Brentuximab vedotin in combination with or without donor lymphocyte infusion for patients with Hodgkin lymphoma after allogeneic stem cell transplantation.

In our study, we evaluated the safety and efficacy of Brentuximab vedotin (BV) with or without the addition of donor lymphocyte infusion (DLI) after allogeneic stem cell transplantation (allo-SCT) in 16 patients with advanced Hodgkin lymphoma (HL). Thirteen patients with relapsed HL after allo-SCT received BV as treatment for active disease. Three patients without progression of HL after allo-SCT received BV as consolidation. Twelve patients had been previously exposed to BV for treatment of relapse after autologous-SCT. Ten out of 16 patients received BV in combination with DLI. Among the 13 patients treated for active disease, CR and PR was observed in 7 and 2 patients, respectively. With a median follow-up of 13 months, 13 out of 16 patients are alive, while 3 died because of disease progression. The median PFS was 6 months. DLI-associated GVHD occurred in seven patients. Five patients with GVHD required immunosuppression, and in all cases, GVHD resolved after a short course of low dose steroids, implying that an anti-GVHD modulating effect could be induced by the concurrent administration of BV. No serious adverse event was observed in any of the patients.

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

Allogeneic stem-cell transplantation (SCT) is a potentially curative therapy for lymphoid malignancies. Myeloablative conditioning is associated with high non-relapse mortality (NRM). Reduced-intensity condition (RIC) reduces NRM but relapse rate is increased. Novel regimens with intensive anti-malignancy activity but limited toxicity are of benefit. We evaluated outcomes of 144 lymphoma patients given allogeneic SCT with RIC consisting of fludarabine and treosulfan (FT, n=50), intravenous-busulfan (FB2, n=38) or melphalan (FM, n=56). Sixty-nine patients (48%) had chemo-sensitive disease and 75 (52%) had chemo-refractory disease at SCT. The median follow-up is 39 months (4-149). Three-year survival was 67, 74 and 48% after FT, FB2 and FM, in chemo-sensitive disease (P=0.14) and 34, 11 and 17% in chemo-refractory disease, respectively (P=0.08). Three-year NRM was 24, 24 and 54% (P=0.002), whereas relapse mortality was 22, 34 and 18%, respectively (P=0.13). Multivariate analysis identified a high comorbidity-score, chemo-refractory disease and FM as associated with shortened survival. In conclusion, FB2 is associated with low NRM and good results in chemo-sensitive disease, but with higher relapse mortality rates. FM controls disease better, but with high NRM. FT probably balances these outcomes more optimally. It is as safe as FB2 and as cytoreductive as FM, resulting in improved outcome, mostly in advanced disease.

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

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=106) or reduced-toxicity (RTC) conditioning (FB4, fludarabine and myeloablative BU dose, n=85). The 5-year NRM was 29%, 20% and 18% after FT, FB2 and FB4, respectively (P=NS). Multivariate analysis (MVA) identified comorbidity score (HCT-CI) >2 and advanced disease as adverse factors with no independent impact of regimen. The 5-year relapse rate was 36%, 47% and 40%, respectively (P=0.17). MVA identified advanced disease as the major adverse factor, while FT had significantly lower relapse rate (hazard ratio 0.6, P=0.03). The 5-year survival (OS) was 37% with advanced disease. HCT-CI >2 and age ≥ 50 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=NS) and 33%, 9% and 28% in advanced disease, respectively (P=0.02). FT is an RTC regimen with intensive anti-leukemia effect in MAC non-eligible patients.

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

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.