Comparison of chlorambucil plus obinutuzumab vs ibrutinib in previously
untreated CLL patients: an Italian CLL campusretrospective real-life study
INTERIM ANALYSIS
Andrea Visentin, MD PhD16 Luglio 2020
• Obinutuzumab plus chlorambucil (G-CHL) and ibrutinib (IB) single agent arefirst-line treatments for CLL patients unable to receive fludarabine-basedtherapy.
• There is no head-to-head comparison (Cross-trial comparison, iLLUMINATEG-CHL vs G-IB, ELEVATE TN G-CHL vs G-A vs A).
• Only a few retrospective studies assessed the real-life efficacy of G-CHL inthe real-life setting (the biggest is ERIC study which recruited 437 patients)
Background
CAGLIARI
TORINO
ASTI
ALESSANDRIA
CATANZARO
COSENZA
FERRARA
FIRENZE
PADOVA
PERUGIA
ROMA SapienzaUCSC
SIENA
MILANO Poli
VERONATREVISO
Recruiting centers
Study design
104 patientstreated with G-CHL
102 patients
excluded 2 patientswith 17p- and/or
TP53 mutation
180 patientstreated with IB
80 patients
excluded 100patients with TP53
abnormalities
Retrospective study16 italian hematological centers
284 patients
• 102 patients, 67 males and 35 females;• median age 74.7±6.6 years, 20 patients were ≥ 80 years old;• 48 had a CIRS score ≥6, range 2-18;• The median Cl. creatinine 61.2±17.5ml/min, for 69 patients was <70ml/min;• 61 patients had an advanced Rai stage (III-IV), 41 were at stage 2;• IGHV status was assessed in 84% of patients, 27 were U-IGHV and 56 M-IGHV• FISH was performed to all patients: 11 del11q-, 21 +12, 34 del13q-, 36 normal;
• 6/42 had NOTCH1 mutation.
Patients
• After a median follow-up of 20.1 months:
- 20 patients relapsed,
- 14 patients required a next treatment,
- 10 died (2 CLL, 2 cardiologic disease, 2 pneumonias, 3 sepsis),
- no-one developed Richter syndrome.
Patients
• 96 patients were evaluable for response, ORR was 86% according to iwCLL.• 83 and 47 were assessed locally MRD on peripheral blood and bone marrow.
Results
25%
61%
10%3%
0%
20%
40%
60%
80%
100%
1
RESPONSE RATE
PD
SD
PR
CR
42%
45%
14%
0%
20%
40%
60%
80%
100%
1
PB MRD
not done
MRD+
uMRD4
9%
40%
51%
0%
20%
40%
60%
80%
100%
1
BM MRD
not done
MRD+
uMRD486%
Efficacy
0 5 10 15 20 25 30 35 400
20
40
60
80
100
months from starting treatment
Per
cent
of e
vent
Progression Free Survival
Median PFS 33.4 months24 months PFS 67.4%
0 5 10 15 20 25 30 35 400
20
40
60
80
100
months from starting treatmentP
erce
nt o
f eve
nt
Time to Next Treatment
24 months TTNT 83.3%
0 5 10 15 20 25 30 35 400
20
40
60
80
100
months from starting treatmentP
erce
nt o
f eve
nt
Overall Survival
24 months OS 89.2%
• The 2 years PFS, TTNT and OS was 67%, 83% and 89%, respectively.
Efficacy – biologic risk stratification• The PFS is better low-risk patients (i.e. M-IGHV and/or 13q-).• We can see a plateau for M-IGHV patients!
0 5 10 15 20 25 30 35 400
20
40
60
80
100
months from starting treatment
Perc
ent o
f eve
nt
Progression Free SurvivalU-IGHV
M-IGHV
Log-rank test, p=0.0299
0 5 10 15 20 25 30 35 400
20
40
60
80
100 Progression Free Survival
months from starting treatmentP
erce
nt s
urvi
val
N13q-
+1211q-
Log-rank test, p=0.0117
0 5 10 15 20 25 30 35 400
20
40
60
80
100
months from starting treatment
Per
cent
of e
vent
Progression Free SurvivalCRPR
SD/PD
Log-rank test, p<0.0001
Efficacy – deep of response• The mPFS was 7.8, 29.8 and 37.7 months for patients in SD/PD, PR and CR.
• The 2-year PFS for uMRD4 in the pb was 81.6% and 50.3% for MRD+.
0 5 10 15 20 25 30 35 400
20
40
60
80
100
months from starting treatmentP
erce
nt o
f eve
nt
Progression Free SurvivaluMRD4
MRD+
Log-rank test, p=0.0038
0 5 10 15 20 25 30 35 400
20
40
60
80
100Progression Free Survival
months from starting treatmentP
erce
nt s
urvi
val
uMRD4
MRD+Log-rank test, p=0.0548
Safety• Obinutuzumab was premedicated in 98% of cases, according to local policy.
• Infusion reactions occurred in 36% of patients, but only 5 grade 3 eventswere recorded.
• All the 8 infusions of obinutuzumab were completed by 81% of patients andchlorambucil was reduced or discontinued by 36 patients.
• Neutropenia G≥3 24%, anemia G≥3 6%, thrombocytopenia G≥3 10% ofpatients.
• 25% developed an infective event, 13% were G3 or higher (most commonwere pneumonia, but also 1 spondylodiscitis and 1 pulmonary aspergillosis).
• 2 atrial fibrillation, 2 secondary cancers and 1 TLS were also recorded.
Study design
104 patientstreated with G-CHL
102 patients
180 patientstreated with IB
80 patients
Retrospective study16 italian hematological centers
284 patients
excluded 2 patientswith 17p- and/or
TP53 mutation
excluded 100patients with TP53
abnormalities
1L IBRUTINIB in patients with TP53 abnormalities
0 10 20 30 400
20
40
60
80
100 TP53 abnormalities
months from starting treatment
Pro
gres
sion
Fre
e S
urvi
val
100 patientsMedian follow-up 22 months24 months PFS 81.5%
• Phase 1b-2 untreated, 2 patients TP53 abnO’Brien, Lancet Oncol 2014
• Phase 2 TP53 abn, 35 patients TNFarooqui, Lancet Oncol 2015
• Phase 2 NIH, 35 patients TP53 abnAhn, Blood 2018
• Phase 3 Resonate-2, 12 patients TP53mBurger, Leukemia 2019
• Phase 3 Alliance, 15 patients TP53 abnWoyach, NEJM 2018
total 99 patients
Study design
104 patientstreated with G-CHL
102 patients
180 patientstreated with IB
80 patients
Retrospective study16 italian hematological centers
284 patients
excluded 2 patientswith 17p- and/or
TP53 mutation
excluded 100patients with TP53
abnormalities
G-CHLn = 102
IBRUTINIBn = 80
p values
Age (median±sd) 74.7 ± 6.6 69.2 ± 6.9 0.1064Age ≥75 years 35 26 0.8747Gender (M/F) 67/35 42/38 0.0935Cl. creatinine (median±sd) 61.2 ± 17.5 66.7 ± 14.0 0.0011Cl. creat. <70ml/min 69 38 0.0061Rai stage III-IV 61 37 0.0743
IGHV status (U/M) 27/56 56/14 0.0001FISH (11q-/+12/13q-/N) 11/21/34/36 13/18/20/27 0.5417
Patients characteristics
0 5 10 15 20 25 30 35 400
20
40
60
80
100
months from starting treatment
Perc
ent s
urvi
val
Progression Free Survival
G-CHL
IBLog-rank test, p=0.0012
Suvival analysis - overall
0 5 10 15 20 25 30 35 400
20
40
60
80
100
months from starting treatmentPe
rcen
t sur
viva
l
Time to Next Treatment
G-CHL
IBLog-rank test, p=0.0128
• Overall, Ibrutinib improves both PFS and TTNT.
Suvival analysis
• Improvement was significant only in U-IGHV patients.
0 5 10 15 20 25 30 35 400
20
40
60
80
100 Progression Free Survival
months from starting treatment
Perc
ent s
urvi
val
G-CHL U-IGHVIB U-IGHV
Log-rank test, p=0.0007
0 5 10 15 20 25 30 35 400
20
40
60
80
100Progression Free Survival
months from starting treatmentPe
rcen
t sur
viva
l
G-CHL M-IGHV
IB M-IGHV
Log-rank test, p=0.1946
Conclusions• Thanks to CLL campus we were able to gather data from 284 who weretreated with ibrutinib or G-CHL as first line therapy in the real-life setting.
• The Italian experience with G-CHL confirms the great activity and safety ofthis treatment, in particular for patients able to reach a CR.
• Most centers are developing flow-cytometry MRD assessment.
• Ibrutinib provides a high rate disease control in CLL with TP53 abnormalities.
• Continuous treatment with ibrutinib provides a better disease managementin CLL patients unfit for fludarabine-base therapy, but some on them canachieve a long-term disease control with a fixed duration obinutuzumab-based chemoimmunotherapy.
Future perspettive• Complete the analysis among G-CHL to describe the clinic-biological featuresassociated with a higher rate of CR/uMRD4 and longer PFS.
• Real-life comparison of second line therapy with ibrutinib vs venetoclax-rituximab in patients with chronic lymphocytic leukemia.
• Maybe joining our strength CLL campus and….ERIC, UK forum, USA/Mato?
GRAZIE PER L’ATTENZIONE