A 36-year-old male with acute myeloid leukaemia and cardiac issue

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Dr. Maruf Reza Kabir

Phase-B resident

Particulars of the patient

• Name- Atiqur Biswas Mukul
• Age- 36 year
• Sex- Male
• Address- Pallabai, Mirpur, Dhaka
• Occupation- Sub-Inspector of Police
• Date of admission- 20/11/21

• Generalized bodyache for 15 days
• H/O sudden severe chest pain, 10 days back

• pain over chest, upper abdomen, back
• insidious onset, mild to moderate, continuous, relieved partially by painkillers
• not related to movement, often exaggerate during breathing
• 10 days back-
• sudden severe chest pain
• no vomitting, sweating

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• shortness of breath
• sudden onset
• no cough
• chest pain during respiration

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• no H/O
• fever
• weakness, palpitaion
• burning micturiton, throat pain, joint pain
• bleeding menifestation
• nodular swelling in any part of body
• contact with TB patient
• normal bowel and bladder habit

General examination-

• Appearence- normal
• Body built- obese
• Anaemia- absent
• Jaundice- absent
• Bony tenderness- absent
• Oedema- absent
• Lymphadenopathy- absent

• Temperature- 98.4 F
• RR- 18/m
• Pulse- 82/m
• BP- 130/70
• Wt- 59kg

Systemic examinations-

• Respiratory system-
• breath sound diminished from 4th ICS below downwards
• bronchial breath sound in between 3rd & 4th ICS
• decrease vocal resonance
• no added sound

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• other systemic examination- no abnormality

• Mr. Mukul, 36 year old policeman, normotensive, non diabetic, hailing from presented with generelized bodyahe for 15 days.
• chest, upper abdomen, back
• insidious onset, mild to moderate, continuous, relieved partially by painkillers
• not related to movement, often exaggerate on exertion

• H/O-
• sudden severe chest pain
• no vomitting, sweating
• shortness of breath
• sudden onset
• no cough
• chest pain during respiration
• no fever, weakness, bleeding menifestation

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after initial evaluations-

cardiac origin- ?constrictive pericarditis

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incidental findings

high leucocyte count with 50% blast & thrombocytopenia

• ECG- Ischaemic changes involving lead I, II, aVL, V1-V6
• Echocardiogram-
• effusion constrictive pericarditis
• LVEF 60%
• Chest Xray- Cardiomegaly
• USG abdomen- mild hepatomegaly with fatty change, cystitis
• Repeat Echo- no regional wall motion abnormality, jerky IVS, EF 56%
• Cardiac biomarker- normal

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• repeat Chest Xray- fishy fishy
• HRCT chest
• right sided consolidation with bilateral pulmonary inflammatory lesion
• bilateral pleural effusion
• sputum examination- Gram positive cocci, few pus cells, no yeast
• pleural fluid study
• MT
• COVID test- negative
• respiratory medicine consultation and treatment accordingly

BMS- 01/11/21

• Cellularity: Hypercellular
• M:E ratio: Increased
• Erythropoiesis: Depressed, mainly normoblastic
• Granulopoiesis: Hyperactive, shift to left, majority (>50%) of cells are atypical looking mononuclear cells resembling myeloblast
• Lymphocytes: normal
• Plasma cell: normal
• Comment: Suggestive of acute myeloid leukaemia

• Flowcytometry- 05/11/21
• Gated 57% blast
• moderate expression of CD33, CD13, CD34, dim MPO, CD 38, HLA DR
• acute myeloid leukaemia- M2
• Cytogenetic study
• AML-ETO t(8,21), NPM1, inv16, BCR-ABL, FLT3-ITD, PML-RARA- negative

• Induction with DA 3+7

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• regular cardiac monitoring
• strong supportive care

Scenario 1: patient with cardiomyopathy

• A 57-year-old man, 2 week h/o weakness and mild dyspnea
• h/o MI 11 months back
• total count was 43K, 90% blasts, Hb 7.8 g/dL, PLT 22K
• bone marrow was diffusely infiltrated with blast
• normal chest radiograph
• echocardigram- mildly reduced left ventricular systolic function with EF 42%

• Can standard induction & consolidation therapy be given to this patient?
• if not, what are the alternatives?
• What is the best way to monitor the cardiac disease?
• Is there a role for cardioprotective agents?

• standard induction therapy with very close cardiac monitoring
• because of the potential toxicity with cardiomyopathy, a LVEF of 45% as the threshold for using anthracyclines has been suggested

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• Alternative therapeutic options-
• avoid anthracyclines & alternate with high dose cytarabine- 1.5 g/m2 given over 1 hour twice daily for 6 days
• Gemtuzumab ozogamicin
• Amsacrine-based regimen

Scenario 2: patient with ACS

• A 45-year-old man presented with chest pain and anemia
• Cardiac CT- normal systolic function, but significant narrowing of the right coronary artery, acute coronary syndrome (ACS) was diagnosed.
• TLC count was 10K with 20% blasts. BM were diagnostic for AML
• Is the treatment of AML feasible in the setting of ACS?
• What is the optimal antiplatelet therapy?
• Should coronary intervention precede induction?

• Immediate medical therapy with aspirin, beta-blockers, allopurinol, hydration, correction of electrolyte imbalances and maintenance of Hb level 8 g/dL
• Hydroxyurea is indicated for a rapidly increasing blast count
• If ischemic symptoms subside, monitor the patient without initiating induction therapy for 5 to 7 days

• If the patient remains stable and without symptoms, induction or remission can be started
• Active coronary disease increases the risk for anthracycline toxicity. This risk needs to be balanced against the importance of using anthracyclines
• Therefore, standard anthracycline doses or high-dose cytarabine is a reasonable option for induction

• Aspirin is the drug of choice & maintain platelet count above 30K
• Addition of anticoagulation or other antiplatelet agents may reduce the death risk but increases the risk of bleeding & should be avoided
• if signs or symptoms of ischemia persist- PCI
• Intractable ischemia must be resolved prior to initiating induction therapy

Scenario 3: patient with newly diagnosed AML

• A 55-year-old woman with AML
• h/o DM and diabetic nephropathy with a creatinine of 3.0 mg/dL, but does not require dialysis

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• What precautions are necessary?
• What is the best approach to induction and postremission therapy?
• Are there required chemotherapy dose adjustments?

• The earliest issue is tumor lysis syndrome
• An elevated creatinine is an independent risk factor for TLS
• In cases of severe TLS, leukapheresis may be considered
• Careful monitoring to avoid fluid overload or volume depletion
• Use loop diuretics to increase urine flow rate
• Administration of NaHCO3 is no longer recommended because of concern for metabolic alkalosis
• Allopurinol can be administered in doses adjusted, Rasburicase may be used

• Cytarabine is generally metabolized by liver cytidine deaminase, dose reduction is not required for standard doses (400 mg/m2 per day).
• When higher doses are given (2-3 g/m2) to patients with renal dysfunction, neurotoxicity has been observed
• The recommended dose-
• if ccr 46-60 ml/min- 60% of the dose
• ccr 31-45 ml/min- 50%
• ccr 30 ml/min- consider alternative agent
• Among anthracyclines, daunorubicin has the greatest fractional renal clearance, the common recommendation to reduce the dose by 50% for a creatinine 3 mg/dL

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Scenario 4: patient with renal dysfunction

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• Is AML therapy feasible in patients on chronic dialysis?
• Should the goals of AML therapy be altered because of kidney disease?
• What chemotherapy regimens can be safely administered?

• Hemodialysis is an effective treatment of intractable fluid overload, hyperkalemia, hyperuricemia, hyperphosphatemia or hypocalcemia
• Awareness and rapid response to early signs of infections are of particular importance, because life-threatening infections are common among chronic dialysis patients even without leukemia

• The induction regimen and chemotherapy doses are similar
• Anthracyclines are not eliminated by hemodialysis, no dose augmentation is required
• As postremission therapy, high-dose cytarabine should be avoided due to potential neurotoxicity
• Repeating the induction regimen for 1 to 2 cycles or, alternatively, administer mitoxantrone and etoposide in reduced doses
• Allogeneic transplantation

Scenario 5: patient with hepatitis

• Anti HBc is the most sensitive test for previous exposure to hepatitis B
• Induction and consolidation therapy can be given at standard doses
• Entecavir is the most commonly used agent as prophylaxis, which should be continued for a total of 6 to 12 months. Monitoring- DNA viral load.
• For patients risk of drug resistance the preferred agent is tenofovir
• In the presence of HBVr, with high HBV DNA levels and frank hepatitis, prompt use of antiviral therapy does not permit the use of chemotherapy for AML
• Current guidelines do not recommend prophylaxis for HCV

Scenario 6: patient with cirrhosis

• A 58-year-old man with cirrhosis (chronic alcohol abuse) with portal hypertension manifested by mild ascites and edema and mixed-lineage leukemia
• serum albumin is mildly low at 3.0 g/dL
• PT and aPTT slightly prolonged
• Can patient receive treatment of AML?
• What is the preferred regimen?
• Are there dose modifications of chemotherapeutic agents needed?

• potential issues- third spacing of fluid, hepatic dysfunction with drug metabolism, portal hypertension and variceal bleeding, malnutrition and coagulopathy
• Child-Pugh score is an important tool for determining the prognosis
• Coagulation abnormalities need to be very closely monitored
• maintain a platelet count 20k throughout induction

• anthracyclines are metabolized primarily by the liver, dose modifications are required
• 75% of dose if total bilirubin 1.5-3 mg/dL, AST 60-180
• 50% if total bilirubin 3.1-5 mg/dL, AST >180
• do not administer daunorubicin if total bilirubin is >5 mg/dL
• cytarabine is partially detoxified in the liver, administer 50% of the total dose for any elevation in AST or ALT or total bilirubin >2 mg/dL
• regarding HiDAC for consolidation- numerous potential complications and risk of cerebellar toxicity, so rarely administer HiDAC in this clinical condition

• Decitabine is eliminated by cytidine deaminase found in liver, most clinical trials involving decitabine and azacitidine excluded patients with significant liver disease
• patient with cirrhosis and a bilirubin level >5 mg/dL, low-dose cytarabine may be used
• The one theoretic exception where underlying cirrhosis may not preclude treatment is APL
• all-trans retinoic acid has been proposed as a treatment of cirrhosis of the liver because this agent decreases liver fibrosis by reducing TGFβ1, IL-6 and type I collagen.

Scenario 7: patient with COPD

• A 62-year-old woman, heavy smoker, known pulmonary emphysema and secondary pulmonary HTN, presents with pancytopenia and 30% blasts on BM examination. At rest, she is comfortable with oxygen saturation of 90% but even ordinary physical activity causes undue dyspnea
• What is the best first-line therapy in this woman?
• What can be achieved beyond remission?
• Are there special recommendations for such patients?

• AML with COPD are usually excluded from clinical trials
• In a large retrospective study, following intensive induction therapy, grade 3-4 respiratory complications requiring support (16%) & respiratory failure (8%)
• pulmonary hypertension raises the mortality from sepsis
• So, considering the age treatment plan need to be compromised
• comorbidity index assement
• use of hypomethylating agent
• comprehensive pulmonary function evaluation

Scenario 8: patient with ICH

• A 57-year-old woman with acute myeloid leukemia 6 weeks following an ICH
• she currently can manage her daily life activities but requires assistance for mobilization
• Currently TLC 45k, 90% blasts, Hb 11.2 g/dL, PLT 90k, coagulation test- normal
• No new neurological abnormalities are present
• What is the risk of rebleeding in the central nervous system (CNS)?
• And how does this impact on the therapy for AML?

• In a patient with a prior ICH, BP control reduces recurrent CNS bleeding risk by 50%
• urgent chemotherapy to control the blast is indicated because hyperleukocytosis is associated with increasing bleeding risk
• platelet count threshold of 50k has been suggested (no convincing data)
• maintain the platelet count above 30k during induction therapy
• Induction with attenuated anthracycline doses should be avoided
• In older patients, in whom the risk of rebleeding is significantly high consider less myeloablative therapy, such as hydroxyurea, low-dose cytarabine, or hypomethylating agents

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