Presentation Slides - Hairy Cell Leukemia Foundation

Report
Subcutaneous Cladribine for HCL in
the BRAF era
Francesco Forconi (MD, DM, PhD, FRCPath)
Cancer Research UK Centre and Haematology Department
Southampton University Hospital Trust
email: [email protected]
CLADRIBINE I.V. AND S.C. IN HCL
• Intravenous Cladribine-iv2CdA
– 0.7 mg/kg single cycle
• Continuous 0.1 mg/kg daily over 7
days
• 2-hour 0.1 mg/kg daily over 7 days
• Subcutaneous Cladribine -sc2CdA
– 0.7 mg/kg single cycle
– 100% bioavailability
Juliusson et al, Lancet 1993, J Clin Oncol 1996
Juliusson , NIH, Bethesda, 2010
INFECTIONS WITH CLADRIBINE
Intravenous Cladribine (iv2CdA)
sc2CdA reduction in NHL
– 0.7 mg/kg single cycle
– 42% febrile episodes
0.5 mg/kg/cycle
0.7 mg/kg/cycle
55%
– 13% documented infections
Saven (Scripps), Blood , 1998
Infections (%)
Neutropenia (%)
7
30
8
33
Subcutaneous Cladribine (sc2CdA)
In indolent non-Hodgkin lymphomas other
than HCL:
– at the dose of 0.7 mg/kg/cycle, efficacy of
sc2CdA is similar to iv2CdA
– reduction to 0.5 mg/kg/cycle determines
equivalent efficacy and lower toxicity
p=.003
53
Response (%)
Duration (months)
p=.0001
57
12
7
p=.72
p=.21
Betticher (SAKK), J Clin Oncol 1998
ICGHCL2004 protocol
EudraCT code: ICGHCL2004
2CdA s.c.
0.1 mg/kg/day
Arm A
Arm B
5 days
7 days
PATIENTS
EudraCT code: ICGHCL2004
ARM A
156 patients
(randomised)
24 centers
Central revision
WHO 2001 criteria
• morphology
• HCL phenotype
• CD11c +
• CD19 +
• CD20 +
• CD25 +
• CD27 –
• CD38 –
• CD103 +
• FMC7 +
WHO 2008 criteria
• ANXA1 + (IHC)
- HC>1010/L
- Spleen > 10 cm
- Refractory
Classic HCL
Median follow-up
62 months
ARM B
NON HEMATOLOGICAL GRADE 3-4 TOXICITY
NO
YES
P=,017
Infections or FUO
NO
YES
P=,012
Hospitalization days 7-30
Higher infection rate and hospitalization in standard dose (Arm B) than in reduce dose (Arm A)
RESPONSES TO SUBCUTANEOUS 2CDA
■ CR/PR
■ mR/NR
p=0.7
100
80
60
40
20
0
Arm A
Arm B
~50% patients investigated for BRAF V600E mutation: no differences in response rates
ENDPOINTS OF SURVIVAL AFTER TREATMENT
TFI: Treatment free interval (2° treatment)
OS: Overall survival
TFI and OS
Arm A
Arm A
Arm B
% surviving
% Treatment free
Arm B
p=0.9
p=0.58
Time to 2° tratment (months)
Overall survival (months)
~50% patients investigated for BRAF V600E mutation: no differences in survivals
MOLECULAR PROGNOSTIC MARKERS OF TFI IN BRAF+ HCL
Multiple Ig isotype
M-IG
IgM
IgD
IgG
UM-IG
IgA
P<.001
AID +
Ongoing SHM
•HCL has a very stabe genomic profile
10
RAF-MEK Pathway
BCR Signaling Pathway
V600E
LYN
RAF
Vemurafenib
PI3K
P
PIP3
P
PDK
AKT
P
Dasatinib
MEK
GS-1101
Ibrutinib
RAS
ERK
PLC
2
BLNK
P
BTK
P
SYK
RAS
CD79B
P
P
CD79A
RTK
IP3
DAG
Ca2+
PKC
Fostamatinib
RAF1
survival
proliferation
transformation
NFAT
survival
ERK
JNK
p38
MYC
JUN
ATF2
apoptosis
proliferation
IKK
NFκB
migration
Conclusions
• Cladribine at reduced doses has lower toxicity and
similar efficacy
• BRAF mutational status: critical to identify patients non
benefiting from Cladribine?
• New effective treatments (if/when required):
• HCL express high levels of multiple Ig isotypes that are functional
• Surface Ig and signaling is irrespective of BRAF V600E
• BCR-inhibitors act on the tumor component that signals through BCR
• BCR-inhibitors as an alternative strategy?
• Markers to identify poor outcome in BRAF+ HCL
Slide 12

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