CAN ALL BE MANAGED WITHOUT  CHEMOTHERAPY/TRANSPLANT?

YES….

Robin FoàHematology, ‘Sapienza’ University, Rome

Barcelona, COHEM, 6‐8 September 2012

Standard-risk: median DFS = 3.2 years

years from CR

p<0.0001

Standard: 85 events 47Intermediate: 56 events 34High: 91 events 75

Intermediate-risk: median DFS = 1.6 years

High-risk: median DFS = 0.62 years

GIMEMA: DFS According to Cytogenetic- Molecular Risk Groups

Mancini et al, Blood 2005

BCR/ABL+ALL1/AF-4

Imatinib in Adult Ph+ ALL: GIMEMA LAL 0201B Study

Evaluable: 37 patients

Median age 68; range 61 – 89

Hematologic CR 100%

Vignetti et al. Blood 2007;109:3676–3678

Enrolled: 45 patients

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 LAL1205 Protocol

55 patients enrolled  53 patients evaluable. Median age 53.6 years 

(range 23.8‐76.5)WBC (median) 18.8/mm3

(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)

GIMEMA LAL 1205 (Ph+ ALL)

Foà et al. ASH, EHA & BLOOD 2011

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. IInd 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

A 91 YEAR OLD ALL PATIENT…

N: 39 – events: 19

GIMEMA LAL 0201‐B Overall survival

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)

Age cohorts

<.0001

GIMEMA LAL 2000: BCR/ABL+ 27.7% 

Affy

met

rix

norm

aliz

ed v

alue

s

Nup214Nup214ABL1ABL1ABL1ABL1ABL1ABL1

5600

756

0 07

430 0

643

0 06

190 0

819

0 08

120 0

812

0 08

HH22OO

Chiaretti et al, Haematologica 2007

T‐ALL and ABL rearrangements

GENE EXPRESSION PROFILE OF PRE‐B ALL

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 strongsignature. 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

gain 1q and gain1q23

331

gene

s

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

Max S. Topp, Wuerzburg

University Medical Center, Germany

Abs #252

N. treated patients: 18Adverse 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. 

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

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, …