One hundred and ten adult patients with non-Hodgkin's lymphoma (NHL) received an autologous hematopoietic cell transplant (ABMT) from 1988 to 1993. All received a uniform preparative regimen of cyclophosphamide, BCNU and etoposide (CBV). Twenty-one percent had low grade histologies, 54% intermediate grade, and 25% high grade. Median follow-up of 48 survivors is 100 months. Kaplan–Meier 10 year overall survival and relapse-free survival for the entire group is 42% and 32%, respectively. Fifty patients were in complete remission 2 years post transplant. With additional follow-up, patients with high grade malignancies are cured, while patients with intermediate or low grade histologies were at continued risk of relapse up to 5 years post transplant. Of 39 patients in complete remission 5 years post transplant, none have relapsed with additional extended follow-up. We conclude that patients with NHL treated with ABMT, if in CR 5 years post transplant, are at very low risk of relapse with extended follow-up, suggesting the possibility of cure for all histologies, including those with low grade NHL.
ABMT is the treatment of choice for patients with relapsed intermediate and high grade NHL.1,2,3,4,5,6,7 Promising data exist concerning ABMT for selected patients with follicular non-Hodgkin's lymphoma.8,9,10,11,12,13,14 However, relatively short follow-up of ABMT for low grade histologies and a lack of published prospective randomized trials have led to questions regarding the efficacy of ABMT for such patients. Given the indolent nature of follicular lymphomas, very long-term follow-up is needed to adequately assess the efficacy of dose-intensive therapy.
In 1997 we originally reported on 110 adult patients receiving a uniform chemotherapy only preparative regimen (cyclophosphamide, BCNU and etoposide (CBV)) receiving ABMT from 1988 to 1993 and demonstrated that if in complete remission 2 years post transplant, patients with high grade NHL were cured.15 This is a follow-up report of that cohort of patients, with a median follow-up of 48 survivors of 100 months.
Patients and methods
One hundred and ten adult patients with NHL underwent ABMT at The Cleveland Clinic Foundation from 1988 to 1993. Every patient receiving ABMT with a diagnosis of NHL from 1998 to 1993 is included in this report. All patients underwent pathologic review and histologic classification was assigned according to the Working Formulation.16
The age-adjusted International Prognostic Index (IPI)17 was calculated. All patients had either relapsed after initial induction chemotherapy or failed to achieve a complete remission with initial induction chemotherapy. ‘Sensitive’ disease was defined as regression of tumor to salvage chemotherapy with reduction of tumor size by at least 50%. Eligibility criteria included a cardiac ejection fraction >50%, normal serum bilirubin, and either a normal serum creatinine or a creatinine clearance of >60 ml/min. All patients were treated on protocols reviewed and approved by The Cleveland Clinic Foundation Institutional Review Board, with informed consent obtained from all patients. Histologic characteristics of the patients are shown in Table 1, and clinical parameters are shown in Table 2. The detailed clinical data for the 23 patients with follicular NHL is shown in Table 3.
All patients received CBV (etoposide (VP-16) 2400 mg/m2 continuous intravenous infusion over 36 h on day −9 and day −8; cyclophosphamide 1800 mg/m2 daily intravenously over 2 h × 4 days on days −7, −6, −5 and −4; BCNU 600 mg/m2 over 2 h on day −3; bone marrow and/or peripheral blood progenitor cell (PBPC) infusion on day 0).
Bone marrow and PBPC processing and supportive care
Before 1991, patients received autologous bone marrow alone without the infusion of post-transplant cytokines. From 1991 to 1993, patients received G-CSF (5 μg/kg/day for 7 days, with PBPC collection beginning on the 5th day of G-CSF administration) primed PBPCs with or without autologous bone marrow.
Additionally, patients received G-CSF 16 μg/kg/day starting on day +1 after transplantation until neutrophil engraftment (10 × 109/l on 2 consecutive days). Forty-three percent of patients received autologous bone marrow alone; 36% received autologous marrow with PBPCs; 21% received PBPCs alone.
Patients were hospitalized for the delivery of high-dose chemotherapy and were discharged after adequate hematologic recovery occurred. Platelet or RBC transfusions were administrated when the platelet count was <15 000/×109/l or hemoglobin was <8.5 g/dl, respectively. All blood products were irradiated before infusion. Broad-spectrum antibiotics were administered for febrile neutropenic episodes.
Descriptive statistics are summarized for categorical variables as frequencies and percentages, and for continuous variables as either the mean and standard deviation or the median and range, as appropriate. Survival (OS) is defined as the time from BMT to death or final follow-up; relapse-free survival (RFS) is defined as the time from transplantation to relapse of the original histology, death, or final follow-up.
OS and RFS estimates and curves were calculated using the Kaplan–Meier method, and compared among subgroups using the log-rank test.
Cox proportional hazards analysis was used to identify multivariate correlates of both OS and RFS; a stepwise selection procedure was used which allowed variables to enter the model if P < 0.10 but required P < 0.05 for the variables to remain in the final model.
Thirteen variables were considered: age at transplant, gender, number of courses of prior chemotherapy (0–1, 2 or more), prior radiation therapy (yes, no), bulk of largest mass (<10 cm, >10 cm), bone marrow involvement at diagnosis (yes, no), response to salvage chemotherapy (sensitive, resistant), histology (low grade, intermediate grade, high grade), Karnofsky performance status, stage (II, III, IV), LDH at the time of transplant (normal, elevated), type of procedure (bone marrow only, stem cells only, both), and age-adjusted international index risk factors (0–1, 2–3). Estimated survival was generated from the resulting Cox model for two extreme patient profiles: patients with all of the risk factors and patients with none of the risk factors. All analyses were conducted using SAS software. All statistical tests were two-sided; P < 0.05 was used to indicate statistical significance.
Overall survival for the entire cohort of patients at 5 and 10 years post transplant is 48% and 42%, respectively. RFS 5 and 10 years post transplant is 36% and 33%, respectively. Five year OS for low grade, intermediate grade, and high grade histologies were 65%, 44% and 43%, respectively (P = 0.07, log-rank test), as shown in Figure 1. Five year RFS for low grade, intermediate grade, and high grade histologies were 43%, 31% and 43% (P = 0.32, log-rank test), as shown in Figure 2.
A multivariate analysis revealed that an elevated LDH at the time of transplant was the most significant correlate of decreased OS and RFS, as shown in Table 4. RFS by LDH is shown in Figure 3. Other variables correlating with decreased OS and RFS were age at transplant, two or more courses of prior chemotherapy, and resistance to salvage chemotherapy.
To illustrate the importance of these variables, Figure 4 shows projected RFS of a best case profile (age <45, <2 prior chemotherapy courses, sensitive disease, and normal LDH) vs a worst case profile (age greater than 45, >2 prior chemotherapy courses, chemo-resistant, and elevated LDH).
Fifty-four patients have relapsed. The time to relapse varied by histologic subtypes: 12 patients with low grade histologies relapsed at a mean of 22 months post transplant; 31 intermediate grade histology patients at a mean of 10 months post transplant; and 11 high grade histology patients at a mean of 3 months post transplant (low vs high, P = 0.002; intermediate vs high; P = 0.001, low vs intermediate, P = 0.039; log-rank test). Survival after relapse varied by histologic subtype as well; patients with low grade histologies survived a median of 25 months after relapse, compared with 7 months and 2 months for intermediate and high grade histologies, respectively (P < 0.001; log-rank test). Survival following relapse is shown in Figure 5.
The 2 year evaluation point
Fifty patients were alive and disease-free 2 years post transplant. With additional follow-up, 100% of patients (12 of 12) with high grade malignancies remained free from relapse; 18 of 22 (82%) with intermediate grade histologies remained free from relapse; and 10 of 16 (62%) with low grade histologies were free from relapse. This is shown graphically in Figure 6.
The 5 year evaluation point
Thirty-nine patients were alive and in complete remission 5 years after ABMT: nine patients with low grade histology, 18 with intermediate grade, and 12 with high grade. With additional 5 year follow-up, 39 of 39 are free from relapse of their original disease.
Ten patients died within 40 days of the transplant of regimen-related causes, five of 47 patients (11%) receiving autologous bone marrow alone, and five of 63 (8%) receiving PBPC ± autologous marrow. No patient has developed secondary leukemia or myelodysplastic syndrome; one patient developed prostate cancer 10 years post transplant and is currently alive, and one patient developed acute lymphoblastic leukemia 7 months after transplant.
To the best of our knowledge, this study represents the longest reported follow-up of patients undergoing autologous transplantation for NHL. Many of our findings confirm data that have been previously described, such as an elevated LDH as the most powerful negative prognostic factor in outcome following ABMT;3,15 sensitivity to salvage chemotherapy is an important prognostic variable,5,6 and patients receiving fewer courses of chemotherapy have a better prognosis than do those who receive multiple courses of salvage chemotherapy prior to ABMT.2 We have also confirmed our observation that patients with high grade lymphomas, if in CR 2 years post transplant, are cured. Our long-term follow-up, however, sheds additional light on ABMT results for follicular lymphomas, and the potential importance of the 5 year evaluation point post transplant.
Follicular lymphomas are biologically more indolent than both intermediate and high grade lymphomas. Indeed, in this study, of those patients destined to relapse after ABMT, the median time to relapse is strikingly different depending on underlying NHL histology, with patients with high grade lymphomas relapsing an average of 3 months post transplant, patients with intermediate grade NHL relapsing 10 months post transplant, and patients with follicular lymphomas relapsing 22 months post transplant. This biologic difference of histologic subtypes makes very long-term follow-up mandatory to adequately address the potential efficacy of ABMT or any therapy for follicular lymphomas.
The natural history of follicular lymphoma is variable. It is possible to identify a subset of poor prognosis patients with follicular lymphoma. An important ECOG study of patients with low grade NHL, relapsing after initial chemotherapeutic treatment, found that those patients achieving a CR or a partial response (PR) that lasted less than 1 year had a 5 year OS of only 33%, as compared with patients who had a CR that lasted longer than 1 year achieving a 5 year OS of 55%.18 Median survival of this data set for patients younger than 60 years old revealed that those achieving a CR lasting more than 1 year had a median survival of 5.9 years, a PR for more than 1 year of 4.2 years; and a CR or PR of less than 1 year of 2.4 years (P < 0.0001). Thus, patients who achieve a short-term clinical response with initial therapy of less than 1 year, do not have a favorable prognosis.
Bastion et al19 have reported the risk of histologic transformation in follicular lymphoma, and its correlation with a grim prognosis. Two hundred and twenty patients were studied, and histologic transformation occurred in 37% of patients, with a median survival after transformation of only 7 months. Patients achieving a CR to initial therapy were far less likely to transform into a higher grade histology than were patients with a PR. The probability of transformation for patients with an initial CR was 24%, compared to 51% for those who achieved PR (P < 0.0001). Thus, those patients not achieving a CR with initial therapy have an inherently worse prognosis than do those who achieve a CR, and they are more likely to suffer from histologic transformation to a more aggressive histology.
Finally, Gallagher et al20 have documented that response to therapy in patients with follicular lymphoma decreases with each successive course of chemotherapy, both in the percentage of patients responding, as well as duration of response.
Our results show that patients with both low grade and intermediate grade histologies of NHL, if in CR 2 years post transplant, were still at risk for subsequent relapse. However, if in CR 5 years post transplant, no relapses have occurred to date with an additional follow-up of 5 years and beyond. Follicular NHL patients in our study were not selected, nor did they represent a particularly favorable group of patients based on the data cited above. Seventy-four percent of follicular NHL patients had two or more courses of prior chemotherapy, and most (87%) were not in complete remission at the time of transplant. Thus, it is unlikely that the favorable results with follicular lymphomas in this study represent a population that was inherently favorable and destined to have a better clinical outcome. The fact that, if in CR 5 years post transplant, no relapses have occurred with subsequent follow-up raises the question of the curative potential of autologous transplantation for all histologies, including follicular histologies. Many authors quote that follicular lymphomas are incurable. However, it has long been known that radiation therapy is potentially curative for stage I and stage II follicular lymphoma.21,22,23,24 Our long-term follow-up, demonstrating that some patients with follicular NHL are alive and disease-free more than 10 years after ABMT, coupled with the fact that no relapses have occurred since the 5 year evaluation point, raised the possibility that there is a plateau in our survival curve, suggesting the possibility of cure for poor prognosis follicular lymphoma patients treated with ABMT.
Most studies concerning ABMT for follicular lymphoma are limited by short follow-up. Recently, however, three studies on this topic have been published with more mature follow-up. Apostolidis et al25 reported a study of 99 patients with follicular lymphoma receiving ABMT as consolidation of second or subsequent remission. Bone marrow was treated in vitro with anti-B cell antibodies and complement. Median follow-up was 5.5 years. Kaplan–Meier estimates the freedom from recurrence at 5 years was 63%, and the authors concluded that prolonged freedom from relapse could be achieved in follicular lymphoma treated with ABMT. A comparison with historical control patients in second or subsequent remission treated with conventional therapy showed a survival advantage for those receiving a transplant (P < 0.001). Freedman et al26 reported 153 patients undergoing ABMT using purged autologous marrow in patients with relapsed follicular lymphoma that were sensitive to salvage chemotherapy. Estimated 8 year disease-free survival was 42%, and few relapses were seen after 5 years. The authors concluded that myeloablative therapy in ABMT might prolong survival for patients with relapsed follicular lymphoma. Horning et al27 published a study of 37 patients with follicular lymphoma in a ‘minimal disease state’ after conventional chemotherapy who subsequently underwent ABMT with purged marrow. Median follow-up was 6.5 years, and estimated 10 year survival was 86%. Survival and freedom from progression outcomes appeared to plateau 5 years post transplant. Two patients suffered late acute leukemia deaths. These data compared favorably to a historical control reference population of patients 50 years or younger with follicular lymphoma.
Our study, coupled with these previous observations, suggests that patients with follicular lymphoma undergoing ABMT are at continued risk of relapse for 5 years post transplant. Thereafter, the risk of relapse is quite rare, and a subset of patients have extended and prolonged survival.
Somewhat surprisingly, we did not have any patient experience secondary myelodysplastic syndrome. One patient developed acute lymphoblastic leukemia less than 1 year following transplant. Others have described rates of secondary myelodysplastic syndrome or secondary leukemia of 8 to 12%.25,26,28 These higher rates have been described in series using total body irradiation as part of the transplant preparative regimen. The EBMT has described radiation therapy as part of the preparative regimen as a risk factor for development of secondary leukemia and myelodysplasia after autografting.29 A recent editorial suggested that radiation therapy as part of the preparative regimen is ‘probably better avoided’ due to increased risk of secondary myelodysplasia.30 Whether our low incidence of secondary myelodysplastic syndrome is a result of a chemotherapy only preparative regimen is possible, but also conjectural.
Non-surgical cures of cancer are uncommon. The curative potential of ABMT in relapsed intermediate and high grade NHL represents a significant therapeutic advance. While any retrospective study, including ours, is limited by potential selection bias, the appearance of a plateau in the survival curve for all histologies 5 years post transplant is noteworthy. In the absence of data from prospective randomized trials of ABMT for follicular lymphoma, it is possible to identify patients with follicular lymphoma who may have a poor outcome, and such patients are reasonable candidates to continue the study of ABMT in follicular lymphoma. Additional strategies to eliminate late toxicities such as secondary myelodysplasia and leukemia, and to further reduce the relapse rate, potentially by immunological therapy, may further enhance the potential benefit of ABMT for all histologies of NHL.
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Bolwell, B., Kalaycio, M., Sobecks, R. et al. Autologous hematopoietic cell transplantation for non-Hodgkin's lymphoma: 100 month follow-up. Bone Marrow Transplant 29, 673–679 (2002) doi:10.1038/sj.bmt.1703525
- autologous bone marrow transplant
- non-Hodgkin's lymphoma
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