Highlights of ASH

Workshop
2nd of March 2024
3:00 PM – 5:00 PM
Conrad Hotel Dubai
Bispecifics: from
Data to Practice
Dr. Samar Ousia
 CD3xCD20 as a Potential Target in R/R B-cell NHL

• Specific and efficacious targeted agents that have manageable safety profiles can help bridge the treatment gap and
improve outcomes in patients with R/R B-NHL
• As CD20 is a validated target in the treatment of B-NHL, bsAbs that simultaneously target CD20 on tumor cells and
CD3 on T cells have demonstrated antitumor activity in patients with R/R B-cell NHL 1-3

Bispecifics in Clinical Development for B-cell NHL

Glofitamab Epcoritamab Mosunetuzumab Odronextamab

Agent
(CD20-TCB)3 (DuoBody®-CD3xCD20)4 (CD20-TDB)5,6 (REGN 1979)7

Company Roche/Genentech Genmab/AbbVie Roche/Genentech Regeneron

Route of administration IV SC IV and SC IV

B-NHL, B-cell non-Hodgkin lymphoma; bsAb, bispecific antibody; IV, intravenous; R/R, relapsed/refractory; SC, subcutaneous
1. Engelberts PJ, et al. EBioMedicine. 2020;52:102625. 2. Buhmann R, et al. J Transl Med. 2013;11:160. 3. Hutchings M, et al. J Clin Oncol. 2021;39(18):1959-70. 4. Hutchings M, et al. Lancet. 2021;398:1157-69.
5. Matasar MJ, et al. Presented at ASH 2020. [Abstract #2096]. 6. Olszewski AJ, et al. Presented at ASH 2020. [Abstract #401]. 7. Bannerji R, et al. Presented at ASH 2020. [Abstract #400].
 Epcoritamab Differentiation Safety: SC formulation and CRS with predictable onset
Epcoritamab has a manageable safety profile with SC administration revealing predictable, predominately
low-grade CRS events mostly occurring after the first full dose.
1
Predictable onset to ease management

Epcoritamab1 Glofitamab2
CRS Timing of CRS CRS Timing of CRS
100% 100%
Grade 1 Grade 2 Grade 3 Grade 4 Grade 1 Grade 2 Grade 3 Grade 4
90% 90%
80% 80%
63% C1
70% 70%
1%
60% 50% 60% 3% 54.5%
50% 50% 12%
3%
3%
40% 15% 13% 40% 30.4%
26.8%
30% 30%
47%
20% 20%
32% 2% 27% 2.0%
10% 1% 1% 2% 10% 0.9%
5% 10% 4%
0% 2% 0%
Overall Priming Inter 1st full 2nd full 3rd full+ Overall C1D8-14 C1D15-21 C2 C3 C4+
N=157 N=154

Time to onset from 1st full dose: 20 h Time to onset from C1D8: 13.6 h
Time to resolution: 2 days Time to resolution: --

Hospitalization: Dose 3 (1st full) Hospitalization: Dose 1

Thieblemont et al. EHA 2022. LBA 2364. Dickinson et al, EHA 2022. S220.
1 2
(potential dose 2 and 3)
Disclaimer: Caution must be taken with cross-trial comparisons due to differences in
treatment protocols and patient populations, as such, these comparisons are illustrative only.
No head-to-head trials have been conducted assessing the superiority of EPCO vs Glofit.
 CRS is an emerging AE within the bispecific class; developing a comprehensive
CRS management plan will be critical
Step Up First Full Post-
Conditioning
Doses Dose Treatment

Days 1,2,3,4 Steroids

(oral)*

EPCO 48 mg dose onward 14%

0.16 mg dose
Tocilizumab
0.8 mg dose CRS Onset (median onset Utilization
20 hours after first full dose)

Day 1 Steroids
Obinutuzumab and (IV)
prophylaxis
(steroids given with 20%
2.5 mg dose 30 mg dose onward Tocilizumab
Glofit first Obin dose)
Utilization
Obin Pre-Treatment: 10 mg dose
• long admin time
• ~20% Grade ≥3 AEs CRS Onset Legend Patient Potentially Hospitalized
Patient Hospitalized
(median onset 14 hours after
first step up dose – C1D8)

*IV steroid administration available as well

CRS diagnosis & Management
Mechanism of Action of T cell Engagers
CAR T Bispecific Antibody
Similarities
• Both CAR Ts and bsAbs bring
together T cells and B cells
• Interaction causes activation
of the T cell and release of
cytokines, granzyme, and
perforin
• Results in T cell mediated
killing of the tumor cell

Differences

CAR T therapy modifies the extracellular Bispecific antibodies induce effector

Binding
antigen-binding domain on T cells T cell binding to the tumor cell
CAR T therapies rely on ex vivo activated Bispecific antibodies use the patient’s
T-cell
and expanded T cells endogenous T cells
bsAb, bispecific antibody; CAR T, chimeric antigen receptor T-cell. Adapted from: Zhukovsky EA, et al. 2016;40:24-35.
 CRS Signs and Symptoms
Clinical manifestations of CRS range from:
Severe life-threatening
Mild, flu-like
to systemic inflammatory
symptoms
response syndrome (SIRS)

Early Signs Late Signs

Must include fever Severe fever (≥105°F; 40.5°C)
Fatigue Hypotension
Headache Capillary leak
Arthralgia Pulmonary edema
Myalgia Cardiac dysfunction
Multiorgan system failure

CRS symptoms can be progressive, must include fever at the onset,

and may include hypotension, capillary leak (hypoxia), and end organ dysfunction

CRS, cytokine release syndrome. Adapted from Kotch C, et al. Expert Rev Clin Immunol. 2019;15(8):813–822.
 CRS graded according to ASTCT consensus criteria

SYMPTOMS GRADE 1 GRADE 2 GRADE 3 GRADE 4

Fever* Temperature ≥ 38°C Temperature ≥ 38°C Temperature ≥ 38°C Temperature ≥ 38°C

WITH EITHER
Requiring 1 Requiring ≥ 2
Not requiring
Hypotension None vasopressor vasopressors,
vasopressors
(± vasopressin) excluding vasopressin

AND/OR
Requiring high-flow
Requiring low‑flow Requiring positive
Hypoxia †
None facemask, NC, NRB
oxygen pressure ventilation
mask, or Venturi mask

CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause ‡

*Fever is defined as temperature ≥ 38°C not attributable to any other cause, with or without constitutional symptoms (e.g., myalgia, arthralgia, malaise). In patients who have CRS receiving antipyretics,
anti-cytokine therapy, and/or corticosteroids, fever is no longer required to grade subsequent CRS severity. In this case, CRS grading is driven by hypotension and/or hypoxia.
†Low-flow nasal cannula is defined as oxygen delivered at ≤6 L/minute. Low flow also includes blow-by oxygen delivery, sometimes used in pediatrics. High-flow nasal cannula is defined as oxygen
delivered at >6 L/minute. Intubation of a patient without hypoxia for the possible neurologic compromise of a patent airway alone or for a procedure is not by definition grade 4 CRS.
‡For example, a patient with temperature of 39.5°C, hypotension requiring 1 vasopressor, and hypoxia requiring low-flow nasal cannula is classified as grade 3 CRS. Both systolic blood pressure (SBP)
and mean arterial pressure (MAP) are acceptable for blood pressure measurement. No specific limits are required, but hypotension should be determined on a case-by-case basis, accounting for age
and the patient’s individual baseline, i.e., a blood pressure that is below the normal expected for an individual in a given environment.
ASCTC, American society for transplantation and cellular therapy; CRS, cytokine release syndrome; NC, nasal cannula; NRB, non‐rebreather.
Adapted from Lee DW, et al. Biol Blood Marrow Transplant. 2019;25:625-638.
 CRS with CAR T and bispecific antibody therapies
100% 93% CAR T BsAbs
Patients with CRS, % 80%
58% 63%
60%
55% 50%
42%
40%

20%

0%
Axi-cel Liso-cel Tisa-cel Odronextamab Glofitamab Epcoritamab

Antipyretic + Antihistamine +
Antipyretic + Antihistamine
Prophylaxis Corticosteroid + Step-up Dosing
+ Corticosteroid* - - - + obinutuzumab -
Time to Onset,
CRS

4 5 3 Not reported 0.6 0.8

median (days)
Anticytokine therapy + Corticosteroids +
Management Anticytokine therapy + Corticosteroids
Interrupt therapy

Time to Resolution,
6 5 7 2 1.3 2
median (days)
Disclaimer: Caution must be taken with cross-trial comparisons due to differences in treatment protocols and patient populations – as such, these comparisons are illustrative only.
Consider the use of prophylactic corticosteroid in patients after weighing the potential benefits and risks.
Axi-cel, axicabtagene ciloleucel; CAR T, chimeric antigen receptor T-cell; CRS, cytokine release syndrome; Liso-cel, lisocabtagene maraleucel; Tisa-cel, Tisagenlecleucel.
Adapted from: 1. Thieblemont C, et al. J Clin Oncol. 2022:JCO2201725. 2. Kim SW, et al. Oral 444. ASH. Dec. 9-13, 2022. 3. Dickinson MJ, et al. N Engl J Med. 2022;387(24):2220-2231.
4. Neelapu. N Engl J Med. 2017. 5. Abramson JS, et al. Lancet. 2020;396(10254):839-8523. 6. Shuster SJ, et al. N Engl J Med. 2019;380(1):45-56.
 General CRS Prevention and Treatment Measures
Prevention
Priming dose
+ Corticosteroids &
antipyretic premedication
• Mitigation strategies to reduce severe CRS are commonly
used with bsAbs
• Step-up dosing reduces the risk of severe CRS
• Premedications are regularly employed with steroids,
antihistamines and acetaminophen or paracetamol
CRS management aims to prevent life-threatening toxicity while sustaining the antitumor effects of the immunotherapy.
BsAb=Bispecific Antibody. CAR-T=Chimeric Antigen Receptor T-cell. CRS=Cytokine Release Syndrome.
FDA=Food and Drug Administration. REMS=Risk Evaluation and Mitigation Strategy.
Salvaris R, et al. Journal of Personalized Medicine. 2021;11(5):355.
Treatment
Interrupt treatment
+ Anticytokine therapy
and/or corticosteroids
• Mild grade 1 CRS is managed with supportive therapy including
infusion discontinuation, IV fluids, antipyretics and antihistamines
• Tocilizumab, an anti IL-6 monoclonal antibody, is the mainstay of
treatment for grade 2 or higher CRS
 Tocilizumab does not efficiently penetrate the blood–brain
barrier and so corticosteroids are used in cases with
significant neurotoxicity or co-existing ICANS
 Alternative options to tocilizumab, such as siltuximab and
anakinra, are also available
 Epcoritamab CRS Prophylaxis and Premedication
Corticosteroids†‡ Antihistamines† Antipyretics†
1st epco Day 1* prednisolone 100 mg IV or PO diphenhydramine 50 mg IV or PO acetaminophen 650 to 1000 mg PO
administration
(priming dose) Days 2-4 prednisolone 100 mg IV or PO

2nd epco Day 8* prednisolone 100 mg IV or PO diphenhydramine 50 mg IV or PO acetaminophen 650 to 1000 mg PO

administration
Cycle 1

(int. dose) Days 9-11 prednisolone 100 mg IV or PO

3rd epco Day 15* prednisolone 100 mg IV or PO diphenhydramine 50 mg IV or PO acetaminophen 650 to 1000 mg PO
administration
(full dose) Days 16-18 prednisolone 100 mg IV or PO

4th epco Day 22* prednisolone 100 mg IV or PO diphenhydramine 50 mg IV or PO acetaminophen 650 to 1000 mg PO
administration
(full dose) Days 23-25 prednisolone 100 mg IV or PO
Cycle 2+

If CRS ≥ grade 2 occurs following the 4th epcoritamab optional, based on whether prior injection optional, based on whether prior
epco Day 29* reactions observed injection reactions observed
administration, 4-day consecutive corticosteroids must also be
administration
repeated for CRS prophylaxis with each epcoritamab dose, until 1 full
(full dose) Day 30-32
dose is administered without subsequent occurrence of CRS grade ≥2.

Premedication with corticosteroids, antihistamines, and antipyretics are mandatory during cycle 1,
and optional during cycle 2 unless CRS grade ≥2 occurs.
*GCT3013-01 and -05: 30 minutes to 2 hours prior to administration of epcoritamab; GCT3013-02: Prior to administration of epcoritamab. †Or dose equivalent.
‡GCT3013-01 and -05: corticosteroids may be reduced to 80 mg to mitigate possible side effects from high dose steroid administration.
IV=Intravenous. PO=Oral. GCT3013-01, GCT3013-02, GCT3013-05 Protocol.
 CRS Grading and Management Guidance
1 Assess for CRS and grade according to ASTCT consensus criteria
SYMPTOMS* GRADE 1 GRADE 2 GRADE 3 GRADE 4
Fever Temperature ≥ 38°C Temperature ≥ 38°C Temperature ≥ 38°C Temperature ≥ 38°C
WITH EITHER
Requiring 1 vasopressor Requiring ≥ 2 vasopressors,
Hypotension None Not requiring vasopressors
(± vasopressin) excluding vasopressin
AND/OR
Requiring high-flow facemask, NC, Requiring positive pressure
Hypoxia None Requiring low‑flow oxygen
NRB mask, or Venturi mask ventilation

*CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause
2 Manage according to CRS grade
Hold
EPCORITAMAB Hold Hold Discontinue if lasts >72h or Discontinue
if 2 events

SUPPORTIVE CARE Provide supportive care such as antipyretics and intravenous hydration
Consider Recommend:
ANTICYTOKINE THERAPY Tocilizumab† 8 mg/kg IV over 1h (not to exceed 800 mg)‡
†In case of concurrent ICANS/neurotoxicity, Tocilizumab †
choose alternative to tociluzumab in certain cases# If CRS is refractory:
Alternative immunosuppressants

Dexamethasone Dexamethasone Start Dexamethasone 10-20 mg IV every 6 h

10-20 mg per day 10-20 mg per day
CORTICOSTEROIDS should be considered
may be initiated
If CRS is refractory: Methylprednisolone 1000 mg/day

TEPKINLY® (epcoritamab).
‡Repeat after at least 8h as needed, max 2 doses in 24h. #Advanced age, high tumour burden, circulating tumour cells, fever refractory to antipyretics Gulf SmPC, Sept 2023.
ICANS Identification & Management
 ICANS Pathophysiology
1 Tumor Environment
ICANS may start with the production
1 2 3
of pro-inflammatory cytokines and
the activation of bystander immune
cells in the tumor microenvironment

2 Blood Stream
Inflammatory cytokines diffuse into
the blood stream and result in
disruption of the BBB

3 CNS
Cytokines can then cross the BBB
causing deleterious activation of
microglia and subsequent neuronal
damage

Despite the clinical features of ICANS being readily recognizable, its pathophysiology remains poorly understood; however,
pro-inflammatory cytokines, disrupted blood brain barrier, and neuronal injury are all implicated in the syndrome.

BBB, blood brain barrier; CAR T, chimeric antigen receptor;

CNS, central nervous system; ICANS, immune effector cell-associated neurotoxicity syndrome. Adapted from Morris EC, et al. Nature Reviews Immunology. 2021:1-2.
 ICANS Signs and Symptoms
Clinical manifestations of ICANS range from:
Expressive aphasia is a
Mild very specific symptom of
neurological to Severe neurotoxicity ICANS developing in 86% of
patients who went on to
symptoms develop severe neurotoxicity. 2

Early Signs Late Signs

Expressive aphasia Global aphasia
Dysgraphia Obtundation
Tremor Stupor
Impaired attention Coma
Apraxia Seizure
Lethargy Cerebral edema
Headache

ICANS typically develops within 10 days of immune therapy usually occurring in the context of CRS;
however, CRS is not required for ICANS and the syndromes can occur independently. 3
Adapted from: 1. Lee DW, et al. Biology of Blood and Marrow Transplantation. 2019;25(4):625-38.
2. Santomasso BD, et al. Cancer discovery. 2018;8(8):958-71.
CRS, cytokine release syndrome; ICANS, immune effector cell-associated neurotoxicity syndrome. 3. UpToDate: ICANS - accessed February 2022.
ICANS graded according to ASTCT consensus criteria
Patients are graded 1 to 4 according to the most severe symptom attributable to ICANS in five domains.
DOMAIN GRADE 1 GRADE 2 GRADE 3 GRADE 4
ICE score 0 (patient unable to
ICE score* ICE score 7 – 9 ICE score 3 – 6 ICE score 0 – 2
perform ICE)
Unarousable, requires vigorous,
Level of
Awakens spontaneously Awakens to voice Awakens only to tactile stimuli or repetitive tactile stimuli to
consciousness
arouse
Clinical seizure that resolves Life-threatening prolonged seizure
rapidly or non-convulsive seizures or repetitive clinical or electrical
Seizure
on EEG that resolve with seizures without return to baseline
intervention in between
Diffuse cerebral edema,
decerebrate or decorticate
ICP / cerebral edema Focal / local edema
posturing, cranial nerve VI palsy,
papilledema, Cushing’s triad
Deep focal motor weakness such
Motor findings
as hemiparesis or paraparesis

*ICE Score Definitions

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

Naming Ability to name 3 objects (eg, point to clock, pen, button) 3 points

Following commands Ability to follow simple commands (eg, “show me 2 fingers” or “close your eyes and stick out your tongue”) 1 point

Writing Ability to write a standard sentence 1 point

Attention Ability to count backwards from 100 by 10 1 point

If patient is unarousable and unable to perform ICE assessment 0 points

ASCTC, American society for transplantation and cellular therapy; ICANS, immune effector cell-associated neurotoxicity syndrome; Adapted from
ICE, impact, confidence, ease; ICP, intercranial pressure. Lee DW, et al. Biol Blood Marrow Transplant. 2019;25:625-638.
 ICANS with CAR T and bispecific antibody therapies
CAR T BsAbs
Patients with ICANS, % 100%

80%
64%
60%

40% 30%
21%
20%
3% 8% 6%
0%
Axi-cel Liso-cel Tisa-cel Odronextamab Glofitamab Epcoritamab

Time to Onset,
9 9 6 Not reported Not reported Not reported
median (days)

Anti-seizure medications Anti-seizure medications

ICANS

Management Corticosteroids Corticosteroids

Cyclophosphamide*

Time to Resolution,
7 11 14 Not reported Not reported Not reported
median
Disclaimer: (days)
Caution must be taken with cross-trial comparisons due to differences in treatment protocols and patient populations – as such, these comparisons are illustrative only.
*For grade 4 ICANS.
Axi-cel, axicabtagene ciloleucel; CAR T, chimeric antigen receptor T-cell; ICANS, immune effector cell-associated neurotoxicity syndrome; Liso-cel, lisocabtagene maraleucel; Tisa-cel, Tisagenlecleucel.
Adapted from: 1. Thieblemont C, et al. J Clin Oncol. 2022:JCO2201725. 2. Kim SW, et al. Oral 444. ASH. Dec. 9-13, 2022. 3. Dickinson MJ, et al. N Engl J Med. 2022;387(24):2220-2231.
4. Neelapu. N Engl J Med. 2017. 5. Abramson JS, et al. Lancet. 2020;396(10254):839-8523. 6. Shuster SJ, et al. N Engl J Med. 2019;380(1):45-56.
 ICANS Treatment
Typical treatment
Glucocorticoids Antiseizure medication

+
• Glucocorticoids are an important component in the supportive • Patients with ICANS are at increased risk for seizures
management of ICANS; however, the optimal timing, dosing, and
• Antiseizure medication should be given to most patients with
duration are not established
suspected ICANS at initial presentation with neurologic symptoms.
• Treatment decisions are often influenced by concomitant CRS
• Prophylactic therapy is also reasonable for patients deemed at
• Administration should begin in grade ≥ 2 ICANS high risk for seizures

Refractory edema
• Refractory cerebral edema with acutely
increasing intracranial pressure (ICP) is a
neurologic emergency
• If edema progresses rapidly despite steroids,
patients require aggressive osmotic
therapies to lower ICP
Other considerations
Tocilizumab Investigational therapies
• Novel approaches to block inflammatory
• In patients with ICANS who do not have
cytokines are under investigation, including:
concurrent CRS, there is no role
for tocilizumab  IL-6 blockade with siltuximab
• For patients with moderate to severe CRS  IL-1 blockade with anakinra
with or without ICANS, tocilizumab +  GM-CSF neutralization with lenzilumab
glucocorticoids is typically given

Treatment of ICANS is supportive and consists primarily of glucocorticoids and antiseizure therapy.
CRS=Cytokine Release Syndrome. ICANS=Immune Effector Cell-Associated Neurotoxicity Syndrome. ICP=Intracranial Pressure.
UpToDate: ICANS - accessed February 2022.
 Epcoritamab Guidance for ICANS Management Based on ASTCT Guidelines

ICANS Grade 1 ICANS Grade 2 ICANS Grade 3 ICANS Grade 4

and/
Supportive Care Anticytokine Therapy or Corticosteroids

Hold epcoritamab until resolution of event. No concurrent CRS: Dexamethasone 10 mg IV every

• Anticytokine therapy not 12 hours
Supportive care per institutional SoC (antipyretics and IV indicated
hydration)
Concurrent CRS: choose alternative
to tocilizumab if possible:
Aspiration precautions
• Anakinra 100 mg or 200 mg SC
Closely monitor neurologic status per day (100 mg every 12 h) until
resolution of neurotoxicity
Prophylactic non-sedating anti-seizure medication until • Siltuximab 11 mg/kg IV over 1
resolution of event hour, one time only

Brain imaging and EEG

Please contact the study medical director for specific questions.

GCT3013-01, GCT3013-02, GCT3013-05, M20-638 Protocol.

 Epcoritamab Guidance for ICANS Management Based on ASTCT Guidelines

ICANS Grade 1 ICANS Grade 2 ICANS Grade 3 ICANS Grade 4

and/
Supportive Care Anticytokine Therapy or Corticosteroids

Hold epcoritamab until resolution of event. No concurrent CRS: Dexamethasone 10 - 20 mg IV every

• Anticytokine therapy not 12 hours
Supportive care per institutional SoC indicated

Concurrent CRS: choose alternative

Aspiration precautions
to tocilizumab if possible:

Closely monitor neurologic status with serial neurologic exams • Anakinra 100 mg or 200 mg SC
to include fundoscopy and consider neurology consult per day (100 mg every 12 h) until
resolution of neurotoxicity
Prophylactic non-sedating anti-seizure medication until • Siltuximab 11 mg/kg IV over 1
resolution of event hour, one time only

Perform brain imaging (e.g., MRI), EEG, and lumbar puncture

Continuous cardiac telemetry and pulse oximetry as indicated

Please contact the study medical director for specific questions.

GCT3013-01, GCT3013-02, GCT3013-05, M20-638 Protocol.

 Epcoritamab Guidance for ICANS Management Based on ASTCT Guidelines

ICANS Grade 1 ICANS Grade 2 ICANS Grade 3 ICANS Grade 4

and/
Supportive Care Anticytokine Therapy or Corticosteroids

Permanently discontinue epcoritamab at the first * or No concurrent CRS: Dexamethasone 10 - 20 mg IV every

second† episode depending on protocol • Anticytokine therapy not 6 hours
indicated If no response, initiate
Management in monitored care or ICU methylprednisolone 1000 mg/day
Concurrent CRS: choose alternative
Supportive care per institutional SoC to tocilizumab if possible:
• Anakinra 100 mg or 200 mg SC
Aspiration precautions per day (100 mg every 12 h) until
resolution of neurotoxicity
Closely monitor neurologic status with serial neurologic exams
to include fundoscopy and consider neurology consult • Siltuximab 11 mg/kg IV over 1
hour, one time only
Prophylactic non-sedating anti-seizure medication until
resolution

Perform brain imaging (e.g., MRI), EEG, and lumbar puncture

Continuous cardiac telemetry and pulse oximetry as indicated Please contact the study medical director for specific questions.
*In the GCT3013-01, -02, and -05 protocols, epcoritamab is permanently discontinued at the first episode of Grade 3 ICANS.
†In the M20-638 protocol, epcoritamab is held until resolution of the first episode of Grade 3 ICANS. For second episode, epcoritamab is permanently discontinued at the discretion of the investigator.
GCT3013-01, GCT3013-02, GCT3013-05, M20-638 Protocol.
 Epcoritamab Initiation: Recommendations for ICANS Grading and Management

ICANS GRADE 1 GRADE 2 GRADE 3 GRADE 4

EPCORITAMAB Hold Hold Discontinue Discontinue

SUPPORTIVE CARE Consider non-sedating anti-seizure medication (eg, levetiracetam) until resolution of ICANS

If no concurrent CRS: If concurrent CRS:

ANTICYTOKINE THERAPY not recommended choose immunosuppressant alternative to tocilizumab if possible

Dexamethasone Dexamethasone 10-20 mg IV every 6h

CORTICOSTEROIDS 10 mg IV every 12h,
up to 20 mg IV every 12h If no response initiate Methylprednisolone 1000 mg/d IV

CRS, cytokine release syndrome; ICANS, immune effector cell associated neurotoxicity syndrome; IV, intravenous; SC, subcutaneous.
TEPKINLY® (epcoritamab). Gulf Summary of Product Characteristics, Sept 2023.
Infection Management
Infections Overview

CAR T –cell therapy has on-target effects : CD19 CAR T –cells result in
depletion of B-cells and a subset of CD19+ plasma cells whereas
BCMA- targeted CAR T-cells lead to plasma cell aplasia. 1-2

This immune system dysregulation and a further disruption by CAR T-

cells leaves patients who undergo CAR T-cell therapy susceptible to
infections.

Underlying hematologic malignancies and immunosuppressive

treatments for toxicities associated to CAR T-cell therapy contribute
further to the immunosuppressive state of the CAR T-cell recipients.

References:
1.
2. Neelapu SS, Tummala S, Kebriaei P, Wierda W, Gutierrez C, Locke FL, et al. Chimeric antigen receptor T-cell therapy—assessment and management of toxicities. Nat Rev Clin Oncol. 2018;15:47–62.
Incidence of Infections in CAR-T cell Monotherapy Trials
The incidence of infections in patients receiving CD19 CAR T-cells varies from 18 to 56 % in prospective clinical trials and 20-60% in
retrospective analyses. The differences in incidence among different studies could be due to patient-related, drug-related factors and
duration of follow up.1
Incidence of infections in different pivotal clinical trials for CD-19 T-cell therapy

TRANSFORM2 TRASCEND2 ZUMA-73 ZUMA-13

Liso-cel (N=89) Liso-cel (N=268) Axi-cel (N=168) Axi-cel (N=108)

Identification Number NCT03575351 NCT02631044 NCT03570892 NCT02348216

Median duration follow-

6 12.3 24.9 15
up (months)
Overall Infection, Any
12 29 25 26
grade (%)
Overall infection,
6 16 8 16
Grade ≥ 3 (%)
Bacterial infections (any
- 13 10 13
grade)
Viral infections ( any
- 10 15 16
grade)

Fungal infections - - 10 -

Disclaimer: Caution must be taken with cross-trial comparisons due to differences in treatment 1. Wudhikarn, K. et al. Infections complications, immune reconstitution, and infection prophylaxis after CD19
protocols and patient populations – as such, these comparisons are illustrative only. No head-to- chimeric antigen receptor T-cell therapy. Bone Marrow Transplantation. 2022; 57:1477-1488.
head trials have been conducted assessing the comparative safety of these agents. 2. BREYANZI Prescribing Information. July 2022.
3. YESCARTA Prescribing Information. November 2022.
Incidence of infections in Bispecific Monotherapy Trials

NHL: Monotherapies in development

Bispecific CD3xCD20 Bispecific Antibodies
antibody
Epcoritamab1 Mosunetuzumab2 Glofitamab3

All-grade infections (%) 45.2 12.6 44

Grade ≥3 infections (%) 16.6 12.6 -

1. Budde EL, et al. Abstract 1628. ASH Annual Meeting. Dec. 9-13, 2022
2. Philipps TJ, et al. Abstract 4251. ASH Annual Meeting. Dec 9-13, 2022
3. Rentsch V et al. Glofitamab Treatment in Relapsed or Refractory DLBCL after CAR T-cell Therapy. Cancers. 2022;14(2516)

Disclaimer: Caution must be taken with cross-trial comparisons due to differences in treatment
protocols and patient populations – as such, these comparisons are illustrative only. No head-to-
head trials have been conducted assessing the comparative safety of these agents.
 ICANS Management Infections

Prophylaxis and Management of Infections

Infection type Prophylaxis actions

• Most guidelines recommend initiating antibacterial prophylaxis during the severe neutropenia period with
absolute neutrophil counts (ANC) lower than 0.5 X 109/L and continue until ANC stays sustained above this level
Bacterial • Fluoroquinolones are most used, but extended-spectrum beta-lactam antibiotics or non-absorbable antibiotics
may be a reasonable alternative depending on the antibiotic sensitivity, allergy profiles and clinical practices at
each center.

• Prophylactic acyclovir is recommended for herpes viral prophylaxis. The duration varies between clinical centers,
but the most common one is at least 3-6 months after CAR-T treatment
Viral
• Patients who are hepatitis carriers or have previous history of hepatitis should receive treatment with entecavir
for at least 6 months along with surveillance for liver function

• Antifungal prophylaxis should be considered in patients with prolonged cytopenia or prolonged systemic
Fungal corticosteroid treatment for CAR T-cell associated events

1. Wudhikarn, K. et al. Infections complications, immune reconstitution, and infection prophylaxis after CD19 chimeric antigen receptor T-cell therapy. Bone Marrow Transplantation. 2022; 57:1477-1488
 ICANS Management Infections

Epcoritamab Management of Infections

TEPKINLY SmPC Gulf version Sept 2023

Epcoritamab Management of Infections

• COVID-19: - managed as per local guidelines

- Due to profound B- cell depletion prolonged positivity can observed
- Individualized consultation with ID to appropriate time to resume
treatment.
• Hypogammaglobulinemia: Ig monitor & IVIG in recurrent infections as
per institutional standards.
• PJP and VZV prophylaxis: universally recommended during treatment
and for six months following treatment discontinuation.
• Latent HBV prophylaxis: recommended as with other CD20 directed
therapies.
Cytopenias
• G-CSF support in neutropenic patients
• Withholding BsAb therapy as per prescribing label
• Balancing disease control with risks of associated with neutropenia
• BsAb therapy may be continued if cytopenia is due to underlying
lymphoma due to BM infiltration or organ infiltration with
sequestration .
• Clinicains should be mindful of potential increase risk of
thrombocytopenia
Tumor flare reaction
• Rare in the setting of BsAb treatment.
• Short term volumetric increase in lymphoma lesions accompanied by
erythema, pain, and fever, can result in local compression or organ
dysfunction, like CRS most frequently after the first dose or first target
dose of BsAb, may occur together with CRS.

• Tumor flare reactions usually responds rapidly to corticosteroid

therapy.
Tumor lysis syndrome
• At present no indication that risk of TLS following BsAb is significantly
different from that of other therapies.
• TLS risk assessment follow the standard of care for patients with
lymphoma.
• TLS monitor and prophylaxis in patients at increased risk based on
factors such as disease histology, tumor burden and baseline renal
fuction.
Final word
• CD3xCD20 BsAbs will be increasing adopted for indolent or aggressive
lymphomas.
• While often mild, BsAb associated CRS can lead to potential life
threatenting complications and require vigilant and proactive
monitoring and management.
• Key differences between neurologic toxicities seen with CAR-T and
BsAb therapy, specifically given low ratesof ICANS-like toxicities
regular neurologic assessment, testing for encephalopathy, and
driving restricyions were not universally recommended for
asymptomatic patients.
Final word
• Recommendations may not applicable in all cases and should never
substitute for individual clinical judjment.
• Recommendations are part of onging effort to provide up-to-date
guidance for clinicians and will be updated as additional information
is available.
• Much work to be done to better understand patient and disease
related risk factors for severe toxicity following BsAbs with
development and refinement of risk stratification tools for more
specific monitoring and management.
Thank Tou