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UPDATES IN CHRONIC
LYMPHOCYTIC LEUKEMIA
TANYA SIDDIQI, MD
DISCLOSURE
• Speaker’s bureau: PCYC, Janssen, Seattle Genetics
• Consultant: Juno therapeutics, Astra Zeneca, BeiGene,
PCYC
Objectives
• Epidemiology
• Diagnosis and workup
• Monoclonal B-lymphocytosis
• Prognostic markers
• Staging
• Treatment initiation guidelines
• Frontline therapeutic options
• Relapsed/refractory therapeutic options
Epidemiology
• Chronic lymphocytic leukemia (CLL) is a low grade
leukemic lymphocytic lymphoma; small lymphocytic
lymphoma (SLL) is a nodal form of the same disease
• CLL/SLL is the most common hematological malignancy
in the Western world; incidence is ~5/100,000 persons
per year in the US
• Median age at diagnosis ~72 years
Muller-Hermlink HK, et al. In: Jaffe ES, Harris NL, Stein H, Vardiman JW, eds. World Health
Organization Classification of Tumours: Pathology and Genetics of Tumours in Haematopoietic
and Lymphoid Tissues. Lyon, France. IARC press, 2001: 195-6.
Epidemiology (cont.)
• Male predominance
• Higher in Caucasians
• ~10% patients with a family history of some lymphoma
• Exact etiology is unknown
Diagnosis and workup
• Rule out masquerading other lymphoma
• History and physical examination; trend of CBCs; B
symptoms (fever, night sweats, unexplained weight
loss); severe fatigue
• Review CBC/differential, peripheral blood smear, flow
cytometry/immunophenotyping: peripheral blood
lymphocytosis with the presence of ≥5000 monoclonal B-
cells/uL is required
• Bone marrow biopsy not needed for diagnosis
Monoclonal B-lymphocytosis (MBL)
• Presence of monoclonal lymphocytosis but with <5000 B-
cells/uL in the peripheral blood and no accompanying
lymphadenopathy or organomegaly by physical
examination or radiographical imaging, cytopenias or
disease-related symptoms is defined as MBL
• Incidence in the US is 3%
• Progression to CLL/SLL can occur @ 1-2% per year
Prognostic markers in CLL/SLL
• Cytogenetics:
– Del13q
– Trisomy 12
– Normal
– Del11q
– Del17p
– Del6q
– TP53 mutations
– Notch1 mutations
– SF3B1 mutations
• IGHV mutation status
• ZAP70
• CD38
• Lymphocyte doubling time
(LDT)
• β2 microglobulin
• Stage of disease by Rai or
Binet staging
CLL Staging
Binet stage Clinical features
A HGB≥10 g/dl, platelets ≥100/L, <3 areas of lymphadenopathy/
organomegaly*
B HGB≥10 g/dl, platelets ≥100/L, ≥3 areas of lymphadenopathy/
organomegaly*
C Anemia (<10g/dl), thrombocytopenia (<100,000/L), or both
*nodal areas: cervical [head and neck], axillary, inguinal (including femoral lymph nodes), spleen, liver
Rai stage Risk category Clinical features
0 Low Lymphocytosis alone
1 Intermediate Lymphadenopathy
2 Intermediate Hepato/splenomegaly
3 High Anemia (<11g/dl)
4 High Thrombocytopenia (<100,000/L)
Who needs treatment?
• International workshop on CLL (iwCLL) guidelines for
treatment initiation
Hallek M, et al. Blood 2018. 131: 2745-2760
iwCLL guidelines for treatment initiation
• progressive marrow failure as manifested by the development of, or
worsening of, anemia and/or thrombocytopenia
• massive (≥6cm below left subcostal margin), progressive, or symptomatic
splenomegaly
• massive (≥10cm in longest diameter), progressive, or symptomatic
lymphadenopathy
• progressive lymphocytosis with an increase of >50% over a 2 month
period or LDT of <6 months
• autoimmune hemolytic anemia and/or thrombocytopenia that is poorly
responsive to corticosteroids or other standard therapy
• constitutional symptoms defined as ≥1 of the following:
(i) unintentional weight loss of ≥10% within the previous 6months
(ii) significant fatigue (ECOG PS ≥2;inability to work or perform usual activities)
(iii) fevers >100.5F or 38C for ≥2 weeks without other evidence of infection
(iv) night sweats for >1 month without evidence of infection
How to pick the right treatment?
• iwCLL guidelines for treatment initiation
• Stage of disease
• Lymphocyte doubling time and symptoms
• Cytogenetic risk
• Fitness of patient
• Response to prior therapy
Therapeutic options for CLL
• Watch and wait
• Radiation
• Immunotherapy
• Chemotherapy
• Combination chemoimmunotherapy
• Novel targeted therapies
• Cellular therapy
• Clinical trials
Frontline therapeutic options
German CLL study group (GCLLSG): frontline treatment
• CLL4 study: FC vs. fludarabine alone
• CLL8 study: FCR vs. FC
– Subgroup with exceptionally good outcome has right age/fitness,
mutated IGHV genes and no del17p/del11q (plateau after 4 yrs;
MRD neg ≥6 yrs later)
Eichhorst BF, et al. Hematol J 2006; 107: 885-91
Hallek M, et al. Lancet 2010; 376: 1164-74
Eichhorst B, et al. Blood 2014; 124: abs.19
CLL8 study: FCR vs. FC
ASH2016 MDACC experience with FCR
Thompson et al., Blood, 2016
German CLL study group (GCLLSG): frontline treatment
• CLL4 study: FC vs. fludarabine alone
• CLL8 study: FCR vs. FC
– Subgroup with exceptionally good outcome has right age/fitness,
mutated IGHV genes and no del17p/del11q (plateau after 4 yrs;
MRD neg ≥6 yrs later)
• CLL10 study: FCR vs. BR
Eichhorst BF, et al. Hematol J 2006; 107: 885-91
Hallek M, et al. Lancet 2010; 376: 1164-74
Eichhorst B, et al. Blood 2014; 124: abs.19
FCR vs. BR
• Phase 3 randomized trial, fit CLL patients (ages 33-81 yrs) with
advanced stage disease, previously untreated, no 17p deletion
• N = 564; 6 cycles of either regimen; median followup 37.1 months
FCR BR P-value
ORR 95% 96% 1.0
CR 40% 31% 0.034 [higher
MRD negative
CRs in FCR arm]
Median PFS 55.2 months 41.7 months 0.001 [better in
<65 years old]
OS at 3 years 91% 92% 0.897
Severe
neutropenia
84% 59% <0.001
Severe
infections
39% 25% 0.001 [especially
in older pts]
Eichhorst B, et al. Lancet Oncol 2016; 17: 928-42
CLL Disease Progression Curve
Adapted from: www.vaccinogeninc.com/sites/default/files/images/Figure_4.jpg
Minimal residual disease (MRD) defined cutoff
Targeted therapies
Ibrutinib vs. CIT in TN CLL
• Cross trial comparison
between ibrutinib therapy in
RESONATE 2 trial and CIT
from published phase 3
trials (CLL8, CLL10, CLL11,
and COMPLEMENT1)
• Age range 61-74 yrs
• Ibrutinib led to longer PFS
compared to CIT, including
in high risk populations
(del17p, del11q, unmutated
IGHV), probably negating
the need for chemo Robak T, et al. Am J Hematol 2018; 93: 1402-10
Ibrutinib – FDA approved
• Ph1b/2 study of 85 CLL pts, mostly high risk
• ORR of 71% (2 CR, 34 PR) + 15-20% PR-L
• At 26 months, estimated PFS was 75% and
OS 83%
• Well tolerated
Byrd JC, et al. N Engl J Med 2013; 369: 32-42
Ibrutinib: RESONATE trial
• Phase 3 trial of ibrutinib
(420mg po daily) vs.
ofatumumab in r/r CLL
• N = 391
• ORR 42.6% (+20% PR-L) vs.
4.1% (p<0.001)
• Median PFS not reached (88%
PFS at 6 months) vs. 8.1
months (p<0.001)
• At 12 months, OS 90% (ibru)
vs. 81% (ofa) (p=0.005)
Byrd JC, et al. N Engl J Med 2014;
371: 213-23
PCYC-1102/1103 Phase 2: 5 year update ASH2016
Patients with CLL/SLL treated with
oral, once-daily ibrutinib (420 or 840 mg/day)
Long-Term Follow-Up
≥SD
*R/R includes patients with high-risk
CLL/SLL, defined as progression of
disease <24 months after initiation of a
chemoimmunotherapy regimen or failure
to respond
Relapsed/Refr
actory* (R/R)
n=101
Treatment Naïve (TN) ≥65 years
n=31
Phase 2 (PCYC-1102) N=132
Extension Study (PCYC-1103)
5-year update, O’Brien et al.
ASH 2016
Disposition TN
(n=31) R/R
(n=101)
Median time on study, months (range) 62
(1–67) 49
(1–67)
Duration of study treatment, n (%) ≤1 year >1–2 years >2–3 years >3–4 years ≥4 years
5 (16%)
0 1 (3%) 1 (3%)
24 (77%)
24 (24%) 14 (14%)
9 (9%) 19 (19%) 35 (35%)
Patients remaining on ibrutinib therapy, n (%) 20 (65%) 30 (30%)
Primary reason for discontinuation, n (%) Progressive disease Adverse event Consent withdrawal Investigator decision Lost to follow-up
1 (3%)
6 (19%) 3 (10%)
0 1 (3%)
33 (33%) 21 (21%)
5 (5%) 11 (11%)
1 (1%)
Ibrutinib Treatment Continued in 65% of TN and 30% of R/R Patients
• After ~5 years of follow-up, 65% of TN and 30% of R/R patients continue treatment on study 5-year update, O’Brien et al. ASH 2016
Cumulative Frequency of Grade ≥3 Adverse Events Over 5-Year Follow-Up
Non-hematologic
≥5%
Hematologic Infectious
Grade 3 Grade 4 Grade 5
R/R R/R R/R TN TN TN
5-year update, O’Brien et al. ASH 2016
3% 3% 3%
55%
76% 71%
29%
10% 14%
0%
20%
40%
60%
80%
100%
Best Response
87% 89% 89%
Median DOR, months (range)
NR (0.0+ to 65.5+) 56.8 (0.0+ to 65.5+) NR (0.0+ to 65.5+)
Median follow-up, months (range)
62 (1 – 67) 49 (1+ – 67) 56 (1+ – 67)
CR
PR
PR-L
TN
(n=31)
R/R
(n=101)
Total (N=132)
NR, not reached. 5-year update, O’Brien et al. ASH 2016
3% 4% 7% 9%
86%77% 76%
65%
9%
9% 7%
6%
0%
20%
40%
60%
80%
100%
Best Response in Patients With High-Risk Abnormalities
79%
97% 90%
Median DOR, months (range)
38.7 (0.0+ to 65.3+) 53.2 (0.0+ to 65.5+) 38.7 (0.0+ to 65.5+) 30.6 (0.0+ to 65.3+)
Median follow-up, months (range)
55 (1+ – 67) 49 (1+ – 67) 55 (1 – 67) 47 (1 – 67)
CR
PR
PR-L
R/R del17p
(n=34)
R/R del11q
(n=35)
R/R Unmutated
IGHV
(n=79)
90%
R/R Complex Karyotype
(n=41)
NR, not reached. 5-year update, O’Brien et al. ASH 2016
Survival Outcomes: Overall Population
NR, not reached.
Median PFS 5-year PFS
TN (n=31) NR 92% R/R (n=101) 52 mo 43%
Progression-Free Survival Overall Survival
Median OS 5-year OS
TN (n=31) NR 92% R/R (n=101) NR 57%
5-year update, O’Brien et al. ASH 2016
Ibrutinib: RESONATE-2 trial
• Ph3, international, open
label, randomized trial of
ibrutinib vs. chlorambucil in
previously untreated older
CLL/SLL patients
• N = 269
• Median age = 73 years
• ORR 86% vs. 35% (p<0.001)
• Significant improvement in
EFS, PFS and OS with single
agent ibrutinib compared to
Clb
Burger JA, et al. N Engl J Med 2015 Dec 17;373(25):2425-37
RESONATE-2 update
• PFS was significantly improved
for ibrutinib across high-risk
subgroups, including del11q and
unmutated IGHV gene
• OS analysis resulted in 2-yr
survival rate estimates of 95%
(ibr) vs. 84% (clb)
• ORR was 92% with ibr vs 36%
with clb (P<0.0001); CR/CRi
within the ibr arm improved from
11% at 18.4 mo to 18% with
longer follow-up of 28.6-mo
RESONATE-2 update, Barr et al.ASH2016
RESONATE-2 update
RESONATE-2 update, Barr et al.ASH2016
• 1 patient on each arm
developed Richter’s
transformation
• 4 patients had disease
progression and
discontinued ibr
• 41% switched from clbibr
• Major hemorrhage in 7%
(ibr) within the first 2 yrs
• Atrial fibrillation in 10% (ibr)
• 79% pts remain on ibr with
median treatment duration
of 28.5 months
Other targeted therapies
• Idelalisib - FDA approved but further trials halted
due to toxicities
• Umbralisib – Phase 3 trials ongoing in CLL; much
better safety profile
• Venetoclax – FDA approved in del17p CLL
• Acalabrutinib – in phase 3 trials ongoing in CLL;
FDA approved for mantle cell lymphoma
• Duvelisib - FDA approved for rel/ref CLL
ASH 2018 update
(frontline therapies)
Abstract 6
• Ibrutinib Alone or in Combination with Rituximab Produces Superior
Progression Free Survival (PFS) Compared with Bendamustine Plus
Rituximab in Untreated Older Patients with Chronic Lymphocytic
Leukemia (CLL): Results of Alliance North American Intergroup Study
A041202
– phase 3 study comparing BR (Arm 1) with ibrutinib (Arm 2) and the
combination of ibrutinib plus rituximab (Arm 3)
– age ≥ 65 years with previously untreated, symptomatic CLL
– Between 12/9/2013 and 5/16/2016, 547 pts were registered and
randomized (Arms 1: 183, 2: 182, and 3: 182)
– Median age=71 years; 67% were men
– High-risk Rai stage (stage III/IV) was seen in 54%, unmethylated
Zap-70 in 53%, and del(17p) or del(11q) by local FISH in 28%
– median follow-up of 32 months (mo)
Woyach J, et al. ASH 2018
Abstract 6 (cont.):
– median PFS was 41 mo in Arm 1 and has not been reached in Arms 2
or 3 (Arm 2 to 1 p<0.0001; Arm 3 to 1 p<0.0001; Arm 3 to 2 p=0.48)
– 2-year PFS estimates were 74%, 87% and 88% in Arms 1, 2, and 3
respectively
– no significant differences in OS among arms (p=0.87), median OS has
not been reached for any arm, and 2-year OS estimates were 95%,
90%, and 94% in Arms 1, 2, and 3, respectively
– Grade 3+ treatment-emergent AEs were seen in 428 of 537 evaluable
pts with 61%, 41%, and 38% of pts experiencing Grade 3+ heme AEs
(p<0.0001) and 60%, 72%, and 71% of pts experiencing Grade 3+ non-
heme AEs (p=0.03) in Arms 1, 2, and 3 respectively
– Grade 5 AEs were seen in 5 (2.8%), 14 (7.8%), and 14 (7.7%) pts
(p=0.07); unexplained or unwitnessed death was seen in 2 (1.1%), 7
(3.9%), and 4 (2.2%) pts (p=0.24) in Arms 1, 2, and 3 respectively
Woyach J, et al. ASH 2018
Abstract 6 ( cont.):
– ibrutinib produces
superior PFS to standard
CIT in older pts with CLL
and justifies it as a
standard of care
treatment for pts age 65
and older.
– The addition of rituximab
does not prolong PFS
with ibrutinib.
Woyach J, et al. ASH 2018
Abstract 691
• Ibrutinib + Obinutuzumab Versus Chlorambucil +
Obinutuzumab As First-Line Treatment in Patients with
Chronic Lymphocytic Leukemia or Small Lymphocytic
Lymphoma (CLL/SLL): Results from Phase 3
iLLUMINATE
– international, open-label, randomized phase 3 study
– previously untreated CLL/SLL requiring treatment
– ≥65 years of age or were <65 years old with coexisting
conditions (Cumulative Illness Rating Scale score >6, creatinine
clearance <70 mL/min, and/or del(17p) or TP53 mutation)
– randomized 1:1 to receive ibr (420 mg once daily continuously)
combined with G for a total of 6 cycles, or clb for 6 cycles
combined with G
Moreno C, et al. ASH 2018
Abstract 691 (cont.):
– 229 pts were randomized to ibr-G (n=113) or clb-G (n=116)
– Median age = 71 years (range, 40-87)
– 65% of pts had high-risk genomic features
– median follow-up = 31.3 mo
– ibr-G significantly prolonged PFS compared with clb-G (median
not reached [NR] vs 19.0 mo (P<0.0001)
– PFS rates at 30 mo were 79% and 31% with ibr-G and clb-G,
respectively
– PFS benefit with ibr-G was consistent across subgroups
examined
– ORR was 88% with ibr-G vs 73% with clb-G; complete response
(CR/CRi) rate was also higher with ibr-G (19% vs 8%)
– With ~3 yrs of follow-up, 70% of pts in the ibr-G arm remain on
single-agent ibr
Moreno C, et al. ASH 2018
Abstract 691 (cont.):
– Ibr-G resulted in superior
PFS regardless of high-risk
genomic features,
compared with clb-G
– Response rates and depth
of remission (CR and
undetectable MRD) were
also higher with ibr-G
– Combination therapy with
ibr-G was tolerable
Moreno C, et al. ASH 2018
Late Breaker Abstract-4
• A Randomized Phase III Study of Ibrutinib (PCI-32765)-
Based Therapy Vs. Standard Fludarabine,
Cyclophosphamide, and Rituximab (FCR)
Chemoimmunotherapy in Untreated Younger Patients with
Chronic Lymphocytic Leukemia (CLL): A Trial of the
ECOG-ACRIN Cancer Research Group (E1912)
– treatment-naive individuals with CLL who were age ≤70 and
required therapy
– Patients with deletion 17p- were excluded
– randomly assigned in a 2:1 ratio to receive ibrutinib (420 mg/day
until disease progression) and rituximab for 6 cycles starting in
cycle 2 OR 6 courses of intravenous FCR
Shanafelt T, et al. ASH 2018
LBA-4 (cont.):
– total of 529 patients were accrued between January 31, 2014
and June 9, 2016; 354 patients were assigned to ibrutinib and
rituximab (IR) and 175 to FCR; 19 patients did not start protocol
therapy
– median follow-up of 33.4 months
– IR was superior over FCR in PFS (p<0.0001) and OS (p=0.0003)
– Superior PFS for IR was independent of age, sex, performance
status, disease stage or the presence/absence of del11q23
– IR was also superior to FCR for IGHV unmutated patients
(p<0.0001) but not IGHV mutated patients (p=0.07)
– FCR was more frequently associated with grade 3 and 4
neutropenia (FCR: 44% vs. IR: [23%]; p<0·0001) and infectious
complications (FCR: 17.7% vs. IR: 7.1%; p<0.0001)
Shanafelt T, et al. ASH 2018
LBA-4 (cont.):
– The combination of ibrutinib and rituximab provides superior PFS
and OS relative to FCR for patients with previously untreated
CLL age ≤70
Shanafelt T, et al. ASH 2018
Ibrutinib+FCG (MDACC) – Dr. Nitin Jain
– Ph2 study in younger, previously untreated patients with IGHV-M
– N=43 (1 was later found to have IGHV-U); med age 60 yrs; no
del(17p)/TP53 mutation
– Median followup 18.6 mo
– iFCG x 3 cycles
– ORR 100% at 3 months (17 CR/Cri, all MRD-U; 25 PR); 38/42 (90%)
achieved U-MRD in BM at 3 months
– Responses continue to improve over time (6 months (n=35): CR/CRi
74%, U-MRD 94%; 12 months (n=28): CR/CRi 86%, U-MRD 100%)
– All 28 pts who reached the 12 month time-point were U-MRD and
stopped ibr; all 28 maintain U-MRD status at a median follow-up of
10.1 months (range, 1.9-16.7) after stopping ibr without progression
– iFCG achieves high rate of U-MRD in previously-untreated patients
with CLL with IGHV-M CLL. No patient has progressed and all patients
who have stopped ibrutinib maintain U-MRD status.
– Manageable toxicities
– Phase 2 trial in previously unteated and rel/ref CLL
– Previously untreated cohort = 80; median age was 65 yrs (26-83)
– All pts had at least one high-risk feature: del(17p), mutated TP53,
del(11q), unmutated IGHV, or age ≥65 years (yrs)
– Ibrutinib x3 cycles then venetoclax ramp up started
– Ibrutinib continues indefinitely if MRD positive BM at 2 yrs but
venetoclax stops at 2 yrs
– median follow-up for all pts is 9.6 months
– After 3 months of IBR monotherapy, the majority pts were in PR; after
addition of VEN, increasing proportions of pts achieved CR/CRi and
BM U-MRD remission; no pt has had CLL progression
– Combined VEN and IBR is an effective, safe, and chemotherapy-free
oral regimen for pts with high-risk treatment-naïve CLL. Responses
were noted in older adults and across all high-risk subgroups. Adverse
event profile was similar to what has been reported individually with
IBR and VEN.
Ibrutinib + venetoclax (MDACC) – Dr. Nitin Jain
Other frontline trials
• Acalabrutinib in Treatment-Naive (TN) Chronic
Lymphocytic Leukemia (CLL): Updated Results from the
Phase 1/2 ACE-CL-001 Study – Dr. John Byrd
• Obinutuzumab+ibrutinib+venetoclax (frontline and
relapsed/refractory Ph2 trial) – Dr. Kerry Rogers
• CLL14 study: Prospective, open-label, multicenter
randomized phase III trial to compare the efficacy and safety
of a combined regimen of obinutuzumab and venetoclax vs.
obinutuzumab and chlorambucil in previously untreated
patients with CLL and coexisting medical conditions
– Accrual completed summer 2016 but results not presented yet
Relapsed/refractory therapeutic options
Murano trial update: ASH 2018 - Dr. John Seymour
• Venetoclax + rituximab (VR) vs. BR x6 cycles [V continued for 2
yrs]
• Randomized ph3 trial for rel/ref CLL
• 389 pts were enrolled in VenR (n=194) or BR (n=195) arms
• superior PFS of VenR over BR shown in ASH 2017
• Med followup now 36 months
• With all pts off treatment, continued substantial benefit was
observed with VenR, with PFS and OS superior to BR
• no new safety signals; most pts were able to complete
treatment.
• rate of CLL progression in the first 12 mo after Ven completion
was modest (13%), supporting the feasibility and safety of a
time-limited VenR duration
Ibrutinib + venetoclax (CLARITY trial) – Dr. Peter Hillmen
– Ph2 trial
– N = 54
– 10/51 (20%) of patients had 17p del, 13/54 (25%) 11q del (but
not 17p), and 40/53 (75%) had unmutated IGVH genes
– Ibrutinib for 8 weeks then venetoclax ramp up
– Stopping options built in if MRD neg
– After 6 months of combined ibrutinib plus venetoclax,
undetectable MRD was achieved in 19/49 (39%) patients in
peripheral blood (PB) and 12/49 (24%) in bone marrow (BM)
– After 12 months of combined therapy all patients had responded
by IWCLL criteria and 23/40 (58%) had achieved a complete
remission (CR or CRi)
– undetectable MRD (MRD4) was achieved in 23/40 (58%)
patients in PB and 17/41 (41%) in BM
Other rel/ref trials
• Phase I/II Study of Umbralisib (TGR-1202) in Combination
with Ublituximab (TG-1101) and Pembrolizumab in
Patients with Relapsed/Refractory CLL and Richter’s
Transformation – Dr. Anthony Mato
• Obinutuzumab+ibrutinib+venetoclax (frontline and
relapsed/refractory Ph2 trial) – Dr. Kerry Rogers
Cellular therapy
• Allogeneic hematopoietic cell transplantation
– N=694 (retrospective)
– High risk disease
– 2 yr-NRM 28%
– 5 yr EFS 37%
• CAR-T cells
Schetelig J, et al. ASH 2015 abs
CD19 specific CAR-T cells in CLL
• N = 14; median cell dose = 7.5x10^8 cells
• 4 CRs (29%), 4 (29%) PRs, ORR 57%
• CAR-T cells detectable 3 yrs later in some
• Ph2 randomized study ongoing to determine best cell dose (n=18,
ORR39%, CR 17%)
• Expected toxicities: B cell aplasia, delayed TLS and cytokine
release syndrome Porter D, et al. Blood 2013; ASH abs. 4162
Porter D, et al. Blood 2013; ASH abs. 873
CD19 specific CAR-T cells (cont.)
Mato A and Porter D. Blood 2015; 126: 478
• CAR-T cell therapy may potentially be a good alternative to
RIC alloHCT for very high risk patients
• Other targets being evaluated include CD20, CD23, ROR1
CD19 CAR-T cells in ibrutinib-refractory CLL
• N = 24, median age 60 yrs
• MTD 2x10^6 CAR-T cells/kg; CD8+:CD4+ CAR-T cells 1:1
• 19 ibrutinib ref, 3 ibrutinib intolerant, 2 had not progressed on ibrutinib;
6 were ref to venetoclax; 23 had complex karyotype and/or del17p
• 20 pts (83%) had CRS and 8 pts (33%) had neurotoxicity
• ORR at 1 month in 19 of 20 restaged pts who had received Flu/Cy and
CAR-T cells at or below MTD was 74% (4/19 CR, 10/19 PR)
• 15/17 patients (88%) with marrow disease before CAR-T cells had no
disease by flow cytometry after CAR-T cells; 12 underwent deep IGH
sequencing and 7 had no malignant IGH sequences detected in marrow
• Absence of the malignant IGH clone in marrow of patients with CLL who
responded by IWCLL criteria was associated with 100% progression-
free survival and overall survival (median 6.6 months follow-up) after
CAR-T cell immunotherapy
Turtle C, et al. J Clin Oncol 2017; 35 (26): 3010-20
ASH ABSTRACT #300
Rapid MRD-negative Responses in Patients With
Relapsed/Refractory CLL Treated With Liso-cel,
a CD19-Directed CAR T-cell Product:
Preliminary Results From TRANSCEND CLL 004,
A Phase 1/2 Study Including Patients With High-risk
Disease Previously Treated With Ibrutinib
Tanya Siddiqi,1 Jacob D. Soumerai,2 William G. Wierda,3 Jason A. Dubovsky,4
Heidi H. Gillenwater,4 Lucy Gong,4 Alan Mitchell,4 Jerill Thorpe,4 Lin Yang,4 Kathleen A. Dorritie5
1City of Hope National Medical Center, Duarte, CA, USA; 2Center for Lymphoma, Massachusetts General Hospital, Boston, MA, USA; 3The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 4Juno Therapeutics, a Celgene Company, Seattle, WA,
USA; 5University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
Transcend CLL 004 Phase 1 study design (NCT03331198)
Dose Level Dose Treated (N=16)
–1 2.5 × 107 CAR+ T cells --
1 5 × 107 CAR+ T cells 6
2 1 × 108 CAR+ T cells 10
Key Eligibility
• Relapsed/refractory CLL/SLL
• Failed or ineligible for BTKia
• High-risk diseaseb: failed ≥ 2 prior therapies
• Standard-risk disease: failed ≥ 3 prior therapies
• ECOG PS 0–1
Dose-escalation: mTPI-2 Designc
28-day DLT period
Primary Objective
• Determine recommended dose
• Safety
Exploratory Objectives
• Antitumor activity
• Pharmacokinetic profile
aFailure defined as SD or PD as best response, or PD after previous response, or discontinuation due to intolerance
(unmanageable toxicity). Ineligibility defined as requirement for full-dose anticoagulation or history of arrhythmia. bComplex cytogenetics abnormalities, del(17p), TP53 mutation, or unmutated IGHV. cGuo W, Wang SJ, Yang S, et al.
Contemp Clin Trials. 2017;58:23-33.
BTKi, Bruton's tyrosine kinase inhibitor; CAR, chimeric antigen receptor; CLL, chronic lymphocytic leukemia; DLT,
dose-limiting toxicity; ECOG PS, Eastern Cooperative Oncology Group Performance Status; IGHV, immunoglobulin
heavy chain variable region; mTPI, modified toxicity probability interval; PD, progressive disease; SD, stable disease;
SLL, small lymphocytic lymphoma.
Data on file 21 September 2018.
Key study assessments
aBaseline refers to screening or if patient received bridging
therapy, baseline disease assessments were repeated pre-
lymphodepletion. bResponse assessment by iwCLL criteria
(Hallek M et al. Blood. 2008;111(12):5446-5456). cCompleted when CR or PR with residual
lymphadenopathy are suspected. dIn PB by 6-color flow
cytometry (10-4) and, for those who are undetectable by
flow, in BM by Immunoseq NGS (10-6).
BM, bone marrow; CR, complete response; CT, computed
tomography; CY, cyclophosphamide; FLU, fludarabine;
iwCLL, International Workshop on Chronic Lymphocytic
Leukemia;
MRD, minimal residual disease; NGS, next-generation
sequencing; PB, peripheral blood; PR, partial response.
MRDc,d
CT/PETb
BM Examc
Months Post–Liso-cel
1 3 6 9 12 18 24 Baselinea
FOLLOW-UP
On-study: 24 months
Long-term: up to 15 years
after last liso-cel treatment
Liso-cel
manufacturing 100% success rate to date
Enrollment &
apheresis
Measurable disease
reconfirmed
Screen Liso-cel
2–7 days
after FLU/CY
Lymphodepletion
FLU 30 mg/m2 and
CY 300 mg/m2 × 3 days
Bridging therapy
allowed
Baseline characteristics
aAt least 3 chromosomal aberrations.
b7 patients progressed on venetoclax; 1 patient had best response of SD after 3 months of treatment.
Characteristic All Patients
(N=16)
Age, median (range) y 64.5 (51–76)
Male, n (%) 8 (50.0)
Stage, n (%)
Rai Stage III/IV 10 (62.5)
Binet Stage C 10 (62.5)
High-risk features (any), n (%) 12 (75.0)
TP53 mutation 10 (62.5)
Complex karyotypea 8 (50.0)
Del (17p) 7 (43.8)
Prior lines of therapy, median (range) 4.5 (2–11)
Prior ibrutinib, n (%) 16 (100.0)
Ibrutinib relapse/refractory, n (%) 13 (81.3)
Ibrutinib progression and prior venetoclax,b n (%) 8 (50.0)
All Grades Grade ≥ 3 Treatment-related
Grade ≥ 3
Any TEAE, n (%) 16 (100.0) 16 (100.0) 9 (56.3)
Anemia 14 (87.5) 11 (68.8) 4 (25.0)
Thrombocytopenia 13 (81.3) 12 (75.0) 5 (31.3)
Cytokine release syndrome
12 (75.0) 1 (6.3) 1 (6.3)
Neutropenia 10 (62.5) 10 (62.5) 6 (37.5)
Leukopenia 9 (56.3) 9 (56.3) 5 (31.3)
Hypokalemia 8 (50.0) 0 0
Pyrexia 6 (37.5) 0 0
Lymphopenia 5 (31.3) 5 (31.3) 5 (31.3)
Nausea 5 (31.3) 0 0
Diarrhea 4 (25.0) 0 0
Febrile neutropenia 4 (25.0) 3 (18.8) 1 (6.3)
Headache 4 (25.0) 0 0
Insomnia 4 (25.0) 0 0
Tremor 4 (25.0) 0 0
TEAEs Reported in ≥ 20% of patients (n=16)
AE, adverse event; DL, dose level; DLT, dose-limiting toxicity;
TEAE, treatment-emergent adverse event. • 1 DLT of grade 4 hypertension was reported in DL2
• No Grade 5 AEs have been reported
Serious AEs
All Patients
(N=16)
Any serious AEs of any grade, n (%)
7 (43.8)
Lung infection 3 (18.8)
Aphasia 1 (6.3)
Blood fibrinogen decreased 1 (6.3)
Encephalopathy 1 (6.3)
Febrile neutropenia 1 (6.3)
Hypertensiona 1 (6.3)
Hyponatremia 1 (6.3)
All serious AEs were of grade ≥ 3 and all were reversible
a1 DLT of grade 4 hypertension was reported in
DL2. AE, adverse event; DL, dose level; DLT, dose-limiting toxicity.
AEs of Special Interest (none were Grade 4/5)
aNeurologic events are treatment-related events defined by the Investigator. bEncephalopathy n=1; aphasia
n=1; confusional state and encephalopathy n=1.
AE, adverse event; CAR, chimeric antigen receptor; DL, dose level; CRS, cytokine release syndrome.
Total DL1 DL2
(N=16) (n=6) (n=10)
CRS – any grade, n (%) 12 (75.0) 6 (100.0) 6 (60.0)
Median time to first onset, d (range) 6.5 (1–10) 6.5 (1–9) 5.0 (2–10)
Median duration, d (range) 5.5 (2–30) 5.5 (3–30) 5.5 (2–13)
Grade 3, n (%) 1 (6.3) 0 1 (10.0)
Neurologic events (NE)a – any grade, n (%) 6 (37.5) 2 (33.3) 4 (40.0)
Median time to first onset, d (range) 10.0 (4–21) 16.0 (11–21) 8.0 (4–11)
Median duration, d (range) 6.5 (2–20) 4.0 (2–6) 8.0 (3–20)
Grade 3b, n (%) 3 (18.8) 2 (33.3) 1 (10.0)
Any, n (%)
CRS or NEa 13 (81.3) 6 (100.0) 7 (70.0)
CRS and NEa 5 (31.3) 2 (33.3) 3 (30.0)
Tocilizumab and/or dexamethasone use 11 (68.8) 4 (66.7) 7 (70.0)
Tumor lysis syndrome – any grade, n (%) 2 (12.5) 1 (16.7) 1 (10.0)
Grade 3, n (%) 2 (12.5) 1 (16.7) 1 (10.0)
Response Rates
Total DL1 DL2
Best Overall Response, n (%) (N=16) (n=6) (n=10)
ORR 13 (81.3) 6 (100.0) 7 (70.0)
CR/CRi 7 (43.8) 5 (83.3) 2 (20.0)
PR/nPR 6 (37.5) 1 (16.7) 5 (50.0)
SD 2 (12.5) 0 2 (20.0)
PD 1 (6.3) 0 1 (10.0)
CR, complete response; CRi, complete remission with incomplete blood count recovery; DL, dose level; nPR, nodular partial remission; ORR, overall response rate; PD,
partial disease; PR, partial remission; SD, stable disease.
Total DL1 DL2
Response at 30 Days Post–liso-cel, n (%)
(N=16) (n=6) (n=10)
ORR 12 (75.0) 6 (100.0) 6 (60.0)
CR/CRi 5 (31.3) 3 (50.0) 2 (20.0)
PR/nPR 7 (43.8) 3 (50.0) 4 (40.0)
Response at 3 Months Post–liso-cel, n (%)
(N=10) (n=6) (n=4)
ORR 8 (80.0) 5 (83.3) 3 (75.0)
CR/CRi 5 (50.0) 3 (50.0) 2 (50.0)
PR/nPR 3 (30.0) 2 (33.3) 1 (25.0)
Minimal residual disease
uMRD4 at any time point, n (%) Total DL1 DL2
(N=15) (n=6) (n=9)
Blood, flow 11 (73.3) 6 (100.0) 5 (55.6)
(N=8) (n=5) (n=3)
Bone marrow, NGS 7 (87.5) 4 (80.0) 3 (100.0)
CR, complete response; DL, dose level; iwCLL, International Workshop on Chronic Lymphocytic Leukemia; NGS, next-generation sequencing; PR, partial remission;
uMRD4, undetectable minimal residual disease sensitivity 10-4.
• 11 of 15 (73.3%) patients had uMRD4 in blood by flow at
Day 30
–All continue to remain undetectable at latest follow-up
• 5 patients have post-dose follow-up at Month 6
–All continue to maintain uMRD4 response (CR, n=4
and PR, n=1 by iwCLL criteria)
JCAR017 Conclusions
Liso-cel demonstrated promising activity in a heavily pretreated patient
population with high-risk CLL, all of whom had received prior ibrutinib
• Liso-cel toxicities were manageable at both dose levels tested
– Low rates of grade 3 CRS (6.3%) and neurologic events (18.8%)
• High best ORR (81.3%) and a CR/CRi rate (43.8%)
– Responses have deepened over time at 3- and 6-month follow-up
– CR continues in 5 of 6 patients with at least 3 months of follow-up
• Early uMRD4 responses were observed in a majority of patients
(73.3%) and were maintained at 3 and 6 months
• Following analysis of dose escalation data and selection of a RP2D,
the phase 2 portion of the trial will open for accrual (expected 1H
2019)
1H, first half; CLL, chronic lymphocytic leukemia; CR, complete response; CRi, complete remission with incomplete blood count recovery; CRS, cytokine release syndrome;
uMRD4, undetectable minimal residual disease sensitivity 10-4; NE, neurologic events; ORR, overall response rate; RP2D, recommended phase 2 dose.
Overall Conclusions
• Explosion of novel therapies for CLL in recent years,
including monoclonal antibodies (like obinutuzumab),
small molecule inhibitors of various kinases (like BTK
and PI3K) and the antiapoptotic pathway (especially
Bcl2), and CD19-specific CAR-T cells
• These novel, non-chemotherapeutic agents may do
away with the need for standard chemoimmunotherapy
in CLL, especially in older/unfit patients
• Combination studies are underway to improve outcomes
further
Acknowledgements
• Patients and their families/friends
• Nurses and colleagues at City of Hope National Medical
Center
• Mentors
– Robin Joyce, MD
– Steven Rosen, MD
– Stephen Forman, MD
