Case Study: Relapsed/Refractory CLL

Guy’s and St Thomas’ NHS Foundation Trust

Karen Stanley

Case study

• “Mick”, 72 year old retired plumber, married with 3 children

• Stage B CLL, diagnosed 2003

• Medical history: OA, Hep B core AB +ve, IDDM (steroid induced, 2013), Bronchiectasis

Treatment history

• Chlorambucil & prednisolone (2004)

• Chlorambucil & prednisolone (2006)

• Fludarabine & cyclophosphamide (FC) x 3 (2008) complicated by CMV pneumonitis requiring ITU stay

• FC & rituximab (FCR) x 3 (2012) for symptomatic disease & splenomegaly → continued progression

• RESONATE study (Jan 2013) - received ofatumumab → progression

• Ibrutinib� (July 2013) - after 8 months developed severe skin

reaction with haemhorrhagic blisters → discontinued

• Idelalisib� & Rituximab (Nov 2014) - some disruption with Grade 2

diarrhoea after 5 months, but continued treatment as per SmPC1

Treatment history

Idelalisib Summary of Product Characteristics (SmPC): Available at www.medicine.org.uk/eMC

Laboratory & CT results

Jan 2017- WBC ↑34, plts ↓70, Hb ↓110g/L,

multiple small volume nodes (3cms axilla), splenomegaly (20cms) – CLL progression

What next?

What would you do now?

• Stop idelalisib�

• Continue idelalisib treatment at full dose

• Treat with chlorambucil + obinutuzumab

• Treat with rituximab + bendamustine

• Treat with Venetoclax�

Target a different pathway → BCL-2

• BCL-2 protein blocks programmed cell death (apoptosis)1,2

• 95% of CLL cases express high level of BCL-2 expression documented compared to normal peripheral blood lymphocytes3

• Increased expression of BCL-2 allows cancer cells to evade apoptosis, implicated in resistance to chemotherapy3

Venetoclax (1)

• Venetoclax is an oral BCL-2 inhibitor which helps restore apoptosis independent of TP53 functional status increasing cancer cell death• Approved in December 2016 as monotherapy for the treatment of patients

with CLL:in the presence of 17p deletion or TP53 mutation in adult patients who are unsuitable

for or have failed a B-cell receptor pathway inhibitor.

or

in the absence of 17p deletion or TP53 mutation in adult patients who have failed both chemoimmunotherapy and a B-cell receptor pathway inhibitor

Venetoclax (2)

• In the M13-982 study (n=107), venetoclax demonstrated an overall response rate of 79% in heavily pre-treated CLL patients

• MRD was evaluated in 93/158 patients who achieved CR, CR or PR

27% (42/158) of patients were MRD negative in the peripheral blood, including 16 patients who were also MRD negative in the bone marrow

Venetoclax in relapsed/refractory CLL (17p del)

• Median time to first response: 1 month (range: 0.5–4.4)

• Median time to CR/Cri: 9.8 (range 2.7–31.1)

*One patient discontinued after the first venetoclax dose, one patient died after 3 weeks of treatment due to liver dysfunction not related to venetoclax, and one patient had pseudo obstruction of the small bowel mesentery and retroperitoneum during dose ramp up and discontinued the study.Stilgenbauer S et al. Abstract S771.European Haematology Association 22nd Congress, 25 June 2017, Madrid, Spain.

20

40

11

57

4050

19 20

33

2 0 02 0 30

102030405060708090

100

All patients (N=158) Previously untreated (n=5) Prior BCRI (n=18)

Perc

enta

ge p

atie

nts

CR/CRi nPR/PR SD PD NE*

ORR 77%

ORR 80%ORR 61%

“Mick” & Venetoclax

• Accessed via named patient programme Jan 2017

• Gradual 5 week ramp up schedule due to high risk of TLS in early clinical trials (trials put on hold temporarily 2012 because of deaths from TLS)

• Day 1→ 20mgs- 6 hours post oral dose: PO4 = 1.49, push oral fluids 3 L

• Day 2→ 20mgs- PO4 1.46, WCC ↓10

“Mick” & Venetoclax (2)

• Day 8 → 50mgs PO4 2.3, Ca 1.96, K+ 5.1GFR 52 ml/min, - admitted for monitoring for TLS, biochemistry normalised in 24 hours

• Day 15 →100mgs• Day 22 →200mgs• Continued weekly increases: 200mgs →400mgs with no further

evidence of TLS

Risk assessment and treatment of TLS

5

Laboratory TLSvs

Clinical TLS

Prophylaxis / monitoring based on TLS Risk

TLS risk

Oral (1.5 -2 L) Oral (1.5 - 2 L) and consider additional IV if tolerated

Oral (1.5 - 2 L) and IV (150-200 mL/hr as tolerated)

HYDRATION

Ensure adequate hydration throughout dose-titration, particularly 2 days prior to and the days of dosing at initiation and each subsequent dose increase; IV fluids based on TLS risk or who cannot maintain adequate oral hydration.

Anti hyperuricaemic agent(If available, consider rasburicase if baseline uric acid is elevated)

Anti hyperuricaemic agent (e.g., allopurinol)

ANTI-HYPERURICEMIC AGENTS

Start anti-hyperuricemic agents 2 to 3 days prior to first dose, which may be continued through the titration phase based on the ongoing risk of TLS. Subjects allergic to allopurinol must use another uric acid reducer.

Outpatient Monitoring(subsequent ramp-up doses)

• Pre-dose, 6-8, 24 hrs*

Outpatient Monitoring• Pre-dose, 6-8, 24 hrs* (at

1st dose of 20 mg and 50 mg)

• Pre-dose at subsequent ramp-up doses

In hospital Monitoring(1st dose of 20 and 50 mg)

• Pre-dose, 4, 8, 12, 24 hrs*

Outpatient Monitoring• Pre-dose, 6-8, 24 hrs* (at 1st dose of 20

mg and 50 mg)

• Pre-dose at subsequent ramp-up doses

Consider hospitalization if CrCl < 80ml/min at 1st dose of 20 mg and 50 mg

Correct pre-existing blood chemistry abnormalities prior to initiation of treatment. Monitor blood chemistry in real time (turn around < 2 hrs): potassium, uric acid, phosphorus, calcium, and creatinine

*24 hrs labs: Do not administer the next dose until 24-hour blood chemistry results have been evaluated.

BLOOD CHEMISTRY MONITORING

Anti hyperuricaemic agent (e.g., allopurinol)

Low High

1. Coutre et al. Pan Pacific Lymphoma Conference, July, 2016

Medium

17

Dose titration

• The 5-week dose titration schedule is designed to gradually reduce tumour burden (debulk) and decrease the risk of TLS

TLS, tumour lysis syndrome.AbbVie. Venetoclax Summary of Product Characteristics. 2018.

Week Dose1 20 mg once daily on Days 1–7

2 50 mg once daily on Days 8–14

3 100 mg once daily on Day 15–21

4 200 mg once daily on Days 22–28

5 onwards 400 mg once daily until disease progression or unacceptable toxicity

Adverse reactions

• Very common AEs (≥1/10) of any grade: Upper respiratory tract infection, neutropenia, anaemia, hyperphosphataemia, diarrhoea, vomiting, nausea, constipation, fatigue

• Common AEs (≥1/100 to <1/10) of any grade: Sepsis, pneumonia, urinary tract infection, febrile neutropenia, lymphopenia,TLS, hyperkalaemia, hyperuricaemia, hypocalcaemia, blood creatinine increased

• The most frequently reported serious adverse reactions (>2%) pneumonia, febrile neutropenia, TLS

AE, adverse events; TLS, tumour lysis syndrome.AbbVie. Venetoclax Summary of Product Characteristics. 2018.

Toxicity management

• Assess for risk of TLS (tumour burden, GFR) and anti-hyperuricemics given accordingly

• Patients needs to drink 1.5–2L water starting 2 days before initiation of treatment

• During titration phase patients need weekly appointments on days 1 and 2 of each week and/or should be admitted if risk of TLS is great

• Urgent FBC/U&Es, TLS bloods 6–8 hours post dose

• On day 2 of each week urgent FBC/U&Es, TLS bloods before next dose administered

• Prompt discussion of any blood counts/chemistry out of range

FBC, full blood count; GFR, glomerular filtration rate; TLS, tumour lysis syndrome; U&E, urea and electrolytes.AbbVie. Venetoclax Summary of Product Characteristics. 2018.

Toxicity management (2)

• Ensure infection prophylaxis:

Aciclovir 200 mg TDS

co-trimoxazole 480 mg M/W/F²

• Not recommended with strong or moderate CYP3A inhibitors1

e.g. ciprofloxacin, clopidogrel, fluconazole, amiodarone

M/W/F, Monday, Wednesday and Friday; TDS, three times per day.

1. AbbVie. Venetoclax Summary of Product Characteristics. 2018; 2. Personal speaker communication

How is “Mick” now ?

• Some grade 3 neutropenia- Day 70, dose reduced to 300mgs which he continues on (GCSF x 3 times/ week)

• WBC 6.8 x 10⁹/L, lymphocytes 3.5 10⁹/L, neutrophils 1.2, plts 120 x 10⁹/L

• No palpable adenopathy or splenomegaly

• Well, had 2 × caravan holidays this year

Case Study: Relapsed/Refractory HD

Guy’s and St Thomas’ NHS Foundation Trust

Karen Stanley

Meet “Leo”28 year old waiter diagnosed December 2016 with stage 4 Nodular Sclerosing Hodgkin Lymphoma (nodal above and below diaphragm, lung & pleura) after 6/12 hx of itch, night sweats and weight loss (5 kgs)

No past medical hx of note

January 2017 ABVD (RATHL approach)

March 2017 Interim PET after 2 ABVD = DV 5 → partial metabolic response with residual pulmonary & nodal disease- commenced BEACOPP 14 (x 4 cycles)

June 2017 DV 3 → CMR

“Leo” (2)February 2018 - New onset bone pain (R) humerus, femur, LUQ pain, 2kgs weight loss

• PET/ CT → extensive disease relapse with nodal disease above and below the diaphragm, lung and bone involvement; stage IV, conformed on bx

• March 2018 Commenced salvage chemotherapy- R DHAP x 2Clinical response after c#1, stem cell mobilisation post #2

• PET/ CT DV5= new (R) neck disease, some response in other areas

• June 2018 Commenced Brentuximab

• PET/ CT Post 5 cycles (October 2018) = DV5- left pulmonary node ↑ size & intensity

What next?

1. Bendamustine

2. Salvage- mini BEAM, ESHAP, ICE

3. Nivolumab

4. Pembrolizumab

5. CAR-T cells

6. Clinical trial

Pembrolizumab• Targets and blocks a protein called PD-1 on the surface of T cells, stimulating

the T cells immune system to recognise and destroy the cancer cells

• 200 mg every 3 weeks by intravenous infusion (30 mins), until disease progression or unacceptable toxicity

• Salvage & bridge to allogenic transplant- response assessment after 4 cycles (3 months)

• (If) responsive → transplant by 6 months or continue on for 2 years or unacceptable toxicity

Response rates (KEYNOTE-087 trial, n= 210)

• Clinically effective based on response rates but effect on OS unknown

• PFS 11.1 months

• Median OS 17-19 months, median 13 cycles received

• Response rate 69% (74% failed auto + BV, 57% refractory to all tx)

• PR 42%, CR 24.7%

• 57% proceeding to allogenic stem cell transplant

• Progressive disease → no longer eligible for transplant

• Treatment continued up to 24 months (for those unable for transplant)

Side effects• Generally well tolerated (Chen et al, 2017)

• Common (10%): nausea, pain & swelling in joints, diarrhoea, dry skin, fatigue, IRR, hypothyroidism

• Less common (>1%): loss of appetite, headaches, dry mouth, breathlessness, dry mouth/ eyes, constipation, flu like symptoms, liver changes, allergic reaction, peripheral oedema

• Rare (<1%): IDDM, sepsis, pancreatitis, hepatitis, insomnia, myasthenia, jaundice, renal failure, neuropathy, hypertension

Immune- related adverse events• Leads to attenuation of immune response to prevent auto- immunity

• By unbalancing the immune system immune- related adverse events (IRAEs) occur

• Most respond to D/C and steroids (Shindiapina et al, 2018)

IRAEs

RashAcute pneumonitisColitisThyroiditisHypophysitisHepatitisPancreatitisRheumatoid arthritisType 1 diabetesUvetitis

Immune-related AE’s • Pneumonitis

• Colitis- risk of perforation

• Nephritis

• Endocrinopathies- IDDM, hypothyroidism (pituitary function)

• Hepatitis- grade 2 ↑AST, ↑ALT, ↑bilirubin (monitor during tx)

• Skin reactions- SJS

• Grade 1-2 → treatment withheld until recovery

• Grade 3- 4 → treatment discontinued

• Grade 4 Haematological toxicity- withhold until recovery

Special considerations• Increased rates of GvHD and VOD have been observed in allogenic SCT both

pre and post pembrolizumab

• Allogenic SCT pre = acute GvHD (including fatal) observed to be higher in those with GvHD post SCT (El Cheikh et al 2017)

• Need to consider

• Allogenic SCT post = GvHD and VOD observed

• Careful consideration of benefit of therapy versus risk of GVHD

• Time between last dose PD-1 and allo. did not predict GvHD

• Tx with PD-1 2yrs post SCT= 55% GvHD (Haverkos et al, 2017)

“Leo” now…

• Has had 3 x infusions of Pembrolizumab

• Nausea and fatigue (grade 2)

• Due response assessment in 3 weeks

Thank you