Scott D. Rowley, MD
Diffuse large B-cell non-Hodgkin lymphoma (DLBCL) is typically a chemotherapy-sensitive malignancy, justifying dose-intense therapy with hematopoietic stem cell transplantation (HSCT) for patients unlikely to achieve cure with standard-dose regimens. The value of autologous HSCT was demonstrated in the PARMA study, which randomized patients with relapsed but chemotherapy-sensitive large-cell lymphomas to salvage therapy consisting of several cycles of cisplatin/cytarabine/dexamethasone (DHAP) with or without dose-intense chemotherapy with autologous bone marrow transplantation.1
The actuarial probability of 5-year event-free survival (EFS) was 46% for patients randomized to transplantation compared with 12% for patients who received DHAP without dose-intense therapy. Patient eligibility criteria included age <60 years, no history of bone marrow or central nervous system involvement, and chemotherapy sensitivity; thus, transplantation was greatly restricted to a small subset of patients otherwise eligible for this treatment. Subsequently, most phase II studies demonstrated efficacy of dose-intense therapy for patients with chemorefractory disease or other adverse-risk features.2
The primary cause of failure of dose-intense therapy with autologous transplantation is posttransplant relapse, which raises the questions of patient eligibility and treatment strategies. The recently published CORAL study examined the outcome of transplantation for patients classified by the inclusion of rituximab in initial treatment and by duration of initial remission.3
EFS probabilities ranged from about 20% to 50% (duplicating the results of the PARMA study), with the highest probability enjoyed by patients who received initial chemotherapy regimens without rituximab and with an initial remission >12 months’ duration. Virtually all patients now referred for dose-intense therapy for recurrent or refractory DLBCL will have received rituximab, requiring patient-specific evaluation and treatment plans.
Identification of Patients With Favorable Risk Features
Chemotherapy–refractory disease continues to be a primary predictor for posttransplant relapse. Functional staging with PET scanning defines a group of patients with a higher probability of progression-free survival (PFS). A dramatic difference in survival was found in 1 study that reported a 81% probability of PFS for patients in complete response defined by PET scanning after pretransplant salvage therapy undergoing dose-intense therapy compared to 35% for patients not achieving a complete response (P
Most clinical studies of autologous transplantation allowed only limited salvage therapy before the dose-intense cycle. What is not known is the effect of administering multiple salvage regimens in order to achieve a complete remission by PET criteria on transplant outcome, although in this study of PET staging a greater number of salvage regimens was correlated with lower PFS.4
PET negativity could be a surrogate for disease sensitivity to the initial salvage regimen, but otherwise be of no predictive value for transplant outcome. Conceivably, patients may lose the option of dose-intense therapy because of treatment-related toxicities if multiple cycles of salvage therapy are administered in an unsuccessful attempt to achieve PET negativity, and PET response should not be used as an exclusion criterion for dose-intense therapy. PET scanning should be a component of pretransplant evaluation, and, if serial salvage regimens are intended in order to achieve ultimate PET negativity, HSC should be collected earlier in the treatment strategy before severe hematological toxicity is incurred. Patients should be allowed to proceed to autologous (or allogeneic) HCT even if PGT positive, before nonhematological toxicities preclude these treatment options.