Figure 2.
Representative series of carHLH manifestations in select patients. (A) Subject develops grade 1 CRS on day +8 following CD22 CAR T-cell infusion and was treated with supportive care only, without pharmaceutical intervention. Despite full resolution of manifestations at the time, he progresses to develop hyperferritinemia and transaminitis, corresponding with carHLH, but was otherwise systemically well without evidence for fever/hypotension. Cytokine profiling reveals a secondary peak of IFNγ, MIP-1α, and IL-8, but IL-6 remains low. Bone marrow at restaging demonstrates an MRD− complete remission with evidence for increased macrophages without hemophagocytosis. Left image: modified Giemsa stain (50 ×/10, oil lens) of bone marrow aspirate shows increased macrophages. Right image: CD163 immunohistochemical staining of bone marrow core biopsy (brown) highlights increased macrophages, some containing hemosiderin; no hemophagocytosis present (counterstained with hematoxylin). (B) Subject develops CRS on day +10 following CAR T-cell infusion, reaches max CRS grade 2. CRS manifestations (fevers) were resolving without intervention of tocilizumab or steroids, and corresponding cytokine profiling reveals rise and fall in all 4 cytokines that are profiled. In the context of CRS, carHLH symptoms start to manifest. Ferritin progressively increases followed by transaminitis prompting brief steroid utilization (<48 hours), leading to resolution of manifestations (some of which were already declining), however was given in the context of worsening cytopenias (not shown). Again, a secondary peak of select cytokines, including IFNγ, MIP-1α, and IL-8 is seen, but IL-6 remains low. Bone marrow at restaging demonstrates an MRD-negative complete remission with evidence for increased macrophages without hemophagocytosis. Modified Giemsa stain (50 ×/10, oil lens) of bone marrow aspirate shows 2 macrophages, of which 1 contains hemosiderin pigment (left); CD163 immunohistochemical staining of bone marrow core biopsy (brown) highlights increased macrophages in a hypocellular marrow. No hemophagocytosis present (counterstained with hematoxylin). (C) Subject develops CRS on day +5 and has several days of fever and an initial rise in cytokines (max CRS grade 2) with resolution. However, 48 hours later there is a recrudescence of fevers and with ongoing and higher fevers, tocilizumab and subsequently steroids are administered. In this more complicated patient, fever is ongoing with the onset of carHLH, showing an example where manifestations clearly overlap. However, elevations in ferritin mirror elevations in IFNγ (samples upper limit was 2860 pg/mL, and diluted levels were substantially higher). Bone marrow at restaging demonstrates a very hypocellular marrow with an MRD− complete remission with evidence for active hemophagocytosis (which resolved on a subsequent evaluation). Left image: modified Giemsa stain (50 ×/10, oil lens) of bone marrow aspirate shows hemophagocytic macrophages; right image: CD163 immunohistochemical staining of bone marrow core biopsy (brown) highlights increased macrophages with hemophagocytosis (counterstained with hematoxylin).

Representative series of carHLH manifestations in select patients. (A) Subject develops grade 1 CRS on day +8 following CD22 CAR T-cell infusion and was treated with supportive care only, without pharmaceutical intervention. Despite full resolution of manifestations at the time, he progresses to develop hyperferritinemia and transaminitis, corresponding with carHLH, but was otherwise systemically well without evidence for fever/hypotension. Cytokine profiling reveals a secondary peak of IFNγ, MIP-1α, and IL-8, but IL-6 remains low. Bone marrow at restaging demonstrates an MRD− complete remission with evidence for increased macrophages without hemophagocytosis. Left image: modified Giemsa stain (50 ×/10, oil lens) of bone marrow aspirate shows increased macrophages. Right image: CD163 immunohistochemical staining of bone marrow core biopsy (brown) highlights increased macrophages, some containing hemosiderin; no hemophagocytosis present (counterstained with hematoxylin). (B) Subject develops CRS on day +10 following CAR T-cell infusion, reaches max CRS grade 2. CRS manifestations (fevers) were resolving without intervention of tocilizumab or steroids, and corresponding cytokine profiling reveals rise and fall in all 4 cytokines that are profiled. In the context of CRS, carHLH symptoms start to manifest. Ferritin progressively increases followed by transaminitis prompting brief steroid utilization (<48 hours), leading to resolution of manifestations (some of which were already declining), however was given in the context of worsening cytopenias (not shown). Again, a secondary peak of select cytokines, including IFNγ, MIP-1α, and IL-8 is seen, but IL-6 remains low. Bone marrow at restaging demonstrates an MRD-negative complete remission with evidence for increased macrophages without hemophagocytosis. Modified Giemsa stain (50 ×/10, oil lens) of bone marrow aspirate shows 2 macrophages, of which 1 contains hemosiderin pigment (left); CD163 immunohistochemical staining of bone marrow core biopsy (brown) highlights increased macrophages in a hypocellular marrow. No hemophagocytosis present (counterstained with hematoxylin). (C) Subject develops CRS on day +5 and has several days of fever and an initial rise in cytokines (max CRS grade 2) with resolution. However, 48 hours later there is a recrudescence of fevers and with ongoing and higher fevers, tocilizumab and subsequently steroids are administered. In this more complicated patient, fever is ongoing with the onset of carHLH, showing an example where manifestations clearly overlap. However, elevations in ferritin mirror elevations in IFNγ (samples upper limit was 2860 pg/mL, and diluted levels were substantially higher). Bone marrow at restaging demonstrates a very hypocellular marrow with an MRD− complete remission with evidence for active hemophagocytosis (which resolved on a subsequent evaluation). Left image: modified Giemsa stain (50 ×/10, oil lens) of bone marrow aspirate shows hemophagocytic macrophages; right image: CD163 immunohistochemical staining of bone marrow core biopsy (brown) highlights increased macrophages with hemophagocytosis (counterstained with hematoxylin).

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