Adverse events / Toxicitiesduring

Immunotherapy of Cancer

Endocrinopathies Stig Valdemarsson

Skåne University Hospital 2015 12 05

CASE 1 -- 76 ys old female; Radioiodine 15 years ago; no need for thyroxine

• Acral / finger melanoma • Regional and lung metastasis • Temozolamid: progress; TKI – nilotinib – progress

• Ipililumab; 3 cycles given • Presented with severe headache, tiredness; vomiting • High blood pressure !! No focal neurology; visual disturbances ?

• Lab A: P-Na from 141 to 129 – 120; S/U Osmol 258/586 = SIADH !

• Lab B: FSH/LH low for age : 12 (25-135) / 2.7 (7.7-59) – hypopituitarism !

• Lab C: ACTH 6.5 normal; P-kortisol 319 = intermediate

• Lab D: TSH 0.23 Free T4 9 = central hypothyroidism

• Received iv hydrokortison; subsequent high dose prednisolon; later thyroxine

Reference Pituitary MRwithout and with constrast

Case 1 : follow up 3 months later

Pituitary stalk lesion: diagnosis to be considered

• Lymphocytic infundibulo-hypophysitis • Langerhans cell histiocytosis • Wegener’s • Neurosarcoidosis • Inflammatory infiltrations by infectious diseases.

• Germ cell tumours • Pituicytomas and other tumours • Metastases from lymphoma, breast cancer,

melanoma etc

Hypofysitis; middle aged women ( verified at exploration )

50 ys old female; previously op malignant melanoma. Admitted to neurology. MR sella lesion; skeletal destruction.

Progressiv pituitary insufficiency. Transsfenoidal exploration. PAD: metastasis from malignant melanoma

Pituitary endocrine evaluation

• Look for anterior lobe disturbances ✓ pituitary – gonadal hypofunction

✓ secondary adrenal insufficiency

✓ central hypothyroidism

• Look for posterior lobe DI symptoms

✓ polyuria - nocturia - and polydipsia

✓ note thirst and high P-Na !!

Blood sampling – anterior pituitary function ?

F-pre MP Oestradiol + FSH / LH ( low+ inappro. normal/low? ) F-postMP FSH / LH ( not increased ? ) M Testo+SHBG + FSH/LH ( low + inappro. normal/low ?)

F+M P-kortisol + ACTH ( low + not increased ?) P-kortisol < 100 nmol/L substitute 100 – 250 treat if suspected / control soon 250 – 450 control, might be normal > 450 sufficient

F+M Free T4 + TSH ( low + not appropriately increased )

F+M IGF-1 : ( GH deficiency ? – evaluated at follow-up ) F+M Prolaktin – increased ? Pituitary stalk disruption ? Prolaktinoma ? Drugs ?

Diabetes insipidus ?Symptoms: • Polyuria • Thirst Polydipsia --- day and night !! • Note increased P-Na !

Diagnosis: • Increased P-Na + low/ inappropriate low / not

increased osmolality in urin + typical symtoms

• Thirst test in unclear cases

Pituitary insufficiency - substitution

• Hydrocortison iv in acute setting

followed by oral hydrocortison 20 – 30 mg / d

• ( Fludrocortison / aldo / seldom indicated )

• Thyroxin; only after hydrocortison !

• Desmopressin if needed

• Next case

Case 2: Thyroid and pembrolizumab• 59 ys old man ; no previous thyroid disorder

• Malignant melanoma 2007; progress 2014

• Ipililumab from Jan 2015 • Steroids for severe toxocodermia • Progress

• Pembroluzimab from April 24th 2015

• May 13th 2015 abnormal thyroid function tests at regular follow up • Moderate thyreotoxic symptoms • Increased pulse rate • Admitted for evaluation of thyroid disturbance

Thyroid scintigraphy; 99mTc Note low up-take: ---thyroiditis? ---Iodine block after CT contrast

Scintigraphy - information

Normal thyroid structure

Enlargded thyroid • isthmus 9 mm • low ecogenecity

Pembrolizumab and tyreotoxicosis

Right lobe Left lobe

Thyroid and pembrolizumab Conti..

• Thyroid lightly enlargded; diffuse; not tender • TSH suppressed Free T4 67 - 92 ( 12-22 ) Free T3 14 – 18.6 (3.6-6.3) • TSH Rec Ab : neg TPOAb : neg

• 99mTc Scint --- no/low uptake

• Ultrasound -- general hypoecogenicity; moderately enlargded vascularisation not increased --- Thyroiditis ? Autoimmun thyroid disease ?

Conclusion: • probable inflammatory process with hormone release; • no nodes; not Graves´

Beta blocker; discontinue pembrolizumab ?

Follow up: Free T4 max > 99 pmol/L; -- subsequent sponaneously decreasing Free T4; nadir 3.7 with TSH increased to 21

Thyroxin substitution initiated

Thyroiditis – inflammation in thyroid

Autoimmune

-- various manifestationes

-- TPOAk (TgAk) positiv

• Hashimoto

• Atrofisk

• Spontaneous / ”silent”

• Post partum • Fokal

• Juvenil

Non – autoimmune -- various patophysiologies -- TPOAk negativ

• Subakut; de- Quarvain • Bakteriel • Riedel • Iodine - amiodarone • Radioiodine • Trauma

• PD-1 ? CTLA-4 ? • TKI ( sunitinib and other )

Thyroiditis – T4 / T3-typical development over time

Thyroiditis: treatment ?

• Beta – blocker

• Consider steroids

-- local tender symtom ?

-- probably no effect on outcome ( de Quervain )

• Watchful follow- up / 2 – 3 weeks

• Thyroxin if hypothyroid / at least if prolonged

• Anti-thyroid drugs not indicated

Induction of Painless Thyroiditis in Patients ReceivingProgrammed Death 1 Receptor Immunotherapy for

Metastatic Malignancies

…. clinical trial to receive anti-PD-1 mAb therapy (2–10 mg/kg IV infusion over 30 minutes, every 3 weeks) … continued

n=6: Toxic phase 3 – 6 weeks from start; duration 4 weeks before hypotyroid n=4. Hypothyroid 6 – 8 weeks from start

Nivolumab in Resected and Unresectable Metastatic Melanoma:Characteristics of Immune-Related Adverse Events and Association

with Outcomes Morganna Freeman-Keller e al Oct 2015

Adverse effects / FASS / Sweden

Nivolumab

• Pnumonitis • Colitis • Hepatitis • Nephritis • Endocrine -- pituitary -- adrenal -- diabetes type 1 -- thyroid - hypothyroidism - hyperthyroidism - thyroiditis

Pembrolizumab

• Pnumonitis • Colitis • Hepatitis • Nephritis • Endocrine -- pituitary -- adrenal -- diabetes type 1 -- thyroid - hypotyroidism - hypertyroidism - thyroiditis

Tc – scintigrafi; man, sunitinib -- supprimerat TSH höga FT4 och FT3

-- lågt – inget upptag som vid tyreoidit

Lymfocytär tyreoidit / Hashimoto

Subacute tyreoiditis; polynuclear cell

Autoimmun tyreoidit Hashimoto

UL: TSH 30 efter 9 cykler Sutent

Hashimoto’s Thyroiditis

Immunmodulering:CTLA-4: interaktion mellan APC och T-cell

Ipilimumab - YERVOY

• CTLA-4 hämmare

• Melanom – dissiminerat

• Autoimmuna reaktioner – hos 72% ( n=325 ) efter 4 behandlingar - tyreoidea – tyreoidit mest sannolik mekanism hypotyreos; hypertyreos ( mindre vanligt )

- hypofysit ACTH svikt / TSH svikt - primär binjuresvikt / Addison - colit - hepatit

CTLA-4 hämmare och Hypofysit

CTLA-4 i TSH, ACTH och FSH/LH celler

PD-1 interference

+ hormonproducerande follikulär tyreoideacancer

Nyström et al ”Thyroid Disease in Adults” 2011

Follikelcellen

Hormonsyntes

Jodomsättning

Regleras av TSH

Ultrasound; normal thyroid structure ( small size )

Germinom. The most common location is the pineal region or posterior ventricle

followed by the suprasellar region.

65 årig kvinna. Tidigare op malign tumör i lunga och ÖNH. Vid utredning av hypofysinsufficiens påvisas expansiv process med recidivbenägenhet. Så småningom anger PAD kronisk hypofysit.

Inom 1 år efter sista op plötslig progess med ny synnedsättning; regress av suprasellär utbredning efter hög dos steroider

Pituitary stalk met från breast cancer presenting with DI symtoms

Pitutiary stalk lesions contin ..

• The diagnosis of lesions determining pituitary stalk thickness is challenging

• The identification of the underlying condition may require a long-term follow-up.