Uso de anticorpos monoclonais anti- PD1/PDL1 e anti-ctl4 como ponte para transplante

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Uso de anticorpos monoclonais

anti-PD1/PDL1 e anti-CTL4 como ponte

para transplante

Vanderson Rocha, MD, PhD

Professor de Hematologia, hemoterapia e terapia celular ICESP/HC-FMUSP, São Paulo

Diretor Presidente da Fundação Pro-Sangue, São Paulo

Médico coordenador da unidade de transplante do Hospital Sírio-Libanês Professor de Hematologia da Universidade de Oxford, Reino Unido

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Bloqueio do PD-1 reverte a inibição das céls.T e restaura ação antitumoral

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LINFOMA DE HODGKIN

QUAL O PAPEL DO ANTI PD1/PDL1 NO TRATAMENTO DE PACIENTES

COM LH RR/RC COMO PONTE PARA TMO AUTOLOGO?

(5)

Check Point Inhibitors

Malignant cells of classical HL

are characterised by genetic

alterations at the 9p24.1

locus, leading to

overexpression of PD-1

ligands and evasion of immune

surveillance.

(6)

Prior Treatments

Start/End

dates of

Treatment

Outcome/Response

to Treatment

Comments

BEACOPP (Bleomicin, Etoposide, Adryamicin, Cyclophosphamide, Vincristine, Procarbazine, Prednisone) Dec 2013 – Jun 2014

Progressive disease after 5 cycles

Salvage therapy

DHAP (Dexametasone, Cytarabin, Cisplatin)

Jul 2014 – Sep 2014 Partial remission after 4 cycles + 2 cycles

Radiotherapy (36Gy mediastinal area -until Jan 2015) – CRu Aug 2015 PET/CT

-Progressive disease

IGEV (Ifosfamide, Gemcitabine, Vinorelbine)

Sep 2015 – Dec 2015

PR Patient sent to our

service to ASCT PET/CT (Mar 2016)

-Progressive disease

ESS, male, 19 years old

Dec 2013 – diagnosis of CHL-NS, CS IIXB (X=mediastinal mass), initially treated in Santarem, Pará

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• Mar 2016 - progressive disease and BM infiltration • CS IVB

• Biopsy of cervical lymph node - CHL activity

• May 2016 – pulmonary tuberculosis – treatment started on • 26 May 2016

• ASCT not recommended

• Public Health Services in Brazil - Brentuximab is not available • PET/CT before anti-PD1 - compassionate use program –

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• 18 Aug 2016 – 1st _{dose anti-PD1 3mg/kg every 2 weeks, IV}

• Adverse events:

• 50 minutes after infusion

 fever (39°C), chills, tachycardia (160bpm) and hypotension

Treatment: diphenhydramine hydrochloride 50mg EV, Dipyrone EV, Hydrocortisone 100mg EV

Reversal of clinical symptoms

• 48 hours after infusion

 unilateral diplopia (left eye) followed by paralysis of the ocular globe (6th _{cranial pair)}

MR scan: no intracranial lesions CSF negative

Reversal of symptoms after 1 week without therapy

• 1st _{Sep 2016 – 2}nd _{dose anti-PD1 3mg/kg, IV}

• 15 Sep 2016 – thrombocytopenia G2 – anti-PD1 not done

• 22 Sep 2016 - 3rd _{dose anti-PD1 3mg/kg, IV}

10 Aug 2016

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Follow-up

•Fever and night sweats disappeared 48 hours after anti-PD1 infusion •Gain of 6 kg in the last month

•Disappearance of peripheral lymphadenopathy

•Improvement in anemia – Hb=12.4 g/dL (22 Sep 2016)

PET/CT pre-anti-PD1 PET/CT pos-anti-PD1

•Auto transplant in November 2016, platelets transfusion dependent for 6

months

•Went back to Santarem in June 2017, doing very well

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Check Point Inhibitors

Malignant cells of classical HL

are characterised by genetic

alterations at the 9p24.1

locus, leading to

overexpression of PD-1

ligands and evasion of immune

surveillance.

(11)

(12)

CA209-205: Desenho do Estudo

a_{Patients could elect to discontinue nivolumab and proceed to hematopoietic SCT} b_{ORR per the 2007 IWG criteria}

CR = complete remission; DOR = duration of response; IRRC = independent radiologic review committee; IWG = International Working Group; ORR = objective response rate; PD = progressive disease; PR = partial remission; SCT = stem cell transplantation; SD = stable disease

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Características basais (N=23)

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Desfecho Primário: Taxa de remissão objetiva

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SLP (Comitê Revisor Independente)

NA = not available

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Taxa de Resposta Objetiva – Desfecho Primário

Parâmetro de Eficácia IRCC (n = 80) 12 months 18 months

Taxa de Resposta Objetivaa

Número (%) de Respondedores, IC de 95%

54 (67.5) (56.1 - 77.6)

54 (67.5)

56.1, 77.6

Taxa de remissão completa

Número (%) de Respondedores, IC de 95% 6 (7.5)

(2.8 -15.6)

10 (12.5)

(6.2 - 21,8)

Taxa de remissão parcial

Número (%) de Respondedores, IC de 95% (48.4, 70.8)48 (60)

44 (55.0)

(43.5 - 66.2)

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Sobrevida Livre de Progressão – Desfecho secundário

Parâmetro de Eficácia

IRRC (n = 80)

SLP

Mediana (95% CI) (meses)

d

Taxa em 12 meses, % (95% CI)

Taxa em 18 meses, % (95% CI)

Taxa em 20 meses, % (95% CI)

14.65 (10.51 - 19.58)

50.8 (38.3 - 62.0)

47.4 (35.0 - 58.8)

35.1 (23.1 - 47.3)

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Segurança: EAs≥10%

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Clinical Results with Anti-PD-1 Antibodies in Patients with Relapsed and Refractory Hodgkin Lymphoma

Agent Number of patients treated Previous stem cell transplantation Previous brentuximab vedotin Overall Response Rate Reference

Pembrolizumab 31 _autologous)71% (all 100% 65% Armand et al. ASH meeting. Blood 2015 abstract 584

Nivolumab 23 _autologous)78% (all 78% 87%

Ansell et al, NEJM, 2015

Ansell et al. ASH meeting.Blood 20 15

abstract 583

Nivolumab 12 _allogeneic)100% (all Not reported 88%

Herbaux et al. ASH meeting.

Blood 2015 abstract 3979

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INIBIDORES DE CHECKPOINT E

ALO-TCTH

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Considerações

• Cenários: pré-aloTMO -> antic. residuais Anti-PD1 podem

persistir

pós-aloTMO-> CTL’s do doador ativadas pelo

bloqueio do PD-1

• Os ligantes do PD-1 integram a ”auto-tolerância” e seu

bloqueio desencadeia o GVHD

• Simultaneamente, este bloqueio permite atividade GVT sem

GVHD grave

HERBAUX et al. Recommendations for managing PD-1 blockade in the context of allogeneic HCT in Hodgkin lymphoma: taming a necessary evil. blood® 5 JULY 2018 | VOLUME 132, NUMBER 1

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Anti-PD1 pré e pós AloTMO

GVHD

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AloTMO após uso de anti-PD1

• Inelegíveis ao ATMO ou recidiva após ATMO possuem péssimo prognóstico com mediana de sobrevida de 2 anos

• BV com altas taxas de resposta (75%), entretanto muitos irão recair ou terão utilizado BV em 1ª linha

• Nivomulab e Pembrolizumab aprovados neste contexto com ORR de ~70%

• Ainda assim, dados de estudos fases 1/2 mostram que a maioria recai após 1 a 2 anos -> aloTMO com potencial curativo

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AloTMO após uso de anti-PD1

• RIC associado com 25-40% de sobrevida livre de doença

Como manejar aqueles pacientes respondedores aos anti-PD1?

• Opção 1: aloTMO para aprofundar resposta

• Opção 2: manter o anti-PD1 na esperança de sustentar resposta, sem os riscos do TMO

(25)

Merryman et al. Blood 2017

Check Point Inhibitors

pre-Allo-HSCT in

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Relapse

NRM

N = 39, anti-PD1 @ median 62 days (7-260) prior to HCT

Allo-HSCT can be safely performed

in patients after checkpoint inhibitors

(27)

Allo-HSCT can be safely performed in

patients after checkpoint inhibitors

OS

PFS

N = 39, anti-PD1 @ median 57 days (7-260) prior to HCT

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Merryman et al. Blood 2017

A febrile syndrome is observed in a

number of patients after prior anti-PD1

aGVHD: 1-yr CI of gr 2-4 44%, gr 3-4

23%

, gr 4 13%

cGVHD: 1yr 41%.

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Nivolumab after Allo-HSCT (n=20)

Characteristics Value

Age in years [median (range)] Sex: F/M

ECOG Performance Status 0-1 N. Prior lines of therapy

BV failure (pre or post-allo-SCT) Interval allo-SCT – relapse (mo) Interval allo-SCT – nivolumab administration (mo)

Patients with prior history of GVHD

33 (20-51) 9/11 15 pts (75%) 7 (4 – 13) 100% 8.5 (2 – 59) 23 (2 – 111) 10 pts aGVHD / 3 pts cGHVD Retrospective analysis

N = 20 patients with relapsed HL after allo-SCT Nivolumab 3 mg/kg iv every 2 weeks

No immunosuppressive tx for the last 4 weeks

No prior history of grade 4 aGVHD / extensive cGVHD

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Nivolumab after Allo-HSCT. Progression

Free Survival and Overall Survival of the

Series

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Haplo Post-CY and checkpoint inhibitors

Schoch BM et al, Blood 2016

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Haplo Post-CY and checkpoint inhibitors

• The incidence and severity of GvHD seen in

patients who received checkpoint inhibitors was

similar to that seen in pts without checkpoint

inhibitors.

• GvHD was seen in patients treated with

checkpoint inhibitors prior to alloBMT, but was

generally mild and readily controlled.

• In patients treated with checkpoint inhibitors after

alloBMT, the only case of GvHD occurred after the

patient received DLI.

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Allo-HSCT in Nivolumab Studies

Patients could proceed directly to HSCT or undergo salvage therapy prior to allo-HSCT Cohort B n = 80 Cohort A n = 63 CheckMate 205 (phase 2) CheckMate 039 (phase 1) Allo-HSCT: n = 5

Nivolumab 3 mg/kg every 2 weeks

Allo-HSCT: n = 44

• Outcomes post–allo-HSCT were collected prospectively in CheckMate 205 and retrospectively in CheckMate 039

• Stem cell source, preparative regimen, and additional safety data were collected retrospectively Cohort C n = 100 BV before and/or after auto-HSCT n = 23 Relapsed cHL with ≥2 previous systemic cancer therapies _naïveBV BV after auto-HSCT

Relapsed cHL after auto-HSCT

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38

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39

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40

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41

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42

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43

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44

• Check point inhibitors are very effective / acceptable

toxicity profile drugs for patients with relapsed /

refractory HL

• Check point inhibitors can be used “as a bridge” to

allo-HSCT as well as to treat relapses after the

procedure

• High incidence of GVHD after allo-HSCT when used

to treat disease relapse after it

• Which patients should we take to allo-HSCT? When?

…… Still more questions than answers

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Anti-PD1 após aloTMO

• Modelos murinos sugerem maior mortalidade relacionada a aGVHD quando anti-PD1 administrado precocemente

• Recomendação: evitar uso de anti-PD1 até o D+180

* Se necessária a utilização, optar por baixas doses-> 0,5mg/kg • Manejo do teGVHD

1ª linha: corticoides em altas doses ( 2mg/kg)

Para os não respondedores: ATG ; inib. de calcineurina + fotoaférese

Schoch LK, Borrello I, Fuchs EJ, et al. Checkpoint inhibitor therapy and graft versus host disease in allogeneic bone marrow transplant recipients of haploidentical and matched products with post-transplant cyclophosphamide [abstract]. Blood. 2016; 128(22). Abstract 4571.

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Anti CTLA4 e tratamento da recaida apos alo

TMO

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Ipilimumab in post-HCT relapse

• Phase 1/1b multicenter trial

• 28 patients enrolled, 22 receiving 10 mg/kg

• 12 pts with AML (4 with extramedullary

disease), 2 with MDS and 14 with other

hematologic malignancies.

• Overall resposes (10 mg/kg): 23% CR, 9% PR

and 27% decreased tumor burden.

• 14% developed GVHD.

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Complete respose in all 4 AML pts with extramedullary relapse.

Davids et al., NEJM 2016;375:143-53. PET/CT Scan of a Patient with Extramedullary Relapse of AML in the left breast after 7 and 13 Weeks of Ipilimumab Dosing. At week 7, the size of the mass and its FDG avidity increased, possibly due to tumorflare, as with continued ipilimumab dosing by week 13 the mass had decreased significantly both in size and FDG avidity.