Autologous bone marrow or stem cell transplantation has had an important role in the treatment of aggressive lymphoma for several decades. The important results of the PARMA study1 demonstrated that patients in first relapse who remained chemosensitive had improved progression-free and overall survival compared to patients who continued to receive standard-dose salvage therapy. Based on that trial, salvage autologous bone marrow transplantation became the standard of care for these patients and resulted in a long-term progression-free survival rate of approximately 50%.
Consolidation Strategy
If salvage bone marrow transplantation is effective, would consolidation bone marrow transplantation immediately after initial chemotherapy further improve the survival of advanced-stage, aggressive lymphomas? Over the past 2 decades, numerous randomized studies demonstrated no improvement in overall survival when all patients received consolidative autologous bone marrow transplantation or stem cell transplantation (which has largely replaced bone marrow transplant). However, multiple subset analyses of these trials did suggest there might be a benefit in the subgroup of patients with high-intermediate– or high-risk characteristics, as defined by the International Prognostic Index (IPI).
The S9704 trial was designed to answer that question. In the midst of accrual to the S9704 trial, the results of the initial treatment of patients with aggressive lymphoma improved approximately 15% as a result of the introduction of chemoimmunotherapy with R-CHOP (rituximab [Rituxan] plus cyclophosphamide, doxorubicin, vincristine, and prednisone). Therefore, S9704 was amended to use R-CHOP as the standard induction therapy.
As we recently reported in the The New England Journal of Medicine,2 and as reviewed in this issue of The ASCO Post, the trial showed that progression-free survival was improved, but there was no overall survival improvement for the entire study population. However, a secondary subset analysis suggested a major overall survival benefit for a small subset of patients with high-risk characteristics.
Clinical Impact
The question remains: How should the results of S9704 affect clinical practice? It is very clear that the group of patients who might benefit from upfront consolidative autologous stem cell transplantation has decreased with every large randomized trial. The patients with high-risk characteristics are a small fraction of the overall population with aggressive lymphoma.
The numbers are such that it is highly unlikely that a randomized trial restricted to the high IPI subset of patients will ever be conducted. The prognosis of this subset remains poor even in the era of R-CHOP. Thus, for younger, otherwise healthy patients with high-risk lymphoma, initial treatment with R-CHOP followed immediately by autologous stem cell transplantation seems a reasonable alternative.
However, even as we now evaluate this randomized trial, the world of lymphoma treatment has changed and is poised to change even more dramatically. Our understanding of the biology of aggressive lymphomas has been altered in the past few years as a result of molecular profiling. We now divide diffuse large B-cell lymphoma into the germinal center B-cell (GCB) and the activated B-cell (ABC) subtypes. Each not only has distinctive biology but also potentially different targetable pathways.
The details of the S9704 high-risk cases are still being analyzed—recall that the trial was designed in 1997—but the poorer prognosis of the ABC subtype would suggest that this group might be enhanced for that biology. Likewise, the recent recognition of the poor prognosis of the “double-hit” and “triple-hit” lymphomas (translocations involving c-myc, bcl-2, and bcl-6) suggests that those subtypes may also be overexpressed in the high-risk group.
Further Considerations
In addition, recent studies have demonstrated that the results of salvage stem cell transplantation have changed since the PARMA trial. In the postchemoimmunotherapy era, it appears that fewer than 50% of patients who were initially treated with R-CHOP, relapsed, and then had salvage therapy followed by stem cell transplantation have long-term survival. This suggests that the subset of diffuse large B-cell lymphoma patients who experienced increased survival with R-CHOP were part of the group of patients who could be salvaged by autologous bone marrow transplantation in the CHOP era.
Thus, although autologous bone marrow transplantation might be the current recommended therapy for high-risk diffuse large B-cell lymphoma patients, we will likely see the development of novel targeted treatments that will also be studied in these patients. ■
Dr. Fisher is President and CEO, Fox Chase Cancer Center-Temple Health, and Chair, SWOG Lymphoma Committee.
Disclosure: Dr. Fisher reported no potential conflicts of interest.
References
1. Philip T, Guglielmi C, Hagenbeek A, et al: Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin’s lymphoma. N Engl J Med 333:1540-1545, 1995.
2. Stiff PJ, Unger JM, Cook JR, et al: Autologous transplantation as consolidation for aggressive non-Hodgkin’s lymphoma. N Engl J Med 369:1681-1690, 2013.
