Curr Hematol Malig Rep DOI 10.1007/s11899-015-0277-y
B-CELL NHL, T-CELL NHL AND HODGKIN LYMPHOMA (J ARMITAGE, SECTION EDITOR)
Non-Hodgkin Lymphoma in Children John T. Sandlund 1
# Springer Science+Business Media New York 2015
Abstract The non-Hodgkin lymphomas (NHLs) of childhood include high-grade mature B cell lymphoma [Burkitt lymphoma (BL), diffuse large B cell lymphoma (DLBCL), and primary mediastinal large B cell lymphoma (PMLBCL)], anaplastic large cell lymphoma (ALCL), and lymphoblastic lymphoma (LL). The prognosis for children with NHL is generally excellent, although there are some higher risk groups. In this regard, PMLBCL is generally associated with a poorer outcome than BL or DLBCL of comparable stage. The longterm event-free survival for children with ALCL is approximately 70 %. Novel biological agents, including those that target CD-30 or ALK, may hold promise for improving treatment results. Children with LL are treated with regimens derived from those used to treat acute lymphoblastic leukemia (ALL). Recent biological study of LL may provide insights into revising treatment stratification. The challenge in pediatric NHL, a group that already has a relatively good prognosis, is to improve treatment outcome without increasing concerning late effects.
Keywords Non-Hodgkin lymphomas . Burkitt lymphoma . Diffuse large B cell lymphoma . Acute lymphoblastic leukemia . B cell lymphoma
This article is part of the Topical Collection on B-cell NHL, T-cell NHL and Hodgkin Lymphoma * John T. Sandlund [email protected] 1
St Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
Introduction The non-Hodgkin lymphomas (NHLs) of childhood are primarily comprised of high-grade mature B cell lymphomas, anaplastic large cell lymphoma (ALCL), and lymphoblastic lymphoma (LL) [1, 2]. There have been recent advances in both our understanding of pathobiology and the development of novel therapeutic approaches for these subtypes in children. High-Grade Mature B Cell Lymphomas The high-grade mature B cell lymphomas include Burkitt lymphoma (BL), diffuse large B cell lymphoma (DLBCL), and primary mediastinal large B cell lymphomas (PMLBCL) [1]. Long-term event-free survival for high-grade mature B cell NHLs collectively is approximately 80–90 %[3–6]; however, for PMLBCL, the outcome is poorer at ~70 % regardless of contemporary treatment approach [7, 8•]. There is clearly a need for further refinement in both the diagnosis and management of pediatric mediastinal large B cell lymphoma (Fig. 1) [9]. In an attempt to improve the outcome for PMLBCL, a successfully used adult regimen, dose-adjusted EPOCH-rituximab regimen (DA-EPOCH-R) [10] is currently under investigation in children with promising preliminary results [11••]. In an effort to improve upon the already excellent treatment result for the other high-grade mature B cell lymphomas, while at the same time attempting to reduce the risk of unwanted late effects of therapy, the incorporation of immunotherapeutic agents into existing successful strategies has been piloted [12•, 13•, 14]. Anaplastic Large Cell Lymphoma Various treatment strategies have been studied in children with ALCL. Regardless of treatment approach, the long-term event-free survival is approximately 70 % [15–21]. In the USA, histology-based approaches for large cell lymphoma (CHOP, APO) have been
Curr Hematol Malig Rep
A. Refinement in Diagnosis PMBL
HL
DLBCL
B. Refinement in Therapy Conventional Chemotherapy
Biological Targets • CD20 • CD30 • NFκB • JAK/STAT
IFRT (?)
Early Response • FDG-PET • MDD/MRD
Fig. 1 a Refinement in diagnosis: Among cases of MLBL, the histological distinction between PMBL, DLBCL, and HL may be difficult. b Refinement in therapy: Refinement in therapy may include the incorporation of novel biological targeting agents, involved field radiation, and improved methods of measurement of early response to therapy. MLBL mediastinal large B cell lymphoma, PMBL primary mediastinal large B cell lymphoma, HL Hodgkin lymphoma, IFRT involved field radiation, MDD minimal disseminated disease, MRD minimal residual disease (reproduced with permission; Sandlund JT and Choi JK; Blood, 2013) [9]
studied [16, 17], whereas in Europe, regimens derived from those to treat children with Burkitt lymphoma (ALCL99) have been studied [15] [18–20]. Although vinblastine was shown to be active as a single agent in recurrent ALCL [22], its incorporation into two different frontline regimens for children with newly diagnosed ALCL failed to improve long-term outcome [23, 24•]. In the search for novel approaches to improve treatment outcome, recent attention has focused on the use of biological agents which target either CD-30 (brentuximab vedotin) [25] or ALK (crizotinib) [26••]. These agents have been studied in children with recurrent ALCL and are currently being examined in those with newly diagnosed ALCL. The use of minimal residual disease (MRD) technology to measure both minimal disseminated disease (MDD; measurable disease before therapy starts) and MRD (measurable disease after
therapy starts) has been shown to have prognostic significance in ALCL as has been shown for other pediatric NHL histological subtypes [27, 28••, 29••]. This data may permit the further tailoring of risk-adapted therapy for children with ALCL. Lymphoblastic Lymphoma Children with lymphoblastic lymphoma have historically been treated with regimens that have been used successfully in children with T cell acute lymphoblastic leukemia (T-ALL). The 5-year event-free survival rates with contemporary therapy are approximately 80–90 % [30–33]. There has been an effort to identify high-risk patients so that novel approaches can be used to improve outcome for the 10–20 % that fail frontline therapy. Reliable clinical indicators of prognosis have not been identified [30, 34]. MDD at diagnosis was shown in a Children’s Oncology Group study to have prognostic significance at both the 1 and 5 % level of detection [35]. Subsequent trials were developed to intensify therapy for these patients. More recently, an attempt to identify high-risk patients on the basis of tumor biology was studied and reported [36•, 37]. These results may be used for treatment stratification in upcoming trials. This review will highlight some of these recent advances, which include the study of DA-EPOCH-R in children, the incorporation of immunotherapeutic agents for high-risk high-grade mature B cell lymphomas, the preliminary results from trials studying novel biological agents in ALCL, MRD/ MDD determination in ALCL, and the identification of biological features with prognostic significance in pediatric LL (Table 1).
High-Grade Mature B Cell Lymphomas PMLBCL Contemporary high-grade mature B cell NHL treatment approaches have resulted in an inferior outcome for children and adolescents with primary mediastinal large B cell lymphoma (PMLBCL) compared to that achieved for those with diffuse large B cell lymphoma (DLBCL). Seidemann et al. reported a 5-year event-free survival of 70 % for those enrolled on Berlin-Frankfurt-Munster (BFM) multicenter trials, which included chemotherapy as previously described, and no involved field radiation [7]. Gerrard et al. subsequently reported a 5-year event-free survival of 66 % for those with stage III mediastinal large B cell lymphoma enrolled on the FAB/LMB 96 trial [8, 38•]. Therapy included multiagent chemotherapy as described and no involved field radiation therapy. Clearly, novel approaches are required to improve upon these results. Dunleavy et al. reported a 93 % event-free survival (median follow-up, 5 years) for adults (median age, 30 years;
Curr Hematol Malig Rep Table 1
Contemporary initiatives with therapeutic intent for pediatric NHL
Histology
Intervention
Status
Study number or key references
BL and DLBCL PMLBCL T-LB NHL
Rituximab randomization DA-EPOCH-R (adult-based infusional regimen) Stratification based on MDD Stratification based on biology (LOH6q and NOTCH1 mutations)
Ongoing Ongoing Ongoing Planned
NCT01595048 NCT01595048, [10, 11••]
ALCL
Incorporation of targeting agents (BV, crizotinib) Stratification based on MDD, MRD, and ALK antibody titer Refinement in measurement of response evaluation using more sensitive DI and Path technologies
Ongoing Planned Ongoing and planned
NCT01979536 [28••, 29••] [50]
All histologies
[36•]
BL Burkitt lymphoma, DLBCL diffuse large B cell lymphoma, PMLBCL primary mediastinal large B cell lymphoma, DA-EPOCH-R dose-adjustedEPOCH-rituximab, T-LB NHL T cell lymphoblastic lymphoma, MDD minimal disseminated disease, BV brentuximab vedotin, MRD minimal residual disease, ALK anaplastic lymphoma kinase, DI diagnostic imaging, Path, pathology
range, 19–52) with primary mediastinal B cell lymphoma using the dose-adjusted EPOCH-rituximab regimen (DA-EPOCH-R) [10]. Although anthracycline cumulative doses were high with this regimen (up to 500 mg/m2 in one patient), no significant cardiotoxicity was reported. These results prompted the BFM to study this regimen in 15 children and adolescents (median age, 16 years; range, 11.5–17.8 years) as part of the B cell NHL-BFM04 study in 2010 [11••]. Concern regarding possible late cardiac toxicity in this younger patient population prompted investigators to cap the maximum dose of doxorubicin at 360 mg/m2. A 2-year event-free survival of 92 % was reported (median follow-up, 19.2 months). Longer follow-up will be needed to evaluate late cardiac toxicity; some studies indicate significant toxicity at doses that exceed 250 mg/m2 [39]. The current Children’s Oncology Group (COG) international high-grade mature B cell lymphoma collaborative protocol features a DA-EPOCH-R arm for those with PMLBCL (anthracycline dosage not capped) (NCT01595048). Immunotherapy The incorporation of immunotherapeutics such as rituximab into frontline treatment for adults with CD20+ B cell lymphomas has resulted in improved outcome [40, 41]. The outcome for children with high-grade mature B cell lymphomas is excellent with conventional cytotoxic agents, and the role of immunotherapeutics has yet to be clarified. In an effort to address their role, several clinical trials which incorporate rituximab in the treatment plan for patients with newly diagnosed Burkitt lymphoma or diffuse large B cell lymphoma have been conducted [12•, 13•, 14]. The BFM designed a trial for children less than 19 years of age with newly diagnosed CD-20+ mature B cell lymphomas (Burkitt lymphoma, n=67; diffuse large B cell lymphoma, n=15) which featured the administration of single agent rituximab on day 1 of a window
phase before conventional cytotoxic chemotherapy was administered on day 5 [14]. Responses were measured on day 5 with responders defined as those with ≥25 % decrease in size of at least one lesion (or bone marrow or peripheral blood blasts) and no evidence of disease progression. They identified 36 responders among 87 evaluable patients. The rituximab was well tolerated and did not preclude delivery of conventional cytotoxic therapy per protocol. A pilot study was performed by the Children’s Oncology Group which examined the feasibility of delivering rituximab concurrently with LMB-based chemotherapy to children with high-grade mature B cell lymphomas (Burkitt lymphoma, 56 %; diffuse large B cell lymphoma, 22 %; and primary mediastinal B cell lymphoma, 9 %) [12•]. Forty-five children with stage III/IV disease were treated according to the group B arm of the LMB 96 regimen, which was modified to include four to six doses of rituximab. They reported a 3-year event-free survival of 93 % for the 45 eligible patients enrolled. Forty patients with either Burkitt leukemia (n=25) or CNS+ Burkitt lymphoma +/− leukemia (n=15) were treated according to the group C arm of LMB 96 which was modified to include four to six doses of rituximab [13•]. A 3-year event-free survival of 90 % was reported. In both the BFM study featuring a rituximab window plus conventional therapy in newly diagnosed children with CD-20+ high-grade mature B cell lymphomas and the COG pilot studies which featured rituximab plus conventional LMB-based therapy, a tolerable toxicity profile for rituximab was reported. It remains to be determined whether the incorporation of rituximab into frontline conventional B-NHL therapy improves outcome compared to conventional chemotherapy without rituximab. The current COG international randomized trial is designed to answer this question in high-risk patients in the context of LMB-based therapy (NCT01595048). Other immunotherapeutics are also being examined for high-grade B cell lymphomas. For example, Schuster et al. treated nine children with either relapsed/
Curr Hematol Malig Rep
refractory Burkitt lymphoma/leukemia or diffuse large B cell lymphoma with FBTA05 (an anti-CD3 × anti-CD20 trifunctional bispecific antibody; also called lymphomun) with encouraging results. Of note, one patient with relapsed Burkitt leukemia achieved a complete response with single agent lymphomun. The preliminary results regarding the activity of lymphomun will need to be confirmed in studies comprising a much larger cohort.
Anaplastic Large Cell Lymphoma Novel Agents The development of novel targeting agents has provided opportunities for new therapeutic approaches to the management of ALCL in children and adolescents. Surface CD30 is commonly expressed in ALCL [1]. Brentuximab vedotin, an antibody drug conjugate which links auristatin to anti-CD30, has been shown to be active in young adults and adolescents with CD30+ ALCL [25]. In a phase I study of brentuximab vedotin, two adults with recurrent ALCL achieved a CR [25]. Pro et al. published the results of a subsequent phase II study of brentuximab vedotin in adolescents and young adults (age range, 14–76) [42•]. Among the 58 enrolled on study, 86 % had an objective response (OR; median duration 12.6 months), 57 % had a complete response (CR; median duration 13.2 months), and 29 % had a partial response. The authors concluded that brentuximab vedotin was very active in patients with relapsed ALCL and should be considered for frontline therapy. The t(2;5) chromosomal translocation, which is the most common cytogenetic abnormality in pediatric ALCL, results in an NPM-ALK chimeric fusion product and subsequent expression of ALK [43–46]. ALK expression is detected in the majority of pediatric ALCL cases as compared to approximately 50 % of adult cases [47]. Crizotinib, a small molecule inhibitor of ALK, has been shown to be very active in patients with recurrent ALCL [26••]. Mosse et al. reported that among nine children with recurrent ALCL treated with single agent crizotinib, there were seven CRs, one PR, and one with stable disease. The activity of both brentuximab vedotin and crizotinib in those with recurrent ALCL led to their incorporation into the current frontline COG ALCL trial for children and adolescents (NCT01979536). Minimal Residual Disease Technology The level of minimal disseminated disease (MDD) at the time of diagnosis in children with various histological subtypes of NHL has been shown to have prognostic significance [27, 35, 48]. The BFM has demonstrated the prognostic significance of both qualitative and quantitative measurements of MDD in the bone marrow in children with ALCL [27]. Mussolin et al.
proposed a risk stratification for pediatric ALCL based on both qualitative measurement of NPM-ALK transcripts in bone marrow/peripheral blood analyzed by RT-PCR (MDD) and plasma ALK antibody titers using an immunocytochemical approach at the time of diagnosis [28••, 49]. At the time of diagnosis, over half of the children (59 %) had detectable MDD and the vast majority (96 %) had a detectable ALK antibody response. The authors identified three biological risk groups (bRG) based on these two factors. The high-risk group (bHR) was defined as MDD+ and Ab titer 1/750 (31 % of cases). All other cases were considered intermediate risk (48 % of cases). Progressionfree and overall survival by risk group included 28 and 71 % for bHR cases, 68 and 83 % for bIR cases, and 93 and 98 % for bLR cases. Multivariate analysis of risk factors demonstrated that only bHR and histology other than common type were predictive of a higher risk of treatment failure [28••]. The authors proposed that MDD and anti-ALK antibody measurements be used in future multicenter trials for pediatric ALCL. In a subsequent publication by Damm-Welk et al., the combination of MDD level at diagnosis and minimal residual disease (MRD) level before the second course of chemotherapy could also be used to identify high-risk ALCL patients [29••]. The cumulative risk of relapse among those that were MDD+ and MRD+ (81+8 %) was higher than that for those who were either MDD+ and MRD− (31+9 %) or MDD− (15+5 %) (p < 0.001). Five-year survival was also inferior for the MDD+/MRD+ group as compared to the MDD+/MRD− and MDD− groups (65+9 %, 92+5 %, and 91+3 %, respectively; p
B-CELL NHL, T-CELL NHL AND HODGKIN LYMPHOMA (J ARMITAGE, SECTION EDITOR)
Non-Hodgkin Lymphoma in Children John T. Sandlund 1
# Springer Science+Business Media New York 2015
Abstract The non-Hodgkin lymphomas (NHLs) of childhood include high-grade mature B cell lymphoma [Burkitt lymphoma (BL), diffuse large B cell lymphoma (DLBCL), and primary mediastinal large B cell lymphoma (PMLBCL)], anaplastic large cell lymphoma (ALCL), and lymphoblastic lymphoma (LL). The prognosis for children with NHL is generally excellent, although there are some higher risk groups. In this regard, PMLBCL is generally associated with a poorer outcome than BL or DLBCL of comparable stage. The longterm event-free survival for children with ALCL is approximately 70 %. Novel biological agents, including those that target CD-30 or ALK, may hold promise for improving treatment results. Children with LL are treated with regimens derived from those used to treat acute lymphoblastic leukemia (ALL). Recent biological study of LL may provide insights into revising treatment stratification. The challenge in pediatric NHL, a group that already has a relatively good prognosis, is to improve treatment outcome without increasing concerning late effects.
Keywords Non-Hodgkin lymphomas . Burkitt lymphoma . Diffuse large B cell lymphoma . Acute lymphoblastic leukemia . B cell lymphoma
This article is part of the Topical Collection on B-cell NHL, T-cell NHL and Hodgkin Lymphoma * John T. Sandlund [email protected] 1
St Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
Introduction The non-Hodgkin lymphomas (NHLs) of childhood are primarily comprised of high-grade mature B cell lymphomas, anaplastic large cell lymphoma (ALCL), and lymphoblastic lymphoma (LL) [1, 2]. There have been recent advances in both our understanding of pathobiology and the development of novel therapeutic approaches for these subtypes in children. High-Grade Mature B Cell Lymphomas The high-grade mature B cell lymphomas include Burkitt lymphoma (BL), diffuse large B cell lymphoma (DLBCL), and primary mediastinal large B cell lymphomas (PMLBCL) [1]. Long-term event-free survival for high-grade mature B cell NHLs collectively is approximately 80–90 %[3–6]; however, for PMLBCL, the outcome is poorer at ~70 % regardless of contemporary treatment approach [7, 8•]. There is clearly a need for further refinement in both the diagnosis and management of pediatric mediastinal large B cell lymphoma (Fig. 1) [9]. In an attempt to improve the outcome for PMLBCL, a successfully used adult regimen, dose-adjusted EPOCH-rituximab regimen (DA-EPOCH-R) [10] is currently under investigation in children with promising preliminary results [11••]. In an effort to improve upon the already excellent treatment result for the other high-grade mature B cell lymphomas, while at the same time attempting to reduce the risk of unwanted late effects of therapy, the incorporation of immunotherapeutic agents into existing successful strategies has been piloted [12•, 13•, 14]. Anaplastic Large Cell Lymphoma Various treatment strategies have been studied in children with ALCL. Regardless of treatment approach, the long-term event-free survival is approximately 70 % [15–21]. In the USA, histology-based approaches for large cell lymphoma (CHOP, APO) have been
Curr Hematol Malig Rep
A. Refinement in Diagnosis PMBL
HL
DLBCL
B. Refinement in Therapy Conventional Chemotherapy
Biological Targets • CD20 • CD30 • NFκB • JAK/STAT
IFRT (?)
Early Response • FDG-PET • MDD/MRD
Fig. 1 a Refinement in diagnosis: Among cases of MLBL, the histological distinction between PMBL, DLBCL, and HL may be difficult. b Refinement in therapy: Refinement in therapy may include the incorporation of novel biological targeting agents, involved field radiation, and improved methods of measurement of early response to therapy. MLBL mediastinal large B cell lymphoma, PMBL primary mediastinal large B cell lymphoma, HL Hodgkin lymphoma, IFRT involved field radiation, MDD minimal disseminated disease, MRD minimal residual disease (reproduced with permission; Sandlund JT and Choi JK; Blood, 2013) [9]
studied [16, 17], whereas in Europe, regimens derived from those to treat children with Burkitt lymphoma (ALCL99) have been studied [15] [18–20]. Although vinblastine was shown to be active as a single agent in recurrent ALCL [22], its incorporation into two different frontline regimens for children with newly diagnosed ALCL failed to improve long-term outcome [23, 24•]. In the search for novel approaches to improve treatment outcome, recent attention has focused on the use of biological agents which target either CD-30 (brentuximab vedotin) [25] or ALK (crizotinib) [26••]. These agents have been studied in children with recurrent ALCL and are currently being examined in those with newly diagnosed ALCL. The use of minimal residual disease (MRD) technology to measure both minimal disseminated disease (MDD; measurable disease before therapy starts) and MRD (measurable disease after
therapy starts) has been shown to have prognostic significance in ALCL as has been shown for other pediatric NHL histological subtypes [27, 28••, 29••]. This data may permit the further tailoring of risk-adapted therapy for children with ALCL. Lymphoblastic Lymphoma Children with lymphoblastic lymphoma have historically been treated with regimens that have been used successfully in children with T cell acute lymphoblastic leukemia (T-ALL). The 5-year event-free survival rates with contemporary therapy are approximately 80–90 % [30–33]. There has been an effort to identify high-risk patients so that novel approaches can be used to improve outcome for the 10–20 % that fail frontline therapy. Reliable clinical indicators of prognosis have not been identified [30, 34]. MDD at diagnosis was shown in a Children’s Oncology Group study to have prognostic significance at both the 1 and 5 % level of detection [35]. Subsequent trials were developed to intensify therapy for these patients. More recently, an attempt to identify high-risk patients on the basis of tumor biology was studied and reported [36•, 37]. These results may be used for treatment stratification in upcoming trials. This review will highlight some of these recent advances, which include the study of DA-EPOCH-R in children, the incorporation of immunotherapeutic agents for high-risk high-grade mature B cell lymphomas, the preliminary results from trials studying novel biological agents in ALCL, MRD/ MDD determination in ALCL, and the identification of biological features with prognostic significance in pediatric LL (Table 1).
High-Grade Mature B Cell Lymphomas PMLBCL Contemporary high-grade mature B cell NHL treatment approaches have resulted in an inferior outcome for children and adolescents with primary mediastinal large B cell lymphoma (PMLBCL) compared to that achieved for those with diffuse large B cell lymphoma (DLBCL). Seidemann et al. reported a 5-year event-free survival of 70 % for those enrolled on Berlin-Frankfurt-Munster (BFM) multicenter trials, which included chemotherapy as previously described, and no involved field radiation [7]. Gerrard et al. subsequently reported a 5-year event-free survival of 66 % for those with stage III mediastinal large B cell lymphoma enrolled on the FAB/LMB 96 trial [8, 38•]. Therapy included multiagent chemotherapy as described and no involved field radiation therapy. Clearly, novel approaches are required to improve upon these results. Dunleavy et al. reported a 93 % event-free survival (median follow-up, 5 years) for adults (median age, 30 years;
Curr Hematol Malig Rep Table 1
Contemporary initiatives with therapeutic intent for pediatric NHL
Histology
Intervention
Status
Study number or key references
BL and DLBCL PMLBCL T-LB NHL
Rituximab randomization DA-EPOCH-R (adult-based infusional regimen) Stratification based on MDD Stratification based on biology (LOH6q and NOTCH1 mutations)
Ongoing Ongoing Ongoing Planned
NCT01595048 NCT01595048, [10, 11••]
ALCL
Incorporation of targeting agents (BV, crizotinib) Stratification based on MDD, MRD, and ALK antibody titer Refinement in measurement of response evaluation using more sensitive DI and Path technologies
Ongoing Planned Ongoing and planned
NCT01979536 [28••, 29••] [50]
All histologies
[36•]
BL Burkitt lymphoma, DLBCL diffuse large B cell lymphoma, PMLBCL primary mediastinal large B cell lymphoma, DA-EPOCH-R dose-adjustedEPOCH-rituximab, T-LB NHL T cell lymphoblastic lymphoma, MDD minimal disseminated disease, BV brentuximab vedotin, MRD minimal residual disease, ALK anaplastic lymphoma kinase, DI diagnostic imaging, Path, pathology
range, 19–52) with primary mediastinal B cell lymphoma using the dose-adjusted EPOCH-rituximab regimen (DA-EPOCH-R) [10]. Although anthracycline cumulative doses were high with this regimen (up to 500 mg/m2 in one patient), no significant cardiotoxicity was reported. These results prompted the BFM to study this regimen in 15 children and adolescents (median age, 16 years; range, 11.5–17.8 years) as part of the B cell NHL-BFM04 study in 2010 [11••]. Concern regarding possible late cardiac toxicity in this younger patient population prompted investigators to cap the maximum dose of doxorubicin at 360 mg/m2. A 2-year event-free survival of 92 % was reported (median follow-up, 19.2 months). Longer follow-up will be needed to evaluate late cardiac toxicity; some studies indicate significant toxicity at doses that exceed 250 mg/m2 [39]. The current Children’s Oncology Group (COG) international high-grade mature B cell lymphoma collaborative protocol features a DA-EPOCH-R arm for those with PMLBCL (anthracycline dosage not capped) (NCT01595048). Immunotherapy The incorporation of immunotherapeutics such as rituximab into frontline treatment for adults with CD20+ B cell lymphomas has resulted in improved outcome [40, 41]. The outcome for children with high-grade mature B cell lymphomas is excellent with conventional cytotoxic agents, and the role of immunotherapeutics has yet to be clarified. In an effort to address their role, several clinical trials which incorporate rituximab in the treatment plan for patients with newly diagnosed Burkitt lymphoma or diffuse large B cell lymphoma have been conducted [12•, 13•, 14]. The BFM designed a trial for children less than 19 years of age with newly diagnosed CD-20+ mature B cell lymphomas (Burkitt lymphoma, n=67; diffuse large B cell lymphoma, n=15) which featured the administration of single agent rituximab on day 1 of a window
phase before conventional cytotoxic chemotherapy was administered on day 5 [14]. Responses were measured on day 5 with responders defined as those with ≥25 % decrease in size of at least one lesion (or bone marrow or peripheral blood blasts) and no evidence of disease progression. They identified 36 responders among 87 evaluable patients. The rituximab was well tolerated and did not preclude delivery of conventional cytotoxic therapy per protocol. A pilot study was performed by the Children’s Oncology Group which examined the feasibility of delivering rituximab concurrently with LMB-based chemotherapy to children with high-grade mature B cell lymphomas (Burkitt lymphoma, 56 %; diffuse large B cell lymphoma, 22 %; and primary mediastinal B cell lymphoma, 9 %) [12•]. Forty-five children with stage III/IV disease were treated according to the group B arm of the LMB 96 regimen, which was modified to include four to six doses of rituximab. They reported a 3-year event-free survival of 93 % for the 45 eligible patients enrolled. Forty patients with either Burkitt leukemia (n=25) or CNS+ Burkitt lymphoma +/− leukemia (n=15) were treated according to the group C arm of LMB 96 which was modified to include four to six doses of rituximab [13•]. A 3-year event-free survival of 90 % was reported. In both the BFM study featuring a rituximab window plus conventional therapy in newly diagnosed children with CD-20+ high-grade mature B cell lymphomas and the COG pilot studies which featured rituximab plus conventional LMB-based therapy, a tolerable toxicity profile for rituximab was reported. It remains to be determined whether the incorporation of rituximab into frontline conventional B-NHL therapy improves outcome compared to conventional chemotherapy without rituximab. The current COG international randomized trial is designed to answer this question in high-risk patients in the context of LMB-based therapy (NCT01595048). Other immunotherapeutics are also being examined for high-grade B cell lymphomas. For example, Schuster et al. treated nine children with either relapsed/
Curr Hematol Malig Rep
refractory Burkitt lymphoma/leukemia or diffuse large B cell lymphoma with FBTA05 (an anti-CD3 × anti-CD20 trifunctional bispecific antibody; also called lymphomun) with encouraging results. Of note, one patient with relapsed Burkitt leukemia achieved a complete response with single agent lymphomun. The preliminary results regarding the activity of lymphomun will need to be confirmed in studies comprising a much larger cohort.
Anaplastic Large Cell Lymphoma Novel Agents The development of novel targeting agents has provided opportunities for new therapeutic approaches to the management of ALCL in children and adolescents. Surface CD30 is commonly expressed in ALCL [1]. Brentuximab vedotin, an antibody drug conjugate which links auristatin to anti-CD30, has been shown to be active in young adults and adolescents with CD30+ ALCL [25]. In a phase I study of brentuximab vedotin, two adults with recurrent ALCL achieved a CR [25]. Pro et al. published the results of a subsequent phase II study of brentuximab vedotin in adolescents and young adults (age range, 14–76) [42•]. Among the 58 enrolled on study, 86 % had an objective response (OR; median duration 12.6 months), 57 % had a complete response (CR; median duration 13.2 months), and 29 % had a partial response. The authors concluded that brentuximab vedotin was very active in patients with relapsed ALCL and should be considered for frontline therapy. The t(2;5) chromosomal translocation, which is the most common cytogenetic abnormality in pediatric ALCL, results in an NPM-ALK chimeric fusion product and subsequent expression of ALK [43–46]. ALK expression is detected in the majority of pediatric ALCL cases as compared to approximately 50 % of adult cases [47]. Crizotinib, a small molecule inhibitor of ALK, has been shown to be very active in patients with recurrent ALCL [26••]. Mosse et al. reported that among nine children with recurrent ALCL treated with single agent crizotinib, there were seven CRs, one PR, and one with stable disease. The activity of both brentuximab vedotin and crizotinib in those with recurrent ALCL led to their incorporation into the current frontline COG ALCL trial for children and adolescents (NCT01979536). Minimal Residual Disease Technology The level of minimal disseminated disease (MDD) at the time of diagnosis in children with various histological subtypes of NHL has been shown to have prognostic significance [27, 35, 48]. The BFM has demonstrated the prognostic significance of both qualitative and quantitative measurements of MDD in the bone marrow in children with ALCL [27]. Mussolin et al.
proposed a risk stratification for pediatric ALCL based on both qualitative measurement of NPM-ALK transcripts in bone marrow/peripheral blood analyzed by RT-PCR (MDD) and plasma ALK antibody titers using an immunocytochemical approach at the time of diagnosis [28••, 49]. At the time of diagnosis, over half of the children (59 %) had detectable MDD and the vast majority (96 %) had a detectable ALK antibody response. The authors identified three biological risk groups (bRG) based on these two factors. The high-risk group (bHR) was defined as MDD+ and Ab titer 1/750 (31 % of cases). All other cases were considered intermediate risk (48 % of cases). Progressionfree and overall survival by risk group included 28 and 71 % for bHR cases, 68 and 83 % for bIR cases, and 93 and 98 % for bLR cases. Multivariate analysis of risk factors demonstrated that only bHR and histology other than common type were predictive of a higher risk of treatment failure [28••]. The authors proposed that MDD and anti-ALK antibody measurements be used in future multicenter trials for pediatric ALCL. In a subsequent publication by Damm-Welk et al., the combination of MDD level at diagnosis and minimal residual disease (MRD) level before the second course of chemotherapy could also be used to identify high-risk ALCL patients [29••]. The cumulative risk of relapse among those that were MDD+ and MRD+ (81+8 %) was higher than that for those who were either MDD+ and MRD− (31+9 %) or MDD− (15+5 %) (p < 0.001). Five-year survival was also inferior for the MDD+/MRD+ group as compared to the MDD+/MRD− and MDD− groups (65+9 %, 92+5 %, and 91+3 %, respectively; p
