Pediatric lymphoproliferative and immune dysregulation disorders (PLPID) represent potentially lethal conditions with varied clinical presentation, frequently associated with IFNγ pathologic inflammation. The goal of this study is to describe immune activation in a PLPID cohort and safety and efficacy of JAK-STAT pathway inhibition with ruxolitinib.
Medical charts review identified PLPID patients treated with ruxolitnib at Texas Children’s Hospital from 2015-2023. PLPID was defined as persistent lymphadenopathy, lymph organ involvement, or organ lymphocytic infiltration >3 months. Response to therapy (complete, partial, or no) was determined by a generated PLPID score, which evaluates clinical and laboratory features across ruxolitinib treatment (Table 1). Toxicity was graded with CTCAE.
PLPID scoring system.
| Clinical criteria | 0 | 1 | 2 |
|---|---|---|---|
| Recurrent fever | No fever = body temperature < 37.5°C | Recurrent fever >38.5 | |
| Fatigue | No | Yes | |
| Recurrent infections: | No infections | ≤3 infections in 6 months | >3 infections in 6 months |
| Infections treated at: | Home | Hospital | ICU |
| Lymphadenopathy | Normal size | ≤2 lymph nodes enlarged (physical examination or imaging) | >2 lymph nodes enlarged (physical examination or imaging) |
| Liver involvement | Normal ALT, AST, bilirubin | ALT, AST increased <5 times bilirubin increased <3 times | ALT, AST increased >5 times bilirubin increased >3 times |
| Splenomegaly | Normal size | Enlarged | |
| Respiratory failure | No | Nasal canula | O2 supplement, mechanic ventilation |
| Enteropathy | No | <5 loose stools per day, no blood in stool, wounds in perianal area require local treatment | Bloody diarrhea, >5 loose stools per day, wounds in perianal area. Require surgical treatment |
| Arthralgia/Arthritis | No | Mild intermittent pain, NSAIDs as needed (1-2 times a week) | Persistent pain, requiring frequent use of NSAIDs |
| Dermatitis | No | Yes | |
| CNS findings | No | Yes | |
| Laboratory values | |||
| Cytopenia* | No | In one cell line | Bicytopenia/pancytopenia |
| CRP | <10 mg/l | 10-50 mg/l | >50 mg/l |
| Ferritin | <500 ng/ml | 500-2,000 ng/ml | >2,000 ng/ml |
| CXCL9 | ≤647 pg/ml | 648 – 5,000 pg/ml | >5,000 pg/ml |
| IL-18 | 89-540 pg/ml | 541 – 3,000 pg/ml | >3,000 pg/ml |
| sIL2R | Level within the reference values | Level > reference values <3,000 U/ml | >3,000 U/ml |
| CD-163 | Level within the reference values | Level > reference values <3,000 U/ml | >3,000 U/ml |
| Neopterin | <16.5 nmol/l | 16.5 – 45 nmol/l | >45 nmol/l |
| CSF WBC | 0-5/CU mm | >5/CU mm |
| Clinical criteria | 0 | 1 | 2 |
|---|---|---|---|
| Recurrent fever | No fever = body temperature < 37.5°C | Recurrent fever >38.5 | |
| Fatigue | No | Yes | |
| Recurrent infections: | No infections | ≤3 infections in 6 months | >3 infections in 6 months |
| Infections treated at: | Home | Hospital | ICU |
| Lymphadenopathy | Normal size | ≤2 lymph nodes enlarged (physical examination or imaging) | >2 lymph nodes enlarged (physical examination or imaging) |
| Liver involvement | Normal ALT, AST, bilirubin | ALT, AST increased <5 times bilirubin increased <3 times | ALT, AST increased >5 times bilirubin increased >3 times |
| Splenomegaly | Normal size | Enlarged | |
| Respiratory failure | No | Nasal canula | O2 supplement, mechanic ventilation |
| Enteropathy | No | <5 loose stools per day, no blood in stool, wounds in perianal area require local treatment | Bloody diarrhea, >5 loose stools per day, wounds in perianal area. Require surgical treatment |
| Arthralgia/Arthritis | No | Mild intermittent pain, NSAIDs as needed (1-2 times a week) | Persistent pain, requiring frequent use of NSAIDs |
| Dermatitis | No | Yes | |
| CNS findings | No | Yes | |
| Laboratory values | |||
| Cytopenia* | No | In one cell line | Bicytopenia/pancytopenia |
| CRP | <10 mg/l | 10-50 mg/l | >50 mg/l |
| Ferritin | <500 ng/ml | 500-2,000 ng/ml | >2,000 ng/ml |
| CXCL9 | ≤647 pg/ml | 648 – 5,000 pg/ml | >5,000 pg/ml |
| IL-18 | 89-540 pg/ml | 541 – 3,000 pg/ml | >3,000 pg/ml |
| sIL2R | Level within the reference values | Level > reference values <3,000 U/ml | >3,000 U/ml |
| CD-163 | Level within the reference values | Level > reference values <3,000 U/ml | >3,000 U/ml |
| Neopterin | <16.5 nmol/l | 16.5 – 45 nmol/l | >45 nmol/l |
| CSF WBC | 0-5/CU mm | >5/CU mm |
A previous study highlighted the difficulty in both diagnosing pathological inflammation and determining effective treatment approaches in PLPID. The 10-year survival rate of this cohort was 72.4%.
In this study, 26 patients (median age 8.1 years [1.9-21.7]) with PLPID were treated with ruxolitinib for immune dysregulation and pathologic inflammation. Underlying diseases included HLH, macrophage activation syndrome, STAT GOF, Kikuchi disease, T cell large granular lymphocytic leukemia, and inflammatory bowel disease.
Patients demonstrated activation of IFN-γ pathway, reflected by CXCL9 (median 16108 pg/mL), T cell activation (sIL2r: median 222 5U/ml), macrophage activation (ferritin: median 239 5ng/ml, CD163: median 2886 ng/ml), inflammasome activity (IL-18: median 17058 pg/ml). Twenty patients required ruxolitinib in combination with other immune modulators; 6 received only ruxolitinib, 4 of whom as a frontline therapy.
Based on PLPID score, overall response to ruxolitinib in a 2-year period was 69.2% (3.8% complete response; 65.4% partial response—Figure 1). Most patients exhibited a partial response with improvements in temperature, energy levels, splenomegaly, enteropathy, lymphadenopathy, malnutrition, infection frequency, and severity. Interestingly, most partial responders with initially elevated CXCL9 saw decreased levels with normalization in two of them within 6 months. Most adverse events were grade 3-4 cytopenias, transaminitis, and infections. Overall survival was 88.5% at a median follow-up of 1.1 years (range: 2 weeks to 7.1 years), with six patients undergoing BMT.
Response status in individual patients over 2-year period of ruxolitinib treatment.
Response status in individual patients over 2-year period of ruxolitinib treatment.
PLPID represents a clinically challenging population at risk for poor outcomes with few biomarkers and no guidelines for treatment. Ruxolitinib demonstrated efficacy and safety and represents a potential “precision” therapy for PLPID patients with a pathologic IFNy signature.
