Sirolimus is effective in relapsed/refractory autoimmune cytopenias: results of a prospective multi-institutional trial.
Patients with autoimmune multilineage cytopenias are often refractory to standard therapies requiring chronic immunosuppression with medications with limited efficacy and high toxicity. We present data on 30 patients treated on a multicenter prospective clinical trial using sirolimus as monotherapy. All children (N = 12) with autoimmune lymphoproliferative syndrome (ALPS) achieved a durable complete response (CR), including rapid improvement in autoimmune disease, lymphadenopathy, and splenomegaly within 1 to 3 months of starting sirolimus. Double-negative T cells were no longer detectable in most, yet other lymphocyte populations were spared, suggesting a targeted effect of sirolimus. We also treated 12 patients with multilineage cytopenias secondary to common variable immunodeficiency (CVID), Evans syndrome (ES), or systemic lupus erythematosus (SLE), and most achieved a CR (N = 8), although the time to CR was often slower than was seen in ALPS. Six children with single-lineage autoimmune cytopenias were treated and only 2 responded. Sirolimus was well tolerated with very few side effects. All of the responding patients have remained on therapy for over 1 year (median, 2 years; range, 1 to 4.5 years). In summary, sirolimus led to CR and durable responses in a majority of children with refractory multilineage autoimmune cytopenias. The responses seen in ALPS patients were profound, suggesting that sirolimus should be considered as a first-line, steroid-sparing treatment of patients needing chronic therapy. The results in other multilineage autoimmune cytopenia cohorts were encouraging, and sirolimus should be considered in children with SLE, ES, and CVID. This trial was registered at www.clinicaltrials.gov as #NCT00392951.
Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA;
Karen L
KL
Bride
Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA;
Tiffaney
T
Vincent
Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA; Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, PA;
Kim
K
Smith-Whitley
Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA; Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, PA;
Michele P
MP
Lambert
Division of Bone Marrow Transplantation and Immune Deficiency, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH;
Jack J
JJ
Bleesing
Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA;
Alix E
AE
Seif
Department of Pediatrics, New York University Langone Medical Center, New York, NY; and.
Catherine S
CS
Manno
Division of Pediatric Hematology, Oncology and Bone Marrow Transplant, Medical College of Wisconsin, Children's Hospital of Wisconsin, Milwaukee, WI.
James
J
Casper
Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA;
Stephan A
SA
Grupp
Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA;
David T
DT
Teachey
D000293:Adolescent; D000328:Adult; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D005500:Follow-Up Studies; D006402:Hematologic Diseases / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007223:Infant; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D009367:Neoplasm Staging; D011379:Prognosis; D011446:Prospective Studies; D016879:Salvage Therapy; D020123:Sirolimus / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015996:Survival Rate; D014018:Tissue Distribution; D055815:Young Adult
D007166:Immunosuppressive Agents; D020123:Sirolimus