Ras-Associated Autoimmune Lymphoproliferative Disorder: Retrospective Case Series

Introdaction：

Ras-associated autoimmune lymphoproliferative disorder(RALD)is a rare immune dysregulation syndrome by somatic gain-of-function mutations of either NRAS or KRAS gene in hematopoietic cells. Due to its rarity, there is limited understanding of this disease. In the present study, we aimed to provide new perspectives and methods for understanding and treating this rare immune disease.

Methods:

A retrospective analysis of 6 RALD patients was performed from June 2020 to April 2024 at our center. All patients were given methylprednisolone (1-2 mg/kg/d) or oral prednisolone (20 mg/d). Complete remission was defined as hematologic recovery, clinical shrinkage of liver and spleen, and these symptoms no recur once the dose of prednisone decreased.

Results:

This case series includes 6 patients, 4 were males and 2 were females. The median age of onset was 7.5 months (range: 2-36 months). Anemia was observed in all patients, splenomegaly and hepatomegaly were seen in 3/6 of the patients. One patient had acute liver failure and jaundice. The median white blood cell count was 5.95(range:4.81-10.31)×10⁹/L, the median hemoglobin 66.5 (range:22-110) g/L, the median platelet 223 (range: 17-397)×10⁹/L, the median lymphocytes count was 3.03 (range:0.5-7.73)×10⁹/L, the median monocytes 0.67(range:0.26-1.27)×10⁹/L, the median neutrophils 1.50(range:1.44-3.03)×10⁹/L, the median MCV 84.4 (range:82.7-105.7)fl, the median MCH 28.7 (range:23.6-31.1) pg, the median MCHC 338(range:279-345)g/L,the median RET 0.0097(range:0.0016-0.1244)×10¹²/L.Bone marrow results showed that erythroid lineages reduced in 4 of 6 patients. Three of these patients had a positive Coombs test. Among the 6 patients, 3 patients had KRAS p.G13D gene mutations (range: 4.10%-42%) and 3 patients had KRAS p.G13C gene mutations (range: 4.7% - 45.6%). No patients had NRAS gene mutations. Chromosome analysis was performed in 6 patients, of which 4 cases had normal karyotype,1 case had a structural abnormality in chromosome 9,and another case had a structural abnormality in chromosome10.

All 6 patients were treated with methylprednisolone (1-2 mg/kg/d) or oral prednisolone (20 mg/d) maintenance therapy. Among all 6 patients, the complete remission (CR) rate was 33.3% (2/6), clinical shrinkage of liver and spleen was observed in 3 patients, one patient's clinical course was complicated by autoimmune events including hemolytic anemia and thrombocytopenia, and recurrent infections. She was treated sequentially with prednisone combined with zanubrutinib, methylprednisolone combined with rituximab for 4 weeks,but this did not result in clinical remission. Therefore, she was given trametinib at a dose of 0.5 mg for 3 days, which led her to hematologic recovery and clinical shrinkage of spleen. To date, evolution to myeloid malignancy has not occurred in any of the 6 patients.

Conclusion：

Our results show that RALD is extremely rare,anemia and hepatosplenomegaly are common. KRAS p.G13D and KRAS p.G13C mutations are the most common mutation types.Glucocorticoids are an effective treatment modality for RALD. RAS targeted drug trametinib could be used as a therapeutic option for RALD.

No relevant conflicts of interest to declare.