Allogeneic Hematopoietic Stem-Cell Transplantation in Patients With Hematologic Malignancies After Dose-Escalated Treosulfan/Fludarabine Conditioning

Allo-SCT with reduced-intensity conditioning (RIC) results in lower non-relapse mortality (NRM), but higher relapse rate than myeloablative conditioning (MAC) in AML/myelodysplastic syndromes (MDS). Novel regimens with intensive anti-leukemic activity, but with limited toxicity will be of benefit. In all, 85 patients with AML/MDS, not eligible for MAC, were given fludarabine-treosulfan conditioning (FT). Outcomes were compared with those in patients given fludarabine-BU RIC (FB2, n ¼ 106) or reduced-toxicity (RTC) conditioning (FB4, fludarabine and myeloablative BU dose, n ¼ 85). The 5-year NRM was 29%, 20% and 18% after FT, FB2 and FB4, respectively (P ¼ NS). Multivariate analysis (MVA) identified comorbidity score (HCT-CI) 42 and advanced disease as adverse factors with no independent impact of regimen. The 5-year relapse rate was 36%, 47% and 40%, respectively (P ¼ 0.17). MVA identified advanced disease as the major adverse factor, while FT had significantly lower relapse rate (hazard ratio 0.6, P ¼ 0.03). The 5-year survival (OS) was 37% with advanced disease. HCT-CI 42 and age X50 were found as adverse factors. The 5-year OS was 46%, 44% and 50% after FT, FB2 and FB4 in early-intermediate-stage disease (P ¼ NS) and 33%, 9% and 28% in advanced disease, respectively (P ¼ 0.02). FT is an RTC regimen with intensive anti-leukemia effect in MAC non-eligible patients.

Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Allo-SCT for AML and MDS with treosulfan compared with BU-based regimens: reduced toxicity vs reduced intensity

Shimoni

Shem‐Tov

Volchek

et al. 2012

“…daily over 30 min from days À6 to À2). [39][40][41][42][43][44][45][46] For patients with unrelated donors, antithymocyte globulin (for example, ATG Fresenius, Fresenius Biotech, Munich, Germany (5-10 mg/kg)) was given i.v. daily from days À3 to À1.…”

Section: Regimensmentioning

confidence: 99%

Treosulfan-based conditioning before hematopoietic SCT: more than a BU look-alike

Danylesko

Shimoni

Nagler

2011

Allogeneic hematopoietic SCT is a curative treatment for a variety of hematological malignancies and genetic diseases. There is a continuous search for novel conditioning regimens that will reduce SCT-related toxicity while retaining maximal antimalignancy effect. Treosulfan (L-threitol-1,4-bis-methanesulfonate; dihydroxybusulfan) was initially used in the treatment of certain solid tumors. Preclinical studies showed that it has a myeloablative effect on committed and non-committed stem cells. It has potent immunosuppressive characteristics, more prominent than its related chemotherapy agent BU, which makes it an attractive candidate for the use in conditioning regimens before allo-SCT. It is also associated with a favorable toxicity profile with little extramedullary toxicity. The combination of fludarabine and treosulfan was explored in several studies in patients not eligible for standard myeloablative conditioning, and data are rapidly emerging. This regimen is associated with consistent engraftment. A limited non-relapse mortality (NRM) rate in the range of 9-28% was observed. This rate is promising considering the patients selected and results from low rates of organ toxicity as well as acute and chronic GVHD. The regimen was also associated with low relapse rates of 5-30% depending on disease status at SCT. Together with low NRM rate, this resulted in favorable survival in the range of 40-80%. Promising results were seen in myelodysplastic syndrome (survival 36-70%) and leukemia in remission (60-70%). Randomized prospective studies will be needed to better define the role of treosulfan-based regimens in SCT.

“…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 aggressive lymphoma, 14 thereby expanding the limited number of high-dose protocols.…”

Section: Introductionmentioning

confidence: 99%

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

Koenigsmann

Casper

Kahl

et al. 2013

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