Lymphoblastic lymphoma (LBL) is a rare disease, most commonly of T-cell origin, that shares biologic features with acute lymphoblastic leukemia (ALL). Indeed, LBL and ALL are considered a single entity (lymphoblastic leukemia/lymphoma, T and B types) in the World Health Organization (WHO) classification of precursor lymphoid neoplasms.
Lymphoblastic lymphoma (LBL) is a rare disease, most commonly of T-cell origin, that shares biologic features with acute lymphoblastic leukemia (ALL). Indeed, LBL and ALL are considered a single entity (lymphoblastic leukemia/lymphoma, T and B types) in the World Health Organization (WHO) classification of precursor lymphoid neoplasms. It occurs most frequently in young adults, predominantly males, and has distinct clinical features including a tendency to involve the mediastinum, bone marrow, and central nervous system (CNS). LBL is an aggressive disease, but potentially curable with prompt initiation of appropriate treatment. Over the past 2 decades, outcomes have improved significantly with an ALL-like approach to management including intensive induction and consolidation phases as well as CNS prophylaxis. However, opinions vary in regard to the most appropriate consolidation therapy and the role of high-dose therapy with autologous (auto) or allogeneic (allo) stem cell transplantation (SCT). In recent years, new agents have become available and the possibility of targeted therapy has been pursued. Against this background, Dr. Sweetenham’s review of the management of LBL in adults is both appropriate and timely.
The standard approach to the management of LBL involves intensive multiagent chemotherapy regimens for induction and consolidation phases with CNS prophylaxis and a maintenance phase lasting 12 to 18 months. In addition, some protocols incorporate prophylactic radiotherapy to the mediastinum. As indicated, the probability of long-term disease-free survival (DFS) after this strategy is ~40% to 60%. A number of regimens have been reported, but none appears to be superior to the rest. In this regard, disease-related factors are likely more important than treatment specifics in determining outcome. This would seem to be the case for the commonly used regimen hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin [Adriamycin], dexamethasone).
For the vast majority of patients with refractory or recurrent LBL after appropriate primary therapy, the prognosis is dismal. Although there are reports of such patients being rescued by high-dose therapy with autoSCT or alloSCT, these individuals represent a small minority of the total, coming as they do from a highly selected group.
High-dose therapy and autoSCT has been used as consolidation of first remission in an attempt to reduce the probability of recurrence and thereby improve DFS. However, the results from such studies have not provided convincing evidence of an advantage over standard consolidation. Unfortunately, an important randomized trial (conducted by Dr. Sweetenham and colleagues) comparing high-dose therapy and autoSCT with standard therapy as consolidation, had to be closed early because of poor patient accrual. In Vancouver, in a population-based study, we have evaluated a protocol based on a hybrid non-Hodgkin lykmphoma (NHL)/ALL chemotherapy regimen in the induction phase followed by consolidation with high-dose therapy and SCT (autologous for the large majority). This approach to management has resulted in long-term DFS for the majority of patients and has the advantage of being completed in full within 3 to 6 months of diagnosis. We therefore continue to employ this in-house protocol for primary therapy of patients with LBL. At the same time, we understand the statement that there is no clear role for SCT as consolidation therapy.
The role of alloSCT in the management of patients with LBL is, for some, an even more contentious issue. Retrospective registry studies comparing outcomes after alloSCT and autoSCT have demonstrated a lower probability of recurrence after allografting but this is offset by a higher probability of transplant-related mortality, resulting in no survival benefit. It is, therefore, reasonable to conclude that for patients undergoing SCT as consolidation of first remission, the majority will be better served with an autograft. However, for a small minority of selected patients-for example, younger individuals deemed to be at high risk of recurrence (such as those with bone marrow involvement at diagnosis) who have a histocompatible sibling-alloSCT may be a reasonable consideration.
The characterization of important pathways in precursor T-cell disease has identified potential targets for new therapies. An example is the demonstration that the mammalian target of rapamycin (mTOR) pathway, which undergoes positive regulation by Notch signaling in T-ALL cells, can be inhibited. Other targets have been demonstrated. Furthermore, nelarabine (Arranon), a prodrug that is demethylated to deoxyguanosine, has been shown to have significant activity in patients with refractory or relapsed T-ALL and T-LBL. Quite appropriately, attention is drawn to the promise of these new approaches.
In summary, LBL is a challenging disease that invariably runs an aggressive course and demands an intensive approach to management. Appropriate treatment results in cure for a significant proportion of patients. However, the disease is unforgiving and, in general, there is no second chance if it is not eradicated by primary therapy. This underscores the importance of selecting the most reasonable strategy for newly diagnosed patients. Promising early results have been reported in the quest for new therapies. Dr. Sweetenham has presented a cogent and sound review of the management of adults with this disease.
Financial Disclosure: The authors have 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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