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. Author manuscript; available in PMC: 2014 Aug 28.
Published in final edited form as: Biol Blood Marrow Transplant. 2007 Jul 16;13(9):1057–1065. doi: 10.1016/j.bbmt.2007.05.012

Long-Term Survival after Autologous Bone Marrow Transplantation for Follicular Lymphoma in First Remission

Jennifer R Brown †,∼,*, Yang Feng , John G Gribben †,∼,*, Donna Neuberg , David C Fisher †,∼,*, Peter Mauch ˆ,&, Lee M Nadler †,∼,*, Arnold S Freedman †,∼,*
PMCID: PMC4147857  NIHMSID: NIHMS29265  PMID: 17697968

Abstract

The role of autologous stem cell transplantation (ASCT) in the treatment of follicular lymphoma is still being defined in the era of antibody therapy. Here we report the long-term 12 year clinical outcomes of patients treated with autologous bone marrow transplantation (ABMT) for follicular NHL in first remission. Between 1988 and 1993, advanced stage follicular NHL patients in need of initial therapy were enrolled on two consecutive prospective treatment trials of either standard dose CHOP induction (83 patients) or high dose CHOP plus G-CSF (20 patients). Patients who achieved an adequate remission with induction therapy underwent conditioning with cyclophosphamide and total body irradiation followed by ABMT in first remission using bone marrow purged in vitro with anti-B cell monoclonal antibodies and rabbit complement (96 patients). At 12 year follow-up, 61% of the patients are alive and 43% remain in continuing complete remission. The only predictors of decreased progression-free survival proved to be histologic bone marrow involvement at time of harvest (HR 2.27 (95% CI 1.3-3.9), p < 0.004) and PCR detectable disease in the bone marrow product after purging (HR 4.18 (95% CI 1.99-8.8), p = 0.0002). No significant predictors of overall survival were identified. These results at 12 year follow-up suggest that a subset of follicular lymphoma patients can experience prolonged survival with ABMT in first remission.

Introduction

The role of high-dose chemoradiotherapy and autologous stem-cell transplantation (ASCT) in the treatment of follicular lymphoma remains controversial, particularly with the advent of antibody-based therapies. Multiple phase II studies in follicular lymphoma have suggested that ASCT can result in prolonged remissions, albeit at the cost of significant toxicity, primarily secondary MDS/AML and now increasingly solid tumors1-14.

Since the initiation of these Phase II studies, multiple randomized trials have now been reported that address the role of ASCT in follicular NHL. For relapsed patients, the European CUP trial found that 2 year PFS was improved from 26% with standard chemotherapy to 55-58% in the combined purged and unpurged ASCT arms, and that 4 year OS improved from 46% to 71-77%15. For patients transplanted in 1st remission, both the German Low-Grade Lymphoma Study Group and the GOELAMS group have reported significantly improved PFS with ASCT, albeit in the GLSG case offset by increased second malignancies11,16. The GELA failed to see any PFS benefit in an intent-to-treat analysis that included patients who did not respond to induction and therefore did not receive ASCT, and with a comparison arm that received 18 months of continuous therapy17. These studies have therefore suggested a benefit of ASCT for relapsed patients with follicular lymphoma, and have been inconclusive with respect to patients in 1st remission, raising the possibility that PFS may be improved, if secondary toxicities could be minimized. In this study we report the very long-term clinical outcomes of a population of follicular lymphoma patients treated with ABMT for consolidation of first remission, with 43% of the patients remaining in continuous complete remission with few late relapses at 12 year follow-up.

Patients and Methods

Selection of Patients and Treatment Protocol

Patient eligibility and selection were identical for each of these two sequential prospective studies. Patients were eligible for high dose therapy and ABMT in first remission following CHOP induction if they met the following criteria: physiologic age 55 years or less; previously untreated follicular low grade B cell non-Hodgkin's lymphoma (NHL) as defined by the Working Formulation (WF), including: follicular small cleaved cell (WF-B), and follicular mixed small cleaved and large cell (WF-C); and CD20 (B1) antigen expression on their lymphoma cells as previously described18. All pathology was reviewed at Brigham and Women's Hospital. Patients had to have advanced stage disease, including IIIB, IIIE, II with masses > 10 cm, or stage IV disease. Patients with stage IV disease with minimal adenopathy (<1 cm) and <5% bone marrow (BM) involvement were excluded. Additional criteria for entry included the absence of comorbid disease of the heart, kidney, lung, and liver and a Karnofsky score above 80%. All protocols were approved by the Dana-Farber Cancer Institute Institutional Review Board, and informed consent was obtained from all patients prior to therapy.

All patients were registered prior to initiation of CHOP; a subset of patients received their CHOP induction with their referring physicans. Eighty-three patients were treated with 6-8 cycles of SD-CHOP (cyclophosphamide 750 mg/m2 IV d1; doxorubicin 50 mg/m2 IV d1; vincristine 1.4 mg/m2 (maximum 2 mg) IV d1; and prednisone 100 mg/d PO d1-5). Twenty patients received 4 cycles of HD-CHOP every three weeks19. This regimen consisted of: cyclophosphamide 1.5 g/m2/d IV d1 and d2; doxorubicin 50 mg/m2 IV d1; vincristine 1.4 mg/m2 (maximum 2 mg) IV d1; and prednisone 100 mg/d PO d1-5. Mesna was given by IV bolus as uroprotectant. G-CSF 5 μg/kg/d SC was given d4-18 of each cycle. No dose modifications were permitted on either protocol. All patients received prophylactic acyclovir and trimethoprim-sulfamethoxazole during each cycle.

At the completion of SD-CHOP or HD-CHOP, patients in CR (< 1 cm lymph nodes and no bone marrow involvement) or minimal disease state (< 2 cm lymph nodes and <20% bone marrow involvement, defined as the percent involvement of the intertrabecular space on iliac crest biopsy) went on to BM harvest within 4 weeks of completing chemotherapy. After SD-CHOP, ten patients (13%) with 1-3 masses > 2 cm received involved field radiotherapy. After completion of HD-CHOP, two patients (11%) with 1 mass > 2 cm received involved field radiotherapy.

In patients not receiving involved field radiotherapy, admission for ABMT was within 4 weeks of BM harvest. Conditioning therapy for ABMT consisted of cyclophosphamide 60 mg/kg infused on each of two consecutive days before radiotherapy. Total body irradiation was administered in fractionated doses (200 cGy) twice daily on three consecutive days (total of 1200 cGy) in all patients. Patients who were treated with SD-CHOP induction did not receive any hematopoietic growth factors following ABMT. All patients who received HD-CHOP induction received hematopoietic growth factors following ABMT. A significant prolongation of neutrophil and platelet engraftment was observed in patients who had received HD-CHOP with G-CSF, as previously reported20. Supportive care was provided as previously described21.

Collection, Processing and Infusion of Marrow

Bone marrow was obtained, treated in vitro with anti-B1 (CD20), -B5, and -J5 (anti-CD10) monoclonal antibodies and rabbit complement, and cryopreserved as previously described21. Nested PCR amplification at the major breakpoint region (MBR) and minor cluster region (mcr) of the bcl-2/IgH rearrangement of t(14;18) were performed as previously described; only those samples in which a rearrangement could be detected in initial diagnostic material were considered evaluable22. No patients were excluded from the protocol after BM harvest. Within 18 h of the completion of total body irradiation the cryopreserved marrow cells were reinfused as previously described21. No subjects treated on these protocols received peripheral blood stem cells.

Follow-Up

All patients had routine physical examinations and laboratory studies, including complete blood counts, every 3 months for the first year, then every 6 months for the second year, then annually following transplantation. Patients underwent bone marrow aspiration and core biopsy for persistently low peripheral blood counts without an obvious explanation. For those patients alive but not continuing to obtain follow-up care at Dana-Farber Cancer Institute, follow-up phone calls to their physicians were made annually.

Classification of MDS

As in our previous reports of MDS in this patient population4, MDS was strictly defined using the French-American-British (FAB) classification system and required bone marrow dysplasia in at least two lineages with peripheral cytopenia(s). Although cytogenetic abnormalities were evaluated, their presence was not diagnostic. Patients with persistent cytopenias after BMT without significant marrow dysplasia, or with alternative explanations for their cytopenias, were not considered to have MDS.

Statistical Methods

Overall survival (OS) is defined as the time from the day of marrow infusion (day 0) to death from any cause. Progression free survival (PFS) is defined as the time from the day of marrow infusion to the first reported outcome event. Outcome events include progression of disease or death from any cause. PFS and OS curves were obtained using the Kaplan-Meier method, with 95% confidence intervals calculated using Greenwood's formula, and compared by the log rank test23,24. The effects of the potential prognostic factors for PFS and OS were assessed using Cox multivariable regression models.

The cumulative incidence of second malignancies or relapse in the presence of competing risks (death without second malignancies or death in remission, respectively) were calculated using competing risk analysis25.

Results

Patient Characteristics

Between April 1988 and June 1993, 103 patients with previously untreated, advanced stage follicular lymphoma were registered on two consecutive protocols of induction chemotherapy followed by ABMT. The characteristics of these patients have been previously described18,20 and are summarized in Table 1. FLIPI scores have been retrospectively assigned for the majority of patients prior to therapy, with 58% having intermediate FLIPI scores. All patients were under 60, and due to the retrospective nature of the data collection, 21% of patients had missing data that if known may have upstaged their FLIPI risk group. There were no statistically significant differences between the patients who received SD-CHOP or HD-CHOP20.

Table 1. Patient Characteristics.

Total Registered 103
Induction
 Standard Dose CHOP 83
 High Dose CHOP 20
Reached minimal disease, underwent ABMT 96 (93%)
 CR 35%
Age (range) 42 (19-57)
Stage
 II 4 (4%)
 III 17 (18%)
 IV 75 (78%)
LDH
 High 11 (11%)
 Normal 64 (67%)
 Missing 21 (22%)
Nodal Sites
 1-4 24 (25%)
 5-8 70 (73%)
 Missing 2 (2%)
FLIPI
 Low (0-1) 24 (25%)
 Intermediate (2) 56 (58%)
 High (3-5) 16 (17%)
 Missing Values* 20 (21%)
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*

21% of patients had missing values assumed to be low-risk in the classification above, which may therefore represent an underestimate of actual FLIPI score.

Following SD-CHOP 77 of 83 patients (93%) achieved a minimal disease state and went on to ABMT. Three patients did not attain a protocol eligible PR, two patients were diagnosed with second tumors (melanoma and seminoma), and one patient declined further therapy. Following 4 cycles of HD-CHOP, 19 of 20 patients were in a minimal disease state, while one patient progressed with a high grade lymphoma within one month of induction therapy. The CR rates to SD-CHOP and HD-CHOP were 36% and 31%, respectively.

Clinical Outcomes

At a median follow-up of 12 years, 61% (95% CI 49.5-70.1) of patients are alive (Figure 1A), and 43% (95% CI 32.3-52.7%) of patients remain in continuing complete remission (Figure 1B). The overall mortality is 41%, with a median progression-free survival of 7.3 years (95% CI 4.3–NA), and median overall survival 15.8 years (95% CI 12.1-NA). 46% (N = 44) of patients have relapsed with follicular lymphoma, with 25% (N = 24) dying of disease, 5% (N=5) dying of other causes and 16% (N= 15) alive following relapse (Table 2). The median time to relapse in patients who have relapsed was 2.3 years; only six relapses have occurred at more than six years post transplant. The cumulative incidence of relapse, with death in remission a competing risk, is 37% at 5 years, and 47% at 10 and 15 years (Figure 2). The median survival following relapse is 6.1 years (95% CI 4.1-9.0). Ten patients have died in remission, 5 due to MDS/AML, 2 early in hospital due to diffuse alveolar hemorrhage (DAH), 1 due to suicide and 2 of unknown causes. The late deaths on the overall survival curve in Figure 1A are deaths in remission, primarily due to MDS.

Figure 1.

Figure 1

Figure 1

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A. Overall Survival: At a median follow-up of 12 years, 61% (95% CI 49.5-70.1) of patients are alive.

B: Progression-Free Survival: At a median follow-up of 12 years, 43% (95% CI 32.3-52.7%) of patients remain in ongoing complete remission.

Table 2. Clinical Outcomes.

Total Subjects Undergoing ABMT 96
Continuous Complete Remission 42 (median F/U 12 yrs)
Relapse (Alive) 44 (15)
Deaths In Remission 10 (10%)
 DAH 2
 MDS/AML 5
 Other 3 (1 suicide, 2 unknown)
Secondary Malignancies (N=27 patients)
 MDS/AML 10
 Non-MDS Heme 2
 Solid 9
  Breast(3); Prostate(1); Rectal(1); Melanoma(1); Renal cell(1); Bladder(1); Anal in situ(1)
 Non-Melanoma Skin 10
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Figure 2. Cumulative Incidence of Relapse.

Figure 2

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The cumulative incidence of relapse, with death in remission taken as a competing risk, was 37% at 5 years and 47% at 10 and 15 years.

Twenty-eight percent of patients (N = 27) have developed a second malignancy, at a median 8.3 years following ABMT. These malignancies include: 10 cases MDS/AML, 2 non-MDS hematologic malignancies, 9 solid tumors and 10 non-melanoma skin cancers (Table 2). The cumulative incidence of second malignancy, with death without second malignancy a competing risk, is 16% at 10 years and is estimated to be 38% at 15 years (Figure 3). 9.4% (N = 9) of patients have died of secondary malignancy (8 MDS/AML, 1 metastatic breast cancer).

Figure 3. Cumulative Incidence of Second Malignancy.

Figure 3

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The cumulative incidence of second malignancy, with death without second malignancy taken as a competing risk, was 16% at 10 years and 38% at 15 years.

Predictors of Progression-Free and Overall Survival

Patient characteristics were investigated for their ability to predict PFS or OS in univariate log-rank analysis. No effect of age at ABMT, stage at diagnosis, gender, hemoglobin, LDH, number of nodal sites, induction therapy (SD-CHOP vs HD-CHOP) or IFRT was observed. No effect of FLIPI score was observed on PFS or OS (data not shown), including when the subgroup of patients with missing data is analyzed separately. Achieving a CR after induction chemotherapy was of borderline significance in predicting PFS (p = 0.05, log-rank test) but was not significant for OS.

Residual bone marrow disease prior to harvest was found to be a significant predictor of PFS in univariate analysis, with subjects with no detectable tumor cells having a 12 yr PFS 50% (95% CI 34.8-63.5%), while those with <5% bone marrow involvement had PFS 38.9% (95% CI 23.3-54.2%) and those with 5-20% bone marrow involvement 12.5% (95% CI 0.7-42%) (p = 0.005 log-rank test; data not shown). No effect was observed on OS, however (data not shown, p = 0.21 log-rank test). When analyzed in a two-group model (bone marrow involved or uninvolved), the results for PFS and OS are similar (data not shown).

The effect of bone marrow purging was also analyzed in 70 patients with known detectable bcl-2 / IgH translocations prior to therapy, who had post-purging bone marrow samples analyzed by PCR. Among the 30 patients whose bone marrow infusion was PCR negative, 7 have relapsed. Among the 40 patients whose bone marrow infusion was PCR positive, 25 have relapsed. The median time to relapse was 4.1 years in the PCR positive group, and has not been reached in the PCR negative group, 25% of whom have relapsed at 7.6 years (p=0.0005, log-rank test). PCR status was a significant predictor of 12 year PFS, at 66.7% (95% CI 46.9-80.5) for the PCR negative group as compared to 26.3% (95% CI 13.6-40.9%) for the PCR positive group (p = 0.001 log rank test, Figure 4). No statistically significant effect was observed on OS, which was 76.7% (95% CI 57.2-88.1) for the PCR negative group and 50.7% (95% CI 33.8-65.3) for the PCR positive group (p = 0.08 log rank test).

Figure 4. PCR Detectable Disease After Purging Predicts PFS.

Figure 4

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12 year PFS was 66.7% (95% CI 46.9-80.5; n=30) for those patients whose post-purging bone marrow was negative by PCR, compared to 26.3% (95% CI 13.6-40.9%; n=40) for those with positive PCR (p = 0.001 log-rank test). No effect was observed on OS (76.7% for PCR negative and 50.7% for PCR positive, p = 0.08 log-rank test).

We investigated the interaction between detectable disease in the bone marrow and the likelihood of achieving PCR negativity after purging. Of evaluable patients without histologically detectable bone marrow disease, 21 of 35 were PCR positive (60%). Of those with <5% bone marrow involvement, 14 of 29 were PCR positive (48%). Only 6 patients with 5-20% bone marrow involvement were evaluable and 5 of 6 were PCR positive (83%; p = 0.99 Exact Kruskal-Wallis test).

A multivariate Cox proportional hazards regression analysis was performed to evaluate the impact of pretransplant factors on PFS and OS. Variables that were investigated include age, gender, stage, LDH, hemoglobin, FLIPI, number of nodal sites, type of induction therapy, CR or PR after induction, presence or absence of residual bone marrow disease and PCR status after purging. The only significant predictors of PFS were presence of residual bone marrow disease (HR 2.27 (95% CI 1.3-3.9), p < 0.004), and detectable disease by PCR (HR 4.18 (95% CI 1.99-8.8), p = 0.0002) (Table 3). Those patients without PCR data were included in the multivariate model, and had an intermediate hazard ratio (HR 2.39 (95% CI 1.06-5.4, p < 0.04). No variables were significant predictors of overall survival in multivariate Cox proportional hazards regression analysis.

Table 3. Predictors of PFS and OS.

PFS: Hazard Ratio p OS: Hazard Ratio p
Residual Bone Marrow Disease 2.27 (1.3-3.9) < 0.004 1.67 (0.87-3.2) 0.12
PCR Detectable Disease 4.18 (1.99-8.8) 0.0002 2.08 (0.9-4.6) 0.069
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This Cox proportional hazards model includes all 96 patients, with three categories for post-purging PCR status: positive, negative and missing. The missing category includes 19 patients whose post-purging PCR was not done, and 7 patients in whom a pre-treatment translocation was not detected by PCR.

Discussion

Since the initiation of the studies reported here, new data have accumulated on the role of ASCT in the treatment of follicular NHL, including data from randomized trials that have failed to demonstrate overall survival benefit. The significant incidence of long-term treatment-related toxicity, particularly MDS / AML, has also become clear in numerous reports1-14. The role of ASCT in the treatment of follicular lymphoma has therefore remained controversial. The very long-term follow-up of this study does suggest that a significant subset of follicular lymphoma patients treated with ASCT for consolidation of first remission can experience prolonged disease-free survival. Given the low frequency of late relapses, these data do raise the question of cure with this modality.

However, given the negative randomized trials, rate of second malignancies and availability of novel standard therapies that include rituximab, ASCT cannot be considered an appropriate standard therapy for follicular lymphoma in 1st remission. If ASCT is to be used routinely in patients with follicular lymphoma, patient selection will be critical. Since this study was designed, the Follicular Lymphoma International Prognostic Index (FLIPI) has been proposed to better standardize patient risk and predict prognosis26. Although the patients enrolled on this study were clinically perceived to be high-risk, most are intermediate risk using the FLIPI score, which is likely in part due to missing data and in part due to their young age. Direct comparison to FLIPI results is difficult, but our observed overall survival of 61% at 12 years appears favorable for patients under 60 with intermediate FLIPI scores26, the closest comparison group. Furthermore, ASCT as used in this study appears to overcome the adverse effects of intermediate to high FLIPI, a finding similar to that of the randomized trials of ASCT in follicular lymphoma in first remission11,16,17. These results also correlate well with two reports that maintenance rituximab after induction may overcome the adverse prognosis of high FLIPI27,28. Taken together these data may suggest that consolidation or maintenance therapy in remission, including ASCT, may counteract the adverse impact of a higher risk FLIPI score. Ultimately, improved risk stratification is needed, and will likely be based on molecular features that are emerging from gene expression microarray studies29.

In this study, the only disease- or ABMT-related factors that predicted 12-year PFS were bone marrow involvement at harvest and PCR-detectable disease in the purged bone marrow product. These factors remain predictive at this very long follow-up. Patients with unmistakable histologic bone marrow involvement were at high risk of early relapse but were too few in number to assess the likelihood of achieving PCR negativity after purging. Patients with bone marrow <5% involved histologically were evenly split with respect to PCR status, likely reflecting two groups of patients: some with true disease involvement who responded to purging, and others in whom the <5% lymphoid aggregates may not have represented actual disease. These possibilities may explain why both bone marrow involvement and PCR status remain significant in the multivariate model. Those patients who were PCR positive had a very high relapse rate, possibly due to a direct effect of tumor contamination of the autograft, but alternatively PCR positivity may be a surrogate marker of aggressive treatment resistant disease. Conversely, 28% of patients with PCR positive bone marrow products remain progression-free, with a suggestion of a plateau on the survival curve. This finding may represent residual DNA contamination without viable cells in the purged product, immunologic control of residual disease or good fortune.

Assessing the true benefit of ASCT has been complicated by the high incidence of 2nd malignancies after ASCT. Deaths in remission primarily due to 2nd malignancy may explain our inability to identify factors predictive of overall survival in this study. The rate of long-term secondary malignancies in this ABMT population treated in 1st remission is comparable to our previously reported rates in the ABMT population treated in 2nd or greater remission4,8, suggesting that earlier use of ASCT does not reduce the incidence of 2nd malignancy. In the GOELAMS randomized trial16 using a TBI-containing regimen, a higher EFS survival for the ASCT arm was offset in overall survival by excess second malignancies. At DFCI, second malignancies have declined since chemotherapy-based conditioning replaced the cyclophosphamide-TBI conditioning regimen used in these studies4.

Ultimately the role of ASCT in the current treatment of follicular NHL remains to be defined, particularly given the advent of nonmyeloablative allogeneic stem cell transplantation30-32, as well as the range of novel antibody-based therapies, radioimmunotherapy and small molecule targeted inhibitors increasingly available for the treatment of this disease. Since the initiation of these studies, the addition of rituximab to chemotherapy has significantly improved PFS and OS in follicular lymphoma, with additional benefit likely from maintenance therapy33-35. Nonetheless, rituximab-containing therapies explored to date are not likely to be curative and may therefore need to be considered in combination, perhaps with ASCT. The GITMO group recently reported a 30% improvement in 3 yr EFS for upfront rituxan-containing high-dose therapy in comparison to R-CHOP, raising the possibility that ASCT outcomes may also be improved by these novel therapeutic approaches36. The similarity in ABMT outcomes reported here in DFCI patients treated in 1st remission, and our recently reported outcomes of patients treated in 2nd remission at DFCI and St Bartholomew's Hospital in London (Rohatiner et al, in press), suggest that follicular lymphoma patients treated with ASCT whether in 1st or slightly later remission may achieve similar benefits with similar risk of second malignancy. Given the findings of the randomized CUP trial suggesting benefit of ASCT in 2nd remission, this time point may be the most appropriate for further investigation of the role of ASCT in follicular lymphoma, likely in combination with rituximab.

Acknowledgments

We are indebted to the nurses, medical oncology fellows, housestaff and social workers of the Dana-Farber Cancer Institute and Brigham and Women's Hospital for their excellent care of these patients. We thank the technicians of the Connell-O'Reilly Cell Manipulation Laboratory and the Blood Component Laboratory of the Dana-Farber Cancer Institute for processing of the bone marrow.

This work was supported in part by NIH grants K23 CA115682 to JRB and CA34183 to PM. ASF is supported in part by NIH grant 2P01CA092625.

Footnotes

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