Immunosuppression for Patients with Low and Intermediate Risk Myelodysplastic Syndrome: A Prospective Randomized Multicenter Trial Comparing Antithymocyte Globulin + Cyclosporine with Best Supportive Care: SAKK 33/99.
Authors: Passweg Jakob R. , Giagounidis Aristoteles , Simcock Mathew , Aul Carlo , Dobbelstein Christiane , Stadler Michael , Ossenkoppele Gert , Hofmann Wolf K. , Tichelli Andre , Ganser Arnold 
Published: April 2020

Abstract
Immunosuppressive treatment has been reported to improve cytopenia in some patients with myelodysplastic syndrome (MDS). The combined use of anti-thymocyte globulin (ATG) and cyclosporine (CSA) has been shown to be most effective in patients with immune mediated marrow failure. This trial was designed to assess the impact of immunosuppression on hematopoiesis, transfusion requirements, transformation and survival in MDS. 88 transfusion dependent patients were randomized to receive ATG+CSA (15mg/kg of horse ATG (Lymphoglobuline, Genzyme) for 5 days and oral CSA for 180 days) or best supportive care (BSC), stratified by treatment center and IPSS risk score between 2001 and 2006. The primary endpoint was best response at 6 months. Patients in the BSC arm crossed-over to ATG+CSA after 6 months or earlier in the event of progression: Eligible patients had an ECOG performance status ≤ 2 along with a transfusion dependency of &lt; 2 years duration. Patients with MDS types CMMoL and RAEBt or treatment related MDS were not included in the trial. Statistical analyses consisted of comparisons of response rates and durations between treatment arms and time-to-event analyses including overall-survival (read as time from randomization to all-cause mortality) and transformation-free survival (event defined as death, transformation to higher grade MDS or leukaemia). Also evaluated was medical resource utilization and hematological and non-hematological toxicities.
table 1 ATG+CSA BSC Patients: n 45 43 Age: median years (range) 62 (23–75) 65 (24–76) Sex: n male (%) 25 (56) 35 (81) IPSS score: n (low/int-1/int-2/high/na) (8/24/7/1/4) (8/25/5/0/5) MDS type: n (RA/RAS/RAEB-I/RAEB-II/hypoplastic) (21/6/9/0/9) (18/8/11/2/4)
Five patients in the ATG+CSA arm did not receive treatment for various reasons whilst 13 patients in the BSC arm crossed-over on to ATG+CSA treatment. At 6 months there were 13 patients with a hematologic response (CR + PR) vs. 29 without in the ATG+CSA arm, compared to 5 with vs. 35 without in the BSC arm (p = 0.04, adjusted for the interim analysis): For various reasons no information was available for the remaining 6 patients. Transformation-free survival probability estimates at 2 years were 42% (23–60%) for patients receiving ATG+CSA and 44% (25–62%) for patients receiving BSC (p-value: 0.50). In total 29 deaths occurred; 15/45 patients randomized to receiving ATG+CSA and 14/43 patients receiving BSC. Overall survival probability estimates at 2 years were 49% (28–66%) for patients receiving ATG+CSA and 61% (40–76%) for patients receiving BSC (p-value: 0.90). The vast majority of adverse events occurred early after randomization, with particularly high WHO hematological toxicity gradings in both treatment arms. There were 24 SAEs; 17 in the ATG+CSA arm and 7 in the BSC arm. Reported SAEs were heterogeneous and included the most common types of infectious and inflammatory complications.
Conclusions: In this open label randomized phase III trial of patients with transfusion dependent low and intermediate risk MDS, treatment with ATG + CSA appears to be associated with hematologic response in a subset of patients without apparent impact on transformation-free- and overall- survival.