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Journal of Clinical Oncology logoLink to Journal of Clinical Oncology
. 2019 Jul 8;37(28):2556–2570. doi: 10.1200/JCO.19.00525

Late Health Outcomes After Contemporary Lymphome Malin de Burkitt Therapy for Mature B-Cell Non-Hodgkin Lymphoma: A Report From the Childhood Cancer Survivor Study

Matthew J Ehrhardt 1,✉, Yan Chen 2, John T Sandlund 1, Elizabeth C Bluhm 3, Robert J Hayashi 4, Kerri Becktell 5, Wendy M Leisenring 6, Monika L Metzger 1, Kirsten K Ness 1, Kevin R Krull 1, Kevin C Oeffinger 7, Todd M Gibson 1, Mitchell S Cairo 8, Thomas G Gross 9, Leslie L Robison 1, Gregory T Armstrong 1, Yutaka Yasui 1, Melissa M Hudson 1, Daniel A Mulrooney 1
PMCID: PMC7001792  PMID: 31283408

Abstract

PURPOSE

The widely used, risk-based Lymphome Malin de Burkitt (LMB) chemotherapy regimen has improved survival rates for children with mature B-cell non-Hodgkin lymphoma (NHL); however, associated late effects remain understudied. We assessed late health outcomes after LMB treatment in the Childhood Cancer Survivor Study.

PATIENTS AND METHODS

Multivariable regression models compared chronic health conditions, health status, and socioeconomic and neurocognitive outcomes between survivors of NHL treated with the LMB regimen (n = 126), survivors of NHL treated with non-LMB regimens (n = 444), and siblings (n = 1,029).

RESULTS

LMB survivors were a median age of 10.2 years (range, 2.5 to 20.5 years) at diagnosis and 24.0 years (range, 10.3 to 35.3 years) at evaluation. Compared with siblings, LMB survivors were at increased risk for adverse health outcomes. However, survivors of NHL treated with LMB and non-LMB regimens did not differ with regard to risk of having any chronic health conditions, impaired health status, neurocognitive deficits, or poorer socioeconomic outcomes. Increased risk for the following specific neurologic conditions was observed in LMB survivors compared with non-LMB survivors: epilepsy (relative risk [RR], 15.2; 95% CI, 3.1 to 73.4); balance problems (RR, 8.9; 95% CI, 2.3 to 34.8); tremors (RR, 7.5; 95% CI, 1.9 to 29.9); weakness in legs (RR, 8.1; 95% CI, 2.5 to 26.4); severe headaches (RR, 3.2; 95% CI, 1.6 to 6.3); and prolonged arm, leg, or back pain (RR, 4.0; 95% CI, 2.2 to 7.1). The survivors from the group C LMB risk group (n = 50) were at the highest risk for these conditions; however, except for worse functional status (odds ratio, 2.7; 95% CI, 1.2 to 5.8), they were not at increased risk for other adverse health status or socioeconomic outcomes compared with non-LMB survivors.

CONCLUSION

Survivors treated with LMB and non-LMB regimens are largely comparable in late health outcomes except for excess neurotoxicity among LMB survivors. These data inform treatment efforts seeking to optimize disease control while minimizing toxicity.

INTRODUCTION

Five-year survival rates for children with non-Hodgkin lymphoma (NHL) have steadily improved and now exceed 80%.1 Historical treatments for this heterogeneous disease have included a variety of chemotherapeutic agents and sometimes radiation. Histology-directed approaches have diversified NHL treatment,2 rendering investigations of late effects challenging and limiting thorough evaluation of risk factors for adverse outcomes.3

Evolution of therapy has altered therapeutic exposures that may substantially influence long-term health. Specifically, mature B-cell lymphoma (approximately 60% of pediatric NHL) treatment changed in the 1990s with the optimization of the Lymphome Malin de Burkitt (LMB)2,4-11 and Berlin-Frankfurt-Münster12-16 regimens. For example, a series of LMB trials demonstrated that cranial radiation could be replaced by intensifying CNS-directed therapy with high-dose systemic and intrathecal chemotherapies without compromising cure.2,4,9-11 Treatment is now composed of a highly effective, risk-based (groups A, B, and C) approach distinct from other NHL regimens (Table 1). The success of LMB therapy was recently bolstered by promising results from the integration of rituximab,17,18 prompting consideration of therapy reductions to mitigate toxicity. However, late health outcomes after LMB have not been reported and are necessary to inform potential therapeutic reductions.

TABLE 1.

Cumulative Chemotherapy Exposures in Recent LMB-Based Mature B-Cell Lymphoma Studies

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Widespread LMB use in North America began in the mid-1990s; therefore, the recently expanded Childhood Cancer Survivor Study (CCSS) cohort (survivors treated from 1987 to 1999) provides an opportunity to study the long-term health effects of this valuable regimen. The objectives of this study were to determine whether intensification of chemotherapy through the use of the LMB regimen has increased the risk of late health conditions compared with historically used, non-LMB regimens and to inform future treatment modifications designed to mitigate late toxicity.

PATIENTS AND METHODS

Study Design

The CCSS is a retrospective cohort of 5-year survivors of childhood cancer from participating institutions across North America. The CCSS protocol was approved by the institutional review boards from each center, all study participants provided informed consent, and the methods have been previously described.19-21 The original CCSS cohort (survivors of cancer diagnosed between 1970 and 1986) was expanded to include survivors diagnosed between 1987 and 1999. Characteristics of both groups are available on the CCSS Web site.22 Given the overlap with the onset of contemporary LMB therapy in the 1990s, our investigation uses only the CCSS expansion cohort. Treatment exposures were obtained from medical records.

Participants

Participants with International Classification of Diseases for Oncology morphology codes potentially including mature B-cell lymphomas were reviewed for eligibility (Fig 1). Although the CCSS attempts to collect discrete treatment protocol names (eg, LMB group B) or trial mnemonics (eg, Children’s Cancer Group 5961, Pediatric Oncology Group 8719; non-LMB regimens are provided in the Data Supplement), they are not uniformly provided for all participants, prohibiting direct identification of treatment regimen based solely on this parameter. In such instances, diagnosis, treatment dates, and chemotherapy combinations and cumulative exposures were reviewed to identify survivors treated according to a known B-cell regimen. For LMB protocols, corresponding low-risk (group A), medium-risk (group B), and high-risk (group C) groups were identified. Similarly, individuals enrolled in or treated according to known lymphoblastic leukemia or lymphoma or anaplastic large-cell lymphoma protocols were identified and excluded. Because contemporary LMB therapy (LMB96 onward) does not include radiation, individuals who received up-front radiation in combination with an LMB regimen were excluded (n = 3). Because radiation was used before contemporary LMB therapy, non–LMB-treated participants who received radiation were not excluded from the comparison group. Individuals believed to have survived relapsed or refractory disease were identified through a combination of self-report, treatment per a relapsed protocol, and/or timing of exposure to chemotherapy agents to be excluded for sensitivity analyses. These selections were chosen to focus on the evaluation of the cost of surviving contemporary versus historical curative treatment regimens.

FIG 1.

FIG 1.

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CONSORT diagram. (*) International Classification of Diseases for Oncology (ICD-O) codes and diagnoses that were not considered mature B-cell non-Hodgkin lymphoma (NHL) included the following: M9670/3, malignant lymphoma, small lymphocytic not otherwise specified (NOS); M9671/3, malignant lymphoma, lymphoplasmacytic; M9672/3, malignant lymphoma, small cleaved cell, diffuse; M9673/3, malignant lymphoma, lymphocytic, intermediate differentiation, diffuse; M9675/3, malignant lymphoma, mixed small and large cell, diffuse; M9685/3, malignant lymphoma, lymphoblastic; M9690/3, malignant lymphoma, follicular NOS; M9691/3, malignant lymphoma, mixed small cleaved and large cell, follicular; M9698/3, malignant lymphoma, large cell, follicular NOS; M9700/3, mycosis fungoides; M9702/3, peripheral T-cell lymphoma NOS; M9709/3, cutaneous lymphoma; M9713/3, angiocentric T-cell lymphoma; M9714/3, large-cell (Ki-1 positive) lymphoma; M9720/3, malignant histiocytosis; and M9760/3, immunoproliferative disease NOS. (†) ICD-O codes and diagnoses potentially consistent with mature B-cell NHL included the following: M9590/3, malignant lymphoma NOS; M9591/3, malignant lymphoma, non-Hodgkin NOS; M9595/3, malignant lymphoma, diffuse; M9680/3, malignant lymphoma, large cell, diffuse NOS; M9686/3, malignant lymphoma, small cell, noncleaved, diffuse; and M9687/3, Burkitt lymphoma NOS. (‡) One Lymphome Malin de Burkitt (LMB)–treated participant was identified by a listed LMB protocol but could not be categorized into Group A, B, or C because chemotherapy doses were not provided. CCG, Children’s Cancer Group; POG, Pediatric Oncology Group.; CCSS, Childhood Cancer Survivor Study.

Outcomes

Chronic health conditions (cataracts, hypothyroidism, cardiomyopathy, stroke, growth hormone deficiency, osteoporosis, problems with eating, epilepsy, balance problems, tremors, weakness in legs, weakness in arms, sensory neuropathy, migraines, severe headaches, and prolonged pain in arms, legs, and/or back) were assessed and assigned Common Terminology Criteria for Adverse Events severity grades on the basis of survey response.23 Obesity was defined as a body mass index (BMI) of 30 kg/m2 or greater (age ≥ 20 years) or as 95th percentile or higher of age- and sex-specific US norms (age < 20 years). Participants age 15 to 44 years at assessment were considered to have decreased fertility if they reported having tried for 1 year or more to become pregnant without success. Obesity and fertility were not assigned severity grades or considered in time-to-event analyses (chronic condition models) because onset dates were often unknown. Subsequent malignant neoplasms (SMNs) were self-reported and confirmed by central pathology report review. Late mortality (> 5 years from diagnosis) was identified through linkage with the National Death Index.24

Health status was assessed from questionnaires according to published methods.25,26 Mental health assessments used the Brief Symptom Inventory-18, with poor mental health assigned to those with sex-specific T-scores of 63 or greater on the Global Severity Index or any two of the Depression, Anxiety, or Somatization subscales,27 whereas general health, functional status, activity limitations, and cancer-related pain and anxiety were assessed according to survey responses.26

The following socioeconomic status outcomes were dichotomized: annual household income (< v ≥ $60,000), educational attainment (< v ≥ college degree [individuals ≥ 25 years old]), marital status (ever married or have lived as married v single [individuals ≥ 30 years old]), insurance status (insured v uninsured), and living independently (living in military or university housing, alone, or with spouse or partner, roommates, children, or friends v living with parents or relatives, in nursing care, or with a caregiver [individuals ≥ 21 years old]).

A subset of patients completed additional follow-up that included a neurocognitive assessment using the CCSS Neurocognitive Questionnaire, a self-report measure validated for adult survivors of childhood cancer, normalized to a large cohort of survivor siblings, that assesses the following four domains: task efficiency, emotional regulation, organization, and memory.28 T-scores of 62.82 of greater (≥ 90th percentile of the sibling score distribution) are classified as impaired.

Statistical Analysis

Demographic characteristics were compared between LMB-treated and non–LMB-treated survivors and between LMB-treated survivors and siblings using χ2 tests, with bootstrapping of families to account for potential within-family correlation of survivors and siblings.29 Standardized mortality ratios (SMRs) were calculated using published age-, sex-, and calendar year–specific US mortality rates30 beginning 5 years from NHL diagnosis until date of death or last date of National Death Index mortality ascertainment (December 31, 2013). Standardized incidence ratios were calculated by dividing the number of observed SMNs by the age-, sex-, calendar year–, and race-matched number of expected SMNs from the SEER Program.31

Piecewise exponential models, adjusted for sex, race, and attained age (natural cubic splines with knots at 10 to 30 years old with 5-year intervals), were used to evaluate the rate of developing specific chronic health conditions, whereas risk of having any condition (grades 1 to 5) among survivors treated with LMB chemotherapy, survivors treated with non-LMB chemotherapy, and siblings was assessed adjusting for sex, race, attained age, alcohol use, smoking, BMI, and physical activity. At-risk time was considered from cohort entry to the earliest of onset of the chronic condition of interest, SMN diagnosis, death, or completion of the last questionnaire. Only the first occurrence of a specific chronic condition was considered. Survivors who developed a chronic condition before cohort entry were included in analysis of developing any chronic health condition because additional conditions could have subsequently developed; however, specific chronic condition analyses excluded those who developed the condition before cohort entry.

Multivariable logistic regression was used to evaluate the prevalence of obesity, decreased fertility, poor health status, lower socioeconomic outcomes, and impaired neurocognitive function between groups, excluding survivors who developed an SMN before questionnaire completion. Obesity and decreased fertility models were adjusted for sex, race, and age at questionnaire completion. Health status, sociodemographic, and neurocognitive outcome models were adjusted for sex and age at questionnaire completion. The generalized estimating equation was used to account for within-family correlation of survivors and siblings.32 Effects of specific treatment exposures were assessed using the methods described earlier for outcomes with sufficient numbers of patients. All previously described analyses were repeated after excluding survivors with relapsed or progressive disease to understand the implications of additive therapy.

RESULTS

We identified 126 survivors of mature B-cell NHL treated with LMB and 444 survivors treated with non-LMB regimens between 1987 and 1999 (Table 2). The median age of LMB survivors was 10.2 years (range, 2.5 to 20.5 years) at diagnosis and 24.0 years (range, 10.3 to 35.3 years) at evaluation. Non-LMB survivors were slightly older at evaluation than LMB survivors (29.2 v 24.0 years, respectively; P < .001). LMB-treated survivors, compared with non-LMB survivors, were more likely to have received prednisone (95% v 67%, respectively; P < .001), etoposide (39% v 26%, respectively; P = .005), and cytarabine (87% v 61%, respectively; P < .001). Although LMB survivors, compared with non-LMB survivors, received higher mean cumulative doses of intravenous methotrexate (17,019.9 v 5,413.3 mg/m2, respectively; P < .001), intrathecal methotrexate (102.2 v 83.3 mg/m2, respectively; P = .001), and etoposide (2,118.5 v 1,621.0 mg/m2, respectively; P = .002), they received lower doses of vincristine (7.8 v 15.8 mg/m2, respectively; P < .001). The mean cumulative cyclophosphamide and doxorubicin doses did not differ between the two groups. Only 15% of non–LMB-treated survivors received radiation.

TABLE 2.

Demographic, Lymphoma, and Treatment Characteristics of Survivors of Mature B-Cell Lymphoma in the CCSS Cohort Diagnosed Between 1987 and 1999

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Mortality

Survivors treated with LMB chemotherapy experienced similarly increased mortality risk (SMR, 3.1; 95% CI, 0.8 to 8.0; P = .082) compared with survivors treated with non-LMB regimens (SMR, 3.9; 95% CI, 2.6 to 5.5; P < .001). However, LMB survivors did not statistically differ from the general population.

Chronic Health Conditions

Survivors and siblings experienced a number of chronic health conditions (Fig 2). In multivariable models adjusted for sex, race, attained age, alcohol use, smoking, BMI, and physical activity, LMB and non-LMB survivors did not differ with respect to having any grade 1 to 5 condition (relative risk [RR], 1.7; 95% CI, 0.97 to 3.0; P = .074). However, both survivors treated with LMB (RR, 3.7; 95% CI, 2.1 to 6.4; P < .001) and survivors treated with non-LMB regimens (RR, 2.2; 95% CI, 1.5 to 3.1; P < .001) were more likely to report chronic health conditions compared with siblings (Table 3). LMB and non-LMB survivors did not differ with regard to risk of infertility, obesity, cataracts, hypothyroidism, cardiomyopathy, stroke, growth hormone deficiency, osteoporosis, problems with eating, weakness in arms, sensory neuropathy, or migraines. However, LMB survivors were at greater risk for specific neurologic conditions compared with non-LMB survivors, including epilepsy (RR, 15.2; 95% CI, 3.1 to 73.4; P < .001); balance problems (RR, 8.9; 95% CI, 2.3 to 34.8; P = .002); tremors (RR, 7.5; 95% CI, 1.9 to 29.9; P = .004); weakness in legs (RR, 8.1; 95% CI, 2.5 to 26.4; P < .001); severe headaches (RR, 3.2; 95% CI, 1.6 to 6.3; P < .001); and prolonged pain in the arms, legs, or back (RR, 4.0; 95% CI, 2.2 to 7.1; P < .001). In separate models (Data Supplement), group C survivors were among those at greatest risk for epilepsy (RR, 22.4; 95% CI, 4.3 to 115.7; P < .001); balance problems (RR, 11.3; 95% CI, 2.5 to 50.4; P = .002); tremors (RR, 12.8; 95% CI, 3.1 to 53.8; P < .001); weakness in legs (RR, 17.8; 95% CI, 5.4 to 58.0; P < .001); sensory neuropathy (RR, 3.6; 95% CI, 1.3 to 9.4; P = .011); migraines (RR, 2.7; 95% CI, 1.2 to 5.9; P = .016); severe headaches (RR, 4.5; 95% CI, 2.1 to 9.8; P < .001); and prolonged pain in the arms, legs, and back (RR, 5.2; 95% CI, 2.5 to 10.6; P < .001), compared with non-LMB survivors, with a notably higher prevalence of these conditions compared with groups A and B combined. In models adjusted for sex, race, years since diagnosis, and attained age, there were no associations identified between individual chemotherapeutic agents and report of a grade 1 to 5 chronic health condition (Data Supplement).

FIG 2.

FIG 2.

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Percentage of individuals with chronic health conditions among mature B-cell lymphoma survivors treated with Lymphome Malin de Burkitt (LMB) and non-LMB regimens and siblings between 1987 and 1999 in the Childhood Cancer Survivor Study. (*) Does not include fertility or obesity because onset date was often unknown.

TABLE 3.

Prevalence and Risk of Chronic Health Conditions in Survivors of NHL Treated With LMB Regimens and Non-LMB Regimens and in Siblings

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SMNs

Among survivors treated with LMB chemotherapy, with a mean follow-up time of 9 years (range, 2 to 17 years; 1,165 person-years), none developed an SMN. Conversely, among non–LMB-treated survivors, the SMN incidence rate was 2.2 per 1,000 person-years (5,871 total person-years), representing a standardized incidence ratio of 4.4 (95% CI, 2.5 to 7.1).

Health Status

After adjusting for sex and age at questionnaire, LMB survivors reported similar general health, mental health, functional status, activity limitations, and cancer-related pain and anxiety compared with non-LMB survivors. Compared with siblings, LMB-treated survivors reported poorer general health (odds ratio [OR], 3.1; 95% CI, 1.7 to 5.8; P < .001), mental health (OR, 3.1; 95% CI, 1.5 to 6.2; P = .001), functional status (OR, 5.9; 95% CI, 3.1 to 11.2; P < .001), and activity limitations (OR, 3.2; 95% CI, 1.6 to 6.3; P < .001; Table 4). In separate models (Data Supplement), group C survivors were at increased risk for poorer functional status (OR, 2.7; 95% CI, 1.2 to 5.8; P = .014) compared with non-LMB survivors; however, they did not differ with respect to other health status or socioeconomic outcomes. In models adjusted for sex, race, and age at questionnaire, no associations were identified between individual chemotherapeutic agents and health status outcomes (Data Supplement).

TABLE 4.

Health and Socioeconomic Status in Survivors of NHL Treated With LMB Regimens and Non-LMB Regimens and in Siblings

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Socioeconomic Status

In models adjusted for sex and attained age at questionnaire, LMB survivors were not at increased risk for lower household income, being uninsured, having received less than a college degree, never marrying, or living dependently compared with non-LMB survivors. Compared with siblings, both LMB and non-LMB survivors were at risk for having lower household income (OR, 2.0; 95% CI, 1.3 to 3.0; P = .001 and OR, 1.8; 95% CI, 1.4 to 2.3; P < .001, respectively), having not received a college education (OR, 2.2; 95% CI, 1.2 to 3.8; P = .008 and OR, 1.5; 95% CI, 1.1 to 2.0; P = .005, respectively), and being uninsured (OR, 2.0; 95% CI, 1.2 to 3.3; P = .005 and OR, 1.9; 95% CI, 1.4 to 2.6; P < .001, respectively), but they were not at increased risk for never marrying or dependent living (Table 4).

Neurocognitive Status

For a subset of the cohort who had completed an additional follow-up survey that included neurocognitive outcomes (LMB survivors, n = 56; non-LMB survivors, n = 233; siblings, n = 340), the median duration of follow-up was 18.5 years (range, 15.1 to 23.7 years) in LMB survivors and 23.1 years (range, 15.9 to 29.1 years) in non-LMB survivors. In models adjusted for sex and age at questionnaire, LMB survivors were not at increased risk for reporting impaired memory, organization, emotional regulation, or task efficiency compared with either siblings or non-LMB survivors (Table 5).

TABLE 5.

Neurocognitive Function in Survivors of NHL Treated With LMB Regimens and Non-LMB Regimens and in Siblings

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Sensitivity Analysis

Excluding survivors who potentially experienced relapse (two LMB survivors and 28 non-LMB survivors), we saw the same patterns of chronic disease (including neurologic conditions), health status, socioeconomics, and neurocognitive relationships identified in the aforementioned results (Data Supplement).

DISCUSSION

The current study comprehensively reports late-occurring chronic health conditions, health status, socioeconomic outcomes, and neurocognitive outcomes for survivors of mature B-cell NHL treated with contemporary LMB chemotherapy. Although LMB-treated survivors report more chronic health conditions and worse health and socioeconomic status compared with siblings, outcomes compared similarly to survivors treated with non-LMB regimens, although the spectrum of conditions prevalent within each group differed significantly. Differences between LMB and non-LMB survivors were noted in the neurologic system, predominantly in the highest risk (group C) LMB survivors, suggesting an association with therapy intensification for these individuals.

Recent success incorporating rituximab into the LMB backbone17,18 has prompted discussion of therapy reductions; however, poor salvage rates for survivors who experience disease relapse give pause to these considerations.33,34 Our findings provide much needed late toxicity data to inform these critical decisions and new front-line protocol development. LMB survivors (predominantly group C) demonstrated excess risk for several neurologic conditions compared with survivors treated with non-LMB therapy. Although much of the LMB regimen’s success can likely be attributed to the addition of high-dose methotrexate, cytarabine, and intrathecal prophylaxis, it is not surprising that these agents might increase risk for adverse neurologic conditions. It is reassuring, however, that only a small proportion of our LMB survivors reported these conditions (Fig 2) and that measures of impairment in overall health status, with the exception of functional status, were not increased compared with non–LMB-treated survivors. Thus, although the LMB regimen has inarguably intensified therapy and improved survival rates, our data suggest that these changes have not significantly increased the prevalence of overall morbidity for the majority of survivors (groups A and B) compared with previous regimens.

Although associations between higher doses of methotrexate and neurocognitive impairment have been identified in other disease groups,35,36 the same was not observed in our cohort. This is likely a limitation of our relatively small proportion of LMB survivors reporting neurocognitive outcomes. Although additional investigation is needed before definitive conclusions can be made regarding the effects of LMB therapy on neurocognition, our findings are reassuring, in particular given that despite LMB-associated intensification of CNS-directed therapy, approximately 15% to 20% of patients still experience relapse37 and poor salvage rates,33,34 supporting the continuation of this approach. Although the recent addition of rituximab to high-risk patients improved the 1-year event-free survival rates from 82% to 94%,17,18 additional follow-up is required to determine the sustainability of this effect, as well as the contribution of specific cytotoxic agents given within the context of a rituximab-containing regimen, to inform future iterations of LMB therapy.

These results should be interpreted within the context of the following limitations. First, survivors were not identified strictly by treatment protocol enrollment. The precise chemotherapy each survivor received may, therefore, have varied slightly from expected doses; however, our selection criteria and detailed cumulative dose review minimize this variation. Although it would have been informative to compare high-risk LMB and non-LMB survivors, incomplete stage reporting in CCSS precluded such an analysis. In addition, no LMB-treated survivors received radiation, and most relapses occurred in the non-LMB group. Although this may have affected the respective late effects observed, these characteristics are inherently associated with long-term survivors of each respective treatment group; therefore, this strategy was critical to understanding the cost of cure resulting from each approach. We observed a greater than anticipated proportion of LMB group C survivors. This is largely a result of inclusion of Children’s Cancer Group 5911 study survivors (Orange regimen v LMB89 group C–like treatment) and should not alter our findings. We could not address late effects for the equally effective Berlin-Frankfurt-Münster regimen as a result of preferential LMB use in North America. In addition, the sample size and low frequency of events precluded our ability to robustly assess treatment exposures and specific health outcomes. We were reassured, however, by the low event frequency and that LMB chemotherapy doses largely fall within acceptable ranges regarding late toxicity. Notably, our neurocognitive results represent a subset of the cohort with additional follow-up and, therefore, may reflect participation bias. Finally, although our overall follow-up duration is relatively short, it represents the longest to date for LMB survivors and informs a critical gap in the literature.

In summary, the successful LMB chemotherapy regimen has not substantially increased overall morbidity but has altered the spectrum of health conditions experienced by survivors of mature B-cell lymphoma. These data will inform development of future LMB-based protocols, while continued follow-up will determine the future trajectory of the late health impacts of LMB therapy.

ACKNOWLEDGMENT

We are grateful for the considerable efforts of the research, clinical, and administrative staff who support Childhood Cancer Survivor Study and the survivors and their families from whom it is our privilege to learn.

Footnotes

Presented, in part, at the 58th Annual Meeting of the American Society of Hematology, San Diego, CA, December 3-6, 2016.

Supported by National Cancer Institute Grant No. CA55727 (principal investigator G.T.A.), Cancer Center Support (Core) Grant No. CA21765 to St Jude Children’s Research Hospital (principal investigator C. Roberts), and the American Lebanese Syrian Associated Charities (Memphis, TN).

AUTHOR CONTRIBUTIONS

Conception and design: Matthew J. Ehrhardt, John T. Sandlund, Robert J. Hayashi, Wendy M. Leisenring, Monika L. Metzger, Kirsten K. Ness, Kevin C. Oeffinger, Mitchell S. Cairo, Leslie L. Robison, Gregory T. Armstrong, Melissa M. Hudson, Daniel A. Mulrooney

Financial support: Leslie L. Robison, Gregory T. Armstrong

Administrative support: Leslie L. Robison

Provision of study materials or patients: Leslie L. Robison, Gregory T. Armstrong, Melissa M. Hudson

Collection and assembly of data: Matthew J. Ehrhardt, Kerri Becktell, Wendy M. Leisenring, Mitchell S. Cairo, Leslie L. Robison, Gregory T. Armstrong, Melissa M. Hudson

Data analysis and interpretation: Matthew J. Ehrhardt, Yan Chen, John T. Sandlund, Elizabeth C. Bluhm, Robert J. Hayashi, Wendy M. Leisenring, Monika L. Metzger, Kevin R. Krull, Kevin C. Oeffinger, Todd M. Gibson, Mitchell S. Cairo, Thomas G. Gross, Leslie L. Robison, Yutaka Yasui, Melissa M. Hudson, Daniel A. Mulrooney

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Late Health Outcomes After Contemporary Lymphome Malin de Burkitt Therapy for Mature B-Cell Non-Hodgkin Lymphoma: A Report From the Childhood Cancer Survivor Study

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.

Robert J. Hayashi

Consulting or Advisory Role: Otonomy

Travel, Accommodations, Expenses: Otonomy

Monika L. Metzger

Research Funding: Seattle Genetics

Kevin R. Krull

Patents, Royalties, Other Intellectual Property: Royalties from Wolters Kluwer

Mitchell S. Cairo

Consulting or Advisory Role: Jazz Pharmaceuticals, Nektar

Speakers' Bureau: Jazz Pharmaceuticals, Servier

Research Funding: Jazz Pharmaceuticals, Pfizer, Celularity, Leadiant Biosciences

Melissa M. Hudson

Consulting or Advisory Role: Coleman Supportive Oncology Initiative for Children with Cancer, Oncology Research Information Exchange Network, Princess Máxima Center

No other potential conflicts of interest were reported.

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