Manifestations of carHLH, treatment approach and reasons for initiation of therapy
| Minor criteria* . | n . | Pt . | Peak CRS Gr . | Day of CRS onset . | Toci use (d) . | Day of carHLH onset . | CarHLH manifestations meeting definition . | Pertinent labs (peak values) . | Additional findings . | Steroid utilization (duration, d)† . | Anakinra for carHLH (duration, d) . | Indication for initiation of carHLH therapy . | ICU Utilization (duration, d) . | Outcome . |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 2 | 7 | 1 | 1 | 8 | No | 25 | Hepatic transaminitis, coagulopathy | AST = 320 ALT = 304 T. bili = 0.7 Ferritin = 124 200 | — | — | — | — | — | Full resolution without intervention |
| 2 | 3 | 8 | Yes (10) | 14 | Hepatic transaminitis, coagulopathy | AST = 263 ALT = 100 T. bili = 0.7 Ferritin = 194 210 | — | Steroids* (1 d) | – | — | ICU for hypotension & tachycardia associated with CRS (3 d) | Full resolution without intervention. (*Steroids given for 24 h specifically for neurotoxicity associated with CRS) | ||
| 3 | 2 | 10 | No | 17 | Hepatic transaminitis, coagulopathy | AST = 382 ALT = 190 T. bili = 0.6 Ferritin = 232 350 | Persistent fevers, new onset cytopenias | Steroids‡ (2 d) | — | Persistent/worsening signs of inflammatory response | ICU for hypotension associated with CRS (2 d) | Full resolution with treatment | ||
| 4 | 1 | 10 | Yes (15) | 16 | Hepatic transaminitis, hyperbilirubinemia, coagulopathy | AST = 358 ALT = 545 T. bili = 4.2 Ferritin = 422 950 | Fever, hypertension | Steroids‡ (5 d) | — | Persistent/worsening signs of inflammatory response | — | Full resolution with treatment | ||
| 5 | 2 | 8 | No | 12 | Hepatic transaminitis, coagulopathy | AST = 390 ALT = 57 T. bili = 1.3 Ferritin = 194 800 | Acute kidney injury (grade 1) | — | — | — | — | Full resolution without intervention | ||
| 6 | 3 | 9 | Yes (11) | 14 | Hepatic transaminitis, hyperbilirubinemi, hemophagocytosis | AST = 477 ALT = 200 T. bili = 1.9 Ferritin = 174 890 | — | — | Anakinra (17 d) | Persistent/worsening signs of inflammatory response | ICU for monitoring with new decrease in EF prior to CRS (5 d) | Full resolution with treatment | ||
| 7 | 2 | 7 | Yes (8) | 10 | Hepatic transaminitis, coagulopathy | AST = 1464 ALT = 448 T. bili = 0.7 Ferritin = 349 750 | coinfection at CRS onset with b. cereus† | Steroids‡ (49 d) | Anakinra (35 d) | Persistent/worsening signs of inflammatory response | Transferred to ICU for CNS hemorrhage (>1 mo) | CNS hemorrhage (grade 4); carHLH resolving | ||
| 3 | 9 | 8 | 2 | 7 | No | 9 | Hepatic transaminitis, coagulopathy, hemophagocytosis | AST = 503 ALT = 251 T. bili = 0.7 Ferritin = 154 700 | — | — | — | — | ICU for hypotension & hypoxia associated with CRS (2 d) | Full resolution without intervention |
| 9 | 2 | 7 | Yes (10) | 10 | Hepatic transaminitis, hyperbilirubinemia, coagulopathy, hypoxia | AST = 762 ALT = 259 T. bili = 3.4 Ferritin = 430 340 | — | Steroids‡ (1 d) | — | — | ICU for fever, tachycardia and hypotension associated with CRS (4 d) | Full resolution with treatment, proceeded to HSCT | ||
| 10 | 3 | 4 | Yes (6) | 7 | Hepatic transaminitis, coagulopathy, hypoxia | AST = 1483 ALT = 634 T. bili = 0.6 Ferritin = 303 790 | Hypertension | Steroids‡ (31 d) | — | Persistent/worsening signs of inflammatory response | ICU for hypotension & hypoxia associated with CRS (8 d) | Full resolution with treatment | ||
| 11 | 1 | 6 | Yes (9) | 10 | Hepatic transaminitis, coagulopathy, hemophagocytosis | AST = 660 ALT = 1670 T. bili = 1.1 Ferritin = 187 280 | — | Steroids (8 d)† | Anakinra (24 d)§ | Persistent/worsening signs of inflammatory response | — | Full resolution with treatment | ||
| 12 | 2 | 7 | Yes (11) | 18 | Hepatic transaminitis, coagulopathy, hemophagocytosis | AST = 631 ALT = 759 T. bili = 1.4 Ferritin = 208 020 | Hypertension | Steroids (7 d) | — | Persistent/worsening signs of inflammatory response | — | Full resolution with treatment | ||
| 13 | 3 | 5 | Yes (7) | 11 | Hypoxia, hyperbilirubinemia, hemophagocytosis | AST = 64 ALT = 64 T. bili = 2.6 Ferritin = 218 680 | Had concurrent progressive CD22 neg disease | Steroids (>25 d) | — | Persistent/worsening signs of inflammatory response | ICU for hypotension & hypoxia associated with CRS (8 d) | Full resolution with treatment, received interim anti-leukemia therapy and went to HSCT | ||
| 14 | 3 | 5 | Yes (5) | 9 | Hepatic transaminitis, hyperbilirubinemia coagulopathy, renal insufficiency | AST = 846 ALT = 184 T. bili = 6.6 Ferritin = 271 600 | Fevers | Steroids‡ (>2 mo) | Anakinra (prolonged >1 mo) | Persistent/worsening signs of inflammatory response | ICU for hypotension associated with CRS, developed renal insufficiency (14 d) | Full resolution with treatment, proceeded to HSCT | ||
| 15 | 2 | 5 | Yes (18) | 18 | Hepatic transaminitis, coagulopathy, hemophagocytosis | AST = 1336 ALT = 557 T. bili = 0.9 Ferritin = 565 510 | Fevers | Steroids‡ (41 d) | Anakinra (prolonged >1 mo) | Persistent/worsening signs of inflammatory response | ICU for persistent fever & tachycardia associated with CRS (3 d) | Full resolution with treatment; proceeded to HSCT | ||
| 16 | 2 | 5 | Yes (10) | 14 | Hepatic transaminitis, hypoxia, coagulopathy | AST = 568 ALT = 290 T. bili = 0.7 Ferritin ≥100 000 | Hypertension | Steroids‡ (43 d) | Anakinra (∼1 mo) | Persistent/worsening signs of inflammatory response | — | Full resolution with treatment; proceeded to HSCT | ||
| 4 | 4 | 17 | 3 | 9 | Yes (11) | 22 | Hepatic transaminitis, hyperbilirubinemia coagulopathy, renal insufficiency, hypoxia | AST = 1096 ALT = 109 T. bili = 7.0 Ferritin = 590 100 | Developed gram-negative sepsis following carHLH onset, leading to multiorgan failure, new onset cytopenias, fever | Steroids (21 d) | — | Multi-organ failure with concurrent bacteremia | ICU for hypotension with CRS (2 d); subesquent ICU transfer for multiorgan failure due to concurrent sepsis (21 d) | Died of complication of sepsis (carHLH resolving) |
| 18 | 2 | 7 | Yes (11) | 14 | Hepatic transaminitis, coagulopathy, hypoxia, hemophagocytosis | AST = 1293 ALT = 428 T. Bili = 0.7 Ferritin = 162 454 | + concerns for CAR neurotoxicity | Steroids‡ (5 d) | — | Persistent/worsening signs of inflammatory response | ICU for mental status changes associated with CRS (4 d) | Full resolution with treatment; proceeded to HSCT | ||
| 19|| | 2 | 7 | Yes (9) | 15 | Hyperbilirubinemia, hypoxia, hemophagocytosis, coagulopathy | AST = 215 ALT = 231 T. Bili = 3.7 Ferritin = 881 29 | — | Steroids‡ (9 d) | Anakinra (11 d) | Persistent/worsening signs of inflammatory response | — | Full resolution with treatment; proceeded to HSCT | ||
| 20 | 2 | 8 | Yes (12) | 15 | Hepatic transaminitis, hyperbilirubinemia, hypoxia, hemophagocytosis, coagulopathy | AST = 806 ALT = 313 T. bili = 3.5 Ferritin = 319 290 | — | Steroids‡ (15 d) | Anakinra (9 d) | Persistent/worsening signs of inflammatory response | ICU for hypertension (4 d) | Full resolution with treatment | ||
| 5 | 1 | 21 | 1 | 6 | Yes (9) | 12 | Hepatic transaminitis, coagulopathy, pulmonary manifestations, renal insufficiency | AST = 406 ALT = 188 T. bili = 3.8 Ferritin = 419 380 | Hypertension, respiratory distress, pulmonary infiltrates on radiologic evaluations with oxygen requirement. | Steroids‡ (prolonged ≥3 mo) | Anakinra (prolonged >1 mo) | Persistent/worsening signs of inflammatory response | ICU for hypertension requiring nicardipine drip, respiratory distress requiring BiPAP (27 d) | Full resolution with treatment (protracted course) |
| Minor criteria* . | n . | Pt . | Peak CRS Gr . | Day of CRS onset . | Toci use (d) . | Day of carHLH onset . | CarHLH manifestations meeting definition . | Pertinent labs (peak values) . | Additional findings . | Steroid utilization (duration, d)† . | Anakinra for carHLH (duration, d) . | Indication for initiation of carHLH therapy . | ICU Utilization (duration, d) . | Outcome . |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 2 | 7 | 1 | 1 | 8 | No | 25 | Hepatic transaminitis, coagulopathy | AST = 320 ALT = 304 T. bili = 0.7 Ferritin = 124 200 | — | — | — | — | — | Full resolution without intervention |
| 2 | 3 | 8 | Yes (10) | 14 | Hepatic transaminitis, coagulopathy | AST = 263 ALT = 100 T. bili = 0.7 Ferritin = 194 210 | — | Steroids* (1 d) | – | — | ICU for hypotension & tachycardia associated with CRS (3 d) | Full resolution without intervention. (*Steroids given for 24 h specifically for neurotoxicity associated with CRS) | ||
| 3 | 2 | 10 | No | 17 | Hepatic transaminitis, coagulopathy | AST = 382 ALT = 190 T. bili = 0.6 Ferritin = 232 350 | Persistent fevers, new onset cytopenias | Steroids‡ (2 d) | — | Persistent/worsening signs of inflammatory response | ICU for hypotension associated with CRS (2 d) | Full resolution with treatment | ||
| 4 | 1 | 10 | Yes (15) | 16 | Hepatic transaminitis, hyperbilirubinemia, coagulopathy | AST = 358 ALT = 545 T. bili = 4.2 Ferritin = 422 950 | Fever, hypertension | Steroids‡ (5 d) | — | Persistent/worsening signs of inflammatory response | — | Full resolution with treatment | ||
| 5 | 2 | 8 | No | 12 | Hepatic transaminitis, coagulopathy | AST = 390 ALT = 57 T. bili = 1.3 Ferritin = 194 800 | Acute kidney injury (grade 1) | — | — | — | — | Full resolution without intervention | ||
| 6 | 3 | 9 | Yes (11) | 14 | Hepatic transaminitis, hyperbilirubinemi, hemophagocytosis | AST = 477 ALT = 200 T. bili = 1.9 Ferritin = 174 890 | — | — | Anakinra (17 d) | Persistent/worsening signs of inflammatory response | ICU for monitoring with new decrease in EF prior to CRS (5 d) | Full resolution with treatment | ||
| 7 | 2 | 7 | Yes (8) | 10 | Hepatic transaminitis, coagulopathy | AST = 1464 ALT = 448 T. bili = 0.7 Ferritin = 349 750 | coinfection at CRS onset with b. cereus† | Steroids‡ (49 d) | Anakinra (35 d) | Persistent/worsening signs of inflammatory response | Transferred to ICU for CNS hemorrhage (>1 mo) | CNS hemorrhage (grade 4); carHLH resolving | ||
| 3 | 9 | 8 | 2 | 7 | No | 9 | Hepatic transaminitis, coagulopathy, hemophagocytosis | AST = 503 ALT = 251 T. bili = 0.7 Ferritin = 154 700 | — | — | — | — | ICU for hypotension & hypoxia associated with CRS (2 d) | Full resolution without intervention |
| 9 | 2 | 7 | Yes (10) | 10 | Hepatic transaminitis, hyperbilirubinemia, coagulopathy, hypoxia | AST = 762 ALT = 259 T. bili = 3.4 Ferritin = 430 340 | — | Steroids‡ (1 d) | — | — | ICU for fever, tachycardia and hypotension associated with CRS (4 d) | Full resolution with treatment, proceeded to HSCT | ||
| 10 | 3 | 4 | Yes (6) | 7 | Hepatic transaminitis, coagulopathy, hypoxia | AST = 1483 ALT = 634 T. bili = 0.6 Ferritin = 303 790 | Hypertension | Steroids‡ (31 d) | — | Persistent/worsening signs of inflammatory response | ICU for hypotension & hypoxia associated with CRS (8 d) | Full resolution with treatment | ||
| 11 | 1 | 6 | Yes (9) | 10 | Hepatic transaminitis, coagulopathy, hemophagocytosis | AST = 660 ALT = 1670 T. bili = 1.1 Ferritin = 187 280 | — | Steroids (8 d)† | Anakinra (24 d)§ | Persistent/worsening signs of inflammatory response | — | Full resolution with treatment | ||
| 12 | 2 | 7 | Yes (11) | 18 | Hepatic transaminitis, coagulopathy, hemophagocytosis | AST = 631 ALT = 759 T. bili = 1.4 Ferritin = 208 020 | Hypertension | Steroids (7 d) | — | Persistent/worsening signs of inflammatory response | — | Full resolution with treatment | ||
| 13 | 3 | 5 | Yes (7) | 11 | Hypoxia, hyperbilirubinemia, hemophagocytosis | AST = 64 ALT = 64 T. bili = 2.6 Ferritin = 218 680 | Had concurrent progressive CD22 neg disease | Steroids (>25 d) | — | Persistent/worsening signs of inflammatory response | ICU for hypotension & hypoxia associated with CRS (8 d) | Full resolution with treatment, received interim anti-leukemia therapy and went to HSCT | ||
| 14 | 3 | 5 | Yes (5) | 9 | Hepatic transaminitis, hyperbilirubinemia coagulopathy, renal insufficiency | AST = 846 ALT = 184 T. bili = 6.6 Ferritin = 271 600 | Fevers | Steroids‡ (>2 mo) | Anakinra (prolonged >1 mo) | Persistent/worsening signs of inflammatory response | ICU for hypotension associated with CRS, developed renal insufficiency (14 d) | Full resolution with treatment, proceeded to HSCT | ||
| 15 | 2 | 5 | Yes (18) | 18 | Hepatic transaminitis, coagulopathy, hemophagocytosis | AST = 1336 ALT = 557 T. bili = 0.9 Ferritin = 565 510 | Fevers | Steroids‡ (41 d) | Anakinra (prolonged >1 mo) | Persistent/worsening signs of inflammatory response | ICU for persistent fever & tachycardia associated with CRS (3 d) | Full resolution with treatment; proceeded to HSCT | ||
| 16 | 2 | 5 | Yes (10) | 14 | Hepatic transaminitis, hypoxia, coagulopathy | AST = 568 ALT = 290 T. bili = 0.7 Ferritin ≥100 000 | Hypertension | Steroids‡ (43 d) | Anakinra (∼1 mo) | Persistent/worsening signs of inflammatory response | — | Full resolution with treatment; proceeded to HSCT | ||
| 4 | 4 | 17 | 3 | 9 | Yes (11) | 22 | Hepatic transaminitis, hyperbilirubinemia coagulopathy, renal insufficiency, hypoxia | AST = 1096 ALT = 109 T. bili = 7.0 Ferritin = 590 100 | Developed gram-negative sepsis following carHLH onset, leading to multiorgan failure, new onset cytopenias, fever | Steroids (21 d) | — | Multi-organ failure with concurrent bacteremia | ICU for hypotension with CRS (2 d); subesquent ICU transfer for multiorgan failure due to concurrent sepsis (21 d) | Died of complication of sepsis (carHLH resolving) |
| 18 | 2 | 7 | Yes (11) | 14 | Hepatic transaminitis, coagulopathy, hypoxia, hemophagocytosis | AST = 1293 ALT = 428 T. Bili = 0.7 Ferritin = 162 454 | + concerns for CAR neurotoxicity | Steroids‡ (5 d) | — | Persistent/worsening signs of inflammatory response | ICU for mental status changes associated with CRS (4 d) | Full resolution with treatment; proceeded to HSCT | ||
| 19|| | 2 | 7 | Yes (9) | 15 | Hyperbilirubinemia, hypoxia, hemophagocytosis, coagulopathy | AST = 215 ALT = 231 T. Bili = 3.7 Ferritin = 881 29 | — | Steroids‡ (9 d) | Anakinra (11 d) | Persistent/worsening signs of inflammatory response | — | Full resolution with treatment; proceeded to HSCT | ||
| 20 | 2 | 8 | Yes (12) | 15 | Hepatic transaminitis, hyperbilirubinemia, hypoxia, hemophagocytosis, coagulopathy | AST = 806 ALT = 313 T. bili = 3.5 Ferritin = 319 290 | — | Steroids‡ (15 d) | Anakinra (9 d) | Persistent/worsening signs of inflammatory response | ICU for hypertension (4 d) | Full resolution with treatment | ||
| 5 | 1 | 21 | 1 | 6 | Yes (9) | 12 | Hepatic transaminitis, coagulopathy, pulmonary manifestations, renal insufficiency | AST = 406 ALT = 188 T. bili = 3.8 Ferritin = 419 380 | Hypertension, respiratory distress, pulmonary infiltrates on radiologic evaluations with oxygen requirement. | Steroids‡ (prolonged ≥3 mo) | Anakinra (prolonged >1 mo) | Persistent/worsening signs of inflammatory response | ICU for hypertension requiring nicardipine drip, respiratory distress requiring BiPAP (27 d) | Full resolution with treatment (protracted course) |
ALT, alanine aminotransferase (U/L); AST, aspartate aminotransferase (U/L); Gr, grade; CRS, cytokine release syndrome (graded as per ASTCT consensus criteria); ferritin reported as µg/L; T.bili, total bilirubin (mg/dL).
Minor criteria include: hepatic transaminase levels ≥grade 3 or bilirubin ≥grade 3, pulmonary manifestations ≥grade 3 (eg, edema or hypoxia), Renal insufficiency ≥grade 3, coagulopathy, evidence for hemophagocytosis on a bone marrow evaluation.
Treatment does not distinguish when steroid utilization was for typical CRS alone or initiated only for CarHLH, given that carHLH is an extension of CRS, therefore accounting for a discrepancy between our prior publication in Shah et al16; however, among those with steroid utilization the majority received only short course steroids, and anakinra was initiated specifically for treatment of evolution of carHLH symptomatology in 7 patients.
Steroids initiated for treatment of CRS.
Received anakinra alone for carHLH at a later time point.
Subject was given anakinra to prevent further deterioration of clinical status in context of clinical picture consistent with carHLH, prior to ferritin reaching 100 000 ug/(preemptive). However, due to otherwise indistinguishable clinical appearance prior to intervention and up-trending ferritin at time of anakinra administration, patient was classified as carHLH positive for purposes of all analyses.