Lymphoblastic lymphoma (LBL) is a rare disease, comprising about 2% of all non-Hodgkin lymphomas (NHLs) in adults. 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.
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. 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.
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. Differences in T-cell receptor genotypes have also been reported between cases designated as LBL vs ALL. As a result, the clinical distinction between these two entities still has relevance, and treatment approaches specific to LBL continue to be investigated.
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.
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.
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. 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. 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.
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. 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. 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. 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.
For the minority of patients who relapse after first-line therapy, standard-dose second-line chemotherapy regimens produce very low response rates-typically less than 10%. Reported median overall survival rates are less than 1 year in most series.[11-13] As a result, transplant strategies have been used for patients with relapsed or refractory disease, with variable results. The largest retrospective series from Europe reported on 41 patients who underwent autologous stem cell transplantation in second complete remission after various second line salvage regimens. The reported 3-year actuarial progression-free and overall survival rates were 30% and 31%, respectively. Responsiveness of the disease to second-line therapy given prior to stem cell transplantation was the most important prognostic factor in this and other series.
In view of this finding, patients with relapsed and refractory disease should be treated with conventional-dose salvage therapy to induce a second remission before high-dose therapy. Even in the setting of apparent chemoresistance to a second-line regimen, stem cell transplantation should still be considered, since the reported long-term disease-free survival, even in this situation, is close to 20%.
Allogeneic stem cell transplantation has potential advantages over autologous stem cell transplant, partly related to the use of a donor marrow with no potential for contamination with lymphoma, and partly due to the immunologic effect of “graft vs lymphoma.” Since lymphoblastic lymphoma affects younger adults, the potential for regimen-related mortality from allogeneic stem cell transplantation is relatively low, thereby increasing the potential for long-term disease-free survival after this approach. However, existing data do not demonstrate a clear benefit to allogeneic compared with autologous transplantation. A large, retrospective, matched analysis from Europe compared 314 adult patients undergoing allogeneic transplantation with 1,332 patients who received autologous transplants for lymphoblastic lymphoma. The higher relapse rate observed in patients undergoing autologous transplants was offset by the higher transplant-related mortality in the allogeneic group, such that overall survival was higher for patients receiving autologous transplants.
The International Bone Marrow Transplant Registry (IBMTR) has reported similar results for 128 patients receiving autologous transplants compared with 76 receiving allogeneic transplants from human leukocyte antigen (HLA)-identical sibling donors. Relapse rates were higher for autologous recipients, whereas transplant-related mortality was higher in allogeneic recipients. Long-term disease-free survival was the same in both groups.
In the absence of any clear data showing the superiority of allogeneic transplantation in this disease, autologous stem cell transplantation is the standard transplant approach for consolidation of first or second remission.
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Based on early experience with nonintensive induction regimens in lymphoblastic lymphoma, the central nervous system was identified as a frequent site of relapse in up to 30% of relapsing patients. Sequential studies from Stanford University identified the benefit of central nervous system prophylaxis as a component of first-line therapy, reducing the incidence of central nervous system relapse to less than 5%. The use of cranial irradiation as a modality for central nervous system prophylaxis has largely been abandoned because of concerns for late neuropsychological toxicity. The use of high-dose systemic agents such as methotrexate and cytarabine results in equivalent rates of central nervous system relapse compared with cranial irradiation.
• Mediastinal Radiation-Despite the high frequency of mediastinal involvement at presentation in lymphoblastic lymphoma, mediastinal relapse is relatively infrequent. Some protocols include mediastinal irradiation as a component of induction therapy, although the benefit of mediastinal radiation is unclear. Favorable results have been reported for a regimen including mediastinal radiation, although relapses were observed in the mediastinum in patients who received radiation to this site.
A single-center retrospective series of 43 patients who achieved a complete remission after initial induction chemotherapy included 19 who received mediastinal irradiation. None of these patients experienced a relapse in the mediastinum. Of 24 patients who did not receive mediastinal radiation, 8 relapsed at this site. However, this analysis is confounded since the majority of patients who received radiation therapy had been treated with HyperCVAD induction, and no difference in overall or disease-free survival was seen for those who received mediastinal radiation.
Current evidence does not support the use of mediastinal radiation.
Prognostic factors for adults with lymphoblastic lymphoma are poorly defined. Some reports have suggested a worse outcome for patients with the precursor B-cell phenotype but this has not been confirmed in more recent retrospective studies. For those with precursor T-cell disease, genetic abnormalities have been described in up to 30%, especially involving α and β T-cell receptor loci and 9p deletion, but these have not been shown to have prognostic significance. Gene-expression profiling has identified molecular subtypes of precursor T-cell lymphoblastic disease characteristic of stages in thymocyte maturation and may identify prognostic subgroups. For example, patients with HOX11 appear to have a more favorable outcome, possibly related to the lower frequency of expression of bcl-2. Gene-expression profiles associated with TAL1 or LYL1 are more drug resistant and have higher levels of bcl-2.
Prior to the development of the International Prognostic Index (IPI), the most widely used prognostic factors for lymphoblastic lymphoma were those described at Stanford University, which identified patients as “low risk” if they had either less than Ann Arbor stage IV disease or Ann Arbor stage IV but without bone marrow or central nervous system involvement, and with a serum lactate dehydrogenase level less than 1.5 times the upper limit of normal. The 5-year freedom-from-relapse rate was 94% in this low-risk group, compared with only 19% for all other patients. The prognostic value of the IPI has been confirmed in three small studies. Although these studies show clearly inferior survival in patients with three adverse factors, the IPI did not discriminate between patients with zero, one, or two factors, and its clinical utility is therefore limited. At present, no reliable data support a risk-stratified approach to this disease.
Recent evidence implicating the NOTCH pathway in precursor T-cell disease has implicated components of this pathway as potential therapeutic targets. Components of this pathway converge on the mammalian target of rapamycin (mTOR) pathway. Blockade of mTOR and NOTCH pathways in vitro results in synergistic suppression of T-ALL , suggesting that mTOR inhibitors may have a role in the treatment of precursor T-cell disease.
Other potential new targets identified by gene expression include CARD10, a caspase recruitment domain family member involved in apoptotic signaling via NFκB.
Encouraging activity has been described in T-ALL for nelarabine (Arranon), a prodrug that is demethylated in T cells to 9-β-D-arabinofuranosyl-guanine (Ara-G). A phase II study in relapsed/refractory T-ALL and T-LBL reported an overall response rate of 41%, with a complete response rate of 31% and a 20% 1-year overall survival. These results were encouraging, particularly since some patients achieved sufficiently durable remissions to be able to undergo subsequent stem cell transplantation.
Financial Disclosure:The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article
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