TLI-ATG Conditioning and Allogeneic Transplantation for Patients with MDS and MPN

Background: The Myelodysplastic Syndromes (MDS) and Myeloproliferative Neoplasms (MPN) primarily affect older patients ineligible for myeloablative allogeneic hematopoietic cell transplantation (allo HCT). The preparative regimen of Total Lymphoid Irradiation (TLI) and Anti-Thymocyte Globulin (ATG) permits the establishment of donor hematopoiesis that is necessary for the graft versus malignancy effect but is protective against acute Graft versus Host Disease (aGVHD), presumably due to the enrichment of tolerogenic recipient NK-T cells (Lowsky et al., NEJM 2005, Kohrt et al, Blood 2009). Here we report the outcomes of patients with MDS and MPN treated with TLI-ATG and allo HCT.

Methods and Patients: Patients received TLI (cumulative dose1200 cGy) and ATG (7.5 mg/kg). GVHD prophylaxis consisted of Cyclosporine A and Mycophenolate Mofetil. Of 51 consecutive patients treated between August 2004 and December 2010, the median age was 63 years (range 50-73). The initial diagnosis was de novo MDS (n=24), CMML (n=6), MPN (n=8), and therapy-related MDS (t-MDS, n=13). Among patients with de novo MDS, the IPSS-R score (Greenberg et al., Blood 2012) at the time of HCT was Very High or High (17%), Intermediate (23%), Low or Very Low (53%) or unknown/indeterminate (7%). Patients received mobilized peripheral blood from matched related (45%), 10/10 matched unrelated (45%), or mismatched unrelated donors (10%).

Results: The median follow up for living patients was 3.2 years (range 1.5-7). The three-year overall survival (OS), non-relapse mortality (NRM), and event-free survival (EFS) were 42% (95% CI 28-56%), 8% (0.3-15%), and 31% (18-44%), respectively. The cumulative incidence of aGVHD Grades II-IV was 14% (95% CI 4-23%) and Grades III-IV 4% (0-9%) and did not differ according to allograft source. The three-year cumulative incidence of Chronic GVHD was 33% (20-47%). The three-year cumulative incidence of progression was not significantly different for patients with MDS (60%, 95%CI 44-73%), MPN (88%, 71-95%), or t-MDS (45%, 15-70%). MDS patients with IPSS-R Very High and High Risk scores all had progressive disease within the first 100 days. In contrast, patients with Intermediate Risk scores had equivalent progression-free survival rates with those in the Very Low and Low risk groups (Hazard Ratio for progression 1.25, 0.36-4.32).   Patients with donor CD15>90% at day 28 (40% of patients) defined a group with a low likelihood of disease progression (Odds Ratio 0.20, p=.01).

Discussion: For patients with MDS and MPN, TLI/ATG conditioning was associated with low rates of acute GVHD and NRM. Patients whose IPSS-R scores at the time of HCT were Intermediate, Low, and Very Low had significantly lower risks of disease progression than those with High or Very High risk scores, suggesting early transplantation with TLI/ATG may result in better long-term outcomes.