WELCOME TO JOURNAL CLUB

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PRESENTED BY

Dr. Nowreen Afroj Chowdhury

Phase B Resident

Department Of Haematology

BSMMU

INTRODUCTION

• Acute myeloid leukemia (AML) is a devastating disease
• Incidence progressively increases with advancing age.
• Currently, only ∼40% of younger and 10% of older adults are long-term survivors.
• If untreated, the overall prognosis of AML remains dismal.
• Initiation of therapy at diagnosis is usually urgent.
• One of the barriers to successful AML therapy is pre existing organ dysfunction

• Common pre treatment comorbidities:
• Cardiomyopathy
• IHD
• CRF, with and without dialysis
• hepatitis and cirrhosis
• COPD
• ICH

Patient with cardiomyopathy

• A 57-year-old man with P/H/O IHD with MI 11 months ago
• WBC count 43K /L, 91% blasts, Hb 7.8 g/dL, platelets 22K /L
• Chest X Ray Normal
• Echo - mildly reduced left ventricular systolic function with EF 42%

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• Way to monitor and establish the cardiac disease?

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Evaluation of LVEF

• multigated acquisition scan (MUGA)
• echocardiography (preferably, 3- dimensional)
• Cardiac MRI (gold standard not routine clinical practice)

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• Can standard therapy be given to such patient?

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If LVEF more or equal to 45% standard anthracyclines dosage can be used with close monitoring

Choice of anthracyclines :

• epirubicine
• mitoxantrone
• liposomal encapsulation

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• If not, what are the alternatives?

• Induction with high dose cytarabine ( 1.5 gm /m2 over 1 hour twice daily for 6 days) followed by same regimen for 2 cycles as consolidation
• Gemtuzumab ozogamicin (substitute for daunorubicin )

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• Is allogeneic transplantation possible?

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RIC allogeneic SCT can be considered with high risk AML

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• Is there a role for cardioprotective agents?

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Minimize IV infusion , correction of electrolyte imbalance

LVEF evaluation before each cycle

Use of dexrazoxane as a chelator that may prevent anthracycline damage(not used outside clinical trial)

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Patient with ACS

• A 45-year-old man with H/O new onset of chest pain and anemia.
• Cardiac CT - normal systolic function, but significant narrowing of the right coronary artery
• white blood count 10 K /L with 20% blasts.
• BM aspiration and biopsy AML

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• Is the treatment of AML feasible in ACS?
• What is the optimal antiplatelet therapy?
• Should coronary intervention precede induction?

• Immediate medical therapy : aspirin, beta-blockers, allopurinol, hydration, correction of electrolyte imbalances and maintenance of hemoglobin level at least 8 g/dL
• Hydroxyurea if indicated
• If ischemic symptoms subside, delaying induction for 5 to 7 days
• If the patient remains stable and without symptoms, induction must be started
• Avoiding anthracycline and HiDAC use is a reasonable option for induction
• Aspirin use throughout the induction while maintaining platelet >30K

• If symptoms of ischemia persist despite optimal therapy, PCI with bare metal stent prior to induction
• Following PCI dual antiplatelet therapy to reduce stent thrombosis
• Clopidogrel discontinuation 14 days after PCI
• If PCI not performed prior to induction, it has to be done during post remission period

Patient with CRF without dialysis

• A 55-year-old woman with newly diagnosed AML
• H/O DM with CRF and creatinine 3.0 mg/dL, but does not require dialysis

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• What precautions are necessary?

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• earliest issue is TLS
• In severe TLS, leukapheresis may be considered
• Avoid fluid overload and or volume depletion
• Use of loop diuretics
• No sodibicarbonate as in severe RF metabolic alkalosis is developed
• Allopurinol/ rasburicase use

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• Are dose adjustments required?

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• The anthracyclines are primarily eliminated by liver and kidney
• Reduce daunorubicin dose by 50% if creatinine > 3 mg/dL
• Cytarabine is generally metabolized by liver, so no dose reduction in standard doses (<400 mg/m2 per day)
• when higher doses are given (2-3 g/m2 ) in patients with renal failure, neurotoxicity observed, so not recommended as consolidation

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• What is the best approach to induction and post remission therapy?

• Reduced dose daunorubicine and standard-dose cytarabine (100 mg/m2 per day for 7 days) can be administered as induction even with very low creatinine clearance
• Consolidation options:
• Identical induction regimen
• Combination of mitoxantrone plus etoposide (Mitoxantrone does not require dose adjustment and etoposide needs dose adjustment).

75% of the total dose if creatinine clearance is 10 to 50 mL/minute

50% of the dose if creatinine clearance is <10 mL/minute.

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Patient with renal dysfunction with dialysis

• What if a patient on chronic dialysis presents with AML?

• Is AML therapy feasible in patients on chronic dialysis? What chemotherapy regimens can be safely administered?

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• Haemodialysis to balance electrolytes and prevent TLS
• “3 + 7” with reduced anthracycline dose (50%)
• HiDAC is avoided
• As consolidation repeating induction regimen for 1 to 2 cycles or, mitoxantrone and etoposide in reduced dose
• Allogeneic transplantation is not recommended

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• Is the goal of AML therapy altered because of kidney disease?

A newly diagnosed AML patient with favorable prognosis based on the dialysis comorbidity scale, curative intent therapy is reasonable

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Patient with hepatitis

• A 26-year-old woman with AML
• The liver and renal function tests are normal
• HBsAg positive,anti-HBc positive and anti-HBS negative.

• Is there an antiviral agent and recommended duration for prophylaxis? What is the best way to monitor response to antiviral therapy?

• Prophylaxis is essential for HBV carrier receiving AML treatment
• Lamivudine is most commonly used antiviral for a total of 6 to 12 months. Entecavir is an alternative to lamivudine, tenofovir is preffered with prior reactivation of HBV
• monitoring of response by DNA viral load

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• Do doses of therapy need to be adjusted? Is allogeneic transplantation can be undertaken?

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• Induction and consolidation therapy can be given at standard doses, and if indicated, allogeneic transplantation can be undertaken with prophylaxis

• Are the guidelines similar if patient presents with frank reactivation of hepatitis and abnormal liver enzymes?

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• In HBV reactivation , with high viral load and frank hepatitis, management is complex, as use of antiviral therapy does not permit the use of standard chemotherapy

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• What if the patient is a carrier of hepatitis C?

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• Antiviral prophylaxis is not recommended in asymptomatic HCV carriers or in those with non cirrhotic hepatitis but is recommended with cirrhosis

Patient with cirrhosis

• A 58-year-old man with AML and decompensated Alcoholic liver cirrhosis
• The serum albumin is 3.0 g/dL
• PT and APTT slightly prolonged

• Can patients with cirrhosis receive treatment of AML?

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• The treatment of AML patient with cirrhosis is complicated.
• many may not be candidates for intensive chemotherapy
• The Child-Pugh score is an important tool for determining the prognosis
• Coagulation abnormalities need to be monitored with aggressive replacement for any evidence of bleeding
• platelet count should be >20K/L throughout induction

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• Are dose modifications of chemotherapeutic agents needed?

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• Anthracyclines (Daunorubicine)dose modification is required

75% of the total dose if bilirubin is 1.5 to 3 mg/dL &/or the aspartate transaminase (AST) is 60 to 180U/L

50% dose if bilirubin is 3.1 to 5 mg/dL and/ or the AST is >180U/L

no daunorubicin if bilirubin is >5 mg/dL

• Cytarabine is partially detoxified in the liver

50% of the total dose for any elevation in the AST or alanine transaminase or total bilirubin >2 mg/dL

• What is the preferred regim?
• HiDAC is not recommended
• Hypomethylating agents decitabine and azacitidine are excluded
• If bilirubin level >5 mg/dL , low-dose cytarabine 7- to 10-day course (50 mg/m2 per day)is recommended
• Allo SCT is not for decompensated cirrhosis except Child I cirrhosis RIC Allo SCT can be considered
• ATRA is a proposed treatment for cirrhosis. In APL with cirrhosis, ATRA will be continued with no dose modification

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Patient with COPD

• A 62-year-old woman, heavy smoker, suffering from pulmonary emphysema and secondary pulmonary HTN with sec AML
• pancytopenia on PBF and 30% blasts on BM examination
• comfortable at rest with SpO2 of 90% but ordinary physical activity causes undue dyspnea

• What is the best first-line therapy ?
• What can be achieved beyond remission?
• Are there special recommendations for such patients?

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• A large retrospective study, after standard induction therapy, grade 3-4 respiratory complications occur in 16% patients and 8% patients developed respiratory failure
• pulmonary hypertension increases mortality from sepsis
• The Sorror comorbidity index is evaluated
• A Sorror index of 3 is the cutoff for poorer outcome
• induction mortality is close to 85% with Sorror score 3 or more

• Hypomethylating therapy for “low proliferative” leukemia as well as in frail patients
• >70 years of age either standard induction or hypomethylating agents
• 60 to 70 years old, longer survival has been reported with standard induction
• For patients with an adverse karyotype, a reasonable strategy is to use hypomethylating therapy for 3 to 4 months followed by RIC allo-HCT

Patient with ICH

• A 57-year-old woman with acute myelomonocytic leukemia 6 weeks following an ICH
• currently requires walker assistance for mobilization
• white blood count is 45 K/L with 90% blasts with Flt3-ITD mutation. Hb% 11.2 g/dL and platelet count is 90K/L. Blood coagulation test results are normal

• What is the risk of rebleeding in CNS?And how does this impact on the therapy for AML?

• HTN control reduces recurrent CNS bleeding risk by 50%
• urgent antileukemia therapy to reduce blast count because hyperleukocytosis is associated with increasing bleeding risk
• platelet count threshold of 50K/L ( no convincing data to support)
• maintain platelet count above 30 K /L during standard therapy

• Induction with attenuated anthracycline doses should be avoided
• In older patients, risk of rebleeding is high, less myeloablative therapy, such as hydroxyurea, low-dose cytarabine, or hypomethylating agents are considered

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THANK YOU