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

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1 Safety and Hazard Management: Patients at risk of toxicities, triage pathways and policies management Asha Mathew Advanced Nurse Practitioner and Team Lead, Buckinghamshire NHS Trust

2 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

3 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

4 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)

5 Diagnosis of CLL Blood test Presence of >5 x 10 9/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

6 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 10 9/ L Massive lymph node >10cm in diameter Massive, progressive or symptomatic lymphadenopathy or hepatosplenomegaly Autoimmune cytopenia poorly responsive to immunosuppression Extra nodal involvement (www. Accessed November 2018) (International Workshop on CLL 2008)

7 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 (Accessed on November 2018)

8 Staging of CLL - Binet system Stage Characteristics Treatment Risk Stage A With fewer than 3 enlarged nodes With no anaemia or thrombocytopenia Watch and wait Low Stage B With 3 or more enlarged lymph nodes No anaemia or thrombocytopenia Potentially start treatment Intermediate Stage C HB < 10 g/l and platelets < 100 x 10 9 /l regardless of Lymphoid areas involved Treatment High risk (Accessed on November 2018)

9 Treatment pathway for CLL (pathway for Oxford and Bucks) Consider any trials if available Fit < 70 years Few comorbidities FCR 6 cycles Meets IWCLL criteria for treatment FISH for del(11q) and del(17p) TP53 by sequencing Consider IGHV mutation status1 TP53 intact Less fit > 70 years, few comorbidities OR < 70 years + comorbidities Bendamustine 70mg m 2 &rituximab x 6 Obinutuzumab & Chlorambucil TP53 mutated Frail > 70 years + comorbidities Ibrutinib 420 mg daily Ofatumumab & Chlorambucil chlorambucil single agent if very frail or consider Idelalisib & Rituximab for patients with cardiac comorbidity or need warfarin for anticoagulation *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 therapies 2 www. (Accessed Nov 2018)

10 Ibrutinib- Adverse effects Bleeding related events Atrial Fibrillation Hypertension Fatigue Neutropenia Skin Cancer Drug interactions Rash and erythema Viral reactivation Headache Arthralgia Diarrhoea

11 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 First Second Third Fourth Dose modification after recovery Restart at 420 mg daily Restart at 280 mg daily Restart at 120 mg daily Discontinue treatment Ibrutinib smpc (August 2018) Accessed October Barr et al, Blood 2017.

12 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.

13 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.

14 Management of complications continued Ibrutinib - Atrial Fibrillation Most cases appear in 1 st 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

15 Idelalisib Side effects Rash Diarrhoea Raised LFTs Pneumonitis Raised risk of PJP and CMV Neutropenia Fatigue Idelalisib SmPC (date accessed: November 2019)

16 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. Idelalisib SmPC (date accessed: November 2019)

17 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. Idelalisib SmPC (date accessed: November 2019)

18 Dose modification continued.. Neutropenia Treatment 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 dose Monitor ANC weekly Withhold Idelalisib Monitor ANC weekly until ANC>0.5 Resume treatment at 100 mg twice daily Idelalisib SmPC (date accessed: November 2019)

19 Management Algorithm Grade 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) Treatment Administer standard dose of loperamide: initial dose 4 mg followed by 2 mg every 4 hours, or after every unformed stool Reassess 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;.

20 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: budesonide a 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 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

21 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 SmPC (date accessed: November 2019)

22 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 SmPC (date accessed: November 2019)

23 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 SmPC (date accessed: November 2019)

24 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. Idelalisib SmPC (date accessed: November 2019)

25 Venetoclax- dose Titration Optimal patient management Day 0 Obtain pre-dose full bloods for medical review prior to the first dose administration. Day 1 8am Administer Venetoclax 20 mg following the medical review of TLS risk assessment. Treatment should be given only of the blood abnormalities are fully corrected. 2-4 pm Obtain bloods 6-8 hours post first dose, and full medical review for TLS and correct if any abnormalities. Day 2 8 am Blood test 24 hours post first dose, full review, correct if any abnormalities prior to second dose Days 3-7 Instruct patient to take subsequent daily doses at the same time of each day as day 2

26 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)

27 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.

28 Venetoclax- Side effects Tumour Lysis Syndrome (TLS) Neutropenia Diarrhoea Fatigue Nausea / vomiting Drug interaction Respiratory infection

29 Venetoclax -Management of adverse effects TLS Risk Assessment Risk of TLS should be assessed/monitored in all patients pre-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.

30 TLS Risk assessment for Venetoclax Risk of TLS should be assessed/monitored in all patients pre-treatment and before each dose titration step Low Medium High Tumour Burden All Lymph nodes with < 5 cm and ALC M<25 x10 9/L Any lymph node >5 cm to<10cm or ALC >25x109/L Any lymphnode >10cm or LN>5cm and ALC>25x109/L Renal function Creatinine clearance 80 ml/min increases the risk Other co-morbidities Risk might be increased with other co-morbidities including splenomegaly, abnormal baseline blood results, dehydration and inability to tolerate hydration

31 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)

32 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.

33 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