Abstract

Acute myeloid leukemia (AML) is a devastating disease with an incidence that 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. Barriers to successful therapy for AML are the attendant toxicities directly related to chemotherapy or those associated with inevitable aplasia. Organ dysfunction often further complicates such toxicities and may even be prohibitive. There are few guidelines to manage such patients and the fear of crossing the medico-legal abyss may dominate. Such clinical scenarios provide particular challenges and require experience for optimal management. Herein, we discuss select examples of common pretreatment comorbidities, including cardiomyopathy, ischemic heart disease; chronic renal failure, with and without dialysis; hepatitis and cirrhosis; chronic pulmonary insufficiency; and cerebral vascular disease. These comorbidities usually render patients ineligible for clinical trials and enormous uncertainty regarding management reigns, often to the point of withholding definitive therapy. The scenarios described herein emphasize that with appropriate subspecialty support, many AML patients with comorbidities can undergo therapy with curative intent and achieve successful long-term outcome.

Introduction

Although the initial therapy of acute myeloid leukemia (AML) has been standardized and forms the backbone of clinical trials, many patients do not receive conventional therapy at diagnosis due to existing or potential comorbidities which cause much anxiety among patients and clinicians. Herein, we present 8 selective, but common, clinical vignettes describing, with subspecialty advice, a pragmatic approach to the management of patients with AML who present with varying degrees of organ dysfunction. Adhering whenever possible to standard therapy had been the guiding principle in suggesting the optimal antileukemic therapy.1  The primary focus is on induction and consolidation with only general reference to allogeneic transplantation.

Scenario 1: patient with cardiomyopathy

A 57-year old man was admitted with a 2-week history of generalized weakness and mild dyspnea. He was found to have intermediate-risk AML (normal karyotype, no nucleophosmin [NPM1], CCAAT/enhancer-binding protein [CEBPA], or Fms-related tyrosine kinase 3 [FLT3]–internal tandem duplication [ITD] mutations identified). His past medical history is remarkable for ischemic heart disease with a myocardial infarction 11 months prior to admission. Otherwise, he was in good health. On admission, his white blood cell count was 43 × 109/L, with 91% blasts, hemoglobin 7.8 g/dL with platelets 22 × 109/L. The bone marrow (BM) was diffusely infiltrated with blast cells. He was afebrile with a normal chest radiograph. The echocardiogram revealed mildly reduced left ventricular systolic function with an ejection fraction (LVEF) of 42%.

Questions

  • Can standard induction and consolidation therapy be given to this patient with cardiomyopathy and, if not, what are the alternatives?

  • Can such a patient undergo allogeneic transplantation?

  • What is the best way to monitor the cardiac disease?

  • Is there a role for cardioprotective agents?

Cardiac dysfunction in newly diagnosed patients with AML is not an uncommon problem encountered in practice, particularly among older patients. This is even more relevant in the current era when standard induction therapy is given to an ever increasing older population. As anthracyclines form the core of induction therapy in AML, any cardiac dysfunction may limit the optimal treatment that can be given.

Several issues need to be considered. First, the most common approach to monitor cardiac function is the evaluation of LVEF. Radionuclide angiography measuring multigated blood pool imaging (multigated acquisition scan) or echocardiography (preferably, 3-dimensional) are commonly used. For added accuracy in marginal cases, as in this patient, measurement of LVEF by magnetic resonance imaging is considered by many to be the gold standard.2  However, we do not incorporate it into routine clinical practice. In general, because of the potential for progressive toxicity in a patient with cardiomyopathy, a LVEF of 45% as the threshold for using anthracyclines in the treatment of AML has been suggested3,4  (Table 1). Although such a cutoff is necessarily arbitrary, it is the most commonly used value for eligibility to large cooperative oncology group clinical trials in AML. Given the need to optimize the therapy in AML and being fully cognizant of the risk/benefit considerations, it may be entirely reasonable to offer standard induction therapy with very close cardiac monitoring. The choice is very individualized and will take into account the patient’s age, performance status, and any comorbidities.

Table 1

Select precautions and recommendation for AML therapy in patients with heart disease

Specific supportive care considerationsInduction therapyPostremission strategy
LVEF <45%3,4  1. Minimize IV infusions 1. HiDAC or 7+3 1. Repeated HiDAC 
2. Repeat LVEF evaluation prior to each chemotherapy cycle 2. If anthracycline used, consider epirubicin or mitoxantrone 2. RIC allo-SCT may be considered for high-risk AML 
Ischemic heart disease15,17  1. Aspirin + beta-blocker 1. If possible, postpone induction for few days Based on leukemia risk stratification and LVEF 
2. Maintain hemoglobin >8 g/dL 2. Use HiDAC 
3. Avoid anthracycline 
4. Aspirin throughout induction 
1. PCI prior to induction if active ischemia despite maximal noninvasive therapy  If not performed prior to induction, PCI is indicated for pending coronary obstruction prior to chemotherapy 
2. Bare metal stent 
Specific supportive care considerationsInduction therapyPostremission strategy
LVEF <45%3,4  1. Minimize IV infusions 1. HiDAC or 7+3 1. Repeated HiDAC 
2. Repeat LVEF evaluation prior to each chemotherapy cycle 2. If anthracycline used, consider epirubicin or mitoxantrone 2. RIC allo-SCT may be considered for high-risk AML 
Ischemic heart disease15,17  1. Aspirin + beta-blocker 1. If possible, postpone induction for few days Based on leukemia risk stratification and LVEF 
2. Maintain hemoglobin >8 g/dL 2. Use HiDAC 
3. Avoid anthracycline 
4. Aspirin throughout induction 
1. PCI prior to induction if active ischemia despite maximal noninvasive therapy  If not performed prior to induction, PCI is indicated for pending coronary obstruction prior to chemotherapy 
2. Bare metal stent 

allo-SCT, allogeneic stem cell transplantation.

There are also alternative therapeutic options. One approach would be to avoid anthracyclines and offer this patient induction with high-dose cytarabine at doses that are adjusted for his age. Although several dosing options can be considered, our own preference, based on published experience, is a dose of 1.5 g/m2 given over 1 hour twice daily for 6 days.5  Gemtuzumab ozogamicin has also been used as a substitute for daunorubicin,6  although this is currently unavailable in much of the world. An amsacrine-based regimen has also been proposed,7  but this is not commonly used nowadays.

Several methods have been reported to potentially reduce the risk of progressive toxicity from anthracyclines.8  These include infusional administration of anthracyclines, or the use of the anthracenedione, mitoxantrone.9-12  Liposomal encapsulation, in various formulations, has been suggested to reduce cardiotoxicity,13  but there are no compelling data to support such a recommendation. There has been considerable discussion about the use of dexrazoxane as a chelator that may prevent anthracycline damage by binding to free iron radicals. Given the theoretic risk of retarding the desired clinical benefit, outside of a clinical trial we do not recommend any of these strategies.14,15  Impairment of heart function may restrict standard supportive measures during induction such as antibiotics, transfusions, and electrolyte replacement that are associated with large fluid volumes.

If this patient achieves complete remission with high-dose cytarabine, we would recommend offering postremission therapy with 2 additional cycles of the same regimen.5  Irrespective of the agent used, close ongoing cardiac monitoring remains essential.

The possibility of allogeneic transplantation in such patients is more complex than induction or consolidation therapy, mainly because of the prolonged immune suppression with its attendant complications. However, if the genetic prognostic factors are such that the graft-versus-leukemia effect is considered an essential component for curative therapy, a reduced-intensity conditioning (RIC) allogeneic transplantation can be judiciously considered with very close cardiac monitoring.

Comment

Overall, the outlook for patients with cardiomyopathy, if clinically stable, need not preclude therapy for AML.

Scenario 2: patient with ACS

A 45-year-old man presented with new onset of chest pain and anemia. Cardiac computerized tomography revealed normal systolic function, but with significant narrowing of the right coronary artery (Figure 1). Acute coronary syndrome (ACS) was diagnosed. The white blood count was 10 × 109/L with 20% blasts. BM aspiration and biopsy were diagnostic for AML, molecularly characterized with normal cytogenetics and NPM1, as the only identified mutation.

Figure 1

Coronary computerized tomography demonstrating atherosclerotic occlusion of the right coronary artery.

Figure 1

Coronary computerized tomography demonstrating atherosclerotic occlusion of the right coronary artery.

Questions

  • Is the treatment of AML feasible in the setting of ACS?

  • What is the optimal antiplatelet therapy?

  • Should coronary intervention precede induction?

The combination of ACS and AML presents an unusually complicated predicament. For this patient, immediate medical therapy should include the combination of aspirin, beta-blockers,16,17  allopurinol, hydration, correction of electrolyte imbalances, and maintenance of hemoglobin level of 8 g/dL.18  Hydroxyurea is indicated for a rapidly increasing blast count. If ischemic symptoms subside, we would monitor the patient without initiating induction therapy for 5 to 7 days. If the patient remains stable and without symptoms, induction of remission is warranted.19  Although the patient presents with a normal cardiac function, active coronary disease increases the risk for anthracycline toxicity.15  This risk needs to be balanced against the importance of using anthracyclines for remission induction. Therefore, either 3+7 with standard anthracycline doses or high-dose cytarabine is a reasonable option for induction.20 

Aspirin is the drug of choice for ACS21  and reduces progression to myocardial infarction or death in 30 days from 13.4% to 4.2%.22  Therefore, although there are no established guidelines in this setting, we recommend aspirin throughout induction while attempting to maintain, arbitrarily, the platelet count above 30 × 109/L. The addition of anticoagulation, or other antiplatelet agents, may further modestly reduce the death risk; however, such practice increases the risk of bleeding and should be avoided.

For this patient, if signs or symptoms of ischemia persist, percutaneous coronary intervention (PCI) should be discussed. Intractable ischemia must be resolved prior to initiating induction therapy. The risks of progression to myocardial infarction, life-threatening arrhythmia, and sudden death are increased with stress, electrolyte imbalance, and hypoxia, all common during induction. Therefore, it is suggested that if symptoms of ischemia persist despite optimal medical therapy, revascularization should precede induction therapy. Following PCI, dual antiplatelet therapy is indicated to minimize the risk of stent thrombosis. In most patients with AML, induction should not be significantly delayed. Therefore, implantation of a drug-eluting stent that requires longer duration of dual antiplatelet therapy should be avoided if possible. Because the risk of stent thrombosis peaks during the first 14 days after PCI, and with bare-metal stent decreases thereafter, clopidogrel discontinuation should be considered 14 days after PCI to coincide with the development of induction-related severe thrombocytopenia.

Comment

Overall, the presence of ACS should not discourage aggressive therapy for AML.

Scenario 3: patient with newly diagnosed AML

A 55-year-old woman presents with newly diagnosed AML. Biallelic mutation in CEBPA is detected with a normal karyotype. She has a history of diabetes mellitus and diabetic nephropathy with chronic renal failure and a creatinine of 3.0 mg/dL, but does not require dialysis.

Questions

  • What precautions are necessary?

  • What is the best approach to induction and postremission therapy?

  • Are there required chemotherapy dose adjustments?

The treatment of a patient with newly diagnosed AML and chronic renal failure presents several challenges. A joint effort between the hematologist and nephrologist is required. The earliest issue which needs attention is the potential for tumor lysis syndrome (TLS). An elevated pretreatment serum creatinine >1.4 mg/dL is an independent risk factor for the development of both laboratory and clinical TLS.23  In cases of severe TLS, leukapheresis may be considered, even at leukocyte levels lower than the standard threshold for leukapheresis.24  In a patient with impaired renal function, intensive fluid administration needs to be carefully monitored to avoid fluid overload or volume depletion. We use loop diuretics to increase urine flow rate. The administration of sodium bicarbonate is no longer generally recommended.25  Moreover, in patients with severe renal failure it is contraindicated because of concern for metabolic alkalosis that may develop due to the retention of sodium bicarbonate. Allopurinol can be administered in doses adjusted for the degree of renal function.26  Rasburicase may be used if needed.

The best approach to induction and postremission therapy in a patient with chronic renal failure is unknown. Because cytarabine is generally metabolized by liver cytidine deaminase, dose reduction is not required when standard doses (<400 mg/m2 per day) are administered.27  However, when higher doses are given (2-3 g/m2) to patients with renal dysfunction, neurotoxicity has been observed.28  In a study of 110 patients with AML given high-dose cytarabine, among patients with estimated creatinine clearance <60 mL per minute, 76% were complicated by neurotoxicity compared with 8% of those with creatinine clearance >60 mL per minute.28  The recommended dose adjustments are as follows: if the creatinine clearance is 46 to 60 mL per minute, administer 60% of the dose; if the creatinine clearance is 31 to 45 mL per minute, administer 50% of the total dose; and if the creatinine clearance is <30 mL per minute, consider an alternative agent29  (Table 2). However, despite such an elegant algorithm, given the concerns of neurotoxicity (admittedly often reversible28 ) and hepatotoxicity, we do not administer high-dose cytarabine to patients with renal impairment. We maintain this practice even among patients with core-binding factor AML for whom it has been suggested that high-dose cytarabine may be particularly effective in prolonging survival.30 

Table 2

Select precautions and recommendation for AML therapy in patients with renal or hepatic dysfunction

Specific supportive care considerationsInduction therapyPostremission strategy
Renal failure27,29,32  1. Caution with fluid balance 1. “3+7” with regular cytarabine dose 1. Mitoxantrone + etoposide preferred 
2. Loop diuretics 2. Reduce daunorubicin by 50% if creatinine >3 mg/dL 2. Dose-adjusted HiDAC not recommended 
3. Avoid sodium bicarbonate 
4. Leukapheresis for TLS prevention 
5. Adjust allopurinol dose 
Dialysis27  Use dialysis to balance electrolytes and prevent TLS “3+7” with reduced anthracycline dose: depending on anticipated prognosis from the renal disease Repeat induction regimen 
Hepatic cirrhosis65,66  Careful monitoring for coagulopathy Dose reduction based on bilirubin blood level  
If bilirubin >5 mg/dL, maximum cytarabine
dose is 50 mg/m2 
Specific supportive care considerationsInduction therapyPostremission strategy
Renal failure27,29,32  1. Caution with fluid balance 1. “3+7” with regular cytarabine dose 1. Mitoxantrone + etoposide preferred 
2. Loop diuretics 2. Reduce daunorubicin by 50% if creatinine >3 mg/dL 2. Dose-adjusted HiDAC not recommended 
3. Avoid sodium bicarbonate 
4. Leukapheresis for TLS prevention 
5. Adjust allopurinol dose 
Dialysis27  Use dialysis to balance electrolytes and prevent TLS “3+7” with reduced anthracycline dose: depending on anticipated prognosis from the renal disease Repeat induction regimen 
Hepatic cirrhosis65,66  Careful monitoring for coagulopathy Dose reduction based on bilirubin blood level  
If bilirubin >5 mg/dL, maximum cytarabine
dose is 50 mg/m2 

“3+7”, 3 days of daunorubicin and 7 days of cytarabine.

The anthracyclines are primarily eliminated by renal and hepatic aldoketo reductase and biliary excretion. Less than 20% is eliminated in the urine.27  Of all anthracyclines, pharmacokinetic data are most robust for doxorubicin.31  Yet, there are no consistent recommendations regarding the need for dose reduction.32-34  Among anthracyclines, daunorubicin has the greatest fractional renal clearance, and we follow the common recommendation to reduce the dose by 50% for a creatinine >3 mg/dL.32 

With dose reduction for anthracyclines and standard-dose cytarabine (100 mg/m2 per day for 7 days by continuous induction), such conventional induction chemotherapy can be administered even to patients with very low creatinine clearance. As consolidation, one could give the identical induction regimen, but we would use the combination of mitoxantrone plus etoposide. The dose of mitoxantrone does not require adjustment.32,35,36  Etoposide is primarily eliminated by the liver and kidney, but pharmacokinetics are apparently the same in patients with end-stage renal disease as in normal individuals.37  Therefore, dose modifications are regarded as empiric. We adjust the dose and administer 75% of the total dose if the creatinine clearance is 10 to 50 mL per minute and give 50% of the dose if the creatinine clearance is <10 mL per minute.29 

Scenario 4: patient with renal dysfunction

What if a patient on chronic dialysis presents with AML?

Questions

  • 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?

Considerations related to impaired renal function, as outlined above, also apply to patients on chronic dialysis (Table 2). Ironically, hemodialysis is an effective treatment of intractable fluid overload, hyperkalemia, hyperuricemia, hyperphosphatemia, or hypocalcemia38  and its frequency can be adjusted to prevent life-threatening electrolyte abnormalities.

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.39  Furthermore, among chronic dialysis patients, asymptomatic carriers of resistant bacteria are prevalent.40-42 

A curative approach to AML may be futile among patients in whom the predicted survival due to their kidney disease is short even prior to the development of leukemia.43,44  Realistic expectations and the desired goals of therapy must be discussed between the patient, family, nephrologist, and hematologist. For a newly diagnosed AML patient who has a favorable prognosis based on the dialysis comorbidity scale,43,44  AML therapy with curative intent is reasonable.

The induction regimen and chemotherapy doses are similar to those described above for patients with severely impaired renal function. Because anthracyclines are not eliminated by hemodialysis, no dose augmentation is required.31 

As postremission therapy,45  high-dose cytarabine should be avoided due to potential neurotoxicity.46  We would recommend repeating the induction regimen for 1 to 2 cycles or, alternatively, administer mitoxantrone and etoposide in reduced doses. Allogeneic transplantation in patients on chronic dialysis has been reported.47,48  Ordinarily, we do not consider it except in rare cases of a young highly motivated individual who has a very poor-prognosis genotype.

Comment

Renal dysfunction presents a significant barrier to treatment of AML. Meticulous attention to metabolic abnormalities and chemotherapy dose adjustment are critical.

Scenario 5: patient with hepatitis

A 26-year-old woman presents with core-binding factor AML with the t(8;21)(q22;q22) translocation. Her past medical history is unremarkable. She now resides in the United Kingdom, has traveled extensively as part of a diplomat’s family, and was born in China where she spent the first 6 years of her life. In her metabolic profile, the liver and renal function tests are normal. The patient is hepatitis B surface antigen (HBsAg)-positive and antibody to hepatitis B core antigen (anti-HBc)-positive. Antibodies to hepatitis B surface antigen (anti-HBS) are negative.

Questions

  • Do doses of induction and consolidation need to be attenuated?

  • Would such a serologic profile preclude an option of allogeneic transplantation?

  • Is there an optimal antiviral agent and recommended duration for prophylaxis?

  • Are the guidelines similar if such a patient presents in frank reactivation of hepatitis with markedly abnormal liver enzymes?

  • What is the best way to monitor response to antiviral therapy?

  • Should every AML patient, even if they have not lived in high-risk areas, be screened for hepatitis B virus?

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

This patient clearly is a carrier of hepatitis B virus and is at significant risk for hepatitis B virus (HBV) reactivation (HBVr). In general, HBsAg and anti-HBc are positive in such patients. Anti-HBc is the most sensitive test for previous exposure to hepatitis B and may be positive in the absence of detectable HBsAg. In rare cases, both the surface antigen and antibodies to the core antigen may be negative, whereupon prior exposure can be detected by sensitive polymerase chain reactions (PCRs) for DNA load. However, this is not part of routine practice in most parts of the world.

Prophylaxis is essential for patients receiving severe immunosuppressive therapy. AML induction and consolidation therapy certainly fall into this category.49  The efficacy of such prophylaxis has been demonstrated in several controlled trials.50,51  With prophylaxis, induction and consolidation therapy can be given at standard doses, and if indicated, allogeneic transplantation can be undertaken. The presence of antibody to HBsAg may offer some protection, but this is probably insufficient to discard prophylaxis.52 

Whether patients who are at low risk for HBVr should be screened is controversial. However, given the high risk of morbidity and mortality (∼25%),53  and in light of the marked efficacy of prophylaxis, we routinely screen all newly diagnosed AML patients for HBsAg and anti-HBc.54,55 

Lamivudine remains the most commonly used agent as prophylaxis, which should ordinarily be continued for a total of 6 to 12 months. The ideal monitoring of response uses DNA viral load. However, lamivudine is associated with a high rate of developing drug resistance over time (>20% at 1 year). Therefore, in those parts of the world where cost is not the primary determining factor, therapy with next-generation nucleotide analogs should be given to AML patients. Entecavir is an alternative to lamivudine, and is particularly suitable for naive patients with no history of resistance to therapy or prior reactivation.56  In the latter case, the preferred agent is tenofovir disoproxil fumarate.

In the presence of HBVr, with high HBV DNA levels and frank hepatitis, prompt use of antiviral therapy does not in itself permit the use of standard chemotherapy for AML. Management of such cases is complex, leads to significant delays and, often, discontinuation of therapy. Considerable experience is needed in navigating the risks of progressive hepatic failure with ongoing immunosuppression.57-59 

In patients with cancer, reactivation of hepatitis C virus (HCV) is far less common and associated with significantly lower rates of severe hepatitis than HBV reactivation.60  Current guidelines by the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America do not recommend prophylaxis for HCV reactivation, certainly not in asymptomatic carriers or in those with noncirrhotic hepatitis.61  Among patients with cirrhosis, the risk of life-threatening reactivation is greater.62 

Nevertheless, this is clearly an area of flux in the era of novel therapies for HCV. There has been a suggestion that patients receiving potent immunosuppressive targeted therapies should be closely monitored for potential development of hepatic flare,63  but this is controversial in a new era of clinical investigations, and there are no special guidelines for patients with AML.

Comment

Although not proven, AML and its therapy are sufficiently immunosuppressive to recommend prophylaxis for all carriers of hepatitis B. Prophylaxis is not recommended for carriers of hepatitis C.

Scenario 6: patient with cirrhosis

A 58-year-old man with cirrhosis (Figure 2) of the liver attributable to chronic alcohol abuse is found to have AML with the mixed-lineage leukemia translocation t(4;11)(q21;q23). He has evidence of portal hypertension as manifested by mild ascites and edema of the lower extremities. The serum albumin is mildly low at 3.0 g/dL and the prothrombin time and partial thromboplastin time are slightly prolonged.

Figure 2

Photomicrograph of a cirrhotic liver illustrating well developed fibrous septa separating irregular regenerative nodules. The hepatocytes show mild steatosis (hematoxylin and eosin stain, original magnification ×40).

Figure 2

Photomicrograph of a cirrhotic liver illustrating well developed fibrous septa separating irregular regenerative nodules. The hepatocytes show mild steatosis (hematoxylin and eosin stain, original magnification ×40).

Questions

  • Can patients with cirrhosis receive treatment of AML?

  • What is the preferred regimen?

  • Are there dose modifications of chemotherapeutic agents?

The treatment of a patient with cirrhosis of the liver and newly diagnosed AML is complicated. Underlying cirrhosis of the liver presents a number of potential issues. These include third spacing of fluid, hepatic dysfunction with perturbed drug metabolism, portal hypertension and variceal bleeding, malnutrition and coagulopathy due to impaired synthetic function as well as thrombocytopenia related to splenic sequestration. As a result, many patients may not be candidates for intensive chemotherapy. The Child-Pugh score is an important tool for determining the prognosis of patients with cirrhosis.64  Coagulation abnormalities need to be very closely followed, with aggressive replacement for any evidence of bleeding. In general, we would maintain a platelet count >20 × 109/L throughout induction. The therapeutic strategy depends on drug metabolism and dose modification in the setting of hepatic dysfunction.

Because anthracyclines are metabolized primarily by the liver, dose modifications based on the total bilirubin and hepatic transaminases are required.65,66  For example, we give 75% of the dose of daunorubicin if the total bilirubin is 1.5 to 3 mg/dL and/or the aspartate transaminase (AST) is 60 to 180, 50% dose if the total bilirubin is 3.1 to 5 mg/dL and/or the AST is >180; we do not administer daunorubicin at all if the total bilirubin is >5 mg/dL.65,66  For cytarabine, because the drug is partially detoxified in the liver, we adjust the dose and administer 50% of the total dose for any elevation in the AST or alanine transaminase67  or total bilirubin >2 mg/dL.68  Regarding high-dose cytarabine (HiDAC) for consolidation, theoretically the same criteria for dose modification apply. However, given the numerous potential complications in a patient with cirrhosis of the liver and the risk of cerebellar toxicity, we rarely administer HiDAC in this clinical condition.69,70 

Decitabine is eliminated by cytidine deaminase which is found intracellularly in the liver. Most clinical trials involving decitabine and azacitidine excluded patients with significant liver disease. Azacitidine has the potential for hepatotoxicity in patients with liver disease.71,72  Therefore, we do not administer hypomethylating agents to patients with significant preexisting hepatic impairment.

In practice, a patient with cirrhosis and a bilirubin level >5 mg/dL is precluded from optimal induction and consolidation therapy. Low-dose cytarabine may be used; however, our practice is to offer a 7- to 10-day course of cytarabine at a dose not exceeding 50 mg/m2 per day, given that with standard-dose cytarabine 35% of patients can achieve complete remission (CR).

Allogeneic transplantation is obviously hazardous and we would not do it for anyone with uncompensated cirrhosis. However, in a patient with Child I cirrhosis, who is in CR, we would consider RIC transplantation.

The one theoretic exception where underlying cirrhosis may not preclude treatment of AML may be patients with acute promyelocytic leukemia.73  In fact, in preclinical models, all-trans retinoic acid has been proposed as a treatment of cirrhosis of the liver because this agent decreases liver fibrosis by reducing transforming growth factor β 1, interleukin-6, and type I collagen.74,75 

Comment

Cirrhosis of the liver presents a serious dilemma; dose reduction is often required and curative options are usually precluded if associated with severe hyperbilirubinemia.

Scenario 7: patient with COPD

A 62-year-old woman, heavy smoker, known to suffer from pulmonary emphysema (Figure 3) and secondary pulmonary hypertension, 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. In retrospect, her hemoglobin was falling slowly during the last year and severe dysplastic changes are evident in the BM. Unfavorable-risk AML is diagnosed after trisomy 8 and deletion 7 are reported by rapid fluorescence in situ hybridization evaluation.

Figure 3

This lung shows centrilobular emphysema with dropout of alveolar walls surrounding the bronchiole (hematoxylin and eosin stain, original magnification ×4).

Figure 3

This lung shows centrilobular emphysema with dropout of alveolar walls surrounding the bronchiole (hematoxylin and eosin stain, original magnification ×4).

Questions

  • What is the best first-line therapy in this woman?

  • What can be achieved beyond remission?

  • Are there special recommendations for such patients?

AML patients with chronic obstructive lung disease (COPD) are usually excluded from clinical trials. Therefore, data addressing outcome of such patients are scanty. In a large retrospective study, following intensive induction therapy, grade 3-4 respiratory complications requiring support were present in 16% of AML patients and 8% developed respiratory failure.76,77  In addition, pulmonary hypertension raises the mortality from sepsis.78  At the age 62 years, with COPD, patients with AML that evolved from myelodysplastic syndrome need to overcome significant obstacles inherent in intensive chemotherapy.

The Sorror comorbidity index assigns 2 or 3 points for moderate or severe pulmonary abnormalities such as in this patient.79  A Sorror index of 3 is the cutoff for poorer allogeneic hematopoietic cell transplantation (allo-HCT) outcome even if RIC is carried out80,81  that similarly applies to intensive induction therapy.82,83  Given an induction mortality of close to 85% for patients with a Sorror score of 3 or more, the risk of using optimal induction therapy is probably excessive. Hypomethylating therapy may be an alternative to intensive induction as it may be efficacious for “low proliferative” leukemia as well as in frail patients.84-87  Yet, although hypomethylating agents are better tolerated by patients with comorbidities, the CR rate is only 18% to 24%. A similar 2- to 3-year survival can be expected in patients over 70 years of age following either standard induction or hypomethylating agents.87  In contrast, in patients 60 to 70 years old, longer survival has been reported if intensive induction is used (25% vs 5% to 8%). For patients with COPD with a slowly proliferating leukemia or with an adverse karyotype, a reasonable strategy is to use hypomethylating therapy for 3 to 4 months followed by RIC allo-HCT.88-91 

For this patient, we would initiate comprehensive pulmonary function evaluation as results of pulmonary function tests are predictive for long-term outcome of allo-HCT.92,93  If the patient has a comorbidity score of 3 or greater, and this is consistent with the bedside clinical assessment, we would initiate induction therapy with hypomethylating agents. We would not ordinarily proceed with allogeneic transplantation in this setting. If, on the other hand, the comorbidity score is <3 and the patient is clinically judged as able to tolerate intensive myelosuppression, we would initiate standard induction, recognizing the potential for pulmonary and infectious complications. Intensive support throughout induction is essential as every effort must be made to avoid mechanical ventilation.

As a heavy smoker, this patient is at a particularly high risk for invasive pulmonary infection.94  Maintaining a high index of suspicion and initiating antifungal prophylaxis are indicated.

Comment

The management of AML patients with COPD is fraught with hazards. In the absence of unequivocal guidelines, the approach to therapy requires experience, careful judgment, and subspecialty support.

Scenario 8: patient with ICH

A 57-year-old woman is diagnosed with acute myelomonocytic leukemia 6 weeks following an intracranial hemorrhage (ICH) involving her right basal ganglia. At the time of the ICH, the blood counts were normal. Her medical history is remarkable only for untreated hypertension. Following successful rehabilitation, she currently can manage her daily life activities but requires walker assistance for mobilization. Currently, her white blood count is 45 × 109/L with 90% blasts. No metaphases are available for analysis, but Flt3-ITD mutation is detected by PCR. The hemoglobin is 11.2 g/dL and the platelet count is 90 × 109/L. Blood coagulation test results are normal. No new neurological abnormalities are present.

Questions

  • 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, blood pressure control reduces recurrent CNS bleeding risk by 50%.95  In addition, urgent antileukemia therapy with the aim to control the blast count is indicated because hyperleukocytosis is associated with increasing bleeding risk.96-98  A platelet count threshold of 50 × 109/L has been suggested, although there are no convincing data to support this.99  The risk of rebleeding decreases with time from the primary bleeding event. In this patient, given that she is 6 weeks after the acute event, we would, arbitrarily, maintain the platelet count above 30 × 109/L during standard induction therapy. Such a recommendation may be analogous to guidelines for a similar clinical scenario regarding the use of anticoagulation following ICH.100  Induction with attenuated anthracycline doses should be avoided as the severity of thrombocytopenia is identical for daunorubicin (45-90 mg/m2) doses in both younger and older patients with AML.101,102 

In older patients, in whom the risk of rebleeding is significantly high and allogeneic transplantation is not a practical option, we consider less myeloablative therapy, such as hydroxyurea, low-dose cytarabine, or hypomethylating agents.100,103 

This patient has a high risk for CNS involvement based on the myelomonocytic lineage morphology and leukocytosis104-106  but there is no firm evidence to suggest a connection between ICH and CNS involvement of leukemia.107  Although ICH preceded the diagnosis of leukemia by 6 weeks and the patient has poorly controlled hypertension as a risk factor for ICH, we would evaluate for the presence of CNS leukemia with a lumbar puncture and imaging.

Comment

Patients with ICH can receive optimal induction therapy, provided the platelets are kept at relatively safe levels.

Conclusion

In conclusion, the presentation of patients with preexisting comorbidities is common and the therapy is challenging. Although certainly not all-encompassing, select common scenarios were presented emphasizing practical approaches for patients who nevertheless require therapy. The catastrophic prognosis for untreated AML often permits and encourages the adoption of pragmatic risk taking. With appropriate subspecialty support, many patients with AML who present with organ dysfunction can be treated successfully.

Acknowledgments

The authors acknowledge the following physicians for their subspecialty advice: Mark Klutstein, Yoav Luria, Arthur Kerner, Daniel Kurnik, Sergio Girlat, William Travis, Richard Steingart, Jinru Shia, and Carlos Flombaum. The authors also thank Hillard Lazarus and Aaron Rapoport for review of the manuscript and helpful suggestions. Finally, the authors thank Sonia Kamenetsky for assistance in the preparation of this manuscript.

Authorship

Contribution: Y.O., M.S.T., and J.M.R. wrote the paper.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Yishai Ofran, Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, 8, Ha’Aliya St, Haifa 31096, Israel; e-mail: y_ofran@rambam.health.gov.il.

References

References
1
Mengis
 
C
Aebi
 
S
Tobler
 
A
Dähler
 
W
Fey
 
MF
Assessment of differences in patient populations selected for excluded from participation in clinical phase III acute myelogenous leukemia trials.
J Clin Oncol
2003
, vol. 
21
 
21
(pg. 
3933
-
3939
)
2
Foley
 
TA
Mankad
 
SV
Anavekar
 
NS
, et al. 
Measuring left ventricular ejection fraction – techniques and potential pitfalls.
Eur Cardiol
2012
, vol. 
8
 
2
(pg. 
108
-
114
)
3
Todaro
 
MC
Oreto
 
L
Qamar
 
R
Paterick
 
TE
Carerj
 
S
Khandheria
 
BK
Cardioncology: state of the heart.
Int J Cardiol
2013
, vol. 
168
 
2
(pg. 
680
-
687
)
4
Barrett-Lee
 
PJ
Dixon
 
JM
Farrell
 
C
, et al. 
Expert opinion on the use of anthracyclines in patients with advanced breast cancer at cardiac risk.
Ann Oncol
2009
, vol. 
20
 
5
(pg. 
816
-
827
)
5
Rowe
 
JM
Neuberg
 
D
Friedenberg
 
W
, et al. 
Eastern Cooperative Oncology
A phase 3 study of three induction regimens and of priming with GM-CSF in older adults with acute myeloid leukemia: a trial by the Eastern Cooperative Oncology Group.
Blood
2004
, vol. 
103
 
2
(pg. 
479
-
485
)
6
Brunnberg
 
U
Mohr
 
M
Noppeney
 
R
, et al. 
Induction therapy of AML with ara-C plus daunorubicin versus ara-C plus gemtuzumab ozogamicin: a randomized phase II trial in elderly patients.
Ann Oncol
2012
, vol. 
23
 
4
(pg. 
990
-
996
)
7
Kessler
 
T
Mohr
 
M
Müller-Tidow
 
C
, et al. 
Amsacrine containing induction therapy in elderly AML patients: comparison to standard induction regimens in a matched-pair analysis.
Leuk Res
2008
, vol. 
32
 
3
(pg. 
491
-
494
)
8
Oliveira
 
GH
Al-Kindi
 
SG
Caimi
 
PF
Lazarus
 
HM
Maximizing anthracycline tolerability in hematologic malignancies: Treat to each heart’s content.
Blood Rev
2016
, vol. 
30
 
3
(pg. 
169
-
178
)
9
Eschenhagen
 
T
Force
 
T
Ewer
 
MS
, et al. 
Cardiovascular side effects of cancer therapies: a position statement from the Heart Failure Association of the European Society of Cardiology.
Eur J Heart Fail
2011
, vol. 
13
 
1
(pg. 
1
-
10
)
10
Yeh
 
ET
Bickford
 
CL
Cardiovascular complications of cancer therapy: incidence, pathogenesis, diagnosis, and management.
J Am Coll Cardiol
2009
, vol. 
53
 
24
(pg. 
2231
-
2247
)
11
Wouters
 
KA
Kremer
 
LC
Miller
 
TL
Herman
 
EH
Lipshultz
 
SE
Protecting against anthracycline-induced myocardial damage: a review of the most promising strategies.
Br J Haematol
2005
, vol. 
131
 
5
(pg. 
561
-
578
)
12
Alderton
 
PM
Gross
 
J
Green
 
MD
Comparative study of doxorubicin, mitoxantrone, and epirubicin in combination with ICRF-187 (ADR-529) in a chronic cardiotoxicity animal model.
Cancer Res
1992
, vol. 
52
 
1
(pg. 
194
-
201
)
13
Yamaguchi
 
N
Fujii
 
T
Aoi
 
S
Kozuch
 
PS
Hortobagyi
 
GN
Blum
 
RH
Comparison of cardiac events associated with liposomal doxorubicin, epirubicin and doxorubicin in breast cancer: a Bayesian network meta-analysis.
Eur J Cancer
2015
, vol. 
51
 
16
(pg. 
2314
-
2320
)
14
McMurray
 
JJ
Adamopoulos
 
S
Anker
 
SD
, et al. 
Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology; ESC Committee for Practice Guidelines
ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC.
Eur J Heart Fail
2012
, vol. 
14
 
8
(pg. 
803
-
869
)
15
Smith
 
LA
Cornelius
 
VR
Plummer
 
CJ
, et al. 
Cardiotoxicity of anthracycline agents for the treatment of cancer: systematic review and meta-analysis of randomised controlled trials.
BMC Cancer
2010
, vol. 
10
 pg. 
337
 
16
Sarkiss
 
MG
Yusuf
 
SW
Warneke
 
CL
, et al. 
Impact of aspirin therapy in cancer patients with thrombocytopenia and acute coronary syndromes.
Cancer
2007
, vol. 
109
 
3
(pg. 
621
-
627
)
17
Yusuf
 
SW
Iliescu
 
C
Bathina
 
JD
Daher
 
IN
Durand
 
JB
Antiplatelet therapy and percutaneous coronary intervention in patients with acute coronary syndrome and thrombocytopenia.
Tex Heart Inst J
2010
, vol. 
37
 
3
(pg. 
336
-
340
)
18
Qaseem
 
A
Humphrey
 
LL
Fitterman
 
N
Starkey
 
M
Shekelle
 
P
Clinical Guidelines Committee of the American College of Physicians
Treatment of anemia in patients with heart disease: a clinical practice guideline from the American College of Physicians.
Ann Intern Med
2013
, vol. 
159
 
11
(pg. 
770
-
779
)
19
Sekeres
 
MA
Elson
 
P
Kalaycio
 
ME
, et al. 
Time from diagnosis to treatment initiation predicts survival in younger, but not older, acute myeloid leukemia patients.
Blood
2009
, vol. 
113
 
1
(pg. 
28
-
36
)
20
van Dalen
 
EC
van der Pal
 
HJ
Kremer
 
LC
Different dosage schedules for reducing cardiotoxicity in people with cancer receiving anthracycline chemotherapy.
Cochrane Database Syst Rev
2016
, vol. 
3
 pg. 
CD005008
 
21
Willard
 
JE
Lange
 
RA
Hillis
 
LD
The use of aspirin in ischemic heart disease.
N Engl J Med
1992
, vol. 
327
 
3
(pg. 
175
-
181
)
22
The RISC Group
Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary artery disease.
Lancet
1990
, vol. 
336
 
8719
(pg. 
827
-
830
)
23
Montesinos
 
P
Lorenzo
 
I
Martín
 
G
, et al. 
Tumor lysis syndrome in patients with acute myeloid leukemia: identification of risk factors and development of a predictive model.
Haematologica
2008
, vol. 
93
 
1
(pg. 
67
-
74
)
24
Ganzel
 
C
Becker
 
J
Mintz
 
PD
Lazarus
 
HM
Rowe
 
JM
Hyperleukocytosis, leukostasis and leukapheresis: practice management.
Blood Rev
2012
, vol. 
26
 
3
(pg. 
117
-
122
)
25
Coiffier
 
B
Altman
 
A
Pui
 
CH
Younes
 
A
Cairo
 
MS
Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review.
J Clin Oncol
2008
, vol. 
26
 
16
(pg. 
2767
-
2778
)
26
Dalbeth
 
N
Stamp
 
L
Allopurinol dosing in renal impairment: walking the tightrope between adequate urate lowering and adverse events.
Semin Dial
2007
, vol. 
20
 
5
(pg. 
391
-
395
)
27
Fissell
 
WH
Earl
 
M
Finkel
 
KW
Howard
 
SC
Pharmacokinetics of anti-cancer chemotherapy in renal insufficiency and dialysis.
Renal Disease in Cancer Patients
2014
Amsterdam, The Netherlands
Academic Press Elsevier
(pg. 
251
-
269
)
28
Damon
 
LE
Mass
 
R
Linker
 
CA
The association between high-dose cytarabine neurotoxicity and renal insufficiency.
J Clin Oncol
1989
, vol. 
7
 
10
(pg. 
1563
-
1568
)
29
Kintzel
 
PE
Dorr
 
RT
Anticancer drug renal toxicity and elimination: dosing guidelines for altered renal function.
Cancer Treat Rev
1995
, vol. 
21
 
1
(pg. 
33
-
64
)
30
Appelbaum
 
FR
Kopecky
 
KJ
Tallman
 
MS
, et al. 
The clinical spectrum of adult acute myeloid leukaemia associated with core binding factor translocations.
Br J Haematol
2006
, vol. 
135
 
2
(pg. 
165
-
173
)
31
Yoshida
 
H
Goto
 
M
Honda
 
A
, et al. 
Pharmacokinetics of doxorubicin and its active metabolite in patients with normal renal function and in patients on hemodialysis.
Cancer Chemother Pharmacol
1994
, vol. 
33
 
6
(pg. 
450
-
454
)
32
Lichtman
 
SM
Wildiers
 
H
Launay-Vacher
 
V
Steer
 
C
Chatelut
 
E
Aapro
 
M
International Society of Geriatric Oncology (SIOG) recommendations for the adjustment of dosing in elderly cancer patients with renal insufficiency.
Eur J Cancer
2007
, vol. 
43
 
1
(pg. 
14
-
34
)
33
Niscola
 
P
Vischini
 
G
Tendas
 
A
, et al. 
Management of hematological malignancies in patients affected by renal failure.
Expert Rev Anticancer Ther
2011
, vol. 
11
 
3
(pg. 
415
-
432
)
34
Janus
 
N
Thariat
 
J
Boulanger
 
H
Deray
 
G
Launay-Vacher
 
V
Proposal for dosage adjustment and timing of chemotherapy in hemodialyzed patients.
Ann Oncol
2010
, vol. 
21
 
7
(pg. 
1395
-
1403
)
35
Alberts
 
DS
Peng
 
YM
Bowden
 
GT
Dalton
 
WS
Mackel
 
C
Pharmacology of mitoxantrone: mode of action and pharmacokinetics.
Invest New Drugs
1985
, vol. 
3
 
2
(pg. 
101
-
107
)
36
Aronoff GB, ed. Drug Prescribing in Renal Failure: Dosing Guidelines for Adults. 5th ed. Washington, DC: American College of Physicians; 2007
37
Stewart
 
CF
Use of etoposide in patients with organ dysfunction: pharmacokinetic and pharmacodynamic considerations.
Cancer Chemother Pharmacol
1994
, vol. 
34
 
suppl
(pg. 
S76
-
S83
)
38
Jones
 
GL
Will
 
A
Jackson
 
GH
Webb
 
NJ
Rule
 
S
British Committee for Standards in Haematology
Guidelines for the management of tumour lysis syndrome in adults and children with haematological malignancies on behalf of the British Committee for Standards in Haematology.
Br J Haematol
2015
, vol. 
169
 
5
(pg. 
661
-
671
)
39
Vogelzang
 
JL
van Stralen
 
KJ
Noordzij
 
M
, et al. 
Mortality from infections and malignancies in patients treated with renal replacement therapy: data from the ERA-EDTA registry.
Nephrol Dial Transplant
2015
, vol. 
30
 
6
(pg. 
1028
-
1037
)
40
Nguyen
 
DB
Lessa
 
FC
Belflower
 
R
, et al. 
Active Bacterial Core Surveillance (ABCs) MRSA Investigators of the Emerging Infections Program
Invasive methicillin-resistant Staphylococcus aureus infections among patients on chronic dialysis in the United States, 2005-2011.
Clin Infect Dis
2013
, vol. 
57
 
10
(pg. 
1393
-
1400
)
41
Crowley
 
L
Pitcher
 
D
Wilson
 
J
Guy
 
R
Fluck
 
R
UK Renal Registry 16th annual report: chapter 15 epidemiology of reported infections amongst patients receiving dialysis for established renal Failure in England from May 2011 to April 2012: a joint report from Public Health England and the UK Renal Registry.
Nephron Clin Pract
2013
, vol. 
125
 
1-4
(pg. 
295
-
308
)
42
Zacharioudakis
 
IM
Zervou
 
FN
Ziakas
 
PD
Rice
 
LB
Mylonakis
 
E
Vancomycin-resistant enterococci colonization among dialysis patients: a meta-analysis of prevalence, risk factors, and significance.
Am J Kidney Dis
2015
, vol. 
65
 
1
(pg. 
88
-
97
)
43
Beddhu
 
S
Bruns
 
FJ
Saul
 
M
Seddon
 
P
Zeidel
 
ML
A simple comorbidity scale predicts clinical outcomes and costs in dialysis patients.
Am J Med
2000
, vol. 
108
 
8
(pg. 
609
-
613
)
44
Cohen
 
LM
Ruthazer
 
R
Moss
 
AH
Germain
 
MJ
Predicting six-month mortality for patients who are on maintenance hemodialysis.
Clin J Am Soc Nephrol
2010
, vol. 
5
 
1
(pg. 
72
-
79
)
45
Rowe
 
JM
Optimal induction and post-remission therapy for AML in first remission.
Hematology Am Soc Hematol Educ Program
2009
, vol. 
2009
 (pg. 
396
-
405
)
46
Rubin
 
EH
Andersen
 
JW
Berg
 
DT
Schiffer
 
CA
Mayer
 
RJ
Stone
 
RM
Risk factors for high-dose cytarabine neurotoxicity: an analysis of a cancer and leukemia group B trial in patients with acute myeloid leukemia.
J Clin Oncol
1992
, vol. 
10
 
6
(pg. 
948
-
953
)
47
Bischoff
 
ME
Blau
 
W
Wagner
 
T
, et al. 
Total body irradiation and cyclophosphamide is a conditioning regimen for unrelated bone marrow transplantation in a patient with chronic myelogenous leukemia and renal failure on hemodialysis.
Bone Marrow Transplant
1998
, vol. 
22
 
6
(pg. 
591
-
593
)
48
Perry
 
JJ
Fleming
 
RA
Rocco
 
MV
, et al. 
Administration and pharmacokinetics of high-dose cyclophosphamide with hemodialysis support for allogeneic bone marrow transplantation in acute leukemia and end-stage renal disease.
Bone Marrow Transplant
1999
, vol. 
23
 
8
(pg. 
839
-
842
)
49
Ludwig
 
E
HBV reactivation in immunosuppressed patients: prevention or containment?
Hepatology
2014
, vol. 
59
 
6
(pg. 
2062
-
2064
)
50
Yeo
 
W
Chan
 
PK
Ho
 
WM
, et al. 
Lamivudine for the prevention of hepatitis B virus reactivation in hepatitis B s-antigen seropositive cancer patients undergoing cytotoxic chemotherapy.
J Clin Oncol
2004
, vol. 
22
 
5
(pg. 
927
-
934
)
51
Fukushima
 
N
Mizuta
 
T
Tanaka
 
M
, et al. 
Retrospective and prospective studies of hepatitis B virus reactivation in malignant lymphoma with occult HBV carrier.
Ann Oncol
2009
, vol. 
20
 
12
(pg. 
2013
-
2017
)
52
Yeo
 
W
Zee
 
B
Zhong
 
S
, et al. 
Comprehensive analysis of risk factors associating with hepatitis B virus (HBV) reactivation in cancer patients undergoing cytotoxic chemotherapy.
Br J Cancer
2004
, vol. 
90
 
7
(pg. 
1306
-
1311
)
53
Roche
 
B
Samuel
 
D
The difficulties of managing severe hepatitis B virus reactivation.
Liver Int
2011
, vol. 
31
 
suppl 1
(pg. 
104
-
110
)
54
Reddy
 
KR
Beavers
 
KL
Hammond
 
SP
Lim
 
JK
Falck-Ytter
 
YT
American Gastroenterological Association Institute
American Gastroenterological Association Institute guideline on the prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy [published correction appears in Gastroenterology. 2015;148(2):455].
Gastroenterology
2015
 
148(1):215-219
55
Artz
 
AS
Somerfield
 
MR
Feld
 
JJ
, et al. 
American Society of Clinical Oncology provisional clinical opinion: chronic hepatitis B virus infection screening in patients receiving cytotoxic chemotherapy for treatment of malignant diseases.
J Clin Oncol
2010
, vol. 
28
 
19
(pg. 
3199
-
3202
)
56
Huang
 
YH
Hsiao
 
LT
Hong
 
YC
, et al. 
Randomized controlled trial of entecavir prophylaxis for rituximab-associated hepatitis B virus reactivation in patients with lymphoma and resolved hepatitis B.
J Clin Oncol
2013
, vol. 
31
 
22
(pg. 
2765
-
2772
)
57
Visram
 
A
Feld
 
JJ
Defining and grading HBV reactivation.
Clin Liver Dis
2015
, vol. 
5
 
2
(pg. 
35
-
38
)
58
Kamitsukasa
 
H
Iri
 
M
Tanaka
 
A
, et al. 
Spontaneous reactivation of hepatitis B virus (HBV) infection in patients with resolved or occult HBV infection.
J Med Virol
2015
, vol. 
87
 
4
(pg. 
589
-
600
)
59
Lan
 
JL
Chen
 
YM
Hsieh
 
TY
, et al. 
Kinetics of viral loads and risk of hepatitis B virus reactivation in hepatitis B core antibody-positive rheumatoid arthritis patients undergoing anti-tumour necrosis factor alpha therapy.
Ann Rheum Dis
2011
, vol. 
70
 
10
(pg. 
1719
-
1725
)
60
Torres
 
HA
Davila
 
M
Reactivation of hepatitis B virus and hepatitis C virus in patients with cancer.
Nat Rev Clin Oncol
2012
, vol. 
9
 
3
(pg. 
156
-
166
)
61
American Association for the Study of Liver Diseases and the Infectious Diseases Society of America
HCV guidance: recommendations for testing, managing, and treating hepatitis C.
 
Available at http://hcvguidelines.org/. Accessed March 2016
62
Coppola
 
N
Pisaturo
 
M
Guastafierro
 
S
, et al. 
Increased hepatitis C viral load and reactivation of liver disease in HCV RNA-positive patients with onco-haematological disease undergoing chemotherapy.
Dig Liver Dis
2012
, vol. 
44
 
1
(pg. 
49
-
54
)
63
Yazici
 
O
Sendur
 
MA
Aksoy
 
S
Hepatitis C virus reactivation in cancer patients in the era of targeted therapies.
World J Gastroenterol
2014
, vol. 
20
 
22
(pg. 
6716
-
6724
)
64
Pugh
 
RN
Murray-Lyon
 
IM
Dawson
 
JL
Pietroni
 
MC
Williams
 
R
Transection of the oesophagus for bleeding oesophageal varices.
Br J Surg
1973
, vol. 
60
 
8
(pg. 
646
-
649
)
65
Perry MC, ed. The Chemotherapy Source Book. 2nd ed. Baltimore, MD: Williams and Wilkins; 1996
66
Haddadin
 
S
Perry
 
MC
Perry
 
MC
Chemotherapeutic agents: idarubicin.
The Chemotherapy Source Book
2012
5th ed
Philadelphia, PA
Lippincott Williams and Wilkins
(pg. 
659
-
739
)
67
Floyd
 
J
Mirza
 
I
Sachs
 
B
Perry
 
MC
Hepatotoxicity of chemotherapy.
Semin Oncol
2006
, vol. 
33
 
1
(pg. 
50
-
67
)
68
Koren
 
G
Beatty
 
K
Seto
 
A
Einarson
 
TR
Lishner
 
M
The effects of impaired liver function on the elimination of antineoplastic agents.
Ann Pharmacother
1992
, vol. 
26
 
3
(pg. 
363
-
371
)
69
Donehower
 
RC
Karp
 
JE
Burke
 
PJ
Pharmacology and toxicity of high-dose cytarabine by 72-hour continuous infusion.
Cancer Treat Rep
1986
, vol. 
70
 
9
(pg. 
1059
-
1065
)
70
King
 
PD
Perry
 
MC
Hepatotoxicity of chemotherapy.
Oncologist
2001
, vol. 
6
 
2
(pg. 
162
-
176
)
71
Bellet
 
RE
Mastrangelo
 
MJ
Engstrom
 
PF
Custer
 
RP
Hepatotoxicity of 5-azacytidine (NSC-102816) (a clinical and pathologic study).
Neoplasma
1973
, vol. 
20
 
3
(pg. 
303
-
309
)
72
Weiss
 
AJ
Metter
 
GE
Nealon
 
TF
, et al. 
Phase II study of 5-azacytidine in solid tumors.
Cancer Treat Rep
1977
, vol. 
61
 
1
(pg. 
55
-
58
)
73
Yamane
 
A
Tsukamoto
 
N
Saitoh
 
T
, et al. 
Successful treatment by all-trans retinoic acid in a patient with acute promyelocytic leukemia complicated by liver cirrhosis and polycystic kidney.
Intern Med
2009
, vol. 
48
 
18
(pg. 
1691
-
1694
)
74
Hisamori
 
S
Tabata
 
C
Kadokawa
 
Y
, et al. 
All-trans-retinoic acid ameliorates carbon tetrachloride-induced liver fibrosis in mice through modulating cytokine production.
Liver Int
2008
, vol. 
28
 
9
(pg. 
1217
-
1225
)
75
Wang
 
L
Potter
 
JJ
Rennie-Tankersley
 
L
Novitskiy
 
G
Sipes
 
J
Mezey
 
E
Effects of retinoic acid on the development of liver fibrosis produced by carbon tetrachloride in mice.
Biochim Biophys Acta
2007
, vol. 
1772
 
1
(pg. 
66
-
71
)
76
Atallah
 
E
Cortes
 
J
O’Brien
 
S
, et al. 
Establishment of baseline toxicity expectations with standard frontline chemotherapy in acute myelogenous leukemia.
Blood
2007
, vol. 
110
 
10
(pg. 
3547
-
3551
)
77
Al Ameri
 
A
Koller
 
C
Kantarjian
 
H
, et al. 
Acute pulmonary failure during remission induction chemotherapy in adults with acute myeloid leukemia or high-risk myelodysplastic syndrome.
Cancer
2010
, vol. 
116
 
1
(pg. 
93
-
97
)
78
Tsapenko
 
MV
Herasevich
 
V
Mour
 
GK
, et al. 
Severe sepsis and septic shock in patients with pre-existing non-cardiac pulmonary hypertension: contemporary management and outcomes.
Crit Care Resusc
2013
, vol. 
15
 
2
(pg. 
103
-
109
)
79
Sorror
 
ML
Maris
 
MB
Storb
 
R
, et al. 
Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT.
Blood
2005
, vol. 
106
 
8
(pg. 
2912
-
2919
)
80
Sorror
 
M
Storer
 
B
Sandmaier
 
BM
, et al. 
Hematopoietic cell transplantation-comorbidity index and Karnofsky performance status are independent predictors of morbidity and mortality after allogeneic nonmyeloablative hematopoietic cell transplantation.
Cancer
2008
, vol. 
112
 
9
(pg. 
1992
-
2001
)
81
Yamamoto
 
W
Ogusa
 
E
Matsumoto
 
K
Maruta
 
A
Ishigatsubo
 
Y
Kanamori
 
H
Predictive value of risk assessment scores in patients with hematologic malignancies undergoing reduced-intensity conditioning allogeneic stem cell transplantation.
Am J Hematol
2014
, vol. 
89
 
9
(pg. 
E138
-
E141
)
82
Giles
 
FJ
Borthakur
 
G
Ravandi
 
F
, et al. 
The haematopoietic cell transplantation comorbidity index score is predictive of early death and survival in patients over 60 years of age receiving induction therapy for acute myeloid leukaemia.
Br J Haematol
2007
, vol. 
136
 
4
(pg. 
624
-
627
)
83
Savic
 
A
Kvrgic
 
V
Rajic
 
N
, et al. 
The hematopoietic cell transplantation comorbidity index is a predictor of early death and survival in adult acute myeloid leukemia patients.
Leuk Res
2012
, vol. 
36
 
4
(pg. 
479
-
482
)
84
Cashen
 
AF
Schiller
 
GJ
O’Donnell
 
MR
DiPersio
 
JF
Multicenter, phase II study of decitabine for the first-line treatment of older patients with acute myeloid leukemia.
J Clin Oncol
2010
, vol. 
28
 
4
(pg. 
556
-
561
)
85
Fenaux
 
P
Mufti
 
GJ
Hellström-Lindberg
 
E
, et al. 
Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia.
J Clin Oncol
2010
, vol. 
28
 
4
(pg. 
562
-
569
)
86
Lübbert
 
M
Rüter
 
BH
Claus
 
R
, et al. 
A multicenter phase II trial of decitabine as first-line treatment for older patients with acute myeloid leukemia judged unfit for induction chemotherapy.
Haematologica
2012
, vol. 
97
 
3
(pg. 
393
-
401
)
87
Quintás-Cardama
 
A
Ravandi
 
F
Liu-Dumlao
 
T
, et al. 
Epigenetic therapy is associated with similar survival compared with intensive chemotherapy in older patients with newly diagnosed acute myeloid leukemia.
Blood
2012
, vol. 
120
 
24
(pg. 
4840
-
4845
)
88
Gerds
 
AT
Gooley
 
TA
Estey
 
EH
Appelbaum
 
FR
Deeg
 
HJ
Scott
 
BL
Pretransplantation therapy with azacitidine vs induction chemotherapy and posttransplantation outcome in patients with MDS.
Biol Blood Marrow Transplant
2012
, vol. 
18
 
8
(pg. 
1211
-
1218
)
89
Bally
 
C
Thépot
 
S
Quesnel
 
B
, et al. 
Azacitidine in the treatment of therapy related myelodysplastic syndrome and acute myeloid leukemia (tMDS/AML): a report on 54 patients by the Groupe Francophone Des Myelodysplasies (GFM).
Leuk Res
2013
, vol. 
37
 
6
(pg. 
637
-
640
)
90
Garelius
 
H
Grund
 
S
Stockelberg
 
D
Induction with azacytidine followed by allogeneic hematopoietic stem cell transplantation in a Jehovah’s Witness with acute monocytic leukemia.
Clin Case Rep
2015
, vol. 
3
 
5
(pg. 
287
-
290
)
91
Ahn
 
JS
Kim
 
YK
Min
 
YH
, et al. 
Azacitidine pre-treatment followed by reduced-intensity stem cell transplantation in patients with higher-risk myelodysplastic syndrome.
Acta Haematol
2015
, vol. 
134
 
1
(pg. 
40
-
48
)
92
Walter
 
EC
Orozco-Levi
 
M
Ramirez-Sarmiento
 
A
, et al. 
Lung function and long-term complications after allogeneic hematopoietic cell transplant.
Biol Blood Marrow Transplant
2010
, vol. 
16
 
1
(pg. 
53
-
61
)
93
Piñana
 
JL
Martino
 
R
Barba
 
P
, et al. 
Pulmonary function testing prior to reduced intensity conditioning allogeneic stem cell transplantation in an unselected patient cohort predicts posttransplantation pulmonary complications and outcome.
Am J Hematol
2012
, vol. 
87
 
1
(pg. 
9
-
14
)
94
Caira
 
M
Candoni
 
A
Verga
 
L
, et al. 
SEIFEM Group (Sorveglianza Epidemiologica Infezioni Fungine in Emopatie Maligne)
Pre-chemotherapy risk factors for invasive fungal diseases: prospective analysis of 1,192 patients with newly diagnosed acute myeloid leukemia (SEIFEM 2010-a multicenter study).
Haematologica
2015
, vol. 
100
 
2
(pg. 
284
-
292
)
95
Chapman
 
N
Huxley
 
R
Anderson
 
C
, et al. 
Writing Committee for the PROGRESS Collaborative Group
Effects of a perindopril-based blood pressure-lowering regimen on the risk of recurrent stroke according to stroke subtype and medical history: the PROGRESS Trial.
Stroke
2004
, vol. 
35
 
1
(pg. 
116
-
121
)
96
Nowacki
 
P
Zdziarska
 
B
Fryze
 
C
Urasiński
 
I
Co-existence of thrombocytopenia and hyperleukocytosis (‘critical period’) as a risk factor of haemorrhage into the central nervous system in patients with acute leukaemias.
Haematologia (Budap)
2002
, vol. 
31
 
4
(pg. 
347
-
355
)
97
Kim
 
H
Lee
 
JH
Choi
 
SJ
Kim
 
WK
Lee
 
JS
Lee
 
KH
Analysis of fatal intracranial hemorrhage in 792 acute leukemia patients.
Haematologica
2004
, vol. 
89
 
5
(pg. 
622
-
624
)
98
Chen
 
CY
Tai
 
CH
Tsay
 
W
Chen
 
PY
Tien
 
HF
Prediction of fatal intracranial hemorrhage in patients with acute myeloid leukemia.
Ann Oncol
2009
, vol. 
20
 
6
(pg. 
1100
-
1104
)
99
Zuckerman
 
T
Ganzel
 
C
Tallman
 
MS
Rowe
 
JM
How I treat hematologic emergencies in adults with acute leukemia.
Blood
2012
, vol. 
120
 
10
(pg. 
1993
-
2002
)
100
Broderick
 
J
Connolly
 
S
Feldmann
 
E
, et al. 
American Heart Association/American Stroke Association Stroke Council; American Heart Association/American Stroke Association High Blood Pressure Research Council; Quality of Care and Outcomes in Research Interdisciplinary Working Group
Guidelines for the management of spontaneous intracerebral hemorrhage in adults: 2007 update: a guideline from the American Heart Association/American Stroke Association Stroke Council, High Blood Pressure Research Council, and the Quality of Care and Outcomes in Research Interdisciplinary Working Group.
Circulation
2007
, vol. 
116
 
16
(pg. 
e391
-
e413
)
101
Fernandez
 
HF
Sun
 
Z
Yao
 
X
, et al. 
Anthracycline dose intensification in acute myeloid leukemia.
N Engl J Med
2009
, vol. 
361
 
13
(pg. 
1249
-
1259
)
102
Löwenberg
 
B
Ossenkoppele
 
GJ
van Putten
 
W
, et al. 
Dutch-Belgian Cooperative Trial Group for Hemato-Oncology (HOVON); German AML Study Group (AMLSG); Swiss Group for Clinical Cancer Research (SAKK) Collaborative Group
High-dose daunorubicin in older patients with acute myeloid leukemia [published correction appears in N Engl J Med. 2010;362(12):1155].
N Engl J Med
2009
, vol. 
361
 
13
(pg. 
1235
-
1248
)
103
Dayyani
 
F
Mougalian
 
SS
Naqvi
 
K
, et al. 
Prediction model for mortality after intracranial hemorrhage in patients with leukemia.
Am J Hematol
2011
, vol. 
86
 
7
(pg. 
546
-
549
)
104
Cassileth
 
PA
Sylvester
 
LS
Bennett
 
JM
Begg
 
CB
High peripheral blast count in adult acute myelogenous leukemia is a primary risk factor for CNS leukemia.
J Clin Oncol
1988
, vol. 
6
 
3
(pg. 
495
-
498
)
105
Rozovski
 
U
Ohanian
 
M
Ravandi
 
F
, et al. 
Incidence of and risk factors for involvement of the central nervous system in acute myeloid leukemia.
Leuk Lymphoma
2015
, vol. 
56
 
5
(pg. 
1392
-
1397
)
106
Cheng
 
CL
Li
 
CC
Hou
 
HA
, et al. 
Risk factors and clinical outcomes of acute myeloid leukaemia with central nervous system involvement in adults.
BMC Cancer
2015
, vol. 
15
 pg. 
344
 
107
Jourdan
 
E
Dombret
 
H
Glaisner
 
S
Micléa
 
JM
Castaigne
 
S
Degos
 
L
Unexpected high incidence of intracranial subdural haematoma during intensive chemotherapy for acute myeloid leukaemia with a monoblastic component.
Br J Haematol
1995
, vol. 
89
 
3
(pg. 
527
-
530
)