CAR T-Cell in Myeloma:Dealing with Adverse Events and Toxicities

Deepu Madduri, MDAssistant Professor of Medicine

Icahn School of Medicine at Mount SinaiTisch Cancer Institute

New York, NY

Biological Consequences Following Car T-cell Infusion

Orlowski et al. Br J Haematol 2016

Cytokine Release Syndrome (CRS)

• Supraphysiologic production of cytokines due to activation of the T-cells as well as other immune cells (monocytes, macrophages)– Murine models show macrophages amplify the severity of CRS and are the source of IL-6, IL-1, IFN-

γ and nitric oxide (NO)– Other Cytokines of importance include TNF-α, IL-2, IL-10, MCP-1, MIP

• CAR-T cells differ in the manufacture and CAR-T constructs resulting in different timing of activation and cytokine profiles

• CRS can start as early as day 1 or as late as day 7-10• Highest risk during first 10-14 days• Severity may correlate with dose of T-cells and tumor burden• Severity correlates with lab markers: CRP, ferritin, IL-6, and IFN-γ

Giavridis et al. Nat Med. 2018; 24:731Norelli et al. Nat Med. 2018; 24:739

CAR T-cells Complications

• Most important toxicity:– Cytokine release syndrome (CRS)– Neurotoxicity (ICANS)

• Tumor lysis syndrome – Related to tumor burden and response– Management is same as tumor lysis syndrome in other settings

• Cytoreduction related toxicities– Infections– Cytopenias (* may also be due to CAR-T)

• On target, off tumor toxicity– Tumor associated antigen expressed on normal tissues

Cytokine Release Syndrome Affects Multiple Organ Systems

Various CAR-T Grading Scales

Adapted from Porter, D et al. J of Hematology & Oncology 2018 11(18).

ASTCT CRS Grading

Lee et al. Biol Blood Marrow Transplant 25 (2019) 625-638.

CRS Parameters Grade 1 Grade 2 Grade 3 Grade 4

Fever ≥ 38.0 C ≥ 38.0 C ≥ 38.0 C ≥ 38.0 C

Hypotension NonePresent and or improved with IVF

Requiring one vasopressor +/-vasopressin

Requiring multiple vasopressors (vasopressin not counted)

Hypoxia None≤ 6 L/min O2 by nasal cannula or blow-by

> 6 L/min O2 by nasal cannula, face mask, non-rebreather mask, or Venturi mask

Requiring positive pressure (CPAP, BiPAP, mechanical ventilation)

CRS Management: One of Many Proposed Guidelines

Riegler et al, Ther Clin Risk Manag 2019; 15:323-335. (adapted from Neelapu et al, Nat Rev Clin Onc 2017)

Clinical Course

• 71-year old male with primary refractory MM• FC conditioning chemotherapy days -5 to -3• BCMA CAR-T cell infusion on day 1• Fevers started (T curve) on day 1 (4-6 hours post infusion) treated with acetaminophen• Fevers worsened with rapid rise in CRP on day +2, slight somnolence, severe fatigue,

tremor• Your next steps would be:

– IV Broad Spectrum Antibiotics– Acetaminophen– Tocilizumab– Steroid– Anakinra– All of the above

Clinical Course

• Toci given 8 mg/kg• On day+2 8 pm, significant improvement, high fevers disappeared, somnolence resolved;

Neuro exams/CARTOX-10 normal• Day+5 normal mentation during evening rounds, slight tremor in right hand• 6am day+6 pt with AMS, unable to speak in full sentences with delayed responses, unable

to write his daily sentence, fever 38• Your next steps would be:

– Tocilizumab– Steroid– Anakinra– All of the above

Patient CRS ICANS Toxicities Timeline

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Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Day 9 Day 10

Temperature

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10/01/19 10/02/19 10/03/19 10/04/19 10/05/19 10/06/19 10/07/19 10/08/19 10/09/19 10/10/19

CRP mg/L CRP mg/LTemperatureFerritin

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10/01/19 10/02/19 10/03/19 10/04/19 10/05/19 10/06/19 10/07/19 10/08/19 10/09/19 10/10/19

Column1Neurotoxicity

Tocilizumab Tocilizumab + decadron

CRS

Management of ICANS

• Tests– Baseline exam, encephalopathy (ICE) screening q shift– Post infusion screening with ICE and motor assessment 1-2x/day– Daily handwriting– MRI brain to look for cerebral edema– Consider lumbar puncture with opening pressure measurement

• Treatment– Grade 3 ICANS → corticosteroids: dexamethasone 10mg q 6 h, rapid taper over

3-5 days. Some intervene at grade 2 ICANS– Cytokine intervention : IL 1RA (Anakinra), direct IL6 blockade (Siltuximab)

• Seizure prophylaxis

CARTOX-10 vs. ICE

CARTOX Tool Immune-Effector Cell-Associated Encephalopathy (ICE) Tool

Orientation: orientation to year, month, city, hospital, president: 5 points

Orientation: orientation to year, month, city, hospital: 4 points

Naming: name 3 objects (e.g. point to clock, pen, button): 3 points

Naming: 3 objects (e.g. point to clock, pen, button): 3 points

Following Commands: (e.g. show me two fingers or close your eyes and stick out your tongue): 1 point

Writing: ability to write a standard sentence (e.g. our national bird is the bald eagle): 1 point

Writing: ability to write a standard sentence (e.g. our national bird is the bald eagle): 1 point

Attention: count backwards from 100 by ten: 1 point Attention: count backwards from 100 by ten: 1 point

* Replaces one of the orientation questions with a command following assessment, scoring unchanged

Lee et al. Biol Blood Marrow Transplant 25 (2019) 625-638.

Immune Cell-Associated Neurotoxicity Syndrome (ICANS)

Lee et al. Biol Blood Marrow Transplant 25 (2019) 625-638.

Neurotoxicity Domain Grade 1 Grade 2 Grade 3 Grade 4

ICE Score 7 - 9 3 - 6 0 - 2 0 (unarousable and unable to perform ICE)

Depressed Level of Consciousness

Awakensspontaneously

Awakens to voice Awakens only to tactile stimulus

Unarousable or requires vigorous, repetitive tactile stimulus. Stupor or coma.

Seizure N/A N/A Any clinical seizure, focal or generalized that resolves rapidly; non-convulsive seizure on EEG that resolves with intervention

Life-threatening prolonged seizure (>5 min); or repetitive clinical or electrical seizures without return to baseline in between.

Motor findings N/A N/A N/A Deep focal motor weakness such as hemiparesis or paraparesis

Raised ICP/cerebral edema

N/A N/A Focal/local edema on neuroimaging

Diffuse cerebral edema on neuroimaging; decerebrate or decorticate posturing; or cranial nerve VI palsy; or papilledema, or Cushing’s triad.

Tocilizumab Used for Initial CRS Management

• Tocilizumab is a humanized, immunoglobulin G1κ (IgG1κ) anti-human IL-6R mAb• Initially used for treatment of rheumatoid arthritis, now as of October 30, 2017,

approved for CAR-T induced CRS• Prevents IL-6 binding to both cell-associated and soluble IL-6Rs and therefore found to

prevent severe or life-threating CRS.• The recommended dose of tocilizumab is 8mg/kg with an option to repeat the dose if no

clinical improvement in symptoms within 24 to 48 hours.• Long half life so keep that in mind when repeating multiple doses especially if CRP is

down trending• Symptoms resolve within a few hours of administration

Corticosteroids as Second Line Agent for CRS

• Corticosteroids are generally considered second line therapy for CRS• Can have widespread effects on the immune system and can cause adverse effect on the

antitumor activity of adoptively transferred T cells.• So far, low dose steroids haven't been associated with negative responses • Dexamethasone 10 mg IV every 6 hours and/or methylprednisolone 1mg/kg/day and

occasionally 1 gm q day if severe refractory CRS

Anakinra as a Second Line or Third Line Agent for CRS

• Phase 1 CART19 in pediatric B-ALL– 0.5 – 10 x 10e6 CAR T cells/kg

• First 23 pts got toci +/- steroids only for DLT• Next 20 pts got toci +/- dex (5-10 mg q6-12hrs) if:

– Persistent temp ≥ 39 despite anti-pyretics for 10 hrs– Persistent/recurrent hypotension after initial fluid bolus– Any O2 supplementation

Late Toci Early Toci p value

All CRS 91% 95% ns

Got Toci 22% 50% 0.03

Got Steroids 17% 30% 0.5

Severe CRS 30% 15% 0.3

All Neuro 48% 50% ns

Severe Neuro 22% 25% ns

MRD- CR 91% 95% nsGardner et al, ASH 2016, #586

Infectious Prophylaxis with CAR-T

• No clear standard, our approach– Most patients are on acyclovir and continue this– If neutropenic then oral antibiotic prophylaxis and fungal prophylaxis– If neutropenic and febrile, broaden oral antibiotic prophylaxis to intravenous antibiotics– Initiate IVIG pre-lymphodepletion and continue monthly for the 1st 6 months

Growth Factor and Transfusion Supportive Care for CAR-T

• Data on growth factor support is unclear• Our approach has been

– Support with G-CSF if needed when neutropenic regardless of day of CAR-T– Hold off on adding any GM-CSF during the CAR-T cell therapy hospitalization– Transfuse per institutional guidelines, RBC transfusion if <7 (<8 if symptomatic), platelet

transfusion if <10,000

CAR-T is Done, What to Look Out for in Your Clinic?

• Pancytopenia– Could persist for months– Transfusions as needed– G-CSF for ANC < 500– Sargramostim as needed if severe cytopenias

• Hypogammaglobulinemia– IVIG pre lymphodepletion– Every month for 6 months and during winter months if

recurrent infections• Infections

– CMV PCR check q month– Viral panel and blood cultures, abx if fevers

• Vaccines schedule

Raje et al. Oral Presentation ASCO 2018

Conclusion

• CAR-T cell therapy is an up and coming strategy for a curative approach in multiple myeloma

• It is effective in inducing deep (MRD & PET neg) and durable responses in patients:– Chemo-refractory– High-risk genetics

• Toxicity profile is easily manageable