Patients with Myelodysplastic Syndrome (MDS) with cytopenias have limited treatment options to improve blood counts apart from immune-modulatory drugs (IMIDS), hypomethylating agents (HMA), cytokines and transfusional support. Immune dysregulation is common in MDS and occurs in up to 35% of pts (LR Silverman, Cancer Med, 2017). Expanded T-cell clonal populations in the peripheral blood and bone marrow in the presence of MDS may play a role in aggravating MDS related cytopenias, increasing the need for transfusions or exacerbating symptoms. Intravenous immunoglobulin (IVIG) may interact with Fc receptors on T cells or have suppressive effects on the concurrent large granular lymphocytic leukemia (LGL) clone. Targeted therapy with IVIG could be a novel strategy to mitigate the cytopenias in MDS and other bone marrow failure pts.
We reviewed in a single-center series 27 consecutive pts who had either MDS, aplastic anemia (AA), or a myeloproliferative neoplasm (MPN) along with an LGL clone seen on TCR-rearrangement studies and/or peripheral blood flow cytometry in the blood and/or bone marrow. Of the 27 pts, 22 had MDS, 2 had MPN, and 1 each with AA, LGL, or Multiple Myeloma. IVIG was initially used as a single agent administered at a dose of 500mg/kg/day over 4 hours once weekly x4 weeks. After "induction", administration was changed to every other week, and then in responding pts, the interval was extended to every 3-4 weeks. In pts with a stable response, IVIG was discontinued and pts observed. After the initial 4 pts, pts were treated concurrently with prednisone 20 mg/d with a taper over 4 weeks, except in pts in which prednisone was a relative contra-indication. Overall hematologic improvement was determined by MDS IWG 2006 criteria, while hemolytic response was determined to be either a complete normalization (CR) or a partial normalization (PR) if there was >50% improvement in deviation from normal LDH, reticulocytes, indirect bilirubin, or haptoglobin values from baseline.
All pts received IVIG administered at 500mg/kg, once weekly, to be spaced out maximally as tolerated. 74% (20/27) of pts received steroids. Baseline characteristics of the pt population: median age of 70 years (range 39-87), representing 21 males and 6 females. Of the pts with MDS evaluable for risk stratification by IPSS-R criteria [n=18], 3 were very low, 5 low, 6 intermediate, 2 high, and 2 very high risk categories. By WHO criteria, the greatest representation was 11/20 RCMD, followed by 3/20 with RAEB2. Baseline cytogenetics [n=21] included 3 pts with very poor, 2 poor, 3 intermediate, 11 good, and 2 very good risk profiles. Pts had a range of 0-6 mutations, most common were SETBP1, ASXL1, TP53 (n=4) and SRSF2, U2AF1, PDGFRB (n=3). 24/27 pts had positive TCR beta and 13/27 had positive TCR gamma gene rearrangements. ORR for any cytopenia was 77.8% (21/27), and for any hemolytic response was 76.2% (16/21). ORR for individual cell lines included: 59.2% (16/27) erythroid, 48.1% (13/27) neutrophil, and 33.3% (9/27) platelet responses. For hemolytic responses, CR/PR rate were measured by LDH (29.6%/11.1%), bilirubin (22.2%/14.8%), retic (33.3%/14.8%), and haptoglobin (22.2%/11.1%). For the 14 MDS pts with very low, low, and intermediate IPSS-R risk, ORR was: 64.3% (9/14) any cytopenia, 35.7% (5/14) erythroid, 50.0% (7/14) neutrophil, 14.3% (2/14) platelets. Combined CR+PR rates for hemolysis in the lower risk categories were 42.9% LDH, 21.4% bili, 42.9% retic, 28.6% haptoglobin responses. For the 5 non-MDS pts, ORR for any cytopenia was 100%, and 60% for any hemolytic response. There were no reported significant adverse events with IVIG administration.
IVIG can be used as a first line treatment for pts with autoimmune cytopenias associated with LGL clones and MDS (along with other hematological malignancies). Treatment with IVIG yields an ORR of 77.8% in the entire cohort and 64.3% in pts with lower risk MDS, with a reduction in hemolysis as well. This report expands on a previous analysis and demonstrates further evidence of efficacy for the use of IVIG in treating cytopenias exacerbated by LGL T-cell clones. IVIG therapy can permit a delay in the start of an HMA or IMID treatment, lowering transfusion burden, and increasing ANC to help prevent infectious complications. Further evaluation in a larger cohort of pts is warranted. Studies exploring the mechanism of action are underway.
Navada:Onconova Therapeutics Inc: Research Funding. Silverman:Onconova Therapeutics Inc: Patents & Royalties, Research Funding; Celgene: Research Funding; Medimmune: Research Funding.
Asterisk with author names denotes non-ASH members.
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