Hematopoietic Stem Cell Transplantation for Refractory or Recurrent Non-Hodgkin Lymphoma in Children and Adolescents

Article Outline

• Abstract
• Introduction
• Patients and Methods
  • Data Collection
  • Inclusion Criteria
  • Study Endpoints
  • Statistical Analysis
• Results
  • Hematopoietic Recovery
  • Acute and Chronic GVHD
  • Transplantation-Related Mortality
  • Relapse or Progression
  • Event-Free Survival
• Discussion
• Acknowledgments
• References
• Copyright

We examined the role of hematopoietic stem cell transplantation (HSCT) for patients aged≤18 years with refractory or recurrent Burkitt (n=41), lymphoblastic (n=53), diffuse large B cell (DLBCL; n=52), and anaplastic large cell lymphoma (n=36), receiving autologous (n=90) or allogeneic (n=92; 43 matched sibling and 49 unrelated donor) HSCT in 1990-2005. Risk factors affecting event-free survival (EFS) were evaluated using stratified Cox regression. Characteristics of allogeneic and autologous HSCT recipients were similar. Allogeneic donor HSCT was more likely to use irradiation-containing conditioning regimens, bone marrow (BM) stem cells, be performed in more recent years, and for lymphoblastic lymphoma. EFS rates were lower for patients not in complete remission at HSCT, regardless of donor type. After adjusting for disease status, 5-year EFS were similar after allogeneic and autologous HSCT for DLBCL (50% vs 52%), Burkitt (31% vs 27%), and anaplastic large cell lymphoma (46% vs 35%). However, EFS was higher for lymphoblastic lymphoma, after allogeneic HSCT (40% vs 4%; P < .01). Predictors of EFS for progressive or recurrent disease after HSCT included disease status at HSCT and use of allogeneic donor for lymphoblastic lymphoma. These data were unable to demonstrate a difference in outcome by donor type for the other histological subtypes.

Key Words: Non-Hodgkin lymphoma, Allogeneic hematopoietic stem cell transplantation, Autologous hematopoietic stem cell transplantation

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Introduction 

More than 95% of pediatric non-Hodgkin lymphoma (NHL) is high-grade disease, in contrast to adult NHL, in which low-grade and indolent disease predominate [1]. The 4 major histological subtypes of NHL in children and adolescents are Burkitt, lymphoblastic, diffuse large B cell (DLBCL), and anaplastic large cell lymphoma [1]. Current results using intensive chemotherapy regimens are excellent even for patients with stage III/IV disease. Long-term event-free survival (EFS) is between 60% and 90%, depending on histological subtype 2, 3, 4, 5, 6, 7, 8, 9. Long-term survival is only 10%-20% for refractory or recurrent Burkitt, DLBCL, and lymphoblastic lymphoma 10, 11, 12, 13, but up to 60% for refractory or recurrent anaplastic large cell lymphoma 13, 14.

A Children's Cancer Group (CCG) study for relapsed pediatric lymphoma found an EFS of 25% for all children with NHL, and for those with chemosensitive disease, EFS was similar with or without autologous hematopoietic stem cell transplantation (HSCT) [15]. The French Society of Pediatric Oncology (SFOP) reported a 3-year disease-free survival (DFS) of 45% for relapsed anaplastic large cell lymphoma with similar DFS after chemotherapy or autologous HSCT for patients in second complete remission (CR2) [14]. In another report from the SFOP, for patients with relapsed mature B-cell NHL (diffuse large B cell [DLBCL] and Burkitt lymphoma), all who did not undergo HSCT succumbed to the disease, and in those who underwent HSCT, the 3-year overall survival was only 27% [16]. The European Lymphoma Bone Marrow Transplantation Registry reported a 5-year EFS of 40% for 89 pediatric patients with refractory/recurrent Burkitt or DLBCL who underwent autologous HSCT [17]. None of the patients with primary refractory disease or chemoresistant relapse survived. Because their study spanned the period 1979-1991, only 10 patients received what would be considered modern first-line therapy, thereby raising concerns as to the applicability of their report in the current era. Several other reports on HSCT for pediatric NHL have included more than one histological subtype, are limited to relatively small numbers of patients, or have included children in a larger series that included adults. Consequently, the role of allogeneic HSCT compared with autologous HSCT for patients in CR2 or recurrent NHL is of interest to the pediatric oncologist 13, 15, 18, 19, 20, 21, 22, 23, 24. The purposes of the present study were to identify prognostic factors affecting outcomes and to assess the optimal donor source for children and adolescents treated with HSCT for refractory or recurrent NHL.

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Patients and Methods 

Data Collection 

Data on patients undergoing HSCT were obtained from the Statistical Center of the Center for International Blood and Marrow Transplant Research (CIBMTR). The CIBMTR is a voluntary working group of more than 500 transplantation centers worldwide that report patient, disease, and transplant characteristics and outcome data on consecutive transplantations to a Statistical Center at the Medical College of Wisconsin. The Institutional Review Board of the Medical College of Wisconsin approved the study design.

Inclusion Criteria 

The study included patients aged≤18 years in CR2 or subsequent CR (ie, complete disappearance of all known disease for≥4 weeks) and refractory/recurrent NHL (ie, relapse or progression, defined as increase in size of sites of disease [≥ 25% increase in largest diameter] and/or new disease sites and/or histological evidence of disease) who received an autologous or allogeneic HSCT as their first transplantation. Patients who had received an autologous transplant before allogeneic transplantation were excluded (n=13). All patients received a myeloablative (MA) transplantation conditioning regimen and underwent transplantation between 1990 and 2005. Ninety autologous transplant recipients and 92 allogeneic transplant recipients were eligible.

Study Endpoints 

Neutrophil recovery was defined as achieving an absolute neutrophil count (ANC) of≥0.5 × 10⁹/L for 3 consecutive days, and platelet recovery and unsupported platelet count>20×10⁹/L for 7 days. The incidence of grade II, III, and IV acute graft-versus-host disease (aGVHD) [25] and chronic GVHD (cGVHD) [26] were determined for allogeneic HSCT. Deaths occurring in continuous remission were defined as treatment-related mortality (TRM). Progression was defined as progressive disease (≥ 28 days from HCST) or recurrent disease in patients who achieved remission posttransplantation. Progression could follow a period of “stable” disease posttransplantation, or partial remission. Progression/recurrence represented an increase in size of sites of disease (≥ 25% increase in largest diameter) and/or new disease sites and/or histological evidence of disease. EFS was defined as survival without recurrent or progression of lymphoma.

Statistical Analysis 

The probability of EFS was calculated with the Kaplan-Meier estimator [27]. For analysis of EFS, relapse or progression of disease or death from any cause was considered an event, and surviving patients were censored at last follow-up. The incidence of neutrophil and platelet recovery, aGVHD and cGVHD, TRM, and relapse/progression were calculated using the cumulative-incidence-function method [27]. For hematopoietic recovery and GVHD, death without the event was the competing event. For TRM, relapse/progression was the competing event, and for relapse/progression, TRM was the competing event. Confidence intervals (CIs) were calculated using log-transformation.

Stratified Cox regression models were built for analysis of risk factors for relapse/progression and EFS [28]. Models were stratified by disease (Burkitt, lymphoblastic, DLBCL, or anaplastic large cell lymphoma) and donor type (autologous or allogeneic). Multivariate models were built using stepwise forward selection, with a P value of ≤ .05 considered to indicate statistical significance. Our primary objective was to determine whether there was an advantage to offering an allogeneic HSCT over autologous HSCT for patients with refractory/recurrent NHL. Other variables considered were age (≤ 10 years vs 11-18 years), sex, performance score (90-100 vs<90), interval from diagnosis to HSCT (< 6 vs 6-12 vs>12 months), disease status (≥ CR2 vs not in remission), graft type (bone marrow [BM] vs peripheral blood [PB]), and year of HSCT (1990-1994 vs 1995-1999 vs 2000-2005). Allogeneic transplants were grouped together regardless of donor type. Before combining HLA-matched sibling and unrelated donor transplant recipients, analyses were preformed to detect differences in transplantation outcome; none were found except for a higher incidence of grade II-IV aGVHD in unrelated donor transplant recipients (data not shown). There was no difference in survival rates between recipients of HLA-matched sibling and unrelated donor transplants. No effect of transplantation center on EFS was found [29]. All analyses were performed using SAS version 9.1 (SAS Institute, Cary, NC). All P values are 2-sided.

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Results 

Table 1 sumarizes patient, disease, and transplant characteristics by donor type. Patients with lymphoblastic lymphoma were more likely than those with the other histological subtypes to undergo allogeneic HSCT. Allogeneic HSCT recipients were more likely to receive an irradiation-containing conditioning regimen, receive a BM graft, and to have undergone transplantation recently. Sixteen patients underwent HSCT for primary induction failure, 14 of whom received an autologous transplant. Approximately 65% of the autologous and allogeneic transplant recipients received 1 or 2 lines of therapy before transplantation, and 35% received 3-5 lines of therapy before transplantation. More than half of the allogeneic recipients received a graft from an unrelated donor, the majority of which were HLA-mismatched. Twenty percent of allogeneic transplant recipients received antithymocyte globulin (ATG) as part of transplantation conditioning. The median follow-up of surviving patients is approximately 6 years after autologous HSCT and 4.5 years after allogeneic HSCT.

Table 1. Patient, disease, and transplant characteristics

	Autologous, n (%)	Allogeneic, n (%)	P value
Number of patients	90	92
Age at transplantation, years
≤10	26 (29)	29 (32)
11-18	64 (71)	63 (68)
Performance score before transplantation			.12
<90%	17 (19)	29 (32)
≥90%	70 (78)	60 (65)
Unknown	3 (3)	3 (3)
Disease			< .001
Diffuse large cell	35 (38)	17 (19)
Lymphoblastic	14 (16)	39 (42)
Burkitt	17 (19)	24 (26)
Anaplastic	24 (27)	12 (13)
Interval from diagnosis to transplantation			.54
<6 months	9 (10)	5 (5)
6-12 months	30 (33)	33 (36)
≥12 months	51 (57)	54 (59)
Disease status before transplantation			.65
≥CR2	43 (48)	47 (51)
Relapse or progression	47 (52)	45 (49)
Interval from diagnosis to first relapse∗			.18
<6 months	15 (20)	29 (32)
6-12 months	23 (30)	21 (23)
>12 months	38 (50)	40 (44)
Conditioning regimen			< .001
TBI + cyclophosphamide	25 (28)	74 (80)
TBI + other agents	10 (11)	5 (6)
Busulfan + cyclophosphamide	4 (5)	13 (2)
Cyclophosphamide + etoposide	26 (29)	0
∗ Other	25 (27)	0
Graft type			< .001
Bone marrow	39 (43)	75 (82)
Peripheral blood	51 (57)	17 (18)
Year of transplantation			< .001
1990-1994	47 (52)	12 (13)
1995-2005	43 (48)	80 (87)
Type of donor
HLA-identical sibling	NA	43 (47)
Unrelated†		49 (53)
Median (range) follow-up, months	71 (2-142)	43 (2-157)

CR indicated complete remission; TBI, total body irradiation.

Hematopoietic Recovery 

The incidence of neutrophil recovery (day +28) was 87% (95% CI=73%-96%) after allogeneic HSCT and 74% (95% CI=62%-85%) after autologous HSCT. The corresponding incidences at day +100 were 93% (95% CI=77%-100%) and 90% (95% CI=75%-99%), respectively. The incidence of platelet recovery (day +100) was 67% (95% CI=54%-78%) following allogeneic HSCT and 76% (95% CI=62%-88%) following autologous HSCT. In 47 patients, neutrophil and/or platelet recovery was not achieved because of either disease progression or death from a transplantation-related complication.

Acute and Chronic GVHD 

Among allogeneic HSCT recipients, the incidence of grade II-IV aGVHD at day +100 was 43% (95% CI=33%-54%; grade II, n=22; grade III, n=11; grade IV, n=5). Fourteen patients developed cGVHD; the 5-year incidence of cGVHD was 16% (95% CI=9%-25%).

Transplantation-Related Mortality 

The 1- and 5-year TRM rates were similar after autologous and allogeneic HSCT: 14% (95% CI=7%-22%) and 24% (95% CI=16%-34%) (P=.08) at 1 and 5 years after autologous HSCT, respectively, and 17% (95% CI=9%-25%) and 25% (95% CI=17%-35%) (P=.15) at 1 and 5 years after allogeneic HSCT, respectively.

Relapse or Progression 

Relapse or progression of disease occurred in 42 patients after autologous HSCT and in 32 patients after allogeneic HSCT. The risk of recurrent or progressive disease was higher in patients who were not in CR at transplantation (relative risk [RR]=2.46; 95% CI=1.50-4.04; P < .01), regardless of donor type. The 90 patients (allogeneic and autologous transplant recipients) who underwent transplantation in CR included 77 in CR2 and 13 in CR3. Given the very few patients who underwent transplantation in CR3, we are unable to provide relapse rates separately for patients in CR2 and CR3. There were no significant differences in the 5-year probability of relapse/progression by donor type for DLBCL, Burkitt lymphoma, and anaplastic large cell lymphoma (Figure 1A, C, and D). The apparent decrease in progression seen in patients with anaplastic large cell lymphoma who underwent allogeneic HSCT did not reach statistical significance. For patients with lymphoblastic lymphoma, the 5-year probability of relapse/progression was lower after allogeneic HSCT compared with autologous HSCT (Figure 1B).

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• Figure 1 

  The probability of recurrent or progressive disease after allogeneic and autologous transplantation for Non-Hodgkin lymphoma: Diffuse Large Cell (1A), Lymphoblastic (1B), Burkitt (1C) and Anaplastic (1D).

Event-Free Survival 

In multivariate analysis, risks of treatment failure (ie, relapse/progression or death; inverse of EFS) were higher for patients who were not in CR at the time of transplantation (RR=2.42; 95% CI=1.62-3.62; P < .01) regardless of donor type, with a 5-year EFS of 28% for autologous HSCT and 20% for allogeneic HSCT. The corresponding probabilities for patients who underwent HSCT in CR2 or CR3 were 40% and 57%, respectively. No effect of the duration of CR1 on EFS was found (RR=0.80; 95% CI=0.58-1.10; P=.16 in patients with a CR1 duration of >12 months compared to≤12 months). The 5-year probabilities of EFS by donor type for Burkitt, DLBCL, and anaplastic large cell lymphoma were similar (Figure 2A, C, and D). The 5-year probability of EFS was higher after allogeneic HSCT compared with autologous HSCT for patients with lymphoblastic lymphoma (Figure 2B). Recurrent or progressive disease was the most frequent cause of death after autologous transplantation (34 of 48 deaths were due to recurrent or progressive disease; 70%) compared to allogeneic transplantation (29 of 50 deaths were due to recurrent or progressive disease; 58%). Deaths from transplantation-related complications were more frequent after allogeneic HSCT (infection, n=8 vs 3; interstitial pneumonitis/adult respiratory syndrome; n=4 vs 6; GVHD, n=1 vs 0; organ failure, n=6 vs 3; other causes, n=3 vs 2).

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• Figure 2 

  The probability of event-free survival after allogeneic and autologous transplantation for Non-Hodgkin lymphoma: Diffuse Large Cell (1A), Lymphoblastic (1B), Burkitt (1C) and Anaplastic (1D).

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Discussion 

The purpose of this study was to identify prognostic factors, including the optimal donor source, in children and adolescents with refractory/recurrent NHL undergoing HSCT. With the current up-front chemotherapy regimens, outcome for pediatric NHL is excellent even for those with advanced (stage III or IV) disease 2, 3, 4, 5, 6, 7, 8, 9. Salvage of patients with refractory or recurrent disease remains very poor, however 10, 11, 12, 13, 14. Because data on front-line therapies for this cohort were not available, patients who underwent HSCT before 1990—before the advent of more aggressive front-line therapies—were excluded from the analysis. EFS was worse for patients not in CR at the time of HSCT independent of donor type, and EFS was superior for patents with lymphoblastic lymphoma after allogeneic HSCT. Our findings confirm and extend the observations of several previous studies. First, salvage rates are higher for large cell lymphoma (DLBCL or anaplastic) compared with small cell lymphoma (Burkitt and lymphoblastic). Second, disease status at transplantation is a strong prognostic indicator 16, 17, 18, 20, 24. Of note, for patients not in CR at the time of transplantation, there appears to be no difference in 5-year EFS after allogeneic HSCT and autologous HSCT (20% vs 28%). Our data also illustrate the complexities of extrapolating results from reports on HSCT in adults with NHL. Our findings differ from those of a study by Levine et al. [21] comparing allogeneic and autologous HSCT for lymphoblastic lymphoma. In that study, fewer than 20% of the study population was aged≤18 years [21]; consequently, the higher TRM after allogeneic HSCT and the absence of a significant difference in EFS after autologous and allogeneic HSCT would be expected and explained by the inclusion of mostly older patients.

Although we found a significantly lower progression rate and improved EFS in patients with lymphoblastic lymphoma after allogeneic HSCT, we were unable to demonstrate a superiority of donor type (autologous vs allogeneic) for Burkitt, DLBCL, or anaplastic large cell lymphoma. It is tempting to speculate that a graft-versus-lymphoma (GVL) effect exists in lymphoblastic lymphoma and perhaps in anaplastic large cell lymphoma as well; however, in our cohort, the numbers were insufficient to allow us to correlate EFS or progression rate with GVHD or to allow examination of differences in EFS for related versus unrelated donor transplant recipients. A recent Berlin-Frankfurt-Munster (BFM) report suggested a benefit of allogeneic HSCT for high-risk anaplastic large cell lymphoma, especially in patients who have relapsed after autologous HSCT [22]. Again, small numbers kept us from examining for an effect of autologous HSCT before allogeneic HSCT.

There are inherent weaknesses in all studies that use data collected by transplantation registries. The outcome of patients who did not undergo HSCT during the study period is unknown, and the decision to offer HSCT or donor choice was not reported. Patients were more likely to receive autologous HSCT early in the study period. This is likely explained by a widespread perception that allogeneic HSCT is superior for pediatric relapsed/refractory NHL. Even though we found no differences in the number of lines of therapy for autologous and allogeneic transplant recipients, in the absence of detailed information on front-line therapies, it is conceivable that the HSCT results in this cohort are biased, as patients may have received front-lines therapies of varying intensity, which could influence EFS after HSCT. We also can speculate that the superior outcome for allogeneic HSCT in the later time period because of improved donor–recipient HLA-matching and improved supportive care, resulting in lower TRM. Although the numbers are small, no differences in outcome over time were observed in the current analysis. Achieving disease control can be very difficult and short-lived, especially in relapsed Burkitt or lymphoblastic lymphoma, and this may influence donor selection. There may exist a bias favoring allogeneic HSCT, as unrelated donor HSCT (50% of allogeneic HSCT) was likely pursued only in patients with more responsive disease and durable remissions. We found no difference in time to transplantation between autologous and allogeneic HSCT in this cohort, however. Disease characteristics, such as involvement of site(s) at diagnosis and relapse, and their impact on HSCT outcome were not examined, because these data were not adequately captured.

Despite these limitations, however, our study population represents the largest pediatric NHL cohort to have received HSCT as salvage therapy. It is unlikely that a randomized study will ever be done to assess the benefit of autologous versus allogeneic HSCT in pediatric NHL, because of the relatively small numbers of patients and the inherent problems of donor availability when considering allogeneic HSCT. Therefore, using data collected by transplantation registries offer an alternative for studying treatment choices, although this is not ideal. We demonstrate that both autologous and allogeneic HSCT can be effective in salvaging children and adolescents with refractory or recurrent NHL and results are superior if CR can be achieved before HSCT. In addition, the data suggest that an allogeneic donor is preferred for patients with lymphoblastic lymphoma.

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Acknowledgments 

Financial disclosure: The CIBMTR is supported by Public Health Service Grant/Cooperative Agreement U24-CA76518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI), and the National Institute of Allergy and Infectious Diseases (NIAID); Grant/Cooperative Agreement 5U01HL069294 from NHLBI and NCI; Contract HHSH234200637015C with the Health Resources and Services Administration (HRSA/DHHS); Grants N00014-06-1-0704 and N00014-08-1-0058 from the Office of Naval Research; and grants from AABB; Aetna; American Society for Blood and Marrow Transplantation; Amgen, Inc; anonymous donation to the Medical College of Wisconsin; Astellas Pharma US, Inc; Baxter International, Inc; Bayer HealthCare Pharmaceuticals; Be the Match Foundation; Biogen IDEC; BioMarin Pharmaceutical, Inc; Biovitrum AB; BloodCenter of Wisconsin; Blue Cross and Blue Shield Association; Bone Marrow Foundation; Canadian Blood and Marrow Transplant Group; CaridianBCT; Celgene Corporation; CellGenix, GmbH; Centers for Disease Control and Prevention; Children's Leukemia Research Association; ClinImmune Labs; CTI Clinical Trial and Consulting Services; Cubist Pharmaceuticals; Cylex Inc; CytoTherm; DOR BioPharma, Inc; Dynal Biotech, an Invitrogen Company; Eisai, Inc; Enzon Pharmaceuticals, Inc; European Group for Blood and Marrow Transplantation; Gamida Cell, Ltd; GE Healthcare; Genentech, Inc; Genzyme Corporation; Histogenetics, Inc; HKS Medical Information Systems; Hospira, Inc; Infectious Diseases Society of America; Kiadis Pharma; Kirin Brewery Co, Ltd; The Leukemia & Lymphoma Society; Merck & Company; The Medical College of Wisconsin; MGI Pharma, Inc; Michigan Community Blood Centers; Millennium Pharmaceuticals, Inc; Miller Pharmacal Group; Milliman USA, Inc; Miltenyi Biotec, Inc; National Marrow Donor Program; Nature Publishing Group; New York Blood Center; Novartis Oncology; Oncology Nursing Society; Osiris Therapeutics, Inc; Otsuka America Pharmaceutical, Inc; Pall Life Sciences; Pfizer Inc; Saladax Biomedical, Inc; Schering Corporation; Society for Healthcare Epidemiology of America; StemCyte, Inc; StemSoft Software, Inc; Sysmex America, Inc; Teva Pharmaceutical Industries; THERAKOS, Inc; Thermogenesis Corporation; Vidacare Corporation; Vion Pharmaceuticals, Inc; ViraCor Laboratories; ViroPharma, Inc; and Wellpoint, Inc. The views expressed in this article do not reflect the official policy or position of the National Institutes of Health, the Department of the Navy, the Department of Defense, or any other agency of the US Government.

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