ABSTRACT: Lymphoblastic lymphoma is a rare disease in adults, primarily affecting patients in their late teens and early 20s. Optimal treatment strategies have been slow to emerge because of the rarity of this disease and the variable distinction in the clinical literature between this condition and acute lymphoblastic leukemia. Although these two conditions are now regarded as a single entity in the WHO Classification of Lymphoid Neoplasms, treatment approaches have developed separately, and recent molecular data suggest that there may be important biologic differences between these conditions that may justify a different treatment approach. Most published data support the use of intensive multiagent chemotherapy induction followed by a consolidation and maintenance phase. Optimal consolidation remains unclear, although there is no clear role of stem cell transplantation after intensive remission induction therapy based on current evidence. Emerging molecular data have identified potential new therapeutic targets with supporting preclinical data.

Lymphoblastic lymphoma (LBL) is a rare disease, comprising about 2% of all non-Hodgkin lymphomas (NHLs) in adults.[1] It is a highly aggressive subtype of lymphoma, most commonly of precursor T-cell origin, occurring most frequently in adolescents and young adults, with male predominance and frequent mediastinal, bone marrow, and central nervous system (CNS) involvement. The pathologic characteristics of LBL at the morphologic, phenotypic, and genetic levels are identical to acute lymphoblastic leukemia (ALL), and the World Health Organization Classification of Lymphoid Neoplasms has unified these entities as precursor T-cell or B-cell lymphoblastic leukemia/lymphoma.[2]

Treatment approaches to LBL in adults have developed separately from those for adult ALL. Patients with predominantly nodal disease at presentation have been designated as having LBL, whereas those with disease primarily in the marrow or peripheral blood have been classified as having ALL. This distinction has varied in the published literature and, coupled with the rarity of LBL, this has meant that optimal treatment approaches for adults with LBL have been difficult to determine. There has been a recent trend toward including patients with LBL on protocols designed for ALL, but emerging data from gene-expression profiling studies point to differences between precursor T-cell and B-cell disease with predominant nodal vs predominant marrow involvement, particularly for genes involved in interactions between malignant cells and the microenvironment.[3] Differences in T-cell receptor genotypes have also been reported between cases designated as LBL vs ALL.[4] As a result, the clinical distinction between these two entities still has relevance, and treatment approaches specific to LBL continue to be investigated.

Treatment

Lymphoblastic lymphoma is a clinically aggressive disease. It typically presents as widely disseminated disease, with frequent bone marrow involvement, bulky mediastinal disease, and a 5% to 10% incidence of CNS involvement at presentation, usually involving the leptomeninges. It is characterized by a high response rate to initial chemotherapy, but with a tendency toward early relapse with the CNS as a common relapse site. Currently used treatment regimens are therefore characterized by relatively intensive induction therapy, the prevention of CNS relapse, and the use of various types of postinduction therapy aimed at reducing the risk for subsequent relapse. Some regimens have included radiation therapy to the mediastinum for patients with high tumor burden at this site.

‘Standard Dose’ Chemotherapy and Chemoradiotherapy Regimens

Early chemotherapy trials adopted regimens designed for less aggressive subtypes of NHL, with poor results.[5-9] For example, a study of 95 adult and pediatric patients treated with various NHL protocols without CNS treatment or prophylaxis reported a complete response rate of only 24%, with fewer than 10% of patients free of disease at 5 years.[5]

TABLE 1
Intensive Induction Regimens for Adult Lymphoblastic Lymphoma

The subsequent adaptation of pediatric protocols including intensive chemotherapy and CNS prophylaxis produce marked improvements in outcomes in adults. For example, regimens such as the LSA₂L₂ regimen, which incorporated intensive chemotherapy with CNS irradiation, produced long-term disease-free survival rates of 60% to 80%. A randomized study confirmed the superiority of this approach for the LSA₂L₂ regimen, which was shown to be superior to a less intensive NHL regimen.[10] More recently, numerous chemotherapy/radiotherapy regimens similar in dose and schedule to ALL regimens have been investigated in adults with LBL.[11-21] Results from these regimens are summarized in Table 1. Common features of all these protocols include intensive remission- induction chemotherapy, central nervous system prophylaxis, a consolidation chemotherapy, and subsequent maintenance therapy for 12 to 18 months. Long-term disease-free survival rates between 40% and 70% are typical of these regimens. 

No optimal standard induction therapy has emerged, although the HyperCVAD regimen (hyperfractionated cyclophosphamide, vincristine, doxorubicin [Adriamycin] dexamethasone) alternating with high-dose methotrexate and cytarabine is widely used in this disease. In a series from M.D. Anderson Cancer center that included 33 adult patients with LBL, this regimen resulted in a complete response rate of 91%, with 3-year actuarial overall and progression-free survival rates of 70% and 66%, respectively.[19] As Table 1 shows, some of these regimens have used high-dose therapy with autologous or allogeneic stem cell transplantation as postremission therapy, although the role of transplant approaches in this context is not clear.

Stem Cell Transplantation as Postremission Therapy in Adult LBL

TABLE 2
Results of First Remission Stem Cell Transplantation in Adults With Lymphoblastic Lymphoma

Studies investigating this approach are summarized in Table 2.[21-26] Most have used autologous stem cell transplantation in this setting, although some have included patients undergoing HLA-identical allogeneic stem cell transplants. Only a minority of these studies include an intent-to-treat analysis. Most report survival rates just from the date of transplant and are therefore subject to substantial selection bias, since poor-risk patients who do not achieve remission to initial induction therapy are excluded from these analyses.

Where true intent-to-treat analyses have been included, the results have been variable, most likely because of the small patient numbers included in these studies. For example, a study of 92 patients from the Groupe D’Etudes des Lymphomes de l’Adulte (GELA) treated with standard NHL-type induction chemotherapy followed by stem cell transplantation reported a median overall survival of 32% at 5 years[25]. A more recent study from Vancouver reported results from 34 adults with lymphoblastic lymphoma, 29 of whom underwent high-dose therapy and autologous or allogeneic stem cell transplantation after induction chemotherapy.[21] The 4-year overall and event-free survival rates were 72% and 68%, respectively. Overall results from the studies summarized in Table 2 show no clear evidence for the superiority of a transplant approach in first remission A small randomized trial compared high-dose therapy and autologous stem cell transplantation with conventional-dose consolidation and maintenance therapy in adult patients with LBL.[27] The 3-year actuarial relapse-free survival rate was 24% for patients receiving conventional consolidation and maintenance therapy, compared with 55% for those receiving high-dose therapy and autologous stem cell transplantation (P = .065). The corresponding rates for overall survival were 45% and 56% (P = .71). 

The results of these studies indicate that the intensity of induction therapy is essential to the achievement of long-term survival, apparently having a greater impact on outcome than does the nature of consolidation or maintenance therapy, even when stem cell transplantation is used. Although direct comparison of these studies is difficult to interpret, those using “standard dose” induction therapy report poor long-term overall and event-free survival, even if the first remission is consolidated with high-dose therapy. For regimens using intensive induction therapy, there is no apparent survival advantage to the use of stem cell transplantation. Stem cell transplantation should be considered an alternative approach to postremission consolidation, producing comparable results to standard consolidation and maintenance after intensive ALL-like induction therapy.