Treatment - PRIME Education · Determine if cytopenia is due to bone marrow infiltration of CLL or are secondary to the CLL as treatment and prognosis are different Autoimmune Cytopenias

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Determine if cytopenia is due to bone marrow infiltration of CLL or are secondary to the CLL as treatment and prognosis are different

Autoimmune CytopeniasAssociated with CLL with or without treatment. Monitor CBC throughout treatment.

Laboratory HallmarksRisk Features

• Advanced disease• Unmutated IGHV• Increased serum beta-2

microglobulin• High expression of

ZAP-70• Purine analog-based

therapy• Fludarabine or

chlorambucil

Symptoms

• Some patients may have no symptoms

• Fatigue• Weakness• Paleness• Jaundice• Fever• Chest pain• Syncope• Splenomegaly

Autoimmune hemolytic anemia

Treatment:ü Corticosteroids manages most cases, especially those caused by warm antibodies

ü IVIg, cyclosporine, and splenectomy should be used in steroid-refractory cases

ü Rituximab is effective for all patients, but is more effective than corticosteroids in those patients with cold antibodies

ü Continuation of fludarabine can be indicated with careful monitoring, but should be avoided if AIHA is associated with fludarabine use

• Hb<11gm/dL in the absence of cytotoxic therapy in last month or other etiology

• Increased unconjugated bilirubin without liver disease OR elevated lactate dehydrogenase OR reduced haptoglobin OR increased absolute reticulocyte count in absence of bleeding

• Direct or indirect evidence of an autoimmune process (positive DAT for either IgG or C3d, or cold agglutinins


• High white blood cell count

• Unmutated IGHV• Positive DAT• ZAP-70 positivity

Symptoms

• Fatigue• Purpura• Petechiae• Hematomas• Nosebleeds or bleeding

from gums• Blood in urine or stool

Immune Thrombocytopenia

Treatment:ü Indicated in patients with platelet counts <30X10⁹/L or signs of bleeding

ü Corticosteroids is first-line choice

ü IVIg, cyclosporine, Rituximab and splenectomy for steroid-refractory cases

ü Romiplostim and eltrombopag for IVIg and splenectomy refractory cases

• Platelet count <100 X10⁹/L, otherwise unexplained• No evidence of hypersplenism, palpable spenomegaly, or bone

marrow failure• Normal or increased megakaryocyte number on bone marrow exam• No cytotoxic treatment in last month• Exclusion of other causes of thrombocytopenia


References:National Comprehensive Cancer Network (NCCN). Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma. (Version 1.2019). https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf. Accessed 09/10/18.; Tsang M. and SA Parikh. Curr Hematol Malig Rep. 2017; 12(1): 29-38.

Determine if cytopenia is due to bone marrow infiltration of CLL or are secondary to the CLL as treatment and prognosis are different

Autoimmune CytopeniasAssociated with CLL with or without treatment. Monitor CBC throughout treatment.


• CLL • Viral Infections such as

EBV, CMV, and human parvovirus B19

Symptoms

• Fatigue• Lethargy• Decreased exercise

tolerance• Pallor

Pure Red Cell Aplasia

Treatment:ü Corticosteroids, cyclophosphamide, cyclosporine, or anti-thymocyte globulin

ü Refractory cases may require allogeneic HCT

ü Patients with evidence of parvovirus B19 infection respond well to IVIg

• Normocytic and normochromic anemia, with Hb<11gm/dL, that is otherwise unexplained

• Absolute reticulocytopenia• Bone marrow with markedly reduced erythroid precursors with

relatively intact leukocyte and megakaryocyte production

Patient Education

Ensure patients are aware of

q The risk of autoimmune cytopenias

q Symptoms of each

q The meaning of laboratory findings and what they mean for treatment

q When to contact healthcare providers

Interprofessional Team

q Regular monitoring and communication of CBC throughout treatment

q Ensure all team members are aware of any new medications

q Evaluate procedures and ensure team members are monitoring patients in a timely manner

q Communicate any lab results


Risk Factors

Atrial Fibrillation (AF)Associated with treatment by Ibrutinib & Acalabrutinib*

Symptoms

• Previous history of cardiac arrhythmias

• History of other cardiovascular pathologies

• Hypertension• Acute infections• Age ≥75 years• Male sex

• Palpitations• Lightheadedness• Dizziness• Fainting• Shortness of breath• Chest discomfort• Fatigue

There are currently no guidelines on managing AF in patients with CLL receiving ibrutinib or acalabrutinib

Management Goals:ü Rate/Rhythm control

ü Stroke prevention

ü Continued chemotherapeutic benefit

• Periodically monitor patients via ECG• If symptoms develop, test with an ECG• Consult a cardiologist if needed

Continuing Therapy

• Interrupt therapy for any Grade 3 or greater toxicity• Once symptoms have resolved to Grade 1 or baseline, carefully restart therapy according to the tables below

Ibrutinib

Toxicity Occurrence Dose Modification After RecoveryStarting dose = 420mg

First Restart at 420mg daily

Second Restart at 280mg daily

Third Restart at 140mg daily

Fourth Discontinue

Acalabrutinib

Toxicity Occurrence Dose Modification After RecoveryStarting dose = 100mg, 2X daily

First Restart at 100mg, 2X daily

Second Restart at 100mg, 2X daily

Third Restart at 100mg, 1X daily

Fourth Discontinue

Adding AF Treatment

• To control AF, beta-blockers or Class Ib antiarrhythmics are preferred to prevent drug-drug interaction• Addition of antiplatelet or anticoagulant therapy should be carefully considered based on bleeding and stroke risks

• Consultation with a cardiologist may be indicated• Non-Vitamin K oral anticoagulants at reduced doses are suggested therapies

* Not FDA approved for CLL treatment, but it is listed by the NCCN as an alternative therapy for CLL treatment in some patient populations.


Atrial Fibrillation (AF)Associated with treatment by Ibrutinib & Acalabrutinib*

Patient Education


q The symptoms of AF: palpitations, lightheadedness etc.

q The symptoms of a stroke: Face drooping, Arm weakness, Speech difficulty, Time to call 9-1-1

q Preventative measures for stroke

q What to do if they suspect they have AF

q Proper medication education

[ Bleeding risks with antiplatelet/anticoagulant therapy

q Limit caffeine intake


q Ensure all team members are aware of the risk and symptoms


q Medication identity and dosages may be different from standard – team members should be aware and communicate

q Consult a cardiologist as needed for diagnosing and/or managing AF

* Not FDA approved for CLL treatment, but it is listed by the NCCN as an alternative therapy for CLL treatment in some patient populations.

References:Khalid et al. Cureus. 2018; 10(5): e2701; Wiczer et al. Blood Adv. 2017; 1(20): 1739-48. Wiczer et al. Blood. 2016; 128(22): 2040.; Imbruvica® (ibrutinib) [package insert]. Janssen Biotech, Horsham, PA 19044, 2013. Calquence® (acalabrutinib) [package insert]. AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850, 2017.


Hematologic ToxicitiesAssociated with all treatments. Monitor CBC throughout treatment.

Laboratory Hallmarks

Grade ANC(x10⁹/L)

High Risk Features

• Advanced disease• Intensive chemotherapy

Symptoms

• Generally, asymptomatic until infection develops

• Some patients may develop ulcers

Management Goals:ü Prevent infections

ü Maintain dose intensity and timing1 (mild) 1.5-<LLN

2 (Moderate) 1.0 - 1.5

3 (Severe) 0.5 - 1.0

4 (life-threatening) <0.5

5 (Death) Death

Generally: interrupt or reduce dose for severe neutropenia

Infection Prevention

Patients with CLL are considered to have an intermediate risk for infections.

During periods of neutropenia - fluoroquinoloneBacterial

• Autologous HCT with mucositis – Fluconazole or Micafungin• High risk for pneumocystis: TMP/SMX or Atovaquone, dapsone, pentamidine if TMP/SMX intolerant

» Alemtuzumab: min of 2 months after alemtuzumab and until CD4 count >200cells/mcL » Idelalisib ± rituximab: at least through active treatment » Purine analog therapy: until CD4 count >200cells/mcL

Fungal

• HSV: Acyclovir, Famciclovir, Valacyclovir during active therapy and possibly longer• VZV: Acyclovir, Famciclovir, Valacyclovir for at least 6-12mo after autologous HCT• Alemtuzumab: high risk for CMV, treat for a minimum of 2mo after therapy

» First line: Valganciclovir, ganciclovir » Resistance or poor tolerance: Foscarnet or Cidofovir

Viral

Use of Myeloid Growth Factors

Patients with CLL are generally not considered for prophylactic use of myeloid growth factors as the risk for febrile neutropenia (FN) isrelatively low (>10%). However, patient factors may increase the risk.

Patient Risk Factors FN or dose-limitingneutropenic event Patient presents with FN

• Age >65years• Poor performance and/or nutritional

status• Multiple comorbid conditions• Advanced cancer disease• History of previous FN• No antibiotic prophylaxis

If in a previous cycle of chemotherapy, a FN or dose-limiting neutropenic event occurred, consider prophylactic use of G-CSF

• If not receiving prophylactic G-CSF and risk factors are present for an infection-associated complication [ Therapeutic MGF

• If not receiving prophylactic G-CSF and no risk factors for infection-associated complications [ No treatment

• Prophylactic G-CSF [ continue

Chemotherapy-Induced Neutropenia & Febrile Neutropenia


Laboratory Hallmarks/Tests

Grade

Risk Features

• Co-morbidities such as bleeding, hemolysis, renal insufficiency

• Bone marrow infiltration of cancer cells

• Iron-sequestering cytokine production

• Immune-suppressive chemotherapy

Symptoms

• Sustained tachycardia• Tachypnea• Chest pain• Dyspnea on exertion• Lightheadedness• Syncope• Severe fatigue

Cancer- and Chemotherapy-Induced Anemia

Hemoglobin(g/dL)

1 (mild) 10-<LLN

2 (Moderate) 8 - 10

3 (Severe) 6.5 - 8

4 (life-threatening) <6.5

5 (Death) Death

Management Goals:ü Prevent or treat deficit of oxygen-carrying capacity in blood

ü Asymptomatic Anemia - Transfusion goal to achieve Hb >7g/dL

ü Symptomatic Anemia - Transfusion goal to prevent symptoms

• Hemoglobin • CBC• Blood smear morphology• Check for hemorrhage,

hemolysis, nutritional status, renal dysfunction, and hormone dysfunction using appropriate tests

If cause of anemia can be determined as separate from chemotherapy, treat as indicated for identified cause


Anemia in Patients with Cancer

Asymptomatic without signficant comorbidities

Patients who refuse transfusion

High risk (progressive decline in Hb with

recent chemotherapy) or Asymptomatic with

comorbidities

Symptomatic

Observe Minimize blood lossConsider red blood cell

transfusion in accordance with goals

Red blood cell transfusion

Periodic re-evaluationConsider erythropoietin

stimulating agents in relation to clotting risk


Monitoring and Dose Modifications for Novel Oral Therapies

Event

Every 2 weeks for the first 6 months of treatment;

weekly while ANC <1.0X10⁹/L

Monitoring

Occurrence Idelalisib Ibrutinib Acalabrutinib Venetoclax

Monthly MonthlyThroughout treatment

period

Grade 1 or 2 Maintain Dose Maintain DoseAny Maintain Dose Maintain Dose

Modify if have neutropenia with infection or fever.

Dose modifications are the same as with Grade 4

Grade 3 Any Maintain Dose

Modify if have thrombocytopenia

with bleeding. Dose modifications are the same as with Grade 4

Modify if have neutropenia with infection or fever.

Dose modifications are the same as with Grade 4.

Once symptoms have resolved to Grade 1 or

baseline restart at 420mg daily

Grade 4

First

Interrupt

Monitor CBC weekly until ANC≥0.5 X10⁹/L or

platelets ≥25 X10⁹/L

Once recoveredresume at

100mg, 2X daily

For thrombocyto-peniaor neutropenia lasting

longer than 7 days: Interrupt treatment,

once resolved to Grade 1 or baseline, resume

therapy at 100mg, 2X daily

Interrupt. Once resolved to Grade 1 or baseline, resume at same dose.

Consider G-CSF therapy.

Once symptoms have resolved to Grade 1

or baseline restart at 280mg daily

Second Interrupt. Once resolved to Grade

1 or baseline, resume treatment at lower dose

(see full prescribing information or “tumor lysis syndrome management” for re-start dose details.)

Once symptoms have resolved to Grade 1

or baseline restart at 140mg daily

Third

Interrupt treatment, once resolved to Grade 1 or

baseline, resume therapy at 100mg daily

Discontinue DiscontinueFourth



Patient Education

q Appropriate infection prevention practices

q Vaccinations to consider as preventative measures

q Caution receiving live vaccines

q Monitor for fever

q When to contact healthcare providers

[ What symptoms should trigger concern?

[ Who to call? Or Where to go? Clinic, hospital?Ensure patients have the right information to receive timely care


q Monitoring and communication of CBC results

q All team members should be practicing infection-preventing strategies

q All lab results and diagnostic testing should be communicated to all team members

q All team members should be aware of any new medications



References:Lalami Y and J Klastersky. Crit Rev in Onc/Hem. 2017; 120: 163-79. National Comprehensive Cancer Network (NCCN). Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma. (Version 1.2019). www.nccn.org. Accessed 09/10/18.; NCCN. Cancer- and Chemotherapy-Induced Anemia. (Version 3.2018). www.nccn.org. Accessed 09/10/18.; NCCN. Prevention and Treatment of Cancer-Related Infections. (Version 1.2018). www.nccn.org. Accessed 09/10/18.; NCCN. Myeloid Growth Factors. (Version 2.2018). www.nccn.org. Accessed 09/10/18. Imbruvica® (ibrutinib) [package insert]. Janssen Biotech, Horsham, PA 19044, 2013. Calquence® (acalabrutinib) [package insert]. AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850, 2017. Venclexta™ (venetoclax) [package insert]. AbbVie, Inc. North Chicago, IL 6006, 2016. Zydelig® (Idelalisib) [package insert]. Gilead Sciences, Inc. Foster City, CA 94404, 2016. National Cancer Institute. Common Terminology Criteria for Adverse Events. (Version 5.0). https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50. Accessed 09/10/2018.


References:National Comprehensive Cancer Network (NCCN). Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma. (Version 1.2019). www.nccn.org. Accessed 09/10/18. Zydelig® (Idelalisib) [package insert]. Gilead Sciences, Inc. Foster City, CA 94404, 2016.

Idelalisib-Associated GI & Hepatotoxic Conditions

Laboratory MonitoringRisk Features

• Concurrent use of other drugs that cause liver damage (should be avoided)

• Alcohol use• Past history of liver

damage

Symptoms

• Stomach pain• Nausea• Fatigue• Dark-colored urine• Light-colored bowel

movements• Jaundice• Loss of appetite• Fever

Hepatotoxicity

Management Goals:ü Prevent serious liver injury

ü Maintain therapeutic benefit of treatment

Every 2 weeks Months 1-3 of treatment

Every 4 weeks Months 4-6 of treatment

Every 1-3 months Rest of treatment course

WeeklyIf ALT/AST rises above 3 (ALT/AST) or 1.5 (bilirubin) X ULN until resolution

Monitor Serum ALT/AST and bilirubin according to the following schedule when treating with idelalisib:

Elevated ALT/AST generally observed in first 12 weeks of treatment and were reversible with dose interruption

Idelalisib Dose Modification for Toxicity

ALT/AST

>3-5 X ULN >5-20 X ULN >20 X ULN

Discontinue IdelalisibWithhold Idelalisib.

Monitor at least weekly until ALT/AST ≤1XULN, then resume at 100mg, 2X daily

Maintain dose

Monitor at least weekly until ALT/AST ≤1XULN

Bilirubin

>1.5-3 X ULN >3-10 X ULN >10 X ULN


Monitor at least weekly until ALT/AST ≤1XULN, then resume at 100mg, 2X daily

Maintain dose

Monitor at least weekly until ALT/AST ≤1XULN

Diarrhea

Moderate(Increase of 4-6 stools per day)


Monitor at least weekly until resolved, then resume at 100mg, 2X daily

Maintain dose

Monitor at least weekly until resolves

Severe or Hospitalization(Increase of ≥7 stools per day) Life-threatening

If there are recurrent elevations in ALT/AST, permanently discontinue Idelalisib

Infusion ReactionsAssociated with treatment by Rituximab, Obinutuzumab, Afatumumab, Alemtuzumab & Bendamustine

High Risk Features Symptoms

• Asthma diagnosis• Atopic patients• Circulating lymphocyte

counts of 25,000 mm³ or higher

• Concurrent autoimmune disease

• Iodine or seafood allergies• Personal history of drug

allergy

• Mucocutaneous symptoms (flushing, urticaria, pruritus)

• Wheezing• Hypotension• Nausea, vomiting,

cramps, diarrhea• Fever• Chills• Muscular pain• Headache

Management Goals:ü Prevent infusion reactions through prophylaxis

ü Stop/slow infusion if symptoms develop

ü Maintain therapeutic benefit of treatment

ü Mitigate serious reactions by recognizing symptoms quickly

Infusion reactions can be any of the following types:

• Hypersensitivity (Anaphylaxis) -- an IgE-mediated reaction

[ Can happen with any drug, more severe upon repeat administration

• Anaphylactoid reactions – systemic reactions that mimic anaphylaxis but are caused by non-IgE-mediated release of mediators

[ May occur at first exposure, milder upon repeat administration

• Complement activation-related pseudoallergy (CARPA) – complement signals triggers the secretion of vasoactive mediators

[ Arises mostly at the first treatment, with no prior exposure

• Cytokine release syndrome -- most common with monoclonal antibodies; thought to be due to the release of cytokines following antibody binding to its target

[ Generally, associated with first infusion, milder upon repeat administration

Prophylaxis


Ofatumumab

Alemtuzumab

Therapy

Rituximab • Antihistamine• Acetaminophen

Obinutuzumab

Pre-medications Timing

• IV glucocorticiod (20mg dexamethasone or 80mg methylprenisolone)

• 650 – 1000mg Acetaminophen• Antihistamine (eg 50mg diphenhydramine)

• All – 650 – 1000mg Acetaminophen

• Patients with a previous IRR: Antihistamine

• Patients with a previous Grade 3 IRR: IV glucocorticoid

• 1000mg Acetaminophen• Oral or IV antihistamine (e.g. 10mg cetirizine)• IV corticosteroid (e.g. 100mg prednisolone)

Can reduce corticosteroid if a Grade 3 or greater infusionreaction did not occur

• 1000mg methyprednisolone or equivalent

Cycle 1; days 1 & 2

Prior to each dose

All other infusions

30min to 2 hours prior to doses 1 & 2

30min to 2 hours prior to doses 3 - 12

Prior to first 3 days of each course


Infusion ReactionsAssociated with treatment by Rituximab, Obinutuzumab, Afatumumab, Alemtuzumab & Bendamustine

Dose Modifications for Infusion Reactions

Ofatumumab

Therapy

All Therapies

Obinutuzumab

Infusion Reaction Dose Modification

Reduce infusion rate to 50% previous infusion rate

Alemtuzumab

Any

Grade 4

Interrupt infusion and manage symptoms; resume as suggested below

Stop infusion, permanently discontinue

Rituximab Grade 1 - 3

Grade 1 - 2

Grade 3

Reduce infusion rate, if symptoms resolve, may continue dose rate escalation

Restart at no more than ½ of previous infusion rate.• If no further symptoms, rate escalation may continue• If experience Grade 3 infusion related symptom at re-challenge – permanently discontinue

Grade 1 - 2

Grade 3

Infuse at ½ of previous infusion rate

Infuse at a rate of 12 mL/hour

Grade 1 - 3 Provide symptom treatment. Discontinue if severe infusion reactions occur

References:Vogel W. Clin J Onc Nurs. 2010; 14(2): E10-21; Roselló S. et al. Ann Oncol. 2017; 28(Supplement 4): iv100-118; Doessanger L and M Banholzer. Clin Transl Immunology. 2015; 4(7): e39; Rituxan® (rituximab) [package insert]. Genentech, Inc. South San Francisco, CA 94080, 1997. ; Gazyva® (obinutuzumab) [package insert]. Genentech, Inc. South San Francisco, CA 94080, 2013. Arzerra® (ofatumumab) [package insert]. Novartis Pharma Corp, East Hanover, NJ 07936, 2009. Lemtrada® (alemtuzumab) [package insert]. Genzyme Corp. Cambridge, MA 02142, 2001.

Patient Education


q The symptoms of infusion reactions

q Prophylaxis requirements

q Monitoring procedures at time of infusion

q When to contact their healthcare provider




q Have a plan prepared for the response to any infusion reaction


High Risk Features

Tumor Lysis Syndrome (TLS)Associated with treatment by Venetoclax, Chemoimmunotherapy & Lenalidomide

Symptoms Laboratory Hallmarks

• Progressive disease after small-molecule inhibitor therapy

• Bulky lymph nodes• Spontaneous TLS• Elevated WBC• Pre-existing elevated uric

acid• Ineffectiveness of

allopurinol• Renal disease or renal

involvement by tumor

• Nausea and vomiting• Shortness of breath• Irregular heartbeat• Clouding of urine• Lethargy• Joint discomfort

• High potassium• High uric acid• High phosphorous• Low calcium• High LDH

Management Goals:ü Prevent

ü Monitor blood chemistry for hyperuricemia and electrolytes

ü Aggressively correct any abnormalities prior to symptom presentation

Best managed if TLS is anticipated and treatment started prior to chemotherapy.

Recommended Prophylaxis and Monitoring for Venetoclax

Tumor Burden Prophylaxis Blood Chemistry Monitoring

LOW:All lymph nodes <5cm AND Absolute lymphocyte count (ALC) <25X10⁹/L

• Oral Hydration (1.5-2L)• Allopurinol or xanthine oxidase

inhbitor (start 2-3 days prior to initiation of venetoclax)

Outpatient:• Pre-dose, 6-8 hours, 24 hours at first

dose of 20mg and 50mg• Pre-dose at subsequent ramp-up

doses

MEDIUM:Any lymph node 5cm to <10cmORALC ≥25 X 10⁹/L*for patients with medium tumor burden and CrCl <80mL/min consider management as high risk

• Oral hydration (1.5-2L) and consider additional intravenous hydration

• Allopurinol or xanthine oxidase inhbitor

Outpatient:• Pre-dose, 6-8 hours, 24 hours at first

dose of 20mg and 50mg• Pre-dose at subsequent ramp-up

doses• Consider hospitalization for patients

with CrCl <80mL/min at first dose of 20mg and 50mg

HIGH:Any lymph node ≥10cmORALC ≥25 X 10⁹/L AND any lymph node ≥5cm

• Oral hydration (1.5-2L) and intravenous hydration (150- 200mL/h as tolerated)

• Allopurinol and febuxostat• Consider rasburicase if baseline uric

acid is elevated

In hospital at first dose of 20mg and 50mg:

• Pre-dose, 4, 8, 12, and 24 hours

Outpatient at subsequent ramp-up doses:• Pre-dose, 6-8 hours, 24 hours


Venetoclax Dose Modification for Toxicity

Event

Tumor Lysis Syndrome (TLS)Associated with treatment by Venetoclax, Chemoimmunotherapy & Lenalidomide

References:Venclexta™ (venetoclax) [package insert]. AbbVie, Inc. North Chicago, IL 6006, 2016; National Comprehensive Cancer Network (NCCN). Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma. (Version 1.2019). https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf. Accessed 09/10/18.

Occurrence Action

Withhold the next day’s dose. If resolved within 24-48 hours of last dose, resume at the same dose

For any blood chemistry changes requiring more than 48 hours to resolve, resume at a reduced dose

For any events of clinical TLS, resume at a reduced dose following resolution

For any occurrence:

Blood chemistry changes or symptoms

suggestive of TLS

300

200

100

50

20

400

300

200

100

50

20 10

Dose at Interruption, mg Restart Dose, mg

Patient Education


q The symptoms of TLS – high fever, difficulty breathing, change in urine etc.

q The importance of hydration and how much water is recommended

q What procedure to follow if symptoms of TLS develop – seek medical attention promptly




q Review blood chemistries in real-time

q Renal consultation and dialysis where appropriate

0. No problem affecting that system1. Current mild problem or past significant problem2. Moderate disability or morbidity and/or requires

first-line therapy

3. Severe problem and/or constant and significant disability and/or hard-to-control chronic problems

4. Extremely severe problem and/or immediate treatment required and/or organ failure and/or severe functional impairment

Rated 0• No problems or healed minor injuries• Past childhood injuries (eg, chickenpox)• Minor surgery (eg, amygdalectomy)• Uncomplicated healed fractures • Other past problems healed without sequel

(eg, pneumonia)

Rated 1• Current medical problem with mild discomfort

or disability, or occasional exacerbations (eg, occasional heartburn relieved with PRN antiacids)

• Minor impact on morbidity• Past significant medical problems not currently an

issue (eg, passage of a kidney stone) • Major surgery (eg, hysterectomy)

Rated 2

• Medical condition that requires daily treatment (first-line therapy; eg, steroids – asthma, H2 blockers – acid reflux)

• Moderate disability or morbidity

Rated 3• Chronic conditions that are not controlled

with first-line therapy (eg, asthma needing continuous corticosteroid therapy)

• Constant significant disability• Severe problem

Rated 4• Extremely severe problem• Any acute condition that requires immediate

treatment (eg, severe bronchospasm, unstable angina)

• Organ failure (eg, end-stage renal disease/dialysis, O2 for COPD)

• Severe sensory impairment (eg, almost complete blindness or deafness, wheelchair-bound)

• Quality of life severely affected, severe functional impairment

Rated 1• Cancer diagnosed in the remote past without

evidence of recurrence or sequel in the past 10 years or skin cancer operated in the past without major sequel (other than melanoma) Rated 2

• No evidence of recurrence or sequel in the past 5 years

Rated 3• Required chemotherapy, radiation, or hormonal

therapy in the past 5 years

Rated 4• Recurrent malignancy, metastasis, or palliative

treatment stage

Scale

Ratings

Rating Malignancies

Cumulative Illness Rating Scale (CIRS)


System/Description Rating/Score

Cardiac• Any cardiac problem? (angina, myocardial infarction, arrhythmia, valve problems)• Any medications take for above?

• Any heart surgery in the past? Vascular

• Any circulatory problem? (peripheral atherosclerotic disease, aneurysm of the abdominal aorta)• Any hypertension or cholesterol problem?• If yes, any medication taken for these problems?

• Any vascular surgery in the past? (bypass graft surgery of lower limbs, carotid endarterectomy) Hematological

• Any blood problem? (anemia, leukemia, hypercoagulability, or any other problem affecting the blood, blood cells, spleen, or lymphatic system)

• If yes, any medication taken for these problems?

Respiratory• Any respiratory problem? (asthma, emphysema, bronchitis, pulmonary embolism)• If yes, any medication taken for these problems? (eg, pressurized aerosols)• Any lung surgery?• Cigarette smoking? How many packs per day? For how long?

Pack years = number of packs per day x the number of years smoked (example: 1 pack per day for 20 years = 20 pack years) Smoker up to 20 pack years: Rated 1 Smoker from 21–40 pack years: Rated 2 Smoker over 40 pack years: Rated 3

EENT (eye, ear, nose, throat, larynx)• Any problem with eyes (glaucoma, cataract, important loss of vision), ears (includes important hearing

impairment), nose, throat, or voice?• Any medication taken for these problems?

Note: Vertigo and dizziness are included in this section, unless they are of neurological origin.

Upper GI• Any problem with stomach or digestion? (includes the esophagus, stomach, and duodenum)• If yes, any medication taken for these problems?• Any surgery for the stomach or the esophagus?

Lower GI• Any intestinal problem? (includes intestinal hernias, constipation, anal problems, incontinence)• If yes, any medication taken for these problems?• Any surgery for the abdomen?

Hepatic and Pancreatic• Any problem in the liver or the pancreas?• Any medication taken for these problems?• Any surgery for the liver or the pancreas?

Note: Cholecystectomy is rated in this section

Renal• Any problem in the kidneys? (impairment in function, infection)• If yes, any medication taken for these problems?• Any surgery for the kidneys?

1 2 3 40

1 2 3 40

1 2 3 40

1 2 3 40

1 2 3 40

1 2 3 40

1 2 3 40

1 2 3 40

1 2 3 40


System/Description Rating/Score

Cumulative Illness Rating Scale (CIRS)

Classification

Genitourinary• Any urinary problem? (lithiasis, incontinence)• If yes, any medication taken for these problems?• Any surgery for the urinary bladder, for renal lithiasis?

Musculoskeletal

• Any problem in the skin, joints, bones, or muscles? (includes arthrosis, osteoporosis, carpal tunnel, and any other skin or musculoskeletal problem)

• Any medication, anti-inflammatory drugs? Infiltrations? Creams prescribed by a doctor?

Note: Fibromyalgia is rated in this section, but it may also be rated in Psychiatric if necessary. Neurological

• Any neurological problem? (cerebrovascular accident, peripheral neuropathy, headaches)• If yes, any medication taken for these problems?• Any surgery for these problems?

Endocrine-Metabolic• Any problem of the thyroid gland, obesity, diabetes, or any other hormonal problem?

For obesity:• Body mass index (BMI) ≥ 30: Rated 1• BMI ≥ 30 + medication or moderate disability: Rated 2• BMI ≥ 45: Rated 3

• Any medication? Surgery for any of these problems?• Any problem with breasts? (dysplasia, cancer)• Surgery for these problems?• Menopause? (or andropause in men) Any hormone? (the same for men in andropause)

Menopause or andropause:• Without hormonotherapy or symptoms: Rated 0• Symptomatic or with hormonotherapy: Rated 1

Psychiatric/Behavioral• Any problem of depression, anxiety, alcohol, drug abuse, or other problems?• Any medication taken for these problems?

Note: Personality problems are rated in this section, but the patient’s chart should be checked.

• (0–56) = sum of score for all scales • Only 1 score is given for each system

Total Score

q < 6 and CrCL > 70 mL/min (GO: suitable for treatment)

q > 6 and CrCL < 70 mL/min (SLOW: suitable for reduced treatment)

q Severe comoribidities and short-life expectancy (NO: suitable for supportive care)


Adapted from: Miller MD, Towers A. A manual of guidelines for scoring the Cumulative Illness Rating Scale for Geriatrics (CIRS-G). Pittsburg, PA: University of Pittsburg; 1991.Hudon C, Fortin M, Soubhi H. Abbreviated guidelines for scoring the Cumulative Illness Rating Scale (CIRS) in family practice. J Clin Epidemiol. 2007;60(2):212.

1 2 3 40

1 2 3 40

1 2 3 40

1 2 3 40

1 2 3 40

References1. Linn BS, Linn MW, Gurel L. Cumulative Illness Rating Scale. J Am

Geriatr Soc. 1968;(16)5:622-626.

2. Hudon C, Fortin M, Soubhi H. Abbreviated guidelines for scoring the Cumulative Illness Rating Scale (CIRS) in family practice. J Clin Epidemiol. 2007;60(2):212.

3. Miller MD, Towers A. A manual of guidelines for scoring the Cumulative Illness Rating Scale for Geriatrics (CIRS-G). Pittsburg, PA: University of Pittsburg; 1991.

4. Salvi F, Miller MD, Grilli A, et al. A manual of guidelines to score the modified cumulative illness rating scale and its validation in acute hospitalized elderly patients. J Am Geriatr Soc. 2008;56(10):1926-1931.

Assessment Before Treatment

Diagnostic Work-up for CLL


When to Perform

Diagnostic Tests

CBC and differential count Always

Test

Immunophenotyping of peripheral blood lymphocytes Always

History, physical, performance status Always

CBC and differential count Always

Marrow aspirate and biopsy When clinically indicated

Serum chemistry, serum immunoglobulin, and direct antiglobulin test Always

Chest radiograph Always

Infectious disease status Always

Additional Tests Prior to Treatment

FISH for del(13q), del(11q), del(17p), add(12) in peripheral blood lymphocytes

CpG-Stimulated metaphase karyotype for complex karyotype

TP53 mutation

IGHV mutational status

Serum β₂-microglobulin

CT scan of chest, abdomen, and pelvis

Always

Possibly - Prognostic Information

Always

Always

Desirable

Not generally indicated

MRI, PET scans

Abdominal ultrasound

Not generally indicated

Possibly


DNA Sequencing

Wild-type

≥2% mutation

Mutated

≤2% mutation

Prognostic Information

References:Hallek M. et al. Blood. 2018; 131(25): 2745-60; National Comprehensive Cancer Network (NCCN). Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma. (Version 1.2019). https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf. Accessed 09/10/18.

UnfavorableNeutralFavorable

TP53

IGHV

≥30%

<30%

<20%

≥30%

≥20%

CD49d <30%

CD38

ZAP70

≥3 unrelated chromosome abnormalitiesin more than one cell

Del(13q) as soleabnormality

+12

Del(11q)

Del(17p)

Karyotype

Interphase cytogenetics (FISH)

Flow cytometry

Normal


References:Hallek M. et al. Blood. 2018; 131(25): 2745-60.

Should My Patient Start Treatment for CLL?

Starting treatment is not the best option for all patients.

Don’t Start Therapy and Monitor

Asymptomatic early-stage disease (Rai stage 0, Binet stage A) with no evidence of progression

Intermediate risk patients (Rai stages I – II,Binet stage B) without active disease

Start Therapy

High Risk Staging (Rai stages III-IV orBinet Stage C)

Intermediate or low risk with active disease

Doctor appointments:every 3-6 months

Evaluate: blood work and physical symptoms

Continue to safely observe. OR: make a decision to

start treatment

Progressive marrow failure – development or

worsening of anemia and/or thrombocytopenia

Progressive lymphocytosis. Increase of ≥50% in two months or lymphocyte

doubling time <6 months

Massive (ie ≥6cm below left costal margin),

progressive, or symptomatic splenomegaly

Massive (ie ≥10cm in longest diameter),

progressive, or symptomatic lymphadenopathy

Signs of Active Disease

Autoimmune complications poorly responsive to

corticosteroidsSignificant fatigueSymptomatic or functional

extranodal involvement

Unintentional weight loss ≥10% within previous

6 months

Fevers ≥100.5˚F or 38.0˚C for 2 or more weeks with no

evidence of infection

Night sweats for ≥1 month without evidence of

infection


References:National Comprehensive Cancer Network (NCCN). Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma. (Version 1.2019). https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf . Accessed 09/10/18; Hallek M. et al. Blood. 2018; 131(25): 2745-60.; Hallek M et al. Lancet. 2010. 376 (9747): 1164-74; Eichhorst B. et al. Lancet Onc. 2016; 17(7): 928-42. Fishcer K et al. Blood. 2016; 127(2): 208-15.; Goede V. et al. N Engl J Med. 2014; 370(12): 1101-10.; Burger J et al. N Engl J Med. 2015; 373(25): 2425-37.

Evidence-Based and Guideline-Aligned Frontline Treatment for CLL

CLL Patient Requiring First

Treatment

Without TP53 or del(17p)

TP53 mutation or del(17p)

IGHV Mutated IGHV Not Mutated Ibrutinib

Age ≥65, or younger with high CIRS

Age <65y andCIRS <6 Ibrutinib

Fludarabine, cyclophosphamide,

rituximab (Category 1)

Key:• Genetic Markers for Treatment• Patient Characteristics• Preferred Drug Regimens

High CIRS/purine analogs contraindicated

Chlorambucil + obinutuzumab (Category 1)

Chlorambucil + obinutuzumab (Category 1)

Ibrutinib(Category 1)

Ibrutinib(Category 1)

Bendamustine + CD20 monoclonal

antibody

Chlorambucil + ofatumumab

Bendamustine + CD20 monoclonal

antibodyIbrutinib

Chlorambucil + rituximab

Chlorambucil + ofatumumab

Chlorambucil + rituximab

Discontinued due to progression

Venetoclax (preferred)

Idelalisib + rituximab

Chemoimmunotherapy (last option)


Evidence-Based and Guideline-Aligned Treatment for Relapsed/Refractory CLL

Key:• Genetic Markers for Treatment• Previous Treatment• Reason for Discontinuation• Preferred Drug Regimens

CLL Relapse Warranting Therapy

Re-check FISH and TP53 mutation

Ibrutinib first lineChemoimmunotherapy first line

Ibrutinib Discontinued due to Intolerance

Idelalisib + rituximab

Venetoclax + rituximab

VenetoclaxIdelalisib + rituximab

Chemoimmunotherapy (last option)

Consideration of allogeneic HCT

References:National Comprehensive Cancer Network (NCCN). Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma. (Version 1.2019). https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf . Accessed 09/10/18; Byrd J et al. N Engl J Med. 2014; 371(3): 213-23.; Furman R et al. N Eng J Med. 2014; 370 (11): 997-1007.; Hillmen P et al. Blood. 2015; 126(23): 2944. Mato A et al. Annals of Oncology. 2017; 28(5): 1050-6.

Documents

Treatment - PRIME Education · Determine if cytopenia is due to bone marrow infiltration of CLL or are secondary to the CLL as treatment and prognosis are different Autoimmune Cytopenias