Conditioning in allogeneic stem cell transplantation has been widely explored in the last decades, since the introduction of the Reduced Intensity Conditioning (RIC) allowed the extension of the feasibility of allotransplants in previously ineligible patients. Outcome of both treatments remains comparable because of an higher incidence of relapse although reduction of Non Relapse Mortality (NRM) in RIC. Treosulfan is a bifunctional alkylating agent without major extra-haematological toxicities. Here we show the results of a Treosulfan based regimen in use at our Center in patients enrolled in “AlloTreo” trial (Eudract 2005–005182–11).
We analyzed 123 pts transplanted between 2004 and 2011 consecutively enrolled at our center. Patient's median age was 50 years (21–69) and median Sorror comorbidity index was 1 (0–7). Diagnosis: acute myeloid leukemia (41 pts), acute lymphoblastic leukemia (14 pts), Myelodysplastic syndrome (17 pts), Non Hodgkin Lymphoma (23 pts), Hodgkin Lymphoma (5 pts), Myeloproliferative neoplasms (11 pts), and others (12 pts). Fourty-three pts were in first CR, 18 pts were transplanted upfront, 46 pts in persistence of disease; 16 pts in CR2 or CR3. Donor was unrelated (UD) in 57% of pts; source of stem cells were BM, PBSC and CB respectively in 5, 106 and 12 pts. Conditioning was: Treosulfan (14 g/msq for 3 days) and Fludarabine (30 mg/msq for 5 days). In vivo T and B-cell depletion was performed by ATG-Fresenius (10 mg/kg for 3 days) and Rituximab (single 500mg dose) only in pts receiving an UD. GvHD prophylaxis was: Cyclosporine A and short course of Methotrexate, excepting CB. Median CD34+ infused for BM-PBSC was 6.6×106/kg (1–17). Median follow-up was 48 months (1–83).
At day 60 cumulative incidence (CI) of neutrophil engraftment was 93±2%, with a median time 17 days. In evaluable pts molecular chimerism at day 30 was full-donor in 89% thus confirming myeloablative properties of full dose treosulfan. Regimen was very well tolerated, median grade of regimen-related toxicity (CTC score) was 1 (0–4), mostly a transient rise of bilirubin (74%). Grade 4 toxicity was observed in 2 pts, with significant increase of bilirubin without signs of VOD. Grades II-IV aGvHD occurred in 42 pts (34%), grade III-IV in 21 (17%). Among evaluable pts after day 100, 46% developed chronic GvHD, half of which was extensive.
Thirty days, 100 days and 4 years CI of NRM were respectively 2%, 11% and 21%; in multivariate analysis (MVA) an advanced stage of disease (HR=6.4, p=0.01) was associated with increased TRM. 4 years PFS was 44%, in MVA factor associated with a decreased PFS was advanced stage disease at transplant (HR=2.31, p=0.004). Thirty days, 100 days and 4 years CI of relapse were respectively 3%, 15% and 35%; no risk factors found. OS at 4 years was 51%, in MVA once again advanced stage of disease was a risk factor (HR=2.62, p=0.003). Importantly, even if a trend of increased NRM was found in UD transplants, it does not meet the significance criteria; in MVA, indeed, UD were not associated with increased risk of NRM, PFS, RI or worst OS. 57 pts died after transplant, 26 for relapse and 31 for transplant related causes (GvHD 32%, infection 45%).
Treosulfan is a safe and effective myeloablative drug with low toxicities. Use of ATG as in-vivo T-cell depletion guarantees similar results in unrelated donor settings without enhancing NRM or worsening OS. Anti-leukemic effect, rapid engraftment as well as relatively low toxicity and NRM configure this regimen as a possible paradigm of the so called Reduced Toxicity Conditioning. However strategies to ameliorate outcome in advanced diseases are warranted.
No relevant conflicts of interest to declare.
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