ASH Hematology Review Series

CAR T-cell Therapy and Toxicities

David L Porter, MD
Director, Cell Therapy and Transplant
University of Pennsylvania and Abramson Cancer Center, Philadelphia
 Disclosures
• Speaker and members of study team have financial interest due to potential upstream IP and patents and
licensure to Novartis and Tmunity
– COI managed in accordance with University of Pennsylvania policy and oversight

• Funding support for trials: ACGT, LLS, NCI, Novartis

• Advisory board (honorarium): Novartis, Kite, Incyte, Janssen, Jazz, DeCART
• Former member, ABIM Hematology Board exam writing committee (end Oct 2019)
• Employment: Spouse former employee Genentech (compensation included salary and stock)
• Member, Board of Directors, NMDP/Be The Match
• Some studies reported in this presentation were published as abstracts only and/or presented
at a conference. These data and conclusions are included because expert faculty found them
to be important scientific contributions but should be considered preliminary until published in a
peer-reviewed journal
• The views expressed in this presentation are those of the presenter
Cell-Surface Proteins are Targets for New Therapies

CD20 Id CD22 • Many cancer cells have

CD19
HLADR well characterized
CD52 surface proteins
• These proteins can be
targeted to kill the cell
B Cell
with:
– Monoclonal antibody
B Cell
– Engineered antibody
– Immune (T) cells
Adapted from Press O, et al. Cancer J Sci Am. 1998:4(suppl 2):s19–s26.
Rationale for Targeted Cellular Therapy
• Ultimately, targeted cellular immunotherapy could overcome
many limitations of conventional chemotherapy and other
forms of adoptive immunotherapy
• Genetically modified, autologous CAR T cells with redirected
specificity to tumor antigens may combine advantages of:
– Antibody therapy (specificity)
– Cellular therapy (amplified response)
– Vaccine therapy (memory activity)
Targeting CD19 with CAR-
Modified T cells
T cell

• Gene transfer (lentiviral CTL019 cell

vector) to stably express CAR

on T cells confers novel Native
TCR

antigen specificity Anti-CD19

CAR construct

• CAR modified T cells can

CD19

now recognize and kill Dead tumor cell

CD19+ cells (HLA

independent) Tumor cell
Overview of CAR T Cell Therapy

7-14 days
CAR T cells for B cell malignancies: Why all the excitement?
Disease Standard therapy CAR T cells

Relapsed, refractory Almost no probability of 80-90% CR rates

ALL remission or cure 50-60% LFS at 6-12 mo

Relapsed, refractory Almost no probability of 50-70% CR

NHL remission or cure 30-40% DFS

Relapsed, refractory Almost no probability of 50-70% CR

CLL remission or cure 30-40% DFS

Relapsed, refractory Almost no probability of 80%-100 ORR

MM remission or cure 33-74% DFS
 FDA approved CAR T products
There are 5 FDA approved CAR T cell products for 5 indications

Indication
ALL: Pediatric and young adults (up to
age 25)
Relapsed/refractory large B cell
lymphoma (DLBCL, tFL, +/-PMBCL)
R/R Follicular lymphoma
R/R Mantle cell lymphoma
R/R Multiple myeloma
Product
Tisagenlecleucel (tisa-cel)
Tisa-cel
Axicabtagene ciloleucel (axi-cel),
Lisocabtagene maraleucel (liso-cel)
Axi-cel
Brexucabtagene autoleucel (brexu-cel)
Idecabtagene vicleucel (ide-cel)
Cell Therapy Landscape: 2018-2021 View

March 27, 2021

Idecel
(Abecma)
Liso-cel) Feb 2021
Breyanzi
CD19
Brexucabtagene
July 2020
(Tecartus)
CD19

9
Variations in CAR constructs: Co-stimulatory domain in part responsible for
different toxicity profiles and possibly activities1–5
Axicabtagene ciloleucel2 Tisagenecleucel4 Lisocabtagene maraleucel†5
Brexucabtagene autoleucel3

ScFV FMC63 scFV

Hing CD8 Spacer

CD28
4-1BB 4-1BB

CD3
CD3 zeta
CD3 zeta

Axi-cel (Yescarta®) Tisacel Lisocel

Brxucel (Tecartus®) (Kymriah®) (Breyanzi®)
CART19 Cells For Relapsed, Refractory ALL

Structure of a Lenti-virus Lenti-viruses used for T-cell transduction Transduced T-cell attacks a tumor cell
ALL: Rationale for Novel Therapies
• Prognosis for relapsed or refractory ALL poor
• Median survival < 1yr
• 3 yr survival <25%
• Allogeneic SCT for refractory ALL largely ineffective
• There is a desperate need for newer, more effective
therapies for advanced and high risk ALL.
ALL: Overall Response to CTL019

Response N=30 %
Complete
27/30 90%
Response

No response 3/30 10%

Maude SL, Frey N. et al. N Engl J Med 2014;371:1507-1517.

Maude et al, NEJM Feb 2018,378
 CAR T cells for ALL:
• ELIANA is a single arm global study with centralized manufacturing of
tisagenlecleucel
• 25 sites in 11 countries across North America, Europe, Australia, and Asia

FPFV=8 APR 2015

Data cutoff: 23 NOV 2016
Maude et al, NEJM Feb 2018,378
CAR T cells for ALL
• Industrial cell processing of CTL019 therapy
• US manufactured cell therapy with global supply and
chain of custody
• 94% of pts received CTL019 in timely manner
• Toxicity manageable with no deaths due to CRS
• Efficacy Maintained compared to pilot study:
– CR/CRi 82%
– All CRs were MRD negative
Maude et al, NEJM Feb 2018,378
Novartis Ped & AYA ALL: Outcomes Post CART19 (tisagenlecleucel)1

• EFS & OS for entire infused cohort

N=75 Ped&AYA ALL

81%=MRD Neg CR

Only 8 Proceeded to HSCT in CR

Led to FDA approval of

CTL019
(tisagenlecleucel,
Kymriah) Aug 30, 2017.

Maude et al, NEJM Feb 2018,378

Diffuse Large B Cell Lymphoma

• Curable with standard chemo-immunotherapy

in many cases, but….
CAR T cells for relapsed, refractory DLBCL
• Patients with relapsed or refractory (r/r) diffuse large B-cell lymphoma
(DLBCL) have a poor prognosis
– Patients refractory to chemotherapy or relapsing ≤12 months after auto-SCT have low
response rates to subsequent therapy
• ORR 19-36%, CR 8%; PR 18%1
– Patients failing second-line salvage therapy have a poor prognosis2
• Median OS, 4.4 months
• 1-year OS, 23%; 2-year OS, 15.7%

• There is an urgent and high unmet medical need for relapsed and
refractory DLBCL patients
1. Crump M, et al. Blood 2017, 130;1800. “SCHOLAR” study
2. Van den Neste E, et al. BMT. 2016;51:51-57.
Outcomes for R/R DLBCL (“SCHOLAR 1”)

Crump M, et al. Blood 2017, 130;1800. “SCHOLAR” study

 Axicabtagene Tisagenecleuc Lisocabtagene
ciloleucel el maraleucel†

ScFV FMC63 scFV

Hing CD8 Spacer

CD28
4-1BB 4-1BB

CD3
CD3 zeta

CD3 zeta

Kite Novartis BMS

Neelapu SS, et al. N Engl J Med. 2017;377:2531–44.

Axi-cel for aggressive large cell lymphoma1,2
ZUMA-1
Outcome Axicabtagene ciloleucel
Evaluable patients 101
Best ORR 82%
Best CR 54%
Ongoing CR >3 months NR
Ongoing CR >6 months 36%
CRS grade 3–4 13%
Lee scale
NT grade 3–4 28%
Grade 5 AE 1%

1. Neelapu SS, et al. N Engl J Med. 2017;377:2531–44; 2. Locke FL, et al Lancet Oncol. 2019;20:31–42
Axicabtagene Lisocabtagene
Tisagenecleucel
ciloleucel maraleucel†

ScFV FMC63 scFV

Hing CD8 Spacer

CD28
4-1BB 4-1BB

CD3
CD3 zeta

CD3 zeta

Kite Novartis BMS

Schuster SJ, et al. N Engl J Med. 2019;380:45–56.

 Tisa-cel for aggressive large cell lymphoma
Outcomes Juliet (Tisacel)
Evaluable patients 93
Best ORR 52%
Best CR 40%
Ongoing CR >3 months 32%
Ongoing CR >6 months 29%
CRS grade 3–4 22%
Penn scale
NT grade 3–4 12%
Grade 5 AE 0%
Schuster SJ, et al. N Engl J Med. 2019;380:45–56.
Duration of Response, Progression-free Survival, and Overall Survival.

SJ Schuster et al. N Engl J Med 2018. DOI: 10.1056/NEJMoa1804980

 Kite Novartis BMS
(axicabtagene ciloleucel) (tisagenlecleucel) (lisocabtagene maraleucel)

Lancet; 396, 839-852, 2020

CAR T Cells for Aggressive Large Cell Lymphoma
(Side-by-side presentation, not comparison)

Outcomes Zuma 1 Juliet JCAR017

Axicel Tisacel Lisocel

Evaluable pts 101 93 102

Best ORR 82% 52% 75%

Best CR 54% 40% 55%

Ongoing CR >3 mo NR 32% NR

Ongoing CR >6 mo, 36% 29% ~44%
(26% (6/23) with median 24mo f/u; Siddiqui,
iwCART April 2021)

CRS gr 3-4 13% 22% 1%

Lee scale Penn scale

NT, gr 3-4 28% 12% 13%

Grade 5 AE 0 0 0%
N Engl J Med Dec 2017; 377:2531 N Engl J Med 2018 Lancet; 396, 839-852,
N Engl J Med 2017;377:2531-44. 2020
CAR-T therapy in the real world
Historically, treatment outcomes (response and toxicities) are
often different in the real-world setting compared with clinical
trials
• Often administered to patients who would not meet criteria for clinical
trials
• Criteria for treatment, monitoring, and follow up is often different
• Expertise of treating care teams is often different

It is critical to understand not just clinical trial responses but

real-world experience
Pasquini et al. Blood Adv, 4; 5414, 2020.
 Acute Lymphoblastic Leukemia
ALL Characteristic N (%) • Median time from
No. of patients 255 diagnosis to CT; 32 mo.
Disease status at CT • CR rate 85.5%
Primary refractory/relapsed 159 (62) • Among patients with
Morphologic CR 95 (37) MRD assessment
(N=115), 99% were
≥ 5% Blast in marrow prior to CT 84 (33) negative.
• DOR at 12m – 61%
• EFS at 12m – 52%
Poor cytogenetics incl Ph+ ALL 46 (18)
• OS at 12m – 77%
Median prior therapies 3
Prior allogeneic HCT 71 (28)

Pasquini et al. Blood Adv, 4; 5414, 2020.

RWE of Tisagenlecleucel in ALL
Duration of Response for Overall Survival
pts in CR

Pasquini et al. Blood Adv, 4; 5414, 2020.

Comparison of outcomes from CIBMTR with ELIANA

Pasquini et al. Blood Adv, 4; 5414, 2020.

 RWE of Tisagenlecleucel for DLBCL from CIBMTR
NHL Characteristic N (%) • ≥ 65y - 53%
No. of patients 155 • Median f/u 12 mo
Double/triple hit lymphoma 17 (11) • Median time from
Transformed lymphoma 42 (27) diagnosis to CT – 16 mo.
Disease status at CT • ORR 62%
Relapsed/refractory 147 (95) • CR 39.5%.
No resp to last line rx 105 (68) • 6 mo
Prior autologous HCT 40 (26) – DOR 55.3%
>= 3 of lines of prior therapies 45 (71) – PFS 38.7%
– OS 70.7%

Pasquini et al. Blood Adv, 4; 5414, 2020.

RWE of Tisagenlecleucel for DLBCL from CIBMTR
Duration of Response for Overall Survival
pts in CR

Pasquini et al. Blood Adv, 4; 5414, 2020.

Comparison of outcomes from CIBMTR with JULIET trials

Pasquini et al. Blood Adv, 4; 5414, 2020.

CAR T Cells in the Real World-Conclusions
• Many patients would not meet criteria for clinical
trials
• Responses and durability similar to trials
• Toxicity similar to trials (improved toxicity in some
studies)
• Real world experience with tisagenlecleucel mimics
clinical trial outcomes
Choosing a CAR-T product, location of care and
managing patients

It’s all about the toxicity….

CRS, Neurologic Toxicity, B Cell Aplasia
Toxicity: CAR T cells
• No significant acute infusional toxicity
• Tumor lysis syndrome
• Cytokine Release Syndrome (CRS)
• Neurologic toxicity
• B cell aplasia and hypogammaglobulinemia in responding
patients (toxicity or efficacy?)
– Supported with intravenous immunoglobulin (IVIG)
– No excessive or frequent infections
Cytokine Release Syndrome after CAR T Cell Therapy
• Correlates with CAR T activation and expansion resulting in immune
activation.
• Clinical syndrome:
– Onset 1-14 days after infusion, duration 1-10 days
– Fevers in all patients (up to 105/41 deg)
– Myalgias, arthralgias, anorexia, nausea, diarrhea
– Capillary leak, hypotension, hypoxia
– May be self-limited or require anti-cytokine intervention
– CRS-related mortality low but possible
• Biochemical changes
– Marked increase in IL6
– Dramatic elevations in ferritin (MAS/HLH), CRP
CRS toxicities by organ system

Brudno, Blood (2016) 127 (26): 3321–3330.

 CRS after CAR T Cell Therapy
• Almost all responding
patients develop a CRS
• Massive Elevations in IL-6
after CAR T cells in
responding patients
• IFN-g, modest TNF-a
• Mild increases in IL-2
CHP959-117 NR
CHP959-118 CR mild CRS
CHP959-120 CR severe CRS
Anti-IL-6 therapy to treat CAR T Cell Associated CRS
• Tocilizumab
– IL-6 receptor antagonist
– Blocks IL-6 mediated effects

• CRS rapidly reversed with tocilizumab when needed

– Tocilizumab administered on day 2 to 18
– Will early treatment for CRS abrogate response?

• CRS associated with HLH/MAS

– Hemophagocytosis, ferritin >500,000, hemolysis, DIC, altered mental status
• CRS-related mortality 3-10%

Blood. 2014;124(2):188-195
 CRS After CAR T: Ferritin and fever response to tocilizumab
700000
tocilizumab
Tocilizumab: d10
Tocilizumab
600000

500000
Ferritin

400000

Temp
300000

200000

100000

0
- -5 -1 1CRS,
3 5Pt 7 9 11 13 15 17 19 21 23
11 04409-09
Days

DL Porter, unpublished
CRS: Importance of consistent grading schemes
Difficult to compare CRS across studies
• 32-year-old with NHL develops hypotension requiring low
dose pressors after CART19
• Grade 2 on 2014 consensus scale
• Grade 3 on PENN/CHOP scale
• Grade 4 on CTCAE scale

Porter D, et al. J Hematol Oncol. 2018;11:35.

 ASBMT CRS CONSENSUS GRADING SCALE1
CRS Parameter Grade 1 Grade 2 Grade 3 Grade 4
Fever* Temperature ≥38°C Temperature ≥38°C Temperature ≥38°C Temperature ≥38°C
With
Hypotension None Not requiring Requiring a Requiring multiple
vasopressors vasopressor with or vasopressors
without vasopressin (excluding
vasopressin)
†
And/or
Hypoxia None Requiring low-flow Requiring high-flow Requiring positive
‡ ‡
nasal cannula or nasal cannula , pressure (eg, CPAP,
blow-by facemask, BiPAP, intubation and
nonrebreather mask, mechanical
or Venturi mask ventilation)
ASBMT CRS Consensus Grading
Organ toxicities associated with CRS may be graded according to CTCAE v5.0 but they do not influence CRS grading.
⁎Fever is defined as temperature ≥38°C not attributable to any other cause. In patients who have CRS then receive antipyretic or anticytokine therapy such as tocilizumab or steroids, fever is no longer required to
grade subsequent CRS severity. In this case, CRS grading is driven by hypotension and/or hypoxia.
†CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause. 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.
‡ 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.

1Lee et al. BBMT 2018

CRS after CAR T cells: Risk Factors
• Disease characteristics
• Underlying disease (ALL>NHL)
• Disease burden (particularly for ALL)
• Therapeutic characteristics
• Infused CAR T cell dose
• Product variance
• Pre-infusion, lymphodepleting chemotherapy
• Correlates with severe course
• Early onset
• Cytokines and CRP 1Maude et al. NEJM 2014
2Davila et al. SciTranMed 2014
• Concurrent infectious illness 3Lee et al. TheLancet 2015
4Turtle et al. JCI 2016
5Teachey et al. CancerDisc. 2016
6Frey et al. ASCO 2016
CRS Management- Key Points
• CRS presents initially with low grade fevers and flu-like symptoms, and can
escalate.
• Tocilizumab is highly effective in treating severe CRS in majority of patients
– It is potentially life saving therapy, administer within 1 hr of order
• Management should be based on clinical parameters, not laboratory
values
• Follow CRS treatment algorithm
– Ensure tocilizumab onsite prior to infusion
– Every effort should be made to administer tocilizumab within one hour of the
time the order is placed
• It is recommended that patients should remain proximal to the treatment
site for the first 28 days post infusion in case of emergent toxicity.
Neurologic Toxicity
• Less well understood; less defined management
• Symptoms:
➢ Expressive aphasia (esp naming objects/people); perseveration, global aphasia
▪ Often awake and alert
➢ Encephalopathy
➢ Tremor, myoclonus, seizures
➢ Apraxia, dysgraphia

• Onset: within days to 2-3 weeks after CAR T

➢ During or after resolution of systemic CRS

• Self limited; rare cases cerebral edema/death

Neurologic Toxicity
• Mechanism of Toxicity Unclear
• T cell vs Macrophage vs Cytokine Mediated??
• Endothelial Activation: Breakdown BBB6
• CAR T cells are seen in the CSF1-5
• Prevention: Unclear benefit from anti-epileptics
• Treatment:
• No clear response to anti-cytokine treatment
• Corticosteroids are mainstay

• Predictors
• High Disease Burden (ALL), high/rapid CAR T cell expansion, high IL6 on day 15,6

1Maude et al. NEJM 2014; 2Davila et al. SciTranMed 2014; 3Lee et al. TheLancet 2015; 4Kochendorfer al. JCO 2015
5Turtle et al. JCI. 2016 ; 6Gust et al (2017) Cancer Discovery, 7Uptodate
Clinical Features of CART Neurotoxicity Dysgraphia

Mild-to-moderate symptoms
▪ Delirium with preserved alertness
▪ Headache
▪ Dysgraphia (alteration in writing ability)
▪ Tremor
▪ Mild aphasia
▪ Myoclonus
▪ Memory impairment
Severe symptoms
▪ Global aphasia
▪ Focal neurologic deficits
▪ Generalized tonic-clonic seizures
Very severe symptoms Most patients with severe neurotoxicity start with expressive aphasia
▪ Coma (impaired naming and verbal perseveration), which subsequently
evolves into global aphasia, where they appear awake but are mute
▪ Intracranial hemorrhage
and unable to follow commands.
▪ Diffuse cerebral edema
ASBMT CONSENSUS GRADING: ICE SCORE (ADULTS)1

Immune Effector Cell-Associated Encephalopathy (ICE)

• 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 sentence (eg, “Our national bird is the bald eagle”): 1 point
• Attention: ability to count backwards from 100 by 10: 1 point

ICE Score
10, no impairment;
7-9, grade 1 ICANS;
3-6, grade 2 ICANS;
0-2, grade 3 ICANS;
0 grade 4 ICANS (pt unarousable)

1Lee et al. BBMT 2018

ASBMT ICANS CONSENSUS GRADING (ADULTS)1
Neurotoxicit Grade 1 Grade 2 Grade 3 Grade 4
y Domain
ICE score* 7-9 3-6 0-2 0 (patient is unarousable and unable to
perform ICE)
Depressed level of Awakens Awakens to voice Awakens only to tactile Patient is unarousable or requires
†
consciousness spontaneously stimulus vigorous or repetitive tactile stimuli to
arouse. Stupor or coma

Seizure N/A N/A Any clinical seizure focal Life-threatening prolonged seizure (>5
or generalized that min); or Repetitive clinical or electrical
resolves rapidly or seizures without return to baseline in
nonconvulsive seizures on between
EEG that resolve with
intervention
‡
Motor findings N/A N/A N/A Deep focal motor weakness such as
hemiparesis or paraparesis
Elevated N/A N/A Focal/local edema on Diffuse cerebral edema on neuroimaging;
§
ICP/cerebral edema neuroimaging decerebrate or decorticate posturing; or
cranial nerve VI palsy; or papilledema; or
Cushing's triad

1Lee et al. BBMT 2018

 B cell aplasia and hypogammaglobulinemia after CAR T cells
• CD19: An Ideal Tumor Target in B-Cell Malignancies, but is on normal B cells1
– CD19 is not expressed on hematopoietic stem cells1
• CD19 is expressed by most B-cell malignancies1
– CLL, B-ALL, DLBCL, FL, MCL1
• Targeting CD19 can lead to B cell aplasia
B cell lymphomas and CD19 expression
preB-ALL leukemias

Hematopoietic Pro-B Pre-B Immature Mature Activated Memory Plasma

stem cell (IgM) (IgM, IgD) B cell B cell cell
(IgG, IgA) (IgG)
1. Scheuermann RH, et al. Leuk Lymphoma. 1995;18:385-397. Image adapted from Janeway CA, Travers P, Walport M, et al. Immunobiology. 5th ed. New York, NY: Garland Science; 2001:221-293; Scheuermann RH, et al.
Leuk Lymphoma. 1995;18:385-397; and Feldman M, Marini JC. Cell cooperation in the antibody response. In: Roitt I, Brostoff J, Male D, eds. Immunology. 6th ed. Maryland Heights, Missouri: Mosby;2001:131-146.
Monitoring Patients for, and Management of B-Cell Aplasia and
Hypogammaglobulinemia
• Monitor CD19+ B cells
– Predictive of persistence and response in ALL
– Not clear that this is predictive of persistence or response in DLBCL
– B-cell aplasia is associated with hypogammaglobulinemia
• Monitor immunoglobulins every 1-3 months until recovery
– Replete IVIG in a personalized manner for hypogammaglobulinemia
• High-risk patients (history of recurrent infections)
• IgG “very low” (?<200, <400?) even without infections
• Patients with recurrent infections
• In some cases, all patients with IgG < 400
“How I prevent infections in patients receiving CD19-targeted chimeric antigen
receptor T cells for B-cell malignancies”, Blood 2020

Hill, Seo, How I prevent infections in patients receiving CD19-targeted chimeric antigen receptor
T cells for B-cell malignancies, Blood, 2020,
CAR T-cell Therapy and Toxicities- Key Points
• Anti-CD19 CAR T cells are dramatically effective for many
patients with relapsed and refractory B cell malignancies.
– Currently approved for use in relapsed or refractory B cell
malignancies:
• ALL, large B cell lymphoma, FL, MCL and myeloma
• Mechanisms of resistance and relapse:
– Target (CD19) loss
– Loss of CAR T cell persistence
– Ineffective CAR T cells
– “Inaccessible” tumor
CAR T-cell Therapy and Toxicities- Key Points
• Major unique acute toxicities include CRS and neurologic
toxicities
– IL6 is central to CRS
• Effectively managed in most patients with anti-IL6 directed therapy
(tocilizumab) with or without corticosteroids.
– The etiology of neurologic toxicity is less well understood.
• Treatment is with corticosteroids
• Tocilizumab is not effective treatment for NT
• B cell aplasia with hypogammaglobulinemia is a long term
toxicity and correlates with CAR T cell persistence
– Managed with IVIG when appropriate
Case Presentation
• A 24 yo male is 10 months after matched sibling allogeneic
SCT for ALL in CR2. He is off all immune suppression and has
no GVHD. He has evidence of relapse with a WBC of
22,000/ul and 80% lymphoblasts.
– Bone marrow shows diffuse infiltration with blasts
– Flow cytometry shows blasts are CD10, 19 and 20 positive.

• The best long-term treatment recommendation would be:

1. Second allogeneic SCT with a new donor
2. Supportive care and referral for hospice
3. Anti-CD19 directed CAR T cell therapy
 Case Presentation
• Correct answer: #3.
• 2nd allogeneic SCT for relapse, particularly within 1 yr, has a
very low probability of success with extensive morbidity and
mortality.
• CAR T cells has up to 90% CR rate and over 50% long-term
DFS!
• It falls within the indication (relapsed ALL in pts up to age 25)
 Case Presentation
• The patient undergoes leukapheresis.
• He is treated with “bridging chemotherapy” and remains stable over 1 mo.
• Lymphodepleting chemotherapy with fludarabine/cyclophosphamide is given.
• Successfully manufactured CAR T cells are administered.
• 3 days later the patient presents with fever of 101.2F and myalgias.
– HR is 110/min and BP is normal. Exam is unremarkable. The WBC is 3200/ul with
ANC of 1250/ul, hemoglobin 9.8 gm/dl and platelets are 90,000/ul.
• The most likely cause of the fever is:
1. Febrile neutropenia
2. SARS CoV2 pneumonia
3. Cytokine release syndrome
 Case Presentation
• The patient undergoes leukapheresis.
• He is treated with “bridging chemotherapy” and remains stable over 1 mo.
• Lymphodepleting chemotherapy with fludarabine/cyclophosphamide is given.
• Successfully manufactured CAR T cells are administered.
• 3 days later the patient presents with fever of 101.2F and myalgias.
– HR is 110/min and BP is normal. Exam is unremarkable. The WBC is 3200/ul with
ANC of 1250/ul, hemoglobin 9.8 gm/dl and platelets are 90,000/ul.
• The most likely cause of the fever is:
1. Febrile neutropenia
2. SARS CoV2 pneumonia
3. Cytokine release syndrome
Can CAR T cells cure leukemia or lymphoma?
MRD negative responses are frequent
Majority of relapses in ALL, CLL, NHL happen
within first 6-12 mo
Many patients alive in CR well beyond 12mo
• CLL - 10 yrs!
• ALL - 8 yrs!
• NHL - 7 yrs!
Combination therapies are increasing the
proportion of patients achieving “deep” CR
CAR T cells may be curing some patients with
ALL, CLL, NHL
Can CAR T cells cure leukemia or lymphoma?
MRD negative responses are frequent
Majority of relapses in ALL, CLL, NHL happen
within first 6-12 mo
Many patients alive in CR well beyond 12mo
• CLL - 10 yrs!
• ALL - 8 yrs!
• NHL - 7 yrs!
Combination therapies are increasing the
proportion of patients achieving “deep” CR
probably?
CAR T cells may be curing some patients with
ALL, CLL, NHL Likely?
ARE