AML toxicity and and it's brief management

Details description

1. Management of toxicities associated with therapies for Acute Myeloid Leukaemia

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 min utes Peaks around 4-6 hours
Usually resolves around 24 hours

5. Within days Delayed onset emesis >24 hours upto 7 days Fatigue Myelosuppression 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

8. Antiemetic recommendations by EMETIC RISK categories EMETIC RISK CATEGORY ASCO guideline NCCN guideline High risk >90% Prechemo – 5 HT3 R antagonist+ dexa + aprepitant 3 drug combination+/- lorazepam For delayed emesis prevention – dexa + aprepitant 2 drug combination+/- larazepan Moderate risk 30-90% For anthracyclin and CPM Prechemo – 5 HT3 R antagonist+ dexa + aprepitant For delayed emesis prevention – dexa + aprepitant 3 drug combination+/- lorazepam 2 drug combination+/- larazepan Other chemo 5 HT3 R antagonist+ dexa For delayed emesis dexa or 5 HT3 R antagonist Other chemo
5 HT3 R antagonist+ dexa +/- lorazepam
For delayed emesis dexa or 5 HT3 R antagonist +/- lorazepam Low risk 10-30% Prechemo – dexa No drug for delayed emesis prevention Metochlopramide +/- diphenhydramine Dexa +/- larazepan Prochlorperazone +/- lorazepam Minimal risk <10% No antiemetic No routine prophylaxis

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

10. Febrile neutropenia Single oral temperature greater than or equal to 101 F (38.3 C OR A temperature greater than or equal to 100.4 F (38 C) for at least an hour With A n absolute neutrophilic count (ANC) of less than 1500 cells/microliter.

11. Lab tests Complete blood count B lood - Two sets of blood cultures peripheral vein and any venous catheters U rinalysis T hroat cultures R espiratory symptoms - chest x-ray

12. Additional testing may be required in some instances Galactomannan $ bronchoalveolar lavage – fungal infections.
1,3-beta-D-glucan (BDG) – diagnostic biomarker of fungal infections. Procalcitonin – bacterimic sepsis
Patients with unknown chest infiltrate on imaging may benefit from the culture of BAL fluid.

13. NCCN RISK GROUP FOR FEBRILE NEUTROPENIA Low risk grp - < 10 %
no any symptoms/ comorbidity
No need of prophylaxis

14. 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

15. High risk I npatient status when fever developed H ave significant comorbidities or clinical instability H ad allogeneic stem-cell transplantation A nticipated prolonged duration of severe neutropenia (ANC <100 for >7 days) R enal (creatinine clearance <30 mL/min) or hepatic impairment (SGOT/SGPT >5 ULN) U ncontrolled or progressive malignancy P neumonia or complex infection H ave grade 3-4 mucositis MASCC Risk Index score <21 or CISNE score >3

16. Widely used risk assessment tools Multinational Association for Supportive Care in Cancer (MASCC) The Clinical Index of the Stable Febrile Neutropenia (CISNE),

17. Multinational Association for Supportive Care in Cancer ( MASCC )

18. The MAASC index has a max score of 26. Patients with a score greater than 21 – Low Risk And L ess than 21 – High Risk

19. The Clinical Index of the Stable Febrile Neutropenia ( CISNE ),

20. Interpretation 0-2: Consider outpatient management with oral antibiotics ≥3 : Inpatient management

21. IDSA algorithm for management of febrile neutropenia

22. Infectious Disease Society of America ( IDSA ) recommendation

23. Recommendation for prevention of infection Fluoroquinolones - patients who are at high risk
Antifungal prophylaxis with an oral triazole Trimethoprim- sulfamethoxazole (TMP-SMX) Yearly influenza vaccination
nucleoside reverse transcription inhibitor- hepatitis B virus reactivation

24. TREATMENT GUIDELINE Cytarabine Dounorubicin HMA Cladribine / fludarabine Midostaurin Venetoclax Gemtuzumab ozogamicin CPX 351 Ivosidenib / Enasidenib Glasdegib Quizartinib Gilteritinib Sorafenib

25. DAUNORUBICIN Anthracycline Cell Cycle non-specific
More lipid soluble than doxorubicin, wide distribution in heart, liver, lungs, kidney, spleen
Does not cross BBB Metabolised in liver
Dosage: 60 mg/m2

26. Strong vesicant
Baseline cardiac function
Dose limiting (cumulative toxicity): 450 mg/m2
Red orange urine Myelosuppression (leukopenia >> throbocytopaenia )
Hyperpigmentation of nails
Radiation recall skin reaction

27. Cardiotoxicity Acute Arrythmias Conduction abnormalities
ECG changes
Myocarditis
Pericarditis Chronic Dose dependent
Dilated cardiomyopathy
CCF
Increased incidence with cumulative toxicity > 550 mg/m2

28. CYTRABINE 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 .

29. S hort half-life and rapid plasmatic inactivation D ifferent schedules and dose-levels of cytarabine have been adopted for intravenous infusion - L ow Standard H igh Intermediate dose M ost commonly used regimen -100 to 200 mg/m2/d for 5 to 7 days

30. High Dose 2 to 3 g/m2 every 12 h for up to six doses I ntroduced about three decades ago, after the landmark CALGB study published in 1994 U sed primarily in the consolidation phase and upfront in patients with unfavorable, intrinsically drug resistant, oncogenic subtypes (8;21), inv16, del16, t(16;16) Hi gh -dose cytarabine has been the optimal post-remission therapy for patients with AML in first remission not proceeding to allogenic transplantation

31. T oxicity profil e - highly dependent on the dose and schedule of administration. Leukopenia and thrombocytopenia Gastrointestinal toxicity - mild-to-moderate mucositis and diarrhea . Occasionally acute pancreatitis - cytarabine as a continuous infusion

32. Cytarabine syndrome O ccur within 12 h after the start of drug infusion W ith the onset of fever, myalgia, joint and bone pain, maculopapular rash, keratoconjunctivitis , and occasional chest pain M ost likely represents an allergic reaction to cytarabine P atients usually develop symptoms months after the first dose, C orticosteroids R esolve within 24 h when cytarabine is discontinued

33. S/E H igh D ose C ytarabine C ommon major side effects- Biphasic pancytopenia Central nervous system toxicity, Skin eruptions H yperbilirubinemia in > 10% of patients Infection S eizures

34. MYELOSUPPRESION Counts may continue to fall 12-24 days after
Post 5 day infusion , WBC fall biphasic
Nadir at 7-9 days
Brief rise day 12
Falls again, deeper, D15-D24
Rapid rise above baseline next 10 days

35. Acute cerebellar toxicity Dysarthria with truncal and gait ataxia Cerebral syndrome - encephalopathy, psychosis, seizures, and coma. W idespread loss of Purkinje cells in the cerebellum . Begins with somnolence and occasionally an encephalopathy D evelops 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

36. N eurotoxicity P eripheral neuropathies resembling GBS , brachial plexopathy , lateral rectus palsy, optic neuropathy, or an extrapyramidal syndrome Risk factor- Cumulative cytarabine dose, P rior CNS disease R enal impairment H igh -dose therapy (>18 g/m2 per cycle) A ge >50 years

37. Fatal cardiomyopathy - combination with cyclophosphamide. Anaphylaxis - acute cardiopulmonary arrest. GI toxicity - bowel necrosis and esophagus ulceration.

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

39. Occular toxicity E xcessive tearing, photophobia, burning ocular pain and blurred vision O/E C onjunctival injection C entral punctate corneal opacities with subepithelial granular deposits D ecreased visual acuity

40. 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

41. Common side effects B one marrow suppression N ausea , vomiting, diarrhea, stomatitis Bruising A bdominal pain M yalgias H eadache , dizziness, fatigue F ever, rash and pruritus.

42. Uncommon but potentially severe adverse events S evere myelosuppression F ebrile neutropenia Pneumonitis S epsis T umor -lysis syndrome E mbryo -fetal toxicity.

43. V enetoclax BCL2 inhibitor BCL-2 overexpression has been implicated in survival of AML cells and treatment resistance  C ombination 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). 

44. 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

45. 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

46. NAUSEA AND VOMITTING Gastrointestinal disorders are the prominent class of AES - venetoclax as a single agent or in combination studies. Antiematics M etoclopramide Prochlorperazin D olasetron G ranisetron

47. TLS All patients with AML should have WBC < 25,000/µL prior to initiation of venetoclax . Hydroxyurea or leukapheresis can be used for cytoreduction . Prior to first dose of venetoclax , prophylactic measures including adequate hydration and antihyperuricemic agents (allopurinol, rasburicase , etc.), which continue during the ramp-up phase

48. To give or not to give...

49. WHEN TO STOP Reduce dose by 50% for severe liver impairment (Child-Pugh score for cirrhosis). Hold if bone marrow evaluation on days 21 to 28 shows cytoreduction (<5% blasts). In responding patients, consider truncating duration of venetoclax therapy to 7 to 21 days in subsequent cycles discontinue after 2 to 4 cycles if there is no response. 

50. Management approach for venetoclax plus HMA/low-dose cytarabine .

51. DRUG INTERACTIONS

52. FLT3 inhibitors

53. Midostaurin FLT3 inhibitor Given from day 8-21 of induction and consolidation ( HiDAC ) Complete 14 days during induction and consolidation 50 mg BD, 28 cap/carton

54. Toxicities Pneumonitis Nausea/vomiting, diarrhea Fever, mucositis , infections Cardiac issues (in patients age 60 to 70 years)

55. When to stop? Unable to take oral medication because of nausea/vomiting Development of life-threatening cardiac issues Discontinue for possibly drug-related interstitial pneumonitis without infectious etiology Evidence of R/R disease. 

56. Gemtuzumab Ozogamicin 3 mg/m2 (maximum, 4.5 mg/m2) intravenous infusion on days 1,4, and 7 of cycle 1 induction  Liver dysfunction, VOD/SOS, fever, myelosuppression , infusion reactions Induction and consolidation for favorable - or intermediate-risk AML, mild or moderate hepatotoxicity, myelosuppression , or mild or moderate infusion reaction

57. When to stop? Hold or discontinue gemtuzumab ozogamicin for severe hepatotoxicity or bleeding. Discontinue gemtuzumab ozogamicin for VOD/SOS or life-threatening anaphylaxis, or at least 2 months before planned allo -SCT. 

58. Gilteritinib 120 mg OD Liver dysfunction, fever, PRES, DS, myalgia/arthralgia, fatigue, edema   First 6 cycles of therapy, mild to moderate renal impairment, mild DS responding to therapy 

59. When to stop? Severe DS with life-threatening complications or no improvement after 48 hours of steroid therapy; elevated liver function tests (AST and ALT >5× ULN, bilirubin >3× ULN). Restart at 80 mg Pancreatitis is present, restart at 80 mg QTcF >500 ms (1%), adjust medications and restart at 80-120 mg. Discontinue for PRES (1%) or if there is no response after 6 cycles. 

60. Sorafenib 200-400 mg orally twice per day  Skin rash, fatigue, diarrhea , liver, myalgias , marrow hypoplasia, cytopenia Off-label use for mutant FLT3-ITD AML in combination with other HMAs 

61. When to stop? Hold for excessive bleeding and severe cytopenias (consider resuming dose at 200 mg); hold or discontinue drug for severe persistent hypertension or cardiac ischemia or infarction; discontinue for severe skin reactions or if there is no response in 3 months. 

62. Quizartenib 30-60 mg orally once per day  QTcF prolongation (dose related), DS  Hold for significant QTC prolongation or development of cardiac arrhythmias (dose related) per clinical trial or for severe DS with life-threatening complications or no improvement after 48 hours of steroid treatment. 

63. IDH1 and IDH2 Inhibitors Ivosidenib , Enasidenib 500 mg orally once per day  DS, QTc prolongation, cytopenias , high WBC First 6 months, mild to moderate renal and hepatic dysfunction, and mild DS 

64. When to stop? Severe DS with cardiopulmonary compromise requires hospitalization with or without renal dysfunction QTc prolongation >480 ms (resume when <480 ms ) Discontinue for life-threatening cardiac arrythmias , for Guillain-Barré syndrome, or if there is no response (hematologic recovery/blast clearance) after 6 months. 

65. Enasidenib Hold for severe DS with cardiopulmonary compromise requiring emergent hospitalization With or without renal dysfunction Bilirubin 3× ULN or more Reduce dose to 50 mg once per day. Discontinue if there is no response (hematologic recovery or blast clearance) after 6 months. 

66. Glasdegib Sonic hedge-hog inhibitor Used in combination with low-dose cytarabine for older and/or unfit patients with AML 100 mg orally once per day QTc prolongation Muscle spasms (20%), ageusia / dysgeusia (loss or alteration of the sense of taste, 24%), thinning or loss of hair (10%), and asthenia (fatigue) Anemia , hemorrhage , febrile neutropenia, edema , thrombocytopenia, nausea, dyspnea , constipation, and rash.

67. When to stop? Permanent discontinuation: life-threatening cardiac arrythmias or Severe neutropenia or thrombocytopenia > 42 days without overt bone marrow disease

68. Financial Toxicity Secondary cancers, therapy related

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