Clinical Outcome following Autologous and Allogeneic Blood and Marrow Transplantation for Relapsed Diffuse Large-Cell Non-Hodgkin s Lymphoma

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1 Biology of Blood and Marrow Transplantation 12: (2006) 2006 American Society for Blood and Marrow Transplantation /06/ $32.00/0 doi: /j.bbmt Clinical Outcome following Autologous and Allogeneic Blood and Marrow Transplantation for Relapsed Diffuse Large-Cell Non-Hodgkin s Lymphoma Ivan Aksentijevich, Richard J. Jones, Richard F. Ambinder, Elizabeth Garrett-Mayer, Ian W. Flinn The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland Correspondence and reprint requests: Ian W. Flinn, MD, PhD, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Division of Hematologic Malignancies, Cancer Research Building, 1650 Orleans Street, Room 388, Baltimore, MD ( iflinn@tnonc.com). Received January 25, 2006; accepted May 31, 2006 ABSTRACT High-dose chemotherapy followed by blood or marrow transplantation (BMT) is generally considered the best salvage option for patients with relapsed diffuse large B-cell non-hodgkin s lymphoma (DLCL). The relative roles for allogeneic and autologous BMT remain controversial. We reviewed the clinical outcome of 183 patients with relapsed DLCL who underwent BMT at Johns Hopkins University in A total of 45 patients received T-cell depleted HLA-matched allogeneic bone marrow (allo-bmt), and 138 patients received autologous marrow or peripheral blood stem cells (auto-bmt). The allo-bmt recipients had a higher proportion of patients with chemoresistant disease (P.004) and had received more chemotherapy before BMT (P.02). The auto-bmt recipients were older (P <.001) and were of more advanced-stage disease (P.01). The 3-year overall survival (OS) was 23.7% (median survival, 129 days) after allo-bmt and 33.1% (median survival, 263 days), after auto-bmt (log-rank, P.17). The 3-year OS for patients with sensitive disease was 51.9% after allo-bmt and 46.2% after auto-bmt (log-rank, P.38). For patients with resistant disease, the 3-year OS was 12.1% after allo-bmt and 19.1% after auto-bmt (log rank, P.08). In multivariate analysis, significant predictors of death were disease sensitivity (hazard rate [HR], 0.3; 95% confidence interval [CI] ; P <.001), age >40 years (HR, 2.42; 95% CI, ; P <.001), and stage at diagnosis (HR, 1.2; 95% CI, ; P.04). The 3-year event-free survival (EFS) for patients with sensitive disease was 52.7% after allo-bmt and 42.0% after auto-bmt (log-rank, P.29). For patients with resistant disease, the 3-year EFS was 6.2% after allo-bmt and 19.4% after auto-bmt (log-rank, P.1). The 3-year probability of relapse for chemosensitive patients was 30% after allo-bmt and 46.1% after auto-bmt (log-rank, P.25). The 3-year relapse rate in patients with resistant disease was 75.0% after allo-bmt and 69.9% after auto-bmt (log-rank, P.58). In multivariate analysis, only disease sensitivity status (HR, 0.4; 95% CI, ; P <.001) and age >40 years (HR, 1.7; 95% CI, ; P.03) appear to have a significant impact on relapse. Transplant-related mortality (TRM) was the cause of death for 51.1% of allo-bmt recipients and 23.9% of auto-bmt recipients (P <.001). Mortality from lymphoma was 26.6% in allo-bmt recipients and 43.5% in auto-bmt recipients (P.02). Auto-BMT and allo-bmt produced similar survival for patients with relapsed DLCL. For patients with sensitive disease, allo-bmt seemed to provide longer survival with less relapse; however, this was achieved at the cost of greater TRM American Society for Blood and Marrow Transplantation KEY WORDS BMT Lymphoma autologous allogeneic diffuse large cell lymphoma INTRODUCTION Although many patients with aggressive non- Hodgkin s lymphoma achieve long-term remission after standard combination chemotherapy, between 30% and 70% of these patients will eventually relapse [1-4]. Several studies, including the Parma study, have shown that for patients with sensitive relapse, high-dose therapy followed by autologous bone marrow transplantation (auto-bmt) provides a better outcome than standard chemotherapeutic regimens [5-7]. Long-term follow-up of auto-bmt recipients has shown that a substantial 965

2 966 I. W. Flinn et al. number eventually die of lymphoma [5,8-10]. Furthermore, for patients with chemotherapy-resistant disease at relapse, auto-bmt has rarely been able to achieve cure or long-term remissions [11,12]. Although auto- BMT is widely used, these limitations have led to an increased interest in the use of allogeneic BMT (allo- BMT). Previous studies have suggested that compared with auto-bmt, allo-bmt is associated with a lower relapse rate. Allo-BMT has the advantage of avoiding the possible reinfusion of tumor cells and is believed to provide a beneficial graft versus lymphoma (GVL) effect [13]. But the use of allo-bmt is limited by the lack of donor availability and the risk of graft-versushost disease (GVHD); accordingly, it is often restricted to younger patients. Although T-cell depletion of the allograft may improve the tolerability of allo-bmt by decreasing the risk of GVHD, it also may increase the risk of relapse by blunting the GVL effect. Overall survival (OS) has generally been similar after auto-bmt and allo-bmt, because a decreased incidence of relapse is offset by increased procedurerelated mortality with allo-bmt [13]. Unfortunately, previous studies have been limited by small sample size and/or heterogeneity of the study populations [9,13-17]. We retrospectively studied only our patients with pathologically confirmed diffuse large-cell non-hodgkin s lymphoma (DLCL) who had received allo-bmt or auto-bmt for the treatment of relapsed disease. Our institutional approach has always been to prioritize patients under age 60 and with HLA-identical siblings to allo-bmt regardless of disease characteristics. We examined the impact of several factors on outcome for 183 patients (45 allo-bmt recipients and 138 auto-bmt recipients). PATIENTS AND METHODS Patients Between 1985 and 2001, a total of 183 consecutive patients underwent BMT for treatment of relapsed B-cell DLCL at Johns Hopkins University. Only patients with a pathological report confirming the diagnosis of DLCL (International Working Formulation histologic subtypes G and F [18]) were included in the study. Except for patients in whom there was evidence of transformation from a low-grade histology or a component of an indolent lymphoma subtype, no patients with DLCL were excluded from the study because of disease characteristics. Preparative Regimen and Transplantation The BMT preparative regimen included various regimens (Table 1), including Bu/Cy (busulfan 1 mg/kg orally every 6 hours for 4 days and cyclophosphamide 50 mg/kg IV daily for 4 days), Cy/TBI (cyclophosphamide 50 mg/kg IV daily for 4 days and 1200 cgy given as 300 cgy per day for 4 days with the lung shielded beginning on the third day of treatment), and Bu/Cy/VP (busulfan as above with etoposide mg/kg IV on the fifth day and cyclophos- Table 1. Patient Characteristics Allo-BMT Auto-BMT P Number of patients Female Median age at BMT (range), years 36 (18-59) 45 (18-67) <.001 <40 years >40 years Median Ann Arbor stage (range) at diagnosis 2 (1-4) 3 (1-4).01 I II III 8 28 IV 9 56 B symptoms Median no. of prior chemotherapy regimens (range) 2.1 (1-4) 1.9 (1-6).02 < > Median time until BMT (range), days 351 ( ) ( ).7 Disease status at BMT Sensitive Resistant 32 (71.1%) 67 (48.5%) Preparative regimen Bu/Cy Cy/TBI Bu/Cy/VP HC purge Sensitive NA 36.2 Resistant NA 46

3 BMT for Diffuse Large Cell Lymphoma 967 phamide 60 mg/kg on the sixth and seventh days). The preparative therapy was determined by the institutional protocol active at the time and was the same for both allo-bmt and auto-bmt recipients. HLA-matched bone marrow cells from a sibling donor were used for allo-bmt. No patient in this series received mobilized peripheral blood stem cells. All allo-bmt patients in this study received a T-cell depleted product. The allo-grafts were T-cell depleted by counterflow centrifugal elutriation, which in previous studies produced a graft with CD3 cells/kg (range, CD3 cells/kg) and CD34 cells/kg (range, CD34 cells/kg) [19,20]. This process was modified in later patients to add back CD34 cells selected from the small cell fraction of cells produced by elutriation that were previously discarded. This change enhanced the engraftment characteristics of the graft and increased the number of CD34 cells to CD34 cells/kg, but it also increased the mean number of T-cells in the allograft to CD3 cells/kg. Autografts were harvested and cryopreserved before the BMT preparative therapy was administered. After 1997, all autografts consisted of mobilized peripheral blood stem cells. Before 1994, 82 autologous marrow grafts were treated with 4-hydroperoxycyclophosphamide (4-HC), as described previously [21]. As part of auto-gvhd induction studies, 79 of the auto-bmt recipients were treated with cyclosporine (CSA) and -interferon (IFN) as described previously [22]. Cell reinfusion occurred 1 day after completing Cy/TBI and 1-2 days after completing Bu/Cy or Bu/ Cy/VP. GVHD prophylaxis consisted of cyclosporine A alone until day 180 post-bmt. Supportive care was provided as described previously [23]. Definition and Clinical Outcome A patient s disease status at BMT was classified according to his or her response to the last chemotherapeutic intervention before the transplantation preparative regimen. A patient was categorized as a sensitive relapse if there was at least a 50% decrease in measurable disease. A patient were considered a resistant relapse if the disease had progressed, relapsed within 6 weeks, or exhibited 50% reduction in size after salvage therapy. The major endpoints were OS, eventfree survival (EFS), relapse-free survival (RFS), and mortality. OS was defined as the time from the day of BMT to the day of death or the day of last follow-up. EFS was defined as the time the day of BMT to disease progression or death from any cause. RFS was defined as the time from the day of BMT to disease progression. Transplant-related mortality (TRM) was defined as death associated with the transplantation procedure and not caused by lymphoma. TRM occurring before the first 100 days posttransplantation was defined as early TRM; that occurring after this period, as late TRM. Relapse death was defined as death occurring as a consequence of relapse at any time after BMT. Those patients in whom the cause of death was unknown were censored from TRM and relapse death analysis. Statistics Event time distributions were estimated using the Kaplan and Meier method and compared according to treatment groups by the log-rank test [24,25]. The prognostic significance of continuously distributed variables (ie, age, disease stage, number of prior chemotherapy regimens) was assessed using the proportional hazards model, with hazard rate (HR) expressed per unit change [26]. To adjust for the effect of several prognostic factors simultaneously, the multivariate proportional hazards model was used. HR 1.0 indicates an increased risk for death or relapse in the presence of the prognostic factor; similarly, HR 1.0 indicates a lower risk of relapse or death with the prognostic factor. The Student t-test was used to compare set variables between both groups. All P values reported are 2-sided. RESULTS Patient Characteristics A total of 45 patients received allo-bmt, and 138 received auto-bmt (Table 1). There was no statistically significant difference between the groups in terms of sex distribution (P.4), interval from diagnosis to BMT (P.7), presence of B symptoms (P.08), or type of preparative regimen (P.5). Allo- BMT recipients were significantly younger (median age, 36 years; range, 18-59) than auto-bmt recipients (median age, 45; range, 18-67) (P.001). The Allo- BMT recipients had lower-stage disease at diagnosis compared with the auto-bmt recipients (median stage II vs median stage III, respectively; P.01). At transplantation, resistant disease status was seen in 32 (71.1%) of the allo-bmt recipients and in only 67 (48.5%) of the auto-bmt recipients (P.004). The allo-bmt group had received more previous chemotherapy (average of 2.1 regimens per patient) compared with the auto-bmt group (average of 1.9 regimens per patient) (P.02). Purging of autografts with 4-HC was evenly distributed among patients with sensitive disease and those with resistant disease (P.2). Overall Survival The median OS was 129 days (range, days) for the allo-bmt group and 263 days (range, days) for the auto-bmt group. The 3-year OS after

4 968 I. W. Flinn et al. Figure 1. OS after BMT for relapse DLCL. allo-bmt and auto-bmt was 23.7% and 33.1%, respectively (log-rank, P.17) (Figure 1). The median follow-up for survivors was 1539 days (range, days) for the allo-bmt recipients and 1882 days (range, days) for the auto-bmt recipients (P.47). Differences in survival were observed when patients were stratified according to transplantation modality and disease sensitivity status at transplantation (log-rank, P.001) (Figure 2). For patients with sensitive disease, the 3-year OS was 51.9% after allo- BMT and 46.2% after auto-bmt (log-rank, P.38). Although the median OS was not reached for the allograft recipients with sensitive disease, it was 475 days (range, days) for the auto-bmt recipients. The median follow-up for survivors with sensitive disease status at BMT was 1539 days (range, days) after allo-bmt and 1998 days (range, days) after auto-bmt (P.29). Poor survival rates were observed for patients with chemotherapy-resistant disease at the time of transplantation. With a median OS of 107 days (range, days) for the allo-bmt recipients and 160 days (range, days) for the auto-bmt recipients only 12.1% of the allo-bmt recipients and 19.1% of the auto-bmt recipients were alive at 3 years (logrank, P.08). Median follow-up time for survivors with resistant disease was 1093 days (range, days) after allo-bmt and 1816 days (range, days) after auto-bmt (P.87). In univariate analysis, only disease sensitivity at transplant (sensitive vs resistant disease) HR, 0.4; 95% confidence interval [CI], ; P.001), age ( 40 years old vs 40 years old: HR, 1.9; 95% CI, ; P.001), and number of prior chemotherapy regimens ( 2 vs 2 treatments: HR, 1.6; 95% CI, ; P.05) were shown to have a statistically significant effect on mortality (Table 2). This was Figure 2. OS after BMT for relapse DLCL according to disease sensitivity status at BMT.

5 BMT for Diffuse Large Cell Lymphoma 969 Table 2. Predictor of Death in Univariate Analysis Predictor HR 95% CI P Allo-BMT* Sensitive disease <.001 Female Month to BMT Age (>40 years) <.001 Stage at diagnosis >2 prior chemotherapy regimens GVHD *Versus auto-bmt. Versus resistant disease. Versus male. Continuous. confirmed in multivariate analysis (Table 3) in which predictors of death were disease status (sensitive vs resistant disease: HR, 0.3; 95% CI, ; P.001), and patient age ( 40 years old vs 40 years old: HR, 2.4; 95% CI, ; P.001). In the multivariate analysis, stage at diagnosis was also found to be a predictor of death (stage as a continuous value: HR, 1.2; 95% CI, ; P.04). The transplantation preparative regimen had no impact on survival (data not shown). Event-Free Survival With a median follow-up time of 95 days (range, days) and 155 days (range, days), the probability of a patient surviving 3 years without death or relapse was 19.1% after allo-bmt and 30.9% after auto-bmt (P.2). Disease sensitivity status at transplantation had a significant impact on the EFS (log rank, P.001) (Figure 3). For patients with sensitive relapse, the probability of 3-year EFS was 52.7% after allo-bmt and 42.0% after auto-bmt (log rank, P.29). The median EFS time was not reached for the allo-bmt recipients and it was 308 days (range, days) for autograft recipients. In patients with resistant disease, with a median follow-up time of 90 (range, days) for allo-bmt recipients and 10 days (range, days) for auto-bmt recipients, the probability of 3-year EFS was 6.2% and 19.4%, respectively (log rank, P.1). Relapse-Free Survival With a median follow-up time of 253 days (range, days) after allo-bmt and 242 days (range, days) after auto-bmt, 55% and 48.1% of patients relapsed in the first 3 years, respectively (P.85). The last patient to relapse after allo-bmt was at 13 months, whereas auto-bmt patients continued to relapse out to 4 years. For patients with sensitive disease status at BMT, the 3-year probability of relapse was 30.0% after allo- BMT and 46.1% after auto-bmt (log-rank, P.25). The median RFS time was not reached by the allo- BMT recipients; it was 1250 days (range, days) for the auto-bmt recipients. For patients with resistant disease status, the 3-year probability of relapsing was 75.0% for allo-bmt recipients and 69.9% for auto-bmt recipients, and the median RFS time was 95 days (range, days) and 123 days (range, days), respectively (log rank, P.58) (Figure 4). In univariate analysis (Table 4), statistically significant predictors of relapse included disease sensitivity to chemotherapy (sensitive vs resistant disease: HR, 0.4; 95% CI, ; P.001) and number of prior chemotherapy regimens ( 2 vs 2: HR, 1.9; 95% CI, ; P.05). In multivariate analysis (Table 5), only disease status (sensitive vs resistant disease: HR, 0.4; 95% CI, ; P.001) and age 40 years (HR, 1.7; 95% CI, ; P.03) were found to be significant predictors of relapse. Although GVHD did appear to increase the risk of relapse in univariate analysis, this did not appear to be the case in multivariate analysis. Transplant-Related Mortality There was a statistically significant difference in TRM between the allo-bmt recipients (51.1%) and the auto-bmt recipients (23.9%) (P.001) (Table 6). Patients with resistant disease at transplantation were more likely to die from transplant-related complications if they received an allo-bmt (62.5%) than if they received an auto-bmt (31.3%) (P.02); however, there was no statistical difference in mortality for patients with sensitive relapse (P.3). TRM in the first 100 days post-bmt was 33.3% for the allo-bmt recipients and 17.4% for the auto-bmt recipients (P.03). After 100 days, TRM remained significantly higher for the allo-bmt recipients (17.8% vs 6.5% for auto-bmt; P.001). Multiorgan failure and infections were the most frequent causes of death in the early posttransplantation period for both groups of patients. GVHD was a significant contributing factor for death in the allo-bmt group (5 patients with acute GVHD and 11 with chronic GVHD in the allo-bmt recipients vs 1 patient with acute and none with chronic GVHD in the autograft recipients). More patients died of relapse in the auto-bmt group (43.5% for the auto-bmt patients vs 26.6% for the allo-bmt patients; P.02). Table 3. Predictor of Death in Multivariate Analysis Predictor HR 95% CI P Sensitive disease <.001 Age (>40 years) <.001 Allo-BMT Stage at diagnosis (continuous)

6 970 I. W. Flinn et al. Figure 3. Event-free survival after BMT for relapse DLCL according to disease sensitivity status at BMT. Graft-Versus-Host Disease In the allo-bmt group, acute GVHD was diagnosed in 17 patients and chronic GVHD in 11 patients. The remaining patients had no evidence of GVHD. In the presence of GVHD, after allo-bmt for sensitive relapse, the median OS was 1036 days (range, days); median OS was not reached for the whole group with sensitive disease. All of the patients with chronic GVHD eventually died of GVHD or other causes. For the patients with resistant disease, GVHD after allo-bmt was associated with a median OS of 111 days (range, days); median OS was 107 days (range, ) days for the whole group with resistant disease. Autologous GVHD had no statistically significant impact on survival or death (data not shown). DISCUSSION Although the efficacy of BMT for patients with DLCL is well established, the relative utility of using autografts versus allografts is less clear. Previous studies of patients with lymphomas have shown that both allo-bmt and auto-bmt provide comparable OS. Independent prognostic factors have included performance status, stage, international prognostic score, sex, age, lactate dehydrogenase level, disease chemotherapy sensitivity status at the time of transplantation, and whether pretransplantation or posttransplantation radiation therapy had been administered [10,12,27-29]. These conclusions have often been drawn from the results of small retrospective studies of patients with often various types of diseases [9,13- Figure 4. Relapse-free survival after BMT for relapse DLCL according to disease sensitivity status at BMT.

7 BMT for Diffuse Large Cell Lymphoma 971 Table 4. Predictor of Relapse in Univariate Analysis Predictor HR 95% CI P Allo-BMT* Sensitive disease <.001 Female Month to BMT Age (>40 years) Stage at diagnosis >2 prior chemotherapy regimens GVHD *Versus auto-bmt. Versus resistant disease. Versus male. Continuous. 17]. The present study represents an analysis of a single-institution set of patients who underwent allo- BMT or auto-bmt for relapsed DLCL. Overall, there were no statistically significant differences in OS and EFS between the allo-bmt and auto-bmt recipients. Although there is a relatively increased TRM after allo-bmt, a higher relapse rate after auto-bmt probably accounts for the lack of difference in OS between these 2 groups. These findings are in agreement with previous studies [14-16]. However, TRM in autograft recipients is higher than has been reported in some other series [12,15-17].It is unclear what can account for this difference, but it may be secondary to posttransplantation adjuvant therapy, such as auto-gvhd induction or patient selection. For patients with sensitive disease, there was a trend for improved survival at 3-years after allo-bmt (51.9%) in comparison to auto-bmt (46.2%). The 3-year EFS for these patients was 52.7% after allo- BMT and 42.0% after auto-bmt. These results support the notion that allo-bmt is a reasonable option for patients at increased risk of relapse after BMT. It is clear, however, that even allo-bmt is insufficient for patients with resistant disease at the time of BMT, in whom very poor outcomes were seen regardless of what type of graft was used (3-year OS 12.1% after allo-bmt and 19.1% after auto-bmt). Allo-BMT was particularly ineffective for these patients, with only 6.2% having a 3-year EFS (vs 3-year EFS of 19.4% after auto-bmt). The poor outcome in patients with chemotherapy-resistant disease regardless of the graft s origin seems to be the result of both a high TRM and a high relapse rate. These findings are Table 5. Predictor of Relapse in Multivariate Analysis Predictor HR 95% CI P Sensitive disease <.001 Age (>40 years) Allo-BMT Stage at diagnosis (continuous) Table 6. Mortality Allo-BMT (n 45) Auto-BMT (n 138) P Total TRM 23 (51.1%) 33 (23.9%) <.001 Sensitive disease 3 (23.0%) 12 (16.9%).3 Resistant disease 20 (62.5%) 21 (31.3%).02 <100 days TRM 15 (33.3%) 24 (17.4%).03 Multiorgan failure 9 16 Infection/sepsis 5 12 Veno-oclusive disease (VOD) 4 3 Myocardial infarction 1 2 GVHD 5 1 Hemmorhage 1 1 Lymphoma 1 4 >100 days TRM 8 (17.8%) 9 (6.5%) <.001 Multiorgan failure 3 7 Infection/sepsis 2 5 Hemmorhage 3 0 Cerebrovascular accident 1 0 GVHD 11 0 Lymphoma 4 7 Relapse death 12 (26.6%) 60 (43.5%).02 Sensitive disease Resistant disease Unknown cause of death 0 7 in agreement with previously published reports [14-16]. The toxicity associated with BMT in these patients highlights the need for new approaches in this patient population. In patients with sensitive disease, the relapse rate for allo-bmt recipients was lower than that in auto- BMT recipients, indicating a possible GVL effect. It is noteworthy that all patients who developed chronic GVHD ultimately died, which likely attenuates the benefit from GVL. As noted earlier, the GVL effect alone is insufficient to improve survival in patients with resistant disease. All of the allo-bmt patients in this study received a T-cell depleted graft. This methodology results in a relative depletion of T cells, although a substantial number of T cells are still included in the allo-graft. This approach may preserve the GVL effect, albeit at in increased risk of GVHD than for a fully T-cell depleted graft. Approaches that separate the GVL effect from GVHD, such as vaccines, have significant potential for these patients. Confirming the results of other studies, we found no difference overall in OS and EFS between allo- BMT and auto-bmt recipients. Response to conventional chemotherapy pretransplantation appears to be highly predictive of outcome for both allo-bmt and auto-bmt recipients. Whether it can be concluded that allo-bmt is superior to auto-bmt for chemosensitive disease remains questionable. The trend for higher and later relapses in patients with sensitive relapse receiving auto-bmt compared to those receiving allo-bmt suggests that allo-bmt should be considered for selected patients with relapsed DLCL. For patients with chemorefractory disease for whom

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