Management der rezidivierten/refraktären akutenlymphatischen Leukämie des Erwachsenen

vom B-Vorläufer-Typ

Dr. med. Nicola Gökbuget

Goethe Universität, Universitätsklinikum, Frankfurt

Potentielle Interessenkonflikte

Speaker honoraria, travel support, advisory board:- Amgen- Celgene- Gilead- Novartis- Pfizer- Jazz Pharmaceuticals- Incyte- Erytech- Shire/Servier

Research support- Amgen- Pfizer- Novartis- Shire/Servier- Jazz Pharmaceuticals- Incyte

Definitions

Definitions: What do we speak about?

During intensive chemotherapyShortly after SCT

Early relapse

Primary refractory ALL

Refractory relapse (2nd relapse)

• Chemotherapy resistance• Genetically unstable clones

After intensive chemotherapyLate after SCT> ca. 18 months after first diagnosis

Late relapse

Outgrowth of silent clones due tolack of immune surveillance a/oracquired additional mutations

SCT - Stem cell transplantation, Stammzelltransplantation

BM Relapse- 5%50%

Combinations of the before mentioned settings

Lymph nodesCNS (CSF, brain)TestisBoneOther extranodal

Isolated extramedullary

BM - Bone marrow, Knochenmark; MRD - minimal residual disease, minimale Resterkrankung; CNS - central nervous system, zentrales Nervensystem; CSF - Cerebrospinal fluid, Zerebrospinalflüssigkeit

Definitions: What do we speak about?

What does MRD mean?

Relapse Risk ↑

Relapse Risk ↓

MRD - minimal residual disease, minimale Resterkrankung

Definitions: Response after Standard Induction/Consolidation

Hematologic Failure (after standard induction/consolidation)> 5% blasts in BM orpersistance of extramedullary diseaseMolecular Failure> 0.01% 5% blasts in BM oroccurrence of extramedullary diseaseMolecular relapse> 0.01%

Results of Chemotherapy in R/R ALL

Differences in outcome of relapsed/refractory ALLGMALL Studies 06/99 – 07/03 (Gökbuget et al, Blood 2012)

Early vs Late Relapse (18 mo)LateN=91CR: 64%OS: 43%

Early:N=200CR: 39%OS: 22%

No CR 1st SN=129CR: 25%OS: 13%

First vs Later SalvageCR 1st SN=95OS: 47%

Chemo: N=378CR: 46%OS: 28%

After SCT:N=169CR: 25%OS: 15%

After Chemo vs After SCT

Survival time is inferior in • early relapses• refractory relapses and• relapses after SCT

Gökbuget N, et al. Blood. 2012; 120(9):1868-76. SCT - Stem cell transplantation, Stammzelltransplantation, CR - complete remission, Komplettremission, OS - overall survival, Gesamtüberleben

Meta-Analysis on the Role of MRD in ALL According to Age - Pediatric vs Adult

Berry et al, Jama Oncology 2017

Overall Survival Pediatric

5 studies, 2876 pts Overall Survival Adult

5 studies, 806 pts

► Treatment of molecular failure is a challenge independent of age

► MRD should be assessed in each and every ALL patient

► Material for establishment of MRD assays should always be collected

MRD - minimal residual disease, minimale ResterkrankungBerry DA, et al. JAMA Oncology. 2017; 3(7):e170580.

Hematologic Failure / Relapse1. Up to 29% survival relapsed ALL is a curable disease, though overall poor

results with standard chemotherapy2. Cure with SCT only3. Essential prognostic factors at relapse:

Time to relapse Response to 1st/later salvage Realisation and disease status at SCT

4. Indication for novel therapies in all types ofrelapse with exception of late relapses (Incidence: 21% only)

Molecular Failure / Relapse1. Poor outcome despite continued chemotherapy2. Cure with SCT possible, but results poorer in MRD positive compared to MRD

negative patients

Standard Management of Relapsed/Refractory ALLConclusions

SCT - Stem cell transplantation, Stammzelltransplantation; MRD - minimal residual disease, minimale Resterkrankung

Novel Therapies

Potential Targeted Therapies in ALLBassan et al, JCO 2018

Surface Markers >90% CD19 (B-Lin)>90% CD22 (B-Lin)

40% CD20 (B-Lin)

80% CD52

10-20% CD33

Bassan R, et al. J Clin Oncol. 2018; JCO2017773648.

Immunotherapy Approaches to the Treatment of Hematologic Malignancies

Major advantage: Targeted therapy with different mechanism of action!

Blinatumomab – Bispecific Antibody CD19-CD3

• Engagement by BiTE® antibody

constructs leads to activation and

polyclonal expansion of T cells

(CD4/CD8) 1

• Activation of T cells requires

presence of target cells2

Transient increase of cytokines

(IL10,IL6, IFNg)

Activity

depends on:

1. Target CD19

2. Functional T-cells

3. Access to blast cells

1. Klinger M, et al. Blood. 2012; 119:6226-33; 2. Baeuerle PA, et al. Cancer Res 2009; 69:4941-4.

TOWER: Blinatumomab in Relapsed / Refractory ALLRandomised Phase 3 vs Standard of Care Chemotherapy

CountriesUSA 15% / EU 66% / ROW 18%

Inclusion criteriaEarly and refractory relapses

Treatments: Randomisation 2:1

Treatment Arm 1: Blinatumomab• 6 wk cycles (4 weeks of blinatumomab CIVI and 2 wk interval)

• 9 μg 1 wk, 28 μg 3 wks

• 2 induction, 4 consolidation, maintenance up to 12 mo

Treatment Arm 2: Investigators choice • FLAG ± anthracycline

• HiDAC based regimen

• HDMTX based regimen

• Clofarabine based regimen

Kantarjian et al, N Engl J Med 2017

Kantarjian H, et al. N Engl J Med. 2017; 376(9):836-847.

Blina SOC

N 271 134

Age (median, years) 41 41Salvage 1 42% 48%Salvage 2 34% 32%Later salvage 25% 20%First remission > 12 mo 0 0Prior SCT 35% 34%Ph+ 0 0Blasts in BM > 50% 74% 78%PB blasts / µl 4400 5000

TOWER: Blinatumomab in Relapsed / Refractory ALL

Kantarjian et al, N Engl J Med 2017

Patient Characteristics

SCT- Stem cell transplantation, Stammzelltransplantation; Ph - Philadelphia; BM - Bone marrow, Knochenmark; PB blasts - peripheral blood blastsKantarjian H, et al. N Engl J Med. 2017; 376(9):836-847.

TOWER: Blinatumomab in Relapsed / Refractory ALLResults of Remission Induction

Kantarjian et al, N Engl J Med 2017

Blina Chemo Chemo treated

Evaluable 271 134 109

CR /CRp /CRi 44% 25% 30%

CR 34% 16%

CRi 1.5% 4.5%

CRp 9% 4.5%

Mol CR (PCR) 76% 48%

Chemo:FLAG±: 45%HDAC: 17%HDMTX: 20%Clofa: 17%

CR – complete remission, Komplettremission; Mol CR – molekulare KomplettremissionKantarjian H, et al. N Engl J Med. 2017; 376(9):836-847.

TOWER: Blinatumomab in Relapsed / Refractory ALLResults of Remission Induction (CR/CRp/CRi) by Subgroups and Outcome by Salvage Line

Kantarjian et al, N Engl J Med 2017

Blina Chemo

Age < 35 yrs 43% 25%> 35 yrs 45% 24%

Salvage lineFirst 53% 35%Second 40% 16%Third 35% 11%

Previous allo SCTYes 40% 11%No 46% 32%

BM blasts50% 34% 21%

Allo SCT- Allogeneic stem cell transplantation, allogene Stammzelltransplantation; BM - Bone marrow, Knochenmark

Dombret et al, Leuk&Lymph, 2019

Kantarjian H, et al. N Engl J Med. 2017; 376(9):836-847.; Dombret H, et al. Leuk Lymphoma. 2019; 60(9):2214-2222.

TOWER: Blinatumomab in Relapsed / Refractory ALLAdverse Events

Kantarjian et al, N Engl J Med 2017

AE >5% in Blina armSAEs

Blina SOCN 267 109Neutropenia 38% 58%Infection 34% 52%Liver enzymes 13% 15%Neurologic 9% 8%CRS 5% 0%Infusion reaction 3% 1%Lymphopenia 1.5 4%Cycles 2 (1-9) 1 (1-4)SAE/100 pts yrs 349 642

Grade >= 3 AEs of interest in at least 3%

CRS - cytokine release syndrome; SAE - serious adverse event, schwere unerwünschte EreignisseKantarjian H, et al. N Engl J Med. 2017; 376(9):836-847.

TOWER: Blinatumomab in Relapsed / Refractory ALLSurvival

Kantarjian et al, N Engl J Med 2017

Overall Survival Survival

Censored at SCT

24% vs 24% subsequent SCT incl. 14% and 9% in CR w/o further therapy

3% and 4% in CR w other therapy1% and 1% after relapse6% and 10% w/o CR

7.7 mo

4.0 mo

SCT- Stem cell transplantation, Stammzelltransplantation; CR – complete remission, Komplettremission; w/o – without, ohneKantarjian H, et al. N Engl J Med. 2017; 376(9):836-847.

Mechanism of action• Binding to surface CD22 receptors of target cells • Internalization as a CD22-ADC complex• ADC traffics from early to late lsyosomes• Linker cleavage and release of inactive calicheamicin• Activated by intracellular thiol groups• Intercalation in DNA • Double-strand DNA break formation • Apoptosis induction• Calicheamicin activity independent of cell cycle

progression

Inotuzumab – Conjugated Antibody CD22

Shor B, et al. Mol Immunol. 2015; 67(2 Pt A):107-16.

INO-VATE: Inotuzumab in Relapsed / Refractory ALLRandomised Phase 3 vs Standard of Care Chemotherapy

CountriesUSA 49% / EU 41% / ROW 10%

Inclusion criteriaRelapsed / refractory ALL including late relapses

Pts with peripheral blasts ≥10,000/μL were excluded

Salvage 2 capped up to

Ino SOC

N 109 109Age (median, years) 47 47Salvage 1 67% 63%Salvage 2 32% 36%Later salvage 0 0First remission > 12 mo 43% 35%Prior SCT 16% 20%Ph+ 13% 17%Blasts in BM > 50% 71% 72%PB blasts / µl 175 39

INO-VATE: Inotuzumab in Relapsed / Refractory ALLPatient CharacteristicsKantarjian et al, N Engl J Med 2016

SCT- Stem cell transplantation, Stammzelltransplantation; Ph - Philadelphia; BM - Bone marrow, Knochenmark; PB blasts - peripheral blood blasts

Kantarjian HM, et al. N Engl J Med. 2016; 375(8):740-53.

INO-VATE: Inotuzumab in Relapsed / Refractory ALLResults of Remission Induction

Kantarjian et al, N Engl J Med 2016

Ino Chemo Chemo treated

Evaluable 109 109 97

CR /CRi 81% 29% 33%

CR 36% 17%

CRi 45% 12%

MRD neg (Flow) 78% 28%

Chemo (N=152):FLAG : 70%HDAC/Mi: 19%HDAC: 11%

CR – complete remission, Komplettremission; MRD - minimal residual disease, minimale ResterkrankungKantarjian HM, et al. N Engl J Med. 2016; 375(8):740-53.

Ino Chemo

Prior remission duration < 12 mo 77% 24%> 12 mo 87% 39%Salvage lineFirst 88% 29%Second 67% 31%Age< 55 yrs 80% 32%> 55 yrs 81% 25%Previous allo SCTYes 76% 27%No 81% 30%BM blasts50% 78% 24%PH+ 79% 44%

INO-VATE: Inotuzumab in Relapsed / Refractory ALLResults of Remission Induction (CR/CRp/CRi) by Subgroups and Outcome by Salvage Line

Kantarjian et al, N Engl J Med 2016

Allo SCT- Allogeneic stem cell transplantation, allogene Stammzelltransplantation; BM - Bone marrow, Knochenmark

Jabbour et al, EHA 2019, Abstract & E-Poster PS950

https://library.ehaweb.org/eha/2019/24th/267251/elias.jabbour.efficacy.and.safety.of.inotuzumab.ozogamicin.in.patients.with.html?f=menu%3D6%2Abrowseby%3D8%2Asortby%3D2%2Amedia%3D3%2Ace_id%3D1550%2Aot_id%3D20966

Kantarjian HM, et al. N Engl J Med. 2016; 375(8):740-53.; Jabbour E, et al. EHA 2019, Abstract & E-Poster PS950.

41% vs 11% directly subsequent SCT

SurvivalKantarjian et al, N Engl J Med 2016

INO-VATE: Inotuzumab in Relapsed / Refractory ALL

Overall Survival Remission Duration=Relapse Free Survival

7.7. mo23% at 2 yrs

6.7 mo10% at 2 yrs

SCT- Stem cell transplantation, StammzelltransplantationKantarjian HM, et al. N Engl J Med. 2016; 375(8):740-53.

SAEsAll cause >= 3 Aes and treatment emergent Aes in either arm

Ino SOCN 139 120Platelets 37% 59%Neutropenia 46% 42%Febrile neutropenia 24% 49%Lymphopenia 16% 28%AST/ALT 5%/3% 5%/3%Bilirubine 4% 3%VOD 9% 1%Cycles 3 (1-6) 1 (1-4)

All cause AE >= Grade III ≥10% incidence in either arm

Kantarjian et al, N Engl J Med 2016

INO-VATE: Inotuzumab in Relapsed / Refractory ALL

Shortly after therapy: N=5After subsequent SCT: N=103/10 in pts with prior SCT

Adverse Events

AE - adverse Event, unerwünschtes Ereignis; SAE - serious adverse event, schweres unerwünschtes Ereignis; VOD - veno occlusive diseaseKantarjian HM, et al. N Engl J Med. 2016; 375(8):740-53.

Blinatumomab – Inotuzumab bei R/R ALL I

• Response rates not comparable • Blina: Early, refractory relapses, includes prior SCT• Ino: Includes late relapses, earlier salvage

• High MRD response rates but different methods

• Remission duration (excluding death) not reported

• OS similar but different patient populations

• Long-term survival in SCT pts only (not clearly reported)

• Potentially high TRM (not clearly reported)

• Better outcomes if used in 1st salvage

• Relapse after SCT: • Blina: 3 months interval• Ino: 4 months interval

SCT- Stem cell transplantation, Stammzelltransplantation; MRD - minimal residual disease, minimale Resterkrankung; OS – overall survival, Gesamtüberleben; TRM - transplant related mortality

Blinatumomab – Inotuzumab bei R/R ALL II

• No data for late relapses

• No data on extramedullary involvement

• No clear role of target expression

• No biomarkers for response prediction clearly defined

• Negative prognostic impact: • Blina: Higher BM blasts• Ino: No clear impact of BM basts; high PB blasts excluded

• Toxicity profile favorable compared to SOC (e.g.infections)

• Different focus of toxicities• Blina: Neurologic events• Ino: VOD (> 65yrs,Bili before SCT, 2 alkylators; prior SCT);

2 (max 3 cycles) before subsequent SCT

• Application mode:• Inotuzumab: wkly infusions 3 wks• Blinatumomab: 4 wk continuous infusion; start inpatient

BM - Bone marrow, Knochenmark; PB blasts - peripheral blood blasts ; SOC - standard of care ; VOD - veno occlusive disease; SCT - Stem cell transplantation, Stammzelltransplantation

Blinatumomab in MRD Positive ALLGökbuget et al. Blood 2018

Selected inclusion criteria:• CD19 positive B-precursor ALL• Hematologic CR• MRD ≥ 10-3

• No prior SCT

Treatment15 μg/m2 as 4 wk civ (=1 cycle)i.th. prophylaxis

Results

Evaluable 110Median age 45 (18-76) yrsIn 2nd/later CR: 35%

MolCR: 78%

Median OS: 36 mo- Mol CR y/n: 40 vs 12 mo

Median RFS: 19 mo- Mol CR y/n: 35 vs 7 mo- 1st / later CR: 25 vs 11 mo

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

CR - complete remission, Komplettremission; MRD - minimal residual disease, minimale Resterkrankung; SCT - Stem cell transplantation, StammzelltransplantationGökbuget N, et al. Blood. 2018; 131(14):1522-1531.

Overall Survival not censoring at SCT and post-blinatumomab chemotherapy

Median (95% CI) follow-up: 30.0 (25.1, 35.4) months

Kaplan–Meier estimate of median OS = 36.5 (95% CI: 19.8, NR) months

Surv

ival pro

babili

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Time (months)

Subjects at risk, n:

110 108 98 89 86 80 62 47 44 37 31 24 16 10 7 4 4 1 0

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54

0.0

0.1

0.2

0.3

0.4

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Censored

Median: 36 mo

Blinatumomab in MRD Positive ALLOverall SurvivalGökbuget et al. Blood 2018

SCT - Stem cell transplantation, Stammzelltransplantation

Gökbuget N, et al. Blood. 2018; 131(14):1522-1531.

Blinatumomab in MRD Positive ALLOverall Survival by MRD Response

MRD - minimal residual disease, minimale Resterkrankung

Gökbuget et al. EHA 2019, Abstract S1619

Gökbuget N, et al. EHA 2019, Abstract S1619.

Blinatumomab in MRD Positive ALL

• High response rates in first and later lines

• No dose step

• Good tolerability

• Significant survival benefit for responders

• Overall results superior in MRD setting compared to cytologic relapse

Kantarjian & Jabbour, ASCO Education Book, 2018

Blinatumomab and Inotuzumab in Different Settings

R/R Ph+ R/R Ph- MRD pos

Trial Ph II Ph II Ph II Ph III BLAST

N pts 45 36 189 271 116

CR/CRh/CRi 36% 69% 43% 45% NA

MRD neg 88% 88% 82% 76% 78%

OS med. 7.1 9.8 6.1 7.7 36

R/R

Single Wkly Ph III Comb. Dose Dose Chemo

49 41 109 70

57% 59% 88% 77%

68% 71% 78% 81%

5 7.3 7.7 11

CR - complete remission, Komplettremission; MRD - minimal residual disease, minimale Resterkrankung; OS – overall survival, Gesamtüberleben

Blinatumomab Inotuzumab

Kantarjian H. & Jabbour E., ASCO Education Book, 2018; 574-578.

Cell Therapies

Example of approach to CAR T-cell production

Davila ML, et al. Int J Hematol. 2014; 99(4):361-71.

Park et al, N Engl J Med 2018

CD19 CAR T-cells in Relapsed/Refractory Adult ALL

Overall Survival Inclusion criteria• R/R ALL or ALL in CR• No specification for type of relapse

Patient Characteristics>5% BM blasts: 51%

Maude et al, N Engl J Med 2018

CD19 CAR T-cells in Relapsed/Refractory Pediatric ALL

Inclusion criteria• R/R ALL or ALL in CR• No specification for type of relapse

Patient CharacteristicsBM infiltration at infusion not reported

Recruited: 92Treated: 75 (81%)CR 3 mo 61/75 (81%)

Intent-to-treat: 61/92 (66%)

Response Rates

Adverse events:CRS: >= grade 3: 46%Neurotoxicity: any 40%;

• CR rates high but no intent to treat analysis

• Few patients, mainly children and young adults

• Relevant toxicities: CRS, neurotoxicity

• Marketing authorization for one product (Tisagenlecleucel) up to

patient age 25 yrs

Results of Clinical Trials with CD19 CAR T-cellsin Adult ALLBassan et al, JCO 2018

CR - complete remission, Komplettremission; CRS - cytokine release syndromeBassan R, et al. J Clin Oncol. 2018: JCO2017773648.

Integrated Strategy

R/R B-precursor ALL: Potential Salvage Strategy

Diagnosis

Early BM/MRDRefractory

Late BM Extramedullary

IndividualConcept

Induction ±Cytoreduction

MRDR/R

Blinatumomabor

Inotuzumab

Blinatumomab Failure/PR/MRD

• Clinical trials• CTL019 (up to 25 years)• Augmented induction + Bortezomib • Clorafabine-based regimens• Flag-Ida (B) • Experimental ‘targeted therapy’

Therapie der R/R ALL: Entscheidungsfindung Immuntherapie

a Alle Substanzen können als Überbrückung zu Transplantation eingesetzt werden, kommen aber auch bei nicht für die Transplantation geeigneten Patienten in Frage

b Es ist empfohlen bei geplanter Transplantation maximal 2 Zyklen Inotuzumab einzusetzen.c Blinatumomab kann bei Patienten eingesetzt werden, die nach Inotuzumab MRD-positiv bleibend Tisagenlecleucel ist nur für Patienten im Alter bis 25 Jahre mit refraktärer ALL oder zweitem oder folgendem Rezidiv zugelassene Die Notwendigkeit einer SZT nach Tisagenlecleucel ist unklar; die Entscheidung kann vom MRD-Verlauf und der CAR-T-Zell-Persistsenz abhängig gemacht werden. f Die Indikation für eine Transplantation hängt nach Blinatumomab und Inotuzumab u.a. auch vom Alter, Vortherapien, Ansprechen und Spenderverfügbarkeit ab.

Wird keine Transplantation durchgeführt, sollte eine Konsolidations-/Erhaltungstherapie erwogen werden.

Dhakala et al, Leuk Lymph, 2019

Blinatumomaba Inotuzumaba,b Tisagenlecleucela,d,e

• MRD Positivität• Hepatotoxizität od.

Vorerkrankung

• Hohe Leukämielast• Neurotoxizität od.

Vorerkrankung

• Rezidiv nach SZT• Versagen anderer

Immuntherapien

Blinatumomab c

Stammzelltransplantationf

Dhakal P, et al. Leuk Lymphoma. 2020; 61(1):7-17.

Relapsed/Refractory ALLChecklist for Decision Making

Subtype Target structures Confirmation in borderline cases (

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