Efficacy of Reduced-Intensity Allogeneic Stem Cell Transplantation in Chemotherapy-Refractory Non-Hodgkin Lymphoma

Biology of Blood and Marrow Transplantation 11:593-599 (2005) 䊚 2005 American Society for Blood and Marrow Transplantation 1083-8791/05/1108-0004$30.00/0 doi:10.1016/j.bbmt.2005.04.005

Efficacy of Reduced-Intensity Allogeneic Stem Cell Transplantation in Chemotherapy-Refractory Non-Hodgkin Lymphoma Robert M. Dean,1 Daniel H. Fowler,1 Wyndham H. Wilson,1 Jeanne Odom,1 Seth M. Steinberg,2 Catherine Chow,3 Claude Kasten-Sportes,1 Ronald E. Gress,1 Michael R. Bishop1 1 Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland; 2Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland; 3Diagnostic Radiology Department, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, Maryland

Correspondence and reprint requests: Michael R. Bishop, MD, Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, CRC 3-3330, MSC 1203, Bethesda, MD 20892-1203 (e-mail: [email protected]). Received January 26, 2005; accepted April 25, 2005

ABSTRACT Chemotherapy sensitivity has been identified as an important prognostic factor in reduced-intensity allogeneic stem cell transplantation (RIST) for non-Hodgkin lymphoma (NHL). However, the effect of uniform salvage chemotherapy before RIST has not been studied prospectively. We examined whether the response to prospectively administered uniform salvage therapy (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and fludarabine) influenced the subsequent outcome of RIST in 28 patients with relapsed or refractory NHL. After RIST, overall survival (OS) at 36 months is 49%, whereas event-free survival (EFS) is 32%. In Cox model analyses, the response to chemotherapy was the best predictor of OS (P ⴝ .0006) and EFS (P ⴝ .0006) after RIST. Differentiating stable disease from progressive disease after salvage chemotherapy strengthened the association with survival. Among chemotherapy-sensitive patients, the median OS and EFS have not been reached. In patients with stable disease, OS and EFS at 24 months are 50% and 25%, respectively. In contrast, only 1 patient with progressive disease during salvage therapy survived longer than 12 months. These prospective data confirm the favorable prognosis for chemotherapy-sensitive NHL after RIST and suggest that chemotherapy resistance is not an absolute contraindication to RIST for NHL patients with stable disease during salvage therapy. © 2005 American Society for Blood and Marrow Transplantation

KEY WORDS Reduced-intensity allogeneic stem cell transplantation apy sensitivity ● Prognosis

INTRODUCTION Curative options are limited for patients with refractory B-cell non-Hodgkin lymphomas (NHL). Conventional-dose chemotherapy seldom achieves durable remissions for indolent or chemotherapy-resistant aggressive NHL [1-3], and autologous hematopoietic stem cell transplantation (HSCT) often fails to improve survival in these settings [4,5]. For such patients, allogeneic HSCT has potential efficacy that is attributed at least in part to immune-mediated graft-versus-lymphoma (GVL) effects [6,7]. However,

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Non-Hodgkin lymphoma

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Chemother-

toxicity and disease progression are significant causes of treatment failure after myeloablative allogeneic HSCT for NHL, and retrospective analyses have identified the response to salvage chemotherapy as an important predictor of both disease-free and overall survival (OS) in this setting [6,8,9]. Reduced-intensity conditioning regimens decrease the acute toxicities associated with transplantation conditioning but increase the reliance on GVL effects for the curative potential of allogeneic HSCT [10,11]. It is therefore unsurprising that recent analyses have found reduced-intensity stem cell transplan593

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tation (RIST), like myeloablative allografting, to be of limited benefit for chemotherapy-resistant lymphoma [12]. However, these studies determined chemosensitivity on the basis of varied salvage regimens administered at different centers before RIST and did not distinguish stable disease from progression when identifying patients as refractory to salvage chemotherapy. Such distinctions may be particularly relevant in the context of reduced-intensity conditioning. These observations and the relative paucity of published data on RIST for NHL make it difficult to fully interpret the role of chemosensitivity in patient selection for this procedure. To help address these issues, we prospectively administered dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and fludarabine (EPOCH-F) as uniform salvage chemotherapy for refractory or relapsed NHL before RIST. On the basis of the demonstrated efficacy of EPOCH salvage therapy in relapsed NHL [13], the EPOCH-F regimen was developed both to control disease and to provide immune suppression before RIST in an effort to augment GVL activity through rapid and complete donor engraftment without myeloablation [14,15]. We hypothesized that this strategy would partially overcome the adverse effect of chemotherapy resistance on long-term outcome after RIST. To evaluate this in a preliminary manner, we studied the association between response to EPOCH-F and survival after RIST, specifically differentiating chemotherapy-resistant patients with stable disease from those with progressive disease (PD).

PATIENTS AND METHODS Eligibility Criteria

Eligibility required NHL that was primary refractory or had progressed after second-line therapy or autologous HSCT. Diagnoses were confirmed by the National Cancer Institute Laboratory of Pathology by using the revised European-American lymphoma classification [16] or the World Health Organization classification [17]. Additional criteria included an age of 16 to 75 years, a Karnofsky performance status ⬎70%, and adequate hepatic, renal, pulmonary, and cardiac function. All patients had an acceptable 6/6 (n ⫽ 28) or 5/6 (n ⫽ 1) HLA-matched sibling donor. The protocol, CC 99-C-0143, was approved by the National Cancer Institute Institutional Review Board [18]. Each patient and donor provided written informed consent before study entry. Salvage Chemotherapy

The salvage regimen and RIST procedure have previously been described [19]. Before allogeneic HSCT, all patients received salvage chemotherapy 594

with EPOCH-F, which consisted of a continuous intravenous (IV) infusion of etoposide (50 mg/m2/d), doxorubicin (10 mg/m2/d), and vincristine (0.5 mg/ m2/d) on days 1 to 3; a cyclophosphamide (600 mg/ m2) IV bolus infusion on day 4; prednisone (60 mg/ m2/d) orally on days 1 to 4; and a fludarabine (25 mg/m2/d) IV bolus infusion on days 1 to 3. Filgrastim (10 ␮g/kg/d) was given subcutaneously from day 5 of each cycle until patients attained an absolute neutrophil count of ⬎1000 cells per microliter for 2 consecutive days. EPOCH-F was administered every 21 days to achieve a target peripheral blood CD4 level ⬍50 cells per microliter before the initiation of transplantation conditioning. Every patient received at least 1 cycle of EPOCH-F. Patients with PD or prohibitive toxicity after 1 or 2 cycles proceeded directly to RIST regardless of the CD4 count. Otherwise, patients proceeded to RIST after 3 cycles of EPOCH-F, regardless of the CD4 count or disease response. Peripheral Blood Stem Cell Mobilization, Collection, and Transplantation

Hematopoietic progenitor cells were mobilized with filgrastim at 10 ␮g/kg/d, and apheresis was performed on days 5 and 6 of filgrastim administration. The reduced-intensity conditioning regimen consisted of fludarabine (30 mg/m2/d) and cyclophosphamide (1200 mg/m2/d) administered concomitantly IV on days ⫺6, ⫺5, ⫺4, and ⫺3 before transplantation. Mesna (1200 mg/m2/d) was given on days ⫺6 through ⫺3 by continuous IV infusion. Cryopreserved cells were thawed and infused on day 0. Filgrastim was administered daily at 10 ␮g/kg from the day of allogeneic HSCT until the absolute neutrophil count was ⬎5000 cells per microliter for 3 consecutive days. Patients received cyclosporine beginning on day ⫺1 before transplantation and continuing until 100 days after allogeneic HSCT and then were tapered to discontinuation by day ⫹180 in the absence of graftversus-host disease (GVHD). Throughout induction chemotherapy and posttransplantation immunosuppression, infection prophylaxis consisted of trimethoprim/sulfamethoxazole, acyclovir, and fluconazole. To avoid potential interactions with vincristine, fluconazole was stopped during EPOCH-F administration. Response Evaluation

All patients underwent computerized axial tomography (CT) of the chest, abdomen, and pelvis and a bone marrow examination immediately before study entry. CT was repeated after each cycle of EPOCH-F; at posttransplantation day ⫹28 and day ⫹100, 6 months, 9 months, and 12 months; and annually thereafter. Bone marrow examination was repeated in all patients at day ⫹28 and day ⫹100. If bone marrow

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involvement was present at baseline, repeat examinations were also performed after the last cycle of EPOCH-F and at 6 and 12 months after RIST. CT and bone marrow studies were obtained at other times if clinically warranted. The following definitions were used for responses to induction chemotherapy during the conduct of the trial. Complete response (CR) was defined according to standard criteria[20] as regression of all lymph nodes to a normal size (ⱕ1.5 cm), resolution of soft tissue masses or palpable organomegaly due to lymphoma, and clearance of bone marrow infiltration (if previously present). Also consistent with standard definitions, partial response (PR) required a minimum 50% reduction in the sum of the products of the diameter of reference lesions without enlargement of other lesions, including the liver and spleen. PD was defined by the appearance of any new lesion or any increase in the sum of the products of the diameter of an existing lesion. Patients who did not meet criteria for PD, PR, or CR by these definitions were categorized as having stable disease. Statistical Analysis

Survival and time to progression were calculated from the date of transplantation until death, progression, or last follow-up, as appropriate, through January 2004. Event-free survival (EFS) considered cases of disease progression or death without progression as treatment failures. Only patients who underwent RIST were evaluable for survival, EFS, or acute GVHD. Patients who survived for less than 100 days after transplantation were not evaluable for chronic GVHD. The probability of survival or EFS was calculated by using the Kaplan-Meier method [21], and the significance of the difference between pairs of Kaplan-Meier curves was calculated with the MantelHaenszel procedure [22]. The Cox proportional hazards model was used to identify which factors were jointly significant in the association with survival or EFS [23]. The factors considered for inclusion in univariate and Cox analyses were age, stage, number of extranodal sites, serum lactate dehydrogenase, International Prognostic Index score at study entry, histologic aggressiveness, duration of disease, previous regimens (number and specific agents), previous autologous HSCT, response to the most recent therapy before enrollment, and response to EPOCH-F. For comparison, the response to EPOCH-F was analyzed by using both the trial definitions and standard criteria. In the univariate analyses, results for the International Prognostic Index score were evaluated at each possible dichotomy and pooled into groups after initial examination of results. Because the International Prognostic Index score was reduced to 2 groups with

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Table 1. Patient Characteristics Variable

Data

Median age at study entry, y (range) Sex Male Female Histology (n) Follicular lymphoma (large-cell transformation, n ⴝ 4) Diffuse large B-cell lymphoma Mantle cell lymphoma Median time from diagnosis to study entry, mo (range) Prior treatment Median number of prior regimens (range) Prior anthracycline-containing regimen Prior fludarabine Prior rituximab Prior autologous HSCT Disease status at study entry Sensitive Resistant Untested Disease stage at study entry Remission I II III IV CNS involvement Bone marrow involvement Other extranodal involvement

48 (31–69) 16 (55%) 13 (45%)

12 13 4 20 (5–149) 3 (1–5) 27 (93%) 4 (14%) 18 (62%) 6(21%) 16 (55%) 11 (38%) 2 (7%) 1 1 4 6 17 5 12 20

(3%) (3%) (14%) (21%) (59%) (17%) (41%) (69%)

HSCT indicates hematopoietic stem cell transplantation; CNS, central nervous system.

different outcomes in the subsequent analysis and because 3 such potential formations exist, the adjusted P value is reported as the unadjusted P value multiplied by 3. Factors associated with an unadjusted P value ⬍.20 were subsequently evaluated in a Cox model. The resulting model parameters were converted to relative risks with associated 95% confidence intervals (CIs) [24]. The relationship between the response to the most recent prior therapy and the response to EPOCH-F on this study (CR/PR versus stable disease versus PD) was evaluated by using an exact CochranArmitage test [25]. All reported P values are 2 tailed. RESULTS Patient Characteristics

Twenty-nine patients were enrolled between July 1999 and September 2002. Baseline characteristics at study entry (Table 1) included a median age of 48 years (range, 31-69 years) and a median of 3 prior treatment regimens (range, 1-5). Most patients had primary (n ⫽ 13) or transformed (n ⫽ 4) diffuse large B-cell NHL. Six patients had received high-dose chemotherapy and autologous HSCT. On the basis of the response to the most recent prior therapy, 16 patients were deemed chemosensitive and 11 were deemed 595

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Table 2. EPOCH-F Induction Chemotherapy No. Cycles Administered 1 2 3 Total patients

Response to EPOCH-F CR

PR

SD

PD

Total Patients

3

1 7

5 1 2

4 5 1

9 (31%) 7 (24%) 13 (45%)

3 (10%)

8 (28%)

8 (28%)

10 (34%)

CR indicates complete response; PR, partial response; SD, stable disease; PD, progressive disease.

chemorefractory at study entry. Two patients were in untested relapse. Induction Chemotherapy

Patients received a median of 2 cycles (range, 1-3) of EPOCH-F (Table 2). In 9 patients, EPOCH-F was discontinued after 1 or 2 cycles, despite the persistence of more than 50 CD4⫹ cells per microliter, because of disease progression. Eight of these patients proceeded to transplantation, and 1 withdrew from the study before RIST and died of progressive NHL. Overall, treatment with EPOCH-F resulted in CRs in 3 patients, PRs in 8, stable disease in 8, and PD in 10. There was no association between the response to prior therapy before study entry and the response to EPOCH-F (exact Cochran-Armitage test; P ⫽ .26). Hematopoietic Recovery and Engraftment

Twenty-eight patients proceeded to transplantation, and 27 were evaluable for hematopoietic recovery and engraftment. Patients received a median 7.83 ⫻ 106 CD34⫹ cells per kilogram (range, 3.46-17.8 ⫻ 106) and 3.36 ⫻ 108 CD3⫹ cells per kilogram (range, 1.67-9.38 ⫻ 108). The median times to neutrophil recovery (⬎500 ⫻ 109/L) and platelet recovery (⬎20 ⫻ 109/L without transfusion) were 9 and 10 days, respectively. Donor engraftment was rapid, with a median total mononuclear cell donor chimerism of 99% at day ⫹14 after transplantation. Donor lymphoid chimerism was complete in most patients (median of 99% at day ⫹14) and was sustained through day ⫹100 in all patients examined. No patient experienced graft rejection or failure. Transplantation Outcome

The median potential follow-up after RIST is 33.4 months. The median OS is 18.1 months, with an actuarial OS of 49% at 36 months. The median EFS is 5.9 months, with an actuarial EFS of 32% at 36 months. Causes of death after RIST included PD (n ⫽ 7), GVHD with (n ⫽ 2) or without (n ⫽ 4) infection, and sudden cardiac death (n ⫽ 1). Grades II to IV acute GVHD occurred in 19 patients (68%). In 4 patients, acute GVHD occurred after cyclosporine 596

was changed to another immunosuppressant because of toxicity (n ⫽ 3) or was discontinued for PD (n ⫽ 1). Fifteen (63%) of 24 evaluable patients developed chronic GVHD. Thirteen patients who developed acute GVHD and 7 who developed chronic GVHD died. Disease progression after RIST occurred in 11 patients, among whom 7 experienced acute GVHD and 4 developed chronic GVHD; 7 of these 11 patients subsequently died. Four patients with PD after RIST received donor lymphocyte infusions (DLI) with (n ⫽ 3) or without salvage chemotherapy. One of these patients is alive with persistent disease, and 3 survive in remission at a median of 24 months after RIST and 18 months after DLI. Neither acute nor chronic GVHD occurred in these 3 patients. Univariate analysis identified patient age, International Prognostic Index score, and response to EPOCH-F as factors potentially associated with OS (Table 3). Cox model analysis of these factors determined that the response to salvage chemotherapy was the best predictor for OS. This association was strongest when salvage response was categorized into 3 groups: CR/PR, stable disease, or PD (hazard ratio, 4.31; 95% CI, 1.85-10.00; P ⫽ .0006; Figure 1). At 24 months after RIST, the estimated OS for patients with chemosensitive or stable lymphoma during EPOCH-F was 80% (95% CI, 48%-94%) and 50% (95% CI, 22%-79%), respectively. The estimated OS for patients with PD during EPOCH-F was 11% at 12 months and could not be estimated at 24 months. Table 3. Results of Univariate Analysis P Value Variable

OS

EFS

Age (up to 60 vs. >60 y) Stage (NED/I/II vs. III/IV) Number of extranodal sites (0–1 vs. >2) Serum LDH (<226 vs. >226) IPI score (0/1 vs. >2) Histology (aggressive vs. indolent) Duration of disease (0–24 vs. >24 mo) Number of previous regimens (0–2 vs. >3) Prior autologous HSCT Prior fludarabine Prior anthracycline Prior rituximab Response to most recent therapy (CR/PR vs. SD/PD) Response to EPOCH-F CR/PR vs. SD/PD CR/PR vs. SD vs. PD

.055 .30 .85 .22 .11* .45 .72 .96 .96 .74 .40 .75

.13 .63 .55 .13 .50* .12 .23 .74 .094 .71 .28 .87

.47

.44

.0038 .0001

.0009 .0007

NED indicates no evidence of disease; IPI, International Prognostic Index; HSCT, hematopoietic stem cell transplantation; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; LDH, lactate dehydrogenase; OS, overall survival; EFS, event-free survival. *P value adjusted to account for pooling of data after initial examination.

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Figure 1. Overall survival after RIST according to response to EPOCH-F. Responses to EPOCH-F were categorized as complete or partial response (CR/PR), stable disease (SD), or progressive disease (PD).

Only 1 patient with PD during induction chemotherapy remained alive at the time of this analysis. Potential factors associated with EFS in the univariate analysis included age, serum lactate dehydrogenase, histology, prior autologous HSCT, and response to EPOCH-F (Table 3). Cox model analysis of these factors determined that the response to EPOCH-F, categorized into 3 groups, was the best predictor for EFS (hazard ratio, 3.06; 95% CI, 1.625.73; P ⫽ .0006; Figure 2). No other variables remained significant in the Cox model when the response to EPOCH-F was included. The estimated EFS at 24 months was 70% (95% CI, 39%-90%) for patients with chemosensitive lymphoma versus 25% (95% CI, 7%-59%) for patients with stable disease. The estimated progression-free survival for patients with PD during EPOCH-F was 11% at 12 months and could not be estimated at 24 months. Compared with patients with PD, those with stable disease before RIST responded more frequently to interventions for disease progression after RIST (Table 4). Specifically, only 4 stable disease patients died from treatment failure after RIST, and 2 others are in continuous CR after salvage chemotherapy and DLI. In contrast, there were no survivors among patients with PD before RIST whose lymphoma subsequently progressed after RIST. Thus, although EFS was similar for patients whose salvage response was stable disease compared with PD, those with stable disease had a better OS.

regimen. EPOCH-F was administered to achieve both disease control and targeted host immune depletion before RIST [26]. This design permitted us to evaluate the relationship between salvage response and RIST outcome more uniformly than was possible in prior analyses. By restaging after each cycle of salvage therapy, we observed that a trend toward disease progression after even 1 cycle seemed sufficient to predict a high risk of treatment failure after RIST. In contrast, for patients with chemosensitive lymphoma or minimally responding stable disease, it may be advantageous to continue salvage chemotherapy for further cytoreduction before RIST. This analysis suggests additional insights into the potential susceptibility of chemotherapy-resistant lymphomas to GVL effects after RIST. We observed, as might be hypothesized, that OS after RIST was more likely for patients with stable disease during salvage therapy than for patients with PD, despite similar EFS for these groups. The improved OS for patients with stable disease occurred principally because some who experienced disease progression after RIST still achieved durable remission with DLI. This suggests that stable disease patients may be more sensitive to GVL effects than those with PD during salvage chemotherapy. This distinction was not evident from prior studies and is potentially important, because some authors have questioned the benefit of RIST for patients without chemosensitive lymphoma [12,27], as defined by achieving a PR or CR with salvage therapy. In this exploratory analysis, classifying the response to salvage chemotherapy for NHL as sensitive (CR/PR), stable, or progressive predicted survival after RIST more accurately than categorizing the salvage response as a dichotomous variable (CR/PR versus stable disease/PD). This is one of the largest single-institution series of RIST for NHL that has been published to date; nonetheless, these results should be interpreted with caution, considering the

DISCUSSION Response to chemotherapy has been identified in retrospective analyses as an important clinical prognostic factor for outcomes after RIST for NHL [12]. Our study confirms and strengthens this observation prospectively by using a single salvage chemotherapy

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Figure 2. Event-free survival after RIST. SD indicates stable disease. 597

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Table 4. Outcomes of Patients after RIST, According to EPOCH-F Response before RIST Treatment Failures after RIST—Current Status EPOCH-F Response CR/PR (n ⴝ 11) SD (n ⴝ 8) PD (n ⴝ 9)

EFS

NRM

Death from PD

Alive with Lymphoma

Alive in CR*

8 1 1

1 2 4

1 2 4

0 1 0

1 2 0

RIST indicates, reduced-intensity stem cell transplantation; NRM, nonrelapse mortality; PD, progressive disease; CR, complete response; PR, partial response; SD, stable disease. *Denotes patients who achieved remission after donor lymphocyte infusion and are currently alive without evidence of disease.

size of each salvage response group. Confirmation of these findings in larger retrospective and prospective studies is highly desirable. We performed this analysis on a relatively small but consistently treated patient population. Although patients with 3 histologic types of NHL were included, this heterogeneity is arguably irrelevant, given the uniformly poor prognosis of refractory NHL regardless of histology [8,12]. Consistent with this assertion, histology was not associated with survival after RIST in the univariate analysis. The strength of the association between salvage response and RIST outcome also argues against histology’s being an important predictor of outcome in this study. A significant number of nonrelapse deaths occurred in this study. Outcomes tended to be better in patients who received the most salvage chemotherapy cycles, most of whom had chemosensitive disease, but we cannot exclude a possible contribution of the salvage regimen to treatment-related mortality after RIST in some patients. In particular, morbidity from GVHD was relatively high compared with other reported studies of RIST. We used single-agent cyclosporine for GVHD prophylaxis, and the incidence of acute GVHD among these patients was similar to that observed with cyclosporine monotherapy after myeloablative allogeneic HSCT [28]. Our subsequent research efforts in RIST have focused on reducing morbidity from GVHD while preserving the engraftment results seen in this study. Disappointingly, most patients with PD during salvage therapy died after RIST; treatment failures resulted equally from relapse and nonrelapse causes. Contrary to our hopes, rapid and complete donor engraftment did not seem to enhance GVL effects sufficiently to overcome disease resistance in this group, and such rapid engraftment likely contributed to the GVHD-related toxicity we observed. The poor survival after RIST for these patients remains a concern and demonstrates that further work is needed to improve outcomes for this high-risk population. Little is known about the biological mechanisms through which chemosensitivity is related to immunemediated GVL effects, but various factors may be relevant. Murine models indicate that the Fas ligand and perforin cytolytic pathways both contribute to 598

GVL activity [29]. Other experimental data suggest that tumor masses may inhibit specific T-cell responses [30]; thus, lymphomas that can be cytoreduced to a minimal disease state before transplantation might be more susceptible to GVL effects. Chemotherapy-induced tumor cell lysis may itself promote GVL activity via increased antigen presentation to allogeneic T cells. In contrast, the growth kinetics of rapidly progressive lymphoma may outstrip the pace at which GVL-mediated tumor cell death occurs. Resistance to cytotoxic agents and to GVL effects may be mediated through common pathways, such as altered susceptibility to apoptotic signals. Further characterization of these relationships may provide better prognostic tools to select NHL patients for allogeneic HSCT. This analysis confirms, in a uniformly treated group of patients with refractory or relapsed NHL, that chemotherapy-sensitive disease has a favorable prognosis after RIST. Additionally, we observed a stronger association between salvage response and OS by separating chemotherapy-refractory NHL patients into 2 groups (stable disease versus PD) than if they were combined. In conclusion, failure to respond to chemotherapy does not necessarily preclude a benefit from RIST and should not be used independently of other factors to exclude NHL patients from this procedure. A more specific characterization of salvage response, such as that used in this study, may more accurately reflect the prognosis of NHL patients undergoing RIST and should be evaluated prospectively in future studies. REFERENCES 1. Philip T, Guglielmi C, Hagenbeek A, et al. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin’s lymphoma. N Engl J Med. 1995;333:1540-1545. 2. Haioun C, Lepage E, Gisselbrecht C, et al. Benefit of autologous bone marrow transplantation over sequential chemotherapy in poor-risk aggressive non-Hodgkin’s lymphoma: updated results of the prospective study LNH87-2. Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol. 1997;15:1131-1137. 3. Freedman AS, Neuberg D, Mauch P, et al. Long-term follow-up of autologous bone marrow transplantation in patients with relapsed follicular lymphoma. Blood. 1999;94:3325-3333.

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