B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA CASE

  • initial remission w/ chemo but quickly followed by skin and marrow relapse <- this is unusual/aggressive
  • blinatumumab and inotuzumab w/o response
  • leukemic lesions in skin
  • (CAR)T-cell targeting CD-19 and CD-22 with refractory/relapsed B-cell lymphoma or ALL
  • relapses long-term outcomes are 10% of event-free probability (generalized badness outcome?)
  • rec’d lymphodepletion the followed by CAR T cells = day 0
  • Day+4 he developed hypoxemia req’ing HFNC c/w Grade 3 CRS
    • rec’d tocilizumab 8mg/kg x1 and dexamethasone 10mg x1
  • this pt case developed CRS 2/2 large population of the CAR T cells (see pic below) where 92% of his cells were CAR T cells:

rituximab targets CD-20

  • naked antibody targeting CD-20

AB-DRUG CONJUGATES IS THE NEW METHOD

  • inotuzumab approved for ALL
    • links anti-CD-22 Ab to chemotx
  • blinatumomab
    • one side CD-3 binds to T-cell; the other side binds CD-19 on surface of B-ALL

drug is the mainstay -> the problem is that remission is not durable

(CAR)T-CELL

  • living therapy of the pt’s own immunity
  • durable
  • pt’s own T-cells usually
  • engineered to recognize tumor Ag of interest
    • different than BMT since that is taking someone else’s immunity and using for the pt
  • T-cell’s req ag presentation to get activated
  • (CAR)T-cells have receptor specific for the tumor ag of interest
    • most commonly they’re CD-19 for B-cell malignancies
    • the CAR can then recognize the tumor cell
    • then, the CAR T cell multiplies, releasing cytokines leading to tumor apoptosis
  • CAR are living therapy; the CAR can live and persist in the body, continuing to provide ongoing assassination of tumors

STEPS TO CAR T CELL THERAPY

  1. removal of T cells via apheresis
  2. T cells are engineered to express the CAR <- 2-6 weeks sometimes for the cells to grow
  3. infusion of the T cells into the pt

TRIALS FOR CAR T-CELLS IN ALL AND DLBCL

  • Tisagenlecleucel is anti-CD19 chimeric antigen receptor
    • Maude N Engl J Med 2018
  • 2017 was the first lay press for ALL CAR T cell for pediatrics; then, followed FDA approval to age of 26 for diffuse large B-cell lymphoma

CYTOKINE RELEASE SYNDROME (CRS)

  • hallmark of CAR therapy
  • supraphysiologic response following immunotherapy
    • hypotension
    • fever
    • capillary leak
  • the peak of CAR T cells after infusion is approx D+7; this correlates with the peak of the inflammatory cytokines and markers (also, D+7)
  • Grade 1 = supportive care
  • Grade 2 = tocilizumab -> IL-6 antagonist FDA approved in 2017 for the treatment of CAR T associated CRS
  • Grade 3 = tocilizumab + steroids (typically, dexamethasone 10mg q6) and alert ICU
  • Grade 4 = methylprednisolone 1g x3

CRS Grading Scale.png

PROBLEMS WITH TOCILIZUMAB/IL-6

  • there’s some areas of the body w/o IL-6 receptors (e.g., the brain)
  • potential for the body to upregulate the IL-6 in the brain causing more severe picture

ANAKINRA/IL-1 ANTAGONIST

  • FDA indication currently is rheumatoid arthritis

SILTUXIMAB/IL-6 ANTIBODY

  • FDA indication is Castleman’s disease

ADVERSE REACTIONS FROM CAR T CELLS/THE IMMUNE EFFECTOR CELLS ASSOCIATED NEUROTOXICITY (ICANS)

  • generally, encephalopathy and delirium, HA, sleep disorder
  • Stanford approach is multi-disciplinary
  • generally, the only intervention other than anti-IL drugs is steroids

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