Lymphoblastic Lymphoma in Childhood and Adolescence

Pediatric Hematology and Oncology, Early Online:1–25, 2013Copyright C© Informa Healthcare USA, Inc.ISSN: 0888-0018 print / 1521-0669 onlineDOI: 10.3109/08880018.2013.789574

REVIEW

Lymphoblastic Lymphoma in Childhoodand Adolescence

Eva Schmidt1 and Birgit Burkhardt2

1Department of Hematology and Oncology, University Hospital Muenster, Germany;2Department of Pediatric Hematology and Oncology, NHL-BFM Study Center, UniversityChildren’s Hospital, Muenster, Germany

Lymphoblastic lymphoma (LBL) are thought to derive from immature precursor T-cells or B-cells.LBL are the second most common subtype of Non-Hodgkin Lymphoma (NHL) in children and ado-lescents. LBL are closely related to acute lymphoblastic leukemia (ALL), the most common type ofcancer in children. Using ALL-type treatment regimen to treat children with LBL was an importantdevelopment in the treatment of LBL. During the last decades, several systematic clinical trialscontributed to the controlled optimization of treatment. Today event-free survival (EFS) can beachieved for 75–90% of patients. However, acute and long-term toxicity, the lack of prognosticparameters and the poor outcome for patients who suffer from refractory or relapsed LBL remainhighly relevant subjects for improvement. To date, the pathogenesis of LBL is poorly understood.Learning more about the biology and pathogenesis of LBL might pave the way for targeted treat-ment to improve survival especially in relapsed and refractory patients.

Keywords adolescents, children, lymphoblastic, Non-Hodgkin lymphoma

1. INTRODUCTION

Non-Hodgkin lymphoma (NHL) is the fourth most common of all cancers in child-hood and adolescence according to data from 2001–2010 of the German ChildhoodCancer Registry (Annual Report, 2011, Germany, http://www.kinderkrebsregister.de/index.php?eID=tx nawsecuredl&u=0&file=fileadmin/DKKR/pdf/jb/jb2011/jb2011 3 1 Routine.pdf&t=1360701080&hash=47fb3185a8f963f22fa3b5251b7efd94).The current WHO (World Health Organization) classification of lymphoid tissuesdifferentiates between acute lymphoblastic leukemia (ALL) and lymphoblastic lym-phoma (LBL) based on the infiltration of the bone marrow. By convention, the termlymphoma is used when the process is confined to a mass lesion with no or minimalevidence of peripheral blood (PB) and bone marrow (BM) involvement [1]. Withextensive BM and PB involvement, lymphoblastic leukemia is the appropriate term.If a patient presents with a mass lesion and lymphoblasts in the BM, the distinctionbetween leukemia and lymphoma is arbitrary [2]. There is no agreed-upon lowerlimit for the percentage of blasts required to establish the diagnosis of ALL. For manytreatment protocols, a figure of 25% BM blasts is used as the threshold for defining

Received 20 March 2013; accepted 21 March 2013; published online 2013.Address correspondence to Birgit Burkhardt, MD, PhD, NHL-BFM Study Center, Department ofPediatric Hematology and Oncology, University Children’s Hospital Munster, Domagkstr. 24,D-48149, Munster, Germany. E-mail: [email protected]

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E. Schmidt and B. Burkhardt

Lin - , CD38-,CD34,

CD45RA-

HSC MPP CLP

Pro-B-cell Pre-Pre-B-cell immature B-cell

pro-T-cellpre-T-cell

cortical T-cellCD8+

cortical T-cellCD4+

TdTCD7cyCD3CD34+/-

TdTCD7cyCD3CD34+/-CD2

antigencontactα/β-Thymocyte

95%

CD34

TdTcyCD79aCD19CD34cyCD22

TdTcyIgMCD19CD34

mature B-cellPre-B-cell

TdTCD10CD19CD34CD22CD38CD45low

sIgMCD20CD19CD10CD23CD22CD38-/+

sIgMcyIgMCD19CD20CD79aCD38

medullaryCD8+

medulllaryCD4+

CD5CD7sCD3CD1aCD2CD4TdT

CD5CD7sCD3CD1aCD2CD8TdT

CD5CD7sCD3CD2CD8

CD5CD7sCD3CD2CD4

peripheral T-cellCD4+

peripheral T-cellCD8+

Bone Marrow Thymus peripheral lymphatic organs

corticalT-cell

TdTCD7cyCD3CD1aCD2CD8CD4

FIGURE 1 LBL correspond to stages of B- and T-cell maturation.Figure 1 illustrates schematically the immunophenotypic profile of early B- and T- cell maturation.Both lineages develop from immature HSCs over multipotent progenitors (MPP) to common lym-phoid progenitor (CLP) and separate from here into B- or T- cell lineage. The early pro-T-cell stateis characterized by the presence of CD7, TdT, and cytoplasmatic CD3 (cyCD3). In the thymus, thecells proceed through different intermediate stages and gain expression of CD2, CD1a, surface CD3(sCD3) and after T-cell receptor rearrangement CD8 and CD4 [1]. After antigen-contact selection,mature cells proceed into peripheral lymphatic organs and the blood. T-LBL are derived from earlyT-cell stages and aberrant expression of additional markers is common [61,114].B-cell development in the bone marrow is a continuous dynamic process [1,115,116]. PB-LBL de-velop from early stages of B-cell development. Aberrant marker expression is common.

leukemia. Whether there are biological differences between ALL and LBL that justifythe distinction of the two diseases is still under debate. Both, ALL and LBL derivefrom precursor B-cells (pB-ALL, pB-LBL) or precursor T-cells (T-ALL, T-LBL).

Although the 5-year event-free-survival (EFS) as well as overall survival in T-LBLand pB-LBL has substantially increased during the last decades, the prognosis of re-lapsed patients remains poor. The intensive treatment regimens are accompanied byhigh toxicity with considerable mortality and morbidity as well as subsequent devel-opment of secondary malignancies. In this review, we will address the current statusof discussion about pathogenesis, diagnosis, and treatment of childhood precursorB-LBL and T-LBL.

2. PATHOGENESIS AND MOLECULAR GENETIC CHARACTERIZATION

Information about pediatric LBL is limited. Current evidence suggests that LBL de-velop from immature T- or B-precursor cells. The lymphocyte development after thedifferentiation of hematopoietic stem cells (HSC) into progenitor cells with multi-lineage potential leads first to lymphoid lineage commitment (common lymphoidprogenitors CMP) before B- and T-cells develop independently from each other (see

Pediatric Hematology and Oncology

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Lymphoblastic Lymphoma in Children and Adolescents

Figure 1). Figure 1 illustrates schematically the immunophenotype of different stagesin lymphocyte maturation. In LBL-diagnosis, the distinction is less strict and aber-rant premature expression of CD79a and myeloid markers is common. The antigen-independent maturation of B-cells occurs in the bone marrow, whereas T-cell matu-ration is set in the thymus [3].

Although it is subject of discussion if T-ALL and T-LBL are separate diseases, theyshare a range of genetic alterations. Due to multiple recombinational effects duringT-cell-maturation, the T-cell receptor (TCR)-genes are predisposed to recombinationwith oncogenes or genes involved in thymocyte development through chromosomaltranslocations. These recurrent translocations are found in 50% of pediatric T-ALLs.Translocations involve most frequently T-cell receptor alpha (TRA) and T-cell recep-tor delta (TRD) at chromosome 14q11–13. The prevalence of these translocations inpediatric T-LBL is not exactly known.

Translocations lead to the fusion of TCR-promoter or enhancer elements withgenes encoding transcription factors (TF) such as TAL1, LYL1 [4], and OLIG1 as repre-sentatives of the basic helix-loop-helix genes. The fusion partners LMO1 and 2 repre-sent a group of cystein-rich LIM-domain-containing TFs, and among the evolutionaryhighly conserved homeodomain containing group of TFs the genes TLX1, TLX3, andgenes of the HOXA-Cluster are found as fusion partners. All these genes are involved inhematopoietic development and altered expression status is prone to promote malig-nant transformation by enhanced proliferation and/or impaired differentiation. Theirmalignancy promoting potential is not exclusive for lymphoid malignancies. More-over, numerous alterations of Hox-genes could be identified in myeloid malignancies.MIB and cMYC are also frequently upregulated in T-LBL. Smock et al. [5] reported thata majority of LBL samples expressed MIB1(59%) and cMYC (77%) in greater than 50%of analyzed cells by immunohistochemistry. It is to discuss if the cMyc overexpresion isdue to NOTCH-signaling perturbation or if other NOTCH-independent mechanismsare involved.

In one study [6] with nine patients (<16 years) overexpression of HOXA9 and LMO2could be detected in five out of nine patients. Compared to T-ALL overexpression ofTLX1 and 3, NUP214-ABL1 and TAL1 appear to be less frequent in T-LBL. In sev-eral studies [7–9], no overexpression of these genes could be detected. Merely onestudy [10] identified overexpression of TLX1 and 2, each in 1/11 pediatric patients.In the same study, two patients showed the STIL-TAL1-fusion. However, large casenumbers are required to confirm this trend. The current literature shows [7,11–13]thatmost chromosomal abnormalities reported in T-LBL have been reported earlier inT-ALL [14,15]. The translocation t(9;17) marks an exception since it is so far exclu-sively found in T-LBL [12, 11,16]. A Japanese study detected this translocation withNOTCH1 as one fusion partner in three out of nine patients with T-LBL [17]. Evidencethat cell cycle regulatory gene loci are frequently affected by chromosomal deletions inT-LBL/T-ALL [18–21] identifies impairment of the cell cycle as a prominent pathome-chanism in T-LBL/T-ALL. Recurrent deletions involve the regions 9p, 6q, and 11q. Ge-netic profiling in T-LBL [22]detected three genetic abnormalities repeatedly: deletionof chromosome 9p21 (CDKN2A and B), deletion of chromosome 13q14 (flanking theRB1-locus, a well described tumor suppressor gene), and gains of chromosome 6q23(MYB-locus). CDKN2A specifically inhibits cyklin/CDK-4/6 complexes that block celldivision during the G1/S-phase [23]. CDKN2A/p16INK4A-loss of function mousemodels display thymic hyperplasia [24]. Fifty percent of T-ALLs show deletion ofCDKN2A [25]. Few data are available to assess the loss of heterozygosity frequency(LOH) in T-LBL. A study with pediatric T-LBL and T-ALL patients detected a frequencyof LOH at the CDKN2A/2B locus of about 50% in both diseases [26]. Two smaller stud-ies detected CDKN2A LOH in 3/12 and 11/12 patients [14,26,27]. Dysregulation of

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NOTCH-Signaling is common in T-ALL/T-LBL. Signaling through the NOTCH recep-tor protein is evolutionary highly conserved and implicated in cell fate choices duringdevelopment and has an important function in self-renewing tissues of the adult or-ganism [28,29]. Active NOTCH1 drives HSCs toward a T-cell fate [30] and expands thepool of immature T-lymphocytes [31]. Ligand binding to the membrane bound recep-tors results in two steps of proteolytical cleavages of the receptor, separating the intra-cellular portion of NOTCH to enter the nucleus and activate the transcriptional targets.A number of genes directly regulated by NOTCH1 could be identified by genome-widechromatin immunoprecipitation arrays and sequencing [32,33]. The oncogenic tran-scription factor cMYC is a prominent downstream target [34]. In addition, inactivatingmutations were identified in FBXW7, an E3 ubiquitin ligase participating in degrada-tion of NOTCH1 and subsequent termination of NOTCH-signaling [35–38]. NOTCH1is considered a hematopoietic proto-oncogene because of its function as a trigger inT-ALL. The transforming activity of NOTCH1 can be interpreted as a reflection of itsnormal function in T-cell development [39]. In 2004, Weng and coworkers [40] iden-tified activating NOTCH1-mutations in 56% of T-ALL-cases examined. This is in linewith observations in pediatric T-ALL [41–44] and T-LBL [14,45–47]. With reference tomutation rate and pattern, no difference between T-LBL and T-ALL could be detected.The gene FBXW7 encodes an E3-ubiquitin-ligase. This enzyme ubiquitinates NOTCH1and induces proteasome mediated degradation. Accordingly, it is hypothesized thatFBXW7 loss of function leads to more NOTCH-signaling by increasing the NOTCH-halflife. The frequency of inactivating FBXW7 mutations is reported to be 10–30% forboth T-LBL and T-ALL [6,14,40–42,44–48].

A recent study suggests an important role for the hedgehog (Hh) signaling pathwayin the development of T-LBL [49]. The gene Smo is shown to be upregulated in murineand human T-LBL contributing putatively to an activation of the Gli/Hh–Signalingpathway whereas a group of microRNAs known to suppress Smo-Expression isdownregulated. Whether these observations apply to pediatric T-LBL needs to beelucidated.

Epigenetic changes are found frequently in tumors of different origin. EZH2 is amember of the polycomb transcriptional repression complex and acts mainly as a genesilencer by methylating specific lysines at histone H3. Simon C. et al. reported that lossof function leads to the development of T-ALL in a murine loss of function model [50].Therefore, EZH2 should be subject of further analysis in regard to its putative contri-bution to the malignant transformations of T-cell progenitors.

Cytogenetic and molecular abnormalities in pB-LBL are considerably less wellcharacterized than in T-LBL. Classical chromosomal aberrations that occur frequentlyin pB- ALL, e.g., hyperdiploidy, t(12;21), t(1;19), and t(9;22) are detected less frequentlyin pB-LBL [51,52]. Few publications report cytogenetic abnormalities in pB-LBL in-cluding the presence of additional material from the 21q locus [52]and segmentalduplication of the MLL-gene [53]. Precursor B-LBLs usually show monoclonal im-munoglobulin rearrangements and lack evidence of somatic hypermutation [54].

Further work is required to develop animal and preferably xenograft models tostudy the development of pB- and T-LBL in vivo to gain more information about thebasic biology.

These models can be used to conduct RNAi and small molecule screens to pave theway to new targeted therapeutic approaches.

3. CLINICAL PRESENTATION

Most patients with T-LBL typically present with mediastinal tumor. Other mani-festations are lymphadenopathy, frequently with cervical and supraclavicular bulky


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disease as well as pleural or pericardial effusions are common. The presence of apredominantly anterior mediastinal mass can cause respiratory symptoms fromcoughing, stridor, dyspnea, edema, elevated jugular venous pressure to acute respi-ratory distress. About 15–20% [55] of patients exhibit bone marrow infiltration. Lessthan 5% show central nervous system (CNS) involvement.

The most frequent sites of involvement in pB-LBL are the lymph nodes, skin, soft tis-sue, and bone [52,56,57]. Compared to T-LBL, these patients are more likely to presentin a stage of limited disease [56]. According to the results of the EORTC-trial (n = 53)bone marrow infiltration was present in 43% of the cases compared to 30% based onthe NHL-BFM data (n = 97). In both reports CNS affection was detected in 6% (EORTC)and 5% (BFM), respectively. Depending on the site of manifestation, the symptomsvary. The median age of diagnosis is not significantly different in pB-LBL (8 years) andT-LBL (8.8 years) [55]. In pB-LBL, there is no difference in gender distribution but T-LBL were 2.5 times more often diagnosed in male patients [55].

4. INITIAL DIAGNOSTICS AND STAGING

The least invasive procedure should be selected to establish the diagnosis of NHL.In case of suspected lymphoma, surgery is only recommended if cytological and im-munophenotypic examination of pleural effusion and ascites cannot confirm the di-agnosis. Staging of pediatric NHL is based on the classification proposed by Murphy1980 (St. Jude Staging system)[58].

The diagnostic workup includes a physical examination, peripheral blood and bonemarrow smears, cerebrospinal fluid (CSF) analysis, and assessment of serum lactatedehydrogenase (LDH) level. The presence of lymphoma cells in the CSF with >5 leuko-cytes and morphologically identified blasts and/or cerebral infiltrates on magneticresonance imaging and/or cranial nerve palsy not caused by an extradural mass is re-quired for the diagnosis of CNS-involvement. All patients should undergo lymphnode,abdominal, and in case of male patients testicular ultrasound. Depending on the re-sults, the diagnostic procedures can be extended by magnet resonance imaging (MRI)or, if necessary, computerized tomography (CT).

According to data from the NHL-BFM group [55]pediatric patients diagnosed withT-LBL present in 97% of cases with stage III-IV-disease compared to 65% stage III-IV-disease in pB-LBL.

5. PATHOLOGY AND IMMUNOPHENOTYPING

The diagnosis of LBL can be assured by cytomorphological and immunological (flowcytometry, FACS) analysis of malignant effusion or by histological and immunohis-tochemical analysis of paraffin embedded biopsies. If the diagnosis is based on flowcytometry, the criteria agreed upon by the European Group for Immunophenotyp-ing of Leukemias (EGIL) are frequently used whereas histologic diagnosis after tumorbiopsy is based on the WHO-criteria.

CytomorphologyCytomorphological analysis is performed according to the French-American-British(FAB-) classification for hematological malignancies. LBL typically show FAB-L1 orless often FAB-L2 cytomorphologic features.

Immunological Classification by FACS – Analysis (see Table 1)The criteria of the European Group for Immunophenotyping of Leukemias (EGIL)has been accepted worldwide as a standard for immunophenotypic diagnosis.


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TABLE 1 Schematic Summary of Diagnostic Criteria According to the EGIL (European Group forImmunophenotyping of Leukemias) or WHO – Criteria[1]. Aberrant Marker-Expression isCommon, e.g., Approximately 10% of T-LBL Stain Positive for the B-cell Marker CD79a [61].

Immunological analysis by flowcytometry according to EGIL-criteria

Histopathological classificationaccording to WHO-criteria [1]

Lymphobasticlymphoma ofprecursor-B-cell-lineageall

CD19 pos., and/or CD79a pos. and/orCD22 pos. (at least 2/3 pos.) TdTpos. and HLA-DR pos.

Expression of cyCD79a, CD19,cyCD22 (at least 2/3 positive),TdT, HLA-DR usually negativefor surface immunoglobulin(sIg) and positive for CD10variable expression of CD34

Pro B No further antigens for differentiation CD19 pos., cyCD79a pos., cyCD22pos., nuclear TdT pos.

Common ALL - type(WHOintermediate stage)

CD10 pos. CD10 pos.

Pre-B Cytoplasmatic (cy)IgM pos., surface(s) Ig negative

Cy-11-chain pos., sIg neg.

Lymphoblasticlymphoma ofT-cell-lineage all

Cytoplasmic or membrane boundCD3 pos., mostly TdT pos., HLA-DRneg. and CD34 neg.

TdT and cyCD3 line specificity:TCR, CD3 differential diagnosis:pan-cytoceratin

Pro T CD7 pos. Pos. for cyCD3, CD7; neg. for CD1a,CD2; CD34 +/ -

Pre-T CD2 pos. and/or CD5 pos. and/orCD8 pos.

Pos. for cyCD3, CD7, CD2; neg. forCD1a, CD34 +/ -

IntermediateT/cortical T

CD1a pos. Pos. for cyCD3, CD7, CD2, CD1a,sCD3; neg. for CD34

MatureT-cell/medullary T

Membrane-bound CD3 pos., CD1aneg.

Pos. for cyCD3, CD7, CD2, sCD3;neg. for CD1a, CD34

α/β + T-cell Anti TCR α/βγ /δ + T-cell Anti TCR γ /δ

Cytoplasmatic and nuclear markers are considered positive if found in at least 10% ofthe lymphoma cells. For surface markers applies the rule that they have to be detectedon at least 20% of the lymphoma cells [59].

T-LBL are cytoplasmic or membranebound CD3 and mostly TdT positive and arefurther subclassified into pro-T, pre-T, intermediate T, and mature T-cell phenotypedefined as follows: pro T-cell phenotype stains positive for CD7, pre-T-cell phenotypestains positive for CD2 and/or CD5 and/or CD8. Intermediate phenotype stains posi-tive for CD1a and mature T-LBL express membrane-bound CD3 with CD1a negativity.In addition to TdT, the most specific markers to indicate the precursor nature of T- lym-phoblasts are CD99, CD34, and CD1a [60].

Lymphoblastic lymphomas of precursor B-cell lineage express at least two of thethree markers CD19, CD79a, and CD22. They also stain positive for TdT, PAX5, andHLA-DR. Lymphomas of the common-ALL type stain positive for CD10. Pre-B-LBLcan be identified by their positivity for cytoplasmic IgM and no expression of surfaceimmunoglobulin. Early-B-cell lymphoma are defined as lymphoma morphologicallyFAB L1 or L2 but surface immunoglobulin (sIg) is identified by flowcytometry. Thesepatients should be treated as having lymphoblastic lymphoma.

Histopathological DiagnosisFor the histopathological diagnosis of LBL, the WHO criteria are widely accepted.Interestingly, the EGIL criteria and the WHO criteria are not identical, although theWHO guidelines for lineage determination and subtyping of precursor cell neoplasmare mainly derived from flow cytometry analyses of ALL. In consequence, the WHO


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guidelines are not directly transferable to the histopathological procedures necessaryto diagnose LBL as discussed by Oschlies et al., 2011[61]. Based on the analysis of 193patients with LBL, an algorithm for immunohistochemical staining was developed[61] to address the problem of challenging morphologic and immunophenotypicalvariants. Accordingly, the diagnosis of LBL requires typical morphology, confirmationof precursor cell immunophenotype, detailed lineage definition, and subtyping by ad-ditional stainings and/or genetic analysis. TdT-expression has been identified as thebest marker for determining the precursor cell nature of a lymphoma. In TdT nega-tive lymphoma with typical lymphoblastic morphology, either expression of CD1a orCD34, coexpression of CD79a and CD3, or coexpression of CD4 and CD8 can be usedto determine the precursor cell nature of lymphoma.

The histopathological diagnosis of pB-LBL according to the WHO requires expres-sion of TdT, CD79a, HLA-DR, CD19, and CD22. Most of these lymphomas expressCD10, and some of them express CD34. They stain usually negative for surface im-munoglobulin [1,62–64]. PAX5 is generally considered the most sensitive and specificmarker for B-lineage in sections [65].

6. TREATMENT AND OUTCOME

The treatment of pediatric LBL has been revolutionized by treatment with ALL-typechemotherapy. Almost all current protocols are either based on the 10-drug LSA2-L2–regimen developed at Memorial Sloan Kettering Cancer Center for ALL-treatment[66] or the NHL-BFM protocol for LBL, which is derived from the ALL-BFM-protocol[67,68, 57, 69]. The main difference is the earlier application of L-asparaginase and thepresence of high-dose methotrexate (MTX) during consolidation (protocol M) in theBFM-regimen. Initially, local radiation therapy was mandatory in both original proto-cols.

The original LSA2-L2 protocol was divided into induction, consolidation, andmaintenance therapy. The 21-day induction phase included administration of cy-clophosphamide (1 × 1200 mg/m2), daunorubicine (2 × 60 mg/m2), vincristine (3 ×2.25 mg/m2), prednisone (60 mg/m2 × 14 days) and intrathecal MTX three times.Radiation therapy was applied for all patients with bulky disease in the primary tu-mor site (any measurable tumor >5 cm) during the early induction or consolidationphase. The consolidation therapy consisted of cytarabine (14 × 150 mg/m2), thiogua-nine (75 mg/m2 for 14 days), L-asparaginase (6000 IU/m2 for 11 days), carmustine (1 ×60 mg/m2), and two times intrathecal MTX. The maintenance therapy regimen com-prised thioguanine, cyclophosphamide, hydroxyurea, daunorubicin, vincristine, andoral and intrathecal MTX. These drugs were given in 5-day courses: 4 days of S-phasespecific drugs followed by 1 day of a cell cycle independent agent [70]. Patients withlimited disease (stage I and II) received a cumulative dose of 8400 mg/m2 cyclophos-phamide and 240 mg/m2 daunorubicin for 2 years. Patients with advanced disease(stage III and IV) received a cumulative dose of 15,600 mg/m2 cyclophosphamide and300 mg/m2 daunorubicin.

Mora et al. reported in 2003 [71] an update on patients with LBL treated according tothis protocol between 1971 and 1990. With a median follow up of 20 years, the overallEFS was 75% (71/95 patients).

The successful trial NHL-BFM90 consisted of an induction, consolidation, rein-duction (for advanced stages III and IV), and maintenance therapy. The inductiontherapy included the administration of prednisone (60 mg/m2 dl–28), vincristine(4 × 1.5 mg/m2), daunorubicin (4 × 30 mg/m2), L-asparaginase (8 × 10,000 IU/m2),cyclophosphamide (2 × 1000 mg/m2), cytarabine (4 × 4 days 75 mg/m2) and 6-mercaptopurine (60 mg/m2) orally from day 36 to day 63. Intrathecal MTX was


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administered five times during induction therapy. For CNS positive patients, two ad-ditional intrathecal therapies are provided. Consolidation therapy, or “protocol M” in-cluded beside continuous oral therapy with 6-mercaptopurine (60 mg/m2) four timeshigh-dose MTX (5g/m2) and four times intrathecal MTX. The reinduction therapy in-cluded dexamethasone (10 mg/m2 for 21 days and additional 9 days of tapering) inaddition to vincristine (4 × 1.5 mg/m2), doxorubicin (4 × 30 mg/m2), L-asparaginase(4 × 10,000 IU/m2), cyclophosphamide (1 × 1000 mg/m2), cytarabine (2 × 4 days75 mg/m2), and oral 6-thioguanine (60 mg/m2). Intrathecal MTX was given twiceduring reinduction. Maintenance therapy consisted of 6-mercaptopurine (60 mg/m2)daily and MTX 20 mg/m2 weekly up to a total therapy duration of 24 months [69].

Although the development of these therapy protocols meant a major step towardcuring pediatric patients from LBL, unanswered questions remain. Numerous trialsand protocols have been developed on the BFM or LSA2-L2 backbone to increaseevent free survival (EFS) as well as overall survival (OS) and to reduce toxicity withinthe established therapy regimen.

Limited Disease (Stages I and II)Ninety-seven percent of pediatric patients with T-LBL and 65% of pB-LBL present withadvanced stage III and IV disease impairing the knowledge of patients with limiteddisease due to low case numbers [55]. Therefore, the question how much treatment isnecessary for patients with limited disease is under debate.

After switching to ALL-like regimen, the prognosis of limited disease LBL has im-proved. Pinkel et al. [72] reported 12 out of 14 patients with stage I and II lymphoblasticlymphoma treated with local irradiation and “total therapy,” a multidrug ALL-like reg-imen remained in CR 1 to 10 years. In the original single center study EFS at 5 yearsfor patients with localized disease (n = 8) treated according to the LSA2-L2 treatmentplan was 88% [71].

The CCG (children’s cancer group) trial 502 was initiated to compare LSA2-L2 in-cluding high-dose MTX with ADCOMP. A total of 143 patients with NHL were treatedaccording to the LSA2-L2–regimen and 138 patients were treated according to theADCOMP regimen [73]. EFS rates were not significantly different but treatment withADCOMP resulted in an EFS 10% lower than LSA2-L2 (74% and 64%). Therefore, AD-COMP was considered unlikely to be the superior treatment. The 5-year event-free sur-vival for patients with localized disease was 84% as compared to 67% for patients pre-senting with disseminated disease [73]. There were four treatment failures within 28patients with localized disease. In addition, all patients were treated with local irradi-ation, later proven to be “overtreatment” for limited stage disease.

Similar results were reported for eight patients with localized T-LBL included intothe French LMT81 trial [74] and treated according to the LSA2-L2-protocol with addi-tional administration of high-dose MTX. All patients reached a CR. The recorded EFSat 29 months for these patients was 73 ± 8%. Two deaths occurred, both in CR. Therewas no relapse reported.

In the trial NHL-BFM, 90 patients with localized disease underwent induction,consolidation, and maintenance therapy without reinduction and cranial irradiation.Only 4 out of 105 patients presented limited stage T-LBL were included [69]. All re-sponded well to the therapy and no relapse occurred. Because of the low case number,statistical analysis is not possible.

The Italian protocol AIEOP LNH-92 modified the LSA2-L2 therapy by adding high-dose MTX and maintenance therapy with 6-mercaptopurin and oral MTX with a to-tal treatment duration of 11 months for stages I/II, and 24 months for stages III/IV-disease, respectively. Again, the patient number (n = 5) is limited. The EFS for patientswith localized disease was 100%.


Pedi

atr

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atol

Onc

ol D

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om in

form

ahea

lthca

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om b

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orth

east

ern

Uni

vers

ity o

n 05

/05/

13Fo

r pe

rson

al u

se o

nly.


Ducassou [75] summarized the results for pB-LBL patients enrolled into the trialsLMT96, EORTC 58881, and EORTC 58951. Six patients each with stage I and stage IIdisease were treated according to the EORTC-protocols based on a NHL-BFM back-bone. Four patients with stage I and two patients with stage II disease were treatedaccording to the LMT96 protocol. In contrast to the BFM-based EORTC protocols thetrial LMT96 included no early risk stratification based on disease stage. In the EORTC-protocols patients with limited disease (stages I and II) were treated in the less inten-sive low-risk arm. When patients failed to achieve CR or good partial response after in-duction, the therapy regimen was switched to the more intensive high-risk arm. In theLMT-96 protocol, the maintenance therapy was reduced to 12 months for patients withstage I–III disease compared to a maintenance therapy of 18 months for patients withstage IV disease. The EFS was not significantly different between the trials LMT96 andEORTC 58881 and 58951. No relapses were observed. The largest number of patientswith limited disease LBL was presented by Termuhlen et al. (2012) [76] and included42 pB-LBL and 14 T-LBL. Patients were treated according to the CCG-BFM-protocolwith reinduction and a maintenance therapy up to 24 months. The EFS at 5 years was90% for pB-LBL patients and 100% for T-LBL patients. Five patients relapsed (4 pB-LBLand 1 T-LBL). Response to salvage therapy was poor, so four out of five patients diedand one was lost to follow up [76].

Two secondary malignancies occurred (AML and Ewing’s sarcoma).With the current protocols the response rates of limited stage LBL are high.

Further work is required to reduce toxicity of current treatment plans e.g. to evalu-ate the impact of the re-induction in BFM based protocols and to identify the patientswho will not respond to current therapy protocols. The response rates to salvage ther-apies are low with subsequently poor outcome.

Advanced Stage Disease (Stages III and IV)Most pediatric patients get diagnosed in advanced stage of disease [55]. Many treat-ment protocols are based on modified LSA2-L2 or NHL-BFM-protocols. The value ofspecific single agents for the successful treatment of pediatric LBL is not clear.

The pediatric oncology group designed a trial (POG 8704) to test the hypothesisthat addition of high-dose asparaginase to the consolidation therapy improves thesurvival of patients with ALL and advanced stage LBL. A total of 167 patients withadvanced stage (III and IV) LBL were randomized to receive a consolidation therapywith or without high-dose asparaginase. The therapy included administration of vin-cristine, prednisone, doxorubicin, cyclophosphamide, asparaginase, teniposide, cy-tarabine, and mercaptopurine according to local institutional protocols. Asparaginasewas administered weekly over 20 weeks by intramuscular injection. For LBL, the high-dose asparaginase treatment arm was significantly superior to the control regimenwith 4-year continuous complete remission rates (CCR) of 78% (±5%) compared to64% (±6%) in the control arm (p = .048) [77]. However, the increased rate of secondarymalignancies in the high-dose asparaginase arm (7/84 vs. 1/83 in the control group)limits the use of high-dose asparaginase.

To date, the best survival data could be obtained from the trial NHL-BFM90.Patients with T-LBL were treated according to the above described chemotherapy.Patients with stages III and IV received induction, extracompartment protocol M, rein-duction, prophylactic cranial radiotherapy, and maintenance up to a total therapy du-ration of 24 months. The response was evaluated at day 33 and at the end of inductiontherapy. Presence of >70% of residual tumor at day-33 was answered by treatment inthe BFM-ALL high-risk protocol (two patients). The 5-year-pEFS was 90% for all 105


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ity o

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/05/

13Fo

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patients [69]. Eight patients (seven with stage III and one with stage IV) relapsed anddied. For patients with stage III disease 5-year pEFS was 90% ± 3%, for stage IV-disease95% ± 5%. Sixty-four patients achieved complete tumor response at day 33 resultingin a pEFS at 5 years of 95% ± 2% compared to 89% ± 5% for 37 patients with resid-ual tumor at day 33. [69]. These data are contrasting with a retrospective analysis byShepherd and coworkers [78] who suggest that tumor response at the end of induc-tion therapy poses a higher risk for treatment failure. Patients who failed to respond tofrontline therapy showed an extremely poor survival rate. Until today, the EFS and OSrates of the NHL-BFM-90 trial could not be exceeded by any other study.

Central Nervous System Directed Therapy and Prophylactic Cranial RadiationCentral nervous system (CNS) prophylaxis is considered an important element of alllymphoblastic lymphoma protocols. However, the modalities differ in between treat-ment plans. CNS prophylaxis consists of intrathecal therapy (MTX single or triple ther-apy with additional hydrocortisone or prednisolone and cytarabine), cranial radio-therapy, and chemotherapeutic agents administered orally or intravenously that havethe ability to pass the blood/brain barrier.

All currently used regimens show comparable rates of CNS-relapse (details seeTable 2).

Role of Prophylactic Cranial IrradiationBecause of relevant late effects of cranial irradiation, three trials tested the omissionor prophylactic cranial irradiation (pCRT).

The aim of the trial NHL-BFM 95 was to test against the historical controls of thetrials NHL-BFM 86 and 90 whether prophylactic cranial irradiation can be omitted inCNS negative patients with stage III/IV and sufficient response at day 33. A total of156 LBL patients were evaluable compared to 165 patients of the historical controls.In the trial NHL-BFM95 an EFS at 5 years and DFS were 82 ± 3% and 88 ± 3% forpatients without pCRT compared to 88 ± 3 and 91 ± 2% for the historical controls [79].According to the statistical plan of the trial, the omission of pCRT was accepted.

The therapy regimen of the EORTC trial 58881 was based on the BFM-protocol andconfirmed previously obtained results from the trial NHL-BFM95. Cranial irradiationwas omitted even for patients with CNS involvement at diagnosis (n = 3; 1/3 sufferedrelapse). A total of 121 pediatric patients with T-LBL were included and achieved anEFS of 78% ± 4%. Omission of cranial radiotherapy did not influence the rate of iso-lated CNS relapse [27]. Patients with complete response to the 7-day prephase (n =16) reached an EFS of 100% at 6 years compared to 14% for patients with no response(n = 7) to prephase. The overall survival rate at 6 years was 86%.

The St. Jude trial NHL13 was designed to further improve cure rates and to minimizelong-term toxicity for pediatric patients with advanced LBL. It was based on the St.Jude T-ALL protocols including intensive intrathecal chemotherapy for CNS-directedtherapy and excludes prophylactic cranial irradiation. Thirty patients with stage III and11 patients with stage IV LBL were enrolled (33 T-LBL, 5 pB-LBL, 3 LBL not furtherclassified). The 5-year EFS was 83% ± 6% [80]. The authors conclude that prophylacticcranial irradiation was not required to achieve an excellent treatment outcome.

Role of High-Dose MethotrexateTwo recently reported trials intended to evaluate the value of high-dose methotrexatein the treatment of pediatric LBL; because of superiority in EFS and toxicity profile, theNHL-BFM-protocol was used as a backbone in more recent trials. Abromowitch re-ported in 2008[81] that the results of a trial designed to determine whether a regimenwithout HD-MTX results in the same outcome as published from the trial NHL-BFM90


Pedi

atr

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Onc

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om in

form

ahea

lthca

re.c

om b

y N

orth

east

ern

Uni

vers

ity o

n 05

/05/

13Fo

r pe

rson

al u

se o

nly.

TAB

LE2

Sum

mar

yof

rece

ntc

linic

altr

ials

for

ped

iatr

icLB

Lw

ith

resp

ectt

on

um

ber

ofin

clu

ded

pat

ien

ts,t

um

orst

age,

trea

tmen

tin

clu

din

gC

NS

pro

ph

ylax

isan

dth

erap

y,p

EFS

and

rela

pse

.Ab

bre

viat

ion

s:H

D-M

TX

:hig

h-d

ose

met

hot

rexa

te;C

R:c

ran

iali

rrad

iati

on;t

rip

leth

erap

y:in

trat

hec

alth

erap

yw

ith

hyd

roco

rtis

one,

cyta

rab

ine,

met

hot

rexa

te(M

TX

);it

h.:

intr

ath

ecal

;in

d.:

ind

uct

ion

ther

apy;

con

s.:c

onso

lidat

ion

ther

apy;

HD

-asp

.:h

igh

-dos

eas

par

agin

ase

ther

apy;

mai

nt.

:mai

nte

nan

ceth

erap

y;re

-in

d.:

rein

du

ctio

nth

erap

y;C

TX

:ch

emot

her

apy.

Tri

al/

Ref

eren

ceN

o.p

at.

Stag

eT

reat

men

tC

NS

pro

ph

ylax

is/t

her

apy

Tre

atm

ent

du

rati

onL

ocal

irra

dia

tion

pE

FSR

elap

se/

Pro

gres

sion

CN

SR

elap

se

LMT

81[7

4]84

I-IV

Mod

.LSA

2-L2

(+10

×H

D-M

TX

3g/m

2):

2×

Ind

uct

ion

,3×

con

solid

atio

n,5

×m

ain

ten

ance

)

HD

-MT

X,2

4G

yC

Rif

init

ialC

NS

invo

lved

.-in

trat

hec

altr

iple

ther

apy

ifC

NS

isin

volv

ed,i

th.

MT

Xas

stan

dar

dp

rop

hyl

axis

24m

onth

sIf

test

icu

lar

invo

lvem

ent

pre

sen

t;fo

rre

sid

ual

Tum

or

75±

3%I-

II:

73±

8%3×

stag

eII

I10

×st

age

IVto

tal1

3/84

I-II

:no

rela

pse

1/13

CC

G50

2[7

3]14

3LS

A2-

L213

8A

DC

OM

P

IIII

-IV

Mod

.LSA

2-L2

a)vs

.A

DC

OM

Pb

)ra

nd

omiz

atio

n

a):i

.th

.cyt

arab

ine

d0,

MT

Xd

16an

d30

,co

nso

lidat

ion

d7,

d14

,d

21,d

28,m

ain

ten

ance

d1

AD

CO

MP

:d0

+20

cyta

rab

ine

i.th

.,M

TX

i.th

.d16

and

30;

mai

nte

nan

ced

ay0,

1st

cycl

ed

7an

dd

14C

NS-

invo

lvem

ent:

add

itio

nal

i.th

.MT

Xd

9,d

23C

Ran

dsp

inal

irra

dia

tion

Min

.18

mon

ths

For

bu

lkd

isea

sest

arti

ng

day

5in

bot

hre

gim

en

74%

a)64

%b

)I-

II:

84%

III-

IV:6

7%

81 I-II

:4/

28tr

eatm

ent

failu

rep

rim

ary

med

iast

inal

:63

/206

8

PO

G87

04[7

7]16

7II

II-

IVL

ocal

pro

toco

l(P

OG

and

loca

lin

stit

uti

on)

Ran

dom

izat

ion

±H

D-

asp

arag

inas

eat

wee

k20

84p

at.

HD

-asp

arag

inas

e,83

pat

.con

tro

grou

p

i.th

.tri

ple

ther

apy

CN

Sin

volv

emen

t:C

R+

2×

add

.tri

ple

ther

apy

i.th

.(1

×in

d.,

1×

con

s.)

24m

onth

s64

±6%

(con

trol

)78

±5%

(HD

-asp

.)

4834

/83

con

trol

24/8

4H

D-a

sp.

6 2/83 co

ntr

ol4/

84H

D-a

sp.

(Con

tin

ued

onn

extp

age)

Pedi

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form

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orth

east

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Uni

vers

ity o

n 05

/05/

13Fo

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rson

al u

se o

nly.

TAB

LE2

Sum

mar

yof

rece

ntc

linic

altr

ials

for

ped

iatr

icLB

Lw

ith

resp

ectt

on

um

ber

ofin

clu

ded

pat

ien

ts,t

um

orst

age,

trea

tmen

tin

clu

din

gC

NS

pro

ph

ylax

isan

dth

erap

y,p

EFS

and

rela

pse

.Ab

bre

viat

ion

s:H

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TX

:hig

h-d

ose

met

hot

rexa

te;C

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ran

iali

rrad

iati

on;t

rip

leth

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y:in

trat

hec

alth

erap

yw

ith

hyd

roco

rtis

one,

cyta

rab

ine,

met

hot

rexa

te(M

TX

);it

h.:

intr

ath

ecal

;in

d.:

ind

uct

ion

ther

apy;

con

s.:c

onso

lidat

ion

ther

apy;

HD

-asp

.:h

igh

-dos

eas

par

agin

ase

ther

apy;

mai

nt.

:mai

nte

nan

ceth

erap

y;re

-in

d.:

rein

du

ctio

nth

erap

y;C

TX

:ch

emot

her

apy.

(Con

tin

ued

)

Tri

al/

Ref

eren

ceN

o.p

at.

Stag

eT

reat

men

tC

NS

pro

ph

ylax

is/t

her

apy

Tre

atm

ent

du

rati

onL

ocal

irra

dia

tion

pE

FSR

elap

se/

Pro

gres

sion

CN

SR

elap

se

NH

LB

FM90

[69]

105

I-IV

NH

L-B

FMd

ay33

resp

onse

stra

tifi

cati

onif

<70

%tu

mor

regr

essi

onA

LLh

igh

risk

arm

stag

eII

Ian

dIV

:ad

dit

ion

alre

-in

du

ctio

n,C

R

Ind

uct

ion

:MT

Xi.

th.d

1,15

,29,

45,5

9if

CN

Sin

volv

emen

tad

dit

ion

ald

8an

dd

22;p

roto

colM

d8,

22,3

8,50

,re

-in

du

ctio

n,C

R

24m

onth

s90

%3

1

NH

LB

FM95

[79]

169

III-

IVM

od.N

HL-

BFM

90N

oC

R24

mon

ths

78±

3%3

EO

RT

C58

881

[27]

119

T-LB

LI-

IV(5

5p

at.

III-

IV)

BFM

-ALL

No

CR

Incr

ease

dri

skV

ery

hig

hri

skif

min

oror

no

resp

onse

toIn

du

ctio

nR

and

.In

terv

.:H

D-M

TX

(n=

26)

vs.H

D-M

TX

+cy

tara

bin

e(n

=29

),m

ain

t.6-

MP

(n=

25)

p.o.

vs.i

.v.(

n=

23)

i.th

MT

X:I

nd

.:d

1,8,

22C

ons.

:d9,

23,3

7,51

HD

MT

XIn

terv

al4

×H

D-M

TX

+/-

cyta

rab

ine

Re-

ind

uct

ion

Dex

a1

×i.

th.M

TX

24m

onth

s78

±3%

183

CO

Gp

ilot

[84]

77T-

LBL

6p

B-L

BL

2b

iph

en.

III-

IVM

od.L

SA2-

L2in

clu

din

gH

D-M

TX

CR

+SR

ifC

NS

pos

itiv

e(1

8Gy

+6G

y)In

d.i

.th

cyta

rab

ine

d0,

7,14

,21

i.th

.MT

XC

ons.

d14

,21,

HD

MT

X1g

mai

nte

n.:

Pu

lse

Ai.

th.

MT

X,P

uls

eC

HD

-MT

X

12m

onth

sN

o75

±5%

13 9d

eath

s(8

/9w

ith

in7

mon

ths)

2

Pedi

atr

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atol

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ol D

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d fr

om in

form

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ity o

n 05

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al u

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nly.

CO

G 5971

[81]

257

T-LB

LC

NS

pos

itiv

eex

cl.

III-

IVC

CG

-BFM

wit

hou

tH

D-M

TX

NH

L-B

FMw

ith

HD

-MT

Xw

ith

inte

nsi

fica

tion

wit

hou

tin

ten

sifi

cati

onin

ten

sifi

edan

thra

cycl

ine

and

cycl

oph

osp

ham

ide

adm

inis

trat

ion

du

rin

gin

du

ctio

nan

dre

ind

uct

ion

acco

rdin

gto

BFM

pro

toco

l24

mon

ths

83±

4%85

±4%

83±

4%83

±4%

LNH

92[8

5]47

T-LB

L8

pB

-LB

LI-

IVM

od.L

SA2-

L2In

d.:

3×

trip

le,2

×H

D-M

TX

con

s.:3

×tr

iple

,3×

HD

-MT

Xm

ain

t.I:

2×

trip

le,2

×H

D-M

TX

CN

S+:H

D-C

ytar

abin

em

ore

i.th

.th

erap

yC

R

III-

IV24

mon

ths

mai

nt.

Ian

dII

11m

onth

s

69±

6%st

age

Ian

dII

:10

0%

3p

rogr

essi

on1/

3al

ive

13re

l.11

die

d

1p

B-L

BL

12T-

LBL

St.J

ud

e13

[80]

33T-

LBL

5p

B-L

BL

3n

otd

et.

III-

IVM

od.“

Tota

l13“

regi

men

Ind

.Con

s.(H

DM

TX

)M

ain

t.,R

ein

d.

HD

-MT

Xye

ar

CN

Sn

eg.:

15×

i.th

.tri

ple

(2×

Ind

.,2

×C

ons.

,11

×fi

rst)

year

mai

nt.

)C

NS+

:s.a

.2×

add

.Du

rin

gIn

d.

5×

add

.Du

rin

gth

e1s

tyea

rn

oC

R

120

wee

ks83

±6%

3re

l.2

×lo

cal

1×

BM

+C

NS

2/3

salv

aged

byal

loge

nic

SCT

1

pB E

OR

TC

[75]

53p

B-L

BL

21Pa

t.LM

T96

17Pa

t.E

OR

TC

5888

115

pat

.E

OR

TC

5895

1

I-IV

I10

II9

III9

IV25

EO

RT

C:

Low

risk

arm

LMT

96:1

2m

onth

mai

nte

nan

ce(I

-III

)A

vera

geri

skar

m->

Hig

hri

skar

m,

Ifn

oC

Raf

ter

pro

toco

l1A

LMT

96

EO

RT

C4

×H

DM

TX

(5g/

m2)

no

CR

MT

Xi.

th.D

1,8,

22,

38,5

2,in

terv

al:D

9,23

,37,

51re

-in

d.D

38M

ain

t.D

22of

6p

erio

ds

of10

wee

ksT

rip

lefo

rA

RLM

T96

7×

HD

MT

X(3

g/m

2)M

TX

i.th

.:D

1,8,

22,

1×in

MA

CA

O1

18G

yC

Rfo

rp

at.w

ith

CN

Sin

v.

LMT

96:

12–1

8m

onth

sE

OR

TC

:2

year

s

82%

6re

lap

ses

2×

pro

gres

si-

ontr

eatm

ent

rela

pse

:C

TX

+D

exa

(Cyt

arai

n,

mit

ox,.

Asp

,et

op.7

/8al

loge

nic

SCT

Tota

l:al

l5

dea

thd

ue

toP

D3

dea

ths

2

(Con

tin

ued

onn

extp

age)

Pedi

atr

Hem

atol

Onc

ol D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y N

orth

east

ern

Uni

vers

ity o

n 05

/05/

13Fo

r pe

rson

al u

se o

nly.

TAB

LE2

Sum

mar

yof

rece

ntc

linic

altr

ials

for

ped

iatr

icLB

Lw

ith

resp

ectt

on

um

ber

ofin

clu

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and whether early intensification of anthracykline and cyclophosphamide wouldfurther improve disease-free survival. A total of 257 patients with stage III and IV LBLwere randomized to one of four arms.

The 3-year EFS of the HD-MTX versus none is 85% ± 4% versus 83% ± 4% and theearly intensification versus none is 83% ± 4% versus 83% ± 4%. The early intensifica-tion led to a higher level of toxicity with higher frequencies of grade III-IV neutropenia,anemia, thrombocytopenia, and more toxicity-related mortality [82, 81]. The resultsinterpreted that HD-MTX might be omitted and substituted by an increased numberof intrathecal treatment and that early intensification of therapy does not improve EFSin LBL for patients without CNS involvement. Notably, the maintenance treatment inthat trial was intensified by cycles of vincristine and prednisone compared to standardmaintenance of the NHL-BFM trials with MTX and mercaptopurin. This impairs theinterpretation of the results compared to NHL-BFM data.

The Pediatric Oncology Group (POG) phase 3 randomized trial 9404 [83] was de-signed to test whether addition of four cycles HD-MTX to the standard multiagentDana Farber Cancer Institute (DFCI) chemotherapy would reduce the number of earlyevents and subsequently prolong EFS. CNS prophylaxis consisted of 11 doses of tripleintrathecal therapy as well as cranial radiation (18 Gy). Patients with CNS involvementreceived two additional doses of intrathecal medication during induction and consol-idation. A total of 66 T-LBL patients were randomized into the no HDMTX treatmentarm and 71 into the HDMTX treatment arm [83]. The EFS at 5 years for all T- LBL pa-tients was 85% (±3%). EFS at 5 years was 82 ± 5% for patients with HD-MTX comparedto 88% ± 4% for LBL treated without HD-MTX. The cumulative incidence of CNS re-lapse was not significantly different between the two arms. In contrast to recent pro-tocols, all patients were treated with cranial irradiation as part of the CNS-directedtreatment that complicates the conclusion of the trial.

Duration of TreatmentThe therapy of LBL is rather long with its total duration of 24 months in most protocols.Therefore, the COG (children’s oncology group) performed a pilot trial with reducedtreatment duration. Eighty-five children and adolescents with stage III/IV LBL (77 T-LBL and 6 B-LBL, 2 biphenotypic LBL) were included [84]. Patients achieving completeresponse after induction and consolidation received shortened but intensified main-tenance therapy for a total duration of 12 months. The 5-year EFS was 78% ± 5%. Theshortening of maintenance therapy for a specific group of patients did not lead to aninferior rate of EFS at 5 years. Four patients (5%) died to toxicity-related deaths (sim-ilar to data reported by Uyttebrock et al. (2008) [27]) and 13 patients suffered relapse.The reported overall survival of relapsed patients was 33% ± 14%.

The AIEOP LNH-92 protocol was a modified LSA2-L2 therapy used for T- and pB-LBL including induction, consolidation, and maintenance treatment with a total du-ration of 24 months for stages III /IV-disease. CNS positive patients received an inten-sified therapy with high-dose cytarabine, increased number of intrathecal therapy andHD-MTX administrations, and cranial irradiation. Fifty-five patients were enrolled.EFS at 9 years was 69% for all patients (including five patients with limited diseasesee above). Neither toxic deaths nor secondary tumors were observed. Outcome wascomparable to most international protocols for LBL but inferior to recent trials that in-cluded reinduction treatment or a higher intensity therapy for high stage disease [85].

Corticosteroid in InductionTwo recent trials addressed the role of the steroids in induction treatment. Reiteret al. (2012) [86] presented the results of the randomized trial EURO-LB 02 which wasperformed by the European inter-group cooperation on Non-Hodgkin Lymphoma in


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children and adolescents (eicnhl). The backbone of the trial was based on the trialNHL-BFM90. This trial was designed to test whether the use of dexamethasone(10 mg/m2) in induction can increase pEFS compared to prednisone (60 mg/m2). Andin a second randomization, it was tested whether the total duration of treatment canbe reduced in T-LBL patients from 24 months to 18 months. The trial had to be pre-maturely closed due to an increased rate of toxic deaths (12/319). Therefore, the num-bers required to answer the randomized questions were not achieved and the resultsare only descriptive. A total of 319 patients were included in the trial and 186 patientswere randomized for the first randomization. There was no difference in EFS (84% bothgroups) but with significantly higher toxicity grade III/IV in the dexamethasone arm(hematotoxicity, infection, and peripheral neurotoxicity). A total of 119 patients par-ticipated in the second randomization that showed no difference in EFS between thetwo arms of total treatment duration.

Uyttebrock and Coworkers (2012) presented the results of the randomized phase IIItrial EORTC CLG comparing dexamethason in a lower dose (6 mg/m2/day) with pred-nisone (60 mg /m2/day) in induction therapy of patients with T-LBL [87]. Seventy-fourpatients were randomized for dexamethason (n = 37) or prednisone (n = 37). Overallsurvival was 92% for the prednisolone arm compared to 81% for the dexamethasonearm. Compared to previous results of the EORTC EFS in the prednisone arm was im-proved but dexamethasone led to an increased risk of mortality (4/37) in CR.

Precursor B-Cell Lymphoblastic LymphomaFocusing on the rarer subtype of pB-LBL Ducassou and coworkers (2011) [75] re-ported the outcome of the patients with pB-LBL enrolled in the trials LMT96, EORTC58881, and EORTC 58951 as mentioned above. For pB-LBL treatments derived fromALL-therapy with a maintenance phase lasting several months is considered the mostappropriate and superior to short pulse therapy [88]. For localized disease shorterregimen have shown to be successful [89]. A total of 53 patients with B-LBL were in-cluded into the above mentioned trials: 21 patients were treated according to LMT96,17 according to EORTC 58881 and 15 according to 58951. EORTC 58881 [90–92] and58951 [93] are derived from BFM ALL-therapy. The LMT 96–regimen included anearly intensification at day-8 with the adjunction of cyclophosphamide and high-dosemethotrexate [94]. Compared to the EORTC-protocols (four continuous IV perfusionsof 5 g/m2 MTX over 24 h) the LMT96 included seven perfusions of 3 g/m2 over 3 h. Ac-cording to the LMT 96 protocol, patients with CNS involvement were treated with cra-nial radiotherapy (18 Gy) whereas there is no RT in the EORTC–protocols. The differ-ences between the results of each protocol were nonstatistically significant, althoughthe LMT 96 showed a trend to inferiority with an EFS at 5 years of 69% compared to100% (EORTC 58951) and 82% (EORTC 58881). Except disease stage, no prognosticfactors could be identified. St. Judes stage I-III was superior in OS and EFS (96%, CI82–99) compared to stage IV (72%). Eight children experienced relapse (n = 6) or pro-gressive disease (n = 2). All of these children died.

7. TOXICITY AND SECONDARY MALIGNANCIES

Acute toxicity, whether a modified LSA2-L2- or BFM–backbone is used for treatment,plays a major role in morbidity and mortality, mainly infectious complications, pan-creatitis, and thrombotic events directly associated with the administered chemother-apy. The rate of treatment-related deaths ranges from 5.6% [75], 4.7% [74], 3/281 (1%)[73], 4/257 (1.5%) [81], 3/137 (2.2%) [83] to no toxic deaths [69]. The main reason oftreatment-related deaths are infections.


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Concerning late effects, the NHL-BFM group showed that within a total of 345 LBLpatients osteonecrosis was observed in 8.4% of patients (29/345), with slightly higherfrequencies in females compared to males. The median age was 14 years ± 3.3y in pa-tients who suffered from osteonecrosis compared to 8.4 ± 4.4 years in patients withoutosteonecrosis [95].

The development of secondary malignancies is recognized as a late effect ofchemotherapy among survivors of cancer. A total of 547 LBL patients enrolled between1981 and 2003 in the NHL-BFM trials led to a rate of secondary malignancies of 6.3%(9 5% CI: 2.4%–10%) [96]. In a French trial with 53 patients [75] 3 /53 (6%) patientsdeveloped secondary malignancies, Sandlund et al. (2009) [80], observed 1/41 sec-ondary malignancies. Abromowitch reported 2/257 [81] and Asselin 3/137 [83] sec-ondary malignancies. A large study with 167 patients diagnosed with LBL observedeight secondary malignancies [77] with a significantly higher rate in the high-dose as-paraginase arm (7/84 compared to 1/83).

The entity of tumors comprise predominantly of AML/MDS (24/33 of cases men-tioned in the above trials), but other tumors such as melanoma, glioblastoma, astrocy-toma, myeloid sarcoma, and papillary carcinoma. The specific rates of secondary neo-plasms in the different trials are difficult to compare due to the differences in follow-uptime. However, the problem of secondary malignancies highlights the need for morespecific therapies with less toxicity.

8. TREATMENT OF PROGRESSIVE DISEASE AND RELAPSE

Although extensive progress has been made in the frontline treatment in pediatric LBLpatients, 10%–20% of patients present with refractory or recurrent disease. For thosepatients, EFS of 50% after second-line treatment with HD-chemotherapy and autol-ogous stem cell transplantation (SCT) have been reported by the Korean group [97].The Japanese group reported an overall survival of 43% [1].

The NHL-BFM group [16] presented the characteristics, treatment, and outcomeof children with relapsed LBL after uniform intensive frontline NHL-BFM therapy. Atthe time of relapse, patients affected by LBL relapse were treated according to ALL-Rez BFM-strategies [98] or intensified ALL-BFM-HR courses [99] to achieve a secondremission as a prerequisite for allogenic SCT. Only one out of six patients with pB-LBLrelapse could be successfully treated; this specific patient received haploidentical allo-genic bone marrow SCT due to the lack of a matched donor. Similar poor results wereobserved in the 28 patents with relapsed T-LBL of whom only four patients are alive;all four had undergone allogeneic SCT. Univariate analysis of prognostic parametersfor the outcome after progression or relapse identified therapy with allogeneic SCT asthe only positive prognostic parameter. However, most patients did not reach a secondCR or good PR after relapse and subsequently were not eligible for allogeneic SCT. In-terestingly, the rate of relapses was lower in the NHL-BFM series compared to otherprotocols, but after NHL-BFM frontline most relapsed patients failed salvage therapycompared to other groups [97,100]. This might be attributed to the intensive frontlineNHL-BFM therapies. However, large randomized trials are missing and larger patientgroups are necessary to assess the value of allogeneic stem-cell transplantation.

These data raise the question if intensive induction chemotherapy narrows the pos-sibilities for salvage therapy due to toxicity limits. There is a need for new less toxic buteffective agents in the first line as well as in salvage therapy to make a second remis-sion possible. During the last 20 years, no new drugs made their way into the majortrials.

New immunotherapies like blinatumumab, a bispecific antibody designed to linkB-cells and T-cells resulting in T-cell activation and a cytotoxic T-cell response against


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CD19 expressing cells, are promising alternatives for pB-LBL. A dose finding trial forrelapsed pB-ALL in children is ongoing (NCT01471782). Good treatment results couldbe observed in three cases of pB–ALL treated with Blinatumomab for relapse after al-logeneic stem-cell transplantation. All patients reached a complete remission [101].

Other alternatives include nucleoside analogon like, e.g., nelarabine. FDA approvalwas granted after publication of two phase-II trials, one in pediatric patients, one inadult patients (for summary see Cohen et al. 2006[102]). The pediatric patient groupsuffering from T-ALL or T-LBL consisted of 39 patients who had relapsed or had beenrefractory to two or more induction regimens. CR to nelarabine treatment was ob-served in five (13%) patients and CR with incomplete hematologic or bone marrowrecovery was observed in nine (23%) patients [103]. Another phase I trial [104] includ-ing pediatric patients with relapsed or refractory T-ALL/T-LBL noted CR in 2/4 treatedwith nelarabine. Children’s Oncology Group study AALL00P2 was designed to assessthe feasibility and safety of adding nelarabine to an NHL-BFM86-based chemotherapyregimen in children with newly diagnosed high-risk T-ALL [105]. Five-year EFS for allpatients receiving nelarabine (n = 70) was 73% versus 69% for those treated withoutnelarabine (n = 16). Further trials are required to evaluate the position of nelarabinewithin the treatment of pediatric patients with T-LBL.

Clofarabine is also explored for ALL/LBL treatment. In a phase II trial, clofarabinewas used in combination with etoposide and cyclophosphamide for patients with re-lapsed or refractory ALL [106]. Twenty-five patients were included. The overall re-sponse rate was 44% (7 CR, 4 CRp). It is noteworthy that six patients (24%) died becauseof treatment-related adverse events associated with infection, hepatotoxicity, and/ormultiorgan failure. Therapy with clofarabine was reviewed by Hijiya et al. [107].

9. PROGNOSTIC FACTORS

To date, advanced lymphoblastic lymphoma has been treated with ALL-likechemotherapy regimen. As the 5-year EFS rates are acceptable, it might be askedwhether patients with favorable risk profiles might be “overtreated.” However, theproblem is that currently no validated parameters are in use to identify patients with afavorable risk profile. Therefore, a sufficient risk stratification is urgently needed to pre-vent unnecessary toxicity, e.g., osteonecrosis, and treatment-related mortality as wellas secondary malignancies and to identify the patients who profit from more intensiveregimen. It is of special importance to detect the 10%–30% of patients who have a highrisk of relapse in order to adapt therapy regimen early in addition to the stratificationsthat are already in place.

So far, parameters as age, sex, stage, presence of mediastinal mass, level of serumlactate dehydrogenase could not be consistently identified as prognostic markers.There are few exceptions. Tubergen et al. [73] reported an unfavorable prognostic riskfor children older than 14 years, based on the results of the trial CCG502. Analysis of theoutcome of T-LBL patients treated within different NHL-BFM trials detected a lowerEFS in adolescent females (57% ± 17%) compared to males with comparable clini-cal characteristics (92% ± 6%) [108]. Based on the COG pilot trial Abromowitch et al.[84] identified CNS involvement as prognostic factor, although the case numbers (2/3)were low.

Analysis of the EORTC 58881 trial led to the identification of response to therapyas a prognostic factor [27]. Complete clinical and radiological response after 7 days ofprephase with prednisolone and one intrathecal injection with MTX led to EFS ratesat 6 years of 100% compared to the resistant group (14%). These data could not be con-firmed by other groups so far.


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As reported by Bonn et al. [46], T-LBL patients registered in the NHL-BFM studycenter were tested for chromosome 6q loss of heterozygosity (LOH). LOH 6q16 wasdetected in 25 of the 217 analyzed patients (12%) and significantly related to pooroutcome in T-LBL exhibiting significantly lower pEFS rates (27 ± 9% vs. 86 ± 3%). Itremains to be explored to identify affected putative tumorsuppressor gene(s) in thedeleted chromosomal region. In 60% of 116 patients NOTCH1 mutations could be de-tected [46]. Presence of NOTCH1 mutations were associated with favorable outcome(pEFS 84 ± 5% vs. 66 ± 7%). Interestingly, NOTCH1 mutations and LOH 6q16 occurredalmost exclusively independent from each other. Comparable results were previouslyshown by Callens and coworkers [45]. Fifty-four patients with T-LBL treated accord-ing to the EURO-LB02 protocol were screened for NOTCH1- and FBXW7-mutations.NOTCH1 or FBXW7 mutations were found in 55% of all T-LBL patients and its presencewas associated with improved EFS (p < .01) and overall survival (p < .01).

A risk stratification according to the marker profile should be considered a subjectof clinical trials.

Detection of minimal residual disease (MRD) could be successfully introduced intoALL-treatment plans. Clonal TCR-gene arrangements and aberrant immunopheno-typic profiles are used to monitor the disease. Attempts have been made to translatethis method for LBL using a flow cytometry-based approach to detect submicroscopicsystemic disease [109,110]. To date, the position of MRD and minimal disseminateddisease (MDD)-monitoring in risk stratification or relapse/progression prediction isnot clear. To evaluate the possible benefit of MDD/MRD–diagnostics prospective stud-ies particularly for patients with advanced disease are necessary.

10. THE ROLE OF FDG-PET IN THE MANAGEMENT OF CHILDHOOD LYMPHOMA

Fluorodeoxyglucose positron emission tomography (FDG-PET) has been identified asa useful tool in the staging of Hodgkin’s lymphoma. As reviewed by Shankar et al. [111],FDG-PET results justify changes in staging and therapy. In Hodgkin’s lymphoma, thecharacter of residual tissue is predicted by FDG-PET.

Although proven advantageous compared to CT for adult NHL-patients as a toolin primary staging [112], the role of FDG-PET in childhood NHL diagnostics and re-sponse evaluation lacks systematic data from clinical trials. Desperately in need ofprognostic markers, the value of FDG-PET for response evaluation in lymphoblasticlymphoma should be further explored. The appropriate time for FDG-PET-diagnosticsto assess treatment response should be determined in prospective clinical trials to es-tablish a response-based treatment stratification. Such trial might reveal specific as-pects associated with pediatric LBL treatment. It was recently reported, e.g., that PET-diagnostics in childhood LBL face challenges due to high doses of corticosteroids thattransiently change FDG-uptake pattern, e.g., increased superficial facial uptake andreduced hepatic uptake as shown in 7 pediatric patients with T-LBL after a 4-week in-duction period [113]. FDG-uptake at sites of lymphoma manifestation may potentiallybe affected. Based on these observations, the interpretation of FDG-PET has to be per-formed with caution. Taken into consideration the additional toxicity and risk due toradiation and possibly anesthesia, to date, there is no evidence for the use of FDG-PETin the treatment protocols of lymphoblastic lymphoma except clinical trials.

CONCLUSION

The LSA2-L2 and the NHL-BFM protocols for LBL were successful therapy regi-men. The best results for EFS and overall survival published so far are based onthe trial NHL-BFM90 [69]. This was used as a backbone for numerous trials. Local


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irradiation therapy could be safely removed. And even prophylactic cranial irradia-tion can be omitted under the premise of sufficient systemic CNS prevention. The trialNHL-BFM95 deleted prophylactic cranial irradiation [79] without inferior outcome.These results could be confirmed after analysis of the EORTC trial 58881 [27] as well asby the St. Jude trial NHL-13 [80].

Two recently communicated trials aimed at evaluating the value of high-dose MTX.The results of the COG A5971 showed similar results for patients with and with-out high-dose methotrexate. However, all patients received intensified maintenanceand those without HD-MTX received a total of 21 doses intrathecal MTX [81]. In thePOG trial 9404, patients were randomized to receive HD-MTX or not. The resultsshowed no statistically significant difference in outcome for LBL. However, all patientswere treated with prophylactic cranial irradiation of 18 Gy. Therefore, future trials areneeded to evaluate the role of HD-MTX in pediatric LBL who do not receive prophylac-tic irradiation and an acceptable number of intrathecal MTX and no intensified main-tenance. Two trials focused on the role of dexamethasone versus prednisone in in-duction. Both, with the caveat of descriptive but not confirmatory statistics, showed asimilar outcome for the treatment with prednisone compared to dexamethasone dur-ing induction therapy [86,87] but higher toxicity was observed in the dexamethasonetreatment arm.

Due to relevant acute and long-term toxicity, clinical trials are urgently needed toimprove treatment in the sense of reducing toxicity and increasing EFS. These aimsmight be achieved by the identification and validation of prognostic parameters fortreatment stratification as well as by the evaluation of new effective drugs.

Declaration of InterestThe authors report no conflicts of interest. The authors alone are responsible for thecontent and writing of the paper.

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Lymphoblastic Lymphoma in Childhood and Adolescence

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