demonstrated that rituximab can be given as part of a preparative regimen safely and may also be given after the transplant as a means of reducing relapse, although this has not been tested in Phase III trials 43, 44. The impact of rituximab on tumor immunosurveillance and cGVHD will need to be evaluated in prospective studies.
Allo-SCT is a therapy that will be used later in the disease course, and given current clinical practice, patients will have received multiple applications of rituximab (with or without chemotherapy). Results from carefully constructed prospective clinical trials that focus on discrete patients groups with a common histology will be required to allow allo-SCT to become 1 of the standard options that are available to patients with FL. Although RICSCT techniques improve the availability of allo-SCT to patients with FL in general, caution must be applied while interpreting results with short follow-up, and consideration should be given to more proved strategies such as myeloablative allo-SCT in eligible patients.
Acknowledgments
J.K. collected and analyzed data and wrote the manuscript. G.P. analyzed data and wrote the manuscript. R.T., V.G., and J.H.L. wrote the manuscript. H.M. collected and analyzed the data and wrote the manuscript. We would like the recognize the work of the support staff, nurses, and physicians who have been members of our team, as well as the institutions in our referral area who have provided prompt, exemplary care for these patients.
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PII: S1083-8791(08)00151-1
doi:10.1016/j.bbmt.2008.04.007
© 2008 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
Volume 14, Issue 7 , Pages 775-782, July 2008
