CLL campus Visentin

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


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


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


erce

nt s

urvi

val

N13q-

+1211q-


0 5 10 15 20 25 30 35 400

20

40

60

80

100


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


erce

nt o

f eve

nt

Progression Free SurvivaluMRD4

MRD+


0 5 10 15 20 25 30 35 400

20

40

60

80

100Progression Free Survival


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


102 patients


80 patients


284 patients


TP53 mutation


abnormalities

1L IBRUTINIB in patients with TP53 abnormalities

0 10 20 30 400

20

40

60

80

100 TP53 abnormalities


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


102 patients


80 patients


284 patients


TP53 mutation


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


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


Perc

ent s

urvi

val

G-CHL U-IGHVIB U-IGHV


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


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

CLL campus Visentin

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