The document details the adverse effects and management of chemotherapy agents, particularly cytarabine, doxorubicin, and venetoclax used in treating acute myeloid leukemia (AML). It addresses specific toxicities like myelosuppression, gastrointestinal issues, and neurotoxicity, highlighting the grading of neutropenia risk and the protocols for managing complications. Additionally, it emphasizes the importance of monitoring and adjusting treatment based on patient response and toxicity levels.

2. COMMON TERMINOLOGY CRITERIA FOR
ADVERSE EVENTS

3. IMMEDIATE
Allergic
-Infusion related
-Anaphylactic
Pain at infusion site
-Irritant
-Vesicant
Urine discolouration
-Doxorubicin
-Mitoxantrone

4. • Nausea, vomiting
Within few mins
Peaks around 4-6 hours
Usually resolves around 24 hours

5. Within days
• Delayed onset emesis
>24 hours upto 7 days
• Fatigue
• Myelosuppression
Usually at nadir
Mucositis
Febrile neutropenia
• Diarrhea, constipation
• Reduced appetite
• Metallic taste

6. Within weeks
• Alopecia
Cisplatin, doxorubicin
• Peripheral neuropathy
Platins
• Dry skin, pigmentation
• Nail changes
• Ototoxicity (cisplatin)
• Sterility
• Amenorrhoea
• Memory dysfunction
• Cardiotoxicity

7. EMETOGENIC CHEMOTHERAPY

10. GRADING OF NEUTROPENIA
• Grade 1- ANC >1500
• Grade 2-ANC 1000-1500
• Grade 3-ANC 500- 1000
• Grade 4- ANC < 500

11. NCCN RISK GROUP FOR Febrile neutropenia
• Low risk grp - < 10 %
• no any symptoms/ comorbidity
• No need of prophylaxis
• INTERMEDIATE RISK GRP – 10-20 %
• Prior Radiation therapy/chemotherapy
• Persistent neutropenia
• Tumor affecting BM
• Recent sx /open wound
• Liver failure
• Kidney failure
• Agr 65 or more and receiving chemotherapy

12. • High risk
• inpatient status when fever developed
• have significant comorbidities or clinical instability
• had allogeneic stem-cell transplantation
• anticipated prolonged duration of severe neutropenia (ANC <100 for >7 days)
• renal (creatinine clearance <30 mL/min) or hepatic impairment (aspartate transamina
transaminase >5 times upper limit of normal)
• uncontrolled or progressive malignancy
• pneumonia or complex infection
• have grade 3-4 mucositis
• MASCC Risk Index score <21 or CISNE score >3

14. • Since 1974, cytarabine is used either alone or in combination with an
anthracycline (daunorubicin or idarubicin) in virtually all induction
regimens for AML and as a component of consolidation and
maintenance programs after remission .

15. • short half-life and rapid plasmatic inactivation
• different schedules and dose-levels of cytarabine have been adopted
for intravenous infusion
• low
• Standard
• high
• more recently- intermediate cytarabine doses
• most commonly used regimen -100 to 200 mg/m2/d for 5 to 7 days

16. high-dose
• 2 to 3 g/m2 every 12 h for up to six doses
• introduced about three decades ago, after the landmark CALGB study
published in 1994
• it became central to the improvement in the treatment of patients with
AML .
• used primarily in the consolidation phase and upfront in patients with
unfavorable, intrinsically drug resistant, oncogenic subtypes (8;21), inv16,
del16, t(16;16)
• high-dose cytarabine has been the optimal post-remission therapy for
patients with AML in first remission not proceeding to allogenic
transplantation

18. • The toxicity profile of cytarabine is highly dependent on the
dose and schedule of administration.
• Leukopenia and thrombocytopenia occure - days 7 and 14 after
drug administration.
• Gastrointestinal toxicity -mild-to-moderate mucositis and
diarrhea.
• Occasionally acute pancreatitis has been reported in patients
receiving cytarabine as a continuous infusion

19. Cytarabine syndrome
• occur within 12 h after the start of drug infusion
• with the onset of fever, myalgia, joint and bone pain, maculopapular
rash, keratoconjunctivitis, and occasional chest pain
• most likely represents an allergic reaction to cytarabine
• patients usually develop symptoms months after the first dose,
• corticosteroids
• resolve within 24 h when cytarabine is discontinued

20. high dose cytarabine
• 2 to 3 g/m2 with each dose
• common major side effects
1. biphasic pancytopenia
2. central nervous system toxicity,
3. skin eruptions
4. hyperbilirubinemia in > 10% of patients
5. infection
6. seizures

21. Acute cerebellar toxicity
• dysarthria with truncal and gait ataxia
• cerebral syndrome - encephalopathy, psychosis, seizures, and
coma.
• widespread loss of Purkinje cells in the cerebellum .
• begins with somnolence and occasionally an encephalopathy
• develops two to five days after beginning treatment
• may also be delayed, occurring up to 3–8 days after treatment has
begun.
• severe cerebellar toxicity - treatment discontinuation

22. neurotoxicity
• peripheral neuropathies resembling GBS , brachial plexopathy, lateral
rectus palsy, optic neuropathy, or an extrapyramidal syndrome
• Risk factor-
• cumulative cytarabine dose,
• prior CNS disease
• renal impairment
• high-dose therapy (>18 g/m2 per cycle)
• age >50 years

23. • fatal cardiomyopathy - combination with cyclophosphamide
• Anaphylaxis -acute cardiopulmonary arrest
• GI toxicity -bowel necrosis and esophagus ulceration

24. Cytarabine lung
• Subacute respiratory failure
• Diffuse changes on chest radiographs
• Dx of exclusion

25. Occular toxicity
• excessive tearing, photophobia, burning ocular pain and blurred
vision
• o/e
• conjunctival injection
• central punctate corneal opacities with subepithelial granular
deposits
• decreased visual acuity

26. HMAs
• MOA – hypomethylation of DNA
• Drugs
Azacytidine
Dacitabine
• Azacytidine 75 mg/m2 × 7 days
• Dacitabine 20 mg /m2 × 5 days
• Started with veneticlax on day 1
• 28-day cycles

27. Common side effects
• bone marrow suppression
• nausea, vomiting, diarrhea, stomatitis
• Bruising
• abdominal pain
• myalgias
• headache, dizziness, fatigue
• fever, rash and pruritus.

29. Uncommon but potentially severe adverse
events
• severe myelosuppression
• febrile neutropenia
• Pneumonitis
• sepsis
• tumor-lysis syndrome
• embryo-fetal toxicity.

30. venetoclax
• BCL2 inhibitor
• BCL-2 overexpression has been implicated in survival of AML cells
and treatment resistance
• combination with AZA/ DAC) or low-dose cytarabine (LDAC) for
the treatment of newly diagnosed AML in older patients (≥ 75 years)
or in those with comorbidities precluding the use of intensive
induction chemotherapy (DiNardo et al., 2020; Wei et al., 2020).

31. Neutropenia
• In the case of grade 3 neutropenia with infection/fever or grade 4
neutropenia at first occurrence, venetoclax interruption is
recommended until return to grade 1 or baseline level, followed by
administration of venetoclax at its pre-interruption dose.
• For second/subsequent occurrences, venetoclax should be
interrupted and subsequently resumed following dose-reduction
guidelines

33. Management
• Remission status by bone marrow assessment should be considered
to guide the management of neutropenia
• Grade 4 neutropenia (ANC < 500/ µL) –G-CSF and antimicrobial
prophylaxis, can be used if clinically indicated for neutropenia

35. NAUSEA AND VOMITTING
• Gastrointestinal disorders are the prominent class of AES - venetoclax
as a single agent or in combination studies.
• Antiematics
• metoclopramide
• Prochlorperazin
• dolasetron
• granisetron

37. Drug interactions