Romidepsin-CHOEP followed by high-dose chemotherapy and stem-cell transplantation in untreated Peripheral T-Cell Lymphoma: results of the PTCL13 phase Ib/II study

Abstract

The standard treatment for young patients with untreated PTCLs is based on anthracycline containing-regimens followed by high-dose-chemotherapy and stem-cell-transplantation (HDT + SCT), but only 40% of them can be cured. Romidepsin, a histone-deacetylase inhibitor, showed promising activity in relapsed PTCLs; in first line, Romidepsin was added with CHOP. We designed a study combining romidepsin and CHOEP as induction before HDT + auto-SCT in untreated PTCLs (PTCL-NOS, AITL/THF, ALK-ALCL), aged 18–65 years. A phase Ib/II trial was conducted to define the maximum tolerated dose (MTD) of Ro-CHOEP, and to assess efficacy and safety of 6 Ro-CHOEP as induction before HDT. The study hypothesis was to achieve a 18-month PFS of 70%. Twenty-one patients were enrolled into phase Ib; 7 dose-limiting toxicities were observed, that led to define the MTD at 14 mg/ms. Eighty-six patients were included in the phase II. At a median follow-up of 28 months, the 18-month PFS was 46.2% (95%CI:35.0–56.7), and the 18-month overall survival was 73.1% (95%CI:61.6–81.7). The overall response after induction was 71%, with 62% CRs. No unexpected toxicities were reported. The primary endpoint was not met; therefore, the enrollment was stopped at a planned interim analysis. The addition of romidepsin to CHOEP did not improve the PFS of untreated PTCL patients.

Prognostic impact of pretreatment cell‐free DNA concentration in newly diagnosed peripheral T‐cell lymphomas

“…Overall, baseline [cfDNA] was assessable in 75 patients, whose characteristics and outcome are listed in Tables S1-S5 and overlap with those of the population enrolled in the PTCL13 study. 10 Cell-free DNA concentration, expressed in ng of cfDNA/ mL of plasma (ng/mL), had a median value of 19.1 ng/mL (range: 2.27-1082) and it was associated with clinical risk factors (Figure 1A-E). There was a strong association between high [cfDNA] and a high IPI (median cfDNA: IPI 0-2 = 12.27, IPI 3-5 = 63.86 ng/mL, p < 0.0001) and PIT scores (median cfDNA: PIT 0-1 = 14.20, PIT 2-4 = 31.22 ng/mL, p = 0.0006), increased LDH levels (median cfDNA: normal LDH = 10.1, increased LDH = 40 ng/mL p < 0.0001) and poor performance status (median cfDNA: Eastern Cooperative Oncology Group performance status of 0 = 12.27, performance status ≥1 = 37 ng/mL, p = 0.0003).…”

“…Thus, the aim of this study was to assess whether pretreatment [cfDNA] in plasma was associated with clinical risk factors and prognosis in patients enrolled in the PTCL13 clinical trial (NCT02223208), whose plasma samples were prospectively collected. This was a multicentre phase Ib‐II study that included newly diagnosed patients affected by peripheral T‐cell lymphoma, not otherwise specified (PTCL‐NOS), anaplastic lymphoma kinase‐negative anaplastic large‐cell lymphoma (ALK‐ALCL) and nodular T‐follicular helper lymphoma (nTFHL), whose results have been recently published 10 . Patients received 6 cycles of chemotherapy combined with romidepsin, followed by consolidation with haematopoietic stem cell transplantation, in those who achieved a response to induction and were eligible to the procedure.…”

“…This was a multicentre phase Ib-II study that included newly diagnosed patients affected by peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), anaplastic lymphoma kinase-negative anaplastic large-cell lymphoma (ALK-ALCL) and nodular T-follicular helper lymphoma (nTFHL), whose results have been recently published. 10 Patients received 6 cycles of chemotherapy combined with romidepsin, followed by consolidation with haematopoietic stem cell transplantation, in those who achieved a response to induction and were eligible to the procedure.…”

Final results of a phase II study of CHOEP plus lenalidomide as initial therapy for patients with stage II–IV peripheral T‐cell lymphoma

“…11,12 Similarly, a phase III trial comparing romidepsin plus CHOP versus CHOP failed to meet its primary endpoint of PFS, 13 and a related phase II trial of romidepsin plus CHOEP and HDT/ASCR failed to meet a prespecified PFS. 14 These trials demonstrate that the addition of an active agent to chemotherapy may not result in increased survival, although a critical distinction in the above examples is that alemtuzumab and romidepsin significantly increased toxicity compared with standard chemotherapy (which was not observed with BV-CHP). In our trial, lenalidomide added excess hematologic toxicity which prevented patients from actually completing induction.…”

“…However, two randomized phase III trials of alemtuzumab plus CHOP versus CHOP showed no increase in survival owing to increased toxicity 11,12 . Similarly, a phase III trial comparing romidepsin plus CHOP versus CHOP failed to meet its primary endpoint of PFS, 13 and a related phase II trial of romidepsin plus CHOEP and HDT/ASCR failed to meet a prespecified PFS 14 . These trials demonstrate that the addition of an active agent to chemotherapy may not result in increased survival, although a critical distinction in the above examples is that alemtuzumab and romidepsin significantly increased toxicity compared with standard chemotherapy (which was not observed with BV‐CHP).…”