Ten-Year Follow-Up of Pediatric Patients With Non-Hodgkin Lymphoma Treated With Allogeneic or Autologous Stem Cell Transplantation

Transcription

1 Pediatr Blood Cancer 23;6: Ten-Year Follow-Up of Pediatric Patients With Non-Hodgkin Lymphoma Treated With Allogeneic or Autologous Stem Cell Transplantation Lisa Giulino-Roth, MD,,2 Rosanna Ricafort, MD, 3 Nancy A. Kernan, MD, Trudy N. Small, MD,,2 Tanya M. Trippett, MD, Peter G. Steinherz, MD,,2 Susan E. Prockop, MD, Andromachi Scaradavou, MD, Michelle Chiu, BA, Richard J. O Reilly, MD,,2 and Farid Boulad, MD,2 * Background. Autologous or allogeneic hematopoietic stem cell transplant (SCT) is often considered in patients with relapsed or refractory non-hodgkin lymphoma (NHL) but there are limited data on the use of SCT for the treatment of NHL in the pediatric setting. Procedure. To evaluate the role of SCT for children with NHL, we reviewed 36 consecutive pediatric patients with NHL who underwent an allogeneic (n ¼ 2) or autologous (n ¼ 5) SCT at our institution between 982 and 24. Pathologic classification included: lymphoblastic lymphoma (n ¼ 2), Burkitt lymphoma (BL) (n ¼ 5), diffuse large B-cell lymphoma (n ¼ 4), anaplastic large cell lymphoma (ALCL) (n ¼ 3), peripheral T cell lymphoma (n ¼ ), and undifferentiated NHL (n ¼ ). Donor source for allogeneic-sct recipients was an HLA-matched related donor (n ¼ 5), a matched unrelated donor (n ¼ 4), or a mismatched donor (related n ¼ ; unrelated n ¼ ). Twenty-eight patients (78%) had chemotherapy responsive disease at the time of transplant (either CR or PR). Results. Overall survival (OS) and disease-free survival (DFS) were 55% and 53% with a median follow-up of 9.75 years. Outcomes were similar in patients receiving autologous and allogeneic-sct (DFS 53% in both groups). Patients with ALCL had a DFS of 76.9%. In contrast, of five patients transplanted for BL, none survived. DFS among patients with chemotherapy sensitive disease was 6%, compared with 25% among patients with relapsed/refractory disease (P ¼.9). Conclusions. Allogeneic and autologous SCT offer the prospect of durable, disease-free survival for a significant proportion of pediatric patients with relapsed or refractory NHL. Survival is superior among patients with chemotherapy sensitive disease. Pediatr Blood Cancer 23;6: # 23 Wiley Periodicals, Inc. Key words: allogeneic stem cell transplant; autologous stem cell transplant; non-hodgkin lymphoma; pediatric INTRODUCTION Significant improvements have been made in the treatment of pediatric non-hodgkin lymphoma (NHL) where event-free survival has increased from 3% in the 97s [,2] to 6 95% today [3 4]. The outcome for children with relapsed or refractory disease, however, remains poor [5]. Autologous or allogeneic hematopoietic stem cell transplant (SCT) is often considered in an attempt to improve survival in patients with relapsed or refractory disease but there are limited data on the use of SCT for the treatment of NHL in the pediatric setting. In adults, auto-sct has demonstrated a superior outcome when compared with chemotherapy alone for the treatment of relapsed NHL [6,7]. The indications for auto-sct versus allo-sct are not clearly defined. Allo-SCT offers the prospect of a tumor-free graft with the potential for a graft-versus-lymphoma effect. Increased transplant-related mortality (TRM) associated with allo-sct, however, may balance the decrease in relapse rate. As a result, the overall survival for adults with NHL who receive an allo-sct is equivalent to that seen in patients who receive an auto-sct [8 22]. In the pediatric population there have been few studies describing outcome following allo-sct or auto-sct for the treatment of NHL. Most studies report patient cohorts pooled from the multiple institutions. One large multi-institutional study described the collective experience of 82 children with NHL who underwent auto-sct or allo-sct as registered by the Center for International Blood and Marrow Transplant Research, which included over 5 transplant centers [23]. The remaining reports have been limited by small numbers and patient selection [24 29]. We report the outcome of 36 consecutive pediatric patients with NHL who underwent either allo-sct (n ¼ 2) or auto-sct (n ¼ 5) at our institution with a median follow-up of 9.75 years. PATIENTS AND METHODS Patients Retrospective data were collected on 36 consecutive patients with NHL who underwent auto-sct or allo-sct at Memorial C 23 Wiley Periodicals, Inc. DOI.2/pbc Published online 3 August 23 in Wiley Online Library (wileyonlinelibrary.com). Sloan-Kettering Cancer Center between 982 and 24. The diagnosis of NHL and the histologic subtype were based on morphologic and immunophenotype. Lymphoma classification was updated to reflect the most recent WHO classification Schema [3]. Data were collected on histology, treatment prior to SCT, disease status at the time of SCT, conditioning regimen, donor graft characteristics, and outcome after SCT. Disease status and response to chemotherapy at the time of SCT were defined according to the following criteria: CR, no evidence of disease determined clinically, radiographically, or pathologically; PR, 5% decrease in sum of products of the diameters of each measurable lesion, along with the documented presence of residual disease; relapsed-refractory (REL-REF), less than 5% decrease in the size of measurable lesions, or relapsedprogressive disease (REL-PROG), appearance of new lesions or enlargement of previous sites of disease. Patients with residual CNS or bone marrow disease were classified as REL-REF or REL- PROG. Hematopoietic recovery was defined by: () neutrophil engraftment as the first day of an absolute neutrophil count >5 6 for 3 consecutive days and (2) platelet engraftment as the first day of unsupported platelet count >5 3 /ml for 3 Additional Supporting Information may be found in the online version of this article at the publisher s web-site. Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York; 2 Department of Pediatrics, Weill Cornell Medical College, New York, New York; 3 Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York Conflict of interest: Nothing to declare. Lisa Giulino-Roth and Rosanna Ricafort contributed equally to this work. Correspondence to: Farid Boulad, 275 York Ave, New York, NY bouladf@mskcc.org Received 4 March 23; Accepted 2 July 23

2 Allo- and Auto-SCT for Pediatric NHL 29 consecutive days. The diagnosis of graft-versus-host disease (GVHD) was made based on clinical assessment with pathologic biopsies when indicated. Acute and chronic GVHD were graded according to consensus criteria [3,32]. Remission status of all patients was determined by physical examination, bone marrow aspiration, lumbar puncture, chest radiographs, CT scans, gallium scans, PET scans, and MRI as appropriate. Disease-free survival (DFS) was measured as the time from transplant to relapse or death, and overall survival (OS) was measured as the time from transplant to death or the end of the study period. A waiver for HIPAA authorization and informed consent was obtained from the institutional review board. Statistical Analysis The primary endpoints of this study were OS and DFS. For DFS, relapse, disease progression, and death were considered events. Surviving patients were censored at September 2, 22. The Kaplan Meier estimate was used to compute OS/DFS probability over time. The cumulative incidence function was used to estimate the probabilities for TRM and relapse. Univariate analyses were performed using the log-rank test [33]. Mulitvariate analysis was performed using a Cox proportional hazards model with the end points of DFS and OS. RESULTS Patient Characteristics The patient characteristics are summarized in Table I and Supplemental Tables I and II. Between December 982 and December 24, 36 consecutive pediatric patients with NHL underwent either allo-sct (n ¼ 2) or auto-sct (n ¼ 5) at MSKCC. Histologic diagnoses included anaplastic large cell lymphoma (ALCL) (n ¼ 3, including one case of cutaneous disease), lymphoblastic lymphoma (LBL) (n ¼ 2), Burkitt lymphoma (BL) (n ¼ 5), diffuse large B-cell lymphoma (n ¼ 4), peripheral T-cell lymphoma (n ¼ ), and undifferentiated lymphoma (n ¼ ). Of note, all patients with ALCL had anaplastic lymphoma kinase (ALK)-positive tumors. Therapy prior to SCT was based on histologic subtype and standard of care at the time of treatment. Treatment regimens are summarized in Supplemental Tables I and II. In the autologous graft setting, purging with 4-hydroxyperoxy cyclophosphamide was performed in 3 of 5 cases as previously described [34]. The decision of auto-sct versus allo-sct was made based on the donor characteristics, histologic subtype, and history of bone marrow disease. Allo-SCT was preferred in the setting of an available matched sibling, a history of significant bone marrow disease, or in the case of LBL where there may be a graft versus lymphoma effect. TABLE I. Patient Characteristics All patients Allo-SCT Auto-SCT P-value Number of patients 36 2 (58%) 5 (42%) Age (years) 6 Range Median Gender 9 Male 25 5 (7%) (67%) Female 6 (29%) 5 (33%) BMT time period (57%) 6 (4%) (43%) 9 (6%) Diagnosis.2 Lymphoblastic 2 (52%) (7%) ALCL 3 5 (24%) 8 (53%) DLCL 4 2 (%) 2 (3%) BL 5 2 (%) 3 (2%) PTCL (5%) Undifferentiated (7%) Tumor stage.3 I (7%) II 2 2 (3%) III 3 2 (57%) 8 (53%) IV 3 9 (43%) 4 (27%) Disease status at SCT Chemotherapy responsive disease 28 5 (7%) 3 (87%) 9 CR CR CR PR Chemotherapy unresponsive disease 8 6 (29%) 2 (3%) 6 Refractory 6 5 Progressive 2 ALCL, anaplastic large cell lymphoma; DLBCL, diffuse large B-cell lymphoma; BL, Burkitt lymphoma; PTCL, peripheral T-cell lymphoma; CR, complete remission.

3 22 Giulino-Roth et al. Lymphoma subtypes were equally represented in the auto-sct and allo-sct categories with the exception of LBL where of 2 patients underwent allo-sct (P ¼.2). Other patient characteristics were similar in the auto-sct and allo-sct groups. Twentyeight patients (78%) had chemotherapy responsive disease at the time of SCT (either CR or PR). This included one patient who was transplanted in CR for high-risk stage IV peripheral T-cell lymphoma. Among the patients with chemotherapy responsive disease, 5 (54%) underwent allo-sct and 3 (46%) underwent auto-sct. Among eight patients with relapsed disease six (75%) received an allogeneic graft and two (25%) received an autologous graft. Transplant Characteristics The transplant characteristics are summarized in Table II. Twenty-one patients (58%) underwent allo-sct, 5 patients (42%) underwent auto-sct. Donors for allo-sct patients included an HLA-matched sibling (n ¼ 5, 7%), HLA-matched unrelated donor (n ¼ 4, 9%), mismatched related donor (n ¼, 5%) and mismatched unrelated donor (n ¼, 5%). GVHD prophylaxis for allo-sct patients consisted of T-cell depletion (n ¼, 48%), or TABLE II. Transplant Characteristics Graft Allogeneic (N ¼ 2) Autologous (N ¼ 5) Donor N/A HLA-matched sibling 5 HLA-matched unrelated 4 MM related MM unrelated Cytoreduction a TBI/Thio/Cy 9 8 TBI/Cy 8 TBI-other 4 Non-TBI based b 3 3 Stem cell source PBSC 6 BM 2 8 PBSC þ BM GVHD prophylaxis N/A T-cell depletion CSA, MTX 4 CSA, steroids 5 CSA, alemtuzumab MTX MM, mismatched; TBI, total body irradiation; Thio, thiotepa; Cy, cyclophosphamide; PBSC, peripheral blood stem cells; BM, bone marrow; GVHD, graft versus host disease; CSA, cyclosporine; MTX, methotrexate. a Cytoreductive regimens: hyperfractionated TBI (,375,5 cgy); Thio (5 mg/kg/dose 2); Cy (6 mg/kg/dose 2). TBI-other includes TBI/etoposide (25 mg/m 2 3); TBI/etoposide/Cy and TBI/cytarabine (3 gm/m 2 8); b Non-TBI-based regimens: (i) Thio ( mg/kg 3) and Cy (6 mg/kg 2), (ii) Thio (25 mg/m 2 /dose 2), busulfan ( mg/kg or 4 mg/m 2 /dose QID 3 days), and melphalan (5 mg/m 2 /dose 2), and (iii) a reduced-dose intensity conditioning with fludarabine (25 mg/m 2 /dose 5 days) and melphalan (7 mg/m 2 / dose 2). Busulfan ( mg/kg/dose QID 2 days), Melphalan (5 mg/ m 2 2) and Thio (2 mg/m 2 2), and one patient was conditioned with BEAM (BCNU 3 mg/m 2 ; VP-6 mg/m 2 BID 8; cytarabine 2 mg/m 2 BID 8; melphalan 4 mg/m 2 ). post-transplant immunosuppression (n ¼, 52%). Cytoreduction was total body irradiation (TBI) based in 3 of 36 (83%) patients. Among patients receiving a T-cell depleted graft, the most common cytoreduction regimen was TBI, thiotepa, and cyclophosphamide (TBI/Thio/Cy) (n ¼ 7, 7%). In patients who received an unmodified allogeneic graft, the most frequently used cytoreduction was TBI and cyclophosphamide (n ¼ 6, 54%). Patients with extensive prior radiotherapy, defined as dose >24 Gy, or cardiotoxicity received non-tbi-based regimens (Table II). Hematopoietic Recovery Of the 36 patients in this cohort, 2 patients died at 23 and 25 days post-transplant prior to engrafting. Of the remaining 34 evaluable patients, successful hematologic engraftment occurred in 33 (97%). The one patient who failed to engraft had received an autologous bone marrow transplant with CD34þ cells/kg. The time to engraftment was not statistically different in the auto-sct and allo-sct groups (P ¼.69). The median time to granulocyte recovery in the overall cohort was 2 days (range: 9 35 days); days (range: 9 2 days) in the auto-sct group and 3 days (range: 9 35 days) in the allo-sct group. The median time to platelet recovery was 38 days (range: days) for the auto-sct group and 35 days (range: 8 64 days) for the allo-sct group. The time to neutrophil recovery was similar in the patients who received peripheral blood and bone marrow derived grafts (median days, 2.5 days, respectively, P ¼ 9), as was the time to platelet recovery (median 23 days, 32 days, respectively, P ¼ 89). Graft-Versus-Host Disease Five patients (24%) developed grade II-IV acute GVHD including patients in the T-cell depleted (n ¼ 2) and unmodified (n ¼ 3) groups. The two patients who developed GVHD after a T- cell depleted graft both had unrelated donors, one with a mismatched donor and one with a matched donor. The three patients who developed GVHD after an unmodified graft all had matched sibling donors. Five patients (24%) developed chronic GVHD (cgvhd) including three patients with a history of grade II IV acute GVHD. Four of five patients who developed cgvhd received unmodified grafts from matched sibling donors followed by post-transplant immune suppression. One patient with cgvhd received a T-cell depleted graft from a mismatched unrelated donor. One patient died of complications related to cgvhd. Transplant-Related Mortality Six patients died of transplant related complications including patients in the allo-sct (n ¼ 4, 9%) and auto-sct (n ¼ 2, 3%) groups. There was no significant difference in the rate of TRM in the two cohorts (P ¼ ). The causes of death were infection (n ¼ 4), hepatic veno-occlusive disease (n ¼ ) and cgvhd (n ¼ ). Relapse Relapse occurred in 6 of 8 evaluable patients in the allo-sct group and in 5 of 3 evaluable patients in the auto-sct group. The time to relapse ranged from to 23.2 months post-transplant. Among the patients who relapsed, 8 had been transplanted with REL-PROG or REL-REF disease. The remaining three patients were transplanted in CR or PR. Relapse rate was 28% among allo-

4 SCT patients and 33% among auto-sct patients, however, this difference is not statistically significant (P ¼ 2). There was no difference in relapse rates among patients with and without GVHD. OS among the patients who relapsed after SCT was 9%. The majority of patients died of disease (n ¼ 9). One patient died of sepsis. One patient with ALCL was successfully salvaged with reinduction chemotherapy without the need for secondary transplant and is alive and disease free at 6 months follow-up from allo-sct. A Propor on Allo- and Auto-SCT for Pediatric NHL 22 Chemosensitive Disease = 64.2% n=28 Resistant Disease = 25% n=8 Overall Survival and Disease-Free Survival With a median follow-up of 9.75 years, 2 of 36 patients are alive and disease free, with an OS and DFS of 55% and 53%, respectively. OS and DFS are not statistically different in the auto-sct and allo- SCT groups (Fig. ). Among the allo-sct group, there was no difference in OS or DFS in the matched-related (n ¼ 5) versus matched-unrelated (n ¼ 4) donor groups (P ¼ 3 and 8, respectively). Patients who entered transplant with chemotherapy responsive disease demonstrated a superior outcome compared to patients with REL-REF or REL-PROG disease (DFS 6% vs. 25%, P ¼.9) (Fig. 2). In a multivariate analysis, both OS and DFS were superior among patients with chemosensitive disease (P ¼.3 for both OS and DFS) and patients with ALCL (P ¼.2 and.4, respectively). Since there was significant overlap between these two factors, neither independently predicted outcome. Outcome by Histologic Diagnosis Five patients with BL underwent auto-sct (n ¼ 3) or allo-sct (n ¼ 2). Two patients were transplanted in remission (CR2, CR3) and three patients were transplanted in relapse. All five patients A Proportion B Proportion.2. Auto-SCT = 53.33% n=5 Allo-SCT= 57.4% n= Auto-SCT = 53.33% n=5 Allo-SCT = 52.38% Fig.. The probability of overall survival (A) and disease-free survival (B) after autologous or allogeneic transplant. B Propor on Resistant Disease = 25% n=8 died, four due to relapsed disease at 3 months after SCT, and one due to TRM less than month following auto-sct. Twelve patients with LBL underwent auto-sct (n ¼ ) or allo- SCT (n ¼ ). Eight patients (67%) entered transplant with chemotherapy sensitive disease, the remainder had relapsed disease. The one patient who received an auto-sct died of TRM one month after SCT. Among the patients who received an allo- SCT, OS and DFS were 5% with a median follow-up of 2 years. The causes of death in this group were veno-occlusive disease (n ¼ ), cgvhd (n ¼ ), sepsis (n ¼ 2), and disease (n ¼ ). There was no survival difference in the allo-sct group among patients who received a T-cell depleted graft when compared with those who received a conventional graft (OS 4%, 67% respectively; P ¼ 37). Thirteen patients with ALCL, including one patient with cutaneous ALCL, received a SCT. Eight patients underwent an auto-sct and five patients underwent an allo-sct. All patients were transplanted with chemotherapy sensitive disease (CR, n ¼ 8 or PR, n ¼ 5). OS and DFS in this group were 83.3% and 76.9%, respectively. Four patients with diffuse large B-cell lymphoma (DLBCL) received an auto-sct (n ¼ 2) or allo-sct (n ¼ 2). One patient was transplanted with refractory disease; the remainder of patients had chemosensitive disease (CR, n ¼ or PR, n ¼ 2). The OS and DFS in this cohort were each 5%. Two patients died of disease at 6 and 22 months after transplant. Outcome by Transplant Period p=.7 Chemosensitive Disease = 6% n=28 p= Fig. 2. The probability of overall survival (A) and disease-free survival (B) in patients with chemotherapy sensitive versus chemotherapy resistant disease. Given the improvements in supportive care and prophylaxis over time, we were interested in evaluating this cohort based on the year

5 222 Giulino-Roth et al. of transplant. Patients who received a SCT prior to 995 had a DFS of 39% compared with a DFS of 67% among patients who underwent SCT in 995 or later. This difference, however, was not statistically significant (P ¼.92), perhaps due to cohort size. The trend toward an improvement in outcome with time was more pronounced in the allo-sct where DFS was 33% prior to 995 compared to 78% after 995 (P ¼.86). In contrast, outcome among auto-sct recipients was similar in the two periods (OS <995: 5%, OS 995: 55.6%, P ¼ 9). DISCUSSION This review details a 3-year single institution experience using hematopoietic stem cell transplantation for the treatment of children with relapsed and refractory NHL. Fifty-three percent of patients in our series are alive and disease-free post-transplantation. Our data indicate that outcome is similar after autologous and allogeneic BMT, and that the strongest predictor of outcome is response to chemotherapy prior to transplantation. Patients who entered SCT with chemotherapy-sensitive disease had a superior DFS compared to those with resistant disease (6% vs. 25%, P ¼.9). Other groups have reported the outcome of children with relapsed/ refractory NHL who underwent SCT using data pooled from various institutions. In a multi-center review, Gross et al. [23] describe 83 children with NHL who underwent auto-sct (n ¼ 9)orallo-SCT (n ¼ 92). In that series, disease classification included DLBCL, LBL, BL, and ALCL. Five-year DFS ranged from 27% to 52% in the majority of the disease-based cohorts. It was, however, poor in patients with LBL following auto-sct (DFS 4%). The St. Jude Children s Research Hospital describes a cohort of 24 children with NHL who underwent auto-sct (n ¼ 9)orallo-SCT(n¼5) with a DFS of 5% [28]. Other studies have focused on patients who received autologous grafts and report DFS ranging from 33% to 7% [25 27]. For patients with relapsed or refractory NHL, there is controversy over the use of chemotherapy alone versus high-dose therapy and auto-sct. The Children s Cancer Group evaluated outcomes with DECAL chemotherapy (dexamethasone, etoposide, cisplatin, cytarabine, and L-asparaginase) followed in a nonrandomized fashion by either allo-sct, auto-sct, or maintenance chemotherapy [5]. The 5-year EFS was 23% for all patients. Although the study was not designed to compare the different therapeutic approaches, the outcome was not different in patients who received chemotherapy alone versus those who underwent SCT. In contrast, a randomized study by Philip et al. [7] compared salvage chemotherapy to high dose chemotherapy followed by auto-sct in adult patients with chemosensitive NHL. EFS was 46% in the autologous transplant group compared to 2% in the group receiving salvage chemotherapy alone (P ¼.). Our results showed a similar DFS of 53% in those receiving an auto-sct implying that auto-sct is a feasible treatment approach for children with relapsed NHL. There are limited reports comparing allogeneic and autologous transplantation in pediatric patients with relapsed or refractory NHL. Gross et al. [23] reports similar outcomes in patients following auto-sct and allo-sct with the exception of patients with LBL where auto-sct was inferior. The Spanish Working Party for BMT in Children also found no difference between the auto- SCT and allo-sct among 46 pediatric patients with relapsed NHL (DFS 57% for both groups) [26]. Other groups have also reported similar outcomes among pediatric patients with NHL transplanted with autologous and allogeneic grafts [28,29]. In our series, outcome in auto-sct and allo-sct cohorts was equivalent with a -year DFS of 53% in each group. Of note, there was a trend toward higher risk disease among patients in the allo-sct group, with more stage III/IV and chemotherapy refractory disease; however, this was not statistically significant (Table I). Histologic classification is likely an important factor in the decision for auto-sct versus allo-sct. LBL is different from other histologic NHL classifications in that an allo-sct may offer a superior outcome due to a graft versus lymphoma effect. In the cohort described by Gross et al., 53 pediatric patients with LBL received an allo-sct (n ¼ 39) or auto-sct (n ¼ 4). DFS in the allo-sct group was 4%, compared to 4% in the auto-sct group [23]. A study by Chopra et al. [35], which included adult and pediatric patients with relapsed LBL, showed that allo-sct was associated with a lower relapse rate (24%) compared to auto-sct (48%, P ¼.35); however, the DFS was not different between the two groups due to higher TRM in the allo-sct group (24% in allo-sct; % in auto-sct, P ¼.6). In our cohort the majority of patients with LBL received allogeneic grafts ( of 2). The one patient who received an autologous graft died 2 months after transplant of regimen-related toxicity. Survival among patients with LBL after an allo-sct was 55% at a median follow-up of 4.3 years. As supportive care for allo-sct improves the benefit for allo-sct for LBL in the form of GVL may now outweigh the risk of TRM. Although previous studies have suggested the efficacy of auto- SCT for BL treated successfully with salvage therapy [36], all five of our patients with BL who received an auto-sct (n ¼ 3) or allo- SCT (n ¼ 2) died; four from relapsed disease and one from TRM. This was, however, a particularly high-risk group with three patients entering transplant with active, chemotherapy resistant disease. Clearly, SCT for chemotherapy-resistant BL is associated with a poor outcome. In contrast, patients with ALCL (n ¼ 3) achieved favorable outcomes after auto-sct or allo-sct (OS, DFS: 83.3%, 76.9%). Previous studies have reported variable outcomes in this disease [23,25,29,37,38]. The largest series, published by the BFM group, describes 55 children with ALCL who underwent auto-sct (n ¼ 39) or allo-sct (n ¼ 6) [29]. Among those who received auto- SCT, the 5-year OS/DFS were 77% and 59%, respectively. Eleven of 6 patients who underwent allo-sct achieved a long-term complete second remission. This group also published an earlier report of 2 patients who underwent allo-sct for ALCL with a 75% 3-year EFS [38]. Gross et al. reported outcomes among patients with ALCL who underwent auto-sct (n ¼ 4) or allo-sct (n ¼ 2). Five-year EFS was 35% and 46% in the auto-sct and allo-sct cohorts, respectively [23]. The improved outcome in our cohort may be explained by the fact that all patients entered SCTwith chemotherapy sensitive disease. Remarkably one patient with ALCL who relapsed after SCT was salvaged with chemotherapy alone. A survival advantage has been reported among patients who enter transplant with chemotherapy sensitive disease. In our cohort, patients with a CR or PR prior to SCT had a DFS of 6% compared with 25% in patients with relapsed disease (P ¼.9). This is consistent with previous reports in children and adults [7,23,26,28,36]. This retrospective study has inherent limitations, which must be considered. Patients received different chemotherapy regimens,

6 Allo- and Auto-SCT for Pediatric NHL 223 SCT conditioning regimens, and supportive care standards, reflecting changes in treatment over the 22-year data collection period. In an effort to evaluate the effect of transplant era on outcome, we compared OS/DFS in patients who received SCT before and after 995. There was a trend toward improved OS/DFS in patients treated since 995 compared to those treated prior to 995. This difference was most pronounced in the allo-sct, likely reflecting improvement in supportive care. Our study is also limited by small sample size, which precludes the evaluation of auto-sct versus allo-sct by histologic subtype, and by the use of T-cell depletion for allo-transplantation. It must also be noted that T-cell depletion was used for GVHD prevention in of 2 patients undergoing allo-sct. The rationale for the use of T-cell depletion is based on our experience with this approach being the most efficient approach for GVHD prophylaxis with overall comparable relapse rates in patients with leukemia or lymphoma [39,4] including LBL. Based on these data with T-cell depletion transplantation, it is unlikely that there is a major difference in the relapse related outcome among patients receiving T-cell depleted versus conventional grafts. In summary, both allo-sct and auto-sct offer the prospect of durable disease-free survival for a significant proportion of pediatric patients with relapsed NHL. The most important predictor of outcome in our cohort was the response to chemotherapy prior to SCT. Among the histologic subtypes, patients with ALCL had the most favorable outcome (DFS 76.9%) perhaps due to an increased number of patients with chemotherapy-sensitive disease. Patients with BL often had chemotherapy-resistant disease and had a dismal outcome. Given our data showing similar outcomes in auto-sct and allo-sct, and based on previous pediatric and adult studies [23 29], the authors recommend that practitioners take the following factors into account when deciding to use auto-sct versus allo- SCT for the treatment of pediatric NHL: () histologic subtype: we recommend auto or allo-sct for all but LBL, and allo-sct for LBL, (2) history of marrow disease: we recommend allo-sct in this setting, (3) donor characteristics: we recommend auto- SCT if no matched related or unrelated donors are available. Given the long-term follow-up documented in this study, with some patients followed 3 years after SCT, studies are currently being conducted to evaluate late effects in this unique patient cohort. ACKNOWLEDGMENT The authors acknowledge Joseph Olechnowicz for his assistance in preparation of the manuscript. REFERENCES. Glatstein E, Kim H, Donaldson SS, et al. Non-Hodgkin s lymphomas. VI. Results of treatment in childhood. Cancer 974;34: Murphy SB, Frizzera G, Evans AE. A study of childhood non-hodgkin s lymphoma. Cancer 975;36: Pulte D, Gondos A, Brenner H. Trends in 5- and -year survival after diagnosis with childhood hematologic malignancies in the United States, J Natl Cancer Inst 28;: Patte C, Auperin A, Michon J, et al. The Societe Francaise d Oncologie Pediatrique LMB89 protocol: Highly effective multiagent chemotherapy tailored to the tumor burden and initial response in 56 unselected children with B-cell lymphomas and L3 leukemia. Blood 2;97: Woessmann W, Seidemann K, Mann G, et al. The impactof the methotrexateadministration schedule and dose in the treatment of children and adolescents with B-cell neoplasms: A report of the BFM Group Study NHL-BFM95. Blood 25;5: Burkhardt B, Zimmermann M, Oschlies I, etal. Theimpact ofage andgenderon biology, clinical features and treatment outcome of non-hodgkin lymphoma in childhood and adolescence. Br J Haematol 25;3: Link MP, Shuster JJ, Donaldson SS, et al. Treatment of children and young adults with early-stage non- Hodgkin s lymphoma. N Engl J Med 997;337: Gerrard M, Cairo MS, Weston C, et al. Excellent survival following two courses of COPAD chemotherapy in children and adolescents with resected localized B-cell non-hodgkin s lymphoma: Results of the FAB/ LMB 96 international study. Br J Haematol 28;4: Cairo MS, Gerrard M, Sposto R, et al. Results of a randomized international study of high-risk central nervous system B non-hodgkin lymphoma and B acute lymphoblastic leukemia in children and adolescents. Blood 27;9: Patte C, Auperin A, Gerrard M, et al. Results of the randomized international FAB/LMB96 trial for intermediate risk B-cell non-hodgkin lymphoma in children and adolescents: It is possible to reduce treatment for the early responding patients. Blood 27;9: Lowe EJ, Sposto R, Perkins SL, et al. Intensive chemotherapy for systemic anaplastic large cell lymphoma in children and adolescents: Final results of Children s Cancer Group Study 594. Pediatric Blood Cancer 29;52: Brugieres L, Le Deley MC, Rosolen A, et al. Impact of the methotrexate administration dose on the need for intrathecal treatment in children and adolescents with anaplastic large-cell lymphoma: Results of a randomized trial of the EICNHL Group. J Clin Oncol 29;27: Le Deley MC, Rosolen A, Williams DM, et al. Vinblastine in children and adolescents with high-risk anaplastic large-cell lymphoma: Results of the randomized ALCL99-vinblastine trial. J Clin Oncol 2;28: Reiter A, Schrappe M, Ludwig WD, et al. Intensive ALL-type therapy without local radiotherapy provides a 9% event-free survival for children with T-cell lymphoblastic lymphoma: A BFM group report. Blood 2;95: Kobrinsky NL, Sposto R, Shah NR, et al. Outcomes of treatment of children and adolescents with recurrent non-hodgkin s lymphoma and Hodgkin s disease with dexamethasone, etoposide, cisplatin, cytarabine, and l-asparaginase, maintenance chemotherapy, and transplantation: Children s Cancer Group Study CCG-59. J Clin Oncol 2;9: Kleiner S, Kirsch A, Schwaner I, et al. High-dose chemotherapy with carboplatin, etoposide and ifosfamide followed by autologous stem cell rescue in patients with relapsed or refractory malignant lymphomas: A phase I/II study. Bone Marrow Transplant 997;2: 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 995;333: Dann EJ, Daugherty CK, Larson RA. Allogeneic bone marrow transplantation for relapsed and refractory Hodgkin s disease and non-hodgkin s lymphoma. Bone Marrow Transplant 997;2: Lazarus HM, Zhang MJ, Carreras J, et al. A comparison of HLA-identical sibling allogeneic versus autologous transplantation for diffuse large B cell lymphoma: A report from the CIBMTR. Biol Blood Marrow Transplant 2;6: Levine JE, Harris RE, Loberiza FR, Jr., et al. A comparison of allogeneic and autologous bone marrow transplantation for lymphoblastic lymphoma. Blood 23;: Peniket AJ, Ruiz de Elvira MC, Taghipour G, et al. An EBMT registry matched study of allogeneic stem cell transplants for lymphoma: Allogeneic transplantation is associated with a lower relapse rate but a higher procedure-related mortality rate than autologous transplantation. Bone Marrow Transplant 23; 3: Schimmer AD, Jamal S, Messner H, et al. Allogeneic or autologous bone marrow transplantation (BMT) for non-hodgkin s lymphoma (NHL): Results of a provincial strategy. Ontario BMT Network, Canada. Bone Marrow Transplant 2;26: Gross TG, Hale GA, He W, et al. Hematopoietic stem cell transplantation for refractory or recurrent non-hodgkin lymphoma in children and adolescents. Biol Blood Marrow Transplant 2;6: Andion M, Molina B, Gonzalez-Vicent M, et al. High-dose busulfan and cyclophosphamide as a conditioning regimen for autologous peripheral blood stem cell transplantation in childhood non-hodgkin lymphoma patients: A long-term follow-up study. J Pediatr Hematol Oncol 2;33: e89 e Brugieres L, Quartier P, Le Deley MC, et al. Relapses of childhood anaplastic large-cell lymphoma: Treatmentresultsinaseriesof4children A reportfromthe FrenchSocietyofPediatric Oncology. Ann Oncol 2;: Bureo E, Ortega JJ, Munoz A, et al. Bone marrow transplantation in 46 pediatric patients with non- Hodgkin s lymphoma. Spanish Working Party for Bone Marrow Transplantation in Children. Bone Marrow Transplant 995;5: Harris RE, Termuhlen AM, Smith LM, et al. Autologous peripheral blood stem cell transplantation in children with refractory or relapsed lymphoma: Results of Children s Oncology Group study A 596. Biol Blood Marrow Transplant 2;7: Sandlund JT, Bowman L, Heslop HE, et al. Intensive chemotherapy with hematopoietic stem-cell support for children with recurrent or refractory NHL. Cytotherapy 22;4: Woessmann W, Zimmermann M, Lenhard M, et al. Relapsed or refractory anaplastic large-cell lymphoma inchildren andadolescents afterberlin-frankfurt-muenster (BFM)-typefirst-linetherapy: ABFM-group study. J Clin Oncol 2;29: Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; Przepiorka D, Weisdorf D, Martin P, et al. 994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant 995;5: Sullivan KM, Agura E, Anasetti C, etal. Chronicgraft-versus-hostdiseaseandother late complications of bone marrow transplantation. Semin Hematol 99;28: Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 966;5: Gulati S, Acaba L, Yahalom J, et al. Autologous bone marrow transplantation for acute myelogenous leukemia using 4-hydroperoxycyclophosphamide and VP-6 purged bone marrow. Bone Marrow Transplant 992;: Chopra R, Goldstone AH, Pearce R, et al. Autologous versus allogeneic bone marrow transplantation for non-hodgkin s lymphoma: A case-controlled analysis of the European Bone Marrow Transplant Group Registry data. J Clin Oncol 992;: Ladenstein R, Pearce R, Hartmann O, et al. High-dose chemotherapy with autologous bone marrow rescue in children with poor-risk Burkitt s lymphoma: A report from the European Lymphoma Bone Marrow Transplantation Registry. Blood 997;9:

7 224 Giulino-Roth et al. 37. Fanin R,Ruiz de Elvira MC, Sperotto A,et al. Autologous stem cell transplantation for Tand null cell CD3- positive anaplastic large cell lymphoma: Analysis of 64 adult and paediatric cases reported to the European Group for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant 999; 23: Woessmann W, Peters C, Lenhard M, et al. Allogeneic haematopoietic stem cell transplantation in relapsed or refractory anaplastic large cell lymphoma of children and adolescents A Berlin-Frankfurt- Munster group report. Br J Haematol 26;33: Jakubowski AA, Small TN, Kernan NA, et al. T cell-depleted unrelated donor stem cell transplantation provides favorable disease-free survival for adults with hematologic malignancies. Biol Blood Marrow Transplant 2;7: Perales MA, Jenq R, Goldberg JD, et al. Second-line age-adjusted International Prognostic Index in patients with advanced non-hodgkin lymphoma after T-cell depleted allogeneic hematopoietic SCT. Bone Marrow Transplant 2;45:48 46.