Progression Free Survival (PFS) in Alemtuzumab Based RIC Allogeneic Transplantation for Myeloma Is Improved with Use of Pre-Emptive DLI (pDLI).
Authors: Ramasamy Karthik , Mahmood Shameem , Pearce Laurence , Lim ZiYi , Ladon Dariusz , Pagliuca Antonio , Devereux Stephen , Mufti Ghulam J. , Schey Stephen 
Published: October 2019

Allogeneic transplantation is the only potentially curative treatment option for myeloma (MM). While reduced intensity conditioning (RIC) regimens are associated with lower transplant related morbidity and mortality (TRM), this approach is offset by an increase in relapse rates in myeloma.

Method & Materials: We conducted a prospective study on the use of pDLI in myeloma patients with declining donor T cell chimerism following alemtuzumab based RIC allogeneic transplants. 19 consecutive patients were recruited. Patients received 100mg of Alemtuzumab 1H in total over 5 days in vivo as part of the pre-transplant conditioning regimen. There were 8 females and 11 males with a median age of 54 years (range: 41–63). Median lines of prior therapy was 2 (1–4), and 17(84%) had at least one prior autograft. 15 patients were transplanted with related donors and 4 unrelated. The median followed up of the cohort was 25.5 months (4–82). Fractionated peripheral blood (PB) and unfractionated bone marrow (BM) chimerism was performed on day 30, 60, 100 and 3–6 monthly thereafter using promega powerplex 16 genetic identity system. The samples were electrophoresed on an ABI 3130 XL capillary sequencer and analysed using Genemapper 4.0 software. Metaphase cytogenetics of unfractionated BM overnight cultures and Y-FISH for sex mismatch transplants was performed at various time points. Escalating doses of pDLI was given to patients with falling donor T cell chimerism (<50%) after Day 100. The starting dose of DLI was 1 × 105 CD3 cells/kg. 6 patients received pDLI with a median number of pDLI infusions of 2.5 (1–4). Overall survival (OS) and PFS was calculated from date of transplant using Kaplan-Meier cumulative survival plot using SPSS 14.0 software in pDLI receiving (Cohort I) and non-pDLI receiving cohort (Cohort II).

Results: 17 patients (84%) responded with CR rate at 100 days of 57%. One patient had primary graft failure and 1 patient had stable disease for a year post transplant. Median OS and PFS for all patients was 24 months (17.6–30.3) and 12 months (7.7–16.2) respectively. TRM at 2 years was 15.5%. In Cohort I, 13 patients did not receive pDLI. 1 patients (7.6%) experienced limited chronic graft versus host disease (cGVHD) with no cases of acute GVHD. In Cohort II, escalated doses of pDLI were administered to 6 patients at declining levels of donor CD3 chimerism in PB without evidence of morphological or cytogenetic relapse. 2/6(33.3%) patients developed cGVHD post DLI. Full donor chimerism was achieved in 4/6 patients, all of whom are long-term survivors. Median OS in Cohort I is 24 months (8.9–41.0) and 17 months (11.3–22.6) in Cohort II (p=NS). Median PFS in Cohort I is 25 months vs 9 months in Cohort II (p= 0.02). Cytogenetics was not helpful in determining requirement for DLI even in sex-mismatched patients. The presence of GvHD did not have a significant impact on OS.

Conclusion: pDLI administration guided by PB CD3 chimerism significantly improves PFS in Alemtuzumab conditioned RIC transplants for myeloma. Monitoring CD3 chimerism and early application of pDLI improves survival with a 5-year survival rate of 20% in multiply treated high risk patients.