State of the Art Oncology in EuropeFont: aaa

Lymphoblastic lymphoma – 2016

UPDATED JULY 2016

1 GENERAL INFORMATION

1.1 Epidemiology

1.1.1 Incidence

Lymphoblastic lymphoma (LBL) is a rare disease accounting for approximately 8% of all lymphoid malignancies (RARECAREnet). In Europe, incidence is estimated by the RARECAREnet project with LBL including the following ICD-O morphology codes 9687, 9727-9729, 9826, 9835-9837 and it is labelled as “Precursor B/T lymphoblastic leukaemia/lymphoblastic lymphoma (and Burkitt leukaemia/lymphoma)”. The project estimated slightly more than 7,000 new cases in 2013 in EU28.
Based on about European 22,800 cases, diagnosed during the period 2000-2007, the annual incidence rate was very low with a rate of 1.5 per 100,000 and with a significant increase of incidence: from 1.37 to 1.61 per 100,000 during the period 2000-2007.
LBL is more frequent in males than females, with a male/female ratio of 1.4. The highest rate was in children (<15 years) with a rate of 3.6 per 100,000, then reduced to 0.8 in people aged 25-64 years aged and increased to 1.7 in the oldest age group of cases (65+ years).
The disease was more frequent in Southern Europe (1.9) and low in Eastern European Countries (1.1) (RARECAREnet).

1.1.2 Survival

For European patients diagnosed 2000-2007, 5-year survival was bad in the oldest patients (65 years or more; 86%) and good in children (0-14 years; 17%) (RARECAREnet). Prognosis was intermediate in adolescents and young adults (15-24 years) and in adults (25-64 years): 5-year survival was 60% and 39%, respectively (RARECAREnet).
In European adults, from 1997-1999 to 2006-2008 survival increased from 30% to 41% (Sant 2014). However, improvements in survival were not homogeneous across Europe, which could be a result of persisting inequalities in the provision of care.
Survival was significantly lower in Eastern and Southern Europe, and higher in Northern Europe in comparison with the UK (reference region) in a model adjusted for age, period, and year of follow-up (Sant 2014).
In European children affected by acute lymphoblastic leukaemia, most Central and Northern European Countries, the UK, Malta, and Italy had a 5-year survival (adjusted for age, sex, and period of diagnosis) higher than the European mean, whereas Bulgaria, Estonia, Latvia, Lithuania, and Slovakia had the lowest (<80%).
Five-year survival increased with a risk of dying for childhood lymphoblastic leukaemia falling on average by 6% per year. The most notable improvements were in Eastern Europe, where 5-year survival rose from 65% in 1999-2001 to 70% in 2005-2007 (Gatta 2014).

1.2 Risk factors

1.2.1 Ionizing radiation

The major studied risk factors for LBL is ionizing radiation during childhood and young adulthood. It is well established that exposure to high doses prenatally and early in life increases cancer rates in human and animals (Anderson 2000) and that foetus and young children are more susceptible to the effect of ionizing radiation than adults. Evidence is based on studies about atomic bomb survivors who received high dose (up to 200 mSv) in an acute dosage (Preston 1994) and from those foetuses who received X-rays in utero with much lower radiation dosages (Lightfoot 2004).  However, other sources such as diagnostic imaging during pregnancy contributes with a lower dosage.

1.2.2 Infections

Several viruses have been found to be involved as factor in the pathogenesis of haematological entities. They are the HTLV-I for acute T cell leukaemia/lymphoma, HIV and HHV-8 for the group of non Hodgkin lymphomas (NHLs). The first (HTLV-I) acts as a direct carcinogen in adult T cell leukaemia/lymphoma; the other viruses as indirect carcinogens. Adult T-cell leukaemia/lymphoma (ATLL) occurs almost exclusively in areas where HTLV-1 infection is endemic (South-Western Japan, the Caribbean, and parts of Africa and South America). The cumulative incidence of ATLL among HTLV-1 carriers was estimated 1% to 5% in endemic areas (Murphy 1989a; Proietti 2005).
ATLL occurs mostly in adults, at least 20 to 30 years after the onset of HTLV-1 infection; this infection mostly occurs during childhood. HTLV-1 can be transmitted from mother to child through breastfeeding and via transfusion of infected blood products or sharing of needles and syringes and via sexual intercourse (Manns 1999). One per cent of all leukaemias is attributable to HTLV-1 (Pisani 1997).
The HIV type 1 operates with immunesoppression and greatly increased in immunosuppressed individuals. Indeed, infection with oncogenic viruses is much more common than the diseases that these viruses cause, and  incidence and severity of these cancers is greatly increased by immunosuppression. HIV-1 is transmitted by sexual intercourse, blood contact, and from mother to infant. Globally, an estimated 35.3 million people were living with HIV (HIV-1 and HIV-2) in 2012. About 95% of new HIV infections occur in less developed regions. In 2012, the prevalence of HIV ranged from less than 0.5% in more developed regions to up to 26% in some Countries in the sub-Saharan Africa (UNAIDS 2013).
Also the Hepatitis C virus (HCV) can cause B-cell non Hodgkin lymphoma. The virus acts via chronic inflammation. HCV can be transmitted by transfusion of blood and blood products, transplantation of solid organs from infected donors, injection drug abuse, unsafe therapeutic injections, and occupational exposure to blood (Alter 2007). Infections agents may be also involved in the aetiology of childhood leukaemia and lymphoma. However, response to infection and, therefore, the likelihood of developing leukaemia or lymphoma may be influenced by other factors including genetic background, socioeconomic status, vaccinations, and length of breastfeeding as they can affect the timing and the magnitude of positive feedback stimulation to lymphoid precursor population in the bone marrow (Lightfoot 2004). Up to now no virus-dependent immunological mechanisms have been positively identified (Lightfoot 2004).

1.2.3 Inherited susceptibility

Infants born with costitutive trisomy 21 or Down syndrome are at increased risk of acute lymphoblastic leukaemia (about 40 fold at age 0-4 years) (Hasle 2000). Common allelic variants in IKZF1, ARID5B, CEBPE, and CDKN2A have been significantly and consistently associated with childhood acute lymphoblastic leukaemia (Papaemmanuil 2009; Trevino 2009; Sherborne 2010).

1.2.4 Occupational exposure

According to IARC, the relation of acute lymphatic leukaemia and lymphoma and occupational benzene exposure is supported by limited evidence (Charbotel 2014). However, the meta-analysis by Vlaanderen et al. found risks increasing with increasing study quality, in all cohort studies. For NHL, the occupational benzene exposure gave a relative risk (RR) of 1.2 and, for acute lymphatic leukaemia, a RR of 1.4-1.7 (Vlaanderen 2011).
Associations with occupational EMF exposure have been suggested (Wang 2000). A meta-analysis of epidemiological studies on the relationship between occupational electromagnetic field exposure and the risk of adult leukaemia gave an increased risk for acute lymphocytic leukaemia (RR: 1.38).
From a pooled analysis of studies participating in the Childhood Leukemia International Consortium (CLIC) the risk to childhood acute lymphoblastic leukaemia (ALL) for paternal occupational pesticide exposure around conception was estimated to be 1.20 (Bailey 2014). The risk appeared to be more evident in children diagnosed at the age of five years or more and those with T cell ALL. The risk is even higher with the home use of pesticides (Bailey 2015). For ALL associated with any pesticide exposure shortly before conception, during pregnancy, and after birth the risks were 1.39, 1.43, and 1.36, respectively. In addition, an increased risk of NHL was suggested with maternal exposure to oil products, unspecified chemicals (Smulevich 1999), and ionizing radiation.
IARC has concluded that there is a causal relationship between lymphoma and several carcinogens with sufficient evidence (rubber industry, 1,3-butadiene) or limited evidence (tetrachlorodibenzo-para-dioxin, poly-chlorinated biphenyls, ethylene oxide, trichloroethylene) (Charbotel 2014).
Autoimmune disorders and immune modulating medications also may lead to NHL (Engels 2005; Ekstrom Smedby 2008). A large pooled analysis, made by the InterLymph Consortium (Ekstrom Smedby 2008), shows that the risk of NHL is associated with only a few autoimmune disorders and that these associations are stronger for some NHL subtypes than others. The study confirmed the link between all NHL and Sjögren syndrome and systemic lupus erythematosus, risks being 6.5 and 2.7 fold higher, respectively. Furthermore, an increased risk of specific T-cell NHL subtypes in celiac disease and psoriasis was assessed. The growing evidence from studies of the occurrence of specific NHL subtypes in inflammatory and infectious conditions suggests a role for chronic immune stimulation implicated in the pathogenesis.
Post-transplant lymphoproliferative disorder (PTLD) is an unusual and troublesome complication of solid-organ transplantation, probably caused by the use of potent immunosuppressive agents.

2. PATHOLOGY AND BIOLOGY

2.1 Morphology

Blasts may be encountered in the PB, BM, or tissue biopsy. On PB smears, lymphoblasts cytological details range from small cells with scant cytoplasm, condensed nuclear chromatin and indistinct nucleoli to larger cells with moderate amounts of cytoplasm, dispersed chromatin, and multiple nucleoli. A few azurophilic cytoplasmatic granules may be present. In tissue sections LBL is generally characterized by a diffuse or, as in lymph nodes and less commonly, paracortical pattern. More rarely and in particular in T-LBL, neoplastic cell may occur in nodules superficially resembling follicular lymphoma (Borowitz 2008c). In some circumstances, eosinophils may occur within lymphomatous infiltrate. Lymphoblasts are cells with intermediate size with round, oval or convoluted nuclear shape, dispersed nuclear chromatin, inconspicuous or small nucleoli, and scanty, faintly basophilic cytoplasm.
Mitoses are frequent; a starry-sky pattern or necrotic areas may be seen. In some instances sclerosis may be present.
There is no correlation between morphology and B or T lineage, and immunophenotyping studies are required to distinguish precursor B- from precursor T-LBL. Although histological features are usually sufficient to distinguish lymphoblastic from mature B- or T-cell neoplasms, a differential diagnosis with blastoid variant of mantle cell lymphoma, Burkitt lymphoma or myeloid leukaemia may arise in some cases, particularly in adults, often if smears are not available. In these cases, immunophenotyping and molecular genetic studies are critical.

2.2 Histochemistry and Immunophenotype

With the aid of histochemistry, the blasts precursor BLBL/ALL and T-LBL/ALL show positivity on Periodic Acid Schiff (PAS) staining, variable positivity for nonspecific esterase and Sudan Black B, and overall negativity for myeloperoxidase.
In LBL, immunohistochemistry and flow cytometry, should be used, whenever possible, in combination more than in other lymphomatous entities. Of greater importance is the characterization of immunophenotype by flow cytometry.

2.2.1 B-LBL

In B-LBL, tumour cells are virtually always positive for B cell markers CD19, CD79a and CD22. They are positive for common acute lymphoblastic leukaemia antigen CD10 (CALLA), CD 24, PAX5 and terminal deoxytransferase (TdT) in most cases, while the expression of CD20 and the lineage independent stem cell antigen CD34 is variable and CD45 may be absent.
The following set of antigens defines the stage of differentiation: pro-B stage (CD19+, cytoplasmatic CD79a+, cytoplasmatic CD22+, and nuclear TdT+); “common” stage (CD10+), pre-B stage (CD20+ and cytoplasmatic mu heavy chain+) (Pilozzi 1998). Surface immunoglobulin is usually absent, but its occurrence does not rule out the possibility of B-LBL. The possible presence of myeloid antigens CD13 and CD33 does not exclude the diagnosis of B-LBL. Although strict correlations between immunophenotypic profiles and molecular alterations are not a rule, some associations may be noted.
In fact, co-expression of CD13, CD33, CD 19, CD 10, and most often, CD34 is associated with the presence of rearrangements involving the TEL (ETV6) gene; this generally occurs within the context of a t(12;21)(p13;q21) that creates an ETV6-RUNX1 fusion gene. On the other hand, cases with MLL translocations, especially t(4;11) usually display CD19+, CD10−, CD24− (i.e., pro-B immunophenotype), and are also positive for CD15. Precursor B-LBL/leukaemia with t(9;22)(q34;q11.2) are typically CD10+, CD19+ and TdT+ and a frequent expression of myeloid associated antigens such as CD13 and CD33; in this subset CD 25 is highly associated, at least in adults (Borowitz 2008a; Borowitz 2008b).
The expression of TdT and lack of surface Ig, hallmarks of mature B cell tumours, are useful in distinguishing B-LBL from more mature B-cell neoplasms. CD19, CD22, CD10, CD79a and, more recently, LMO2 (Natkunam 2007) and SALL4 (Cui 2006) are useful in the differential diagnosis with T-LBL and granulocytic sarcoma. The negativity of cyclin D1 and CD5 with the concomitant expression of TdT differentiates B-LBL from mantle cell lymphoma. In addition, precursor Band T-LBL may be differentiated from acute myelogenous leukaemia (AML) by virtue of their positivity for TdT, taking into account that, with a few exceptions (Rytting 2009), myeloperoxidase is lacking. In a series of 146 LBL paediatric cases, none of the 42 B-LBL patients expressed a pro-B phenotype (CD79a/CD19+ only), 20 were CD10+/IgM + (common type), 5 were CD10+/IgM+ (pre-B) and 17 lacked a reliable IgM immunostaining (of which 15 were CD10+) (Oschlies 2011).

2.2.2 T-LBL

In precursor T-LBL/ALL, neoplastic cells are usually TdT positive and variably express CD1a, CD2, CD3, CD4, CD5, CD7 and CD8. Among these markers, CD7 and cytoplasmatic CD3 (cCD3) are usually positive. The only reliable lineage-specific is surface CD3. CD4 and CD8 are frequently co-expressed; also CD10 may be positive. In addition to TdT, the most specific markers are CD99, CD34 and CD1a.
Myeloid associated antigens CD13 and CD33 are expressed in 19%-31% of cases and their presence does not exclude the diagnosis of T-LBL/ALL. According to the expression pattern of specific markers, the following categories of TLBL/ALL could be identified: early or pro-T (cCD3+, Cd7+, CD2−, CD1a−, Cd4−, CD8−, CD34+/-); pre-T (cCD3+, Cd7+, CD2+, CD1a−, CD4−, CD8−, CD34+/-); cortical-T (cCD3+, Cd7+, CD2+, CD1a+, Cd4+, CD8+, CD34−), and medullary-T (cCD3+, Cd7+, CD2+, CD1a−, CD4°æ, CD8+, CD34− and surface CD3+). T-LBL and ALL share almost completely overlapping features, although “lymphomatous” counterpart tends to show a more mature immunophenotype than the ‘leukaemic’ one (Borowitz 2008c; Bernard 1981; Quintanilla-Martinez 1992). In the aforementioned retrospective analysis 49 out of 90 T-LBL had cortical CD1a+ phenotype, 35 cases had non-cortical phenotype (CD1a-, CD3+), and 6 cases had an insufficient characterisation for subtype attribution. Cortical T-LBL was more often double CD4+/CD8+ than non-cortical, whereas no difference was reported regarding expression of CD34 and CD10. Eleven LBL expressed mixed-lineage phenotype (7 myeloid/B-cell, 2 myeloid/T-cell, 2 B-/T-cell), and 3 cases were undifferentiated expressing only very early hematopoietic cell markers (TdT, CD10). In another series of 180 paediatric T-LBL, about 10% of the cases lacked expression of TdT but were concurrently CD79a+, or expressed myeloid antigens CD33/CD13 or CD34. Moreover, 24 cases expressed an early T-cell phenotype (CD1a-, CD8-, CD5+ [weak], with or without CD34 and CD33 or a pro-thymocyte phenotype (CD1a-, CD8-, CD5+/-, CD34- and CD33), while the majority expressed a subcapsular (CD1a+, CD4+ and CD8+; No. 56) or cortical(CD1a+/-, CD4+ or CD8+; No. 66) thymocyte profile. It is noteworthy that cases of early-T phenotype had a low risk of mediastinal involvement (5%, P=0.031), but they were associated with higher risk of disseminated BM disease (≥1% by flow cytometry, p = 0.0001) (Patel 2012).
The differential diagnosis of T-LBL from a peripheral-T cell lymphoma relies on its expression of non-lineage-specific immature markers, such as TdT or CD99, or in some cases, CD34. Cytoplasmatic without surface expression of CD3 is also a relatively specific and useful finding, although we must be aware of the fact that immunohistochemistry usually does not allow this distinction: the sCD3−/cCD3+ phenotype is therefore best demonstrated by flow cytometry. Moreover, CD1a positivity is also a relatively specific feature, whenever it occurs.
Finally, rare cases of LBL express NK-related antigens, such as CD16 and CD57 (Koita 1997; Nakamura 1997).

2.3 Genetic features

Cytogenetics: due to its rarity, there is very little information on cytogenetic abnormalities in LBL (Geethakumari 2014). A commonly reported abnormality would be the presence of additional chromosome 21 material, which is rare in ALL, in form of trisomy, tetrasomy, or add (21)(q22) (Borowitz 2008b).
Genetics: rearrangement of immunoglobulin (Ig) heavy- and light-chain genes and TR genes is variable in LBL, and may not be lineage-specific. Variable cytogenetic abnormalities have been reported. However, compared with ALL there is relatively few data on the role of cytogenetics or molecular analysis of particular translocations.

2.3.1 B-LBL

Cytogenetics: in French studies regarding B-LBL, 16 of 26 evaluable cases had a normal karyotype, 5 had hyperdiploidy and 5 had other structural abnormalities without abnormal chromosome 21 (Ducassou 2011).
Genetics: the majority of precursor B-cell lymphomas have clonal rearrangements of the Ig heavy chain or less frequently of light chain genes. The rare case of precursor B-LBL should probably be screened for the presence of the bcr-abl translocation because of the poor prognosis associated with that abnormality even if cases with bcr-abl+ B-LBL have not been described. Although the number of cases with cytogenetic aberrations, reported in the literature is small, hyperdiploidy does not seem to be so commonly observed as in B-ALL.
Moreover, some of the characteristic structural cytogenetic changes such as t(9;22), t(1;19) and t(4;11) seen in B-ALL were not found, while additional 21 material as trisomy, tetrasomy or an add (21) (q22) have been detected (Millot 1997). Trisomy and polysomy of chromosome 21 are nonrandom changes frequently seen in ALLs. The 21q22 region is involved in the t(12;21) resulting in the TEL/AML1 fusion gene, and trisomy 21 has been reported to be the most common secondary aberration in TEL/AML1-positive ALL (Maitra 2001).
Data regarding Gene expression profiling (GEP), next-generation sequencing (NGS), and whole exome sequencing (WES) studies, relative to B-LBL are rare. It was postulated that differences with B-precursor ALL might be related to overexpression of genes encoding for chemokine receptors CXCR4 and its ligand, or other adhesion molecules involved in extramedullary migration and homing (Geethakumari 2014).

2.3.2 T-LBL

Cytogenetic: in T-LBL cytogenetic abnormalities involving the 14q11-13 region (T-cell receptor alpha [TRA]/delta [TRD] genes) are frequent (50-70%), and include inv(14)(q11;q32), and chromosomes 9, 10, and 11. Rearrangements of TRB (7q34) and TR gamma (TRG; 7p14.1) genes are also common. The largest cytogenetic study of T-LBL (Sekimizu 2011) showed that 55% of 56 evaluable cases had an abnormal karyotype, including pseudodiploidy (25%), various chromosome deletions (20%), hyperdiploidy, and chromosome translocations (18% each), with many cases of structural abnormalities and translocations involving the 9q34 region (16% and 5% each). One patient had t(9;17) (q34;q23), which is associated with a mediastinal mass without BM involvement. This translocation is typical of T-LBL, and translocations involving 9q34 are significantly more common in T-LBL than T-ALL (p=0.000) (Sekimizu 2011). Cases of T-LBL carrying myeloid hyperplasia or hypereosinophilia have been reported in patients with t(8;13)(p11;q11) in the so-called 8p11 myeloproliferative syndrome (Inhorn 1995).
Genetics: gene expression profiling (GEP), next-generation sequencing (NGS), and whole exome sequencing (WES) studies revealed other differences between T-ALL and T- LBL. The initial GEP studies in paediatric T-LBL suggested upregulation of genes involved in cell adhesion (Raetz 2006; Uyttebroeck 2007). Following studies showed a partially T-LBL-specific gene signature involving genes involved in chemotaxis and angiogenesis, and other differences in genome wide copy number alteration profile (Basso 2011). In a small series of 5 T-LBL paediatric patients studied with NGS/WES, it has been reported that 45 genes were exclusively identified in T-BL but not in T-ALL, some of which had high functional relevance (Bonn 2015).
In addition T-cell receptor gamma or beta chain gene rearrangements may be seen in a significant number of cases, or they may lack rearrangements. T-LBL almost always shows clonal rearrangements of the T-cell receptor beta or gamma chain genes, but there is simultaneous presence of clonal rearrangements of the Ig heavy chain (Rosenquist 1997; Szczepanski 1999). Therefore, these rearrangements are not helpful for lineage assignment.
A French study including both adults and children identified three different TR gene rearrangement subsets (immature: no TR or incomplete TRD rearrangement; mature: biallelic TRD deletion and both TRG and TRB rearrangement; intermediate: TRD, TRG, and TRB rearrangement), with an associated overexpression of HOX11/TLX1 and HOXA9 transcripts in the intermediate TR group (Baleydier 2008). The immature TR subset correlated with the risk of BM involvement, whereas intermediate/mature groups were associated with a predominantly thymic presentation. The BFM Group examined a large number of paediatric T-LBL patients, reporting NOTCH1 mutations (clinically favourable) in 60% and FBXW7 mutations in 18% of 116 evaluable cases, and loss of heterozygosity at chromosome 6q (LOH6q, clinically unfavourable) in 25 of 207 cases (12%) (Bonn 2013). Similarly, a French study reported a NOTCH1/FBXW7 mutation in 55% of 54 patients with TLBL and identified FLASH gene deletion at chromosome 6q as a further molecular marker detectable in 18% of cases (Callens 2012). Moreover, in a series of 49 T-LBL adult patients, the cooperative GRAALL study group reported on the expression of a 4-gene prognostic classifier (NOTCH1, FBXW7, N/K-RAS, and PTEN, see below) (Lepretre 2016). Less frequent is the association of T-LBL with myeloproliferative disorders ranging from the 8p11 myeloproliferative syndrome to a hypereosinophilic syndrome to a subacute or acute myelomonocytic leukaemia. Gene abnormalities detectable in both T-LBL and the myeloid compartment included rearrangements of FGFR1 (Kim 2014) and PDGFRA/B genes (Ondrejka 2014). Patients with PDGFRA/B gene rearrangement and the few ones displaying the NUP214-ABL rearrangement (Baleydier 2008) could benefit of tyrosine kinase inhibitors (TKI) such as imatinib and others. The same therapeutic approach can be employed in the very rare but well-documented cases of T-LBL carrying the BCR-ABL translocation, described in past as lymphoblastic crisis of Philadelphia chromosome-positive ALL.

3. DIAGNOSIS

3.1 Clinical presentation

Lymphoblastic leukaemia/lymphoma occurs more commonly in children than in adults, mostly males. Although the vast majority (80%) of precursor B-cell neoplasms present as acute leukaemias, with BM and PB involvement, a small proportion present with a mass lesion and have<25% blasts (20% according to WHO) in the BM (Table 1). Unlike precursor T-LBL, mediastinal masses and involvement of BM are rare, but lymph nodes and extranodal sites, such as the skin, bone and soft tissue are more frequently involved in B-LBL (Ellin 2014; Maitra 2001; Salloum 1988; Shafer 2008). In most cases, the histological features of B-LBL and T-LBL do not allow distinction between these entities without immunophenotyping (Soslow 1997).
Supradiaphragmatic lymphadenopathy and involvement of the central nervous system (CNS) and testis are also common and most patients have disseminated disease at presentation (Hoelzer 2002a). Similar features also occur in older age groups.

Table 1. Clinical features in adult T-ALL/T-LBL (GMALL results).
Characteristics T-ALL (No. 506) T-LBL (No. 101)
Median age (years) 30 25
Male gender (%) 70 73
Mediastinal mass (%) 66 91
Pleural effusion (%) 1 40
CNS involvement (%) 7 ≤10
Bone marrow infiltration (%) 100 ≤23
CNS: central nervous system; GMALL: German Multicentre Study Group for Adult ALL.

T-LBL patients, compared to those with B-LBL, show younger age, a higher rate of mediastinal tumours or BM involvement (Ellin 2014; Engelhard 1996). Patients are usually males in their teens to twenties and present with lymphadenopathy in cervical, supraclavicular and axillary regions (50%), or with a mediastinal mass (50%-75%) (Streuli 1981). In most patients, the mediastinal mass is anterior, bulky, and associated with pleural effusions, superior vena cava syndrome, tracheal obstruction, and pericardial effusions. They present with stage IV disease (80%) and B symptoms (50%) and in the majority of cases elevated serum lactate dehydrogenase (LDH) levels. Less commonly, patients present extranodal disease (e.g., skin, testis and bone involvement). Abdominal dissemination is unusual, but when is present it involves primarily the liver and spleen.
Although the BM is normal in the majority of cases at presentation, about 60% of patients develop BM infiltration and subsequently leukaemic phase (Copelan 1995). Cerebropinal fluid evaluation is essential to rule out CNS involvement that is uncommon at presentation (5%-10%), except for patients with BM involvement, where a high incidence of CNS infiltration is found.

4. STAGING

4.1 Staging procedures

Complete staging work-up for LBL is similar to those routinely used for other NHL. It includes a full physical examination, complete haematological and biochemical investigations, total-body (head and neck, thorax, abdomen, and pelvis) CT scan, cerebrospinal fluid examination, BM aspirate and biopsy. 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) has recently become an important tool for the management of malignant disease including malignant lymphoma. Although the few data regarding this technique in LBL, in all other aggressive B- and T-cell lymphomas, the intensity of 18F-FDG uptake is high and has been able to identify all regions which were previously interpreted as disease sites on CT scans and or magnetic resonance imaging. Therefore, 18F-FDG-PET will probably replace other imaging techniques. The magnetic resonance imaging (MRI) is useful for a suspect involvement of the spine, skull, and brain structures, or the heart. Since all children and adolescents with LBL require intensive chemotherapy and the role of radiotherapy is controversial, an excessive search for and definition of the anatomic limits of detectable disease is probably unwarranted (Tsukamoto 2007). BM assessment and abdominal staging (hepatic or splenic involvement) in LBL should follow the general statements for all NHL.

4.2 Staging system

Several centres have adopted the St. Jude Children’s Research Hospital staging system (Murphy 1989b) for paediatric patients with LBL in view of the fact that it was devised specifically for staging children with NHLs with disseminated, non-contiguous involvement of nodal and extranodal sites (Table 2).
However, compared to the Murphy staging systems in adult LBL, the Ann Arbor system was able to predict survival more accurately and is, therefore, now used in most centres for adult LBL patients (Coleman 1986).

Table 2. LBL staging systems.
St. Jude children’s research hospital staging system
Stage Characteristics
I Single tumour (extranodal) or single anatomic area (nodal),
with the exclusion of mediastinum or abdomen.
II Single tumour (extranodal) with regional lymph node involvement.
Two or more nodal areas on the same side of the diaphragm.
Two single extranodal tumours with or without regional lymph node involvement on the same side of the diaphragm.
Primary gastrointestinal tract tumour, usually in the ileocecal area, with or without involvement of associated mesenteric lymph nodes only, grossly completely resected.
III Two single tumours (extranodal) on opposite sides of the diaphragm.
Two or more nodal areas above and below the diaphragm.
All the primary intrathoracic tumours (mediastinal, pleural, thymic).
All extensive primary intra-abdominal disease, unresectable, all para-spinal or epidural tumours, regardless of other tumour site(s).
IV Any of the above with initial CNS and/or BM involvement.
Ann Arbor staging system
I Involvement of a single lymph node region (I) or a single extranodal site (IE).
II Involvement of two or more lymph node regions on the same side of the diaphragm (II) or localized involvement of an extralymphatic site (IIE).
III Involvement of lymph nodes regions on both sides of the diaphragm (III) or localized involvement of an extralymphatic site (IIIE) or spleen (IIIs) or both (IIIEs).
IV Diffuse or disseminated involvement of one or more extralymphatic organs with or without associated lymph node involvement. Localized involvement of liver or bone marrow is also considered stage IV.
A Absence of systemic symptoms.
B Presence of systemic symptoms (fever of no evident cause, night sweats and weight loss >10% of body weight in the last 6 months).
X The presence of bulky mass, such as a lesion of 10 cm or more in the longest diameter.

4.3 Response assessment

4.3.1 Clinical response evaluation

The aim of response evaluation is to identify the patients who require salvage therapy. Despite differences in protocol design for timing of response assessment, it is generally performed after one or two chemotherapy courses (e.g., induction I and II in BFM studies). Moreover, it follows some basic principles in accordance with Cheson criteria, based on CT scan evaluation for intrathoracic and abdominal disease (Cheson 1999). With these criteria, a complete remission (CR) was defined as normalisation of any abnormal lymphadenopathy, with a longest transverse diameter not exceeding 1.5 cm, while the designation of unconfirmed CR (CRu) was adopted for patients with a tumour size reduction >75%. PET scan evaluation was encouraged. The assessment of mediastinal reduction in TLBL is of the utmost importance. In the paediatric BFM study (Reiter 2000), a complete chest X-ray clearing on Day 33 (induction I) was considered a CR. Non-CR patients had a CT: in those with 70% or greater tumour reduction treatment was unmodified, whereas it was intensified in case of less than 70% reduction (high-risk). A subsequent CT/MRI reassessment led to mediastinal biopsy for further therapeutic decisions in patients not achieving CR.

4.3.2 PET assessment

PET might be important for the post-induction detection of viable mediastinal tumours, allowing planning intensification therapy without the need of invasive surgical procedures. A population-based retrospective analysis reported that PET was not able to predict clinical outcome of LBL patients, even if the patient number was small, PET was not available at baseline and was not uniformly performed during treatment (Ellin 2014). Two recent studies addressed the question in a better way. In the GMALL trial post-induction, PET results were significantly associated with the response obtained after consolidation I, suggesting an equivalence between CR and PET-negative CRu, which may be informative eliminating the need for intensification of chemotherapy or mediastinal irradiation (Gökbuget 2014). In the GRAALL-Lysa study, PET results did not predict long-term outcome (Lepretre 2016); however, end of induction and CT results correlated significantly with PET data.

4.4 Molecular analysis of minimal residual disease

Reliable molecular markers are now available for monitoring minimal residual disease (MRD) in ALL (Bassan 2009), which could be applied to LBL. In a recently reported series, MRD was studied as a predictive factor for recurrence and as a decisional tool for post-consolidation maintenance (in negative MRD) or SCT (in positive MRD) by using real-time quantitative PCR. With this strategy, MRD was the most significant risk factor for relapse. MRD analysis during early post-remission therapy improved risk definitions and bolsters risk-oriented strategies.
In a recent report (Coustan-Smith 2007), the expression of CD3+/TdT+ was used to detect circulating tumour cells in a childhood T-LBL series. With this strategy, 57% of cases had positive BM samples (defined by >10-3), and patients with negative MRD did not experience systemic relapses, which was detected in one third of MRD-positive patients.
Importantly, this study suggests that diagnostic material is not mandatory to follow-up MRD in T-LBL and that PB samples can substitute BM. The only study to evaluate MRD was the NILG adult trial (Cortelazzo 2012), in which 11 patients were evaluated molecularly, five of whom were MRD positive (45.4%). These were considered high-risk patients and selected for stem cell transplantation (SCT).
These data on follow-up of MRD in TLBL should be confirmed in future studies, and its usefulness in driving therapeutic management should be investigated.

5. PROGNOSIS

5.1 Natural history

LBL is highly aggressive, but frequently curable with current therapy. The prognosis in all age groups has recently dramatically improved with new intensive chemotherapies, similar to those used for ALL, the disease-free survival (DFS) has reached 73%-90% in children and 62%-66% in adults (Reiter 2000; Hoelzer 2002a; Cortelazzo 2012; Neth 2000; Thomas 2004). Localised LBL is notably infrequent, accounting for only 10%-15% of all localised presentations (Pillon 2009). Initial reports suggested that children with localised LBL had poorer outcome with respect to children with non-lymphoblastic paediatric lymphomas (Anderson 1993; Link 1990); however, recent studies do not confirm this previous observations (Pillon 2009; Lones 2002). Localised LBL exhibit late relapses after poly-drugs treatments, sometimes with evolution to ALL (Hvizdala 1988; Patte 1992), whereas this feature has not been reported with more intensified regimens (Jabbour 2006).

5.2 Prognostic factors

Conversely to those reported for adult patients with TALL, reliable prognostic factors have not been identified in T-LBL (Table 3). In T-ALL, the prognostic role of laboratory parameters, like leukocyte counts, immunophenotype, and cytogenetic, varied among trials, whereas clinical parameters, like CNS involvement and mediastinal tumours, were not of prognostic significance. In LBL, a better prognosis has been related to B-phenotype in comparison with T-cell lineage, particularly if treated according to less intensive protocols. In the German Multicentre Trials for Adult Acute Lymphoblastic Leukemia study (GMALL) series on T-LBL the only significant prognostic factor for survival was elevated LDH, while no single risk factor for relapse risk could be identified (Hoelzer 2002a). In the MDACC series (Thomas 2004), only CNS involvement at diagnosis was significantly associated with poorer outcome. In the largest series of childhood LBL (Reiter 2000), no prognostic factors were identified. The minor relevance of single prognostic factors may be a consequence of more effective chemotherapy in adult as well as in childhood LBL.
No chromosomal or molecular abnormalities have consistently shown to carry prognostic significance except for t(9;17)(q34;3) which has been associated with an aggressive clinical course in children (Kaneko 1988).
Several attempts have been made to express risk factors in prognostic indices. However, a convincing prognostic model for adult LBL has not yet been defined (Hoelzer 2002b). A risk stratification system based on the presence or absence of BM or CNS involvement, Ann Arbor stage IV, and the serum LDH level has been proposed (Coleman 1986). Good-risk patients with LBL (defined as stage I–III or stage IV with no BM or CNS involvement and LDH less than 1.5 times normal) had a 5-year relapse-free survival rate of 94% compared with 19% for the poor-risk group. In the GMALL on T-LBL, no significant difference could be detected between low- and high-risk patients according to the Coleman model (Hoelzer 2002b). Furthermore, the relapse-free survival in high-risk patients (66%) was substantially higher compared with the results (19%) in the original publication of the model. When the International Prognostic Index for NHL (INHLPFP 1993) was applied to paediatric LBL patients, the index was not predictive (Reiter 2000), whereas in adult LBL a decreasing survival was observed for increasing number of risk factors (Sweetenham 2001).
Because in LBL no convincing prognostic model is available, new prognostic factors are required to drive SCT indication in first complete remission (CR1). Monitoring of MRD is highly predictive of treatment outcome in adult ALL (Bassan 2009) (see above). In a recently reported study on 280 patients the use of MRD analysis to take therapeutic decisions has been associated with a 5-year OS of 75% in the MRD negative group compared with 33% in the MRD-positive group (p=0.001), regardless of the clinical risk class. Whether this approach is applicable and predictive in patients with LBL remains to be defined. Moreover, PET might improve our ability to detect residual disease at critical sites and treatment steps, affecting treatment decisions. In addition, a new oncogenetic prognostic model was identified by the GRAALL/Lysa study (favourable: NOTCH1/FBXW7 mutation and/or no RAS/PTEN mutation/deletion), with independent prognostic value for EFS, DFS and OS (Lepretre 2016).

Table 3. Prognostic factors.
Reference Study/trial Variable Disorder Effect
Groves 1995 B-phenotype LBL Better prognosis
Hoelzer 2002a GMALL LDH T-LBL Poor survival
Thomas 2004 MDACC CNS involvement LBL Poorer outcome
Kaneko 1998 Japan t(9;17)(q34;3) Childhood LBL Aggressive clinical course
Coleman 1986 Risk system* LBL Better relapse-free survival
Reiter 2000 BFM IPI Paediatric LBL Not predictive
Sweetenham 2001 EBMT/UKLG IPI Adult LBL High IPI related to poor survival
Cortelazzo 2012 NILG MRD Adult LBL MRD associated with poor OS
Lepretre 2016 GRAAL/Lysa NOTCH/FBXW7 Adult LBL Favourable for EFS, DFS and OS
* Stratification system based on the presence or absence of BM or CNS involvement, Ann Arbor stage IV, and the serum LDH level.
IPI: International Prognostic index; MRD: minimal residual disease; OS: overall survival.

6. TREATMENT

6.1 Treatment strategy

Standard therapeutic option for patients with LBL is based on intensive multi-drug leukaemia chemotherapy protocols (Reiter 2000; Hoelzer 2002a; Cortelazzo 2012; Thomas 2004; Hvizdala 1988; Patte 1992; Anderson 1983; Dahl 1985; Weinstein 1983; Wollner 1976; Bouabdallah 1998). These regimens contain 7-10 drugs, such as cyclophosphamide, methotrexate, prednisone, vincristine, cytarabine, thioguanine, l-asparaginase, nitrosoureas, etoposide, and anthracyclines, including intensive intrathecal chemotherapy, on a type C basis.
Chemotherapy regimens do not substantially change for patients with limited or advanced disease.
Therapeutic approaches to LBL had included conventional regimens for NHL, intensive chemotherapy protocols designed for high-grade NHL (Table 4) and protocols for the treatment of ALL (Table 5), with or without prophylactic cranial irradiation and with or without prophylactic or therapeutic mediastinal irradiation. Furthermore, SCT, mostly autologous SCT (ASCT) was included at different extent in treatment strategies.
The treatment of LBL with conventional chemotherapy regimens for NHL has shown relatively low rates of CR and of DFS with most patients relapsing and eventually dying of unresponsive, progressive disease, on a type C basis (Jost 1995).
Intensive protocols designed for aggressive NHL improved CR rate (71%) on a type C basis, but survival was poorer than results obtained with the same regimens in other aggressive lymphomas, with a 5-year overall survival (OS) of 32% and a 5-year event-free survival (EFS) of 22% (Le 2003).
Regimens similar to those used in childhood NHL (e.g., LSA2-L2 protocol), produced a 5-year OS rate of 79% and an EFS of 75% in children with diffuse LBL (Mora 2003). However, in adult patients with LBL, response duration did not improve with these regimens (DFS 35%-44%), except for one study, which included SCT and reached a DFS rate of 75% (Sweetenham 2001). These studies indicated that intensified and prolonged chemotherapy and CNS prophylaxis are important for improving OS in LBL patients, on a type C basis.
Improvements in long-term outcome were achieved with ALL-type regimens for LBL, and in multiple series CR rates of 55%-100% and DFS rates between 45% and 65% have been reported (Hoelzer 2002b; Bouabdallah 1998; Slater 1986; Morel 1992; Zinzani 1996). The strongest evidence of high efficacy of ALL-type chemotherapy in LBL came from a recent report of 105 children with T-LBL. This study showed that with intensive ALL-type regimen, including moderate cumulative doses of anthracyclines and cyclophosphamide and moderate-dose prophylactic cranial irradiation (12 Gy), but no local radiotherapy (RT) an EFS of 90% can be achieved in childhood T-LBL, on a type C basis. Encouraging results have been obtained also in adults with LBL. The estimated 5-year durable remission and survival rates for previously untreated patients were 65% and 51%, respectively for those treated in the German trial with BFM regimens (Hoelzer 2002b) and were 62% and 67%, respectively, for the T-cell subset reported in the MDACC study (Thomas 2004). Recently, a CR rate of 90% and a DFS at 5 year of 72% was described by the Northern Italy Leukemia Group (NILG) in 21 LBL patients treated with an intensive ALL-type protocol, on a type C basis (NILG-ALL no. 09/00) (Cortelazzo 2012). Furthermore, two large adult trials have been recently reported by GMALL and GRAALL. The GMALL study (No. 149), which adopted a 07/2003 ALL-type regimen, showed a significantly better OS in the no MRT cohort depending on a lower relapse risk (15% vs. 31%; p=0.07), probably due to a superior manageability of the chemotherapy program. Interestingly, CR/CRu rates increased during treatment from 34% after induction I to 76% after consolidation I (Gökbuget 2014). The results of GRAALL-Lysa LL03 study (No. 148) employing the paediatric-inspired GRAALL-2003 protocol without MRT were comparable (Lepretre 2016).
In conclusion, with modern intensive adult LBL protocols, the achievement of a late CR and/or a PET-negative CRu status was associated with high probabilities of survival even without additional MRT.
Despite the significant advances achieved in LBL therapy, several issues such as the management of CNS and mediastinal disease and the role of SCT remain matter of debate and research.

Table 4. Cumulative treatment results in adult patients with lymphoblastic lymphoma.
Study result Studies (No.) Patients (No.) Median age (years) CR (%)
(range)
DFS (%)
(range)
Conventional NHL  5  114  28-45  58 (53-17)  36 (23-53)
Modified NHL  5  112  14-22 92 (79-100)  49 (23-56)
High-grade NHL  4  64  25-34  67 (57-84)  51 (35-75)
ALL protocols  18  916  15-78  80 (55-100)  56 (44-76)
ALL: acute lymphoblastic leukaemia; CR: complete remission rate; DFS: disease-free survival; NHL: non-Hodgkin Lymphoma.
(Source: Gökbuget 2008)
Table 5. Main results of ALL-type regimens in adult patients with lymphoblastic lymphoma.
Author and year Patients (No.) Age (years) Induction CNS prophylaxis CR rate
(%)
DFS/EFS
(%)
Hoelzer 2002a 45 25 GMALL 04/89
GMALL 05/93
I.th., CRT 93 62
Thomas 2004 33 28 hyper-CVAD,DX,HDM,
HDAC repeated
I.th. 91 70
Song 2007 34 26 ALL-type induction
+ auto SCT
I.th.
+/– TBI
n.r. 63
Cortelazzo 2012 30 30 NILG-ALL 09/00 I.th., CRT 90 72
Gökbuget 2014 149 17-62 GMALL I.th., CRT 76 OS 65
Lepretre 2016 148 18-59 GRAALL-LYSA LL03 i.th., CRT 91 62
CR: complete remission rate; DFS: disease-free survival; SCT: stem cell transplantation; I.th.: intrathecal chemotherapy;
CRT: cranial irradiation; TBI: total body irradiation; CVAD: C – cyclophosphamide; V – vincristine; A – Adriamycin;
D – dexamethasone; HDM: high-dose methotrexate; HDAC: high-dose cytarabine

6.2 CNS prophylaxis

Initial CNS involvement in LBL is relatively low (3-9%) (Reiter 2000). However, the CNS is a frequent site of relapse in the absence of CNS prophylaxis (Thomas 2004; Sweetenham 1992). The CNS relapse rates range from 3%to 42% in studies using intrathecal chemotherapy prophylaxis alone, from 3% to 15% in studies using a combination of cranial RT and intrathecal therapy, and from 42% to 100% in studies without any CNS-therapy (NHL type regimens) (Thomas 2004). However, prophylactic cranial radiotherapy (PCRT) may carry significant late events in childhood including neuropsychological deficits, mood disturbances, short stature, and secondary malignancies (Langer 2002; Glover 2003; Bongers 2005). These side effects could be avoided if PCRT would be safely omitted from the treatment plan of young LBL patients.
BFM group treated 105 children with T-LBL with an 8-drug induction over 9 weeks followed by an 8-week consolidation including methotrexate (5 g/m2). Patients with early stages were continued on maintenance for 24 months, whereas patients with advanced stage received 8-drug intensification over 7 weeks and cranial RT (12 Gy for prophylaxis) after consolidation, followed by maintenance. Only 1 patient had BM and CNS relapse and local tumour progression (Reiter 2000). In the NHL-BFM 95 trial German cooperative group tested (against historical control of the combined trials NHLBFM90 and NHL-BFM86) whether prophylactic cranial RT (PCRT) could be omitted for CNS-negative patients with stage III-IV LBL with sufficient early response (Burkhardt 2006).
In NHL-BFM 95, one isolated and two combined CNS relapses occurred compared with one combined CNS relapse in NHL-BFM90/86. Five-year DFS was 88% in NHLBFM95 compared with 91% in NHL-BFM90/86. Children’s Leukaemia Group (CLG) recently reported the results of a prospective study in which 121 children with T-LBL were treated for 24 months with BFM protocol omitting prophylactic cranial and local radiotherapy, even for patients with CNS involvement at diagnosis. The EFS and OS rate at 6 years was 77.5% and 86%, respectively. Furthermore, only two patients (1.8%) had an isolated CNS relapse (Uyttebroeck 2008). Other effective radiation-free protocols were developed by the St Jude Hospital (NHL 13 regimen), with only 1 CNS relapse of 41 patients (2.4%) (Sandlund 2009), and by the Children’s Oncology Group (COG), with no CNS relapse of 60 patients treated in one trial (Termuhlen 2012). The same group in another trial did not find any difference in 5-year EFS (80-84%) by type of CNS prophylaxis (intrathecal MTX vs. HD-MTX maintenance) or by intensification of intrathecal MTX, with a cumulative incidence of CNS relapse of only 1.2% (Termuhlen 2013).
Regarding adult patients with T-LBL, in the GMALL study 91% of the 45 patients received CNS irradiation (24 Gy) and all of them had intensive intrathecal therapy. This approach was effective because only one patient (2%) experienced a CNS relapse (Hoelzer 2002a). Other authors retained CRT (Lepretre 2016; Gökbuget 2014). However, the MDACC experience with intensive hyper-CVAD regimen and high-dose methotrexate and cytarabine and 6–8 intrathecal treatments, without CRT, suggests that combination of high-dose systemic chemotherapy and appropriate intrathecal chemotherapy is an adequate CNS prophylaxis, with an isolated CNS relapse rate of 3% (Thomas 2004). Recently a CNS relapse of 0% has been reported in T-ALL adopting a very effective radiation-free prophylaxis which combined MTX 5 g/m2 with intrathecal liposome-associated cytarabine (Bassan 2015).

6.3 Management of mediastinal disease

The majority of patients with T-LBL present with large mediastinal tumours and residual mediastinal tumours after induction therapy are the most frequent reason for not achieving CR. The mediastinum is also a frequent site of recurrence.
Mediastinal RT is an effective local treatment, however it carries several risks such as the development of cardiac disease, radiation pneumonia, secondary malignancies (e.g., breast cancer, bone sarcomas, myelodisplasia, and acute myeloid leukaemia), and other long-term sequelae, especially in long surviving children (Hancock 1993; Bhatia 1996; Ingram 1987). Because of short- and long-term morbidity, mediastinal RT has been eliminated from most paediatric LBL protocols. The largest experience comes from BFM group that reported 90% EFS in childhood T-LBL with intensive ALL-type chemotherapy including moderate cumulative doses of anthracyclines (240 mg/m2) and cyclophosphamide (3 g/m2) and moderate-dose prophylactic cranial irradiation, but no mediastinal RT. The childhood experience with BFM regimen, without consolidation mediastinal RT, using intensive high-dose methotrexate (5 g/m2) resulted in a significantly lower rate of mediastinal relapse (7%). However, this intensive high-dose methotrexate could be associated with significant nephrotoxicity in adults (Reiter 2000).
In the GMALL series of adult T-LBL the mediastinal relapse rate was higher (47% of all relapses), despite similar induction therapy and prophylactic mediastinal irradiation with 24 Gy in 85% of patients. However, consolidation with high-dose methotrexate was less intensive (Ondrejka 2014). The high incidence of mediastinal relapse led these investigators to suggest a higher radiation dose (36 Gy) which minimally reduced the risk of mediastinal recurrence compared with no MRT at all (17% vs. 24%) (Gökbuget 2014). Consolidation mediastinal RT with 30-39 Gy given after a dose-intensive phase of hyper-CVAD in adult T-LBL reduced the incidence of loco-regional relapse in the MDACC study (Thomas 2004). Only 2 out of 17 (12%) patients treated with consolidation irradiation relapsed in the mediastinum and at other sites. Early mediastinal progression occurred before RT in 3 out of 23 (13%) patients for whom RT was planned after 8 courses of intensive therapy. The authors suggest a relevant role of consolidation mediastinal RT with 30-36 Gy, given earlier in the course of the dose–intensive phase, especially in lowly responding patients. In the NILG study, in which MRT was prescribed only to patients with post-induction residual mediastinal mass, a mediastinal recurrence occurred in only 1 of 14 non-irradiated patients (7%), suggesting the value of a selective MRT guided by the early CT results (Cortelazzo 2012). In other studies including high-dose chemotherapy without MRT, the rate of mediastinal relapse was similarly low to very low (Lepretre 2016; Jabbour 2006). Therefore, the routine use of MRT in LBL does not appear necessary and would ideally be based on clear data supporting its success.
The management of residual mediastinal masses in LBL is also controversial. The options include local RT, surgical resection of the residual mass or close observation if the patient is receiving maintenance chemotherapy or if is undergoing a SCT. When resection or biopsy was performed in 10 paediatric T-LBL patients with residual tumour after induction therapy, necrotic tissue was found in all cases (Reiter 2000).
Although PET re-evaluation can help to identify the patients who need supplemental therapy, including MRT, the aforementioned studies from GMALL and GRAALL-Lysa suggest that chemotherapy should not be deferred, and provided that a clinical CR/CRu is achieved after consolidation I (GMALL) or after induction/salvage (GRAALL-Lysa), the risk of failure due to mediastinal progression is low and is not predicted by PET results (GRAALL-Lysa), although a negative PET scan is confirmatory of CR/CRu (GMALL), and is not significantly modified by additional MRT (GMALL) (Gökbuget 2014; Lepretre 2016). Clearly, a most difficult issue is to identify those patients for whom MRT is necessary to prevent a mediastinal recurrence.

6.4 Role of SCT

High-dose chemotherapy supported both by autologous or allogeneic BM transplantation have been used as consolidation therapy in high-risk LBL patients (Bouabdallah 1998; Zinzani 1996; Baro 1992; Sweetenham 1994). Available data suggest that intensive consolidation therapy followed by ASCT or allogeneic SCT may improve the long-term prognosis, but which patients may benefit from SCT remains unclear (Aljurf 2005).
The use of ASCT in adults with LBL in CR1 produced a trend for improved relapse-free survival (24% vs. 55%), but did not improve OS compared with conventional-dose therapy (45% vs. 56%) in a small randomized trial of the European Group for Blood and Marrow Transplantation and the United Kingdom Lymphoma Group. In this study, however, the CR rate of 56% and the relapse-free survival for chemotherapy were probably suboptimal, suggesting the superiority of ASCT on conventional chemotherapy, on a type 2 level of evidence (Sweetenham 2001) However, single centre studies have resulted in 31-77% long-term DFS using ASCT (Jost 1995; Morel 1992; Baro 1992; Sweetenham 2001; Aljurf 2005; Verdonck 1992; Santini 1991; Conde 1999) and in 39-91% in patients receiving allogeneic SCT in CR1 (Sweetenham 1994; Bouabdallah 1998; Baro 1992). The intensity of induction and consolidation therapy may be an important outcome-issue ASCT, on a type C basis (Jost 1995). More recent studies on SCT reported higher OS/EFS rates of 72-84% and 68-76%, respectively (Song 2007; Bersvendsen 2014; Jeong 2015), but these results are not better than those obtainable with modern intensified ALL-type regimens and there was no difference between autologous and allogeneic SCT. In the NILG study, adopting a risk-adapted strategy with autologous/allogeneic SCT reserved to poor responders and/ or MRD+ patients, there were 14 SCTs (11 autologous), with DFS and OS estimates of 77% and 72%, respectively (Cortelazzo 2012).
In patients with more advanced disease (CR>1), ASCT could lead to DFS of 36-50% while allogeneic SCT to DFS of 14-46%, on a type C basis (Morel 1992; Baro 1992; Conde 1999; De Witte 1994; van Besien 1996; Levine 2003).
A retrospective multicentre study on the largest series of LBL patients treated with ASCT (No. 128) or HLA-identical sibling (No. 76) SCT, the latter strategy was associated with fewer relapses than ASCT (at 5-year, 34% vs. 56%; p=0.004), but higher TRM (at 6 months, 18% vs. 3%; p=0.002), which obscured any potential survival benefit, on a type C basis (Levine 2003). Similar data were provided by other authors (Lazarevic 2011). In the GRAALL-Lysa study, the allogenic SCT was offered to patients with high-risk disease defined by CNS involvement or need of salvage chemotherapy to achieve CR/Cru (Lepretre 2016). Seventeen patients had an allogeneic SCT, with an outcome similar to non-SCT patients. Again, these results suggest that an allogeneic SCT may be effective in patients with high-risk features and/or suboptimal response to standard induction/consolidation therapy.
However, the majority of these data must be interpreted carefully as retrospectively analysed SCT patients represent a selected cohort where patients not achieving CR were not considered.
Patients with LBL achieve CR soon and if they relapse they do it on an early stage. Therefore, it can be assumed that these patients are generally not represented in the transplantation group and that many transplanted patients could be cured by previous chemotherapy. Furthermore, several of these studies restricted the use of high-dose therapy to patients defined at poor-risk, although the definition of poor risk has been inconsistent (see Section 5.2). Because at present a convincing prognostic model for LBL is lacking, monitoring of MRD and PET may be useful for establishing a role for SCT in CR1.

6.5 Treatment of relapsed or refractory LBLs

Standard therapeutic option for patients with relapsed LBL has not yet been defined. In these patients, who have a particularly poor outlook, conventional salvage chemotherapy is ineffective (Sweetenham 1994; Philip 1993). The results of ASCT in LBL are inferior beyond first CR, with 47% DFS rate for patients in second CR (Hoelzer 2002b; Aljurf 2005) and 15% for those with resistant disease (Sweetenham 1994). Late relapses (at >1 year) seen with ASCT may be decreased by allogeneic SCT. Salvage treatment should therefore aim to rescue patients for undergoing allogeneic SCT, on a type C basis. In patients without a compatible matched donor, ASCT in second remission is a valid option and collection of peripheral stem cells after frontline treatment has been performed in some series (Hoelzer 2002a). The SMILE regimen (dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide) was used in 11 r/r LBLs, yielding three CRs and 4 partial responses (Chang 2014). Although in some paediatric studies on r/r LBL patients the probability of survival was 25%-50% (Attarbaschi 2005; Won 2006), in the German BFM study, in which only 10% of the patients were resistant or relapsed, the salvage rate was extremely poor (OS 14%), and a long-term survival was only achieved in the few patients receiving an allogeneic SCT (Burkhardt 2009). In adults the results of salvage therapy were even worse. In the GMALL series, only one of 15 r/r patients with T-LBL survived long term (Hoelzer 2002b).
New cytostatic drugs, such as nelarabine and clofarabine and forodesine with specific activity on T-cells, or immunotherapy with T-cell specific antibodies, such as anti-CD3 and anti-CD52 (Alemtuzumab) or inhibitors of proteosome such as bortezomib (Mai 2006) deserve evaluation in future prospective trials.
Nelarabine is a pro-drug that is demethylated to deoxyguanosine and showed a significant activity as single agent in resistant/relapsed (r/r) T-ALL. However, in a GMALL trial, none of 19 patients with r/r T-LBL achieved CR in comparison with 45/107 (45%) with T-ALL (p=0.0004), while in a CALGB study only 4/13 (31%) T-LBL patients obtained a CR (Gökbuget 2011; De Angelo 2007). When nelarabine was combined with etoposide, and cyclophosphamide, 2 paediatric patients with r/r LBL had a partial response in one study (Commander 2010), and three of 5 obtained a CR in another study (Luskin 2015). This drug has been also studied as first-line drug in combination regimens. A recent study by COG in paediatric setting showed that nelarabine is safe when was given with intensive chemotherapy in T-ALL (Winter 2015). Efficacy results from a phase III trial are awaited with interest. Nelarabine in combination with chemotherapy was given to 23 and 17 adult patients with untreated T-ALL and T-LBL, producing a cumulative 3-year OS and DFS rate of 63% and 61%, respectively, with a trend to better results in T-LBL (Jain 2014).
Clofarabine is a second-generation purine nucleoside analog, which has been used in salvage regimens for r/r ALL, especially in the paediatric setting, leading to CR in 30-60% of the cases with a manageable toxicity. However, its activity in r/r T-ALL is lower than for B-lineage ALL, even in combination with cyclophosphamide, etoposide, and other drugs. The CR rates in T-ALL/LBL were 11% (1/9), 12.5% (1/8), and 50% (2/4) (Faderl 2014; Locatelli 2009; Barba 2012).
Forodesine is an orally bioavailable purine nucleoside phosphorylase inhibitor, deserving evaluation in T-LBL.
Another potentially useful agent is bortezomib, the proteasome inhibitor tested with some success in B-lineage ALL (Horton 2013) and under evaluation in a COG randomized trial.
Several new agents are promising for an improved management of r/r ALL and LBL as well. Among them the most innovative are cytotoxic monoclonal antibodies (rituximab, inotuzumab, ozogamycin, blinatumomab) and chimeric antigen receptor-modified T cells (CD19.CAR T) (Maino 2015). However, they are highly active in B-cell ALL, but cannot be used in the great majority of patients with LBL, in whom prevail T-cell phenotype. The anti-CD20 monoclonal antibody rituximab could be used in B-LBL, which is rare and frequently CD20-negative (12/35 CD20+ in one study, i.e., 34%) (Oschlies 2011). Because of that and the limited access to experimental therapy with CAR T cells, inotuzumab and blinatumomab, these items will not be further discussed.
The pan-lymphocyte antigen CD52 is widely expressed by B- and T-cell malignancies and is targeted by the monoclonal antibody alemtuzumab. Alemtuzumab was used to treat a variety of hematopoietic tumours, showing limited activity in ALL (8% CR rate, 0% in T-ALL [0/3]) (Angiolillo 2009) and a not negligible toxicity. The drug is now hardly available.
Of greater interest is the anti-CD30 monoclonal antibody brentuximab vedotin, in relation to the CD30 antigen expression reported in 38% of 34 T-ALL cases (Zheng 2014), Highly effective in r/r CD30+ lymphomas, brentuximab is a serious candidate to implement the concept of immunotherapy in r/r T-LBL.
A group of heterogeneous molecules showed activity against ALL cell lines, mostly mediated by apoptosis induction, in recent in vitro and in vivo studies. Among many NOTCH1 inhibitors are the most interesting ones because of the central pathogenetic role of activating NOTCH1 mutations in T-ALL/LBL. Gamma secretase inhibitors (GSI), blocking NOTCH1 activation, can exert therapeutic activity, with an associated gastro-intestinal toxicity that is mitigated by dexamethasone. In a recent phase I trial eight of 25 adult patients with r/r T-ALL/LBL treated with the BMS-906024 GSI had at least a 50% reduction in bone marrow blast cells (all with T-ALL), and one CR was recorded (Zweidler-McKay 2014). This represents a new promising approach in the treatment of T-LBL.

6.6 Conclusions

Despite the rarity of the disease and the presence of different treatments for adult LBL, a few general statements can be made:

  1. the modern therapy of LBL should follow the same principles of ALL therapy;
  2. taking into account the scarce results of salvage therapy and the optimal results obtained with front-line therapy of paediatric patients a comparable therapeutic approach should be adopted in all patients regardless of age;
  3. a regimen including 5 g/m2 MTX blocks could be part of a highly effective schedule, in which MRT could be safely omitted and low-dose cranial irradiation should be delivered only to patients with advanced disease;
  4. in this context, either allogeneic SCT or autologous SCT are indicated only when the disease has an adverse course and/or specific high-risk situations occur, and preferably within a prospective clinical trial.

Finally, looking for more robust prognostic indicators, the presence of adverse (onco)-genetic abnormalities and the early evaluation of CT/PET and MDD/MRD in the future could allow a more rational, risk oriented use of MRT, SCT, and new-targeted therapies.

 

 

INDEX

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Dr. Sergio Cortelazzo (Author)
Oncology Unit, Humanitas/Gavazzeni Clinic – Bergamo, Italy
e-mail: sergio.cortelazzo@gmail.com

Dr. Andrés Ferreri (Associate Editor)
San Raffaele Scientific Institute – Milan, Italy
mail: ferreri.andres@hsr.it

Prof. Dieter Hoelzer (Reviewer)
J.W. Goethe University – Frankfurt, Germany
e-mail: Hoelzer@em.uni-frankfurt.de 

Dr. Maurilio Ponzoni (Author)
San Raffaele Scientific Institute – Milan, Italy
e-mail: ponzoni.maurilio@hsr.it