GESTIONE DELLE TOSSICITÀ IMMUNO-MEDIATE, QUALI LINEE GUIDA?

Transcription

1 GESTIONE DELLE TOSSICITÀ IMMUNO-MEDIATE, QUALI LINEE GUIDA? Massimo Di Nicola, MD Unit of Immunotherapy and Anticancer Innovative Therapeutics Medical Oncology Department

2 Widespread use of immune-checkpoint blockers Immune Checkpoint Blocking Antibodies Approved by the Food and Drug Administration.

3 Immune-related Adverse Events (irae) By increasing the activity of the immune system, immune checkpoint blockade can, however, induce inflammatory side effects Although any organ system can be affected, immunerelated adverse events most commonly involve the gastrointestinal tract, endocrine glands, skin, and liver

4 Is autoimmunity the Achille s heel of cancer immunotherapy?

5 Epidemiology IRAEs occur in up to 90% of patients treated with anti-ctla4 and in 70% of those receiving anti-pd1/pd-l1 antibodies The most frequently occurring iraes affect skin, colon, endocrine organs, liver and lung. Others are very infrequent, but may be very serious, even lethal, such as neurological disorders and myocarditis Grade 1-2 events are most common in the skin and the bowel, whereas grade 3-4 toxicities are prevalent in the digestive tract The majority of IRAEs occur within 3-6 months of therapy

6 Incidence of iraes based on used ICBs The risk of developing IRAEs appears to be dose-dependent for anti-ctla4 antibodies, but not for anti-pd1 agents

7 CTLA4 and PD1 regulate different stages of T cell response

8 Possible Mechanisms Underlying iraes. 1. Increasing T-cell activity against antigens that are present in tumors and healthy tissue 2. Increasing levels of preexisting autoantibodies 3. Increasing level of inflammatory cytokines 4. Enhancing complement-mediated inflammation due to direct binding of an anti CTLA-4 antibody with CTLA-4 expressed on normal tissue

9 This is the largest series of patients with preexisting autoimmune disease treated with immune checkpoint inhibitors. Ipilimumab was clinically active and was associated with exacerbations of autoimmune disease and conventional ipilimumab-induced iraes that were readily manageable with standard therapies when started in a timely fashion. Ipilimumab therapy may be considered in this setting with vigilant clinical monitoring. JAMA Oncol. 2016;2(2):

10 iraes: Role of the Screening before ICBs TSH reflex Lipasi ANA HBV and HCV screening EBV and CMV

11 Predictive factors? Ipilimumab-treated patients with advanced melanoma have similar outcomes regardless of their HLA-A*0201 status.

12 Predictive factors? The composition of the intestinal microbiota influences the development of inflammatory disorders. An increased representation of bacteria belonging to the Bacteroidetes phylum is correlated with resistance to the development of checkpointblockade-induced colitis. Furthermore, a paucity of genetic pathways involved in polyamine transport and B vitamin biosynthesis is associated with an increased risk of colitis.

13 ICBs: iraes by organ site GI Tract: Diarrhea Abdominal Pain Blood or mucus in the Stools Intestinal Perforation Peritonitis Ileus Liver: Increase of LFTs (AST, ALT) Hyperbilirubinemia Lung Pneumonitis Kidney Renal Insufficiency Skin: Maculopapular Rash Pruritus Vitiligo-like lesions Vasculitis-like reactions Endocrine System: Asthenia Headache Alterations of the mental status Thyiroid Dysfunctions Peripheral Nerves: Mono/Bilateral Hypostenia Sensorial Alterations Paresthesias

14 iraes: Role of monitoring Early identification of adverse reactions and their rapid treatment are a key aspect of the appropriate use of ICBs The patients must be continuously monitored (at least up to 5 months after administration of the last dose) since iraes can occur at any time during therapy or after its suspension

15 iraes: Kinetics Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol Jul 20;30(21):2691-7

16 iraes: ESMO and ASCO Guidelines

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19 iraes: Skin Skin iraes are among the most frequent AEs observed by patients treated with MoAbs inhibiting either CTLA4 (ipilimumab in 43% 45%of the patients) or PD-1 (nivolumab and pembrolizumab in 34%) Usually develop early in the course of treatment Serious skin AEs are rare and do not usually require dose reductions or treatment discontinuation 3 type of skin iraes: Rash-Inflammatory dermatitis; Bulloues dermatotes; SCARS: severe cutaneous adverse reaction, including STS (Steven-Johnson syndrome) and TENS (toxic epidermal necrolysis)

20 Cutaneous Rash

21 Skin Adverse Event Management Algorithm

22 Gastrointestinal Adverse Event GI toxicity is one of the most frequent and is the most severe (grade 3 or higher) of iraes associated with anti- CTLA4 It is usually the first irae leading to anti-ctla4 discontinuation The most common symptom of anti-ctla4-induced enterocolitis is diarrhoea that occurs in 27-54% of treated patients Colon perforation occurred in 1-1.5% of melanoma patients receiving ipilimumab

23 Enterocolitis 3 histologic patterns: - Neutrophilic inflammation - Lymphocytic inflammation (CD8+ in the crypt epithelium) - Combined

24 Gastrointestinal Adverse Event Management Algorithm

25 iraes: Endocrinopathies Pituitary Insufficiency in a patient with metastatic melanoma Presumed Autoimmune Hypophysitis Confusion, fatigue, impotence Headache Low ACTH/cortisol T4, testosterone and/or prolactin Increased pituitary size on MRI Asymptomatic with replacement therapy Slow return of some endocrine function Blansfield JA, Beck KE, Tran K, Yang JC, Hughes MS, Kammula US, et al. Cytotoxic T-lymphocyte-associated antigen-4 blockage can induce autoimmune hypophysitis in patients with metastatic melanoma and renal cancer. J Immunother 2005;28(6):593-8.

26 iraes: Cytokine Release Syndrome Cytokine release syndrome (CRS) is a potentially life threatening toxicity that has been observed following administration of mabs and, more recently, CART-cells CRS is associated with elevated circulating levels of several cytokines including IL-6 and IFNγ Signs and symptoms: Refractory hypotension Respiratory distress Fever above 38.5 Acute renal or hepatic insufficiency Bleeding by DIC Cytopenia (G 2 involving multiple lines), transaminase elevation, coagulopathy, creatinine uptake, ferritin 3000 ng / ml Splenomegaly Treatment: Tocilizumab Patients weighing less than 30 kg: Tocilizumab 12 mg / kg ev Patients weighing 30 kg: Tocilizumab 8 mg / kg iv (not exceeding 800 mg TOTAL)

27 Immunosuppresive drugs Steroid Therapy: Methylprednisolone mg/kg iv die or equivalent Tapering of steroids should be very slow, over 6 weeks Mandatory anti-infective prophylaxis (Bactrim and Valganciclovir) Steroid-refractory iraes: Tumour Necrosis Factor (TNF)-alpha antagonists (Infliximab) Azathioprine Mycophenolate Mofetil (MMF) Infliximab has an immediate therapeutic effect, the other immunosuppressors become effective after several weeks

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30 Baseline vs Late administration of steroids Early steroids No early steroids Late-only steroids No steroids HR 2.60 (95%CI ) HR 0.80 (95%CI ) When an efficient P < immune reaction is activated by P = 0.35 ICI, administration of immunosuppressive therapies does not influence response to treatment Fucà et al WCLC 2018

31 irae: Definitive suspension G2 uveitis, eye pain, blurred vision Non-cutaneous event G 3 which lasts for more than 7 days Pneumonia G 3 Bronchospasm G 3 Hypersensitivity reactions and infusion reactions G 3 Thrombocytopenia G3 over 7 days or associated with bleeding AST-ALT 8 times UNL Bilirubin> 5 times UNL Concomitant increase in AST and ALT> 3UNL and bilirubin> 2 UNL Postponement of more than 6 weeks for failure to resolve the adverse event, unless the timing is imposed by the need for slow decalage of the steroid

32 Take home message

33 FONDAZIONE IRCCS ISTITUTO NAZIONALE DEI TUMORI PROTOCOLLO DIAGNOSTICO TERAPEUTICO IMMUNOTERAPIA E GESTIONE EFFETTI COLLATERALI PDTA- IMMUNOTERAPIA E GESTIONE EFFETTI COLLATERALI Escludere cause infettive. Esami a completamento: coprocoltura, ricerca Cl Difficile, ricerca CMV, PCR, valutare biopsia colica Consulenza: gastroenterologo (eventuale colonscopia, TAC addome); oculista (rischio tossicità oculare associata, Spain et al) Terapia con infliximab (anticorpo anti TNF-α: 5 mg/kg (ripetibile dopo 2 settimane) NB: NON usare infliximab in caso di perforazione o sepsi. S. Cresta, M. Di Nicola, M. Platania, 2018

34 Management of immune-related adverse events: a multidisciplinary approach Radiologist IR Response Criteria ICIs-based Treatment Pneumonitis Renal Insufficiency Pneumologist/ ID Specialist Nephrologist Thyroid dysfunction Hypophysitis Enterocolitis Hepatitis Endocrinologist Gastroenterologist Hepatologist Cutaneous Rash Dermatologist Clinical Immunologist Atypical GB Syndrome Neurologist

35 irae underscores cancer immunotherapy as a double-edged sword in which patients and clinicians must weigh the risk of immunotoxicity against the benefit of tumor destruction

36 Is autoimmunity the Achille s heel of cancer immunotherapy?

37 Early identification of adverse reactions and their rapid treatment are a key aspect of the appropriate use of ICBs

38 Future Perspectives There is hope that the good and bad immune reactions unleashed by immunotherapies can be controlled separately. More support for this idea comes from data on allogeneic bone marrow transplants, used to treat hematological malignancies, in which the goal is to induce graft-versus-leukemia response while avoiding graft-versus-host disease.