Cellule staminali: dal laboratorio alla clinica - Comtecmed.com

CAN ALL BE MANAGED WITHOUT
CHEMOTHERAPY/TRANSPLANT?
YES….
Robin Foà
Hematology, ‘Sapienza’University, Rome
Barcelona, COHEM, 6‐8 September 2012

GIMEMA: DFS According to Cytogenetic-
p

Enrolled: 45 patients
Evaluable: 37 patients
Imatinib in Adult Ph+ ALL:
GIMEMA LAL 0201B Study
Median age 68; range 61 – 89
Hematologic CR 100%
Vignetti et al. Blood 2007;109:3676–3678

GIMEMA LAL1205 Protocol
Dasatinib
Dasatinib 70 mg twice a day (total planned treatment is 12
weeks, i.e. 84 days)
Diagnostic work-up (within 7 d) and immunophenotypic &
molecular monitoring of MRD carried out centrally in Rome

GIMEMA LAL 1205 (Ph+ ALL)
55 patients enrolled
53 patients evaluable. Median age 53.6 years
(range 23.8‐76.5)
WBC (median) 18.8/mm 3
(range 2.2‐132.9)
33 p190, 20 p210
100% CHR
49 CHR (92.5%) already by day +22
No fatalities
OS at 20 months 69.2% (median 30.8 months)
DFS at 20 months 51.1% (median 21.1 months)
Foà et al. ASH, EHA & BLOOD 2011

A 91 YEAR OLD ALL PATIENT…
PC, diagnosed with Ph+ ALL in
September 2007 at the age of
89. Treated with Imatinib alone
(partly at home…). Obtained a
CHR, MRD-, and turned 90...
Drived a car and occasionally
helped in the family garage…
Relapse in June 2009. II nd CR
with Dasatinib. Relapse in
February 2010, responded to
VCR. Died March of heart failure,
at 91, 2½ years from diagnosis.
Courtesy of Prof. G. Pizzolo

GIMEMA LAL 0201‐B
Overall survival
N: 39 – events: 19
Vignetti et al. Blood 2007;109:3676–3678

Age‐Specific Annual Incidence of ALL
(US‐SEER Data, 1998–2002)
Larson RA. Acute Lymphoblastic Leukemia: Older Patients and
Newer Drugs. Hematology 2005:131‐136.

Incidence of molecular aberrations
within B‐ALL (GIMEMA‐AIEOP data)
GIMEMA LAL 2000: BCR/ABL+ 27.7%

Affymetrix normalized values
56007
T‐ALL and ABL rearrangements
43006
19008
12008
H 2 O
Nup214
ABL1
ABL1
ABL1
Chiaretti et al, Haematologica 2007

331 genes
GENE EXPRESSION PROFILE OF PRE‐B ALL
gain 1q and gain1q23
ALL1/AF4 has a unique gene expression
profile, that is comparable in children and in
adults. Overexpression of Flt3, HOXA5 and
HOXA9.
E2A/PBX is also characterized by a strong
signature. Most overexpressed genes: PBX1,
NID2, FAT and several tyrosine kinases. Gain
of 1q behave like E2A/PBX+ samples.
BCR/ABL has a profile characterized by
overexpression of several tyrosine kinases
and cell cycle related genes. More
heterogeneous profile.
No clear pattern is observed for samples
without molecular abnormalities.
Chiaretti et al, Clin Cancer Res, 2005

Ph‐LIKE CASES FOUND BOTH IN CHILDOOD
AND ADULT ALL BEING BCR‐ABL1
NEGATIVE
• Significantly inferior to outcome compared to that of
non‐BCR‐ABL1‐like cases.
• Novel chromosomal rearrangements and sequence
mutations found in high‐risk Ph‐like ALL.
These data support the screening at diagnosis to identify
Ph‐like ALL cases, characterize the genomic lesions
driving this phenotype and determine those that may
benefit from TKI treatment.

Bispecific anti‐CD19/anti‐CD3
• Blinatumomab (MT‐103), BiTE
• A bispecific single‐chain antibody derivative
designed to link B cells and T cells resulting in T‐
cell activation and a cytotoxic T‐cell response
against CD19 expressing cells.
• Promising results in phase I studies, particularly
on MRD clearance.
• A multicenter, multinational protocol aimed at
treating MRD in ALL ongoing started.
• Study ongoing also for relapsed/refractory ALL

Anti‐CD19 BiTE Blinatumomab Induces High Complete
Remission Rate In Adult Patients with Relapsed B‐Precursor
ALL: Updated Results of An Ongoing Phase II Trial
Max S. Topp, Wuerzburg University Medical Center, Germany
Abs #252
N. treated patients: 18
Adverse events: pyrexia and chills, CNS SAE in 4 (1 treatment
withdrawal and 3 temporary interruption). 1 patient treated with
initial dose of 15g/m²/day had a DIC)/cytokine release syndrome
(CRS) with treatment drop‐off. No BiTE related deaths.
Response rate: CR: 12/18 (67%), all MRD‐, including 3 t(4;11) and 1
Ph+
4 HSCT, 2 REL (1 CD19‐), 6 CCR
Conclusions: BiTE induces an unprecedented high rate of
complete hematological and MRD responses in adult
patients with relapsed/refractory B‐precursor ALL.

CAN ALL BE MANAGED WITHOUT
CHEMOTHERAPY/TRANSPLANT?
• Clearly shown that we can induce CRs in virtually all
Ph+ ALL with TKI + steroids (some MRD‐)
• Some patients are long‐lived without having ever
received chemotherapy
• Relapsed/refractory ALL can be induced into CR with
MoAbs alone
• Patients at presentation may respond even better
• Ideally, in such patients one would like to
control/eradicate the residual disease with a more
‘targeted’ strategy
• MoAb, vaccines, DC, expanded NK cells, …