Impact on Progression Free Survival of Autologous Stem Cell transplantation after Consolidation with Alemtuzumab in Chronic Lymphocytic Leukemia.
Authors: Montillo Marco , Ricci Francesca , Tedeschi Alessandra , Miqueleiz Sara , Grillo Giovanni , Vismara Eleonora , Greco Antonino , Veronese Silvio , Morra Enrica 
Published: April 2020

Abstract
The role of an intensified program of autologous stem cell transplantation (ASCT) following a consolidation phase with alemtuzumab (A) in pts with chronic lymphocytic leukemia (B-CLL) who received a fludarabine-based regimen (Fbr) as debulking is still considered questionable. The reported evidence of a prolonged treatment free-survival and survival associated to the absence of minimal residual disease (MRD) in B-CLL pts treated with A doesn’t seem to justify an intensification with ASCT in case of MRD-. We have already reported our experience in B-CLL pts treated with Fbr who after a median period of discontinuation of 16 weeks, received A sc (10 mg x 3/w for six weeks) in order to obtain the maximum response of MRD negative remission. Pts obtaining a successful peripheral blood stem cell harvest (PBSC) were considered eligible for ASCT. After a longer follow-up period we analyze here the outcome of autografted pts. Furthermore results were compared with those of pts treated with the same regimen but excluded from transplant procedure. Overall 48 pts have been considered for the analysis. Twenty-nine pts underwent an ASCT. Mobilization regimen consisted in all but 1 pt of Ara-C (800 mg/ sqm/12h x 3 days) followed by granulocyte colony-stimulating factor (G-CSF) while the last patient received only G-CSF. Reason for exclusion from ASCT procedure in the 19 non transplanted pts was: 9 refusal, 4 progressive disease, 1 evolution to Richter syndrome, 2 priming failure, 3 physician decision. Initially, in the group of non-transplanted pts, 9 (47%) were in stage A, 9 (47%) B, 1 (6%) C; ZAP70 was positive in 4 (21%) cases. Response after consolidation with A was: 7 MRD- CR (37%), 7 MRD+ CR (37%), 1 PRn (5%), 4 PR (21%). As regards the transplanted pts: 9 (31%) were in stage Binet A, 16 (55%) B, 4 (14%) C; ZAP70 was positive in 10 (34%) cases. Disease status after A was as follows: 18 MRD- CR (62%), 6 MRD+ CR (21%), 5 PRn (17%). Median age at transplant was 55 years (range 44–64). In all pts a reassessment of response status was ruled out before transplant to exclude a disease progression. ASCT procedure was performed after a median of 12 mos from last A administration (range 6.5–16.8). One pt who reactivated a virus B hepatitis after consolidation was successfully transplanted after 16.8 mos interval from alemtuzumab. Conditioning regimen consisted of 12 Gy total body irradiation plus cyclophosphamide 120 mg/kg in 21 pts &lt;60 years, and melphalan 180 mg/m2 in 8 pts ≥60 years. Median number of CD34+ cells reinfused was 14x106/kg (range 3.1–41); in 15 cases (52%) the reinfused product was polyclonal for IgH rearrangement. The median time for PMN ≥500/mcL and PLT ≥20,000/mcL recovery was 9 (range 6–10 days) and 10 days (range 3–13 days) respectively. No incidence of grade 3–4 non hematologic toxicity was observed. None of the patients developed CMV reactivation, even in pts who showed a CMV reactivation during A treatment. One patient died (TRM 3.4%) due to a pulmonary fungal infection sustained by Aspergillus terreus. Disease assessment after transplant showed MRD- CR in 25 (86.2%) pts, in the remaining pts 2 MRD+ CR and 1 PRn were detected. In the transplanted population after a median follow-up of 46.3 mos (range 15.2–73.4) from last A administration and 35 mos from ASCT (range 2–59.8 months) 82% of pts are in CR according to NCI WG criteria. After the same follow-up period 20 (69%) pts are still in MRD- CR. Two pts died, one in MRD- CR for a lung cancer and one for fungal infection after transplant, two relapsed, after 45 and 15 mos respectively. In the non-transplanted pts after a median followup of 12 mos (range 1.5–64.2) from A 13 (68%) pts relapsed. Six pts died, 3 for disease progression, 1 for breast cancer, 1 for Richter syndrome and 1 for IMA while in MRD- CR. In conclusion in our experience ASCT following a chemo-immunotherapy confers a long disease free survival at 5 years (82%). Even if the population of non transplanted is not directly comparable, as transplanted pts were selected based on their response and the adequacy of the stem cell harvest, it is remarkable that in those pts the 5 year disease free survival is only of 32%. The in vivo “purging” effect of A given as consolidation facilitated the achievement of an high rate of MRD- PBSC collections. We can speculate that the reduced contamination of the reinfused product translated in sustained molecular remission after transplant. Moreover, this prospective single centre survey showed a low treatmentrelated mortality and absence of secondary MDS.