Progress on the efficacy and potential mechanisms of rapamycin in the treatment of immune thrombocytopenia

Figures & data

Table 1. Rapamycin in the treatment of immune thrombocytopenia.

Author (Ref)	Disease(s)	Patients (n)	Rapamycin schedules	Clinical response	Adverse events (AEs)
Feng YM (24)	R/R ITP	86	Each dosed with 2–4 mg/day of rapamycin. Drug concentration was kept at 5–15 ng/ml, Duration of rapamycin therapy 3 months and tapered 0.5 mg/2 weeks	ORR was 85% (CR 40%, PR45%) at 3M ORR was 65% (CR 33%, PR32%) at 12M The median onset time was 19 days	12% dyslipidemia; 6% increased ALT and AST; 7% canker sores; 5% skin rash, 2% arthralgia; 2% edema of lower extremity; One (1.2%) developed severe interstitial pneumonia
Li Q (32)	Chronic ITP	73	Rapamycin 2 mg/d plus Calcitriol 0.5 µg/d for 6 weeks	ORR was 79.5% (CR 27.4%, PR 52.1%) at 6 weeks	4.2% showed mild GI upset; 2.7% canker sores; 1.4% skin rash, 1.4% RTI (respiratory tract infection); 1.4% secondary hypertension
Mousavi M (31)	Pediatric chronic ITP	30	Loading dose 6 mg/m^2, maintenance dose 2 mg/m^2 (weight >40 kg); 3 mg/m^2 initialed and maintenance dose 1 mg/m^2 (weight < 40 kg); Duration of rapamycin therapy 6 months; Concentration 5–15 ng/ml	After 6 months of therapy, 50% CR and 50% PR. The median onset time was 1 month.	13% mild respiratory infection (sneezing and sore throat) and 13% showed mild GI upset (nausea and abdominal discomfort)
Li J (28)	Chronic ITP	43	Rapamycin (6 mg on d1, then 2 mg/day) plus prednisone (10–20 mg/ day) Responder: continued 3–6 months after PC increased to normal, the median treatment time was 8.48 months Non-responder: 3 months, then switch to another regimen	ORR was 58% (CR 35%, PR 23%), The median onset time was 1.96 months	Two (4.7%) patients developed secondary hypertension; One (2.3%) suffered from respiratory infection; Some experienced mild gastrointestinal reaction such as nausea, vomiting, and diarrhea
Jasinski S (29)	Pediatric persistent ITP	12	Rapamycin was initiated at a dose of 2–2.5 mg/m^2/d and was titrated up to a maximum dose of 4 mg/d Drug concentration 8–15 ng/ml. After achieving a stable PR or CR for 2–3 months, rapamycin dose tapered slowly. Duration of rapamycin therapy 50–881days	ORR was 83% (CR 75%, PR8%)	8% (1/12) hematuria
Li HM (30)	R/R ITP	19	A dose of 1–3 mg/d for adults and 1–2.5 mg/d for children, to maintain t concentration 4–15 ng/ml. Duration of therapy 0.5–1.2 years	ORR at twelfth month was 73.7% and CR kept 52.6%	11.1% mucositis; the incidences of other AEs were less than 5% (rash, hyperlipidemia, fatigue and Irregular menstruation)
Wu C (41)	Refractory CTD-TP (14 SLE, 3 pSS, 3 undifferentiated CTD)	20	2 mg/d for the first 3 d, with a sequential dose of 1 mg/d. Doses were adjusted according to tolerance and to maintain a therapeutic range of 6–15 ng/ml for 6 months	ORR at sixth month was 71.4% and CR kept 64.3%. None of the pSS cases responded to rapamycin	Leukopoenia (15%), prolonged menstrual cycle (15%), elevated serum triglycerides (10%), elevated cholesterol (10%), Cheilitis (5%), slow recovery from muscle strain (5%), rash (5%)
Xie W (43)	APS-TP	7	Initiated at a dose of 1–2 mg once daily and then adjusted primarily based on clinical efficacy and tolerance, with the concentration of ≤15 ng/ml. All patients completed 6 months of rapamycin therapy with a median follow-up of 6 months	ORR at sixth month was 85.7% (6/7) and CR kept 71.4% (5/7)	Only a patient experiencing elevated cholesterol level, with low-density lipoprotein cholesterol (14.3%)

Abbreviations: R/RITP, relapsed and refractory immune thrombocytopenia; ORR, overall response rate; CR, complete response; PR, partial response; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GI, gastrointestinal; PC, platelet count; CTD-TP, connective tissue disease-related thrombocytopenia; SLE, systemic lupus erythematosus; pSS, primary Sjö-gren’s syndrome; APS, antiphospholipid syndrome.

Figure 1. Potential mechanism of rapamycin in ITP: Rapamycin modulates lymphocyte survival and function, including T, B and MDSC cells. Second, Rapa reduced inflammatory factors but increased the expression of anti-inflammatory cytokines. Third, Rapa enhances platelet autophagy.