Risk-adapted, treosulfan-based therapy with auto- and allo-SCT for relapsed/refractory aggressive NHL: a prospective phase-II trial

Abstract

Since the outcome of relapsed/refractory aggressive non-Hodgkin's lymphoma (NHL) is highly variable, a risk-adapted treatment approach was evaluated. After two cycles of DHAP, patients received high-dose treosulfan/etoposide/carboplatinum (TEC) and autologous stem cell rescue. After TEC, low-risk patients with late relapse (41 year after first CR who achieved CR after DHAP received no further treatment. Patients with late relapse who achieved CR or PR only after TEC underwent a second cycle of TEC. High-risk patients with early relapse/refractory disease received treosulfan/fludarabine followed by allogeneic transplantation. Rituximab was added in patients with B-cell lymphoma (86%). At entry, 36% of all 57 patients had refractory disease, 32% early and 32% late relapse. During DHAP treatment, progression occurred in 32% of patients. Of 33 patients who received TEC, 5 received second TEC and 15 allogeneic transplantation. Main toxicity after TEC was oral mucositis (CTC grades 3 and 4 in 50% and 13%, respectively). In total, 42% patients achieved CR. Median OS was 21.4 months for all patients and 32.6 for those who underwent allogeneic transplantation. International prognostic index (IPI) at study entry was highly discriminative at predicting OS (Po0.0001). Risk-adapted, treosulfan-based therapy with auto-and allo-SCT is feasible. Long-term survival is possible with allogeneic transplantation. Keywords: relapsed non-Hogkin's lymphoma; treosulfan; autologous transplantation; allogeneic transplantation; risk-adapted therapy INTRODUCTION High-dose chemotherapy with auto-SCT has been the standard approach for relapsed aggressive non-Hodgkin's lymphoma (NHL) since the PARMA trial, 1 which reported a higher 5-year OS rate (53%) compared with that of conventional chemotherapy only (32%). Disease-free survival after a high-dose therapy is higher in cases of chemosensitive relapse than in cases of chemoresistant relapse, 2 and cytoreductive salvage therapy is more efficient after late relapse than after early relapse. 3 The application of allogeneic transplantation for these patients has evolved at a slower pace, 4-8 and a treatment-related mortality greater than 40% has led to the questioning of its role. 9 Treosulfan is an alkylating agent with a steep dose-response curve. High-dose treosulfan and fludarabine before allogeneic transplantation has shown efficacy with little toxicity in AML and myelodysplastic syndromes. 10,11 Treosulfan has also been investigated as a high-dose therapy before auto-SCT in ovarian cancer and other solid tumors. 12,13 A previous study demonstrated its activity in a high-dose combination regimen for relapsed Bone Marrow Transplantation

Fludarabine and treosulfan compared with other reduced-intensity conditioning regimens for allogeneic stem cell transplantation in patients with lymphoid malignancies

“…There are only limited data on the use of FT in lymphoid malignancies. 30,31 In this study we report the outcomes of a prospective study of FT conditioning in patients with lymphoid malignancies and compare them to outcomes following the more commonly used busulfan and melphalan based RIC regimens.…”

Conditioning with treosulfan and fludarabine for patients with refractory or relapsed non-Hodgkin lymphoma

“…The majority of these patients had chemotherapy-sensitive disease and a remission of ≥1 year; however, only 57% had received rituximab prior to salvage therapy (14). In a recently published study, Gisselbrecht et al (4) established the International Prognostic Index, the duration of remission (<12 vs. >12 months) and the pre-treatment with rituximab as risk factors for the outcome following autologous HSCT. In that study, 396 patients were randomly assigned to receive either R-ICE or R-DHAP as induction therapy, following high-dose BEAM and autologous HSCT.…”

“…Under these conditions, the patients may benefit from the graft-versus-lymphoma (GvL) effect following allo-HSCT, despite target structures still requiring proper definition in NHL. By contrast, autologous transplantation lacking this allo-recognition may not be sufficient, particularly for patients with early relapse (ER) or refractory disease (4). As regards allo-HSCT, reduced-intensity conditioning (RIC) has been used for patients with relapsed or refractory NHL, due to the…”

Impact of bone marrow involvement on outcome in relapsed and refractory transplant eligible diffuse large B-cell lymphoma and transformed indolent lymphoma

“…Out of these, 4 patients (4.9%) had tandem autologous and allogeneic SCT. Highdose chemotherapy regimens foregoing autologous SCT comprised BEAM [29] in 35 patients (61.4%), TEC [30] in 11 patients (19.3%) and other regimens in 11 patients (19.3%). Four patients (4.8%), in which autologous SCT was not executed due to insufficient disease control (n = 3, 3.6%) or failure of stem cell apheresis after induction immunochemotherapy (n = 1, 1.2%), were alternatively referred to allogeneic SCT.…”