Non-Myeloablative Conditioning with Total Lymphoid Irradiation and ATG and Allogeneic Transplantation for Patients with Myelodysplastic Syndrome, Therapy-Related Myeloid Neoplasms, and Myeloproliferative Neoplasms.

The Myelodysplastic Syndromes (MDS) and Myeloproliferative Neoplasms (MPN) are hematopoietic malignancies primarily affecting older patients. Myeloablative allogeneic hematopoietic cell transplantation (allo HCT) is potentially curative for MDS and MPN, but has traditionally been limited to younger patients because of the toxicity associated with high-dose chemoradiotherapy. The preparative regimen of Total Lymphoid Irradiation (TLI) and Anti-Thymocyte Globulin (ATG) permits the gradual establishment of donor hematopoiesis that is necessary for the graft versus malignancy effect. However, TLI-ATG 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.

Between August 2004 and December 2010, 51 patients were treated on an IRB approved Phase II trial. 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). The median time from diagnosis to HCT was 11 months (range 3–160). Among all patients, 41% had progressed to AML at some point preceding HCT. Most patients had received treatment beyond growth factor or transfusion support, including cytotoxic chemotherapy (29%), DNA methyltransferase inhibitors and/or immunomodulatory agents (41%), or cytotoxic chemotherapy and DNA methyltransferase inhibitors (14%). Among the 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%). At the time of HCT, 40% of patients had abnormal marrow cytogenetics. Following provision of informed consent, patients were treated with 10 fractions of TLI (cumulative dose1200 cGy) and ATG (Thymoglobulin, Genzyme, 7.5 mg/kg divided in 5 doses). Primary GVHD prophylaxis consisted of Cyclosporine A and Mycophenolate Mofetil. Patients received G-CSF mobilized peripheral blood progenitor cells from matched related (45%), 10/10 matched unrelated (45%), or mismatched unrelated donors (10%).

The median follow up for living patients was 3.2 years (range 1.5–7) and for all patients was 1.4 years (range 0.1–7). 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%) with median time of onset of 199 days (range 112–475 days). The three-year cumulative incidence of progression was 61% (47–74%) and the median time to progression was 136 days (range 13–292). Rates of progression were not significantly different for patients with MDS (60%, 95%CI 44–73%), MPN (88%, 71–95%), and t-MDS (45%, 15–70%). The presence of abnormal cytogenetics at the time of HCT did not impact risk of progression (p=0.54). However, 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 and progression-free survival rates when compared with those in the Very Low and Low risk groups (Hazard Ratio for progression 1.25, 95% CI 0.36–4.32). CD15 chimerism at day 28 was the most predictive of progression at any subsequent time point. Those with donor CD15>90% donor at day 28 (40% of patients) defined a group with a low likelihood of disease progression (Odds Ratio 0.20, p=.01).

For patients with MDS and MPN, nonablative TLI/ATG conditioning prior to allo HCT was safe and 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 better outcomes than those with High or Very High risk scores. Analysis of CD15 chimerism at Day 28 may identify patients at high risk of progression and offers an early time point for intervention. These data suggest that for patients with MDS, earlier transplantation may result in better long-term outcomes due to lower transplant related risks.

Off Label Use: ATG (Thymoglobulin, Genzyme) for conditioning prior to allogeneic hematopoietic cell transplantation.