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. Author manuscript; available in PMC: 2019 Sep 1.
Published in final edited form as: Br J Haematol. 2018 Jul 9;182(6):859–869. doi: 10.1111/bjh.15491

Overall survival of children and adolescents with mature B cell non-Hodgkin lymphoma who had refractory or relapsed disease during or after treatment with FAB/LMB 96: A report from the FAB/LMB 96 study group

Mitchell Cairo 1, Anne Auperin 2, Sherrie L Perkins 3, Ross Pinkerton 4, Lauren Harrison 1, Stanton Goldman 5, Catherine Patte 2, on behalf of the FAB/LMB 96 International Study Committee
PMCID: PMC6128751  NIHMSID: NIHMS976267  PMID: 29984828

Summary

We determined the risk factors associated with poor survival in children and adolescents with de novo mature B cell non-Hodgkin lymphoma (B-NHL) who had refractory or relapsed disease during or after the French-American-British mature lymphoma B (FAB/LMB) 96 multi-agent chemotherapy. Among the 1,111 registered on study, 104 patients (9.4%) had refractory disease or disease relapse after first complete remission. Among these 104 patients, 28 (27%) patients had refractory disease and 76 (73%) had relapsed disease. The estimated 1- and 2-year overall survival (OS) (95% confidence interval) was 31.5% (23.3–41.0%) and 22.3% (15.3–31.4%), respectively. Prognostic analysis of OS using a Cox multivariate model showed that factors independently associated with OS included lactate dehydrogenase ≥2 upper normal limit [hazard ratio (HR) = 2.86 (1.57–5.2), P=0.0006]; time to failure (>6 months) [HR = 0·59 (0.36–0.97), P=0.038]; and failure in bone marrow [HR = 2.78 (1.65–4.68), P=0.0001]. New therapeutic strategies are required to significantly reduce refractory disease and disease relapse in patients with newly diagnosed mature B-NHL and, more importantly, there is a critical need to develop novel retrieval approaches in patients with chemotherapy-resistant disease.

Keywords: B-cell non-Hodgkin lymphoma, paediatrics, overall survival, chemotherapy

Introduction

The prognosis for children and adolescents with newly diagnosed mature B cell non-Hodgkin lymphoma (B-NHL) has significantly improved over the past 35 years with the use of short intensive multi-agent chemotherapy. The excellent results of children and adolescents with newly diagnosed B-NHL treated on the French-American-British/mature lymphoma B (FAB/LMB) 96 international trial have previously been reported by our group.(Cairo, et al 2007, Cairo, et al 2012, Gerrard, et al 2008, Gerrard, et al 2013, Patte, et al 2007) The 5-year event-free survival for patients with limited disease (Group A) intermediate risk (Group B) and advanced stage (Group C) was 97±0.5%, 89±1.2% and 79±2.7%, respectively (Cairo, et al 2007, Cairo, et al 2012, Gerrard, et al 2008, Gerrard, et al 2013, Patte, et al 2007). Overall, the results demonstrated that only two cycles of therapy are required for limited stage disease, therapy could be reduced in intensity for intermediate risk disease but that patients with most advanced disease (bone marrow [BM] ± central nervous system [CNS] disease) require full intensity FAB/LMB 96 therapy).(Cairo, et al 2007, Cairo, et al 2012, Gerrard, et al 2008, Gerrard, et al 2013, Patte, et al 2007)

The factors that were significantly associated with refractory disease or disease relapse during or after FAB/LMB 96 in children and adolescents with mature B-NHL have been reported.(Cairo, et al 2007, Patte, et al 2007) In a multivariate analysis, initial lactate dehydrogenase (LDH) level (<2 vs ≥ 2 times upper limit of normal [ULN]), and primary site (BM+/CNS+ and mediastinal large B cell lymphomas) were significantly associated with an increased risk of refractory disease or disease relapse in children and adolescents treated on FAB/LMB 96.(Cairo, et al 2007, Patte, et al 2007)

The retrieval and survival rate in children and adolescents who had refractory disease or disease relapse on or after this type of short intensive multi-agent chemotherapy, however, has steadily decreased, presumably secondary to chemoresistant disease.(Atra, et al 2000, Bowman, et al 1996, Cairo, et al 2007, Cairo, et al 2002, Cairo, et al 2012, Cairo, et al 2003a, Cairo, et al 2003b, Gerrard, et al 2008, Gerrard, et al 2013, Magrath, et al 1996, Patte, et al 2007, Patte, et al 2001, Patte, et al 1986, Patte, et al 1991, Pillon, et al 2011, Reiter, et al 1999, Spreafico, et al 2002, Woessmann, et al 2005) Few studies have analysed the outcome of children and adolescents with mature B-NHL who had refractory disease or disease relapse after identical original upfront chemotherapy.(Anoop, et al 2012, Fujita, et al 2008) Jourdain et al (2015) recently reported the results of children and adolescents with de novo B-NHL who had disease failure after different LMB regimens in three consecutive Societe Francaise d’Oncologie Pediatrique (SFOP) studies and excluded patients with induction failure or refractory disease. We therefore analysed the impact of possible risk factors that were associated with significantly decreased overall survival (OS) in children and adolescents treated only on one identical upfront treatment protocol, FAB/LMB 96, and who had either refractory or relapsed disease during or after study completion.

Methods

The FAB/LMB 96 was a cooperative international study from over 161 paediatric oncology centres within 3 paediatric oncology cooperative groups: Children’s Oncology Group (COG: former Children’s Cancer Group institutions in the United States, Canada, and Australia), the United Kingdom Children’s Cancer Study Group and SFOP (France and some centres in Belgium and the Netherlands). This protocol was approved by all of the local Institutional Review Boards and written informed consent was obtained from parents/legal guardians and patients if over 18 years of age in accordance with the Declaration of Helsinki. This protocol was registered with clinicaltrials.gov (NCT00002757)

Eligibility for the FAB/LMB96 study

Children and adolescents with newly diagnosed mature B-lineage NHL with either Burkitt lymphoma (BL), diffuse large B-cell lymphoma, or Burkitt-like lymphoma (BLL) according to the Revised European-American Lymphoma classification and World Health Organization Classification were eligible.(Harris, et al 1994, Murphy 1980, Swerdlow 2008) Staging was performed as previously described by Murphy (1980). Risk classification was defined as low risk (Group A) with resected stage I and abdominal completely resected Stage II; high risk (Group C) with BM involvement L3 blasts ≥ 25% and/or CNS disease; intermediate risk (Group B) was all others.(Cairo, et al 2007, Cairo, et al 2012, Gerrard, et al 2008) Exclusion criteria included congenital or acquired immunodeficiency, prior malignancy and/or prior chemotherapy.(Cairo, et al 2007, Gerrard, et al 2008, Patte, et al 2007)

Eligibility for the current study

Patients included in the FAB/LMB96 study were primary refractory (never obtained a complete response [CR]) or who relapsed after having achieved CR. Complete remission could be achieved anytime during protocol-derived therapy.

Initial treatment

Patients assigned to Group A, B and C therapy were as previously described (Fig 1). (Cairo, et al 2007, Cairo, et al 2012, Gerrard, et al 2008, Gerrard, et al 2013, Patte, et al 2007)

Fig 1.

Fig 1

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Experimental design schema of the French-American-British/mature lymphoma B (FAB/LMB) 96 international study. Each of the induction, consolidation and maintenance cycles were approximately 21 days except for the COP reduction cycle which was only 7 days.

CNS: central nervous system; COP: cyclophosphamide, vincristine and prednisone; COPAD: cyclophosphamide, vincristine, prednisone and doxorubicin; COPADM3: fractioned cyclophosphamide, vincristine, prednisone, doxorubicin and high-dose methotrexate 3 g/m2; COPADM8: fractioned cyclophosphamide, vincristine, prednisone, doxorubicin and high-dose methotrexate 8 g/m2; CYM: cytarabine and methotrexate; CYVE: cytarabine and etoposide; M1,2,3,4: maintenance cycle

Group A

Patients received two courses of cyclophosphamide, vincristine, prednisone and doxorubicin (COPAD) without intrathecal chemotherapy. Each cycle of COPAD was approximately 7 days.

Group B

Patients received a 7-day low dose reduction phase, cyclophosphamide, vincristine and prednisone (COP). Induction therapy consisted of two cycles of fractioned cyclophosphamide, vincristine, prednisone, doxorubicin and high-dose methotrexate 3 g/m2 (HD-MTX) (COPADM). Patients then received two consolidation cycles of cytarabine and methotrexate. Patients on the standard arm (B1) received the continuation phase of COPADM. Patients received intrathecal chemotherapy prophylaxis during all phases of the therapy, as previously described.(Patte, et al 2007) Patients with a favourable response to COP prophase were randomised to therapy reduction with 50% cyclophosphamide delivered in the second induction cycles and/or the elimination of continuation therapy in a 4-arm stratified randomisation as previously described.(Patte, et al 2007) Each induction, consolidation and maintenance cycle was approximately 21 days. Patients with less than a 20% response on day 7 of COP and patients with residual disease after cytarabine and methotrexate were given cytabarine with etoposide (CYVE) intensification therapy for two cycles and four cycles of continuation therapy according to Group C therapy (Fig 1). (Cairo, et al 2007)

Group C

Patients received a 7-day reduction course, COP, as described above.(Cairo, et al 2007) Induction therapy consisted of two cycle of COPADM (with HD-MTX 8 g/m2).(Cairo, et al 2007) Consolidation consisted of high-dose and continuous CYVE.(Cairo, et al 2007) Patients with CNS disease did not receive cranial radiation but received additional intrathecal therapy as well as an additional HD-MTX course between consolidation courses, as previously described.(Cairo, et al 2007) The first continuation cycle consisted of COPADM, and three additional chemotherapy cycles followed in the standard arm of therapy. Patients with a ≥ 20% response after COP reduction were randomised to a standard arm or a reduced arm with simultaneous reduction in chemotherapy during the consolidation phase (CYVE) and the elimination of the three continuation courses, as previously described (Fig 1). (Cairo, et al 2007) Each induction, consolidation and maintenance cycle was approximately 21 days, except for the reduction cycle of COP which was only 7 days.

Retrieval therapy

Patients who had primary refractory or relapsed disease on or off this protocol therapy were re-induced and treated according to the discretion of the treating physician and institutional preferences. There was not a uniform approach either to re-induction chemotherapy, use of immunotherapy and/or the use of stem cell transplantation.

Haematopathology

The initial independent and consensus morphology and immunophenotype from diagnostic materials from each case was evaluated by each of the six haematopathologists from the three national cooperative groups to establish a diagnosis using a standard immunophenotyping panel that included the following antibodies: CD20, CD79a, CD3, CD46RO, TDT, CD30and p80, as previously described.(Cairo, et al 2012, Harris, et al 1994, Swerdlow 2008) There was no requirement for central review of patients who had primary refractory or relapsed disease on or off the therapy above.

Statistical methods

Patients were grouped by risk: Group A (limited), Group B (intermediate) and Group C (advanced). The subgroup analysed in this manuscript only consisted of patients who were primary refractory (never obtained a CR) or suffered disease relapse after obtaining a CR. The primary endpoint was OS, which was the time to death from any cause measured from the date of initial treatment failure. We estimated survival probabilities according to the Kaplan-Meier method. The 95% confidence intervals (CI) of survival rates were estimated according to the Rothman method. The prognostic impact on OS of patient characteristics (gender, age), initial disease characteristics (stage, prognosis group, pathological type of B cell lymphoma, primary site, LDH level, BM involvement and CNS involvement) and failure characteristics (time to failure, type of failure, localization of failure, number of sites of failure) was studied by univariate analysis using log-rank test. All factors were also studied by multivariate analysis using Cox model and backward selection based on Wald statistic with removal of variables with p-value > 0.05. Hazard ratios (HR) are presented with their 95 % CI. A significant association was considered at p-value ≤ 0.05. All reported p-value are two-sided. Analyses were done with SAS version 9.3 (SAS Institute Inc., Cary, NC, USA).

Results

Demographics

Among the 1,111 patients entered on the FAB/LMB 96 trial, 126 patients experienced events. Excluding 18 toxic deaths and 4 second malignancies, there were 104 patients (9.4%) who had primary refractory disease or disease relapse after first CR on or off protocol therapy who were the subject of this analysis. The demographics of the 104 patients who had refractory disease or disease relapse is summarised in Table I. Briefly, 28 (27%) never obtained a CR and were considered primary refractory and 76 (73%) were considered to have relapsed disease after having achieved a CR.

Table I.

Patient initial characteristics

Patients
N %
Academic group
 CCG 46 44
 SFOP 34 33
 UKCCSG 24 23
Male 77 74
Female 27 26
Age
 < 15 years 80 77
 ≥15 years 24 23
Stage
 I 1 1
 II 4 4
 III 58 56
 IV 12 12
 ALL (≥25% in BM) 29 28
Prognosis group
 Group A 2 2
 Group B 66 63
 Group C CNS negative 12 12
 Group C CNS positive 24 23
Histology
 BL/BLL/Burkitt leukaemia 72 69
 DLBCL (not PMBL) 11 11
 PMBL 14 23
 Other NOS 7 (T cell rich, n=2) 7
Primary site
 Thorax 16 15
 Abdomen/Retroperitoneal 59 57
 Head and Neck 8 8
 Peripheral Node 2 2
 B-ALL 14 13
 Other 5 5
LDH
 < 2 NL 30 29
 ≥2 NL 74 71
Bone Marrow /Central Nervous System
 BM−/CNS− 63 61
 BM+/CNS− 17 16
 BM−/CNS+ 5 5
 BM+/CNS+ 19 18
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B-ALL, B cell acute lymphoblastic lymphoma; BL, Burkitt lymphoma; BLL, Burkitt-like lymphoma; BM, bone marrow; CCG, Children’s Cancer Group; CNS, central nervous system; DLBCL, diffuse large B cell lymphoma; LDH, lactate dehydrogenase; NL, normal limit; NOS, not otherwise specified; PMBL, primary mediastinal large B cell lymphoma; SFOP, Societe Francaise d’Oncologie; UKCCSG, United Kingdom Children’s Cancer Study Group.

Treatment failure (primary refractory or relapsed disease) by initial disease stratification

The percentage of patients based on initial FAB risk classification, St. Jude staging classification and primary disease site was determined. The distribution among patients included: 1) risk classification was 2 (2.0%) within Group A, 66 (63%) Group B and 36 (35%) Group C patients; 2) staging classification: I 1 (1%), II 4 (4%), III 58 (56%), IV 12 (12%) and B cell acute lymphoblastic leukaemia (B-ALL) 29 (28%); 3) primary site: abdominal/retroperitoneal 59 (57%), thorax 16 (15%), head and neck 8 (8%), Burkitt leukaemia 14 (13%), other 7 (7%).

Overall survival

The median follow-up after treatment failure was 4.4 years. Only three alive patients were followed less than two years. Seventy-nine deaths occurred. The probability of 1- and 2-year OS was 31.5% (95% CI 23.3–41.0%) and 23.3% (95% CI 15.3–31.4%), respectively (Fig 2). Failure characteristics are depicted in Table II. In univariate analysis using the log-rank test, patients with LDH ≥ 2 ULN at diagnosis (P = 0.004), time to failure ≤ 6 months (P = 0.002), failure as primary refractory disease (P = 0.047) and failure in the BM (P = 0.003) had significantly worse OS (Table III).

Fig 2.

Fig 2

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Probability of overall survival by the Kaplan Meier method of children and adolescents with mature B cell non-Hodgkin lymphoma who had refractory or relapsed disease during or after therapy on the French-American-British/mature lymphoma B (FAB/LMB) 96 international study.

Table II.

Failure characteristics

Patients
N %
Duration between diagnosis and treatment failure
 ≤3 months 17 16
 > 3 – ≤ 6 months 48 46
 > 6 months 39 38
Type of failure
 No CR obtained (refractory) 28 27
 Relapse after CR 76 73
Failure at initial localisation
 No 46 44
 Yes 58 56
Failure in bone marrow
 No 78 75
 Yes 26 25
Failure in central nervous system
 No 73 70
 Yes 31 30
Failure in other sites
 No 64 62
 Yes 40 38
Number of sites of failure
 1 64 62
 2 31 30
 3 7 7
 4 2 2
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CR, complete response.

Table III.

Univariate prognostic analysis of overall survival

Univariate analysis
2-year OS rate Log-rank p-value
Male 16.9%
Female 37.0% 0.10
Age
 < 15 years 23.8%
 ≥15 years 17.5% 0.66
Stage (St. Judes)
 I / II 40.0%
 III 22.8%
 IV / ALL 20.2% 0.45
Prognosis group
 Group A 50.0%
 Group B 25.1%
 Group C 16.7% 0.25
Histology
 Burkitt / Burkitt like 19.1%
 DLBCL (not PMBL) 35.1%
 PMBL 28.6%
 Other NOS 28.6% 0.26
Primary site
 Thorax 26.9%
 Abdomen/Retroperitoneal 20.7%
 B-ALL 7.1%
 Other 38.9% 0.058
LDH
 < 2 NL 41.8%
 ≥2 NL 14.9% 0.0004
Bone Marrow
 Not involved 23.4%
 Involved 20.2% 0.21
Central Nervous System
 Not involved 24.1%
 Involved 16.7% 0.27
Time to failure
 ≤ 6 months 15.4%
 > 6 months 34.5% 0.002
Type of failure
 No CR (refractory) 10.7%
 Failure after CR 26.8% 0.047
Failure at initial localisation
 No 24.8%
 Yes 20.7% 0.84
Failure in bone marrow
 No 26.0%
 Yes 11.5% 0.003
Failure in CNS
 No 23.7%
 Yes 19.4% 0.77
Failure in other sites
  No 21.9%
 Yes 23.0% 0.63
Number of sites of failure
 1 27.2%
 >1 15.0% 0.14
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B-ALL, B cell acute lymphoblastic lymphoma; CI, confidence interval; CNS, central nervous system; CR, complete response; DLBCL, diffuse large B cell lymphoma; HR, hazard ratio; LDH, lactate dehydrogenase; NL, normal limit; NOS, not otherwise specified; OS, overall survival; PMBL, primary mediastinal large B cell lymphoma.

The probability of 2-year OS in children and adolescents with mature B-NHL who had primary refractory disease or disease relapse during or off FAB/LMB 96 with initial LDH of < 2 times ULN versus ≥ 2 times ULN was 41.8% versus 14.9% (P = 0.004) (Fig 3A). The probability of 2-year OS in this same population who did not achieve a CR or failure ≤ vs > 6 months from diagnosis was 15.4% versus 34.5% (P = 0.002) (Fig 3B). The probability in this same population who failed in the BM versus no failure in the BM was 11.5% versus 26%, P = 0.003 (Fig 4).

Fig 3.

Fig 3

Fig 3

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Probability of overall survival by the Kaplan Meier method of children and adolescents with mature B cell non-Hodgkin lymphoma who had refractory or relapsed disease during or after therapy on the French-American-British/mature lymphoma B (FAB/LMB) 96 international study (A) stratified by initial lactate dehydrogenase (LDH) < vs ≥ 2 upper normal limits at the time of diagnosis (P < 0.0004). (B) stratified by time to relapse < 3 months ≤ 6 months versus > 6 months from diagnosis (P = 0.002).

Fig 4.

Fig 4

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Probability of overall survival by the Kaplan-Meier method of children and adolescents with mature B cell non-Hodgkin lymphoma who had refractory or relapsed disease during or after therapy with failure in the bone marrow (P = 0.0001).

The type of failure (primary refractory disease versus relapse after CR) was strongly associated with the time of failure: in all patients except one who had primary refractory disease, the time of failure was less than 6 months from diagnosis; among patients who relapsed, half of the relapses occurred before 6 months from diagnosis and half after 6 months. Among the patients who relapsed, time to failure was associated with OS. But in patients who had a failure within 6 months from diagnosis, the type of failure (primary refractory disease versus relapse) was not associated with OS.

In the Cox multivariate regression analysis, LDH ≥ 2 times ULN at diagnosis (HR = 2·86 [1.57–5.2], P = 0.0006), time to failure (≥ 6 months) (HR = 0·59 [0.36–0.97]) (P = 0.038), and failure in the BM (HR = 2·78 [1.65–4.68], P = 0.0001) remained significant risk factors for OS after backward selection (Table IV). After taking the time of failure into account, type of failure was not more associated with OS.

Table IV.

Final multivariate analysis of overall survival using Cox model with backward selection

HR (95% CI) Wald test p-value
Initial LDH
 < 2 NL 1
 ≥2 NL 2.86 (1.57–5.20) 0.0006
Time to failure
 ≤6 months 1
 > 6 months 0.59 (0.36–0.97) 0.038
Failure in bone marrow
 No 1
 Yes 2.78 (1.65–4.68) 0.0001
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HR, hazard ratio; LDH, lactate dehydrogenase; NL, normal limit.

Discussion

This is the largest analysis performed in a large group of children and adolescents with mature B-NHL who had primary refractory disease or disease relapse during or after initial intensive multi-agent chemotherapy treated uniformly in an international trial. Importantly, these patients were initially treated with a risk-stratified uniform multi-institutional and multiple paediatric cooperative group upfront protocol. Despite retrieval therapy at the discretion of the treating physician, the 1- and 2-year OS was only 31.5% and 22.3%, respectively. Additionally, these data suggest that patients who had refractory or relapsed disease within six months of diagnosis, those with an elevated initial LDH level ≥ 2 times ULN at diagnosis and/or those who failed in the BM have a significantly decreased OS. While initial LDH levels have been identified previously as an independent risk factor for disease failure (Cairo, et al 2002, Cairo, et al 2012, Cairo, et al 2003b, Gerrard, et al 2008, Patte, et al 2007, Patte, et al 2001, Pillon, et al 2004, Reiter, et al 1999), this finding is similar to that of Jourdain et al (2015) who also demonstrated that initial LDH is a significant risk factor for decreased OS in a population who fail on or following initial upfront LMB chemotherapy in three consecutive SFOP studies.

The Children’s Cancer Group previously analysed the OS in 212 children with disseminated large cell lymphoma and focused on the subgroup who relapsed.(Cairo, et al 2002) This retrospective analysis demonstrated a 1-year OS of approximately 31±4.7%.(Cairo, et al 2002) Similarly, 470 children and adolescents with disseminated BL, BLL or Burkitt leukaemia were analysed over a 20-year period.(Bowman, et al 1996) In patients with BL/BLL or B-ALL who relapsed, the 1-year OS was 16%.(Bowman, et al 1996) These results, from an analysis of children and adolescents treated from 1977–1994, are similar to the results of the current study.(Bowman, et al 1996, Cairo, et al 2002) However, the Children’s Cancer Group did not specifically address the prognostic factors associated with OS in those patients who had refractory disease or disease relapse during or after initial mature B-NHL therapy in either of these reports.

FAB risk group classification (Group A vs B vs C) clearly identifies patients with an increased risk of refractory or relapsed disease with the percentage of patients experiencing an adverse event (toxic death, secondary malignancy, refractory or relapsed disease) being 1%, 11% and 21%, respectively. Age was historically considered as a risk factor because adolescents were considered to be at higher risk for failure.(Cairo, et al 2003a, Hochberg, et al 2009) In our analysis, adolescent age at initial presentation did not reach significance as an independent risk factor for OS after refractory disease or disease relapse.(Cairo, et al 2012) Although male gender is predominant in children and adolescent mature B-NHL, there was no significant decreased risk of OS in males versus females in these patients who had refractory disease or disease relapse during or after initial FAB/LMB 96 therapy. Furthermore, the decreased OS in patients with Stage IV disease as a risk factor did not reach significance in the Cox multivariate regression analysis.

One of the most important findings in this study was that the interval from initial diagnosis to refractory disease or disease relapse (less than 6 months) was significantly associated with a decreased OS following initial treatment on FAB/LMB 96. This is similar to the results of the Jourdain et al (2015) The COG demonstrated that in patients with refractory or relapsed lymphoma who achieved a CR/partial response (PR) after reinduction and then underwent cyclophosphamide, carmustine, and etoposide conditioning and autologous stem cell transplantation, those patients whose remission was < 12 vs ≥ 12 months duration had a significantly decreased OS.(Harris, et al 2011) Early haematological relapse appears to denote more resistant disease and commonly results in a significant decrease in OS in children with mature B-NHL as well as those with ALL.(Perkins, et al 2003)

Clearly there is a need to reduce the incidence of refractory or relapsed disease during upfront therapy (especially in group C patients) and to develop more novel and targeted retrieval regimens to circumvent drug resistance in all children and adolescents who have refractory disease or disease relapse on upfront contemporary multi-agent chemotherapy regimens. CD20, the receptor for rituximab, is expressed in more than 98% of all children and adolescents with mature B-NHL.(Perkins, et al 2003) The safety of adding rituximab to children and adolescents with newly diagnosed Stage III/IV mature B-NHL with the B4 and C1 treatment arms of FAB/LMB 96 has been piloted.(Goldman, et al 2013, Goldman, et al 2014, Shiramizu, et al 2011) Reporting for the Berlin-Frankfurt-Munster group, Meinhardt et al (2010) also included the safety and efficacy of rituximab with upfront multi-agent chemotherapy. The benefit of adding rituximab to FAB/LMB 96 therapy in children and adolescents with newly diagnosed high-risk mature B-cell lymphoma/leukaemia was recently reported in the randomised prospective international Inter-B-NHL study.(Minard-Colin, et al 2015) However, the OS in children and adolescents with B-NHL treated with a rituximab-containing chemoimmunotherapy regimen are not significantly better in patients who have disease failure compared to those with chemotherapy only, such as illustrated in this study (Hochberg, et al 2009, Meinhardt, et al 2010).

Numerous regimens, usually incorporating a platinum compound, have been reported to show efficacy in patients with mature B-NHL after disease failure. Gentet et al (1990) and Philip et al (1993) demonstrated the success of CYVE as salvage treatment in refractory mature B-NHL and disease failure. Kobrinsky et al (2001) has reported on the use of dexamethasone, etoposide, cisplatin, cytarabine and L-asparaginase in recurrent/refractory childhood NHL. However, this regimen utilises agents that are currently used today in high-risk mature B-NHL patients as upfront therapy, including corticosteroids, cytarabine and etoposide. Kung et al (1999) and Cairo et al (2001) reported on the use of ifosfamide, carboplatin and etoposide (ICE) for recurrent/refractory childhood NHL. Most recently, Griffin et al (2009) reported a 60% overall response rate (CR + PR) in children and adolescents with mature B-NHL following combination chemoimmunotherapy with rituximab and ICE. Children and adolescents with refractory disease and/or disease relapse mature B-NHL who achieve a CR or PR after reinduction are candidates for a stem cell transplant consolidation. When autologous stem cells can be harvested and are clear of tumour, consolidation with a myeloablative autologous stem cell transplant may be considered.(Bradley and Cairo 2008, Gross, et al 2010, Harris, et al 2011, Kobrinsky, et al 2001) Alternatively, a full intensity or reduced intensity conditioning followed by an allogeneic stem cell transplantation may also be considered in patients with stable or CR/PR after reinduction therapy. (Gross, et al 2010, Satwani, et al 2015)

This retrospective analysis has some limitations. This was a retrospective analysis and was not specifically designed nor powered to address specific risk or prognostic factors that were present at the time of refractory disease or disease relapse and risk of overall long-term OS. However, there are no known genetic and/or molecular factors at disease failure in this population that predict OS after retrieval therapy. Moreover, we do not have information on LDH level at refractory disease or disease relapse, or retrieval or reinduction regimens, nor whether patients received an autologous vs. allogeneic stem cell transplant as consolidation. The majority of these patients did not however receive rituximab in their reinduction therapy as rituximab was not available for children during this time period. Similarly, whether autologous or allogeneic stem cell transplantation was utilised in patients obtaining a CR or PR after retrieval therapy, the results do not indicate an advantage to either stem cell transplantation approach (Pillon, et al 2011). However, the results (OS) were comparable across three paediatric cooperative groups (COG vs SFOP vs UKCCSG) (Table IV). Most importantly, all patients (N=1,111) were treated on the same uniform upfront protocol (FAB/LMB 96), as this represents the largest experience ever reported in children and adolescents with newly diagnosed mature B-NHL.

In summary, these results have demonstrated that initial LDH levels ≥ 2 times ULN, refractory disease or disease relapse less than 6 months from diagnosis and/or failure in the BM are each independently associated with a significant decrease in OS in children and adolescents with mature B-NHL who had refractory or relapsed disease during or after contemporary multi-agent chemotherapy, such as FAB/LMB 96. These results provide critical information to health care providers and families about the chance of survival for children and adolescents with mature B-NHL with refractory or relapsed disease. Future strategies should continue to identify risk factors associated with primary refractory disease or disease relapse, such as tumour cytogenetics or minimal disseminated disease at diagnosis and minimal residual disease following induction therapy, and subsequently design new therapeutic strategies to reduce refractory disease or disease relapse during upfront therapy.(Mussolin, et al 2007, Poirel, et al 2009, Satwani, et al 2015, Shiramizu, et al 2011, Shiramizu, et al 2015) Alternative new retrieval approaches include the identification of new targets, use of new monoclonal antibodies or conjugated antibodies, and novel approaches of cellular and stem cell therapy.(Awasthi, et al 2015, Barth, et al 2013, Cooney-Qualter, et al 2007, Shiramizu, et al 2015) Furthermore, targeting more specific molecular or cellular pathways in children and adolescents with mature B cell lymphoma should be studied in a cooperative setting to improve the long term OS in this poor risk group of patients.(Lee, et al 2017, Pinkerton, et al 2016)

Acknowledgments

The authors would also like to thank the members of the DSMC, Professors Michael Link, Alfred Reiter, David Harrington and Robert Souhami for their diligent oversight of this study. The authors would also like to thank Linda Rahl and Virginia Davenport, RN for their assistance in the administration of this trial and Erin Morris, RN and Virginia Davenport, RN for their editorial assistance in the development of this manuscript, and Richard Sposto, PhD and Jing Fan, MS for statistical support. The authors would also like to thank the other members of the international pathology review panel group (Drs M. Gerrard, K. McCarthy, M. Raphael, M. J. Terrier-Lacombe, M. Lones and A. Wotherspoon) and international cytogenetics review panel (Drs. W. Sanger, N. Heerema, J Swansbury, P Talley, A Bernheim). The authors would finally like to thank all the members and investigators of the Children’s Oncology Group, Société Française d’Oncologie Pédiatrique, and the United Kingdom Children’s Cancer Study Group.

Funding

Research reported in this publication was supported by grants from the Children’s Oncology Group, the National Cancer Institute of the National Institutes of Health under award number U10CA180886 (NCTN Operations Grant); Cancer Research Campaign United Kingdom Children’s Cancer Study Group; Association pour la Recherche Contre le Cancer, La Ligue Nationale Contre le Cancer, Institut-Gustave-Roussy (SFOP), Pediatric Cancer Research Foundation (PCRF) and the St. Baldrick’s Foundation.

Footnotes

Author contribution

MC and CP were primary investigators and RP and SG were principal investigators for FAB/LMB 96 study. MC, AA, SP and CP assisted in the conception of the study and design of the protocol. SP, SG and LH collected the data while MC, AA, RP, SG, CP and SP interpreted the data. AA performed the statistical analysis. MC, AA, SG and CP wrote the manuscript on behalf of the FAB/LMB 96 study group. All authors contributed to the critical review of this manuscript and have approved the final version.

Conflict of interest disclosure

The authors declare no competing interests.

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