CHRONIC LYMPHOCYTIC LEUKEMIA - HOW SHOULD WE INCORPORATE IBRUTINIB INTO FRONT LINE THERAPY? - PHD, MDCM, FRCPC KELLY DAVISON - CARE ...
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Chronic Lymphocytic Leukemia – How
should we incorporate Ibrutinib into front
line therapy?
Kelly Davison
PhD, MDCM, FRCPC
McGill University Health Centre
Disclosures of interest • Consultancy/advisory board participation: – Roche – Janssen – Lundbeck – Abbvie • Honoraria: – Lundbeck
Objectives • To review data supporting personalized treatment decision for front-line CLL in fit and unfit patients • To examine the potential role for novel agents within the Quebec landscape
Background
• Most common type of leukemia in Western
world
– 2 465 new diagnoses, 608 deaths in Canada
(2013)
• Incidence increasing with aging population
• Median age at diagnosis = 72 years
– Median age at start of therapy younger
• Heterogeneous clinical course and response
to therapy
Treatment considerations
• Symptomatic?
– iwCLL 2017 guidelines continue to recommend
observation in the absence of symptoms due to CLL
• Fitness (little consensus on what constitutes “fit”)
– Age (≥ vs < 65)
– CGA (CIRS > vs ≤6), performance status
– Renal function (eGFR ≥ vs < 60 ml/min)
– Clinical judgment
Treatment considerations
Group 1 Group 2 Group 3
• Fit • Less fit • Not fit
• No comorbidities • Comorbidity present • High comorbidity
• Normal life expectancy
Balducci L & Extermann M, Oncologist 2000; 5:224–237.
Treatment considerations
• Symptomatic?
– iwCLL 2017 guidelines continue to recommend
observation in the absence of symptoms due to CLL
• Fitness (little consensus on what constitutes “fit”)
– Age (≥ vs < 65)
– CGA (CIRS > vs ≤6), performance status
– Renal function (eGFR ≥ vs < 60 ml/min)
– Clinical judgment
• Risk profile
– del17p, p53 mutation (del11q, IGHV mutation status,
complex karyotype)
CLL - IPI Lancet Oncology 2016
OS by cytogenetic risk –
FCR (CLL8)
Hallek, The Lancet
RESONATE - design
R
A Ibrutinib 420 mg once
Patients (n = 391) N daily until progression
D or toxicity
• Previously treated O
CLL M
Ofatumumab 300 mg Crossover to
• Age ≥ 65 I
Z IV x 1, then 2000 mg Ib if IRC-
E IV x 11 doses over 24 confirmed PD
1:1 weeks (N = 57)
Stratification factors:
• Refractory to purine analog
• Presence vs absence of del17pRESONATE (PFS) Brown, Leukemia 2018
RESONATE – PFS by
p53 status
Brown, Leukemia 2018RESONATE-17 (r/r CLL)
• Med age 64
• 63% Rai III-IV
• Median prior lines
of therapy = 2
Med f/u: 27.6 mos
ORR: 83%
mDOR: NR
O’Brien, Lancet Oncology 2016Ibrutinib in TN del17p
Extended f/u with med 4.8 yrs (N = 51):
• Estimated 5 yr PFS 74.4% for TN cohort (vs 19.4% for r/r group)
• 5 yr OS 85.3% (TN) vs 53.7% (r/r)
Farooqui, Lancet Oncology 2014; Farooqui, Blood 2018Lessons learned from the
rel/ref and high risk setting
• Ibrutinib should be considered for all patients
with rel/ref disease, particularly if del17p
• Ibrutinib in front-line if del17p/TP53 mutation
– Largely extrapolated from rel/ref population,
though limited data in TN CLL is very compellingAre there other groups of patients for whom ibrutinib should be considered in front-line therapy?
RESONATE-2 - design
R
Patients (n = 269) A Ibrutinib 420 mg once PCYC-1116
N daily until progression extension
• TN CLL/SLL with D or toxicity CLL study
active disease O PD or
• Age ≥ 65 M Chlorambucil 0.5 study
I mg/kg (max 0.8 end N = 55
• If 65-69, ineligible
Z mg/kg) on days 1 and crossed
for FCR
E 15 of 28-day cycle x over to Ib
• del17p excluded
1:1
12
Stratification factors:
• ECOG status (0-1 vs 2)
• Rai stage III-IV vs ≤ IIBaseline characteristics
RESONATE- 2 (PFS) • 88% reduction in the risk of progression or death for patients randomized to ibrutinib • Subgroup analysis of PFS revealed benefit was observed across all subgroups Barr, Blood 2016;128: Abstract 234.
RESONATE-2 (OS) Barr, Blood 2016;128: Abstract 234.
Ibrutinib indications - QC
• In QC, funded for:
– Second-line or subsequent therapy if:
• PA ineligible
• PFS < 36 mos post-PA
• del17p
– First-line therapy for del17p
– First-line therapy therapy without del17p if
ineligible for fludarabine
• “precarious” health due to advanced age, altered renal
function, CIRS ≥ 6What about the fit patient without del17p who is otherwise predicted to do poorly with CIT?
IGHV mutation status
Years from diagnosis
Dahmle, Blood 1999Somatic hypermutation and
B cell development
• Somatic hypermutations are point mutations in the IGHV gene of
activated B cells1,2
• These mutations are necessary for:1,3
– Antibody diversity and maturation
– Proper B cell function as the B cell receptor (BCR) contains a
membrane-bound antibody
IGHV somatic hypermutations are required for normal B cell
function3
References: 1. Janeway CA Jr et al. Immunobiology: The Immune System in Health and Disease. 5th edition. New York: Garland
Science; 2001. 2. García-Muñoz R et al. Ann Hematol 2012;91(7):981-96. 3. Kipps TJ et al. Nat Rev Dis Primers 2017;(3):17008.B-Cell Diversity: VH
Rearrangement and Mutation
VH D JH C
1/51 1/27 1/6 µ
NN
Somatic
mutations
VH in B-cell chronic lymphocytic
leukemia
– Somatic mutations (IGHV-unmutated cells escape an
important step in normal development
Evolution of IGHV-mutated and IGHV-unmutated CLL
• IGHV-unmutated cells
subtypes1,5
originate from B cells
that bypass T-cell
dependent
differentiation and
selection in germinal
centres1-4
References: 1. Kipps TJ et al. Nat Rev Dis Primers 2017;(3):17008. 2. García-Muñoz R et al. Ann Hematol 2012;91(7):981-96. 3.
Stevenson FK et al. Blood 2011;118(16):4313-20. 4. Fabbri G, Dalla-Favera R. Nat Rev Cancer 2016;(3):145-62. Cooper MD. 2015. Nat
Rev Immunol 2015;15(3):191-7.Unmutated IGHV leads to
increased B cell signaling
• In IGHV-unmutated CLL, the BCR recognizes a wider range of self- and
environmental antigens, leading to increased activation of the downstream
pathway1-3
• This is also the case in CLL that uses IGHV genes with limited hypermutations,
such as the IGHV3-21 gene4,5
References: 1. Burger JA, Chiorazzi N. Trends Immunol 2013;34(12):592-601. 2. Stamatopoulos K. Blood 2009;114(17):3508-9. 3.
Dimitrov JD et al. J Immunol 2013;191(3):993-9. 4. Agathangelidis A et al. Blood 2013;119(19):4467-75. 5. Kipps TJ et al. Nat Rev Dis
Primers 2017;(3):17008.Increased B cell signaling
contributes to genetic instability
• Repetitive signaling drives cellular survival and proliferation in IGHV-
unmutated CLL1-3
– As a result, IGHV-unmutated CLL is genetically unstable, with a higher likelihood
of unfavourable genetic and cytogenetic abnormalities, as well as disease
progression3,4
• Del(11q) and del(17p) are negative prognostic factors predominantly
found in IGHV-unmutated CLL5
– Del(11q) occurs in >25% of patients with IGHV-unmutated CLL but only inPFS by IGHV mutation
status (CLL8)
Median f/u 5.9 yrs
Median PFS - NR
Median PFS – 41.9 mo
Fischer, Blood 2016An argument for FCR: FCR300
long-term outcomes
12.8 yr PFS:
53.9%
8.7%
Thompson, Blood 2016FCR300 – secondary cancers
Cancer Number
Secondary Hematologic
Med f/u 12.8 yrs:
AML / MDS 14
Myelodysplasia disorder, unclassified 1 • 14 cases MDS/AML
T-ALL 1 (5%), of whom only
4 received salvage
Mature T-cell NHL 3
therapy for CLL
RT • ? Solid tumors
DLBCL 20 different from
untreated CLL
HL 3 patients
Burkitt’s 1
Solid tumours
Non-melanoma skin cancer 28
Other 23
Thompson, Blood 2016Cumulative incidence of death due to CLL vs other cancers Thompson, Blood 2016
RESONATE-2
Conventional CLL management: First-line therapy
Conventional CLL management:
First-line therapy
Ibrutinib for IGHV
unmutated??A modern algorithm for
front-line treatment of CLL?
Kipps, Nat Rev Dis Primers 2017Ibrutinib in front-line fit patients - caveats • Currently limited published, prospective data in this patient population • Differences in disease biology may make it difficult to extrapolate from older patients’ experience • How targeted inhibitors lead to resistance and/or clonal evolution not well understood • Ongoing trials comparing Ib vs CIT
Ibrutinib vs Chemoimmunotherapy for TN Patients: a Cross-Trial Comparison Robak et al. ASH. 2017 Abstract 1750
Ongoing Phase III Ibrutinib vs
CIT trials – front-line fit
• FLAIR
– Ibrutinib +/- Rituximab vs FCR vs Ibrutinib +
Venetoclax
• ECOG1912
– Ibrutinib + Rituximab vs FCROngoing Phase III Ibrutinib trials – frontline unfit • Illuminate – Ib + Obinutuzumab vs Chl + Obinutuzumab • Alliance – Ibrutinib + Rituximab vs Ibrutinib vs BR • NCT02007044 – Ibrutinib +/- Rituximab Many trials evaluating combinations of novel agents, +/- anti-CD20 antibodies or chemotherapy, underway
Summary • Ibrutinib role expanding as we better understand the limitations of CIT in front-line CLL • Still a role for FCR in fit patients – IGHV mutated >> unmutated • Lesser role for CIT in older individuals, except in the rare patient with true contraindication to Ibrutinib, or for pt preference • Long-term follow up of Ibrutinib toxicity of interst
Merci Thank you
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