Leucemia acuta linfoblastica

F. Ferrara

Boiers C, EHA,2015

EDUCATIONAL PROGRAM

Boiers C, EHA,2015

Boiers C, EHA,2015

Boiers C, EHA,2015

Quiescent leukaemic cells account for minimal

residual disease in childhood lymphoblastic leukaemia.

Boiers C, EHA,2015

The need to eliminate highly quiescent cALL cells providesaplausible explanation for the requirement for prolonged (23 years) maintenance therapy to achieve durable clinicalremissions in cALL.

It also provides a plausible explanation for cALL cases, in whichthe relapse clone resembles the presentation leukaemic clone up to 8 years between diagnosis and relapse.

Boiers C, EHA,2015

Moorman A, EHA, 2015

EDUCATIONAL PROGRAM

Moorman A, EHA, 2015

Moorman A, EHA, 2015CNA: copy number alterations (microdeletions, point mutations)

Moorman A, EHA, 2015

Moorman A, EHA, 2015

Children/adolescents Adults

Most relevant abstracts

One session: Immunotherapy of ALL

EFFICACY AND SAFETY OF INOTUZUMAB OZOGAMICIN (INO) VS STANDARD OF CARE (SOC) IN SALVAGE 1 OR 2 PATIENTS WITH ACUTE LYMPHOBLASTIC LEUKEMIA (ALL): AN ONGOING GLOBAL PHASE 3 STUDY

De Angelo et al, Late Breaking Abstract 2, EHA 2015

In this phase 3 trial (NCT01564784), patients were randomized to

InO (starting dose 1.8 mg/m2/cycle [0.8 mg/m2 on d1; 0.5 mg/m2 on d8 and 15 of a 2128 d cycle [6 cycles])

or

SOC (either FLAG, or HAM, or HD-ARA-C).

A split- design was used for 2 primary endpoints: 1) CR or Cri 2) OS

Secondary endpoints: duration of remission (DOR), MRD-neg;

De Angelo et al, Late Breaking Abstracts 2, EHA 2015

Survival data blinded and expected in 2016

For InO vs SOC, Gr3 hepatobiliary AEs occurred in 9% vs 3% pts;

Any grade veno-occlusive liver disease (VOD) occurredin 15 vs 1 pts (Gr3, 13 vs 1 pts).

More patients proceeded to allogeneic SCT with InO(n=48) vs SOC (n=20)

In the InO arm, 5 VOD cases (2 in pts with prior SCT) occurred during treatment and 10 after subsequentSCT (2 fatal).

TOXICITY

De Angelo et al, Late Breaking Abstracts 2, EHA 2015

INOTUZUMAB OZOGAMICIN IN COMBINATION WITH LOW-INTENSITY CHEMOTHERAPY (MINI-HYPER-CVD) FOR THE FRONTLINE THERAPY IN ELDERLY

PATIENTS (>60 YEARS) WITH ACUTE LYMPHOBLASTIC LEUKEMIA (ALL)

Pts 60 years (yrs) with newly-diagnosed B-cell ALL were eligible.

Mini-hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m2 x 4 doses). Rituximab and intrathecal chemotherapy were given for first 4 courses.

INO was given on Day 3 of each of the first 4 courses. The first 6 pts received 1.3 mg/m2 for cycle 1 followed by 0.8 mg/m2 for subsequent cycles;

Pts 7 onwards received 1.8 mg/m2 for Cycle 1 followed by 1.3 mg/m2 for subsequentcycles.

Jabbour et al, Abs S114, EHA 2015

Jabbour et al, Abs S114, EHA 2015

MiniHCVD-INO in ALL. Outcome

N=28 pts

N=1

Resistant

N=27

responders

22 CR; 5 CRp

N=2

Relapse

N=0

Early death

N=1

Died of PD

N=1

Allo-SCT

N=4

Died in CR/CRp

2 Sepsis

1 Gunshot wound

1 Unknown

N=17

POMP maintenanceN=3

Consolidation

Median follow up of 15 months (4-31)

N=2

Died of PD

Jabbour et al, Abs S114, EHA 2015

CAR-T

T Cells Engineered with a Chimeric Antigen Receptor (CAR) Targeting CD19 Have Long Term Persistence and Induce Durable Remissions in Relapsed,

Refractory ALL.

PENNCHOPMSKCC

EFFICACY AND SAFETY OF CD19-TARGETED 19-28Z CAR MODIFIED T CELLS IN ADULT PATIENTS WITH RELAPSED OR REFRACTORY B-ALL

Park J, Abs S112, EHA 2015

Adult patients with R/R B-ALL underwent leukapheresis, and T cells were transduced with a gammaretroviralvector encoding a CAR construct composed of anti-CD19 scFv linked to CD28 and CD3 signaling domains (19-28z).

All patients received conditioning chemotherapy followedby 13x106 19-28z CAR T cells/kg.

33 patients have been treated, and 32 patients are evaluable for response.

The median age was 54 years (range, 22-74).

12 patients (36%) had Ph+ ALL

11 patients (33%) had prior allo-SCT

14 patients (42%) had 3 prior lines of therapy.

Park J, Abs S112, EHA 2015

19-28z CAR T cells can induce a high CR rate of 91% in adultpatients with R/R ALL.

The risk of sCRS correlates with disease burden and can be effectively managed.

These findings strongly support the use of 19-28z CAR T cellsin adults with R/R ALL and warrants investigation in a phase2 trial.

Park J, Abs S112, EHA 2015

CHIMERIC ANTIGEN RECEPTOR (CAR)-MODIFIED T CELLS TARGETING CD19 INDUCE SUSTAINED REMISSIONS IN CHILDREN

AND YOUNG ADULTS WITH RELAPSED/REFRACTORY ALL

Maude S, Abs S111, EHA 2015

Aims

Establish the safety and efficacy of CTL019 for patients with relapsed/refractoryCD19+ ALL.

Methods

After informed consent, T cells collected from the patient were transduced with a lentiviral vector encoding a CAR composed of anti-CD19 scFv, CD3z, and 4-1BB domains, activated/expanded ex vivo with anti-CD3/anti-CD28 beads, cryopreserved, and then infused. 35/40 patients received lymphodepleting chemotherapy the week prior to cell infusion

93 92

25

93

0

10

20

30

40

50

60

70

80

90

100

CR CR MRD- RELAPSE CRS

Maude S, Abs S111, EHA 2015

RESULTS

Most responding pts developed grade 1-4 CRS at peak T cellexpansion (increases of IL6 and IFN, both up to 1000x, and IL2R).

Treatment for CRS was required for hemodynamic or respiratoryinstability in 37% of patients and was rapidly reversed in all caseswith the IL6-receptor antagonist tocilizumab, together with corticosteroids in 5 pts.

Grade 4 CRS was strongly associated with high disease burdenprior to infusion and with elevations in IL-6, ferritin (suggestingmacrophage activation syndrome) and CRP.

Although T cells collected from pts who had relapsed after allo SCT were median 100% donor origin, no GVHD has been seen.

CRS

Maude S, Abs S111, EHA 2015

Maude S, Abs S111, EHA 2015

PENN University

Maude S, Abs S111, EHA 2015

Single-agent CTL019 immunotherapy can induce potent and durable responses in patients with R/RALL.

CRS was effectively controlled with IL6 blockade.

Long-term disease control is possible withoutsubsequent stem cell transplantation

Conclusions

Maude S, Abs S111, EHA 2015

Such TRUCK T cells are moreover envisioned to be

applied in fields beyond cancer therapy including the

therapy of virus infections, auto-immune diseases

or metabolic disorders.

TRUCK T cells

CAR-T or TRUCK T CELLS : FURTHCOMING ISSUES

For all relapsing patients ?

For first, second or subsequent relapse ?

For patients who are candidate to SCT ?

For the treatment of MRD+ patients ?

Costs and feasibility

QUESTIONS

Is it time for a new integrated diagnostic/prognostic classification(MOL/GEN BASED) in ALL (either for children or adults) ?

Which is the role of new monoclonal antibodies (Blinatumomab, Inotuzumab-GO) in the treatment of ALL ?

Which patiens should receive CART therapy ?