safety and hazard management: patients at risk of

Safety and Hazard Management:Patients at risk of toxicities, triage pathways and policies management

Advanced Nurse Practitioner and Team Lead,Buckinghamshire NHS Trust

Asha Mathew

Objectives

• Overview of CLL• Review the complications of CLL• Treatment pathways of CLL• Explain main side effects/adverse effects of treatment for CLL• Examine how these adverse effects of treatments are dealt with• Improve understanding of priorities for triaging CLL patients in out

patient, inpatient and community settings

Chronic Lymphocytic Leukaemia

• Slow growing cancer of the B Cell lymphocytes• Affects the immune system• Some patients require treatment at diagnosis but not all• Treatment options are improving• Average age of patients is 72

(11% patients are diagnosed under 55yrs)• Incidence higher in men than women• Many patients have co-morbidities• 10 new cases a day in UK

Complications of CLL

• Infections• Anxiety(patients on watch and wait)• High risk transformation - Richter’s syndrome• Auto immune disease mainly ITP and AIHA• Tiredness• Swollen lymph nodes• Anaemia• Thrombocytopenia• Neutropenia (rarely)

Diagnosis of CLL

Blood test – Presence of >5 x 109/L B lymphocytes in peripheral blood sustained for at least 3 months

Immuno phenotype

Molecular genetics test (FISH) Deletion 17 P and other chromosomal deletion

Bone marrow

Signs and symptoms

TP53 status

Flow cytometry

Serum immunoglobulins

Criteria for treatment for CLL

• Weight loss & significant fatigue

• Drenching night sweats

• Unexplained fever

• Anaemia or thrombocytopenia

• Lymphocyte doubling time < 6 months

• Lymphocyte count > 30x/L 109/ L

• Massive lymph node >10cm in diameter

• Massive, progressive or symptomatic lymphadenopathy or hepatosplenomegaly

• Autoimmune cytopenia poorly responsive to immunosuppression

• Extra nodal involvement

(International Workshop on CLL 2008)(www. http://nssg.oxford-haematology.org.uk. Accessed November 2018)

http://nssg.oxford-haematology.org.uk/

Staging of CLL - RAI System Staging Characteristics Treatment Risk

Stage 0: Lymphocytosis; no enlargement of the lymph nodes,

spleen, or liver; red blood cell and platelet counts

are near normal

Watch and wait Low

Stage 1 Lymphocytosis; enlarged lymph nodes; spleen and

liver are not enlarged; red blood cell and platelet

counts are near normal

Potentially

start treatment

Intermediate

Stage II Lymphocytosis; enlarged spleen and liver lymph

nodes may or may not be enlarged; red blood cell

and platelet counts are near normal.

Treatment Intermediate

Stage III Lymphocytosis; lymph nodes, spleen, or liver may or

may not be enlarged; red blood cell counts are low

(anaemia); platelet counts are near normal.

Treatment High

Stage IV Lymphocytosis; enlarged lymph nodes, spleen, or

liver; red blood cell counts may be low or near

normal; platelet counts are low

Treatment High

www.cancer.org/cancer/chronic-lymphocytic-leukemia/detection-diagnosis (Accessed on November 2018)

Staging of CLL - Binet system

Stage Characteristics Treatment Risk

Stage A With fewer than 3 enlarged nodesWith no anaemia or thrombocytopenia

Watch and wait Low

Stage B With 3 or more enlarged lymph nodesNo anaemia or thrombocytopenia

Potentially start treatment

Intermediate

Stage C HB < 10 g/l and platelets < 100 x 109/l regardless of Lymphoid areas involved

Treatment High risk

www.cancer.org/cancer/chronic-lymphocytic-leukemia/detection-diagnosis (Accessed on November 2018)

Treatment pathway for CLL (pathway for Oxford and Bucks)

Consider any trials if available

chlorambucil single agent if very frail

or consider Idelalisib▼& Rituximab for patients with cardiac comorbidity or need warfarin for anticoagulation

Meets IWCLL criteria for treatmentFISH for del(11q) and del(17p)TP53 by sequencingConsider IGHV mutation status1

TP53 intact

Fit< 70 yearsFew comorbidities

Less fit> 70 years, few comorbidities OR< 70 years + comorbidities

Frail> 70 years + comorbidities

FCR – 6 cycles

Bendamustine 70mg m2

&rituximab x 6

Obinutuzumab & Chlorambucil

Ofatumumab & Chlorambucil

TP53 mutatedIbrutinib▼420 mg daily

www. http://nssg.oxford-haematology.org.uk (Accessed Nov 2018)

*Idelalisib is licensed in Europe in combination with an anti-CD20 monoclonal antibody (rituximab or ofatumumab) in adult patients with CLL who have EITHER received at least one prior therapy OR as first-line treatment in the presence of 17p deletion or TP53 mutation in patients who are not eligible for any other therapies2

Ibrutinib- Adverse effects

Bleeding related events

Atrial Fibrillation

Hypertension

Fatigue

Neutropenia

Skin Cancer

Drug interactions

Rash and erythema

Viral reactivation

Headache

Arthralgia

Diarrhoea

Ibrutinib – Dose modification

Treatment with Ibrutinib should be with held if any onset or worsening grade ≥ 3 non-haematological toxicities, grade 3 or more neutropenia with fever or infection & Grade 4 haematological toxicities.

Treatment can restart with the starting dose(420 mg) when the toxicity is resolved or back to baseline.

Studies showed that dose interruption more than 8 days may negatively impact both progression free survival (PFS) and overall survival (OS).

Toxicity occurrence Dose modification after recovery

First Restart at 420 mg daily

Second Restart at 280 mg daily

Third Restart at 120 mg daily

Fourth Discontinue treatment

Ibrutinib smpc (August 2018) Accessed October 2018www.medicines.org.uk/emc/product/3414 Barr et al, Blood 2017.

Management of complications of Ibrutinib

Bleeding related events/risks(based on the experience of Bucks NHS Trust)

• Risk of major bleed is low (only 5%).

• Educate patient regarding the side effects and to report hospital if any bleeding or blood blisters.

• Monitor FBC 4 weekly and keep platelet above 35.

• Clinic/CNS review before each cycle.

• Drug alert card.

• Warfarin or other vitamin K antagonists should not be administered concomitantly with ibrutinib.

• Need to interrupt if any surgical procedure or dental procedure.

• Drug card is given to all patients with contraindications, drug interactions and instruction of

interruption for procedures.

Management of complications

Ibrutinib - Hypertension• Monitor vital signs regularly. • Encourage to monitor BP at home.• Anti hypertensives if needed.• ECG and Echo as needed.• No need of altering the dose.

Neutropenic sepsis and other infections• Monitor blood levels.• Educate patients about responding to fever and infection symptoms.• Use GCSF.• Long term antibiotic prophylaxis.

Management of complications continued…

Ibrutinib - Atrial Fibrillation• Most cases appear in 1st six months

• Understanding cardiac history and documentation.

• Monitor vital signs during each cycle.

• Liase with Cardiology team.

• ECG/Echo if needed

• Anticoagulation - Apixaban is favoured

Idelalisib – Side effects

• Rash

• Diarrhoea

• Raised LFTs

• Pneumonitis

• Raised risk of PJP and CMV

• Neutropenia

• Fatigue

Idelalisib SmPC (date accessed: November 2019)

Idelalisib – Dose modifications 1,2

• Idelalisib should be withheld in the event of elevated liver transaminases Grade 3 or 4 (ALT / AST > 5 x ULN)

• Resume at 100 mg TWICE a day once toxicity returns to ≤ Grade 1 (ALT/AST ≤ 3 x ULN)

• Dose can be re-escalated to 150 mg TWICE a day at clinician’s discretion if the toxicity does not recur.

• If toxicity recurs to Grade 3 or 4: Withhold Idelalisib

• If toxicity returns to ≤ Grade 1, re-initiation at 100 mg TWICE a day may be considered at clinician’s discretion

• Idelalisib must be withheld when diarrhoea /colitis Grade 3 or 4

• Resume at 100 mg TWICE a day once toxicity returned to ≤ Grade 1

• If diarrhoea/colitis does not recur, the dose can be re-escalated to 150 mg twice daily at the discretion of the treating physician.


Dose modification continued...

Pneumonitis suspected:

• Withhold Idelalisib until pneumonitis has resolved, after which re-initiation at 100g TWICE a day may be considered at clinician’s discretion.

• Treatment must be permanently discontinued in the event of moderate or severe symptomatic pneumonitis or organising pneumonia.

Rash• Grade 3 or 4: Withhold idelalisib

• Resume at 100 mg TWICE a day once rash has returns to ≤ Grade 1

• Dose can be re-escalated to 150 mg TWICE a day at treating clinician’s discretion if the toxicity does not recur.


Dose modification continued..

NeutropeniaTreatment with Idelalisib should be withheld in patients while absolute neutrophil count (ANC) is below 0.5. ANC should be monitored at least weekly until ANC is ≥ 0.5.

Resume treatment 100 mg twice daily when ANC> 0.5

ANC 1.0 to <1.5 ANC 0.5- <1.0 ANC less than 0.5

Maintain Idelalisib dosing Maintain doseMonitor ANC weekly

Withhold IdelalisibMonitor ANC weekly until ANC>0.5Resume treatment at 100 mg twice daily


Management AlgorithmGrade 1-2 Uncomplicated Diarrhoea/Colitis

• Obtain patient history and perform physical examination to rule out infection• Instruct patient to:– Stop all lactose-containing products, alcohol and high-osmolar supplements– Drink 8–10 large glasses of clear liquids a day– Eat frequent small meals (e.g. bananas, rice, toast, plain pasta)– Record the number of stools and report symptoms of life-threatening sequelae (e.g. fever or dizziness upon

standing)

TreatmentAdminister standard dose of loperamide: initial dose 4 mg followed by 2 mg every 4 hours, or after every unformed

stool

Reassess 24–48 hours later

Diarrhoea resolving• Continue instructions for dietary modification

• Gradually add solid foods to diet

• Discontinue loperamide after 12-hour diarrhoea-free interval

Diarrhoea unresolved• Follow idelalisib diarrhoea management

recommendation

• Frequent reassessments are needed to ensure unresolved diarrhoea is managed more aggressively

Coutre S, et al. Leuk Lymphoma 2015;.

a Recommended dosage: three 3-mg capsules by mouth once daily (9 mg total). b Based on panel members’ experience, prednisolone 1 mg/kg has been used with tapering off once diarrhoea returns to Grade 1

Coutre S, et al. Leuk Lymphoma 2015;

Management Algorithm Unresolved Grade 2 and Grade 3/4 Diarrhoea

Initial management for unresolved Grade 2 and Grade 3/4 diarrhoea• Perform evaluation and work-up to rule out infection• Interrupt idelalisib• Continue diet instruction• IV fluid supplementation or oral hydration as warranted in case of signs of dehydration or Grade ≥3 diarrhoea or colitis

Infectious aetiology is excluded • If patient can tolerate medication by mouth: budesonidea or oral steroids (prednisolone)b

• OR• If patient is being treated with IV fluid therapy or cannot tolerate medication by mouth: IV steroids

Patient can tolerate medication by mouth• Switch from IV steroids to budesonide or oral steroids

Diarrhoea resolved to Grade ≤1 • Continue instructions for dietary modification• Gradually add solid foods to diet• Consider taper off budesonide and oral steroid• Reinstitute idelalisib at lower dose per clinical judgment; consider concomitant use of budesonide

Idelalisib - management of side effects

Pneumonitis and organising pneumonia• 3% non-infectious pneumonitis• Organising pneumonia- some fatal cases reported.

Management• Patients with respiratory symptoms and no clear bacterial pneumonia or lack of clinical response

to empiric antibiotic treatment, high-resolution computed tomography should be performed.• Idelalisib should be withheld while awaiting the results of culture broncho-alveolar lavage fluid, as

treatment continuation may be fatal in idelalisib-induced pneumonitis• Educate patients to monitor respiratory symptoms throughout the treatment.• Advise to report the new symptoms promptly.• CT chest• Antibiotics as needed


Idelalisib -Management of complications

Hepatotoxicity• The incidence of ALT and AST elevations of any grade is 50%

• Grade ≥3 increases occurring in 5%

• Generally observed within first 12 weeks of starting treatment.

Management• Dose adjustment is not necessary in patients with prior hepatic impairment.

• Careful monitoring of liver functions

• ALT and AST should be monitored frequently, every 2 weeks for first 3months of treatment.

• If grade2 or more ALT elevation, it should be monitored weekly until resolve to Grade1.


Idelalisib - Management of complications

Serious infections (based on the experience at Buckinghamshire Trust)• Treatment with Idelalisib should not be initiated to patients with ongoing infection

(fungal, bacterial or viral).• Pneumocystis Jirovecii pneumonia(PJP) and cytomegalo virus(CMV).• Prophylaxis for PJP should be given throughout the idelalisib treatment and 2-6 months after stopping

treatment. Post treatment prophylaxis duration should be based on clinical judgement . Patient’s risk factors such as use of corticosteroids and prolonged neutropenia need to take into consideration.

• Monitor respiratory symptoms throughout the treatment, and educate patient to report any new respiratory symptoms.

• Regular clinical and laboratory CMV monitoring is recommended in patients with positive CMV at the start of treatment also patients with history of CMV infection.

• CMV PCR should be monitored 4 weekly, throughout the treatment.• Treatment should be discontinued during confirmed CMV viraemia.


Idelalisib- management of complications

Neutropenia• Dose interruption as discussed before.

• Blood counts should be monitored 2 weekly for first 6 months of treatment.

• Weekly monitoring blood count if ANC is less than 1.0.

• Manage neutropenic sepsis as per the local policy.

Rash• Generally present with mild to moderate rash.

• Treatment interruption.

• Treatment with topical and/or oral steroids diphenhydramine.


Venetoclax- dose Titration

Obtain pre-dose full bloods for medical review prior to the first dose administration.

Administer Venetoclax 20 mg following the medical review of TLS risk assessment. Treatment should be given only of the blood abnormalities are fully corrected.

Obtain bloods 6-8 hours post first dose, and full medical review for TLS and correct if any abnormalities.

Blood test 24 hours post first dose, full review, correct if any abnormalities prior to second dose

Instruct patient to take subsequent daily doses at the same time of each day as day 2

Day 0

Day 1 8am

Day 2

2-4 pm

8 am

Days 3-7

Optimal patient management

Venetoclax- Dose modification

Tumour Lysis Syndrome.• Any blood chemistry changes suggestive of TLS or patient experience any symptoms of TLS.• Venetoclax dose should be withhold for the next day. If resolved within 24 to 48 hours of last dose,

treatment with venetoclax can be resumed at the same dose.• If any clinical TLS or blood chemistry changes need more than 48 hours to resolve, treatment should

resume at a reduced dose. If rapid dose escalation is required due to progressive disease, patients have to be admitted for iv hydration and management of TLS.

• Note: When resuming treatment with venetoclax after interruption due to TLS, the instructions for prophylaxis for tumor lysis syndrome should be followed.

• Dose modification for TLS and other toxicities. Continue for 1 week before each escalation.Dose at interruption (mg) Restart dose (mg)400 300

300 200

200 100

100 50

50 20

20 10

Venetoclax- Dose modification

Non haematological toxicities• Treatment should be withheld for any non-haematological toxicities if it is grade 3 or 4.• Once the toxicity is resolved to Grade 1 or to baseline, treatment can restart at the same dose.

No dose modification is required.• If toxicities reoccur, or for any subsequent occurrences, dose modification should be followed as previous

shown table after resolution.• For patients who require dose reductions to less than 100 mg for more than 2 weeks, discontinuation of

venetoclax should be considered.Haematological toxicities• Dose should be interrupted for any grade 3 or 4 neutropenia with infection or fever, or Grade 4

haematological toxicities (except lymphopenia).• To reduce the infection risks associated with neutropenia, granulocyte-colony stimulating factor (G-CSF)

may be administered with venetoclax if clinically indicated. Once the toxicity has resolved to Grade 1 or baseline level, venetoclax therapy may be resumed at the same dose.

• For second or further recurrence, interrupt venetoclax.• GCSF can be considered on physician’s decision.

Venetoclax- Side effects

• Tumour Lysis Syndrome (TLS)• Neutropenia• Diarrhoea• Fatigue• Nausea / vomiting• Drug interaction• Respiratory infection

Venetoclax -Management of adverse effects

Risk of TLS should be assessed/monitored in all patientspre-treatment and before each dose titration step• Assess tumour burden in all patients including radiographic evaluation (CT scan).• Assess blood results for levels relevant to TLS (creatinine, uric acid, potassium,

phosphates, calcium).• Correct any pre-existing abnormal blood levels in creatinine, uric acid, potassium,

phosphates and calcium.During treatment• Even low-risk patients can develop TLS – need to be vigilant at each/every dose

escalation• Ensure appropriate clinic structure to facilitate timely review of laboratory

results/biochemistry.

TLS Risk Assessment

TLS Risk assessment for Venetoclax

Risk of TLS should be assessed/monitored in all patients pre-treatment and before each dose titration step

Tumour

Burden

Renal function

Other co-morbidities

Low Medium High

All Lymph nodes with < 5 cm and ALC M<25 x10 9/L

Any lymph node >5 cm to<10cmor ALC >25x109/L

Any lymphnode >10cmor LN>5cm and ALC>25x109/L

Creatinine clearance 80 ml/min increases the risk

Risk might be increased with other co-morbidities including splenomegaly, abnormal baseline blood results, dehydration and inability to tolerate hydration

TLS Risk management - Venetoclax

Risk of TLS should be assessed/monitored in all patients pre-treatment and before each dose titration step

• Tumour burden should be assessed , including radiographic evaluation(eg. CT scan).

• After assessment , establish TLS risk – Low- high.

• Low risk patients can be managed in outpatients.

• If creatinine clearance <80, with high tumour burden and other co-morbidities need to be hospitalized and monitored for TLS.

• Fluids, Rasburicase or Allopurinol should be administered prior to Venetoclax. (high risk patients)

Venetoclax -TLS prophylaxis/ management

• Tumour burden assessment pre and on each escalation should be done.

• Blood chemistry should be assessed and pre existing abnormalities should be corrected prior to treatment.

• Hydration.

• Advise to drink 2-3 litres of water mainly 2 days prior and on the days of dose escalation.

• I/V fluids if needed.

• Anti-hyperuricaemic agents.

• Anti-hyperuricaemic agents should be administered 2 to 3 days prior to starting treatment for patients with high uric acid levels or at risk of TLS and may be continued through the titration phase.

• Regular blood test.

• TLS management as per the local policy.

Nursing consideration for CLL patients

• Infection• Fatigue• Treatment side-effects• Anxiety - especially patients with watch-and-wait • Monitoring for changes• Clinic reviews• Vaccination• Liaising with GP for ongoing management• Social, financial and psychological support• CNS support • Patient support groups

safety and hazard management: patients at risk of

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