Discussion
neutropenia, chemosensitive relapsed PTCLs, toxicities, thrombocytopenia, PTCL, PTCL-NOS, anaplastic T-cell lymphoma, PTCLs, lymphoma
DISEASE PROGRESSION, REMISSIONS, NEUTROPENIA, ADVERSE EVENTS, THROMBOCYTOPENIA, DISEASE, REMISSION, LYMPHOMA
The treatment of advanced-stage PTCLs is still an unmet clinical need with an overall cure rate of ~45%. The main problem relies on the fact that ~30% of patients are primary refractory or have an early disease progression. In order to improve these disappointing results, we designed a trial to test the combination of romidepsin with chemotherapy before SCT. Based on the results of the Nordic trial, we decided to adopt the regimen CHOEP, with the addition of etoposide to standard CHOP, as induction chemotherapy backbone for our study, devoted to young patients. The rationale was to combine the supposed more effective chemotherapy with an HDAC inhibitor to increase the remission rate before the transplant phase. An increase in remissions would have led to a higher number of patients receiving transplant consolidation, to hopefully improve the final cure rate. Considering the dismal outcome of PTCL, the trial explored also the possibility of upfront allografting for patients only in PR after induction. We and others showed that allogeneic SCT is an effective salvage treatment for chemosensitive relapsed PTCLs [With a Bayesian statistical design during the phase Ib part, we defined romidepsin 14 mg/ms as the MTD. To our knowledge, this is the only trial defining the MTD of romidepsin with CHOEP in a program including a final transplantation. In the French trial, the recommended dose was 12 mg/ms in combination with CHOP, and the same dose was applied to the randomized study, but their study did not include a transplant phase [Unfortunately, the PTCL13 study did not meet the primary endpoint, with a PFS at 18 months of 48% (95% CI: 0.36–0.58) during the planned interim analysis, therefore the trial was stopped due to inefficacy of the experimental combination. Our results are superimposable to those reported by Bachy in the randomized trial, with PFS rates at 1 year and 2 years of 49.8%, and 43.2%, respectively, in the Ro-CHOP arm. The French trial results were obtained without transplantation, thus raising some doubts on its role in the upfront treatment of PTCLs.In our study, the outcome of AITL/THF was similar to PTCL-NOS. This finding, however, must be interpreted with caution because the subgroups are very small and the trial was not powered to see such differences.In the PTCL13 study, the combination was well tolerated, with no unexpected toxicities, and the most frequent adverse events were hematological, in particular grade ≥3 neutropenia (33% of all courses) and thrombocytopenia (34% of all courses). The use of romidepsin had not a detrimental effect on stem cell mobilization. The most frequent cause of treatment discontinuation was disease progression. In agreement with Bachy et al., we can conclude that romidepsin did not ameliorate the prognosis of PTCL patients, when added to chemotherapy, not even in our study that included a final transplant phase. PFS results are superimposable to those obtained with CHOEP alone and HDT by D’Amore et al.One more issue is the role of frontline allogeneic SCT that is a matter of debate since a decade. Recently, a phase III randomized trial on 104 untreated PTCLs patients reported, at a median follow-up of 42 months, a 3-year EFS after allo-SCT of 43%, compared with 38% after auto-SCT and a 3-year OS of 57% versus 70%, respectively. No significant differences were demonstrated between the two arms because the postulated graft-versus-lymphoma effect was counterbalanced by the higher transplant-related mortality in the allo-SCT group. Although the allo-SCT arm had no relapses, supporting a graft versus lymphoma effect [In our study, of the eight patients in PR after six Ro-CHOEP induction, only three underwent allo-SCT, and one died of TRM, supporting the notion that there is no role for frontline allo-SCT.Several biological agents have been tested in combination with chemotherapy, but only brentuximab-vedotin, a monomethyl-auristatin-E-antibody conjugate directed against CD30, used in combination with chemotherapy (A-CHP), showed in a phase III trial an advantage compared to CHOP in the first line treatment of CD30 + PTCLs, with no unexpected toxicities; however, 70% of the enrolled patients were anaplastic T-cell lymphoma, and more than 20% of patients received consolidation with SCT [In conclusion, we think that only a better knowledge of disease biology will allow the design of trials with novel drug combinations specific for genetic subgroups of PTCLs. The recent results of romidepsin plus 5-azacytidine in relapsed/refractory AITL/THF [