Linfoma de Hodgkin

Novos medicamentos

Otavio BaiocchiCRM-SP 96.074

Hodgkin Lymphoma

• Unique B-cell lymphoma

• HRS malignant cells

• Scattered malignant Hodgkin-Reed-Sternberg (RS) cells in a

background of reactive T-cells infiltrate,.

HRS cells interaction with microenvironment

Aldinucci et al. J Pathol 2010 Jul;221(3):248-63

Hodgkin lymphoma: treatment modalities

Hodgkin lymphoma: treatment modalities

Hodgkin Lymphoma: Depletion of malignant cells

• Chemotherapy and Radiotherapy approach

• Autologous stem-cell transplant

• Antibody-drug conjugate: Brentuximab vedotin

ABVD BEACOPP

Hodgkin Lymphoma: Depletion of malignant cells

• Chemotherapy and Radiotherapy approach

• Autologous stem-cell transplant

• Antibody-drug conjugate: Brentuximab vedotin

ABVDBEACOPP

Hodgkin Lymphoma - treatment

Early favorable

Early

unfavorableAdvanced stages

Current guidelines for HL treatment

Treatment

setting

NCCN guidelines, 2016

Treatment

ESMO guidelines, 2014

Treatment

Frontline

• ABVD + IFRT

• Stanford V

• BEACOPP

• BEACOPP followed by ABVD + RT

• ABVD alone

• Individualized treatment may be necessary for older patients and

patients with concomitant disease (2A)

• ABVD or BEACOPP ± RT (I–II,A)

Second-line • Salvage chemotherapy + ASCT • Salvage chemotherapy + ASCT

Third line therapy

• Brentuximab vedotin

• Allo SCT

• No data to support superior outcomes with any treatment;

individualized therapy recommended

• Clinical trial may be appropriate

• Brentuximab vedotin

• Allo SCT

• No data to support superior outcomes with any

treatment; individualized therapy recommended

• Clinical trial may be appropriate

Current guidelines for HL treatment

Treatment

setting

NCCN guidelines, 2016

Treatment

ESMO guidelines, 2014

Treatment

Frontline

• ABVD + IFRT

• Stanford V

• BEACOPP

• BEACOPP followed by ABVD + RT

• ABVD alone

• Individualized treatment may be necessary for older

patients and patients with concomitant disease (2A)

• ABVD or BEACOPP ± RT (I–II,A)

Second-line• Radiotherapy or second-line chemotherapy ± radiotherapy

followed by high-dose chemotherapy + ASCT/allo-SCT

• Salvage chemotherapy + ASCT

• BEACOPP escalated or salvage radiotherapy alone

Third line therapy

• Brentuximab vedotin

• Allo SCT

• No data to support superior outcomes with any treatment;

individualized therapy recommended

• Clinical trial may be appropriate

• Brentuximab vedotin

• Allo SCT

• No data to support superior outcomes with any

treatment; individualized therapy recommended

• Clinical trial may be appropriate

Current guidelines for HL treatment

Treatment

setting

NCCN guidelines, 2016

Treatment

ESMO guidelines, 2014

Treatment

Frontline

• ABVD + IFRT

• Stanford V

• BEACOPP

• BEACOPP followed by ABVD + RT

• ABVD alone

• Individualized treatment may be necessary for older patients and

patients with concomitant disease (2A)

• ABVD or BEACOPP ± RT (I–II,A)

Second-line • Salvage chemotherapy + ASCT • Salvage chemotherapy + ASCT

Third line therapy

• Brentuximab vedotin

• Allo SCT

• No data to support superior outcomes with any treatment;

individualized therapy recommended

• Clinical trial may be appropriate

• Brentuximab vedotin

• Allo SCT

• No data to support superior outcomes with any

treatment; individualized therapy recommended

• Clinical trial may be appropriate

After 1 month

Tb treatment

Bx: Tuberculosis

Pcte sexo feminino, 34 anos

Stage: IVB After C6 ABVD

PET +

Refractory HL?

Interin PET

After C2 ABVD

PET +

Partial Response

34 y/o white female with fever, night sweats and a newly diagnosed advanced stage HL

After C4 ABVD

PET +

Why a biopsy is mandatory?

2nd line therapy for cHLrelapsed refractory disease

• High dose chemotherapy followed ASCT

• Which salvage chemotherapy?

• How to increase CR rate before ASCT?

• How to improve prognosis in high risk patients after ASCT?

2nd line therapy for cHLrelapsed refractory disease

• High dose chemotherapy followed ASCT

• Which salvage chemotherapy?

• How to increase CR rate before ASCT?

• How to improve prognosis in high risk patients?

2nd line therapy for cHLrelapsed refractory disease

• High dose chemotherapy followed ASCT

Salvage chemotherapy - UNIFESP

1. ICE Moskowitz et al. (2001)

2. DHAP Josting et al. (2005)

3. IGEV Santoro et al. (2007)

4. GDP Bartlett et al. (2007)

Do not delay cycles – DHAP14, ICE15 have shown the best

results

CR rate ICE, DHAP, IGEV, GDP - 45 – 60%

Response to salvage therapy predicts post-ASCT

survival

17% in patients with resistant disease (p<0.0001)1

1. Sirohi B et al. Ann Oncol 2008;19:1312–9; 2. Majhail N et al. Biol Blood Marrow Transplant 2006;12:1065–72;;

100

80

60

40

20

0 5 10 15 20

n

Complete response 53

Partial response 96

Resistant 46

Pro

ba

bili

ty o

f O

S (

%)

Time since transplant (years)

Survival correlates with depth of response prior to ASCT1

5-year OS: 79% for patients in CR pre-ASCT

59% in patients with PR

Complete remission is good, but not a pre-requisite!

2nd line therapy for cHLrelapsed refractory disease

• High dose chemotherapy followed ASCT

• Which salvage chemotherapy?

• How to increase CR rate before ASCT?

• How to improve prognosis in high risk patients?

The role of Brentuximab vedotin

BV-bendamustine

Brentuximab vedotin 1.8 mg/kg D1 with bendamustine 90 mg/m2 on

D1-2 q3w for 3 cycles

ORR 92%

76 patients, 80% CR30% used plerixafor

LaCasce, et al. ASH 2016

Brentuximab Vedotin Plus ESHAP (BRESHAP)

GELTAMO

ORR 94%

39 patients, 85% CR

Garcia-Sans, et al. EBMT 2016 (poster)

Use brentuximab vedotin (BV) with salvage chemotherapy

CR rate ICE, DHAP, IGEV, GDP - 45 – 60%

Is it possible to increase CR rate without increasing

toxicity? The role of BV in savage therapy

Brentuximab monotherapy

60 patients

ORR 88%

CR 65% Excellent stem-cell harvest

Chen et al, EBMT 2016 (poster)

B-ICE – ASH 2017 preliminary results

B-DHAP – ISHL 2016 – preliminary results CR 85%

Is it possible to increase CR rate without increasing

toxicity? The role of BV in savage therapy

Hagenbeck et al, Oral ISHL 2016

2nd line therapy for cHLrelapsed refractory disease

• High dose chemotherapy followed ASCT

• Which salvage chemotherapy?

• How to increase CR rate before ASCT?

• How to improve prognosis in high risk patients after ASCT?

AETHERA phase III trial of brentuximab vedotin vs placebo in

relapsed or refractory HL pts at risk of relapse post ASCT

Dose and schedule: Pts were randomized 1:1 to receive 16 21-day cycles of

brentuximab vedotin 1.8 mg/kg IV day 1 or placebo

• Pts who progressed on placebo could receive brentuximab vedotin

Moskowitz C et al. Lancet Oncology 2016

HL, Hodgkin lymphoma; PFS, progression free survival; IRF, independent review facility; OS,

overall survival; mos, months; CR, complete response; PR, partial response; SD, stable disease;

PD, progressive disease; ASCT, autologous stem cell transplantation; BV, brentuximab vedotin;

pts, patients ; R/R, relapsed refractory

AETHERA phase III trial of brentuximab vedotin vs placebo in

relapsed or refractory HL pts at risk of relapse post ASCT

PFS outcome

Brentuximab

vedotin (n=165)

Placebo

(n=164)

Median PFS NR 16 mos

HR (95% CI) 0.50 (0.36, 0.70)

p-value NR

2-year PFS 65% 45%

Moskowitz C et al. Lancet Oncology 2016

Moskowitz C et al. Lancet Oncology 2016

• Consolidation after ASCT with brentuximab vedotin (BV)

demonstrated improved PFS in patients with HL and risk factors for

relapse or disease progression (HR = 0.57, p = 0.001)

• PFS benefit was sustained after 3 years f/u (EHA 2016)

• Consistent benefit observed across subgroups

• Analysis of overall survival did not show a significant difference

between treatment arms.

AETHERA phase III trial of brentuximab vedotin vs placebo in

relapsed or refractory HL pts at risk of relapse post ASCT

Moskowitz C et al. Lancet Oncology 2016

3rd line therapy for cHLrelapsed after ASCT

Current guidelines for HL treatment

Treatment

setting

NCCN guidelines, 2016

Treatment

ESMO guidelines, 2014

Treatment

Frontline

• ABVD + IFRT

• Stanford V

• BEACOPP

• BEACOPP followed by ABVD + RT

• ABVD alone

• Individualized treatment may be necessary for older patients and

patients with concomitant disease (2A)

• ABVD or BEACOPP ± RT (I–II,A)

Second-line• Radiotherapy or second-line chemotherapy ± radiotherapy

followed by high-dose chemotherapy + ASCT/allo-SCT

• Salvage chemotherapy + ASCT

• BEACOPP escalated or salvage radiotherapy alone

Third line

therapy

• Brentuximab vedotin• Allo SCT

• Clinical trial may be appropriate

• Brentuximab vedotin• Allo SCT

• Clinical trial may be appropriate

Five-year survival and durability results of brentuximab vedotin in

patients with relapsed or refractory Hodgkin lymphomaChen et al, Blood 2016

• Single agent brentuximab vedotin can induce durable remissions

• 5-year overall survival rate was 41% and 70% for those who achieved CR

Current guidelines for HL treatment

Treatment

setting

NCCN guidelines, 2016

Treatment

ESMO guidelines, 2014

Treatment

Frontline

• ABVD + IFRT

• Stanford V

• BEACOPP

• BEACOPP followed by ABVD + RT

• ABVD alone

• Individualized treatment may be necessary for older patients and

patients with concomitant disease (2A)

• ABVD or BEACOPP ± RT (I–II,A)

Second-line• Radiotherapy or second-line chemotherapy ± radiotherapy

followed by high-dose chemotherapy + ASCT/allo-SCT

• Salvage chemotherapy + ASCT

• BEACOPP escalated or salvage radiotherapy alone

Third line

therapy

• Brentuximab vedotin

• Allo SCT• Clinical trial may be appropriate

• Brentuximab vedotin

• Allo SCT• Clinical trial may be appropriate

Hodgkin lymphoma: treatment modalities

29

New medications: Cancer immunotherapy

WHEN A T-LYMPHOCYTE MEETS AN ANTIGEN…

CD4 LymphocyteAPC

1. T cells recognize antigens

presented on the MHC by the TCR

(SIGNAL 1)

WHEN A T-LYMPHOCYTE MEETS AN ANTIGEN…

1. T cells recognize antigens

presented on the MHC by the TCR

(SIGNAL 1)

2. The activation or inhibition of T

cells is determined by the

additional ligand–receptor

interactions between T cells and

APCs (or tumour cells) (SIGNAL 2)

1. Release of cytokines (SIGNAL 3)

CD4 LymphocyteAPC

WHEN A T-LYMPHOCYTE MEETS AN ANTIGEN…

1. T cells recognize antigens

presented on the MHC by the TCR

(SIGNAL 1)

2. The activation or inhibition of T

cells is determined by the

additional ligand–receptor

interactions between T cells and

APCs (or tumour cells) (SIGNAL 2)

1. Release of cytokines (SIGNAL 3)

CD4 LymphocyteAPC

Hodgkin Lymphoma: Immune activation

• Allogeneic SCT

• Immune checkpoint inhibitors (inhibitory effect)

• Immune checkpoint activators (activation effect)

34

Activating or inhibitory receptors

Hodgkin Lymphoma: Immune activation

• Immune checkpoint inhibitors (inhibitory effect)

• Immune checkpoint activators (activation effect)

Immune checkpoints in HL

Teach your body to fight tumor

Haematologica cover July 2016

37

Inhibitory receptors

• Regulatory T-cells surround HRS cells(Assis et al, Med Oncol, 2012)

• EBV increases Tregs in tumor

microenvironment(Assis et al, Leukemia & Lymphoma, 2014)

• Increased Tregs in peripheral blood

of patients with cHL at diagnosis.(Silva et al, Clin Leuk, Lymph and Myel, 2015)

Regulatory T-cells in Hodgkin Lymphoma

• Regulatory T-cells downregulate anti-tumor immune response

Regulatory T-cells in Hodgkin Lymphoma

CTLA-4 Inhibitors: Ipililumabmechanism of action

41

Activating or inhibitory receptors

PD-1 Inhibitors in Hodgkin Lymphoma:Pembrolizumab and nivolumab

PD-1 Inhibitors in Hodgkin Lymphoma:Pembrolizumab and nivolumab

Results of PD1 Blocking Antibodies in

Relapsed HL (all pts received BV)

Drug Dose/Schedule

N % ORR % CR ORR in BV treated HL

1st Author

Pembrolizumab(humanized IgG4)

10 mg/kg IV Q 2wks

15 53% 20% 53% (n=15) Moskowitz C

Nivolumab(Fully human IgG4)

3 mg/kg IV Q 2wks

23 87% 17% 89% (n=18) Armand P

Phase 2 trials on going

45

Preliminary Safety and Efficacy of the Combination of Brentuximab Vedotin

and Ipilimumab in Relapsed / Refractory Hodgkin Lymphoma: A Trial of the ECOG-ACRIN Cancer Research Group (E4412)

Stephen Ansell et al, Poster, ASH 2016

• E4412 is a phase 1 study of the combination of BV and the checkpoint

inhibitors ipilimumab (anti-CTLA-4) (IPI) and nivolumab (NIVO)

• 23 patients have been treated with BV + IPI (first cohort)

• BV + IPI was well tolerated

• Overall response BV + IPI was 87% with a CR rate of 62%

• Optimization of this combination strategy is planned with ongoing accrual

to cohorts receiving BV + NIVO and BV + IPI + NIVO.

PD1 Blocking Antibodies:

potential serious side effects

PD1 Blocking Antibodies:

potential serious side effects

• Fulminant type 1 diabetes mellitus with Nivolumab

• Fatal GVHD following Pembrolizumab

• AIHA after nivolumab treatment

• Vitiligo induced by nivolumab

• Myasthenia gravis induced by nivolumab

J Diabetes, 2016

Bone Marrow Transplant. 2016

Oncotarget, 2016

Cancer reviews, 2016

JAMA Oncol, 2016

Single agent activity of novel agents in relapsed

cHL: update 2016

0

25

50

75

100

CR

PR

BrentuximabVedo nn

HDACi

PI3Ki/mTORi

Chemotherapy

PD1/PDL1an bodies

BrentuximabVedo nn

HDACi

PI3Ki/mTORi

Chemotherapy

PD1/PDL1an body

+

Strategy A Strategy B

Courtesy: Prof. Anas Younes

Current and Future Treatment Paradigms

of Hodgkin Lymphoma

Obrigado

baiocchi@unifesp.br

Current and Future Treatment Paradigms of

Hodgkin Lymphoma

ABVD

Platinum-based salvage

Gemcitabine-based salvage

ASCT

No response/relapse

And/or

No response/relapse

?

2002 - 2012 ABVD

Platinum-based salvage

Gemcitabine-based salvage

ASCT

No response/relapse

And/or

No response/relapse

BrentuximabAlloSCT

2012 - 2016 ?

?

?

?

No response/relapse

No response/relapse

2020

?

And/or