O Papel da Imunoterapia na Otimização dos Desfechos em LLAsbtmo2018.com.br/wp-content/uploads/2018/08/02-08-12H45-SS-AMGEN... · SIMPÓSIO SATÉLITE AMGEN O Papel da Imunoterapia

SIMPÓSIO SATÉLITE AMGEN

O Papel da Imunoterapia na Otimização dos Desfechos em LLA

• Otimizando os desfechos pós-transplante em LLA Dr. Peter Bader

• Imunoterapia com Blinatumomabe – quais as possibilidades? Dr. Peter Bader

• Discussão de Caso Clínico Dr. Nelson Hamerschlak

Optimizing transplant outcomes in ALL

Peter Bader

SBTMO 2018 – ALL Satellite Symposium

“Role of MRD and Immunotherapy in Optimizing ALL Treatment Outcomes”

Rio de Janeiro, August 2nd, 2018

3

Objectives

• Risk stratifications before transplant and post transplant based on MRD

• Correlation of MRD status pre-HSCT to outcome

• Relapse major cause for treatment failure

• Brief overview of options to prevent relapse in ALL patients

Cellular therapies

Checkpoint inhibitors

Antibody treatment

4

Stem-Cell Transplantation in Children With Acute Lymphoblastic Leukemia: A Prospective

International Multicenter Trial Comparing Sibling Donors With Matched Unrelated Donors—

The ALL-SCT-BFM-2003 TrialChristina Peters, Martin Schrappe, Arend von Stackelberg, André Schrauder, Peter Bader, Wolfram Ebell,Peter Lang, Karl-Walter Sykora,

Johanna Schrum, Bernhard Kremens, Karoline Ehlert, Michael H. Albert,Roland Meisel, Susanne Matthes-Martin, Tayfun Gungor, Wolfgang

Holter, Brigitte Strahm, Bernd Gruhn,Ansgar Schulz, Wilhelm Woessmann, Ulrike Poetschger, Martin Zimmermann, and Thomas Klingebiel

C. Peters et al.

J Clin Oncol 2015

MSD: 71%

MUD: 69%

MSD: 3%

MUD: 10%MSD: 24%

MUD: 22%

MSD: 79%

MUD: 73%

5

M. Kuhlen et al.

Br J Haematol 2017

Outcome of relapse after allogeneic HSCT in children

with ALL enrolled in the ALL‐SCT 2003/2007 trial

6

Risk Stratification Post-transplant• Relapse is the major cause of treatment

failure

Incidence of relapse: 30-60%

• Curative treatment options are limited

• Treatment of impending relapse?MRD

Chimerism

7

Studies on Chimerism in ALL1999-2003

AuthorNumber

ofpatients

DiagnosisInterval of

investigationsMethods

Relapses

Ferandez-Aviles

Leukemia 2003 40 AL, CMLDay 28, monthly

STRMC associated with

rejection and relapse

Barrios et al.

Haematologica2003

133 ALL, AML monthly STR

In-MC associatedwith relapse in uni and multivariate

analysis

Guimond et al

BR J Haemoalogy

2000

81Leukemia, Lymphoma,

MDSNot specified STR

MC associated with relapse

in children: yes

In adults: no

Schaap

Leukemia 200219/231

AL and othermalignancies

Two times Cytogen. No association

8

Consequences?Role for Pre-emptive Imunotherapy?

T-cells ChimerismRelapse

CC

AR

MC

Donor T-cells

Recipient T-cells

Immunotherapy by

withdrawal of

immunosuppression

or DLI

9

responded to immunotherapy but died of severe infection

with multiple-organ involvement). The third patient did

not respond to low-dose DLI and progressed to frank he-

matological relapse. Two additional DLIs with increasing

cell doses(up to5 106) weregiven. Thepatient’sleukemic

blast cellsdisappeared, and completedonor chimerism was

restored; however, the patient died on day 323 of severe

acuteGVHD of theskin, liver, and intestines.

DISCUSSION

Despite the completion of several studies, the efficacy of

immunotherapy after allogeneic transplantation for acute

leukemia isstill thesubject of debate.6-9,18,37

Theresultsreported heredemonstratethat serial char-

acterization of posttransplantation chimerism offers the

possibility of identifying those patients who are at highest

risk to develop relapse. Moreover, these results show that

many patients with increasing MC, who otherwise face

almost certain relapse and death, can be rescued by addi-

tional immunotherapy. The probability of 3-year EFS in

patientswith increasingMCwas0%in theuntreated group,

but 37% in patients who received early treatment. We ac-

knowledgethat becausethisstudy wasnot randomized, we

cannot rule out selection bias as a factor in our results.

However, the striking difference between the outcomes of

treated and untreated patientsislikely to reflect theeffect of

therapy, as the two groups of patients with increasing MC

with or without prophylactic therapy did not differ with

regard to relevant transplant factorssuch asdonor, typeof

graft, conditioning regimen, or T-cell depletion of thegraft.

A GVL reaction in patientswith ALL issuggested bythe

higher incidenceof relapsein theabsenceof GVHD38-40or

with the use of T-cell–depleted allografts.41 These experi-

mental results impressively mirror our finding that the

highest frequency of increasing MC wasdetectable in those

cohorts that received T-cell–depleted stem cells. Thiscon-

firms that aT-cell depletion substantially reduces theallo-

reactivity of agraft, facilitates therecurrence of autologous

hematopoiesis, and allows theunderlying disease to newly

expand.42-44 Additional support for the GVL effect in pa-

tientswith ALL can befound in astudy from Locatelli et al

in which it wasreported that low-doseCSA reducestherisk

of relapse in children with acute leukemia receiving grafts

from human leukocyte antigen–identical siblings.45 Slavin

Fig 1. Kaplan-Meier analysis of event-free survival (EFS) for all study

patients (N 163). The 3-year EFS estimate was 54%.

Fig 2. Kaplan-Meier analysis of event free survival (EFS) according to chimer-

ism status. CC/LL-MC, complete chimerism/low-level mixed chimerism; de-

MC, decreasing mixed chimerism; in-MC, increasing mixed chimerism.

Fig 3. Kaplan-Meier analysis of event-

free survival (EFS) in patients with in-

creasing mixed chimerism (MC). Pa-

tients with increasing MC (in-MC) who

received additional therapy (A, n 31)

and patients with increasing MC who

did not receive additional treatment (B,

n 15).

Chimerism-Based Pre-Emptive Immunotherapy

www.jco.org 1701

Information downloaded from jco.ascopubs.org and provided by at Unibibliothek on February 12, 2012 from 141.2.86.220Copyright © 2004 American Society of Clinical Oncology. All rights reserved.

P. Bader et al.

J Clin Oncol 2004

Pre-emptive Immunotherapy

10

Author Numberof

patients

Diagnosis Interval ofinvestigatio

ns

Methods Relapses

Formakova

Haematologica 200354

AL, CML and MDS

children

weekly to +100;

monthly

STR

MC associated with rejection and relapse

Immunotherapy was possible

Gorczynska

BMT 200414

ALL, AML

children

weekly to+100;

monthly

STR

In-MC could beconverted by

immunotherapy to CC

Bader

JCO 2004163

ALL

children

weekly to +100;

monthly

STRMC associated with

relapse

Immunotherapy was possible in most patients

Horn

BMT 200820

AL

children

1,3,6,12 months;

In MC bi-weekly

STR

MC associated withrelapse

IT was not possible

Studies on Chimerism and

Intervention

11

• Immunotherapy (WD of immuno-suppression, DLI) is principally effective as pre-emptive treatment

• Chimerism can be used as surrogate marker for identifying patients at risk for impending relapse

However,Not in all patients!

Additional role for MRD?

Conclusion I

12

Impact of MRD prior to HSCTRetrospective Studies

Bader et al., Leukemia 2002

MRD „high“ n=17 pEFS 0.23

EFS

0,0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1,0

0 1 2 3 4 5 6 7 8 9 10Time [Years]

MRD negative n=14 pEFS 0.78

MRD „low“ n=10 pEFS 0.48

p=0,022

n=41

D-2 -3 -4 -5 -6

MW prior

„Semi quantitative“ Dot-Blot Hybridisierung

Knechtli et al., Blood 1998

13

Prospective evaluation

of MRD prior to HSCT

1999-2006

Inclusion criteria

Remission (≥ CR2)

Leukemia DNA from

diagnosis of relapse

BM Sample prior to

HSCT

P. Bader et al.

J Clin Oncol 2009

BFM ALL REZ GroupProspective pre-HSCT MRD Study

14

Probability curves of patients who

were MRD negative or positive by

flow cytometry or deep

sequencing. (A) Relapse risk by pre-

HCT NGS-MRD compared with MFC-

MRD status. (B) OS by pre-HCT NGS-

MRD compared with NGS-MRD status.

n=143

children and

adolescents with ALL

M.A. Pulsipher et al.

Blood 2015

MRD prior to HSCT: Flow versus

NGS

15

• Immunotherapy (WD of immunosuppression, DLI) is principally effective as pre-emptivetreatment


• MRD prior to transplant identifies patients at highest risk for relapse

Influence for current treatment and indication policy

Conclusion II

16

• Immunotherapy (WD of immunosuppression, DLI) is principally effective as pre-emptivetreatment


• MRD prior to transplant identifies patients at highest risk for relapse

• What adds analysis of post transplant MRD?

Conclusion III

17

day +30 +60 +90

gold: MRD negativegrey: MRD < 10E-4blue: MRD ≥ 10E-4

P. Bader et al.

J Clin Oncol 2015

Prognostic value of MRD I

Ped. ALL, n=113

18

Prognostic value of MRD II

day +180 +365

gold: MRD negativegrey: MRD < 10E-4blue: MRD ≥ 10E-4

P. Bader et al.

J Clin Oncol 2015

Ped. ALL, n=113

19

Author Numberof

patients

Diagnosis Investigation Methods Interpretation

Pochon

Br J Haematol. 2014

France

133ALL

children

MRD pre and post

Chimerism

Ig- TCR-RT-PCR

MRE strongly associated withrelapse prior and post.

Window for intervention

Bar

Leuk Res Treat 2014

FHRC

160ALL childrenand adults

MRD pre and post FlowMRD pre and post associtated of

relapse and inferior survival

Logan

BBMT 2014

UCSF/Stanford

29ALL

adultMRD pre and post

Flow MRD predicts relapse

Window for intervention

Bachanova

BBMT 2012

Minneapolis

86ALL childrenand adults

MRD pre

Cord transplantsFlow

MRD neg before transplant improves survival

Terwey

BBMT 2014

Berlin

101 ALL adultsMRD and

chimerism in subpopulation

Ig-TCR-RT-PCR;

STR

Chimerism in subpop predictable; MRD prior and post important; individual diagnosis possible

Balduzzi

Br J Haematol 201382

ALL

childrenMRD prior and post

Ig-TCR-RT-PCR;

MRD pre negative prognosticfactor; MRD post allows

prediction of relapse

Studies MRD Analysis in the setting

of HSCT 2012-2014

20

MRD Pre- and Post-HSCT

Lovisa et al.

Br J Haematol 2018

21

• MRD analysis is very important for stratification into different treatment arms prior to transplant >10-3 MRD prior to allogeneic SCT is independently related to

EFS and to CIR

Treatment modification to reduce MRD load prior to transplant is under investigation

• MRD assessment in BM post transplant is predictive for relapse and survival BM investigations are warranted and recommended on days 30,

60, 100, 200, 300, 365 and at 18 months

Patients who become/remain MRD positive >10-4, have an extremely high risk to relapse

MRD positive >10-3 leads to relapse!

Additional treatment in these patients seems to be warranted.

Final Conclusions

22Cancer immunotherapy

Tumor-antigen-specific T cell

MHC

Checkpoint blockade

anti-CTLA4

anti-PD1

anti-PDL1

T cell clones

CAR T cell

Tumor cell

TCR engineered T cell

BITE

Antibody-drug conjugated

Tumor antigen

Tumor antigen

DLI

NK cell

CIK cell

PDL 1

TCR

Dendritic cell

adapted: Maus et al. Blood, 2014

unspecificspecific

Treatment Options

23

Handgretinger et al.

Leukemia 2011

Nagorsen et al.

Leuk & Lymph 2009

T-cell Engaging Anti-CD19-Antibody Blinatumomab

24

Patient with c-ALL3rd relapse at day 200 after 1st allo-HSCT

-20 0 20 40 60

0

20

40

60

1.010-06

1.010-04

1.010-02

1.01000

1.01002

100 300

Days

cells p

er

nl

Leuko

Neutro

Lympho

MRD

Blinatumomab 2nd HSCT

25

CAR T-Cell Therapy

Lentiviral vector

T cell

CD19

Native TCR

Tumor cell

CTL019 cell

Dead tumor cell

Anti-CD19 CAR construct

26

S.L. Maude et al.

NEJM 2018

CTL019 - Tisagenlecleucel

27


S.L. Maude et al.

NEJM 2018

28


S.L. Maude et al.

NEJM 2018

29

Anti-CD3

IFNγIL-15

CIK

CIK

CIKCIK

CIKCIK

CIKCIK

Day 0 Day 21

IL-2

MNC

IL-2 IL-2 IL-2 IL-2

IFNγ

Anti-CD3

IL-2

Day 0

Day 1

Day 1every 3-4 days

Activation of monocytes, antigen cross-presentation

Mitogenic signals for T lymphocytes

T cell proliferation, survival and cytolytic effector function

Schmidt-Wolf et al. J Exp Med, 1991

Cytokine-induced killer cells

Cytokine-induced Killer Cells (CIK)

30

3 31

65

1 39

59

Day 7 Day 14

1 58

42

Day 21

CD3

CD56

Day 0

9 16

66

CD3+CD56+CD8+CD27+/-CD28-

Cytokine-induced killer cells

CIK

TCR

NCRs

Tumor

Granzyme

Perforin

MHC ICo-stimulation

Tumor peptide

TumorT cell receptor NKG2D receptor

a bCD3CD3

CD3 ζ

Tumor

CIKNKG2D

16xFITC CD3, DAPI, PE NKG2D

Pievani et al. Blood, 2011

Dual-functional capability

Phenotype and Function

31Cytokine-induced killer cells

0 3 6 9 12 18 24 30 360%

10%

50

100

150

0

500

1000

1500

2000

< 1x10-6

1x10-6

1x10-5

1x10-4

1x10-3

1x10-2

1x10-1

1x100

1x101

months post-transplant

#32

chimerism

MRD

T

T-NK

NK

cells/µl

recipientsignal

10 x106 CD3+/kg115

15

Molecular relapse

FFM: c-ALL, CR2, Allogeneic

HSCT (MUD)

32

Summary

• Prevention (and treatment) of relapse after allo-SCT

Options are increasingChances of cure after relapse are critical

Strategies to prevent relapse (MRD, chimerism and pre-emptive therapy!)

Leukemia targeting therapyEmerging: Antibodies

CAR T-cell therapy

LAA cell therapy

Cooperations

Halvard BönigGerman Red Cross Blood Donor Service Frankfurt/Main, Germany

Winfried S. WelsGeorg-Speyer-Haus, Frankfurt/Main, Germany

PhysiciansMichael MerkerShahrzad BakhtiarEva RettingerAndre WillaschAndrea JarischJan Sörensen

Graft Manipulation,Cell Therapeutics Sabine Huenecke Melanie BremmClaudia CappelVerena PfirrmannSibylle Wehner

Mesenchymal Stroma CellsZyrafete KuçiSelim Kuçi

CIK / T Cell TherapyEva RettingerVerena PfirrmannMichael MerkerLisa-Marie PfeffermannSarah OelsnerVida Meyer Molecular Biology

Andre WillaschChristlinde MauracherGitta NozadFariba SoltaniMiriam StaisHermann Kreyenberg

Pediatric Stem Cell Transplantation & Immunology: Peter Bader / Evelyn Ullrich / Thomas Klingebiel

Clinical Trial OfficeVerena PfirrmannBettina SteinmetzTina Homrighausen

OfficeKirsten Schäfer

NK cells / ExperimentalSara TognarelliJuliane WagnerJochen FrühKatja Thoma

Bio MathematicsEmilia Salzmann-Manrique

Participating Institutions Düsseldorf, Germany

Roland Meisel Florian Babor Friedhelm Schuster

Frankfurt/Main, Germany Hubert Serve Gesine Bug

Mainz, Germany Matthias Theobald Eva Wagner Hauptrock Beate

Heidelberg, Germany Johann Greil

34

Treatment strategies:Conventional DLI: Efficacy limited (Kolb et al. 1997)

Leukemia targeted immunotherapy Antibody treatment CD19, CD22, CD52

Cellular therapies: CAR T-cell therapy

CIK cell therapy

Checkpoint inhibition TKI, Dasatinib, JAK-inhibitors, Bortezomib,

Flt3-inhibitors, M-TOR inhibitors, aurora kinase inhibitors, Syk-inhibitors: limited data

Low-dose Chemo-Immunotherapy w/wo DLI

Second allogeneic SCT: EFS poor, 10-30%

Principal Considerations II

Immunotherapy with BlinatumomabWhat are the possibilities?

Peter Bader

SBTMO 2018 – ALL Satellite Symposium

“Role of MRD and Immunotherapy in Optimizing ALL Treatment Outcomes”

Rio de Janeiro, August 2nd, 2018

36

Objectives

• Refractory ALL

• Blinatumomab, Product, clinical development

• Blinatumomab in Children and Adults

TOWER Study; BLAST Study, AND RIALTO Study

Own data in 18 children

Present data from TOWER (AllHSCT in adults withR/R ALL from Phase 3

37

Poor Outcome for Patients with r/r

pB-ALLPediatric patients Adult patients

Standard pB-ALL

CR with frontline chemo 98-99% 85-90%

relapse 15-20% 30-50%

Long-term survival afterearly relapseslate relapses

25%50-60%

8%24%

r/r pB-ALL

Median OS with chemo only - 4.5-8.4 months

5y-median OS with chemo only - 7-10%

Median OS after chemo only - 10 months

Median OS after HSCT 7.4 months 5.8 months

New agents with reduced toxicity are needed to improve outcomes for patients with r/r pB-ALL

38

Bispecific T-Cell Engager:

Blinatumomab

Nagorsen et al. Leuk & Lymph 2009

Baeuerle P.A. et al. Cancer Res. 2009

Bargou R. et al. Science 2008

Topp M.S. et al. Lancet Oncol. 2015

Activation signals promote CTC proliferation

Klinger M. et al.

Blood 2012

Serial lysis of CD19+ B cells

Hoffmann P. et al.

Int J Cancer 2005

39Nagorsen et al. 2012

Blinatumomab – Mode of Action

40

Blinatumomab – Clinical Develpoment

Nagorsen et al. 2012

© Amgen Inc. All Rights Reserved.

A Phase 3, Randomized, Open Label Study Investigating the Efficacy of the BiTE Antibody

Blinatumomab Versus Standard of Care Chemotherapy in Adult Subjects With

Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (ALL)

Study (TOWER) – NCT02013167

42

TOWER Study in Adult r/r pB-ALLS

cre

enin

g/P

re-p

hase

Safe

ty f

ollo

w-u

p

Blinatumomab

cIV infusion

4 weeks on

2 weeks off

2 cycles

SOC

chemotherapy

2 cycles

Consolidation3 cycles

Maintenance 12 months

Ran

do

miz

atio

n


BLAST: A Confirmatory, Single-Arm, Phase 2 Study of Blinatumomab, a Bispecific T-Cell Engager (BiTE)

Antibody Construct, in Patients with Minimal Residual Disease B-Precursor Acute Lymphoblastic

Leukemia (ALL)

Study (BLAST) – NCT01207388

44

BLAST Study in Adult r/r pB-ALL, MRD-based

Scre

enin

g/P

re-p

hase

Safe

ty fo

llow

-up

Long-t

erm

follo

w-u

p

Blinatumomab15 μg/m2 cIV infusion

i.th. prophylaxis

4 weeks on2 weeks off

Up to 4 cycles

HSCT offered to patiens in CR


Open-label, multicentre, expanded access study of blinatumomab* in paediatric and adolescent patients

with relapsed/refractory B-precursor ALL

Study 320 (RIALTO) – NCT02187354

*Blinatumomab is not licensed for use in paediatric patients in the EU

SC-EU-AMG103-00339-06.17

SC-DE-AMG103-00140

46

RIALTO Study in r/r pB-ALLS

cre

enin

g/P

re-p

hase

Safe

ty fo

llow

-up

Long-t

erm

follo

w-u

pBlinatumomab

cIV infusion

4 weeks on

2 weeks off

Up to 5 cycles

HSCT offered to patiens in CR

47

Key Eligibility CriteriaTOWER Study BLAST Study RIALTO Study

Age ≥18 y ≥ 18 y >28 d and <18 y

CD19+ pB-ALL with ≥5% blasts in BM

x x

CD19+ pB-ALL with <5% blasts in BMMRD ≥10E-4 (- ≥10E-3)

x

Ph negative x x x

2nd or later relapse, anyrlps. after HSCT, refractory disease1st relapse w remissonduration <12 months

xxxx

(x) xxx

Adequate liver function x x x

ECOG status ≤2 0 or 1

No prior HSCT x

48

Key Exclusion CriteriaTOWER Study BLAST Study RIALTO Study

Clinical relevant CNS pathology

x x x

Isolated extramedullarydisease

x x

Chemotherapy within 2 wk,Radiotherapy within 2-4 wk

x

x

x

x

x

x

Immunotherapy x

Immunosuppressionwithin 2 weeks

x x

Auto HSCT within 6 wkAllo HSCT within 12 wk

xx

xx

Grade 2-4 aGVHD,Active cGVHD

xx

xx

Abnormal liver orrenal function

xx

xx

49

Study EndpointsTOWER Study BLAST Study RIALTO Study

Primary endpoint: EfficacyOS

Primary endpoint: EfficacyMRD response after 1 cycle(MRD neg with sensitivity of at least 10E-4 by PCR in reference lab)

Primary endpoint: SafetyTreatment-emergent/related AEs

Secondary endpoint:EfficacyEFSRemission rate

SafetyIncidence and severity of AEs

Secondary endpoint:Efficacy (w/wo HSCT)RFSOSDuration of MRD response

SafetyIncidence and severity of AEs

Secondary endpoint:EfficacyCR within first 2 cyclesMRD neg. within first 2 cyclesRFSOSRate of allo-HSCT after CR

50

TOWER Study Blinatumomab vs. Chemo in Adult-ALL

Hagop Kantarjiann et al. NEJM 2017

Prospective 2:1 randomized trial: n=405

Blina: 271 Chemo: 134

Median OSBlina: 7.7 mo Chemo: 4.0 mo

CR/Cri (12 weeks): Blina: 36/44% Chemo: 16/25%

6 months EFS:Blina: 31% Chemo: 12%

Longer remission durationBlina: 7.3 mo Chemo: 4.6 mo

AES grade 3Blina: 87% Chemo: 92%

Treatment with blina resulted in longer OS

51

Zugmaier et al.

Blood 2015

n=36

BLAST Study Blinatumomab in MRD Positive Adult-ALL

52

BLAST Study Blinatumomab in MRD Positive Adult-ALL

Zugmaier et al.

Blood 2015

28% achieved an OS of 30 mo

Survival may be associatedwith MRD response

n=36

53

Results

Evaluable 113Median age 45 (18-76) yrsIn 2nd/later CR: 36%

MolCR: 78%

Median OS: 36.5 mo- Mol CR y/n: 38.9 vs 12.5 mo

Median RFS: 18.9 mo- Mol CR y/n: 23.6 vs 5.7 mo- 1st / later CR: 24.6 vs 11 mo

BLAST Study (Follow-up)Blinatumomab in MRD Positive Adult-ALL

Gökbuget et al.

Blood 2018

MRD response resulted in improved OS and RFS

54

RIALTO Study: Patient

Demographics and Baseline

Characteristics

Locatelli F, et al. ASCO 2017; Abstract 10530 and poster presentation.

Characteristic All patients (N=40)

Male, n (%) 19 (48)

Median (range) age, years 9 (1–17)

Age group, n (%)

1 month to <2 years

2 to <12 years

12 to <17 years

5 (13)

20 (50)

15 (38)

Prior relapses, n (%)

0 (primary refractory)

1

≥2

5 (13)

11 (28)

24 (60)

Prior allogeneic HSCT, n (%) 21 (53)

Bone marrow blasts (local), n (%)

<50%

≥50%

22 (55)

18 (45)

55

RIALTO Study: Response Within

first 2 Cycles


• Median number of cycles started and completed: 2 (range, 1−5)

All patients (N=40)

n/N1* % 95% CI

CR during the first two cycles

<50% blasts

≥50% blasts

t(17;19)

25/40

15/22

10/18

2/2

63

68

56

100

46–77

45–86

31–79

NA

MRD response during the first two cycles†

<50% blasts

≥50% blasts

t(17;19)

19/25

12/15

7/10

2/2

76

80

70

100

55–91

52–96

35–93

NA

HSCT realisation‡

Allogeneic HSCT after CR

Allogeneic HSCT without CR

10/25

3/14

40

21

21–61

5–51

56

RIALTO Study: Overall Survival


Censored at time of allogeneic HSCT N

Median OS, months

95% CI, months

Not censored 40 9.8 7.1–NE

Censored 40 8.3 5.4–9.8

181614121086420

0

0

1

0

1

0

1

0

3

1

7

1

12

4

12

4

15

7

16

8

17

9

22

12

30

18

33

25

33

30

37

37

39

39

40

40

0.0

0.2

0.4

0.6

0.8

1.0

Time (months)

Surv

ival pro

babili

ty

Number of subjects at risk:

Median follow-up: 11.8 months

Not censored Censored

Frankfurt Patients (N=18)

N (%) N (%)

Sex

Male

Female

14

4

(78)

(22)

Age

median [range]

13 years

[2 - 20]

Diagnosis

ALL

B-NHL

17

1

(94)

(6)

Number of SCTs before

treatment

0

1

2

7

10

1

(39)

(56)

(6)

Number of relapses before

treatment

1

2

3

4

9

6

2

1

(50)

(33)

(11)

(6)

Number of Blinatumomab

cycles

1

2

11

7

(61)

(39)

Duration of Blinatumomab

cycle

median [range]

28 days

[2-36]

Course after Blinatumomabmedian post treatment observation period: 1.6 years [25 days – 5.5 years]

Response to

BlinatumomabSCT after treatment

Total Yes (%) No (%)

CR (MRD+/-)8 6 (75) 2 (25)

NR10 7 (70) 3 (30)

Total18 13 (72) 5 (28)

Outcome in Patients with SCTs after

Blinatumomabmedian post SCT observation period: 2.5 years [83 days – 5.4 years]

Response to

BlinatumomabOutcome

Total CR (%) Relapse (%) TRM (%)

CR (MRD+/-)6 2 (33) 2 (33) 2 (33)

NR7 3 (43) 3 (43) 1 (14)

Total13 5 (39) 5 (39) 3 (23)

Outcome of patients without SCT (n=5)

Response to

BlinatumomabOutcome

Total CR (%) Lost to

follow-up

(%) Death (%)

CR (MRD+/-)2 2 (100) 0 (0) 0 (0)

NR3 0 (0) 2 (66) 1 (33)

Total5 2 (40) 2 (40) 1 (20)

Outcome of all patients (n=18)median post treatment observation period: 1.6 years [25 days – 5.5 years]

Response to

BlinatumomabOutcome

Total CR (%) Relapse (%) NRM (%) Lost

to FU

(%)

CR 8 4 (50) 2 (25) 2 (25) 0 (0)

NR10 3 (30) 4 (40) 1 (10) 2 (20)

Total18 7 (39) 6 (33) 3 (17) 2 (11)

Overall survival of patients since begin of

treatment with Blinatumomab

Time since begin of treatment (years)

Ove

rall s

urv

iva

l (%

)

0

20

40

60

80

100

2-y-p= 54.6%, 95%-CI: 32.4% - 92.1%

0 1 2 3 4 5 6

Overall survival of patients with CR vs. patients

with NR after treatment with Blinatumomab

CR includes CR MRD+

Time since end of treatment (years)

Ove

rall s

urv

iva

l (%

)

0

20

40

60

80

100

0 1 2 3 4 5 6

CR: 2-y-p= 71.4%, 95%-CI: 44.7% - 100%

NR: 2-y-p= 45.7%, 95%-CI: 20.3% - 100%

64

Summary• Allogeneic SCT remains the gold standard (highest risk, relapsed patients)

Children and adolescents with ALL

CR1: ultra high risk features, persistent MRD

CR2: - late relapses with pers. MRD- early, very early relapse

>CR2: all patients

Level of MRD prior to transplant is a major predictor for outcome

Antibody treatment Remission induction and improvement; reduce toxicity and clear MRD

post transplant

Adult Patients with r/r ALL

High risk for relapse and TRM irrespective of treatment

Patients with persistent remission after Blinatumomab

Efforts are focusing on minimizing the relapse risk by intensifying therapy upfront and by eradicating MRD using the new available immunotherapies e.g. Blinatumomab

Combining all these modalities (new therapies, conventional chemotherapy and HCT) is challenging.

http://www.sciencedirect.com/topics/medicine-and-dentistry/immunotherapy

http://www.sciencedirect.com/topics/medicine-and-dentistry/chemotherapy

Cooperations

Halvard BönigGerman Red Cross Blood Donor Service Frankfurt/Main, Germany

Winfried S. WelsGeorg-Speyer-Haus, Frankfurt/Main, Germany

PhysiciansMichael MerkerShahrzad BakhtiarEva RettingerAndre WillaschAndrea JarischJan Sörensen

Graft Manipulation,Cell Therapeutics Sabine Huenecke Melanie BremmClaudia CappelVerena PfirrmannSibylle Wehner

Mesenchymal Stroma CellsZyrafete KuçiSelim Kuçi

CIK / T Cell TherapyEva RettingerVerena PfirrmannMichael MerkerLisa-Marie PfeffermannSarah OelsnerVida Meyer Molecular Biology

Andre WillaschChristlinde MauracherGitta NozadFariba SoltaniMiriam StaisHermann Kreyenberg

Pediatric Stem Cell Transplantation & Immunology: Peter Bader / Evelyn Ullrich / Thomas Klingebiel

Clinical Trial OfficeVerena PfirrmannBettina SteinmetzTina Homrighausen

OfficeKirsten Schäfer

NK cells / ExperimentalSara TognarelliJuliane WagnerJochen FrühKatja Thoma

Bio MathematicsEmilia Salzmann-Manrique

Participating Institutions Düsseldorf, Germany

Roland Meisel Florian Babor Friedhelm Schuster

Frankfurt/Main, Germany Hubert Serve Gesine Bug

Mainz, Germany Matthias Theobald Eva Wagner Hauptrock Beate

Heidelberg, Germany Johann Greil

66

Can allogeneic HSCT in ALL be replaced by antibody therapy?

67

Principal Considerations Treatment of acute leukemiaMultimodal chemotherapy protocolsAdults Children and adolescents

Considerable improvement Leukemia free survival:

90% in children and adolescents with ALL

Indications for SCT CR1 only in high risk patients for ALL

Slow response, hypodiploidy, pers. MRD

CR2 Only high risk patients in children and adolescents with ALL

Early, very early relapses and slow MRD clearance in late relapses

CR3 All patients

68

Stem-Cell Transplantation in Children With Acute Lymphoblastic Leukemia: A Prospective

International Multicenter Trial Comparing Sibling Donors With Matched Unrelated Donors—

The ALL-SCT-BFM-2003 TrialChristina Peters, Martin Schrappe, Arend von Stackelberg, André Schrauder, Peter Bader, Wolfram Ebell,Peter Lang, Karl-Walter Sykora,

Johanna Schrum, Bernhard Kremens, Karoline Ehlert, Michael H. Albert,Roland Meisel, Susanne Matthes-Martin, Tayfun Gungor, Wolfgang

Holter, Brigitte Strahm, Bernd Gruhn,Ansgar Schulz, Wilhelm Woessmann, Ulrike Poetschger, Martin Zimmermann, and Thomas Klingebiel

C. Peters et al.

J Clin Oncol 2015

MSD: 71%

MUD: 69%

MSD: 3%

MUD: 10%MSD: 24%

MUD: 22%

MSD: 79%

MUD: 73%

69

Patient with ALL from 2005-2014n=99 in complete remission at the time of first transplantation

N % N %

Sex

Male

Female

60

39

61

39

Age

< 10 years

> 10 years

35

64

35

65

Remission

CR1

≥ CR2

54

45

55

45

Donor

MSD

MUD

Haploidentical

21

67

11

21

68

11

Phenotype

pB-ALL

T-ALL

bi-pheno ALL

82

12

5

83

12

5

Immunotherapy

(WD of CSA or DLI)

Yes

No

29

70

29

71

Frankfurt Experience

S. Bahktiar, submitted

70

n Events 4-y TRM P

━ 49 7 0.14 ±0.05 .129

━ 50 2 0.04±0.02

Ov

era

ll s

urv

iva

l

0 10 20 30 40 50 60

0.0

0.2

0.4

0.6

0.8

1.0

Outcome for ALL2005-2009 versus 2010-2014

months after SCT

TR

M

0 10 20 30 40 50 60

0.0

0.2

0.4

0.6

0.8

1.0

months after SCT

CIR

0 10 20 30 40 50 60

0.0

0.2

0.4

0.6

0.8

1.0

pE

FS

0 10 20 30 40 50 60

0.0

0.2

0.4

0.6

0.8

1.0

n Events 4-y EFS P

━ 49 18 0.63 ±0.07 .365

━ 50 10 0.77±0.06

2010-2014 (n=50) = 87%

2005-2009 (n=49) = 71%

2010-2014 (n=50) = 77%

2005-2009 (n=49) = 63%

n Events 4-y OS P

━ 49 14 0.71 ±0.06 .198

━ 50 6 0.87±0.05

n Events 4-y CIR P

━ 49 11 0.22 ±0.06 .958

━ 50 8 0.19±0.06

S. Bahktiar, submitted

71

CIBMTR Study. Period 2000-2011: Patients n=1458

2y: 50%

Segal et.al: Cancer 2017

72

THANK YOU!

CASO CLÍNICOLEUCEMIA

LINFOBLÁSTICA AGUDA

Nelson Hamerschlak

[email protected]

Caso 1 – Anamnese e Diagnóstico

ID: HAKP, 43a, sexo feminino

QD/HPMA: internou em NOV/2015 com cansaço e dor torácica.AP: NEOPLASIA - CA PAPILIFERO DE TIRÓIDE 2008 – TTDA COM CIRURGIA E RADIOIODOTERAPIA ->hipotiroidismo e dislipidemia EXAME FÍSICO: descorada+

HEMOGRAMA: Hb 11.2 g/dl, leucócitos: 15,9 x109/L (neutro 4400 blastos 9200 = 58% e reaçãoleucoeritroblástica no esfregaço), Plaquetas 148 x109/LDHL: 6580 (normal até 618)

LÍQUOR: POSITIVO

MIELOGRAMA: infiltração por 90% de blastos linfóides (predomínio L1), alguns L2

IF: CD10+/CD19+/CD22+/CD25+fraco/CD34+/CD79a+/CD38+/CD58+/cyIgM negativo / CD20 negativoEGIL II = B COMUM

CARIÓTIPO/FISH: 46,XX der(11)t(1;11)(q12;q25). BCRABL E MLL/KMT2A - NEGATIVOS

BIOLOGIA MOLECULAR (FOUNDANTION): CREBBP (P879fs*49), CXCR4 (R338*-subclonal), YY1AP1(R93C)

Caso 1 – Tratamento e estratificação de risco

HD – LEUCEMIA LINFOBLASTICA AGUDA B (EGIL II - COMUM) – ALTO RISCO COM INFILTRAÇÃO SNC

NEOPLASIA SECUNDÁRIA A TERAPÊUTICA (RADIOIODO PRÉVIO ?)SEM DOADOR (APARENTADO E NÃO APARENTADO) FULLMATCH

TRATAMENTO – GRAALL 2005 (TROCADO RDT CRANIO POR 20 INTRATECAIS TRIPLAS)

- Refratária ao corticóide e pobre resposta precoce (> 1000 blastos após préfase e mieloD8 = 10% blastos por IF) MIGRA PARA O BRAÇO B

- DRM1 (IF) PÓS INDUÇÃO = 0.43% (POSITIVA)

- DRM2 (IF) PÓS CONSOLIDAÇÃO 1 < 0.01% (NEGATIVA)

– OPTADO POR TCPH HAPLO – DOADORA FILHA

Caso 1 – Transplante haploidêntico e seguimento

- MARÇO/16 – TCPH APARENTADO HAPLOIDÊNTICO (FILHA)

- FONTE MEDULA ESTIMULADA (GCSF) E DESERITROCITADA

- CONDICIONAMENTO DE INTENSIDADE REDUZIDA (FLU, MEL 140, THIOTEPA 5MG/KG+ CY PÓS), INCOMPATIBILIDADE ABO MAIOR

- D +45 APLASIA PURA SÉRIE VERMELHA

- D +150 PTLD EBV + MONOMÓRFICO AGRESSIVO EC: IVB – 4 RITUXIMAB + TROCA FKPOR SIROLIMUS REMISSÃO COMPLETA

- IMUNOSSUPRESSÃO – MMF ATÉ D+35 E RETIRADA COMPLETA DE SIROLIMUS – 9/10MESES

- SEM SINAIS DE GVHD AGUDO OU CRÔNICO

Caso 1 – Recidiva (Estudo medular de rotina)

- 1 ANO E 3 MESES - RECIDIVA IMUNOFENOTÍPICA MEDULA ÓSSEA COM SNC LIMPO• APESAR DE STR/QUIMERISMO LINF T > 98% E SEM IMUNOSSUPRESÃO• DRM 0,75%

- TRATAMENTO RESGATE 3 CICLOS BLINATUMOMABE + 1 MADIT (JUNHO/17) CICLO 1 – DRM PRÉ 0,75% DRM PÓS 0,01%CICLO 2 – DRM PRÉ 0,01% DRM PÓS NEGATIVA (<0,01%)

CICLO 3 – TÉRMINO EM OUTUBRO/17

…BUSCA DE NOVO DOADOR MAS SEM SUCESSO NAQUELE MOMENTO…

- NOVEMBRO/17 – INCIADO INFUSÃO DE LINFÓCITOS DO DOADOR (4 DOSES MENSAIS DE DLI)• 1a DLI: CD3 = 1 x 106/kg • 2a DLI: CD3 = 5 x 105/kg • 3a DLI: CD3 = 1 x 106/kg• 4a DLI: CD3 = 8 x 106/kg

FOLLOW UP (última avaliação): JUNHO/18 (1 ANO PÓS RECIDIVA)- Clínica: Alopécia (investigando possibilidade de manifestação de cGVHD)- Hemograma: Hb 13,6 / leuco 4100 (Neutro 2497, Ly 1119) / plaquetas 250 mil- Estudo de medula: DRM NEGATIVA- Hipogamaglobulinemia (pré blina IgG ~ 400 e pós ~ 200)

Caso 1 – DISCUSSÃO

Citogenética:- der(11) t(1;11) (q12;q25) – incomum em LLA e houve descrição desta translocação emalguns casos de neoplasias mielóides consideradas como NEOPLASIA SECUNDÁRIATERAPÊUTICA (RADIOIODO PRÉVIA ?)

Biologia Molecular:- CREBBP (P879fs*49) – resistência a corticoterapia (OBSERVADA NESTE CASO)

Condicionamento e fonte células e DLI (GvL):

- INTENSIDADE DO CONDICIONAMENTO – THIOTEPA 5MG/KG o uso de thiotepa10MG/KG OU TBI > 1000 cGy traria um desfecho melhor ?

- Impacto da DLI na recidiva e do GvL em LLA-B ?

...Seguimento: Quimerismo e DRM...

Obrigado!

Discussão de caso clínico

Nelson HamerschlakJuliana Follone Fernandes

[email protected]

YWHS, 22 anos, sexo masculino F2

Setembro 2015:

Em viagem para a França (Lille) iniciou quadro de febre e dores no

corpo, associado a fraqueza, cansaço e palidez. Realizou hemograma

que evidenciou pancitopenia. Feito mielograma com diagnóstico de

leucose aguda (LLA B), sendo encaminhado para nosso serviço para

tratamento.

Exame físico: hepatoesplenomegalia

Hemograma no diagnóstico:

HB: 4,8

Leuco: 10.800 (não temos o diferencial inicial na França)

Plaquetas: 15.000

Caso clínico


Setembro 2015:

Mielograma: 71% de células de tamanho pequeno a médio, alta

relação núcleo-citoplasmática, cromatina frouxa e citoplasma

escasso, compatíveis com BLASTOS LINFOIDES


Setembro 2015:

Mielograma: 71% de células de tamanho pequeno a médio, alta

relação núcleo-citoplasmática, cromatina frouxa e citoplasma

escasso, compatíveis com BLASTOS LINFOIDES

Cariótipo: 46,XY,t(14;19)(q32;q13.1) [10] / 46,XY [10]

Painel FISH LLA: sugestivo de: translocação do gene IGH em 60%

dos núcleos interfásicos analisados.

LCR negativo

Iniciado tratamento pelo protocolo GBTLI – 2009 – AR RL

D8 – 14% de blastos em SP (308 células)

D15 – Imunofenotipagem de MO: 7,7% de linfócitos B imaturos

anômalos que expressam CD34, CD45 (fraca expressão), CD20

(fraca expressão, CD22 (moderada expressão); correspondendo a

presença de Doença Residual de LLA-B nessa amostra

D 35 – MO com 2,4% blastos linfóides

Imunofenotipagem - 7,7% de células CD19 que expressam

CD34(fraca expressão), CD20(fraca expressão), CD38(fraca

expressão), CD58(fraca expressão) e negativas para CD10,

correspondendo a população linfóide B imatura anômala

falha de indução?


Outubro/Novembro 2015:

Reindução pelo protocolo COG AALL 0232 - consolidação

D14: MO em remissão morfológica e imunofenotípica


Dezembro 2015:

Identificado doador não aparentado 10/10 em registro internacional de

doadores de MO

Janeiro 2016

Transplante doador não-aparentado (10/10)

Fonte: medula óssea

Condicionamento: Irradiação corporal total 1200 cGy + Ciclofosfamida

120mg/Kg + ATG 5mg/Kg

Profilaxia da DECH: Ciclosporina A + MTX

Complicações: DECH pele grau I; reativação CMV

Recuperação neutrofílica: D+18

Reavaliações medulares programadas

D+ 60: DRM negativa; quimerismo 100%





Março 2017 (14 meses pós transplante):

Internação por febre + perda de peso + plaquetopenia

Massa esfenoidal + captação arco costal (PET CT: SUV 10,3)


Março 2017 (14 meses pós transplante):

Mielograma: 68,0% de blastos linfoides

Imunofenotipagem: 76,4% células anômalas: CD10 (fraca expressão),

CD19 (moderada expressão), CD22 (moderada expressão), CD34 (forte

expressão), CD123 (moderada expressão), cyCD79a (fraca expressão), cyIgM

(moderada expressão); sendo compatível com Leucemia Linfoblástica B /

Leucemia Linfoide pré-B

Citogenética com evolução clonal

46,Y,t(X;12)(q24;q13),t(10;16)(q26;p11.2),t(14;19)(q32;q13.1)[7]

Anatomo-patológico lesão esfenoidal: infiltração de mucosa respiratória por

leucemia linfoblástica aguda de imunofenotipo b

Considerado SNC positivo

Tratamento – Protocolo HAM: ARAC 3gm2 12/12h d1-d3-d5 +

mitoxantrone 20mg/m2 d1-d3

Reavaliação Abril 2017 (14 dias após término)

Mielograma: 76,0% blastos linfoides.

Imunofenotipagem: 66,4% blastos, há expressão antigênica

positiva e significativa de CD19(moderada expressão),

CD22(moderada expressão)


Abril 2017:

Tratamento – protocolo TACL (sem antracíclicos): vincristina +

bortezomib + dexa + PEG-asparaginase

Asparaginase suspensa no D22 por pancreatite

Reavaliação Maio 2017

Mielograma: hipocelular sem blastos

Imunofenotipagem: 0,5% de precursores linfoides B anômalas positivos para

CD19, CD22 (fraca a moderada expressão), CD34, CD45 (fraca a moderada

expressão) e negativos para CD10, CD20, CD38 e CD58, correspondendo a

doença residual mínima positiva para LLA-B, nesta amostra.

22/04/2017

Aparecimento de lesões de pele em coxa D e MSD

Aumento da lesão expansiva sólida em parte do seio esfenoidal direito

Biópsia de pele e da massa em esfenóide: mucormicose


Maio 2017:

Blinatumomabe #1 (22/05 a 19/06)

Reavaliação (20/06):

Mielograma: normocelular sem blastos.

Imunofenotipagem: 0,05% de precursores B anômalos que expressam CD10,

CD22, CD34, CD38 (forte expressão), CD45 (fraca expressão), CD81 e HLA-

DR. Essas células são negativas para CD19, CD20, CD58 e CD123.

Julho 2017:


Reavaliação (14/08):

Mielograma: normocelular sem blastos.

Imunofenotipagem: 0,02% de células linfóides B imaturas anômalas que

expressam CD22, CD10, CD34, CD45 (fraca expressão) e CD38. Esta

população é negativa para CD19, CD20 e CD58.

Agosto 2017 – em programação de 2º transplante


29/08: DRM negativa

YWHS, 22 anos, sexo masculino F

2

Setembro 2017

Transplante doador não-aparentado (10/10) – doador diferente do

primeiro transplante

Fonte: sangue periférico

Condicionamento: Bussulfano (AUC 5000) + Fludarabina (150) +

Thiotepa (10) + ATG (5)

Profilaxia da DECH: Ciclosporina A + MTX

Profilaxia secundária de reativação de infecção fúngica: biterapia com

anfotericina lipossomal + posaconazol + transfusão de granulócitos

Complicações: DECH aguda grau II (TGI 2), com boa resposta a

corticoterapia; colite por chlostridium, reativação CMV

Recuperação neutrofílica: D+18

Desmame do CE até D+90, desmame de CsA até D+150


Junho 2018

Atualmente bem, sem intercorrências clínicas

Voltou a faculdade e ao trabalho

Em programação de cirurgia de catarata

Reavaliações medulares programadas




Documents

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